Clinical trial NCT02477800
Conditions: Alzheimer's Disease
Keywords: BIIB037 Aducanumab
Sponsor: Biogen
Start date: 2015-08-13; Completion date: 2019-08-08
Enrollment: 1653 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with early AD. Secondary objectives are to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale (13 items) \[ADAS-Cog 13\], and AD Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) \[ADCS-ADL-MCI\].

Detailed description:

Arms: arm 1: Monthly intravenous (IV) infusion arm 2: Monthly intravenous (IV) infusion
Interventions: intervention 1: Aducanumab (BIIB037) intervention 2: Aducanumab (BIIB037) intervention 3: Placebo
Intervention descriptions: intervention 1: Low dose intervention 2: High dose intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 




Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n 
M A  I nc. 
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T A B L E O F C O N T E N T S 
1.  
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 0  
2.  
LI S T O F A B B R E VI A TI O N S..................................................................................... 1 1  
3.  
S Y N O P SI S ................................................................................................................. 1 3  
4.  
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 6  
4. 1.  
S t u d y Sc h e matic ......................................................................................................... 1 6 
4. 2.  
S c he d ule of E ve nts ..................................................................................................... 1 7  
4. 3.  
A d diti o nal I nf or mati o n ............................................................................................... 2 5  
4. 3. 1.  
S ite Pers o n nel ............................................................................................................. 2 5 
5.  
IN T R O D U C TI O N ...................................................................................................... 2 7  
5. 1.  
P r ofile of Pre vi o us E x perie nce wit h A d uca n u ma b ..................................................... 2 8 
5. 1. 1.  
N o nc li nical E x perie nce ............................................................................................... 2 8 
5. 1. 2.  
C li nical E x perie nce ..................................................................................................... 2 9 
5. 2.  
S t u d y R ati o nale ........................................................................................................... 3 0 
5. 3.  
R ati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 3 0  
5. 3. 1.  
D osi n g  Sc he m e ........................................................................................................... 3 1 
5. 3. 1. 1.  
Place b o- C o ntr olle d Peri o d .......................................................................................... 3 1  
5. 3. 2.  
D osi n g  Sc he m e M o dificati o n ..................................................................................... 3 2 
5. 3. 3.  
L o n g- T er m E xte nsi o n ................................................................................................. 3 3  
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  
6. 1.  
P ri mar y O bj ecti ve a n d E n d p oi nt ................................................................................ 3 4 
6. 2.  
S ec o n dar y O bj ecti ves a n d E n d p oi nts  .........................................................................3 4  
6. 3.  
Te rtiar y O bjecti ves a n d E n d p oi nts ............................................................................. 3 4 
6. 3. 1.  
Te rtiar y O bjecti ves ..................................................................................................... 3 4 
6. 3. 2.  
Te rtiar y E n d p oi nts ...................................................................................................... 3 5 
6. 4.  
L o n g T er m E xte nsi o n O bjecti ves a n d E n d p oi nts ....................................................... 3 6  
6. 4. 1.  
O bje cti ves ................................................................................................................... 3 6  
6. 4. 2.  
E n d p oi nts .................................................................................................................... 3 7  
7.  
S T U D Y D E SI G N ....................................................................................................... 3 8  
7. 1.  
S t u d y O ver vi e w .......................................................................................................... 3 8 


Pr ot oc ol 2 2 1 A D 3 0 1 
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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
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7. 2.  
S t u d y S pecifics ........................................................................................................... 3 9 
7. 2. 1.  
D ose  S us pe nsi o n, M o dificati o n or Ter mi nati o n f or A RI A E ve nts............................. 3 9 
7. 2. 1. 1.  
Dis p ositi o n of A RI A- E cases...................................................................................... 3 9  
7. 2. 1. 2.  
Dis p ositi o n of A RI A- H cases ..................................................................................... 4 1  
7. 2. 1. 3.  
Dis p ositi o n of C oi nci de nt A RI A- H a n d A RI A- E Cases: ........................................... 4 3  
7. 2. 1. 4.  
D ose Re d ucti o n f or S u bj ects De vel o pi n g A RI A: ....................................................... 4 3  
7. 2. 2.  
Inf usi o n I nterr u pti o n ................................................................................................... 4 4  
7. 3.  
O ve rall St u d y D urati o n a n d F oll o w-U p  ..................................................................... 4 4 
7. 3. 1.  
S cree ni n g .................................................................................................................... 4 5  
7. 3. 2.  
Tr eat me nt .................................................................................................................... 4 5  
7. 3. 3.  
F oll o w- U p  ................................................................................................................... 4 6 
7. 4.  
S t u d y St o p pi n g R ules ................................................................................................. 4 6 
7. 5.  
E n d of  St u d y ............................................................................................................... 4 6 
8.  
S E L E C TI O N O F S U BJ E C T S .................................................................................... 4 7  
8. 1.  
In cl usi o n Criteria ........................................................................................................ 4 7  
8. 2.  
E x cl usi o n Criteria ....................................................................................................... 4 8  
8. 3.  
In cl usi o n Criteria f or L o n g- T er m E xte nsi o n .............................................................. 5 1  
8. 4.  
E x cl usi o n Criteria f or L o n g Ter m E xte nsi o n ............................................................. 5 2  
9.  
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A TI O N ............................ 5 3  
9. 1.  
S cree ni n g a n d E nr oll me nt ........................................................................................... 5 3  
9. 2.  
R a n d o mizati o n a n d Re gistrati o n of S u bjects .............................................................. 5 3  
9. 3.  
B li n di n g Pr oce d ures .................................................................................................... 5 3 
1 0.  
D I 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/ OR 
WI 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 5  
1 0. 1.  
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 5 5  
1 0. 2.  
W it 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.  
R e 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 di ficati o n of D ose a n d/ or Treat me nt Sc he d ul e ...................................................... 5 7 
1 1. 3.  
P reca uti o ns .................................................................................................................. 5 7 


Pr ot oc ol 2 2 1 A D 3 0 1 
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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
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1 1. 4.  
C o m plia nce ................................................................................................................. 5 7  
1 1. 5.  
P ri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 5 7 
1 1. 5. 1.  
Pri or a n d C o nc o mita nt T hera p y .................................................................................. 5 7  
1 1. 5. 1. 1.  
All o we d C o nc o mita nt T hera p y ................................................................................... 5 8  
1 1. 5. 1. 2.  
Disall o we d C o nc o mita nt T hera p y .............................................................................. 5 8  
1 1. 5. 2.  
C o nc o mita nt Pr oce d ures ............................................................................................. 5 8  
1 1. 6.  
C o nti n uati o n of Treat me nt .......................................................................................... 5 9  
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 0  
1 2. 1.  
A d uc a n u ma b ............................................................................................................... 6 0  
1 2. 1. 1.  
A d uca n u ma b Pr e parati o n ............................................................................................ 6 0  
1 2. 1. 2.  
A d uca n u ma b St ora ge .................................................................................................. 6 1  
1 2. 1. 3.  
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 6 1  
1 2. 1. 4.  
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 6 1  
1 2. 2.  
P lace b o ........................................................................................................................ 6 1 
1 2. 3.  
A d diti o nal Pr ot oc ol- Desi g nat e d Pr o d ucts .................................................................. 6 1  
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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S......................................................................................................... 6 2  
1 3. 1.  
C li nical Efficac y Assess me nts .................................................................................... 6 2 
1 3. 2.  
P har mac o ki netic Assess me nts .................................................................................... 6 2  
1 3. 3.  
P har mac o d y na mic Ass ess me nts ................................................................................. 6 2  
1 3. 4.  
A d diti o nal Assess me nts .............................................................................................. 6 3  
 
6 3  
1 3. 4. 2.  
A p o E ge n ot y pi n g ........................................................................................................ 6 3  
 
6 4  
1 3. 4. 4.  
Healt h O utc o mes Ass ess me nts ................................................................................... 6 4  
1 4.  
S A F E T Y A S S E S S M E N T S ........................................................................................ 6 5  
1 4. 1.  
C li nical Safet y Ass ess me nts ....................................................................................... 6 5 
1 4. 2.  
L a b orat or y Safet y Assess me nts .................................................................................. 6 5  
1 4. 3.  
Im m u n o ge nicit y Assess me nts .................................................................................... 6 5  
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 ................................................................................................. 6 7  
1 5. 1.  
De fi niti o ns .................................................................................................................. 6 7 


Pr ot oc ol 2 2 1 A D 3 0 1 
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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
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T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
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1 5. 1. 1.  
A d verse E v e nt ............................................................................................................. 6 7  
1 5. 1. 2.  
Seri o us A d verse E v e nt ................................................................................................ 6 7  
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 ................ 6 8  
1 5. 2.  
S afet y Classificati o ns .................................................................................................. 6 8  
1 5. 2. 1.  
I n v esti gat or Assess me nt of E ve nts ............................................................................. 6 8 
1 5. 2. 2.  
Relati o ns hi p of E ve nts t o St u d y Treat me nt ................................................................ 6 8  
1 5. 2. 3.  
Se verit y of E ve nts ....................................................................................................... 6 9  
1 5. 2. 4.  
E x pecte d ness of E ve nts .............................................................................................. 6 9  
1 5. 3.  
M o ni t ori n g a n d Rec or di n g E ve nts .............................................................................. 6 9 
1 5. 3. 1.  
A d verse E v e nts ........................................................................................................... 6 9  
1 5. 3. 2.  
A d verse E v e nts of S peci al I nt erest ............................................................................. 6 9  
1 5. 3. 3.  
Seri o us A d verse E v e nts .............................................................................................. 7 0  
1 5. 3. 4.  
I m me diat e Re p orti n g of Seri o us A d verse E v e nts ....................................................... 7 0 
1 5. 3. 4. 1.  
Deat hs ......................................................................................................................... 7 1  
1 5. 3. 5.  
S us pecte d U ne x pecte d S eri o us A d verse Reacti o ns .................................................... 7 1  
1 5. 4.  
P r oce d ures f or H a n dli n g S pecial Sit uati o ns ............................................................... 7 1 
1 5. 4. 1.  
Pre g n a nc y ................................................................................................................... 7 1  
1 5. 4. 2.  
O ver d ose ..................................................................................................................... 7 1  
1 5. 4. 3.  
Me dical E mer ge nc y .................................................................................................... 7 2  
1 5. 4. 3. 1.  
U n bli n di n g f or M e dical E mer ge nc y ........................................................................... 7 2  
1 5. 5.  
C o ntrace pti o n Re q uire m e nts ...................................................................................... 7 2  
1 5. 6.  
S afet y R es p o nsi bilities ................................................................................................ 7 3  
1 5. 6. 1.  
T he I n vesti gat or .......................................................................................................... 7 3  
1 5. 6. 2.  
B i o ge n ......................................................................................................................... 7 4 
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 ........... 7 5  
1 6. 1.  
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 7 5  
1 6. 2.  
Ef ficac y a n d P har m ac o d y n a mics ................................................................................ 7 5 
1 6. 2. 1.  
A nal ysis P o p ulati o n ................................ .................................................................... 7 5 
1 6. 2. 2.  
Met h o ds of A nal ysis ................................ ................................................................... 7 5 
1 6. 2. 2. 1.  
Ge neral C o nsi derati o ns ............................................................................................... 7 5  
1 6. 2. 2. 2.  
D ose Re gi me ns t o be E v al uate d ................................................................................. 7 5  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
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1 6. 2. 2. 3.  
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts .............................................. 7 6  
1 6. 2. 2. 4.  
A nal ysis of t h e Pri mar y E n d p oi nt............................................................................... 7 7  
1 6. 2. 2. 5.  
A nal ysis of t h e Sec o n dar y E n d p oi nts ......................................................................... 7 7  
1 6. 2. 2. 6.  
Tertiar y E n d p oi nts A nal ysis ....................................................................................... 7 7  
1 6. 3.  
P har mac o ki netics ........................................................................................................ 7 8  
1 6. 3. 1.  
A nal ysis P o p ulati o n .................................................................................................... 7 8  
1 6. 3. 2.  
Met h o d of A nal ysis ..................................................................................................... 7 8  
1 6. 4.  
S afet y .......................................................................................................................... 7 8  
1 6. 4. 1.  
A nal ysis P o p ulati o n .................................................................................................... 7 8  
1 6. 4. 2.  
Met h o ds of A nal ysis ................................................................................................... 7 8  
1 6. 4. 2. 1.  
A d verse E v e nts ........................................................................................................... 7 8  
1 6. 4. 2. 2.  
Cli nical La b orat or y Res ults ........................................................................................ 7 8  
1 6. 4. 2. 3.  
Vital Si g ns .................................................................................................................. 7 9  
1 6. 4. 2. 4.  
E C G ............................................................................................................................ 7 9  
1 6. 4. 2. 5.  
C ol u m bia S uici de Se verit y Rati n g Scale .................................................................... 7 9  
1 6. 5.  
Im m u n o ge nicit y D ata ................................................................................................. 7 9  
1 6. 5. 1.  
A na l ysis P o p ulati o n .................................................................................................... 7 9 
1 6. 5. 2.  
Met h o ds of A nal ysis ................................................................................................... 7 9  
1 6. 6.  
Interi m A nal yses ......................................................................................................... 7 9  
1 6. 6. 1.  
I nteri m F utilit y A n al ysis ............................................................................................. 7 9 
1 6. 6. 2.  
I nteri m S u peri orit y A nal ysis....................................................................................... 7 9 
1 6. 7.  
S a m ple Siz e C o nsi derati o ns ....................................................................................... 8 0  
1 7.  
E T H I C A L R E Q UI R E M E N T S ................................................................................... 8 1 
1 7. 1.  
De clarati o n of Helsi n ki ............................................................................................... 8 1  
1 7. 2.  
Et hi cs C o m mittee/I nstit uti o nal Re vie w B oar d ........................................................... 8 1  
1 7. 3.  
S u bject I nf or mati o n a n d C o nse nt ............................................................................... 8 1  
1 7. 4.  
S u bject Data Pr otecti o n .............................................................................................. 8 2  
1 7. 5.  
C o m pe nsati o n f or I nj ur y ............................................................................................. 8 2  
1 7. 6.  
C o nflict of I nt erest ...................................................................................................... 8 2  
1 7. 7.  
R e gistrati o n of St u d y a n d Discl os ure of St u d y R es ults .............................................. 8 2  
1 8.  
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 8 3  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
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T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
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1 8. 1.  
S t u d y Site I nitiati o n .................................................................................................... 8 3 
1 8. 2.  
Q ua lit y Ass ura nce ....................................................................................................... 8 3 
1 8. 3.  
M o ni t ori n g of t he St u d y.............................................................................................. 8 3 
1 8. 4.  
S t u d y F u n di n g ............................................................................................................. 8 3 
1 8. 5.  
P u blicati o ns ................................................................................................................. 8 3  
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 TI O N ........................ 8 4  
1 9. 1.  
E x ter nal C o ntract Or ga ni zati o ns ................................................................................. 8 4 
1 9. 1. 1.  
C o ntract Researc h Or ga nizati o n ................................................................................. 8 4  
1 9. 1. 2.  
I nteracti ve Res p o nse Tec h n ol o g y ............................................................................... 8 4 
1 9. 1. 3.  
Electr o nic D ata Ca pt ure .............................................................................................. 8 4  
1 9. 1. 4.  
Ce ntral La b orat ories f or La b orat or y Ass ess me nts ..................................................... 8 4  
1 9. 1. 5.  
Ce ntral Facilit y f or Ot her Assess me nts ...................................................................... 8 4  
1 9. 1. 6.  
Ne ur oc o g niti ve Ass ess me nts ...................................................................................... 8 5  
1 9. 2.  
S t u d y C o m mittees ....................................................................................................... 8 5 
1 9. 2. 1.  
A d vis or y C o m mittee ................................................................................................... 8 5  
1 9. 2. 2.  
I n d e pe n de nt Data M o nit ori n g C o m mittee .................................................................. 8 5 
1 9. 3.  
C ha n ges t o Fi nal St u d y Pr ot oc ol ................................................................................ 8 5  
1 9. 4.  
Et hi cs C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y 
C o m pleti o n or Ter mi nati o n ........................................................................................ 8 6  
1 9. 5.  
R ete nti o n of St u d y Data .............................................................................................. 8 6  
1 9. 6.  
S t u d y R e p ort Si g nat or y............................................................................................... 8 6 
2 0.  
R E F E R E N C E S ........................................................................................................... 8 7  
2 1.  
S I 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 0 
 
LI S T O F T A B L E S 
Ta ble 1:  
Place b o- C o ntr olle d Peri o d Sc he d ule .......................................................................... 1 7  
Ta ble 2:  
Brai n M RI, Aria Ma na ge me nt, a n d F oll o w- u p P h o ne Call Sc he d ule D uri n g 
t he Place b o- C o ntr olle d Peri o d .................................................................................... 2 1 
Ta ble 3:  
L o n g- T er m E xte nsi o n Sc he d ule ................................................................................. 2 2  
Ta ble 4:  
Brai n M RI, Aria Ma na ge me nt, a n d F oll o w- U p P h o ne Call Sc he d ule D uri n g 
t he L o n g- Ter m E xte nsi o n ........................................................................................... 2 4 
Ta ble 5:  
D osi n g Sc he m e f or A d u ca n u ma b b y Re gi me n ........................................................... 3 2  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
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Ta ble 6:  
Dis p ositi o n of A RI A- E Cases ..................................................................................... 3 9  
Ta ble 7:  
Dis p ositi o n of A RI A- H ( micr o he m orr ha ge) Cas es .................................................... 4 1  
Ta ble 8:  
Dis p ositi o n of A RI A- H (s u perficial si der osis) Cases ................................................. 4 2  
Ta ble 9:  
D ose Re d ucti o n f or S u bj ects E x perie nci n g A RI A, W h o Res u me Treat me nt 
After S us pe nsi o n ......................................................................................................... 4 3  
Ta ble 1 0:  D ose Gr o u p P o oli n g Strate g y i n t he E v e nt of Treat me nt Gr o u p Ter mi nati o n ........... 7 6  
 
LI S T O F FI G U R E S 
Fi g ure 1:  
St u d y Desi g n ............................................................................................................... 1 6  
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 0  
 
1.  
S P O N S O R I N F O R M A TI O N 
Bi o ge n  M A  I n c. 
2 5 0 Bi n ne y Street  
Ca m bri d ge, M A  0 2 1 4 2  
U nite d S tates 
 
Bi o ge n  I d ec Researc h L i mited  
I n n o v ati 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 ustr alia Pt y Lt d  
S uite 1, Le 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 I d ec J a pa n Lt d.  
Ata g o  Gree n Hills M ori T o wer 
2 6 F  
5 -1, Ata g o 2 -c h o m e  
Mi nat o -k u  
T o k y o 1 0 5 -6 2 2 6  
J a pa n 
 
F or 2 4- h o ur e mer ge nc y me dical s u p p ort c o ntact 
 at 
 
 
Please refer t o t he St u d y Refere n ce M a n ual f or c o m plete c o ntact i nf or mati o n. 
B i o ge n ma y tr a 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 res earc h 
or ga niz ati 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 v erall acc o u nta bilit y f or 
t hese acti vities. 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 1  
 
2.  
LI S T O F A B B R E VI A TI O N S 
1 2 F 6 A  
rec o m bi na nt, h u ma n a nti-β -a m yl oi d i m m u n o gl o b u li n G1 
m o n ocl o nal a nti b o d y wit h a n a mi n o aci d se q u e nce i de ntical t o 
a d uca n u ma b , pr o d uce d i n a differe nt C hi nese ha mster o var y 
cell li ne 
1 8F -fl or beta pir 
Als o k n o w n as fl or beta pir-fl u ori ne-1 8  or 1 8F -A V -4 5 (a m yl oi d 
li ga n d; tra d e na me A m y vi d) 
A β  
β -a m yl oi d  
A A  
Alz hei mer’s Ass ociati o n  
A D  
Alz hei mer’s disease  
A D A  
a nti dr u g a nti b o dies  
A D A S -C o g 1 3  
Alz hei mer’s Disease Assess me nt Scale - C o g niti ve S u bscale 
( 1 3 ite ms) 
A D C S -A D L -M CI  
Alz hei mer’s Disease C o o perati ve St u d y - Acti vities of Dail y 
Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n)  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A p o E  
a p oli p o pr otei n E  
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 
 
 
A S T  
as partate a mi n otra nsferas e  
C D R  
Cli nical De me ntia Rati n g  
c h 1 2 F 6 A  
m uri ne I g G 2a c hi meric versi o n of 1 2 F 6 A or a d uca n u ma b  
C R F  
case re p ort f or m  
C R O  
c o ntract r esearc h or ga nizati o n  
C S F  
cere br os pi nal fl ui d  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
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  
E C  
et hics c o m mittee 
E C G  
electr ocar di o gra m  
E D C  
electr o nic d ata ca pt ure  
E O T  
E n d of Treat me nt  
E Q -5 D  
E ur o Q ol healt h stat us meas ure  
E T  
Earl y Ter mi nati o n  
F U  
f oll o w-u p  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 2  
 
G C P  
G o o d Cli nical Practice  
H b A 1 c 
gl yc os ylate d h e m o gl o bi n  
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  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I B 
I n v esti gat or’s Br oc h ure 
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 nfere nce o n Har m o nisati o n 
I D M C 
i n de pe n de nt data m o nit ori n g c o m mittee 
I g 
i m m u n o gl o b uli n  
I R 
i nf or ma nt rate d 
I R B 
i nstit uti o nal re vie w b oar d 
I T T 
i nte nt-t o-treat 
I V 
i ntra ve n o us(l y) 
I W G 
I nter nati o nal W or ki n g Gr o u p 
L T E  
l o n g-ter m e xte nsi o n 
L P  
l u m bar p u nct ure 
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 M R M  
M i x e d-m o del re peate d  m eas ures  
M M S E  
Mi ni -Me ntal State E x a mi nati o n  
M O C A  
M o ntreal C o g niti ve Assess me nt  
m P D Q -2 0  
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d v ersi o n  
M RI  
ma g n etic res o n a nce i ma gi n g  
NI A  
Nati o nal I nstit ute o n A gi n g  
N PI -1 0  
Ne ur o ps yc hiatric I n ve nt or y -1 0  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P K  
p har mac o ki netic(s)  
R B A N S  
Re peata ble Batter y f or Assess me nt of Ne ur o ps yc h ol o gical 
Stat us  
S A B R  
Safet y a n d Be nefit -Ris k  
S A E  
seri o us a d verse e v e nt 
S A P  
statistical a nal ysis pla n 
S B  
s u m of b o xes 
S B P  
s yst olic bl o o d press ur e 
S D  
sta n dar d de viati o n 
S R  
s u bject rate d 
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  
 
 
U V  
u nsc he d ule d visit  
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 3  
 
3.  
S Y N O P SI S 
Pr ot oc ol N u m ber:  
2 2 1 A D 3 0 1  
Pr ot oc ol Title:  
A P hase 3 M ultice nter, R a n d o mize d, D o u ble -Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he 
Efficac y a n d Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects 
wit h Earl y  Alz hei mer's Disease  
Versi o n N u m ber:  
1. 0  
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 I n dicati o n:  
Alz hei mer’s Disease  
St u d y R ati o nale:  
T he p ur p ose of t his P has e  3 st u d y is t o assess t he efficac y 
a n d safet y of a d uca n u ma b c o m pare d wit h place b o i n 
s u bjects wit h earl y Alz hei mer’s Diseas e ( A D) , i ncl u di n g 
mil d c o g niti ve i m pair me nt ( M CI) d ue t o A D  a n d a s u bset of 
mil d A D .  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y 
t hat rec o g nizes a g gre gate d f or ms of β -a m yl oi d ( A β), 
i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  
I nteri m a nal yses of t h e o n g oi n g m ulti ple d ose st u d y 
( St u d y 2 2 1 A D 1 0 3) h a ve de m o nstrate d tar get e n ga ge m e nt, a 
p har mac o d y n a mic effect o n a m yl oi d re d u cti o n, a n d a n 
effect o n t he Cli nical De me ntia Rati n g ( C D R) -S u m of 
B o x es ( S B) a n d Mi ni -Me ntal State E x a mi nati o n ( M M S E) 
s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treat e d s u bjects.  T h ese res ults 
al o n g wit h t he o bser ve d s afet y a n d t olera bilit y pr ofile 
warra nt f urt her P h ase 3 i n vesti gati o n of a d uca n u ma b i n a 
patie nt p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D 
c o nti n u u m .   
P hase of De v el o p me nt:  
3  
St u d y O bjecti ves a n d 
E n d p oi nts ( place b o -c o ntr olle d 
peri o d  of t he st u d y):  
T he pri mar y o bjecti ve of t he st u d y is t o e val uat e t he effi cac y 
of m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he 
C D R -S B  sc ore as c o m pare d wit h place b o i n s u bjects wit h 
earl y A D .   
T he pri mar y e n d p oi nt t h at relates t o t his o bjecti ve is  t he 
cha n ge fr o m baseli ne  i n C D R -S B  sc ore at Wee k 7 8 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 4  
 
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b as 
c o m pare d wit h place b o o n cli nical pr o gressi o n as meas ure d 
b y  
 M M S E  
 C ha n ge fr o m bas eli ne i n M M S E sc ore at 
Wee k  7 8  
 Alz hei mer’s Disease Assess me nt 
Scale -C o g niti ve S u bscale ( 1 3 ite ms) 
[A D A S -C o g 1 3]  
 C ha n ge fr o m bas eli ne i n A D A S -C o g 1 3 at 
Wee k  7 8  
 Alz hei mer’s Disease C o o perati ve St u d y -
Acti vities of Dail y Li vi n g I n v e nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [A D C S -A D L -
M CI]  
 C ha n ge fr o m bas eli ne i n A D C S -A D L -M CI  
sc ore at Wee k 7 8  
Tertiar y o bjecti ves of t his st u d y are liste d i n Secti o n 6. 3. 1 .   
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 .   
St u d y O bjecti ves a n d 
E n d p oi nts ( D ose -Bli n d 
L o n g -T er m E xte nsi o n):  
T he o bjecti ves are 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 u ca n u ma b i n s u bjects wit h earl y 
A D , a n d t o e val u ate t he l o n g-ter m efficac y of a d u ca n u ma b 
treat me nt as meas ure d b y cli nical, ra di ol o gical a n d 
a d diti o nal assess me nts re p orte d b y t h e s u bject a n d 
i nf or ma nt/care part ner. 
E n d p oi nts f or t he L T E peri o d  of t he st u d y are liste d i n 
Secti o n 6. 4. 2 .   
St u d y Desi g n:  
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h  
d o u ble -bli n d, place b o -c o ntr olle d peri o d f oll o we d b y a n 
o pti o nal 2 4 -m o nt h  d ose -bli n d, L T E  peri o d  
St u d y L ocati o n:  
A p pr o xi matel y  1 5 0 sites gl o ball y  
N u m ber of Pla n ne d S u bj ects:  
A p pr o xi matel y 1 3 5 0 s u bj ects 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 u cte d i n s u bjects  wit h earl y A D , 
i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) 
d ue t o A D a n d a s u bs et of mil d A D acc or di n g t o NI A -A A 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc. 
1 5  
 
criteria.  S u bjects m ust b e  p ositi ve f or a m yl oi d pat h ol o g y as 
meas ure d b y a m yl oi d p ositr o n e missi o n t o m o gra p h y sca n .  
S u bjects m ust be 5 0 t o 8 5 years ol d, a n d a part fr o m t he 
cli nical dia g n osis of earl y A D, t h e y m ust be i n g o o d healt h  
as deter mi ne d b y t he I n v esti gat or, b ase d o n me dical hist or y 
a n d t he Scree ni n g assess me nts .  S u bject e nr oll me nt will be 
m o nit ore d s o t hat a p pr o xi matel y 6 0 % t o 7 0 % A p o E ε 4 
carri ers are e nr olle d .  E nr oll me nt will als o be m o nit ore d, via 
i nteracti ve res p o nse tec h n ol o g y (I R T), s uc h t hat s u bjects 
wit h mil d A D re prese nt  a s mall perce nta ge of t he t otal 
e nr olle d i n t he trial . 
Detaile d criteria are des cri be d i n Secti o n 8 . 
Treat me nt Gr o u ps:  
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d  of t he st u d y a n d 
b ase d u p o n t heir A p o E  ε 4 carri er stat us, s u bjects will be 
assi g ne d t o 1 of 3 treat m e nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 
1: 1: 1 rati o (a d uca n u m a b l o w d ose: a d uca n u ma b hi g h d ose: 
place b o) as f oll o ws:  
A p o E ε 4 c arrier  
     L o w d ose  ( 3 m g/ k g) 
     Hi g h d ose ( 6 m g/ k g)  
     Pl ace b o  
A p o E ε 4 n o n -c arrier  
     L o w d ose ( 6 m g/ k g)  
     Hi g h d ose ( 1 0 m g/ k g)  
     Pl ace b o  
After c o m pleti o n of t he place b o -c o ntr olle d peri o d , s u bjects 
ma y e nter a 2 4 -m o nt h  d ose -bli n d L T E st u d y d uri n g w hic h 
all s u bjects will recei ve a d uca n u ma b .   
D urati o n of Treat me nt a n d 
F oll o w -u p:  
St u d y  d urati o n f or eac h  s u bject partici pati n g i n t he place b o -
c o ntr olle d peri o d  o nl y  will be a p pr o xi matel y 1 0 2 wee ks ( u p 
t o a n 8 wee k Scree ni n g P eri o d, 7 6 wee ks of place b o or 
a d uca n u ma b d osi n g, a n d 1 8 wee ks of f oll o w -u p) .   
F or s u bjects w h o e nter t h e o pti o nal L T E, t h e t otal d urati o n 
will be a p pr o xi matel y 2 0 6 wee ks or 4 7  m o nt hs ( u p t o a n 8 
wee k Scree ni n g Peri o d, 7 6 wee ks of place b o or a d uca n u ma b 
d osi n g, 4 wee ks of f oll o w -u p, 1 0 0 wee ks of d ose -bli n d  
a d uca n u ma b d osi n g, a n d 1 8 we e ks of f oll o w -u p).  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Diseas e   
 
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
1 6  
 
 
4.  
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1 
4. 1.  
St u d y Sc he m atic 
Fi g ure 1:  
St u d y Desi g n 
 
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve; R = ra n d o mizati o n date 
* S u bj ects w h o are assi g ne d t o place b o d uri n g t he place b o-c o ntr olle d peri o d a n d are c o nti n ui n g i nt o t he L T E will be ra n d o mize d i n a 1: 1 rati o t o hi g h a n d 
l o w d ose a d uca n u ma b treat me nt ( base d u p o n t heir A p o E ε 4 carrier stat us). 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
1 7  
 
 
4. 2.  
Sc he d ule of E ve nts 
T a ble 1:  
Pl ac e b o- C o ntr olle d Peri o d Sc he d ule 
St u d y Wee k  
Scree ni n g ( ≤ 
6 0 d a ys 
bef ore D a y 
1) 1 
 
U V 
f or a 
c h a n g
e i n 
A D 
me dic
ati o n  
F U/
E T 2 
D
a y 
1  
4  
8  
1 2  
1 6  
2 0  
2 4  
2 6  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 0  
5 2  
5 6  
6 0  
6 4  
6 8  
7 2  
7 6  
7 8 
( E
O T
) 
9 4  
St u d y D a y  
V
1  
V
2  
V
3  
1  
2 9
±
3  
5 7 ±
3  
8 5
± 3  
1 1 3
± 3  
1 4 1
± 3  
1 6 9
± 3  
1 8 3
± 3  
1 9 7
± 3  
2 2 5
± 3  
2 5 3
± 3  
2 8 1
± 3  
3 0 9
± 3  
3 3 7
± 3  
3 5 1
± 3  
3 6 5
± 3  
3 9 3
± 3  
4 2 1
± 3  
4 4 9
± 3  
4 7 7
± 3  
5 0 5
± 3  
5 3 3
± 3  
5 4 7
± 3  
6 5 9  
± 7  
I niti al 
Scree ni n g 
C o nse nt 3 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F ull I nf or me d 
C o nse nt 4 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 5 
 
 
Eli gi bilit y 
Criteri a  
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 5 
 
 
M e dic al Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol/ Dr u g 
Scree n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1c 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V/ He p atitis/
C o a g ul ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A p o E 
ge n ot y pi n g  
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  
X  
X  
X  
X  
X  
 
 
X  
Ser u m 
P re g n a nc y  
 Test 7 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri ne 
P re g n a nc y 
Test 7 
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
 
X  
P h ysic al 
E x a mi n ati o n  
X  
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
 
X  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
1 8  
 
 
St u d y Wee k  
Scree ni n g ( ≤ 
6 0 d a ys 
bef ore D a y 
1) 1 
 
U V 
f or a 
c h a n g
e i n 
A D 
me dic
ati o n  
F U/
E T 2 
D
a y 
1  
4  
8  
1 2  
1 6  
2 0  
2 4  
2 6  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 0  
5 2  
5 6  
6 0  
6 4  
6 8  
7 2  
7 6  
7 8 
( E
O T
) 
9 4  
St u d y D a y  
V
1  
V
2  
V
3  
1  
2 9
±
3  
5 7 ±
3  
8 5
± 3  
1 1 3
± 3  
1 4 1
± 3  
1 6 9
± 3  
1 8 3
± 3  
1 9 7
± 3  
2 2 5
± 3  
2 5 3
± 3  
2 8 1
± 3  
3 0 9
± 3  
3 3 7
± 3  
3 5 1
± 3  
3 6 5
± 3  
3 9 3
± 3  
4 2 1
± 3  
4 4 9
± 3  
4 7 7
± 3  
5 0 5
± 3  
5 3 3
± 3  
5 4 7
± 3  
6 5 9  
± 7  
Ne ur ol o gic al 
E x a mi n ati o n  
X  
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
 
X  
1 2 -le a d p a per 
E C G  
X  
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
 
X  
Vit al Si g ns 8 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
 
X  
He m at ol o g y, 
Bl o o d 
C he mistr y a n d 
Uri n al ysis  
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
 
X  
R a n d o mi z ati o n  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y Dr u g 
I nf usi o n 
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
 
 
A nti - 
a d uc a n u m a b 
A b 9 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
 
X  
A d uc a n u m a b 
C o nce ntr ati o n 1 0 
 
 
 
X
1 1 
X 
1 1 
 
X 
1 1 
X  
X 
1 1 
X 
1 1 
 
X 
1 1 
X  
 
 
 
 
 
X 
1 1 
X  
 
 
 
 
X  
 
 
 
A m yl oi d P E T 1 4 
 
 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
R B A N S  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C D R  
X  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
X  
X  
M M S E  
X  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
X  
X  
A D C S -
A D L -M CI  
 
X
1 5 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
X  
X  
A D A S -C o g 1 3  
 
X
1 5 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
X  
X  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
1 9  
 
 
St u d y Wee k  
Scree ni n g ( ≤ 
6 0 d a ys 
bef ore D a y 
1) 1 
 
U V 
f or a 
c h a n g
e i n 
A D 
me dic
ati o n  
F U/
E T 2 
D
a y 
1  
4  
8  
1 2  
1 6  
2 0  
2 4  
2 6  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 0  
5 2  
5 6  
6 0  
6 4  
6 8  
7 2  
7 6  
7 8 
( E
O T
) 
9 4  
St u d y D a y  
V
1  
V
2  
V
3  
1  
2 9
±
3  
5 7 ±
3  
8 5
± 3  
1 1 3
± 3  
1 4 1
± 3  
1 6 9
± 3  
1 8 3
± 3  
1 9 7
± 3  
2 2 5
± 3  
2 5 3
± 3  
2 8 1
± 3  
3 0 9
± 3  
3 3 7
± 3  
3 5 1
± 3  
3 6 5
± 3  
3 9 3
± 3  
4 2 1
± 3  
4 4 9
± 3  
4 7 7
± 3  
5 0 5
± 3  
5 3 3
± 3  
5 4 7
± 3  
6 5 9  
± 7  
N PI -1 0  
 
X
1 5 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
X  
E Q -5 D ( S R)  
 
X
1 6 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
X  
E Q -5 D (I R -S)  
 
X
1 6 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
X  
m P D Q -2 0  
 
X
1 6  
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X  
 
X  
C -S S R S  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
X  
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  
C o nc o mit a nt 
t her a 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 D = Alz hei mer’s disease; A E = a d verse e ve nt; A D A S- C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale- C o g niti ve S u bscale ( 1 3 ite ms); A D C S- A D L- M CI  = 
Alz hei mer's Disease C o o perati ve St u d y- Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n); A p o E = a p oli p o pr otei n E; C D R = Cli nical 
De me ntia Rati n g scale;
 ; C- S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; D N A = de o x yri b o n ucleic aci d; E C G = 
electr ocar di o gra m; 
; E Q- 5 D (I R- S) = E Q- 5 D, i nf or ma nt 
re p orte d o n s u bj ect; E Q- 5 D ( S R) = E Q- 5 D, s u bj ect self-re p orte d; E O T = E n d of Treat me nt; E T = Earl y T er mi nati o n; F U = F oll o w- u p; H b A1c  = 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; M M S E = Mi ni- Me ntal State E xa mi nati o n; m P D Q- 2 0 = m o difie d P ercei ve d Deficits Q uesti o n naire- 2 0; 
M RI = ma g netic res o na nce i ma gi n g; N PI- 1 0 = Ne ur o ps yc hi atric I n ve nt or y; P E T = p ositr o n e missi o n t o m o gra p h y; R B A N S = Re p eata ble B atter y f or t he 
Assess me nt of Ne ur o ps yc h ol o gical Stat us; 
; S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit; V 1, V 2, V 3 = Scree ni n g Visit 1, 
Scree ni n g Visit 2 a n d Scree ni n g Visit 3 
 
1 E xa mi nati o ns re q uire d f or assess me nt of s u bj ect eli gi bilit y m ust be perf or me d at V 1.  Brai n M RI ( T a ble 2 ) s h o ul d o nl y be perf or me d o nce t he s u bj ect meets 
eli gi bilit y criteria at V 1 .  A m yl oi d P E T s h o ul d o nl y be perf or me d if t he s u bj ect meets eli gi bilit y criteria at V 1 a n d V 2. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
2 0  
 
 
2 Visit t o be c o m plete d i n cases of earl y ter mi nati o n or f or s u bj ects w h o d o n ot e nr oll i n t he l o n g-ter m e xte nsi o n. 
3 S u bj ects ma y si g n t his o pti o nal f or m f or a n i nitial scree ni n g w hic h all o ws a d mi nistrati o n of t he R B A N S, C D R a n d M M S E o nl y. 
4 All s u bj ects m ust si g n t his i nf or me d c o nse nt, i ncl u di n g s u bj ects w h o ha ve si g ne d t he i niti al scree ni n g c o nse nt o nce t he y ha ve met t he R B A N S, C D R a n d 
M M S E eli gi bilit y criteria. 
5 O nl y f or s u bj ects e nteri n g t he l o n g-ter m e xte nsi o n. 
 
. 
7 Re q uire d f or w o me n of c hil d beari n g p ote ntial o nl y ( See Se cti o n 1 5. 5 ). 
8 Vital si g ns will i ncl u de s yst oli c bl o o d press ure, diast olic bl o o d press ure, heart rate, b o d y t e m perat ure, a n d res pirat or y rat e.  Vital si g ns will be meas ur e d wit h 
t he s u bj ect s u pi ne a n d after t he s u bj ect has bee n resti n g f or at least 1 0 mi n utes. 
9 Sa m ple c ollecti o n f or a nti-a d uca n u ma b a nti b o d y will be perf or me d pri or t o bl o o d c ollecti o n f or a d uca n u ma b c o nce ntrati o n or st u d y dr u g i nf usi o n 
1 0 Bl 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. 
1 1 O ne a d diti o nal bl o o d sa m ple f or a d uca n u ma b c o nce ntrati o n will be c ollecte d bet wee n 1 0 a n d 6 0 mi n utes after c o m pleti o n of t he i nf usi o n a n d li ne fl us h 
 
1 3 Ma y be c ollecte d at a n y p oi nt i n ti me d uri n g Scree ni n g after eli gi bilit y at V 1 is c o nfir me d b ut if c ollecte d o n t he sa me da y as a n M RI, it s h o ul d be c ollecte d 
after t he M RI is perf or me d. 
1 4 Scree ni n g P E T is re q uire d f or all s u bj ects, P E T at Wee k 2 6 a n d Wee k 7 8 will o nl y be c o n d ucte d i n selecte d sites f or s u bj ects w h o are partici pati n g i n t he P E T 
c o h ort. 
1 5 M ust b e perf or me d wit hi n 1 4 da ys of V 1, b ut n ot o n t he sa me da y as t he scree ni n g R B A N S, C D R or M M S E. 
1 6 Ma y be perf or me d at a n y p oi nt d uri n g scree ni n g after t he s u bj ect has met eli gi bilit y criteri a o n t he R B A N S, C D R a n d M M S E. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
2 1  
 
 
T a ble 2:  
Br ai n M RI, Ari a M a n a ge me nt, a n d F oll o w- u p P h o ne C all Sc he d ule D uri n g t he Pl ace b o- C o ntr olle d Peri o d 
St u d y Wee k  
Scree ni n g 1 
( ≤ 6 0 d a ys bef ore 
D a y 1)  
Pl ace b o -C o ntr olle d Peri o d  
U nsc he d ul
e d Visit f or 
A RI A 2 
F U 3 
/ E T 
D a y 1  
2  
6  
1 0  
1 4  
1 8  
2 2  
2 6  
3 0  
4 2  
5 4  
7 8  
9 4  
St u d y D a y  
V 1  
V 2  
V 3  
1  
1 5 ± 3  
4 3 ± 3  
7 1 ± 3  
9 9 ± 3  
1 1 3 ± 3  
1 5 5 ± 3  
1 8 3 ± 3  
2 1 1 ± 3  
2 9 5 ± 3  
3 7 9 ± 3  
5 4 7 ± 3  
8 2 6  
± 7  
F oll o w -u p P h o ne C all  
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
Br ai n M RI 4 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
A d uc a n u m a b  
C o nce ntr ati o n 5 
 
 
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
 
X  
M O C A  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
X  
 
A RI A = a m yl oi d relate d i ma gi n g a b n or malities; E T = Earl y T er mi nati o n; 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; V 1, V 2, V 3 = Scree ni n g Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3 
1 Brai n M RI ( V 2) will n ot b e perf or me d u ntil t he s u bj ect has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1. 
2 Details o n A RI A ma na ge me nt are i n Secti o n 7. 2 . 
3 Assess me nts t o be c o m plete d as part of a n E T Visit or f or s u bj ects n ot e nr olli n g i nt o t he l o n g-ter m e xte nsi o n. 
4 Arterial s pi n la beli n g M RI a n d tas k free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites. 
5 O ne sa m ple will be c ollecte d wit hi n 2 da ys after t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all p har mac o ki netic bl o o d sa m ples o n a 
specifie d case re p ort f or m. 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
2 2  
 
 
T a ble 3:  
L o n g- Ter m E xte nsi o n Sc he d ule 
St u d y Wee k  
 
U V f or a 
c h a n ge i n 
A D 
me dic ati o
n  
F U  
/ E T 
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  
1 5
6  
1 6
0  
1 6
4  
1 6
8  
1 7
2  
1 7
6  
1 8
0  
1 8 2 
( E o
T)  
1 9 8  
St u d y D a y  
5 6 1
± 5  
5 8
9
±
5  
6 1
7
±
5  
6 4
5
±
5  
6 7
3
±
5  
7 0
1
±
5  
7 2
9
±
5  
7 5
7
±
5  
7 8
5
±
5  
8 1
3
±
5  
8 4
1
±
5  
8 6
9
±
5  
8 9
7
±
5  
9 2
5
±
5  
9 5
3 ±
5  
9 8
1 ±
5  
1 0
0 9  
± 5  
1 0
3 7  
± 5  
1 0
6 5  
± 5  
1 0
9 3  
± 5  
1 1
2 1  
±
5  
1 1
4 9  
±
5  
1 1
7 7  
±
5  
1 2
0 5  
±
5  
1 2
3 3  
±
5  
1 2
6 1  
± 5  
1 2 7
5 ±
5  
1 3 8
7 ± 7  
R a n d o mi z ati o n  
X 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o d y W ei g ht  
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  
X  
 
X  
Uri ne P re g n a nc y T est 2 
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  
X  
 
X  
P h ysic al E x a m i n ati o n 
 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
Ne ur ol o gic al E x a m i n ati o n 
 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
1 2 -le a d Pa per E C G  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
Vit al S i g ns 
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  
X  
 
 
He m at ol o g y, Bl o o d 
C he mistr y a n d Uri n al ysis  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
A nti -a d uc a n u m a b  A b 3 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
A d uc a n u m a b  
C o nce ntr ati o n 3 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
St u d y Dr u g I nf usi o n  
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  
 
 
 
A m yl oi d P E T 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
C D R 6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
X  
X  
M M S E
6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
X  
X  
A D A S -C o g 1 3 6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
X  
X  
A D C S -A D L -M CI
6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
X  
X  
N PI -1 0 6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
2 3  
 
 
St u d y Wee k  
 
U V f or a 
c h a n ge i n 
A D 
me dic ati o
n  
F U  
/ E T 
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  
1 5
6  
1 6
0  
1 6
4  
1 6
8  
1 7
2  
1 7
6  
1 8
0  
1 8 2 
( E o
T)  
1 9 8  
St u d y D a y  
5 6 1
± 5  
5 8
9
±
5  
6 1
7
±
5  
6 4
5
±
5  
6 7
3
±
5  
7 0
1
±
5  
7 2
9
±
5  
7 5
7
±
5  
7 8
5
±
5  
8 1
3
±
5  
8 4
1
±
5  
8 6
9
±
5  
8 9
7
±
5  
9 2
5
±
5  
9 5
3 ±
5  
9 8
1 ±
5  
1 0
0 9  
± 5  
1 0
3 7  
± 5  
1 0
6 5  
± 5  
1 0
9 3  
± 5  
1 1
2 1  
±
5  
1 1
4 9  
±
5  
1 1
7 7  
±
5  
1 2
0 5  
±
5  
1 2
3 3  
±
5  
1 2
6 1  
± 5  
1 2 7
5 ±
5  
1 3 8
7 ± 7  
E Q -5 D  (I R -S) 6 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
X  
C -S S R S  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X  
A E R e 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  
C o nc o mit a nt T her a 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 R e 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 D = Alz hei mer’s disease; A E = a d verse e ve nt; A D A S- C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale- C o g niti ve S u bscale ( 1 3 ite ms); A D C S- A D L- M CI  = 
Alz hei mer's Disease C o o perati ve St u d y- Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n); 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; E C G = electr ocar di o gra m; 
 
; E Q- 5 D (I R- S) = E Q- 5 D, i nf or ma nt re p orte d o n s u bj ect; E Q- 5 D ( S R) = E Q- 5 D, s u bj ect self-re p orte d; E O T = E n d of 
Treat me nt; E T = Earl y T er mi nati o n; F U = F oll o w- u p; 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 ;  N PI = Ne ur o ps yc hiatric 
I n ve nt or y; 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. 
 
1 S u bj ects w h o were i n t he place b o gr o u p d uri n g t he place b o-c o ntr olle d peri o d will be ra n d o mize d t o a d uc a n u ma b hi g h a n d l o w d ose ( 1: 1 rati o). 
2 Re q uire d f or w o me n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ). 
 
 
 
 
5 O nl y f or s u bj ects w h o partici pate i n t he P E T c o h ort. 
 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc. 
2 4  
 
 
T a ble 4:  
Br ai n M RI, Ari a M a n a ge me nt, a n d F oll o w- U p P h o ne C all Sc he d ule D uri n g t he L o n g- Ter m E xte nsi o n 
St u d y Wee k  
L o n g -Ter m E xte nsi o n  
U ns c he d ule d 
visit  f or A RI A1 
F U / E T 
8 2  
8 6  
9 0  
9 4  
9 8  
1 0 2  
1 0 6  
1 1 0  
1 2 2  
1 3 4  
1 5 8  
1 8 2  
1 9 8  
St u d y D a y  
5 7 5 ± 5  
6 0 3 ± 5  
6 3 1 ± 3  
6 5 9 ± 5  
6 8 7 ± 5  
7 1 5 ± 5  
7 4 3 ± 5  
7 7 1 ± 5  
8 5 5 ± 5  
9 3 7 ± 5  
1 1 0 7 ± 5  
1 2 4 7 ± 5  
1 3 8 7  
± 7  
F oll o w -u p P h o ne 
C all  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
Br ai n M RI 2 
 
 
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
M O C A  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
A RI A = a m yl oi d relate d i ma gi n g a b n or malities; E T = Earl y T er mi nati o n; 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 
1 Details o n A RI A ma na ge me nt are i n Secti o n 7 . 2. 
2 Arterial-s pi n la beli n g M RI a n d tas k-free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n S u bj ects wit h Earl y Alz hei mer's Disease   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n 
M A I nc. 
2 5  
 
4. 3.  
A d diti o n al I nf or m ati o n  
4. 3. 1.  
S ite Pers o n nel 
F or eac h s u bject, t he Pri nci pal I n vesti gat or ( PI) of t he site will desi g nate t he f oll o wi n g 
i n vestigati o nal site pers o n nel: 
 T w o i n de pe n de nt r ati n g healt h care pr ofessi o nals (t he PI ca n n ot ser ve as a rati n g h ealt h 
care pr ofessi o nal) ; o ne w h o is res p o nsi ble f or a d mi nisteri n g t he Cli nical De me ntia Rati n g 
( C D R) a n d a sec o n d w h o will a d mi nister t he Alz hei mer’s Disease Assess m e nt 
Scale- C o g niti ve S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3], Alz hei mer’s Disease C o o perati ve 
S t u d y- Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n) 
( A D C S- A D L- M CI), a n d t he Mi ni- Me ntal State E xa mi nati o n ( M M S E) 
T he rati n g healt h care pr ofessi o nals m ust n ot be i n v ol ve d wit h a n y ot h er 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 a d verse e ve nts ( A Es), c o nc o mita nt 
t hera p y, la b orat or y data, i ma gi n g data or a n y ot her data t hat ha ve t he p ote ntial of 
reveali n g t he treat me nt assi g n me nt.   
T o e ns ure c o nsiste n c y acr oss sites, rati n g h ealt h care pr ofessi o nals m ust c o m plete t he 
sta n dar dize d st u d y-s p ecific q ualificati o n pr ocess o n cli nical efficac y assess me nt sc ori n g 
pri or t o a d mi nistrati o n of t he s pecific assess me nt at t heir site.  All sites s h o ul d atte m pt t o 
mai ntai n t he sa me rati n g healt h care pr ofessi o nal t hr o u g h o ut t he st u d y f or s pecific 
assess me nts.  Eac h s u bject s h o ul d ha ve t he sa me rati n g healt h care pr ofessi o nal perf or m 
t he s u bject’s s pecifi c rati n g ass ess me nt t hr o u g h o ut t he st u d y.  If a rati n g healt h care 
pr ofessi o nal has t o be re place d, t he ne w rati n g healt h care pr ofessi o nal 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. 
 A treati n g healt h care pr ofessi o nal (t he PI ma y ser ve as a treati n g healt h care 
pr ofessi o nal) w h o is r es p o nsi ble f or t he f oll o wi n g: 
 A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y 1 a n d d uri n g 
ma na ge me nt of A RI A cases. 
 Ma na ge me nt of t h e r o uti ne ne ur ol o gical care of t h e s u bject. 
 Assess me nt (i ncl u di n g assi g n me nt of ca usalit y) a n d treat me nt of A Es.   
 Re vie w of sele cte d he mat ol o g y a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y tr eat me nt s h o ul d be te m p oraril y 
wit h hel d or  per ma n e ntl y disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
S ecti o n 1 0. 1 . 
He mat ol o g y a n d bl o o d c he mistr y dat a will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bj ect.  As wit h ot her la b orat or y a n d cli nical i nf or m ati o n, t hese data 
s h o uld N O T be re vi e we d b y t he rati n g h ealt h care pr ofessi o nals.   
T he r oles of i n de p e n de nt raters a n d treati n g healt h care pr ofessi o nal are N O T i nterc ha n gea ble at 
t he s u bject le vel.  I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc h a n gea ble at t he s u bject 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
2 6  
 
le vel.  If a rater has a d mi nistere d t he C D R t o a s u bject t he y ma y n ot a d mi nister t he ot her 
ne ur oc o g niti ve assess me nts t o t hat s u bject at a n y p oi nt d uri n g t he st u d y. 
 A n u n bli n de d p har macist ( or a ut h orize d desi g nee) will be res p o nsi ble f or t h e 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 t he st u d y bli n d. 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
2 7  
 
5.  
I N T R O D U C TI O N  
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i ncreas e t o 1 3 5. 5 milli o n b y 2 0 5 0 
[Alz hei mer's Disease I nter nati o nal 2 0 1 4 ].   
C li nicall y, A D is a pr o gressi ve ne ur o d e 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 d ecli ne i n c o g niti o n a n d be h a 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 a cti vities of dail y li vi n g [J ac k 2 0 1 3]. 
Pat h ol o gicall y, A D is defi ne d b y t he prese n ce i n t he brai n of e xtracell ular ne uritic pla q ues 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra n e ur o nal ne ur ofi brillar y t a n gles c o m p ose d of 
h y per p h os p h or ylate d ta u pr otei ns.  T he pat h o ge n esis of t hese pla q ues a n d t a n gl es a n d h o w t he y 
co ntri b ute t o t he cli nical s y n dr o me re mai n t o be f ull y el uci date d, b ut t he lea di n g h y p ot hesis —
t he “a m yl oi d casca de” — pr o p oses t hat t he dri vi n g f orce b e hi n d t he diseas e 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 bal a nce b et wee n A β pr o d ucti o n a n d A β cleara nce i n t he 
brai n [Ha r d y a n d Sel k oe 2 0 0 2].   
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n ha vi n g cate g orical sta ges.  E vi de nce s u g gests t he 
pa t h o p h ysi ol o gical c h a n ges b e gi n years bef ore cli nical o nset a n d as t he dis ease pr o gresses 
c o g niti ve i m pair me nts, b e ha vi oral c h a n ges, a n d f u ncti o nal disa bilit y m a nifest [Jac k 2 0 1 3 ].  
Re vise d criteria f or t he cli nical dia g n osis of A D were p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) a n d t he Alz hei mer’s Ass oci ati o n ( A A) [Al be rt 2 0 1 1; Mc K ha n n 2 0 1 1 ; S perli n g 
2 0 1 1 ] a n d t he I nter nati o n al W or ki n g Gr o u p (I W G) [D u b ois 2 0 1 0 ; D u b ois 2 0 1 4 ], an d a gr o u p 
t hat i ncl u de d me m bers fr o m b ot h NI A- A A a n d I W G p u blis he d rec o m me n dati o ns t o har m o nize 
t he criteria [M orris 2 0 1 4 ].  T hese criteria bas e t he dia g n osis of A D o n b ot h cli nical a n d 
bi ol o gical ele m e nts, rec o g nizi n g t he e xiste nce of a n o ncli nical sta ge of t he disease b y acce pti n g 
A D  dia g n oses pri or t o si g ns of d e me ntia usi n g A D bi o mar kers. 
T he scie ntific c o m m u nit y has s hift e d its f oc us t o tar get patie nts i n t he earli er c o urse of t he 
disease c o nti n u u m wit h t he belief t hat t h ose p atie nts are m ore li kel y t o be nefit fr o m a nti-a m yl oi d 
t hera p y.  S u p p orti n g t his h y p ot hesis are res ults fr o m s ola nez u ma b a n d cre n ez u ma b st u dies t hat 
ha ve s h o w n a tr e n d i n sl o wi n g c o g niti ve decli ne i n mil d b ut n ot m o derate A D [D o o d y 2 0 1 4 ; 
Fa ga n 2 0 1 4 ].   
T here are c urre ntl y n o t h era pies t hat m o dif y t he c o urse of A D, b ut se v eral p ote ntial 
disease- m o dif yi n g dr u g ca n di dates are u n der i n v esti gati o n.  T hese ca n di dat es 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 p at h wa y a n d ai m t o 
pr o vi de t hera p e utic be n efit b y re d u ci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F).  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
ag gre gat e d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u bli cati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h sol u ble oli g o mers a n d a m yl oi d pla q ues are ne ur ot o xic [K of fie 2 0 0 9; K uc hi b h otla 2 0 0 8 ; 
Me yer- 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 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
2 8  
 
calci u m h o me ostasis a n d ne ur o nal a cti vit y, as w ell as re d ucti o n of o xi dati ve stress [R oz kal ne 
2 0 0 9 ; S pires-J o nes 2 0 0 9 ].  Si milarl y, p atie nts wit h A D w h o ge nerate d a nti- A β a nti b o dies after 
acti ve i m m u nizati o n wit h a g gre gat e d A β( 4 2) s h o we d sl o wer rates of d ecli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [H oc k 2 0 0 3 ]. 
5. 1.  
Pr ofile of Pre vi o us E x perie nce wit h A d uc a n u m a b   
5. 1. 1.  
N o ncli nic al E x perie nce  
A d uc a n u ma b is a u ni q ue h u ma n, a nti- A β m o n ocl o nal a nti b o d y i de ntifie d a n d deri ve d fr o m 
B l y m p h o c yt es usi n g t he re vers e 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 
repert oir es o btai ne d fr o m c o h orts of healt h y el d erl y h u ma n d o n ors wit h e xcelle nt c o g niti ve 
perf or ma n ce or wit h i m paire d b ut sta ble c o urses were s cree ne d f or me m or y B cells a gai nst 
a g gre gat e d A β.   
I n vitr o st u dies ha v e 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 m m u n o gl o b uli n (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 pr o perties si g nifi ca ntl y re d uce d 
a m yl 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, t hr o u g h a 
micr o glia- me diate d p ha g oc ytic m ec ha nis m.  T hes e data s u g gest a d u ca n u m a b c o ul d pr o vi de 
be nefit b y re d u ci n g pla q ue b ur de n. 
T he t o xic o ki netic pr ofile of a d uca n u m a 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 y n o m ol g us m o n ke ys i n a 4- wee k st u d y.  Of t he 2 s p ecies, t he T g 2 5 7 6 m o use is 
co nsi dere d t he pri mar y p har mac ol o gic all y 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 p are n c h y m a a n d v asc ulat ure.  I n a d diti o n t o t he sta n dar d 
hist o pat h ol o gic al e v al 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) w as 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 ni c 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 treat e d wit h 
s o me anti- 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 ]. 
Fi n di n gs c o nsiste nt wit h a m yl oi d pla q ues a n d vas c ular a m yl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, i ncl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h t his m o del.  I n 
b ot h 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 m a b was w ell 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 v asc ular i nfla m mati o n a n d/ or vasc ular t hic k e 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-treat e 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 
eval uati o n of micr o h e m orr ha ge, c haracterize d b y q ua ntificati o n 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 h e i nci de nce a n d se v erit y of 
he m orr ha ge or cere bral v asc ular i nfla m mati o n w ere c o m para ble i n t he 1 3- wee k a n d 6- m o nt h 
m o us e st u dies.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
2 9  
 
See t he I n vesti gat or’s Br oc h ure (I B) f or d etaile d i nf or mati o n o n n o ncli nical st u dies. 
5. 1. 2.  
Cli n ic al E x perie nce 
A d uca n u ma b h as bee n e val uate d i n o ne c o m plete d si n gle as ce n di n g d ose st u d y ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d os e st u d y ( 2 2 1 A D 1 0 3):  
 S t u d y 2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, st u d y 
of a d uca n u m a b i n s u bjects wit h mil d or m o derate A D.   
T he  pri mar y o bjecti ve w as t o e val uate t he s afet y a n d t olera bilit y of a ra n ge of 
a d uca n u ma b d os es ( 0. 3 t o 6 0 m g/ k g) w h e n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y o bjecti ves were t o assess t he p har mac o ki netic ( P K) a n d 
i mm u n o ge nicit y  of a d u ca n u ma b after si n gle- d ose a d mi nistrati o n.   
A si n g le d ose of a d u ca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d.  
D ose-li miti n g A RI A ( 2 s u bjects wit h A RI A- E [e d e ma] a n d 1 s u bject wit h A RI A- E 
an d A RI A- H [ micr o he m orr ha ge]) was o bser v e d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses b el o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near. 
 S t u d y 2 2 1 A D 1 0 3 is a ra n d o mi ze d, d o u ble- bli n d, place b o-c o ntr olle d m ulti ple d ose 
st u d y of a d u ca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are a m yl oi d 
p ositi ve.  T he st u d y c o m prises a place b o-c o ntr oll e d peri o d wit h s u bjects r ecei vi n g 
m o nt hl y d os es of a d u ca n u ma b (fi x e d d oses of 1, 3, 6, or 1 0 m g/ k g, or titrati o n u p t o 6 
m g/ k g) or pla ce b o f or a year f oll o we d b y a d ose- bli n d l o n g-ter m e xte nsi o n ( L T E ) 
peri o d wit h s u bjects recei vi n g m o nt hl y d oses of a d uca n u ma b.   
T he  pri mar y o bje cti ve of t he st u d y is t o e val uat e t he safet y a n d t olera bilit y of m ulti ple 
d oses of a d uca n u ma b a d mi nistere d m o nt hl y as si n gle I V i nf usi o ns.  T he s ec o n dar y 
o bjec ti ves are t o assess t he effect of a d uca n u m a b o n cere bral a m yl oi d pla q ue c o nte nt 
as meas ure d b y 1 8F -fl or b eta pir p ositr o n e missi o n t o m o gra p h y ( P E T), a n d t o e val uate 
t he P K a n d i m m u n o ge nicit y of a d u ca n u ma b after m ulti ple- d ose a d mi nistrati o n.  
E x pl orat or y o bjecti ves i n cl u de assess me nt of t he effect of a d uca n u ma b o n t he cli nical 
pr o gressi o n of A D as me as ure d b y C D R- s u m of b o x es ( S B ) a n d M M S E.   
T o da te, A RI A h as bee n t he m ost fre q ue nt A E  re p orte d i n t he st u d y.  A RI A- E was 
radi o gra p hic all y m o nit or e d b y m a g netic res o na nce i ma gi n g ( M RI) a n d t y picall y 
o bser ve d earl y i n treat me nt ( bet wee n 2 t o 5 d oses).  I n m ost cases, A RI A- E res ol ve d 
4 t o 1 2 wee ks aft er o nset a n d A RI A- H wa s t y picall y sta ble 2 t o 4 wee ks aft er o nset.  
In ci de nce of A RI A h as b ee n o bser ve d t o be b ot h d ose a n d A p oli p o pr otei n E 4 
(A p o E ε 4) carria ge- d e pe n de nt, es peciall y at t he hi g hest d oses (refer t o t he I B f or 
de tails o n e ve nts of A RI A).   
Pr ot oc ol- defi ne d i nteri m a nal ys es ha ve de m o nstrat e d a d ose- a n d ti me- de p e n de nt 
re d ucti o n of brai n a m yl oi d b ur de n aft er 6 m o nt hs of d osi n g ( Wee k 2 6), wit h 
statistical si g nifica nce ac hie ve d i n t he 3, 6, a n d 1 0 m g/ k g gr o u ps c o m pare d wit h 
place b o, a n d after 1 year of d osi n g ( Wee k 5 4), wit h statistical si g nifica nce ac hie ve d 
i n the 3 a n d 1 0 m g/ k g gr o u ps c o m pare d wit h place b o ( 6 m g/ k g d ata n ot yet 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 0  
 
a vaila ble).  T h e res ults d e m o nstrate tar get e n ga ge me nt (a m yl oi d pla q ues) a n d a 
p ha r mac o d y n a mic effect ( d ose- de p e n de nt a m yl oi d re d ucti o n).  I n a d diti o n res ults 
fr o m t he i nteri m a nal yses s h o we d a n effect at 1 year o n t he e x pl orat or y e n d p oi nts 
C D R- S B a n d M M S E, s u g gesti n g a re d ucti o n i n t h e pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treat e d vers us place b o-treate d s u bjects.  At Wee k 5 4, 
a dj uste d mea n c h a n ge (i n creas e) fr o m baseli ne i n C D R- S B sc ore was s maller f or b ot h 
t he 3 a n d 1 0 m g/ k g gr o u ps c o m pare d wit h place b o, wit h statistical si g nifica nce 
ac hie ve d i n t he 1 0 m g/ k g gr o u p ( 6 m g/ k g d ata n ot yet a vaila ble).  At Wee k 5 2, 
adj uste d mea n c h a n ges ( decreases) i n M M S E sc ore fr o m bas eli ne were statisticall y 
si g nifica nt i n t he 3 a n d 1 0 m g/ k g gr o u ps ( Wee k 5 4 6 m g/ k g data n ot yet a v aila ble).  
R efer t o t he I B f or details o n i nteri m a nal ys es res ults. 
5. 2.  
St u d y R ati o n ale 
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safet y of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di ng s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D an d a s u bset of mil d A D.  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g niz es 
ag gre gat e d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u bli cati 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 yer- L ue h ma n n 2 0 0 8 ] a n d cleara n ce of a m yl oi d pla q ues 
co 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 ].  F or 
t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, w hile pres er vi n g 
gl o bal f u n cti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.   
I nteri m a nal yses of t h e o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve de m o nstrate d tar get 
en ga ge me nt, a P D effect o n a m yl oi d re d u cti o n, a n d a n effect o n C D R- S B a n d M M S E s u g gesti ve 
of a re d u cti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b-tr eate d s u bjects.  T hes e 
res ults al o n g wit h t he o bser ve d safet y a n d t olera bilit y pr ofile warra nt t he f urt her P hase 3 
i n vesti gati o n of a d u ca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D 
co nti n u u m. 
5. 3.  
R ati o n ale f or D ose a n d Sc he d ule Selecti o n 
T he d osi n g re gi me n selecte d f or t his st u d y was base d o n t he P K a n d P D rel ati o ns hi p f or re m o val 
of brai n a m yl oi d a n d effect o n C D R- S B a n d M M S E o bser ve d i n St u d y 2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n s afet y, t olera bilit y, a n d P K data fr o m st u dies 2 2 1 A D 1 0 1 (c o m plete) a n d 
2 2 1 A D 1 0 3 ( o n g oi n g).   
T he d ose- a n d ti me- de pe n de nt re d ucti o n of brai n a m yl oi d b ur de n o bs er ve d wit h a d uca n u ma b 
treat me nt was statisticall y si g nifica nt at d oses of 3, 6 a n d 1 0 m g/ k g after 6 m o nt hs of d osi n g a n d 
at 3 a n d 1 0 m g/ k g after 1 2 m o nt hs of d osi n g ( 6 m g/ k g data n ot yet a vaila bl e).  T he effect o n 
mea n decreas e fr o m b aseli ne i n C D R- S B after 1 2 m o nt hs of d osi n g was o bser ve d at b ot h 3 a n d 
1 0 m g / k g ( 6 m g/ k g d ata n ot yet a v aila ble), wit h st atistical si g nifica n ce ac hi e ve d at 1 0 m g/ k g.  
T he  effect o n mea n decrease fr o m bas eli ne i n M M S E sc ore was statisticall y si g nifica nt at 3 a n d 
1 0 m g / k g.  T hese d ata i n dicate t hat 3 m g/ k g c o ul d be c o nsi dere d a n acce pta ble d ose f or P hase 3 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 1  
 
st u dies; h o we ver, gi ve n t he d ose- de p e n de nt nat ur e of t hese o bser vati o ns, t he use of hi g her d oses 
( 6 a n d 1 0 m g/ k g) c o ul d offer great er be n efit at acce pta ble ris k.   
A R I A h as bee n i de ntifie d as a n e ve nt t hat ma y o cc ur wit h a nti-a m yl oi d tar geti n g dr u g ca n di dates 
a n d is c o nsi dere d a n e ve nt of s peci al i nterest i n t h e a d uca n u ma b pr o gra m.  T o date, t he i nci de n ce 
of A RI A has bee n o bser ve d t o be b ot h d ose a n d A p o E ε 4 carri a ge de p e n de nt, es peciall y at t he 
hi g hest d oses.  I n a n eff ort t o ma xi miz e t he d ose- de pe n de nt a m yl oi d re d u cti o n a n d effect o n 
C D R- S B a n d M M S E t hat ha ve bee n o bs er ve d wit h d oses of 3 m g/ k g a n d hi g her w hile 
mai ntai ni n g A RI A i nci d e nce, se verit y, a n d rel ate d disc o nti n uati o n rate wit hi n acce pta ble le vels, 
a titrati o n re gi me n will be e x pl ore d.  It h as bee n s u g geste d t h at t he A RI A o bser ve d f oll o wi n g 
treat me nt wit h a m yl oi d t ar geti n g a ge nts ma y b e d ue, i n part, t o t he i nitial lar ge re m o val of 
a m yl oi d a n d s u bse q u e nt sat urati o n of peri v asc ular brai n a m yl oi d cleara nce mec ha nis ms [Weller 
2 0 0 8 ].  Sl o w titrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o wer i nitial a m yl oi d re m o val, 
y et tri g ger alter nati ve me c ha nis ms of a m yl oi d cleara nce i n cl u di n g m o n ocl o nal 
a nti b o d y- d e pe n de nt Fc- me diate d micr o glial cleara nce  [Ostr o witz ki 2 0 1 2 ] w hic h w o ul d pre v e nt 
sat urati o n of a m yl oi d cle ara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is 
reac h e d.  Si nce a d u ca n u ma b-i n d uce d A RI A has bee n de m o nstrat e d t o occ ur earl y d uri n g 
treat me nt, wit h m ost cases occ urri n g wit hi n t he first 5 d oses, titrati o n of a d uca n u ma b f or u p t o 6 
d oses pri or t o reac hi n g t he tar get d ose m a y res ult i n re d ucti o n of A RI A i n ci de nce a n d se verit y.   
Gi ve n t he t olera bilit y a n d a p pare nt efficac y of a d uca n u ma b s h o w n t o date, t he d oses t o be teste d 
usi n g  a titrati o n re gi me n are 3 a n d 6 m g/ k g f or A p o E ε 4 carri ers, a n d 6 a n d 1 0 m g/ k g f or A p o E 
ε 4 n o n-carriers.  Titrati o n will start at 1 m g/ k g a n d will escalate t o 3, 6 a n d 1 0 m g/ k g as detaile d 
bel o w.   
5. 3. 1.  
D osi n g Sc he me 
5. 3. 1. 1.  
Pl ac e b o- C o ntr olle d Peri o d 
D oses will be a d mi nistere d a p pr o xi matel y 4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses).  Base d u p o n t heir A p o E ε 4 carrier st at us, s u bjects will be assi g ne d t o 1 of 3 
treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o (a d uca n u ma b l o w d os e: a d uca n u m a b hi g h 
d ose: plac e b o) as f oll o ws ( Ta ble 5  a n d Fi g ure 1 ): 
A p o E ε 4 c arrier 
 L o w d os e ( 3 m g/ k g) 
1  m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereaft er 
 Hi g h d ose ( 6 m g/ k g)  
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t h e ne xt 4 d oses, a n d 6 m g/ k g t hereaft er  
 P lace b o   
Sali ne i nf usi o n 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 2  
 
A p o E ε 4 n o n-c arrier 
 L o w d os e ( 6 m g/ k g)  
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t h e ne xt 4 d oses, a n d 6 m g/ k g t hereaft er   
 Hi g h d ose ( 1 0 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t h e ne xt 2 d oses, 6 m g/ k g f or t h e ne xt 2 
d oses, a n d 1 0 m g/ k g t hereafter 
 P lace b o   
Sali ne i nf usi o n 
T a ble 5:  
D osi n g Sc he me f or A d uc a n u m a b b y Re gi me n  
 
D ose ( M o nt h)  
1  
2  
3  
4  
5  
6  
7  t o 
2 0  
Re gi me n  
D ose ( m g/ k g)  
A p o E 
ε 4 ( +) 
L o w D ose  
1  
1  
3  
3  
3  
3  
3  
Hi g h D ose  
1  
1  
3  
3  
3  
3  
6  
Pl ac e b o  
sali ne 
A p o E 
ε 4 (-) 
L o w D ose  
1  
1  
3  
3  
3  
3  
6  
Hi g h D ose  
1  
1  
3  
3  
6  
6  
1 0  
Pl ac e b o  
sali ne 
5. 3. 2.  
D osi n g Sc he me M o dific ati o n 
A n i n de pe n de nt dat a m o nit ori n g c o m mittee (I D M C) will re vie w u n bli n de d safet y data, i n cl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d u ca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter. 
T he d osi n g s c he me ca n b e m o difie d i n t he f oll o wi n g cir c u msta nces:  
 Safet y a n d t olera bilit y of t he hi g h d ose  
If a n y of t he hi g h d os es pr o p ose d ( 1 0 m g/ k g i n A p o E ε 4 n o n-carriers a n d 6 m g/ k g i n 
A p o E  ε 4 carriers) is d ee me d n ot acce pta ble, e nr oll me nt f or t he hi g h d ose gr o u p(s) 
will  be ter mi nate d a n d s u bjects will n ot be re place d.  S u bjects w h o ha ve alr ea d y bee n 
ran d o mize d t o t he disc o nti n ue d d ose will be d o w n- d ose d t o t he ne xt a vaila ble d ose 
acc or di n g t o t heir A p o E ε 4 carri er stat us.  Defi niti o n of l o w a n d hi g h d ose re gi me ns 
will  be re vise d as des cri b e d i n Secti o n 1 6 .   
 B e nefit of titrati o n  
A titrati o n sc he d ule has b ee n i m ple me nte d i n t his P hase 3 st u d y a n d i n t he o n g oi n g 
m ul ti ple- d ose St u d y 2 2 1 A D 1 0 3.  If, bas e d u p o n re vie w of t he d ata fr o m 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 3  
 
St u d y 2 2 1 A D 1 0 3, titrati o n is n ot dee me d be neficial, it will be eli mi nate d, a n d 
s u bse q uentl y e nr olle d s u bjects w h o are A p o E ε 4 carriers will recei v e a fi x e d d ose of 
3 or 6 m g/ k g a n d n o n-carriers will recei ve 6 or 1 0 m g/ k g.   
5. 3. 3.  
L o n g- Ter m E xte nsi o n  
S u bjects w h o recei ve d 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 w h o e nter t he L T E will 
c o nti n ue t o recei ve t he sa me d ose of a d u ca n u ma b t hat t he y were o n at t he e n d of t he 
place b o- c o ntr olle d peri o d.  S u bjects w h o recei ve place b o d uri n g t he place b o-c o ntr olle d peri o d 
a n d w h o e nter t he L T E p eri o d will be assi g n e d t o 1 of 2 treat me nt gr o u ps, base d u p o n t heir 
A p o E ε 4 carrier stat us, i n a 1: 1 rati o (a d u ca n u ma b l o w d ose: a d uca n u ma b hi g h d ose).  S u bjects 
will  be d ose d usi n g t he s a me re gi me n d escri be d f or t he place b o-c o ntr olle d peri o d (see Ta ble 5  
an d Fi g ure 1 ).   
A n y m o dificati o ns t o t he d osi n g sc he m e (i.e. ter mi nati o n of hi g h d ose gr o u ps a n d re place me nt of 
titrati o n wit h fi x e d d osi n g, as d escri be d i n Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E.   
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 4  
 
6.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S 
6. 1.  
Pri m ar y O bjecti ve a n d E n d p oi nt 
T he pri mar y o bje cti ve of t he st u d y is t o e val uat e t he effi cac y of m o nt hl y d os es of a d uca n u ma b i n 
sl o wi n g c o g niti ve a n d f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R- S B sc ore as 
c o m pare d wit h place b o i n s u bjects wit h earl y A D.  
T he  pri mar y e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m b aseli ne i n C D R -S B  sc ore at 
Wee k 7 8 . 
6 . 2. 
Sec o n d ar y O bjecti ves a n d E n d p oi nts 
A sec o n dar y o bjecti ve is t o assess t he effect of m o nt hl y d oses of a d uca n u m a b as c o m pare d wit h 
place b o o n cli nical pr o gressi o n as meas ure d b y t he M M S E. 
 T he  e n d p oi nt t hat relates to t his o bjecti ve is c ha n ge  fr o m baseli ne i n M M S E sc ore at 
W ee k 7 8 . 
A n ot he r sec o n d ar y o bje cti ve is t o assess t he effect of m o nt hl y d oses of a d u ca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gressi o n as me as ure d b y A D A S- C o g 1 3. 
 T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D A S-C o g 1 3 
sc ore at W ee k 7 8 . 
A n ot he r sec o n d ar y o bje cti ve is t o assess t he effect of m o nt hl y d oses of a d u ca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gressi o n as me as ure d b y A D C S- A D L - M CI. 
 T he  e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D C S-A D L -
M CI sc ore at W ee k  7 8 . 
6 . 3. 
Terti ar y O bjecti ves a n d E n d p oi nts 
6. 3. 1.  
T erti ar y O bjecti ves 
Safet y a n d T olera bilit y 
 T o assess t he safet y a n d t olera bilit y of m o nt hl y d oses of a d uca n u ma b.   
 T o assess  t he i m m u n o ge nicit y of a d u ca n u ma b.   
Bi o mar ker  
 T o a ssess t he effect of a d uca n u ma b o n cere bral a m yl oi d pla q ue c o nt e nt as meas ure d 
b y a m yl oi d P E T i ma gi n g (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects). 
 
 
 
 
 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 5  
 
 
 
 
 
 
 
 
 
 
Ef ficac y 
 T o a ssess t he effect of a d uca n u ma b o n be h a vi or as meas ure d b y t he Ne ur o ps yc hiatric 
In v e nt or y ( N PI- 1 0). 
 T o a ssess t he effect of a d uca n u ma b o n patie nt h ealt h stat us, meas ure d b y E ur o Q ol 
he alt h stat us meas ures ( E Q - 5 D [i nf or ma nt-rat e d a n d patie nt self-re p orte d]). 
 
 
   
 T o a ssess t he effect of a d uca n u ma b o n patie nt self-re p orte d c o g niti ve f u ncti o n, 
mea s ure d b y t he m o difie d Percei ve d Deficits Q uesti o n naire- 2 0 ( m P D Q- 2 0) 
[Le n der ki n g 2 0 1 4 ]. 
 
 
 T o a ssess t he c orrelati o n bet wee n pri mar y e n d p oi nts a n d ke y bi o mar ker e n d p oi nts.   
P har mac o ki netics 
 T o e x pl ore t he p ote ntial relati o ns hi ps bet wee n P K or e x p os ure a n d res p o ns e (e. g., 
cli nical a n d bi o mar ker e n d p oi nts) i ncl u di n g c o variate a nal ysis. 
 T o e x pl ore t he p ote ntial effect of c o- me dicati o ns o n t he P K of a d uca n u ma b usi n g 
p o p ulati o n P K. 
6. 3. 2.  
T erti ar y E n d p oi nts 
Safet y a n d T olera bilit y: 
 In ci de nce of all A Es a n d S A Es.  
 B rai n M RI fi n di n gs i ncl u di n g i nci de n ce of A RI A-E a n d A RI A- H. 
 C li nical la b orat or y s hifts i n re p orte d val u es. 
 C li nicall y si g nifica nt c ha n ges i n vital si g n meas ure me nts a n d electr ocar di o gra ms 
( E C Gs). 
 I n ci de nce of a nti- a d uca n u ma b a nti b o dies i n ser u m.   
B i o mar kers: 
 C ha n ge fr o m bas eli ne i n a m yl oi d P E T si g n al at Wee k 2 6 (i n a s u bs et of s u bjects). 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 6  
 
 C ha n ge fr o m bas eli ne i n a m yl oi d P E T si g n al at Wee k 7 8 (i n a s u bs et of s u bjects). 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
Ef ficac y 
 C ha n ge fr o m bas eli ne i n N PI- 1 0 s c ore at Wee k 7 8. 
 C ha n ge fr o m bas eli ne i n s u bject-self-re p orte d E Q- 5 D i n de x sc ore at Wee k 7 8. 
 C ha n ge fr o m bas eli ne i n i nf or ma nt-rat e d s u bject E Q - 5 D i n de x sc ore at Wee k 7 8. 
 
 
 
 C ha n ge fr o m bas eli ne i n m P D Q- 2 0 at Wee k 7 8. 
 
 
 C orrelati o n bet wee n cli nical a n d bi o mar k er e n d p oi nts o ver ti me.  
P har mac o ki netics 
 S er u m c o nce ntr ati o ns of a d uca n u ma b, p o p ul ati o n P K para meters of a d u ca n u ma b 
i ncl u di n g b ut n ot li mite d t o cleara n ce a n d v ol u mes of ce ntr al a n d peri p h eral 
c o m part me nts. 
6. 4.  
L o n g Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts 
6. 4. 1.  
O b jecti ves 
 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 u ca n u ma b i n s u bjects 
wit h earl y A D .   
 
 
 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 7  
 
6. 4. 2.  
E n d p oi nts 
 T he  i nci de nce of A Es a n d/ S A Es; brai n M RI fi n di n gs (i ncl u di n g t he i nci d e nce of 
A RI A- E a n d A RI A- H); a n d t he i nci de nce of a nti-a d uca n u ma b a nti b o dies i n ser u m 
o ve r t he place b o- c o ntr olle d a n d L T E peri o ds of t h e st u d y. 
 C ha n ge i n t he f oll o wi n g meas ures o ver t he place b o-c o ntr olle d a n d L T E p eri o ds of t he 
st u d y:  
 C D R- S B sc ore. 
 M M S E sc ore.   
 A D A S - C o g 1 3 s c ore.   
 A D C S- A D L- M CI sc ore. 
 A m yl oi d P E T si g nal (i n a s u bset of s u bjects). 
 
 
   
 
   
 
   
 
 
 
 
 
 
 N PI- 1 0 t otal s c ore.   
 I nf or ma nt-rate d E Q- 5 D i n de x sc ore.   
 
   
 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 8  
 
7.  
S T U D Y D E SI G N 
7. 1.  
St u d y O ver vie w 
St u d y 2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, parallel- gr o u p 
st u dy i n s u bjects wit h earl y A D, i ncl u di n g M CI d u e t o A D a n d a s u bs et of mil d A D, f oll o we d b y 
an o pti o nal 2 4- m o nt h d ose- bli n d L T E st u d y.  A p pr o xi matel y 1 3 5 0 s u bjects will be e nr olle d 
acr oss a p pr o xi matel y 1 5 0 ce nters gl o ball y.  T he pri mar y st u d y o bjecti ve is t o e val uate t he 
effic ac y of m o nt hl y d oses of a d uca n u m a b o n t he C D R- S B relati ve t o place b o.  Sec o n dar y 
o bjec ti ves i ncl u de assess me nt of t he effect of m o nt hl y d oses of a d uca n u ma b o n cli nical 
pr o gressi o n as c o m p are d t o place b o.  T he s afet y of m o nt hl y d os es of a d u ca n u ma b will als o be 
eval uate d. 
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a t otal of 2 0 d oses).  S u bjects will be ra n d o mize d t o recei ve 
ad uca n u ma b l o w d os e : ad uca n u ma b hi g h d ose : place b o i n a 1: 1: 1 rati o.  T he ra n d o mizati o n will 
be stratifie d b y site a n d A p o E ε 4 stat us (carrier or n o n-carrier).  S u bject e nr oll me nt will be 
m o ni t ore d s o t hat a p pr o xi matel y 6 0 % t o 7 0 % A p o E ε 4 carri ers are e nr olle d.  E nr oll me nt will 
als o be m o nit ore d, via i nteracti ve res p o nse t ec h n ol o g y (I R T), s uc h t hat s u bj ects wit h mil d  A D 
re pres e nt a s mall perce nt a ge of t he t otal e nr olle d i n t he trial.   
At t he e n d of t he d o u ble- bli n d, place b o-c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
exte nsi o n e ntr y criteria ma y e nter a 2 4- m o nt h l o n g-ter m safet y a n d efficac y e xte nsi o n peri o d, 
wit h all s u bjects recei vi n g a d u ca n u ma b a p pr o xi matel y e ver y 4 wee ks (a t otal of 2 6 d oses).   
T he t otal d urati o n of st u d y partici pati o n f or eac h s u bject o nl y p artici pati n g i n t he place b o-
co ntr olle d peri o d of t he st u d y will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series of 
scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6- wee k 
plac e b o- c o ntr olle d treat me nt peri o d, a n d a s afet y f oll o w- u p peri o d of 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 eac h s u bject partici pati n g i n t he 
place b o- c o ntr oll e d peri o d a n d t he L T E will be u p t o a p pr o xi matel y 2 0 6 wee ks, i ncl u di n g a s eries 
of  scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6- wee k place b o-
co ntr olle d treat me nt peri o d, a 4- wee k f oll o w- u p p eri o d, a 1 0 0- wee k a d uca n u ma b d ose- bli n d 
treat me nt peri o d, a n d a s afet y f oll o w- u p p eri o d of a p pr o xi matel y 1 8 wee ks after t he fi nal d ose.  
T he f oll o w- u p peri o d of 1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half-life i n h u ma ns 
of 1 6 t o 2 4 da ys ( mea n a p pr o xi matel y 2 0 d a ys, base d o n res ults fr o m t he si n gle asce n di n g d ose 
st u dy [ St u d y 2 2 1 A D 1 0 1]) a n d a ntici pate d brai n c o nce ntrati o ns of a d u ca n u ma b of less t ha n o ne-
t hir d t he E C5 0 (i n hi bit or y c o nce ntr ati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or 
bi n di n g fi brillar a m yl oi d at 8 wee ks after t he l ast d ose.   
D ur i n g t h e place b o-c o ntr olle d peri o d, A p o E ε 4 carriers will recei ve place b o, a d uca n u ma b 
3  m g/ k g, or a d u ca n u ma b 6 m g/ k g w hereas A p o E ε 4 n o n-carriers will recei v e place b o, 
ad uca n u ma b 6 m g/ k g, or a d uca n u ma b 1 0 m g/ k g.  A d uca n u ma b will be titrate d f or u p t o 6 d oses 
pr i or t o reac hi n g t h e tar get d ose as s h o w n i n Ta bl e 5  a n d Fi g ure 1 .  S u bjects w h o recei v e d 
ad uca n u ma b i n t he pl ace b o-c o ntr olle d peri o d a n d w h o e nter t he L T E peri o d will recei ve t he 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
3 9  
 
sa me d ose of a d uca n u ma b t hat t he y recei ve d at t h e e n d of t he place b o-c o ntr olle d peri o d ( u p t o 
6 m g/ k g a n d 1 0 m g/ k g i n A p o E ε 4 carriers a n d n o n-carriers, res pecti vel y).  S u bjects w h o 
recei v e d place b o d uri n g t he place b o-c o ntr olle d p eri o d a n d w h o e nter t he L T E peri o d will be 
assi g ne d t o treat me nt bas e d u p o n t heir A p o E ε 4 carrier stat us i n a 1: 1 rati o (a d uca n u ma b l o w 
d ose: a d uca n u ma b hi g h d ose) ; a d uca n u ma b will be titrate d f or u p t o 6 d oses pri or t o reac hi n g t h e 
target d ose f oll o wi n g t he sa me sc he d ule descri b e d f or t he place b o-c o ntr olle d peri o d.   
S ee Secti o n 5. 3. 2  f or det ails of d osi n g sc he me m o dificati o n.   
In di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d t o s u bjects w h o de v el o p A RI A.  See 
S ecti o n 7. 2. 1 . 
In v esti gat ors, st u d y site staff (e x ce pt f or t he desi g nate d u n bli n de d p har macist/tec h nicia n), a n d 
st u dy s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he place b o-
c o ntr olle d peri o d.  D uri n g t he L T E, i n v esti gat ors a n d s u bjects will re mai n bli n de d t o t he 
treat me nt assig n me nt i n t he place b o-c o ntr olle d p eri o d a n d t he a d uca n u ma b d ose f or t he L T E. 
7. 2.  
St u d y S pecifics 
7. 2. 1.  
D ose  S us pe nsi o n, M o dific ati o n or Ter mi n ati o n f or A RI A E ve nts 
Disc o nti n u ati o n of D osi n g f or a Give n S u bject 
T he ce ntr al M RI rea di n g ce nter will re p ort i nci de nt cases of A RI A- E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he Pri nci pal I n vesti gat or wit hi n a s pecifie d ti me aft er o bser vi n g t he fi n di n g o n M RI 
per t he i ma gi n g ma n ual pr oce d ures.  All cas es of A RI A will be re vie we d b y t he S p o ns or a n d t h e 
P ri nci pal I n v esti gat or; decisi o ns o n d osi n g c o nti n u ati o n, i nterr u pti o n, or disc o nti n uati o n will be 
base d o n cli nical s y m pt o ms, a n d t he M RI i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C 
n otificati o n r ules will be o utli ne d i n t he I D M C c harter.  Dis p ositi o n of A RI A- E cases is 
prese nte d i n Ta bl e 6  , A RI A- H ( micr o he m orr h a ge) i n Ta ble 7 , a n d A RI A- H (s u perfi cial 
si derosis) i n Ta ble 8 .   
7. 2. 1. 1.  
Dis p ositi o n o f A RI A- E c ases 
T a ble 6:  
Dis p ositi o n of A RI A- E C ases 
Cli nic al 
S y m pt o m 
Se verit y  
A RI A -E Se ve rit y o n M RI  
Mil d  
M o der ate  
Se vere  
As y m pt o matic  
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule  
S us pe n d d osi n g; o nce A RI A -E 
res ol ves t h e s u bject ma y res u me 
d osi n g at ne xt l o wer d ose  
S us pe n d d osi n g; o nce A RI A -E 
res ol ves, t h e s u bject ma y res u me 
d osi n g at ne xt l o wer d ose  
Mil d  
S us pe n d d osi n g; o nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t h e s u bject ma y res u me d osi n g at ne xt 
l o wer d ose 
M o derate  
Se vere or 
Seri o us  
Disc o nti n ue D osi n g  
 S u bjects w h o de vel o p mil d A RI A- E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 0  
 
d ose.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
ad diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A  a p pr o xi matel y e ver y 4 
wee ks u ntil t he A RI A- E has res ol ve d p er t he ce ntr all y rea d M RI.  T he S p o ns or ma y 
req uire t hat t he s u bjec ts disc o nti n ue d osi n g or c o nti n ue d osi n g at a l o wer d ose le vel 
base d o n re vi e w of safet y a n d M RI d ata. 
 S u bjects w h o de vel o p m o der ate or s e vere A RI A- E, per ce ntr al M RI re a di n g,  w it h 
n o cli nic al s y m pt o ms  at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
ad diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 4 
we e ks u ntil t he A RI A- E has res ol ve d p er t he ce ntr all y rea d M RI.  If t he A RI A- E has 
res ol ve d a n d t he s u bjects re mai n as y m pt o matic, t he s u bjects ma y res u m e tr eat me nt 
b ut at t he ne xt l o wer d ose le vel.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 
co nsec uti ve d oses will be all o we d t o res u me treat me nt.  G ui da nce f or d ose re d ucti o n 
is prese nte d i n Secti o n 7. 2. 1. 4 . 
 S u bjects w h o de vel o p mil d, m o der ate, or s e vere A RI A- E, as per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d or m o der ate cli nic al s y m pt o ms  at a n y ti me d uri n g 
t he st u d y will te m p oraril y s us pe n d tr eat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic 
visi ts f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d 
M O C A a p pr o xi matel y e v er y 4 wee ks u ntil t he A RI A- E has res ol ve d per t he ce ntrall y 
rea d M RI.  If t he A RI A- E has res ol ve d a n d t he cli nical s y m pt o ms ha ve res ol ve d, t he 
s u bject ma y res u me tr eat me nt b ut at t he ne xt l o wer d ose le vel.  O nl y s u bjects w h o 
ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me treat me nt.  
G ui da nce f or d ose re d ucti o n is prese nte d i n Secti o n 7. 2. 1. 4 . 
 S u bjects w h o de vel o p mil d, m o der ate, or s e vere A RI A- E, as per ce ntr al M RI 
re a di n g, acc o m p a nie d b y se vere o r seri o us cli nic al s y m pt o ms  at a n y ti me d uri n g 
t he st u d y will per ma n e ntl y disc o nti n ue tr eat me nt.  S u bjects s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d i n a d diti o n, ha ve a n u nsc he d ul e d visit f or 
a n M RI a n d M O C A a p pr o xi matel y e v er y 4 wee ks u ntil t he A RI A- E h as res ol ve d per 
ce ntrall y rea d M RI. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 1  
 
7. 2. 1. 2.  
Dis p ositi o n of A RI A- H c ases 
T a ble 7:  
Dis p ositi o n of A RI A- H ( micr o he m o rr h a ge) C ases 
Cli nic al 
S y m pt o m 
Se verit y  
Ne w I nci de nt Micr o he m orr h a g es W it hi n 1 2 W ee ks  
≥ 1 a n d ≤ 4  
≥ 5 a n d ≤ 9  
≥ 1 0  
As y m pt o matic  
C o nti n ue d osi n g at c urre nt d ose 
a n d sc he d ule 
S us pe n d d osi n g; o nce A RI A -H is 
sta ble t he s u bject ma y res u me d osi n g 
at ne xt l o wer d ose  
Disc o nti n ue d osi n g  
 
Mil d  
S us pe n d d osi n g; o nce A RI A -H st a bilizes a n d cli nical s y m pt o ms res ol ve, 
t h e s u bject ma y r es u me d osi n g at ne xt l o wer d ose 
M o derate  
Se vere or 
Seri o us  
Disc o nti n ue d osi n g  
 
7. 2. 1. 2. 1.  As y m pt o m atic A RI A- H ( micr o he m o rr h a ge):  
 S u bjects w h o de vel o p a ≥ 1 a n d ≤ 4 ne w i nci de nt micr o he m o rr h a ge(s) wit hi n 1 2 
wee ks at a n y ti me d uri n g t he st u d y ma y c o nti n ue treat me nt at t he c urre nt d ose. 
 S u bjects w h o de vel o p ≥ 5 a n d ≤ 9 ne w i nci de nt micr o he m o rr h a ges  occ urri n g 
wit hi n 1 2 wee ks at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d treat me nt, b ut 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc h e d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 2 wee ks u ntil t he 
mi cr o he m orr ha ge is c o nfir me d as sta ble per t he ce ntrall y rea d M RI.  A 
mi cr o he m orr ha ge is c o nsi dere d sta ble if it is u nc h a n ge d bet w ee n 2 c o ns ec 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 2 wee ks later.  O nce t he 
mi cr o he m orr ha ge is dee me d sta ble, s u bjects ma y res u me treat me nt at t he ne xt l o wer 
d ose.  O nl y s u bjects w h o ha ve n ot misse d m ore t h a n 4 c o nsec uti ve d os es will be 
all o we d t o res u me tr eat m e nt.  G ui da nce f or d ose re d ucti o n is prese nte d i n Secti o n 
7. 2. 1. 4 . 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 2  
 
T a ble 8:  
Dis p osi ti o n of A RI A- H (s u perfici al si der osis) C ases 
Cli nic al 
S y m pt o m 
Se verit y  
Ne w I nci de nt Are as of S u perfici al Si der osis W it hi n 1 2 W ee ks  
1  
2  
> 2  
As y m pt o matic  
C o nti n ue d osi n g at c urre nt d ose 
a n d sc he d ule 
S us pe n d d osi n g; o nce A RI A -H is 
sta ble t he s u bject ma y res u me d osi n g 
at ne xt l o wer d ose  
Disc o nti n ue d osi n g  
 
Mil d  
S us pe n d d osi n g; o nce A RI A -H st a bilizes a n d cli nical s y m pt o ms res ol ve, 
t h e s u bject ma y r es u me d osi n g at ne xt l o wer d ose 
M o derate  
Se vere or 
Seri o us  
Disc o nti n ue d osi n g  
7. 2. 1. 2. 2.  As y m pt o m atic A RI A- H (s u perfici al si der osis): 
 S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis) ma y c o nti n ue treat me nt at t he c urre nt d ose, b ut m ust ha ve 
a n u nsc he d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e v er y 2 wee ks u ntil t he 
s u perficial si der osis is c o nfir me d as sta ble per t he ce ntrall y rea d M RI.  S u perficial 
si der osis is c o nsi dere d st a ble if it is u nc ha n ge d b et 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 2 wee ks later.   
 S u bjects w h o de vel o p  2 f oc al are as of he m osi der osis (s u perfici al si der osis) 
oc c urri n g wit hi n 1 2 wee ks at a n y ti me d uri n g t h e st u d y will te m p oraril y s us pe n d 
treat me nt b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
ad diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 2 
we e ks u ntil t he A RI A- H (s u perfici al si der osis) is c o nfir me d as sta bl e per t he ce ntr all y 
rea d M RI.  S u perficial si der osis is c o nsi dere d sta ble if it is u nc ha n ge d bet w ee n 2 
co nsec uti ve M RIs i ncl u di n g t he i nitial detecti o n M RI a n d t h e M RI p erf or me d 2 
wee ks later.  O nce t he s u perficial si der osis is dee me d sta ble, t he s u bjects ma y res u me 
treat me nt at t he ne xt l o wer d ose.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 
co nsec uti ve d oses will be all o we d t o res u me treat me nt.  G ui da nce f or d ose re d ucti o n 
is prese nte d i n Secti o n 7. 2. 1. 4 . 
7. 2. 1. 2. 3.  S y m pt o m ati c A RI A- H ( micr o he m o rr h a ge(s) or s u perfici al si der osis ): 
 S u bjects w h o de vel o p ≤ 9 ne w i nci de nt micr o he m o rr h a ges or ≤ 2 ne w f oc al are a 
of s u perfici al si der osis  wit hi n 1 2 wee ks a n d mil d or m o derate cli nical s y m pt o ms will 
te m p oraril y s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d,  i n a d diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A 
a p pr o xi matel y e ver y 2 w ee ks u ntil t he A RI A- H ( micr o he m orr ha ge(s)) is c o nfir me d as 
sta ble per t he ce ntrall y rea d M RI.  Micr o he m orr ha ge(s) are c o nsi dere d sta bl e if t he y 
are u nc h a n ge d b et 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 p erf or m e d 2 wee ks later.  O nce t he A RI A- H is dee me d st a ble a n d t he 
cli nical s y m pt o ms ha ve res ol ve d, t he s u bjects ma y res u me treat me nt b ut at t he ne xt 
l o wer d ose le v el.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 c o ns ec uti ve d oses 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 3  
 
will be all o we d t o res u m e treat me nt.  G ui da n ce f or d ose re d u cti o n is prese nte d i n 
S ecti o n 7. 2. 1. 4 . 
 S u bjects w h o e x perie nce se vere cli nic al s y m pt o ms ass oci ate d wit h A RI A-H 
( micr o he m o rr h a ge(s) o r s u perfici al si der osis) will per ma ne ntl y dis c o nti n ue 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d i n 
a d diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 2 
we e ks u ntil t he A RI A- H micr o he m orr ha ge(s) or s u perficial si der osis is c o nfir me d as 
sta ble per ce ntrall y rea d M RI. 
7. 2. 1. 2. 4.  A RI A- H ( mic r o he m o rr h a ge(s) or s u perfici al si der osis ) re q uiri n g per m a ne nt 
disc o nti n u ati o n: 
 S u bjects w h o de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges o r > 2 ne w f oc al are as 
of s u perfici al si der osis  wit hi n 1 2 wee ks re gar dless of cli nical se verit y will 
per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc h e d ule d visit f or a n M RI a n d M O C A 
ap pr o xi matel y e ver y 2 w ee ks u ntil t he A RI A- H micr o he m orr h a ge(s) or s u p erficial 
si der osis is c o nfir me d as sta ble per ce ntral r ea d M RI. 
7. 2. 1. 3.  
Dis p ositi o n of C oi nci de nt A RI A- H a n d A RI A- E C ases: 
S u bjects w h o de vel o p A RI A- H c oi nci d e nt wit h A RI A- E at a n y ti me d uri n g t he st u d y will f oll o w 
A RI A- E g ui deli nes.  Pri or t o res u mi n g tr eat me nt, w here a p plica ble, A RI A- E m ust res ol ve, 
A R I A- H be d ee me d sta bl e, a n d t he s u bject m ust b e as y m pt o matic. 
7. 2. 1. 4.  
D ose Re d ucti o n f or S u bjects De vel o pi n g A RI A: 
D ose re d u cti o n g ui da n ce is prese nte d i n t he Ta bl e 9  bel o w.  If f urt her d ose re d ucti o n is nee d e d, 
t he next l o wer d ose le vel will be use d.  If m ore t h a n 2 d ose re d u cti o ns are nee de d, S p o ns or 
ap pr o val will be re q uire d pri or t o treat me nt c o nti n uati o n. 
T a ble 9:  
D ose Re d ucti o n f or S u bjects E x peri e nci n g A RI A, W h o Res u me Tre at me nt 
Af ter S us pe nsi o n  
C urre nt D ose  
Res u mi n g D ose  
1 0 m g/ k g  
6 m g/ k g  
6 m g/ k g  
3 m g/ k g  
3 m g/ k g  
1 m g/ k g  
1 m g/ k g  
Place b o  
Place b o  
Place b o  
A RI A = a m yl oi d relate d i ma gi n g a b n or malit y 
C urre nt d ose refers t o t he d ose t hat t he s u bj ect was recei vi n g bef ore A RI A was detecte d 
S u bjects w h o de vel o p A RI A d uri n g t h e place b o-c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d os e are eli gi ble t o e nter t he L T E a n d will recei ve t he l o west d ose t hat t he y 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 4  
 
ha ve t olerat e d d uri n g t he place b o- c o ntr olle d peri o d.  A s u bject w h o i s s witc hed t o place b o b ut 
remai ns i n t he st u d y ma y be titrate d t o a d uca n u ma b 1 m g/ k g d uri n g t he L T E. 
7. 2. 2.  
I nf usi o n I nterr u pti o n 
If a n y mil d or m o derate i nf usi o n-relate d reacti o ns (e. g., hea d ac h e, c hills/ri g ors, a n d 
na usea/ v o miti n g) o cc 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 v esti gat or.  After res ol uti o n of 
sy m 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 rat e ma y b e 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 b e restarte d at a rate t hat d o es n ot e x cee d t he 
or i gi nal i nf usi o n r ate.  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.   
R efer t o 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 i nf usi o n rate i nf or mati o n.   
If a se vere i nf usi o n-relat e 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 
ur ticaria or a na p h yla xis occ urs, t he s u bject s h o ul d be disc o nti n ue d fr o m st u d y treat me nt b ut ma y 
remai n i n t he st u d y.  T h e s u bject m ust be a p pr o pri atel y tr eate d i n acc or da n ce wit h l ocal pr actice. 
S e verit y of e ve nts is descri be d i n Secti o n 1 5. 2. 3 . 
7 . 3. 
O ver all St u d y D ur ati o n a n d F oll o w- U p  
T he st u d y p eri o d will c o nsist of scree ni n g, treat me nt, a n d f oll o w- u p. 
T he  d o u ble- bli n d, place b o-c o ntr olle d peri o d of t he st u d y will c o nsist of a n 8- wee k s cree ni n g 
pe ri o d, a 7 6 - w ee k tr eat m e nt peri o d, a n d a s afet y f oll o w- u p peri o d of 1 8 wee ks after t h e fi nal 
d ose.   
S u bjects will ha ve a p pr o xi matel y 3 3 sc h e d ule d cli nic visits d uri n g t he place b o-c o ntr olle d p eri o d, 
an 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: 
 S cree ni n g Visits n o m ore t ha n 6 0 da ys bef ore t he first d ose of st u d y tr eat me nt o n Da y 1 
( visits will be c o n d ucte d o n m ulti ple da ys). 
 2 0  o ut patie nt d osi n g visits. 
 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 aft er eac h of t he first 8 
d oses. 
 3 visi ts f or cli nical assess me nts. 
 
 
 2  visits f or a m yl oi d P E T sca n (i n a s u bset of s u bjects). 
 6  visits f or brai n M RI. 
 1 f oll o w- u p safet y visit at W ee k 9 4 ( o nl y f or s u bjects n ot e nteri n g t he L T E). 
S u bjects w h o meet t he L T E  i ncl usi o n a n d e x cl usi o n criteria will be eli gi bl e t o e nter t he L T E.  
S u bjects w h o e nter t he L T E will ha ve a p pr o xi matel y 4 0 a d diti o nal pla n ne d cli nic visits, 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: 
 2 6 o ut patie nt d osi n g visits.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 5  
 
 8 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 aft er eac h of t he first 8 
d oses. 
 4 visi ts f or cli nical assess me nts. 
 
 
 2  visit f or a m yl oi d P E T sca n (i n a s u bs et of s u bjects). 
 7  visits f or brai n M RI.   
 1 f oll o w - u p safet y visit. 
S u bjects w h o ha ve a c ha n ge i n A D me dicati o n ( ot her t ha n st u d y treat me nt) d uri n g t he 
plac e b o- c o ntr olle d or L T E peri o d s h o ul d ha ve a n u nsc he d ule d visit ; all cli nical assess me nts f or 
t he pri mar y a n d sec o n dar y e n d p oi nts s h o ul d be perf or me d pri or t o t he c ha n ge i n me di cati o n.   
S u bjects w h o e x perie nce A RI A d uri n g t he place b o-c o ntr olle d or L T E p eri o d s h o ul d ha ve 
u nsc he d ule d visits as per t he g ui deli nes i n Secti o n 7. 2. 1 . 
7. 3. 1.  
S cree ni n g 
D uri n g t h e Scree ni n g Visit, u n der a se parate i nitial c o nse nt pr ocess, s u bjects ca n c o m plete t he 
ne ur oc o g niti ve scales ( C D R, M M S E, a n d t he Re peata ble Batter y f or Ass ess me nt of 
Ne ur o ps yc h ol o gic al Stat us [ R B A N S]).  T his i nitial ne ur oc o g niti ve scree ni n g is i nte n de d t o 
red uce t h e b ur de n o n s u bjects a n d sites b y a v oi di n g u n necessar y testi n g if s u bjects d o n ot meet 
ke y i n cl usi o n criteria.  If t he s u bject meets i ncl usi o n criteria f or t hese 3 s cales, t he n 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 m e nts.  
S u bjects ma y als o pr o cee d directl y t o t he f ull c o ns e nt pr ocess, w hi c h 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 ne ur o c o g niti ve assess me nts t hat ha ve e x cl usi o n c ut p oi nts ( C D R, M M S E a n d R B A N S) m ust 
be perf or me d at Scree ni n g Visit 1.  T he A D A S- C o g 1 3, A D C S- A D L -M CI a n d N PI- 1 0 will be 
perf or me d at Scree ni n g Visit 2 wit hi n 1 4 da ys aft er Visit 1 a n d m ust N O T be perf or me d o n t he 
same da y as t he C D R, M M S E a n d R B A N S.  All ot her c o g niti ve assess me nts 
 
 may be perf or me d at a n y ti me d uri n g s cree ni n g after eli gi bilit y is c o nfir me d d uri n g 
S cree ni n g Visit 1.  T he M RI at Scree ni n g Visit 2 s h o ul d be d o ne o nl y after t he s u bject eli gi bilit y 
ba se d o n cli nical a n d l a b orat or y criteria is c o nfir me d d uri n g Scree ni n g Visit 1.  T he P E T sca n at 
S cree ni n g Visit 3 s h o ul d be c o m plete d o nl y aft er t he M RI i n cl usi o n criteri o n is met.   
S u bject eli gi bilit y f or t h e st u d y will be deter mi ne d n o m ore t ha n 6 0 da ys pri or t o st u d y e ntr y.  
S u bjects w h o fail scree ni n g will be per mitte d t o be rescree n e d o nce at t he S p o ns or’s discreti o n.  
S u bjects w h o fail scree ni n g d ue t o P E T, M M S E, C D R, he patitis B or C res ults, or a b n or mal M RI 
fi n di n gs will n ot be all o we d t o re-s cree n.   
7. 3. 2.  
T re at me nt 
Eli gi ble s u bjects will re p ort t o t he st u d y site t o recei ve st u d y tr eat me nt e ver y 4 wee ks f or 
7 6  wee ks ( 2 0 d os es).  All s u bjects w h o meet t he L T E i ncl usi o n a n d e x cl usi o n criteria will be 
eli gi ble t o e nter t he L T E a n d will recei v e st u d y tr eat me nt e ver y 4 wee ks f or a n a d diti o nal 1 0 0 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 6  
 
wee ks ( 2 6 d os es), wit h t he first d ose a d mi nistere d a p pr o xi matel y 4 wee ks after t he fi nal d os e i n 
t he place b o- c o ntr olle d peri o d of t he st u d y. 
7. 3. 3.  
F oll o w- U p 
All s u bjects partici pati n g i n t he place b o-c o ntr olle d peri o d are t o ret ur n t o t he st u d y site 
ap pr o xi matel y 2 wee ks after t he fi nal d os e f or cli nical assess me nts. 
S u bjects partici pati n g i n t he place b o- c o ntr olle d peri o d a n d n ot e nteri n g t he L T E are t o r et ur n t o 
t he st u dy site f or a f oll o w- u p visit at Wee k 9 4 ( 1 8 wee ks after t he last d os e).  T he fi n al st u d y 
visi t f or t hese s u bjects will be Wee k 9 4. 
S u bjects w h o partici pate i n t he L T E are t o r et ur n t o t he st u d y site t o recei ve t heir first L T E d ose 
a p pr o xi matel y 4 wee ks after t heir last d ose i n t he place b o-c o ntr olle d peri o d of t he st u d y.  A 
f oll o w- u p visit will occ ur at W ee k 1 9 8 ( 1 8 wee ks after t he l ast L T E d ose).  T he fi nal st u d y visit 
f or s u bjects partici pati n g i n t he L T E will be Wee k 1 9 8. 
7 . 4. 
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 n y ti me, after i nf or mi n g I n v esti gat ors.  Bi o ge n ( or desi g nee) 
will  n otif y I n 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 plet e d, or ter mi nate d. 
D osi n g ma y b e ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e x cl usi vel y o n s afet y a n d t olera bilit y data or f oll o wi n g t he f utilit y a nal ysis, or at t he discreti o n of 
t he S p o nsor; t heref ore t here are n o st u d y-s p ecific st o p pi n g r ules defi ne d i n t his pr ot oc ol.   
7 . 5. 
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 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 7  
 
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 
T o be eli gi ble t o p artici p ate i n t his st u d y, ca n di d ates m ust meet t he f oll o wi n g eli gi bilit y 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 bili t y t o u n d ersta 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 n e 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 d a nce 
wit h nati o nal a n d l ocal s u bject pri vac y re g ulati o ns. 
2.  A ge d 5 0 t o 8 5  years ol d, i ncl usi ve, at t he ti me of i nf or me d c o ns e 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 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 l ast d ose of st u d y tr eat me nt.  F or f urt her 
de tails of c o ntrace pti ve re q uire me nts f or t his st u d y, please refer t o Secti o n 1 5. 5 . 
4.  M ust  ha ve at least 6 years of e d ucati o n or w or k e x perie nce t o e x cl u de me ntal deficits 
ot her t ha n M CI or mil d A D. 
5.  M ust  ha ve a p ositi ve a m yl oi d P E T sca 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 p er missi ble f or s u bjects n ot partici pati n g i n t he P E T c o h ort.  
P re vi o us P E T sca n i ma ges m ust be s u b mitte d t o t he ce ntr al i ma gi n g v e n d or t o c o nfir m 
st u dy i ncl usi o n criteri a 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 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: 
 A C D R- Gl o bal Sc ore of 0. 5. 
 A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair m e nt.   
 A n M M S E sc ore bet w ee n 2 4 a n d 3 0  (i ncl usi ve). 
7.  A pa rt fr o m a cli nical dia g n osis of earl y A D, t he s u bject m ust be i n g o o d h ealt h as 
deter mi ne d b y t he I n v esti gat or, b ase d o n me di cal hist or y a n d s cree ni n g ass ess me nts. 
8.  M ust  c o nse nt t o a p oli p o pr otei n E ( A p o E) ge n ot y pi n g. 
9.  Ha s o ne i nf or m a nt/care p art ner w h o, i n t he I n vesti gat or’s j u d g me nt, 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 urat e i nf or mati o n a b o ut t he 
s u bject’s c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
be  a vaila ble b y p h o n e 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 d a grees t o atte n d i n pers o n cli nic visits t hat re q uire p art ner i n p ut f or scale 
c o m pleti o n.  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, 
an d t he use of t he s a me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
enc o ura ge d.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 8  
 
8. 2.  
E xcl usi o n Criteri a 
Ca n di dates will be e x cl 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 x cl 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: 
M e dic al Hist ory 
1.  A n y u n c o ntr olle d me dical or ne ur ol o gical/ ne ur o d e ge n erati 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 I n v esti 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 us e, vita mi n B 1 2 de ficie nc y, a b n or mal t h yr oi d 
f u ncti o n, str o ke or ot her cere br o vasc ul ar c o n diti o n, le w y b o d y d e me ntia, fr o nt o-te m p oral 
de me ntia, hea d tr a u ma).. 
2.  C li nicall y si g nifica nt ps yc hiatric ill ness (e. g., u n c o ntr olle d maj or de pressi o n, 
sc hiz o p hre nia, 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.  Tr a nsie nt isc he mic attac k or str o ke or a n y u n e x plai ne d l oss of c o nsci o us ness wit hi n 
1 year pri or t o Scree ni n g. 
4.  B rai n M RI p erf or m e 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:   
 A c ute or s u b- ac ute h e m orr ha ge. 
 P ri or macr o he m orr ha ge ( defi ne d as 1 c m i n dia m eter o n T 2 * se q u e nce) 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 u ct ural or v as c 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). 
 Gr eater 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).   
 C ortical i nfarct ( d efi ne d as > 1. 5 c m i n dia meter).   
 1 lac u nar i nfarct ( d efi 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 s c ore of 3 o n t he a ge-rel ate d 
w hite matter c ha n ges scale [W a 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 I n v esti gat or, mi g ht be a c o ntri b uti n g ca use of 
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 v e nt a satisfact or y 
M RI ass ess me nt f or safet y m o nit ori n g. 
5.  Hist or y of bl ee 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 r es ults o n c oa g ulati o n pr ofile at Scree ni n g, as d eter mi ne d b y t h e 
In v esti gat or. 
6.  P o orl y c o ntr olle d dia b etes mellit us as defi ne d (acc or di n g t o t he Nati o nal 
Gl yc o h e m o gl o bi n Sta n dar dizati o n Pr o gra m) b y a gl yc os ylate d h e m o gl o bi n ( H b A 1c) val ue 
of ≥ 7 %. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
4 9  
 
7.  Hist or y of u nsta bl e a n gi n a, m y o car dial i nf arcti o n, c hr o nic heart fail ure ( Ne w Y or k Heart 
Ass ociati o n Class III or I V), or cli nicall y 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 year pri or t o S cree ni n g. 
8.  C li nicall y si g nifica nt 1 2-lea d E C G a b n or malities, as deter mi ne d b y t he I n v esti gat or. 
9.  U nc o ntr olle d h y pert e nsi o n defi ne d as : a v era ge of 3 s yst olic bl o o d press ur e 
[ S B P]/ diast olic bl o o d press ure [ D B P] rea di n gs > 1 6 5/ 1 0 0 m m H g at Scree ni n g ( bl o o d 
pr ess ure me as ure m e nts e x cee di n g t hese li mits ma y be re peate d as warra nte d b y t he 
I n v esti 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 p ersiste nt S B P/ D B P rea di n gs > 1 8 0/ 1 0 0 m m H g 3 m o nt hs pri or t o 
ran d o mizati o n ( Da y 1) t h at 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 p erte nsi o n. 
1 0.  Hist or y of m ali g na n c y or carci n o ma.  T he f oll o wi n g e x ce pti o ns ma y be ma de after 
disc ussi o n wit h t he S p o ns or:   
 S u bjects wit h ca ncers i n re missi o n m ore t ha n 5 years pri or t o Scree ni n g. 
 S u bjects wit h a hist or y of e x cise d or treate d basal cell or s q ua m o us carci n o ma.   
 S u bjects wit h pr ostate ca ncer i n sit u.  
1 1.  Hist or y of s eiz ure wit hi n 1 0 years pri or t o Scree ni n g. 
1 2.  I n dic ati o n of i m paire d li ver f u ncti o n as s h o w n b y a n a b n or mal li ver f u ncti o n pr ofile at 
Scree ni n g (e. g., re p eate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥ 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 nicall y si g nifica nt b y t he 
I n v esti gat or or re q uiri n g c hr o nic use of s yst e 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 us e 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 
S cree ni n g, or us e of ca n n a bi n oi ds ( prescri pti o n or recreati o nal). 
1 5.  Cli nicall y si g nifica nt s yst e mic ill ness or seri o us i nfecti o n (e. g., p n e u m o nia, se ptice mia) 
wit hi n 3 0 da ys pri or t o or d uri n g Scree ni n g. 
1 6.  Hist or y of or p ositi ve test res ult f or h u ma n i m m u n o deficie nc y vir us ( HI V). 
1 7.  Hist or y of or p ositi ve test res ult at Scree ni n g f or h e patitis C vir us a nti b o d y or he patitis B 
vir us ( defi ne d as p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g] or he p atitis B c ore 
a nti b o d y [ H Bc A b]).  S u bjects wit h i m m u nit y t o he patitis B fr o m pre vi o us n at ural 
i nfecti o n ( defi n e d as ne gati ve H Bs A g, p ositi ve he patitis B s urface a nti b o d y I g G, a n d 
p ositi ve H Bc A b) are eli gi ble t o partici pate i n t he st u d y ( U S Ce nters f or Dis ease C o ntr ol 
a n d Pre ve nti o n’s i nter pretati o n of t he he patitis B s er ol o g y p a nel). 
1 8.  Hist or y of s e vere aller gi c or a na p h ylactic reacti o ns, or hist or y of h y p erse nsiti vit y t o a n y 
of t he i nacti ve i n gre die nts i n t he dr u g pr o d uct (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n). 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 0  
 
1 9.  A n y ot her me dical c o n diti o ns (e. g., re n al disease) t hat are n ot sta ble or c o ntr olle d, or, 
w hic h 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 s afet y or i nterfere wit h 
t he st u d y ass ess me nts. 
M e dic ati o ns 
2 0.  A n y me di cati o ns t hat, i n t he o pi ni o n of t he I n vesti gat or, m a y c o ntri b ute t o c o g niti ve 
i m pair me nt, p ut t he s u bject at hi g h er 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 1.  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 bl e f or at least 4 wee ks  
pri or t o Scree ni n g Visit 1 or use of A D m e 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, gal a 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. 
2 2.  Use of me dic ati o ns wit h platelet a nti-a g gre ga nt or a nti-c oa g ula nt pr o perties (t he use of 
as piri n at a pr o p h yla ctic d ose [ ≤ 3 2 5 m g dail y] is all o we d). 
2 3.  Use of illicit narc otic me dicati o n. 
2 4.  Vacci n ati o ns wit hi n 1 0 da ys pri or t o ra n d o mizati o n ( Da y 1).   
2 5.  Partici pati o n i n a n y acti v e i m m u n ot hera p y st u d y t ar geti n g A β u nless d oc u me ntati o n of 
recei pt of pl ace b o is a v aila ble.   
2 6.  Partici pati o n i n a n y ot her passi ve i m m u n ot hera p y st u d y tar geti n g A β wit hi n 4 8 wee ks 
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 v aila ble.   
2 7.  Partici pati o n i n a n y st u d y wit h p ur p ort e d disease- m o dif yi n g effect i n A D wit hi n 
2 6 wee ks pri or t o Scree ni n g u nless d oc u m e ntati o n of recei pt of place b o is a vaila ble.  
S u bjects w h o de vel o pe d A RI A- E d uri n g a pre vi o us disease- m o dif yi n g trial s h o ul d be 
ex cl u de d.   
2 8.  Partici pati o n i n a pre vi o us st u d y wit h a d uca n u ma b (s u bject is eli gi ble if h e/s he di d n ot 
recei v e acti ve a d uca n u ma b). 
St u dy Pr oce d ures 
2 9.  C o ntrai 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 p ati ble a ne ur ys m 
cli ps, artificial heart val v es, or ot her metal f orei g n b o d y; cla ustr o p h o bi a t hat ca n n ot be 
me dicall y ma na ge d). 
3 0.  C o ntrai n dicati o n t o ha vi n g a P E T s ca 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 y p erse 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 pl y wit h pre vi o us P E T 
sca ns). 
3 1.  A ne gati ve P E T sca n res ult wit h a n y a m yl oi d-tar geti n g li ga n d wit hi n 2 4 wee ks pri or t o 
S cree ni n g. 
3 2.  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 x cee de d b y partici pati n g i n t his st u d y.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 1  
 
3 3.  F or s u bjects w h o c o nse nt t o l u m bar p u nct ure ( L P ), a n y c o ntrai n dicati o ns t o ha vi n g a L P 
(e. g., platelet c o u nt < 1 0 0, 0 0 0/ µ L, l u m bar s pi ne def or mit y).  A n y s y m pt o ms ca use d b y or 
relate d t o t he o pti o nal L P  d uri n g scree ni n g m ust b e res ol ve d pri or t o ra n d o mizati o n.  
S u bjects ma y still partici pate i n t he o verall st u d y e ve n if partici pati o n i n t he o pti o nal L P 
p orti o n is c o ntrai n dicate d.   
Ot he rs 
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 will be per mitte d t o be 
rescree ne d o n ce at t he S p o ns or’s discreti o n, e x ce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R, he patitis B or C, or a b n or mal M RI fi n di n gs. 
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 of 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 n a bilit y t o c o m pl y 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 L o n g- Ter m E xte nsi o n 
T o be eli gi ble t o p artici p ate i n t he L T E, s u bjects m ust meet t he f oll o wi n g eli gi bilit y criteria at 
W ee k 7 8: 
1.  S u bject m ust ha ve c o m plete d t he place b o-c o ntr olle d peri o d of t he st u d y i ncl u di n g t he 
W ee k 7 8 Visit.  S u bject m ust ha ve ta ke n at least 1 4 d oses a n d n ot ha ve misse d m ore t ha n 
4 c o nsec uti ve d oses.  S u bjects w h o d o n ot meet t hese criteria ca n e nter t h e L T E o nl y wit h 
S p o ns or’s a p pr o val. 
2.  M M S E sc ore > 1 5 at t he Wee k 7 8 Visit. 
3.  T he  s u bject ( or t h e s u bject’s le gall y a ut h orize d re prese ntati ve) h as t he a bilit y t o 
u n dersta n d t he p ur p os e a n d ris ks of t he st u d y a n d pr o vi de si g n e d a n d dat e d i nf or me d 
c o nse nt ( or ass e 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 d a nce 
wit h nati o nal a n d l ocal s u bject pri vac y re g ulati o ns. 
4.  F e male s u bjects of c hil d beari n g p ote ntial a n d mal e s u bjects m ust practice effecti ve 
c o ntrace pti o n d uri n g t h e 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. 
5.  A pa rt fr o m a cli nical dia g n osis of A D, t h e 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, bas e d o n me dical hist or y. 
6.  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. 
7.  Ha s o ne i nf or m a nt/care p art ner w h o, i n t he I n vesti gat or’s j u d g me nt, 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 urat e i nf or mati o n a b o ut t he 
s u bject’s c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
be  a vaila ble b y p h o n e 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 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 2  
 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire p art ner i n p ut f or scale 
c o m pleti o n.  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, 
an d t he use of t he s a me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d. 
8. 4.  
E xcl usi o n Criteri a f or L o n g Ter m E xte nsi o n 
S u bjects will be e x cl u de d fr o m e nteri n g t he L T E if at Wee k 7 8 t he y ha ve: 
an y  m e dical or ps yc hiatri c c o ntrai n dicati o n or cli nicall y si g nifica nt a b n or m alit y t hat, i n t he 
o pi ni o n of t he I n v esti gat or, will s u bsta ntiall y i n crease 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 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 3  
 
9.  
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A TI O N 
9. 1.  
Scree ni n g a n d E nr oll me nt 
S u bjects ( or t heir le gall y a ut h orize d re pres e ntati ve, w here a p plica ble) m ust pr o vi de i nf or me d 
c o nse nt bef ore a n y s cree 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 
ca n c o m plete t he ne ur o c o g niti ve scal es ( C D R, M M S E a n d R B A N S) t o det er mi ne st u d y 
eli gi bilit y u n der a se parat e 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 3 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 directl y t o t he f ull c o nse nt pr ocess w hic h 
w o ul d a ll o w t he a d mi nistrati o n of all scree ni n g ass ess me nts.  W he n a s u bject si g ns t he f ull 
i nf orme d c o nse nt f or m (I C F), t h at s u bject is c o nsi dere d t o be e nr olle d i n t h e st u d y.   
T he  f oll o wi n g t ests s h o ul d be re peate d pri or t o d osi n g if t he y were p erf or me d > 6 0 da ys pri or t o 
Da y 1:  c o nfir mati o n of eli gi bilit y criteri a, a b bre vi ate d me dical hist or y, p h ysical e xa mi nati o n, 
E C G, he mat ol o g y, bl o o d c he mistr y, s er u m pre g n a nc y t est, a n d all ne ur o c o g niti ve assess me nts.  
P artici pati n g st u d y sites are re q uire d t o d oc u m e nt all scree n e d ca n di dates i nitiall y c o nsi dere d f or 
i ncl usi o n i n t his st u d y.  If a s u bject is e xcl u de d fr o m t he st u d y, t he reas o ns f or e x cl usi o n will be 
d oc u me nte d i n t he s u bject’s s o urce d oc u m e nts a n d o n t he scree ni n g l o g. 
9. 2.  
R a n d o miz ati o n a n d Re gistr ati o n of  S u bjects 
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra n d o mize d o nl y after all 
ba seli ne assess me nts ha v e bee n c o m plete d a n d t he I n v esti 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 .  N o s u bject ma y be gi n treat me nt pri or t o assi g n me nt 
of  a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y s u bject i de ntificati o n 
n u m ber s or ra n d o mizati o n sc he d ule assi g n me nts t hat are assi g n e 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.  Re scree n e d s u bjects will be assi g n e d a ne w n u m ber.   
S u bjects will be ra n d o mize d t o recei ve a d uca n u m a b l o w d ose: a d uca n u ma b hi g h d ose: place b o 
i n a 1: 1 : 1 rati o.  T he ra n d o mizati o n will be stratifie d b y site a n d A p o E ε 4 st at us (carrier or 
n o n-carrier), s o t h at a p pr o xi matel y 6 0 % t o 7 0 % A p o E ε 4 carri ers are e nr olle d.  E nr oll me nt will 
als o be m o nit ore d, via t h e I R T, s u c h t hat t he p o p ulati o n of s u bjects wit h mil d  A D re prese nts a 
s mall perce nta ge of t he t otal e nr olle d i n t he trial.  S u bjects w h o wit h dra w fr o m t he st u d y ma y n ot 
be  re pla ce d. 
Refer t o t he St u d y R efere 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 
T his st u d y c o nsists of a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d peri o d, f oll o we d b y a 
d ose- bli n de d L T E wit h all s u bjects recei vi n g a d u ca n u ma b.   
F or t he d o u ble- bli n de d place b o- c o ntr olle d peri o d, all st u d y staff w h o c o n d u ct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts.  T he rati n g healt h care 
pr ofessi o nals s h o ul d re m ai n bli n de d t o treat me nt assi g n me nt as w ell as s u bject care ma na ge me nt 
an d o nl y h a ve access t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 4  
 
Secti o n 4. 3. 1 .  As a place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are 
req uire d t o ma n a ge all as pects of st u d y dr u g recei pt, dis pe nsi n g a n d pre parati o n.  T o mai ntai n 
t he st u d y bli n d, it is im 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 bli n de d st u d y tea m, eit her at t he st u d y site or at 
Bi o ge n or its re prese nt ati ves, e xce pt t he u n bli n de d p har macist ( or d esi g n ee), t he u n bli n de d 
p ha r mac y m o nit or, a n d t he u n bli n de d  
 or Bi o ge n safet y staff. 
F or t he L T E, t h e d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d treati n g healt h care 
pr ofessi o nal s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nl y ha v e access t o t he 
i nf or mati o n necess ar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n 
t he st u d y bli n d, it is i m perati ve t hat d ose i nf or m ati o n is n ot s hare d wit h t he s u bjects, t heir 
families, or a n y me m ber of t he bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its 
repres e ntati ves, e x ce pt t h e u n bli n de d p har macist ( or desi g n ee), t h e u n bli n de d p har mac y m o nit or, 
a n d t he u n bli n de d  
 or Bi o ge n s afet y staff.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 5  
 
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/ O R 
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 n e ntl y disc o nti n ue st u d y tr eat 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 v el o ps a n y of t he f oll o wi n g: 
o  A R I A- E acc o m pa nie d b y se vere or seri o us cli nical s y m pt o ms. 
o  S y m pt o matic A RI A- H ( micr o he m orr ha ges or s u p erficial si der osis ) wit h 
severe or seri o us cli nical s y m pt o ms. 
o  A R I A- H wit h ≥ 1 0 micr o he m orr ha ges a n d/ or ≥ 2 f ocal areas of s u p erfici al 
si der osis.   
S ee Secti o n  7. 2. 1  f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d u cti o n d ue t o 
A RI A- E or A RI A- H.  
 T he  s u bject be c 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 
an d pre g na n c y m ust be re p orte d 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. 
 T he  s u bject e x perie nces a me dical e mer ge n c 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 uir es c o nti n ue d treat me nt 
t hat meets e x cl usi o nar y criteria.   
 T he  s u bject e x perie nces a se vere i nf usi o n reacti o n. 
 At t he disc reti o n of t he I n vesti gat or f or me dical r eas o ns. 
 At t he disc reti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce. 
T he reas o n f or disc o nti n uati o n of st u d y treat me nt m ust be rec or d e d i n t he s u bject’s cas e re p ort 
f or m (C R F ). 
S u bjects w h o disc o nti n ue treat me nt s h o ul d re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uir e d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil t he s u bjects wit h dra w c o nse nt.   
1 0. 2.  
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 ws c o nse nt.  
 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 disc reti o n of t he I n vesti gat or or S p o ns or. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 6  
 
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 dr a 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 s h o ul d 
c o m plete t he Earl y T er mi nati o n ( E T) Visit after t h e reas o n f or wit h dr a wal is i de ntifie d.  S u bjects 
s h o uld ret ur n t o t he site as s o o n as p ossi ble t o c o m plete assess me nts as o utli ne d i n t he Wee k 9 4 
( F oll o w- u p [ F U]/ E T) Visit if disc o nti n ui n g d uri n g t he d o u ble- bli n d peri o d of t he st u d y or as 
o utl i ne d i n t he Wee k 1 9 8 (F U/ E T) Visit if disc o nti n ui n g fr o m t he L T E (see Secti o n 4  f or 
de tails).   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 7  
 
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 D H A  f or s p ecific i nstr ucti o ns o n t he ha n dli n g, pre parati o n, 
ad mi nistrati o n, a n d dis p osal of t he st u d y tr eat me nt.   
P lease see Secti o n 4. 2  ( Sc he d ule of E v e nts) f or t h e st u d y dr u g i nf usi o n sc h e d ule d uri n g t he 
place b o- c o ntr olle d a n d L T E peri o ds of t he st u d y. 
A d uca n u ma b is t o be a d mi nistere d b y I V 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 u ca n u ma b st u d y treat me nt. 
1 1. 1. 1.  
A d uc a n u m a b   
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.   
1 1. 1. 2.  
Pl ac e 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. 
1 1. 2.  
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule 
Refer t o Secti o n 7. 2. 1  ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 2  (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at le ast 2 1 da ys a part.  If t he d osi n g i nter val ca n n ot be m et, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y  t he st u d y me dical m o nit or. 
1 1. 3.  
Prec a uti o ns 
N ot a p plica ble. 
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 d e d b y u n bli n de d site staff. 
1 1. 5.  
Pri or a n d C o nc o mit a nt T her a p y a n d Pr oce d ures 
1 1. 5. 1.  
Pri o r 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 h e i nf or me d c o ns e nt a n d 
t he F U/ E T Visit ( Wee k 9 4 or Wee k 1 9 8). 
N o pre me dicati o n (e. g., a nti-aller g y dr u gs, a nti p yretic a nal gesics) s h o ul d be use d pri or t o t he 
start of st u d y dr u g 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. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 8  
 
1 1. 5. 1. 1.  All o w e d C o nc o mit a nt T her a p y 
 Me dic ati o ns f or c hr o nic c o n diti o ns are all o we d 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 bje ct 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 
S cree ni n g Visit 1.   
 S y m pt o matic t h era pies f or A D, i ncl u di n g b ut n ot li mite d t o d o ne p ezil, ri vasti g mi ne, 
gal a nta mi ne, tacri ne, a n d me ma nti ne, are all o we d 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 t hat t he y sta y o n a 
sta ble d ose w hile i n t he st u dy. 
 Va cci n ati o ns wit h li ve or atte n uate d vacci nes are all o we d d uri n g t he st u d y.  
A d mi nistrati o n of a n y v acci nati o n/ b o oster s h o ul d n ot be gi ve n < 1 0 da ys pri or t o a n y 
d osi n g visit a n d f or 1 0 da ys after a d osi n g visit. 
1 1. 5. 1. 2.  Dis all o w e d C o nc o mit a nt T her a p y 
 Me dic ati o ns wit h platelet a nti-a g gre ga nt or a nti-c o a g ul a nt pr o perties, e x ce pt t he use 
of as piri n at a d ose  of ≤ 3 2 5 m g per da y. 
 N o n - pres cri pti o n narc oti c me dicati o n. 
 Im m u n os u p pr essi ve dr u gs (i ncl u di n g s yste mic c ortic oster oi ds).  L o cal c ortic oster oi ds 
a n d cert ai n s yste mic c ortic oster oi ds ma y b e per mitte d at t he S p o ns or ’s discreti o n. 
 P are 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 x c 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 di cati o ns t hat t he y were recei vi n g at e nr oll me nt 
(see all o w e d c o nc o mita nt t hera p y a b o v e) a n d a v oi d starti n g a n y n e w me dicati o ns or her bal 
pre parati o ns d uri n g t h e st u d y peri o d, as it 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 dic all y i n dicate d me di cati 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 
In v esti gat or of a n y c ha n ges i n me dicati o n.  T he c h a n ge s h o ul d be re vie we d b y t he I n vesti gat or 
an d t he st u d y me di cal m o nit or t o deter mi ne w het her t he s u bject’s st u d y tr eat me nt s h o ul d be 
s us pe n de d, wit h t he e x ce pti o n of me dicati o ns use d t o treat A Es, w hic h w o ul d n ot res ult i n 
a ut o mati c wit h dra wal.  Bi o ge n ma y b e 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, a n d all cli nical 
assess me nts f or t he pri m ar y a n d sec o n dar y o bjecti v es s h o ul d be perf or me d pri or t o t he c ha n ge i n 
me dic ati 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 p y) 
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 b et 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 t he F U/ E T Visit, u nless t he 
s u bjects is bei n g f oll o w e d f or st u d y-rel ate d t o xicit y.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
5 9  
 
T he use of c o nc o mita nt t hera pies or pr oce d ures d efi ne d a b o v e m ust be rec or de d o n t h e 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 re g ulat or y re q uire me nts re gar di n g p ostst u d y access will be m et. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 0  
 
1 2.  
S T U D Y T R E A T M E N T M A N A G E M E N T 
St u d y site staff s h o ul d f oll o w t he D H A f or s p ecifi c i nstr ucti o ns o n t he ha n dli n g, pre p arati o n, 
a d mi nistrati o n, a n d dis p osal of t he st u d y tr eat me nt.  T he D H A s u perse des all ot her refere n ces 
(e. g., pr ot oc ol). 
St u d y treat me nt m ust be dis pe nse d o nl y b y a p har macist or a p pr o pri atel y q ualifie d staff.  St u d y 
treat me nt is t o be dis pe ns e d o nl y t o s u bjects e nr olle d i n t his st u d y.  O nce st u d y treat me nt is 
pre pare d f or a s u bject, it ca n be a d mi nistere d o nl y t o t hat s u bject.  St u d y treat me nt vials are f or 
o ne -ti me use o nl y; a n y st u d y treat me nt re m ai ni n g i n t he vial m ust n ot be use d f or a n ot h er 
s u bject. 
1 2. 1.  
A d uc a n u m a b    
R esearc h Na me:  
BII B 0 3 7  
Ge neric Na me:  
A d uca n u ma b 
Tra de N a me(s):  
N ot a p plica ble 
S y n o n y ms:  
F ull y h u ma n, I g G 1, a nti- A m o n ocl o nal a nti b o d y 
A d uca n u ma b is a rec o m bi na nt h u ma n a nti b o d y e x presse d i n a C hi nese h a mster o var y cell li ne 
, p urifie d t o a hi g h de gree of p urit y a n d f or m ulate d as a li q ui d.  A d uca n u ma b is a n 
I g G1 c o nsisti n g of 2 hea v y a n d 2 k a p pa li g ht c hai ns c o n necte d b y i nter-c h ai n dis ulfi de b o n ds.  
  A d uca n u m a b is p urifie d fr o m t he 
me dia  a n d f or m ulat e d as a li q ui d. 
A d uca n u ma b is s u p plie d as a li q ui d dr u g pr o d uct c o ntai ni n g a d u ca n u ma b 5 0 m g/ m L,  
 
 
.  A d uca n u ma b is ma n ufact ure d i n acc or d a nce wit h G o o d 
Ma n ufact uri n g Practices. 
T he c o nte nts of t he la b el will be i n acc or d a nce wit h all a p plica ble re g ulat or y re q uire me nts.  
A d uca n u ma b s h o ul d n ot be use d aft er t he e x pirati o n date. 
1 2. 1. 1.  
A d uc a n u m a b Pre p ar ati o n 
T he  i n di vi d ual pre pari n g a d uca n u ma b s h o ul d caref ull y re vi e w t he i nstr ucti o ns pr o vi de d i n t he 
D H A . 
A d uca n u ma b  is t o be a d mi nistere d b y I V 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 n yt 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 dr u g it s h o ul d n ot be use d.  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 pro ble m i m me diatel y re p orte d t o Bi o ge n. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 1  
 
1 2. 1. 2.  
A d uc a n u m a b St or a ge 
S t 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° 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 f r o m li g ht, pr ot ecte 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 u ca n u ma b is dela ye d f or m ore t ha n 2 h o urs, t he n it s h o ul d be k e pt at 2° t o 8º C u ntil 
use .  If a d mi nistrati o n of t he pre pare d a d u ca n u ma b is dela ye d f or m or e t ha n 2 4 h o urs, it m ust be 
disca r 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 m a b as i nstr ucte d b y Bi o ge n 
(or its desi g n ee), u nless a p pr o ve d f or o nsite destr u cti o n. 
If a n y a d u ca 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 pers o n nel 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 u cti o n 
p oli c y or details of t he m et h o d of destr ucti o n.  Aft er s uc h destr u cti o n, Bi o ge n m ust be n otifie d i n 
wr iti n g of t he d etails of t he st u d y tr eat me nt destr o ye d (e. g., l ot or kit n u m bers, q ua ntities), t he 
da te of destr u cti o n, a n d pr o of of destr u cti o n. 
1 2. 1. 4.  
A d uc a n u m a b Acc o u nt a bilit y 
Ac c 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 h e 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 dat es a n d a m o u nt of st u d y treat me nt recei ve d, t o w h o m 
dis pe nse d (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 ntall y or 
deli beratel y destr o ye d.   
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 treat me nt 
acc o u nta bilit y.  B y t he e n d of t he st u d y rec o n ciliati 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 or ret ur ne d t o Bi o ge n.  A writte n 
ex pla nati o n m ust be pr o vi de d f or a n y discre pa n ci es. 
1 2. 2.  
Pl ace b o  
T he place b o ( 0. 9 % steril e s o di u m c hl ori de f or i nj ecti o n) will be pr o vi de d b y t he site i n t he f or m 
of 1 0 0 ml sali ne I V ba gs.   
1 2. 3.  
A d diti o n al Pr ot oc ol- Desi g n ate d Pr o d ucts 
Refer t o t he D H A f or i nf usi o n-relate d s u p pl y s pecificati o ns. 
F or details o n P E T i ma gi n g li ga n ds, r efer t o t he pr oce d ural ma n u al f or P E T. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 2  
 
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 
P H A R M A C O D Y N A MI C A S S E S S M E N T S 
Refer t o Secti o n 4. 2  f or t he ti mi n g of assess me nts. 
1 3. 1.  
Cli nic al Effic ac 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 efficac y of a d u ca n u ma b :  
 C D R  
 M M S E  
 A D A S -C o g 1 3 
 A D C S- A D L- M CI 
 N PI -1 0 
It is rec o m me n de d t hat cli nical assess me nts be perf or me d at t he sa m e ti me of da y f or p atie nts 
d uri n g t heir st u d y visits.   
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s dail y acti vities a n d c o g niti ve ca p a bilities.   
T he or der of a d mi nistrati o n of t he cli nical assess m e nts is descri be d i n t he St u d y Refere n ce 
G ui de.   
1 3. 2.  
P h ar m ac o ki netic Assess me nts 
Ser u m c o nce ntr ati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y.   
1 3. 3.  
P h ar m ac o d y n a mic Assess me nts 
T he f oll o wi n g t ests will be perf or me d t o assess t h e p har mac o d y na mic pr o perties of a d u ca n u ma b: 
 S erial meas ure m e nt of a m yl oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y a m yl oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects parti ci pati n g i n 
t he P E T c o h ort).   
O nl y sites wit h ca p a bilities of perf or mi n g 1 8F-fl or beta pir  P E T will be all o we d t o 
perf or m t his assess me nt.  I n v esti gat or partici p ati o n i n t his part of t he st u d y is o pti o nal 
an d c o nti n ge nt u p o n a p pr o val b y his/ her et hics c o m mittee ( E C) or i nstit uti o nal re vie w 
b oar d (I R B).  If t he I n v esti gat or is n ot partici pati n g or t he t est is n ot a p pr o ve d b y 
his/ her E C/I R B, t h e rel e v a nt secti o n of t he I C F will n ot be a p plica ble t o t hat site. 
S u bject partici pati o n i n t his part of t he st u d y is o pti o nal at partici pati n g sites.  
I nf or me d c o ns e nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a s e p arate pr oce d ural ma n ual f or P E T.  A p pr o xi matel y 4 0 0 
s u bjects are e x pecte d t o partici pate i n t his part of t he st u d y.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 3  
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
 
 
   
1 3. 4.  
A d diti o n al Assess me nts 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
1 3. 4. 2.  
A p o E ge n ot y pi n g 
W h ole bl o o d sa m ples f or de o x yri b o n ucleic aci d ( D N A) A p o E ge n ot y pi n g will be c ollecte d fr o m 
all s u bjects at t he Scree ni n g Visit.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 4  
 
 
 
 
 
 
   
1 3. 4. 4.  
He alt h O utc o mes Assess me nts 
T he  f oll o wi n g assess me nts will be perf or me d t o e val uate t he effect of a d u ca n u ma b i n s u bjects 
an d care gi vers :  
 E Q -5 D ( S R) 
 E Q -5 D (I R-S)  
 
 
 m P D Q- 2 0  
 
   
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s dail y acti vities a n d c o g niti ve ca p a bilities.   
T he or der of a d mi nistrati o n of t he cli nical assess m e nts is descri be d i n t he St u d y Refere n ce 
G ui de.   
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 5  
 
1 4.  
S A F E T Y A S S E S S M E N T S 
See Secti o n 4. 2  f or t he ti mi n g of ass ess m e 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 s afet y pr ofile of 
ad uca n u ma b: 
 A E a n d S A E m o nit ori n g. 
 P h ysical e x a mi nati o n, i ncl u di n g hei g ht a n d wei g ht. 
 Ne ur ol o gical e x a mi nati o n.  
 Vital si g ns ( b o d y te m perat ure, heart rat e, S B P, D B P, a n d res pir at or y rate). 
 1 2-lea d E C G . 
 B rai n M RI. 
 C o nc o mita nt me dicati o n, t hera p y a n d pr oce d ure m o nit ori n g.   
 M O C A (f or A RI A m o nit ori n g a n d ma na ge m e nt).   
 C ol u m bia S uici de Se verit y Rati n g Scale.   
1 4. 2.  
L a b or at or y S afet y Assess me n ts 
T he f oll o wi n g l a b orat or y assess me nts will be perf or me d t o e val uate t h e safet y pr ofile of 
ad 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. 
 B l 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 hatas e, A L T, A S T, lactate d e h y dr o ge nase, 
ga m ma- gl uta m yl-tra nsf erase, gl uc ose, calci u m, p h os p h or us, bicar b o nat e, c hl ori de, 
s o di u m, p otassi u m. 
 Ur i nal ysis:  c ol or, s p ecifi c 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 x a mi nati o n (if a b n or mal). 
 S er u m a n d uri ne pre g na n c y t est f or w o me n of c hil d beari n g p ote ntial o nl y. 
 C oa g ulati o n, vir ol o g y (i n cl u di n g HI V if dictate d b y l ocal la w), H b A 1c, a n d 
alc o h ol/ dr u g s cree n at Scree ni n g. 
1 4. 3.  
I m m u n o ge nicit y Assess me nts 
Prese nce of ser u m a nti-a d uca n u ma b will be det er mi ne d usi n g a vali dat e d assa y.  A st a 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 ass a y, c o nfir mat or y ass a y, 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 6  
 
a n d titrati o n assa y).  C o nfir me d a nti dr u g a nti b o d y- p ositi ve sa m ples will be teste d f or t he 
prese nce  of a nti- a d uca n u ma b ne utralizi n g a nti b o dies usi n g a v ali date d assa y.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 7  
 
1 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 v er y eff ort m ust be ma de t o r e mai n alert t o p ossi ble A Es.  
If a n A E o cc urs, t h e first c o ncer n s h o ul d b e f or t he safet y of t he s u bject.  If necessar y, 
a p pr o priate m e 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 l e gall y a ut h orize d re prese ntati ve m ust be gi ve n 
t he na mes a n d tele p h o n e n u m bers of st u d y 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 n ce 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 o es n ot necessaril y h a 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 bl e a n d u ni nte n d e d si g n (i n cl u di n g a n 
ab n or mal la b orat or y fi n di n g), s y m pt o m, or diseas e te m p orall y ass ociat e d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct. 
Deter mi nati o n of w h et her a n a b n or m al la b orat or y val ue 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.  Alt h o u g h a b n or mal la b orat or y val ues are t y picall y n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E: 
 A la b orat or y test r es ult t hat meets t he criteria f or a n S A E.  
 A la b orat or y test r es ult t hat re q uires t he s u bj ect t o recei v e s pecifi c c orrecti v e t hera p y. 
 A la b orat or y a b n or malit y t hat t he i n vesti gat or c o nsi ders 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 w ar d me dical occ urre n ce t hat at a n y d ose: 
 R es ults i n deat h.  
 I n t he vi e w of t he I n vesti gat or, pl aces t h e s u bject at i m me diate ris k of deat h (a 
life-t hreat e 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, h a d it occ urre d 
i n a m ore se vere f or m, mi g ht ha ve ca use d d eat 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. 
 R es ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y. 
 Res ults i n a c o n ge nital a n o mal y/ birt h defect. 
A n S A E ma y als o be a n y ot her me dicall y i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y je o p ar dize t he s u bject or ma y re q uir e i nter ve nti o n t o pre ve nt o ne of t h e ot her o utc o mes 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
6 8  
 
liste d i n t he defi niti o n a b o ve.  ( E x a m ples of s uc h me dical e ve nts i ncl u de aller gi c br o nc h os p as m 
req uiri n g i nte nsi ve treat me nt i n a n e mer ge n c 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 pitaliz ati o n.) 
1 5. 1. 3.  
Presc he d ule d or Electi v e Pr oce d ures or R o uti n el y Sc he d ule d Tre at me nts 
A presc h e d ule d or electi ve pr oce d ure or a r o uti nel y sc he d ul e 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 h e d ule d or electi ve pr oce d ure or r o uti nel y sc h e d ule d treat me nt was 
sc he d ule d ( or was o n a w aiti 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 
co 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 h e 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 pr ese 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 v esti gat or bet wee n t he s u bject’s c o nse nt t o parti ci pate i n t he st u d y a n d t h e ti me of 
t he pr oce d ure or treat me nt. 
 T he  presc h e d ule d or electi ve pr oce d ure or r o uti nel y sc h e 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 uir e me nts f or a d mi nistrati o n of t he 
st u d y treat me nt, t he h os pitalizati o n s h o ul d n ot be c o nsi dere d a n S A E u nless 
o ne of t he re q uire me nts i n Secti o n 1 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 assess e d t o deter mi ne t he f oll o wi n g: 
 If t he e v e nt meets t he criteria f or a n S A E as d efi ne d i n Secti o n 1 5. 1. 2 . 
 T he  relati o ns hi p of t he e ve nt t o st u d y treat me nt as defi ne d i n Secti o n 1 5. 2. 2 . 
 T he  se verit y of t h e 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 d efi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es a n d 
S A Es t o t he st u d y treat m e nt. 






Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 1  
 
1 5. 3. 4. 1.  De at hs 
Deat h is a n o utc o me of a n e ve nt.  T he e v e nt t hat r es ulte d i n deat h s h o ul d be rec or de d o n t he 
ap pr o priate C R F.  All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
be c o mi n g a ware of t h e e ve nt.  T he I n vesti gat or s h o ul d ma ke e ver y eff ort t o o btai n a n d se n d 
de at h certificates a n d a ut o ps y re p orts t o 
.  T he t er m deat h s h o ul d be 
rep orte d as a n S A E o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d. 
1 5. 3. 5.  
S us pecte d U ne x pecte d Seri o us A d verse Re a cti o ns 
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d b y t he I n vesti gat or or Bi o ge n t o be rel ate d t o t he st u d y treat me nt a d mi nistere d. 
A p pr o priate p ers o n nel i n Bi o ge n Safet y a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y re p orti n g.  Bi o ge n or desi g n ee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y a ge nci es acc or di n g t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n v esti gat ors i n a bli n de d fas hi o n. 
1 5. 4.  
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns 
1 5. 4. 1.  
Pre g n a nc y 
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y a n d 
f or 2 4 w ee ks after t heir l ast d ose of st u d y dr u g.  If a fe male 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 di ately. 
T he I n vesti gat or m ust re p ort a pre g n a nc y occ urri n g i n a fe male s u bject b y fa xi n g t he a p pr o priate 
f or m t o 
 wit hi n 2 4 h o urs of t he st u d y site staff bec o mi n g a ware of t he 
pr e g na nc y at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u d y refere n ce ma n ual.  T he 
In v esti gat or or st u d y site staff m ust re p ort t he o utc o me of t he pre g n a nc y t o 
 
   
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 mal e 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 os e of st u d y tr eat me nt gi ve n 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 descri b e d i n 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 d e 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 os e f or m 
a n d fa x e d t o 
 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 v er d ose m ust be re p orte d t o 
 e ve n if t he o ver d ose d o es 
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 d e d.  If a n o v er 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 x e d t o  
 
).  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 h e 
d osi n g C R F. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 2  
 
1 5. 4. 3.  
Me dic al E mer g e nc y 
I n a me dical e mer ge n c y re q uiri n g i m me diate atte nti o n, st u d y site staff will a p pl y a p pr o priat e 
me dical i nter ve nti o n, acc or di n g t o c urre nt sta n d ar ds of care.  T he I n vesti gat or ( or desi g nee) 
s h o uld c o ntact t he  
 2 4- h o ur e mer ge nc y m e dical s u p p ort n u m ber.  Refer t o t he St u d y 
Refere n ce G ui d e’s Offici al C o ntact List 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 d y, 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.   
In a me dical e mer ge n c 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 bl y 
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 v esti gat or ca n c o ntact t he  
 
2 4- h o ur e mer ge nc y me di cal s u p p ort n u m ber at 
. 
T he I n vesti gat or m ust d o c 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 m e nts.  
T he I n vesti gat or is str o n gl y a d vise d n ot t o di v ul ge t he s u bject’s tr eat 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 h e me dical e mer ge nc y, n or t o pers o n nel i n v ol ve d 
wit h t he a nal ysis a n d c o n d uct of t he st u d y. 
1 5. 5.  
C o ntr ace pti o n Re q uire me nts 
F or t he p ur p os es of t his st u d y, w o me n of c hil d beari n g p ote ntial are d efi ne d as all w o me n 
p h ysi ol o gicall y ca p a ble of bec o mi n g pre g n a nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns: 
 P ost me n o pa usal:  1 2  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 us e or 6 wee ks after s ur gical bilateral o o p h orect o m y wit h or 
wit h o ut  h ysterect o m y. 
 P ost h ysterect o m y. 
 F e male s ur gical steriliz ati o n (e. g., bilateral t u bal li gati o n). 
F or t he p ur p os es of t he st u d y, hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g: 
 F or fe males of c hil d beari n g p ote ntial: 
 Esta blis he d use of oral, i njecte d, or i m pla nte d h or m o nal met h o ds of 
co ntrace pti o n. 
 P lace me nt of a n i ntra uteri ne de vice or i ntra uteri ne s yste m. 
 Barrier met h o ds of c o ntr ace pti o n wit h use of a s per mici de:  c o n d o m or o ccl 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 us e 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. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 3  
 
 Male se x ual part ners u n d er we nt s ur gical steriliz ati o n wit h t he a p pr o priate 
p ost vasect o m y d o c u me nt ati o n of t he a bse nce of s per m i n t he ejac ul ate. 
 F or males: 
 Vasect o m y wit h ne gati ve se me n a nal ysis at f oll o w- u p. 
 Use  of c o n d o ms wit h s per mici de. 
 F or males a n d fe mal es 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 a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he I n v esti 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 trial.  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost - o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d acce pt a ble met h o ds of 
c o ntrace pti o n. 
Pre g n a 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 t he f oll o wi n g: 
 M o ni t or a n d rec or d all A Es, i ncl u di n g S A Es, re gar dless of t he se v erit y or relati o ns hi p 
t o st u d y treat me nt. 
 De ter mi ne t he s eri 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 ns et a n d res ol uti o n dates of eac h e ve nt. 
 M o ni t or a n d rec or d all pre g n a ncies a n d f oll o w u p o n t he o utc o me of t he pre g n a nc y 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 S A B R ( or desi g nee) wit hi n 
2 4 h o ur s of t he st u d y 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 p ersiste 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 S A B R ( or d esi g n ee) wit hi n 2 4 h o urs of t he st u d y site staff 
be c o mi n g a ware of n e w i nf or mati o n. 
 E ns ur e all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he 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. 
 R e p ort S A Es t o l ocal E C /I R Bs, as re q uire d b y l oc al la w. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 4  
 
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: 
 B ef ore st u d y site acti vati o n a n d s u bject e nr oll me nt, t he Cli nical M o nit or ( 
) is 
res p o nsi ble f or re vie wi n g wit h st u d y 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. 
 B i o ge n ( or desi g nee) is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C /I R Bs, a n d I n vesti gat ors of S A Es, as re q uir e 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 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 5  
 
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 h e e n d p oi nts t o be a nal yz e d are liste d i n Secti o n 6 . 
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 tr eat me nt gr o u p wit h s u m mar y statistics 
( mea n, sta n dar d de viati o n [ S D], me dia n, a n d ra n ge) or wit h fre q ue n c y distri b uti o ns. 
1 6. 2.  
Effic ac y a n d P h ar m ac o d y n a mics 
1 6. 2. 1.  
A n al ysis P o p ul ati o n 
T he i nte nt- t o-treat (I T T) 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 st u d y tr eat me nt (a d u ca n u ma b or place b o), will be us e d f or t he efficac y 
a nal ys es.  F or eac h e n d p oi nt, a d diti o nal c o n diti o ns ma y a p pl y t o t he d efi niti o n of t he p o p ulati o n 
f or t he a n al ysis.  S u bjects will be a nal yze d i n t he gr o u ps t o w hic h t h e y were ra n d o mize d.   
1 6. 2. 2.  
Met h o ds of A n al ysis 
1 6. 2. 2. 1.  Ge ner al C o nsi der ati o ns 
S u m mar y statistics will be prese nt e d.  F or c o nti n u o us e n d p oi nts, s u m mar y statistics will 
g e n erall y i ncl u de: n u m ber of s u bjects wit h data, m ea n, sta n dar d de viati o n, me dia n, a n d ra n ge.  
F or cate g oric al e n d p oi nts, t his will ge nerall y i ncl u de: n u m ber of s u bjects r a n d o mize d or d ose d, 
n u m ber wit h data, a n d t h e perce nt of t h ose wit h d ata i n eac h cate g or y.  St atistical testi n g f or 
effic ac y e n d p oi nts will be ma de bet w ee n eac h a d u ca n u ma b re gi me n a n d pl ace b o.  All statistical 
tests will be 2-si de d. 
1 6. 2. 2. 2.  D ose Re gi me ns t o be E v al u ate d 
T he f oll o wi n g d os e re gi me ns of a d uca n u ma b as c o m pare d wit h place b o will be e val uate d 
 A d uca n u ma b hi g h- d os e re gi me n ( 6 m g/ k g i n A p o E ε 4 carri ers a n d  1 0  m g/ k g i n 
A p o E ε 4 n o n carriers). 
 A d uca n u ma b 6  m g/ k g d ose re gi me n ( 6 m g/ k g i n A p o E ε 4 carriers a n d 
A p o E  ε 4 n o n-carriers). 
 A d uca n u ma b l o w- d ose re gi me n ( 3 m g/ k g i n A p o E ε 4 carri ers a n d 6 m g/ k g i n 
A p o E ε 4 n o n-carriers).   
In t he e ve nt t hat t he pr o p ose d ma xi m u m d ose ( 1 0 m g/ k g i n A p o E ε 4 n o n-carriers or 6 m g/ k g i n 
A p o E ε 4 carriers) is ter mi nate d after t he start of t h e st u d y ( Secti o n 5. 3. 2 ) t he defi niti o n of 
a d uca n u ma b hi g h d ose re gi me n a n d a d uca n u ma b l o w d ose re gi me n will be m o difie d as s h o w n i n 
Ta ble 1 0 .  T he d osi n g m o dificati o n will be e ntirel y bas e d o n i nteri m a nal ysis of o utc o mes t hat 
are i n de p en de nt of, a n d u ni nf or mati ve a b o ut, t he tr eat me nt-relate d efficac y effect.  C o ntr ol of 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 6  
 
T y pe I err or rate is t h us mai ntai ne d wit h o ut a statistical a dj ust me nt f or s uc h a da ptati o ns [C h o w 
a n d C ha n g 2 0 1 1 ]. 
T a ble 1 0:  
D ose Gr o u p P o oli n g Str ate g y i n t he E ve nt of Tre at me nt Gr o u p Ter mi n ati o n 
Tre at me nt gr o u p(s) Ter mi n ate d  
Defi niti o ns of Re vise d P o ole d Tre at me nt 
Gr o u ps f or C o m p aris o n  
A p o E  ε 4 carrier hi g h-d os e  g r o u p( 6 m g/ k g) 
 
L o w: A p o E ε 4 carrier 3 m g/ k g a n d  
n o n -carrier 6 m g/ k g  
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n -carrier 1 0 m g/ k g  
A p o E ε 4 n o n -carrier h i g h-d ose g r o u p ( 1 0 
m g/ k g)  
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n -carrier 6 m g/ k g  
Hi g h: A p o E ε 4 carrier 6 m g/ k g a n d 
n o n -carrier 6 m g/ k g  
A p o E ε 4 carrier  h i g h-d ose g r o u p( 6 m g/ k g)  
A N D  
A p o E ε 4 n o n -carrier h i g h-d ose g r o u p( 1 0 m g/ k g)  
A p o E ε 4 carrier 3 m g/ k g a n d n o n -carrier 
6  m g/ k g  
 
1 6. 2. 2. 3.  C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts 
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws:  a d uca n u ma b hi g h- d os e re gi me n v ers us place b o, a d u ca n u ma b 6 m g/ k g re gi me n v ers us 
plac e b o, a n d a d uca n u ma b l o w- d ose re gi me n v ers us place b o.  I n t he e ve nt of a d osi n g 
m o dificati o n (see T a ble 1 0 ), t he first c o m paris o n is t he a d uca n u ma b hi g h- d ose re gi me n vers us 
plac e b o a n d t h e sec o n d c o m paris o n is t he a d uca n u ma b l o w- d ose re gi me n vers us place b o.  If t he 
first c o m paris o n is statisticall y si g nifica nt ( p ≤ 0. 0 5), t he n t he sec o n d c o m p aris o n will als o be 
ma de  at t he 0. 0 5 α l e vel.  If t he sec o n d c o m paris o n is statisticall y si g nifica nt ( p ≤ 0. 0 5), t he n t he 
t hir d c o m paris o n will als o be ma de at t he 0. 0 5 α l e vel.  H o we v er, all c o m p aris o ns after t h e i nitial 
c o m paris o n wit h p > 0. 0 5 will n ot be c o nsi dere d statisticall y si g nifica nt. 
S ec o n dar y e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  I n or der t o 
co ntr ol f or a T y p e I err or f or t he sec o n dar y e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be  use d a n d will i ncl u de b ot h t he or der of t he s ec o n dar y e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y e n d p oi nts, a se q ue ntial ( cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T y pe I err or rat e d ue t o m ulti ple 
treat me nt c o m paris o ns.  If statistical si g nifica n ce is n ot ac hie ve d f or o ne, t w o or all t hree 
co m paris o ns, all e n d p oi nt(s) of a l o wer ra n k will n ot be c o nsi dere d statisticall y si g nifica nt f or 1, 
2 or all 3 c o m paris o ns, res pecti vel y.   
D ue  t o a c urre nt lac k of s cie ntific c o nse ns us i n t he A D fiel d o n w hic h bi o m ar ker(s) mi g ht b e 
m ost  a p pr o priate, t he sel ecti o n of t he bi o mar k ers a n d met h o d ol o g y f or c o ntr ol of T y p e I err or 
will be pre-s pecifie d i n t he statistical a nal ysis pla n ( S A P).  Ot her wise, t here will be n o m ulti ple 
co m paris o n a dj ust me nts f or t he tertiar y e n d p oi nts.   


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 7  
 
1 6. 2. 2. 4.  A n al ysis of t he Pri m a r y E n d p oi nt 
T he p o p ulati o n f or t he pri mar y e n d p oi nt a nal ysis will be s u bjects i n t he I T T p o p ulati o n wit h a 
baseli ne a n d at least o ne p ost- baseli ne C D R- S B sc ore.  A mi x e d m o del re peate d meas ures 
( M M R M) m o del will be use d as t he pri mar y a nal ysis t o a nal yz e c h a n ge fr o m baseli ne C D R- S B 
usi n g fi x e d effects of treat me nt, ti me, treat me nt- b y -ti me i nteracti o n, baseli n e C D R- S B, baseli ne 
C D R- S B b y ti me, bas eli ne M M S E, a n d baseli ne A p o E ε 4 stat us. 
1 6. 2. 2. 5.  A n al ysis of t he Sec o n d ar y E n d p oi nts 
1 6. 2. 2. 5. 1.  C h a n ge fr o m B aseli ne t o Wee k 7 8 i n M M S E  
T he p o p ulati o n f or t he a n al ysis will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least 
o ne  p ost- baseli ne M M S E val ue.  A M M R M m o del will be use d as t he pri mar y a nal ysis t o 
anal yze c ha n ge fr o m bas eli ne M M S E usi n g fi x e d effects of treat me nt, ti me, treat me nt- b y -ti me 
i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y ti me i nteracti o n a n d baseli ne A p o E ε 4 
stat us  
1 6. 2. 2. 5. 2.  C h a n ge fr o m B aseli ne t o Wee k 7 8 i n A D A S- C o g 1 3 
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost - baseli ne A D A S- C o g 1 3 sc ore.  A M M R M m o del will be use d as t he pri mar y a nal ysis t o 
anal yze c ha n ge fr o m bas eli ne A D A S- C o g 1 3 usi n g fi x e d effects of tr eat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A DA S - C o g 1 3, bas eli ne A D A S- C o g 1 3 b y ti me 
i nteracti o n; baseli ne M M S E a n d baseli ne A p o E ε 4 stat us. 
1 6. 2. 2. 5. 3.  C h a n ge fr o m B aseli ne t o Wee k 7 8 i n A D C S- A D L- M CI 
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost - baseli ne A D C S- A D L-M C I s c ore.  A M M R M m o del will be use d as t he pri mar y a n al ysis t o 
anal yze c ha n ge fr o m bas eli ne A D C S- A D L- M CI usi n g fi x e d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D C S- A D L- M CI, b aseli ne A D C S- A D L- M CI b y ti me 
i nteracti o n; baseli ne M M S E a n d baseli ne A p o E ε 4 stat us. 
1 6. 2. 2. 6.  Terti ar y E n d p oi nts A n al ysis 
1 6. 2. 2. 6. 1.  Pl ac e b o- C o ntr olle d Peri o d 
W here a p pr o pri ate, a M M R M m o del will be use d as t he pri mar y a n al ysis t o a nal yze c ha n ge fr o m 
baseli ne usi n g fi x e d effects of treat me nt, ti me, treat me nt b y ti me i nteracti o n, baseli ne val ue, 
baseli ne val ue b y ti me i nteracti o n, bas eli ne M M S E a n d baseli ne A p o E ε 4 stat us. 
Ot he r wise, a n a nal ysis of c o varia n ce or its n o n- p ara metric e q ui val e nt ma y b e use d t o a nal yz e 
t hese e x pl orat or y e n d p oi nts. 
1 6. 2. 2. 6. 2.  L o n g- Ter m E xte nsi o n 
T he a d diti o nal e n d p oi nts f or t he L T E are c ha n ge fr o m baseli ne o ver t he pl ace b o-c o ntr olle d a n d 
L T E p eri o ds of t he st u d y.  A nal ys es will be pres e nte d b y tr eat me nt gr o u p i n t he 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 8  
 
place b o- c o ntr olle d peri o d usi n g t he place b o-c o ntr olle d peri o d baseli ne.  Details of t he a nal yses 
will be pre-s pecifie d i n t he S A P.   
1 6. 3.  
P h ar m ac o ki netics 
1 6. 3. 1.  
A n al ysis P o p ul ati o n 
T he p o p ulati o n f or P K a n al ysis 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 
st u d y treat me nt, a n d ha d at least 1 meas ura ble a d u ca n u ma b c o n ce ntr ati o n i n ser u m.   
1 6. 3. 2.  
Met h o d of A n al ysis 
T he p o p ulati o n P K c haracteristics of a d u ca n u ma b will be deter mi ne d b y n o nli near mi x e d effects 
a p pr oac h.  C o v ariates t hat mi g ht i nfl ue nce t he dis p ositi o n of a d uca n u ma b (e. g., b o d y wei g ht, 
a ge, se x, i m m u n o ge nicit y, A p o E ε 4 stat us) will be e val uat e d a n d t he p ote ntial e x p os ure-res p o nse 
relati o ns hi ps will be e x pl ore d. 
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 recei v e d at least 1 d os e of st u d y treat me nt 
(i ncl u di n g pla ce b o a n d 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 dat a, E C G, ne ur ol o gical a n d p h ysical e x a mi nati o ns a n d vital si g ns will be 
eval uate d f or safet y. 
1 6. 4. 2. 1.  A d verse E ve nts 
O nl y treat me nt-e m er 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 bl es.  
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. 
I n ci de nce of T E A Es will be s u m marize d b y tr eat m e nt gr o u ps, 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 place b o-c ontr olle d peri o d a n d o ver t he 2 4- m o nt h L T E.  
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 yst e m or ga n class as w ell as f or 
preferre d t er ms wit hi n eac h s yste m or ga n class.  A Es will be c o de d usi n g t h e Me dical Dicti o nar y 
f or Re g ulat or y A cti vities ( Me d D R A).   
1 6. 4. 2. 2.  Cli nic al L a b or at or y Res ults 
La b orat or y d ata 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 p ara m eters, a n d s hifts fr o m baseli ne t o hi g h/ p ositi ve stat us 
f or uri nal ysis will be pres e nte d.  I n a d diti o n, t he s hift fr o m baseli ne t o t he m a 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 cate g orize d 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
7 9  
 
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 statisti cs f or act ual v al ues 
an d c ha n ge fr o m bas eli ne will als o be prese nt e d f or q ua ntitati ve la b orat or y data.   
1 6. 4. 2. 3.  Vit al Si g ns 
T he a nal ysis of vital si g ns will f oc us o n cli nicall y rele va nt a b n or malities. 
1 6. 4. 2. 4.   E C G 
T he  n u m ber a n d p erce nta ge of s u bjects wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or 
a b n or mal A E) will be s u m mariz e d b y treat me nt gr o u p.   
1 6. 4. 2. 5.  C ol u m bi a S uici de Se verit y R ati n g Sc ale 
T he C ol u m bia S uici de Se verit y Rati n g Scale 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 ysis p o p ulati o n f or i m m u n o ge nicit y is defi ne d as all s u bjects i n t he safet y p o p ulati o n 
w h o ha ve at least 1 p ost- d ose sa m ple e val u ate 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 nti-a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.  
1 6. 6.  
I nteri m A n al yses 
1 6. 6. 1.  
I nteri m F utilit y A n al ysis 
A n i nteri m a nal ysis f or f utilit y of t he pri mar y e n d p oi nt will occ ur after a p pr o xi matel y 5 0 % of t he 
s u bjects ha ve c o m plet e d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y aft er u n bli n di n g will perf or m t he i nteri m f utilit y a nal ysis.  T his i n de pe n de nt gr o u p will 
pr ese nt t he u n bli n de d i nt eri m a nal ysis t o t he I D M C.  T he I D M C ma y rec o m me n d ter mi nati n g 
t he st u dy f or f utilit y if it is e vi de nt t hat t he effi cac y of a d uca n u m a b is u nli kel y t o be ac hie ve d.   
T he f utilit y criteria will be disc usse d i n detail i n t he S A P. 
1 6. 6. 2.  
I nteri m S u peri orit y A n al ysis 
A n i nteri m a nal ysis f or s u peri orit y will be perf or m e d after a p pr o xi matel y 5 0 % of t he s u bjects 
ha ve c o m plete d t h e Wee k 7 8 Visit ( or disc o nti n ue d).  T he La n- De mets met h o d wit h O’ Bri e n-
Fle mi n g st o p pi n g b o u n dar y f or efficac y will be us e d.  I n or der t o mai ntai n t he treat me nt bli n d, a n 
i n de pe n de nt gr o u p e xter n al t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d u ct of t he st u d y after 
u n bli n di n g will perf or m t he i nteri m s u peri orit y a n al ysis.  T he i n de pe n de nt gr o u p will prese nt t he 
u n bli n de d i nteri m a nal ysis t o t he I D M C.  T h e ai m of t his i nteri m a nal ysis is t o all o w t he 
p ossi bilit y t o de m o nstrat e treat me nt effect earl y.  T he a nal ysis will be disc usse d i n detail i n t he 
S A P. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 0  
 
1 6. 7.  
S a m ple Size C o nsi der ati o ns 
T he st u d y’s s a m ple siz e is base d, i n part, o n r es ults fr o m a pr ot oc ol-s p ecifi e d i nteri m a nal ysis 
fro m St u d y 2 2 1 A D 1 0 3 w hic h i ncl u de d 1 year data fr o m 1, 3 a n d 1 0 m g/ k g treat me nt gr o u ps. 
A sa m ple siz e of 4 5 0 s u bjects per treat me nt gr o u p will ha ve a p pr o xi matel y 9 0 % p o wer t o det ect 
a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne C D R- S B at Wee k 7 8 bet wee n t he 
2  treat me nt gr o u ps.  T his p o wer calc ulati o n is bas e d o n a 2-si de d t-test ass u mi n g e q ual v aria nce 
wit h a f i nal si g nifica nce le vel of 0. 0 5, a S D of 1. 9 2 a n d a dr o p- o ut rate of 3 0 %.  T he S D esti mate 
of  1. 9 2 f or Wee k 7 8 reflects a 3 9 % i ncrease o v er t he S D  fr o m t he pr ot oc ol-s pecifie d i nteri m 
anal ysis of 1- year data. 
T he ass u me d tr ue m ea n differe n ce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d u cti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o me a n c ha n ge is esti mate d t o be 2. 
T he sa m ple size ma y b e reassesse d i n a bli n de d m a n ner a p pr o xi matel y 3 m o nt hs bef ore 
enr oll me nt is c o m plete if at least 1 5 % of t he data are a v aila ble o n t he pri m ar y e n d p oi nt.  At t his 
i nteri m ti me- p oi nt, t he S D  f or t he pri mar y e n d p oi nt will be esti mate d base d o n t he bli n de d data.  
T he  sa m ple size ma y b e i ncreas e d if t he S D is esti mate d t o be m ore t ha n a p pr o xi matel y 2. 0 7.  I n 
a d diti o n, t he sa m ple size c o ul d be i ncrease d usi n g e xter nal cli nical trial res ults t hat bec o me 
a vaila ble after t he start of t he st u d y. 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 1  
 
1 7.  
E T HI C A L R E Q UI R E M E N T S 
Bi o ge n,  
, a n d t h e I n vesti gat or m ust c o m pl y wit h all i nstr ucti o ns, re g ul ati o ns, a n d 
agree m e nts i n t his pr ot oc ol a n d a p plica ble I nt er nati o nal C o nfere nce o n 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 ulati o ns. 
T he  I n vesti gat or ma y d el e 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 n ce, i n acc or d a nce wit h 
a p plica ble I C H a n d G C P g ui deli nes.  T h e I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priat el 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 d ele gate d 
1 7. 1.  
Decl ar ati o n of Helsi n ki 
T his st u d y will be perf or me d i n ali g n me nt wit h t he et hical pri nci ples o utli n e d i n t he Decl arati o n 
of Helsi n ki. 
1 7. 2.  
Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 
T he I n vesti gat or m ust o btai n E C/I R B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uir e d st u d y 
d oc u me nts pri or t o starti n g t he st u d y.  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 uir e me nts.   
If t he I n vesti gat or m a kes a n y c ha n ges t o t he I C F, Bi o ge n m ust a p pr o ve t h e c ha n ges bef ore t h e 
I C F is s u b mitte d t o t he E C.  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 
ap pr o val, t he I C F m ust n ot be altere d wit h o ut t he a gree m e nt of t he rele va nt E C a n d Bi o ge n. 
It is t he res p o nsi bilit y of t he I n v esti gat or(s) 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 d a nce wit h c urre nt a p plica ble re g ul ati o ns. 
Bi o ge n m ust recei ve a l etter d oc u me nti n g E C/I R B a p pr o val, w hic h s p ecificall y i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y.  Pr ot oc ol a me n d me nts 
will  be s u bject t o t he sa me re q uir e me nts as t he ori gi nal pr ot oc ol. 
A pr o gress r e p ort m ust be s u b mitte d t o t he E C/I R B at r e q uire d i nter vals a n d n ot less t ha n 
a n n uall y. 
At t he c o m pleti o n or ter mi nati o n of t he st u d y, t h e i n vesti gati o nal site m ust s u b mit a cl ose- o ut 
letter t o t he E C/I R B a n d Bi o ge n 
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 st u d y-relate d acti vities u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d 
assess me nts, 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 pres e ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or d a nce wit h l ocal pr actice a n d re g ulati o ns.  S u bjects ca n c o m plet e t he ne ur oc o g niti ve scales 
( C D R, M MS E a n d R B A N S) as a n i nitial scree ni n g u n der a se parat e c o nse nt pr oc ess.  If t h e 
s u bject meets i ncl usi o n criteria f or t h ese 3 scales, t he f ull c o nse nt pr ocess m ust be c o m plete d 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 2  
 
pri or t o t he a d mi nistrati o n of f urt her s cree ni n g ass ess me nts.  S u bjects ma y als o pr ocee d directl y 
t o the 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 n efits a n d ris ks of t he st u d y, a n d 
t hat stu d y partici p ati 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 gall y 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 
co nsi der w het h er t o parti ci pate i n t he st u d y. 
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, care gi ver a n d/ or le gall y 
aut h orize d re pres e ntati ve.  T he si g n e d a n d dat e d I C F will be retai ne d wit h t he st u d y rec or ds.  
L ocal re g ul ati 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 ur e) 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 b y l ocal la w (e. g., Pr otecte d Healt h I nf or m ati o n 
a ut h orizati o n i n N ort h A merica). 
T he s u bject will n ot be i de ntifie d b y n a me i n t he C R F or i n a n y st u d y re p orts a n d t hese re p orts 
will  be use d f or researc h p ur p oses o nl y.  Bi o ge n, its part ner(s) a n d desi g nee(s), E C/I R Bs, a n d 
vari o us g o v er n me nt he alt h a ge ncies ma y i ns p ect 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 d ata c o nfi de ntial. 
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 v era 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 vesti gat ors s h o ul d a d dress a n y p ot e ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
Bi o ge n or its part n er[s]) wit h t he s u bject bef ore t he s u bject ma kes a decisi o n t o partici pat e i n the 
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 h e st u d y a n d p ost st u d y res ults re gar dless of o ut c 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 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 3  
 
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 bjects pri or t o c o m pleti o n of a st u d y i nitiati o n visit, 
co n d ucte d b y Bi o ge n.  T his i nitiati o n visit will i ncl u de a det aile d re vie w of t he pr ot oc ol a n d 
st u dy pr oce d ures. 
1 8. 2.  
Q u alit y Ass ur a nce 
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 m e d b y Bi o ge n or t he 
reg ulat or y a ut h orities ma y wis h t o perf or m o nsite a u dits.  T he I n vesti gat or will be e x pecte d t o 
co o perat e wit h a n y a u dit 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-rel ate d m o nit ori n g b y pr o vi di n g direct access t o s o urce data 
an d t o t he s u bjects’ me di cal hist ories. 
T he Cli nical M o nit or(s) will visit t he I n v esti gat or(s) at re g ul ar 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. 
D uri n g t h ese visits, C R Fs a n d s u p p orti n g d o c 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 nci es or o missi o ns will be res ol ve d.   
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 pr ot oc ol a d here nce, q ualit y of data, st u d y treat me nt acc o u nta bilit y, c o m plia nce wit h 
reg ulat or y re q uire me nts, a n d c o nti n ue d a d e q uac y of t he i n vesti gati o nal site a n d its facilities. 
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 d etails are pr o vi d e d i n 
t he separate c o ntr act(s) bet wee n t he i nstit uti o n, I n vesti gat or, a n d Bi o ge n.   
1 8. 5.  
P u blic ati o ns 
Details are i n cl u de d i n t he cli nical trial a gree me nt f or t his st u d y. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 4  
 
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 TI O N 
1 9. 1.  
E xter n al C o ntr act Or g a niz ati o ns 
1 9. 1. 1.  
C o ntr act Rese a rc 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 p ects of t he st u d y i ncl u di n g, b ut n ot li mite d t o, 
st u dy i nitiati o n, m o nit ori n g, a n d m a na ge m e 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 I n v esti 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 n e d or ra n d o mize d, t he I R T v e n d or will 
pr o vi de eac h st u d y site wit h a p pr o priate trai ni n g, access ri g hts a n d a user m a 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 ur e 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 - bas e d ele ctr o nic dat a ca pt ur e ( E D C) t o ol de v el o pe d b y  
 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 o r L a b or at or y Assess me nts 
Bi o ge n has s electe d a ce ntral la b orat or y s er vice t o perf or m all sta n dar d he mat ol o g y, bl o o d 
che mistr y, a n d uri nal ysis 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, 
an d s hi p all uri ne, bl o o d, 
, 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, 
bi o mar ker, 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 n e 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.  
 
. 
La b orat ories p erf or mi n g s pecializ e d testi n g will be i de ntifie d i n re g ulat or y d o c u me ntati o n.  
T hese la b orat ories will use a p pr o priat el y v ali date d or q ualifie d assa ys t o test st u d y s a 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 b ee n s electe d b y Bi o ge n t o rea d a n d i nter pret all M RIs f or t his 
st u d y wit hi n t he timefra 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 R I 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 Pri nci pal I n vesti gat or 
a n d t he S p o ns or.  F or t h e p ur p oses of st u d y c o n d u ct, t he M RI i nter pretati o ns fr o m t he ce ntr al 
rea der will prevail o ver t h ose fr o m t he l ocal ra di ol o gist.   
T he  ce ntr al 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 s cree ni n g s ca n f or 
eli gi bilit y criteria. 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 5  
 
1 9. 1. 6.  
Ne ur oc o g niti ve Assess me nts 
Bi o ge n sele cte 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 
an d o versi g ht.  T he st u d y raters 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 d y 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 oj ect-s pecific pla ns. 
1 9. 2.  
St u d y C o m mittees 
1 9. 2. 1.  
A d vis or y C o m mittee 
A n a d vis or y c o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u d y 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y.  T he a d vis or y c o m mittee will meet at 
least 4 ti mes a year t o m o nit or s u bject accr ual a n d t o m o nit or c o m plia nce wit h t he pr ot oc ol at 
i n divi d ual st u d y sit es.  T he a d vis or y c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g  t he st u d y.   
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x perts i n A D  me dici ne a n d statistics.  
B i o ge n will desi g nate o n e of t he partici pati n g I n v esti gat ors t o be t h e c hair pers o n of t he a d vis or y 
co m mittee. 
1 9. 2. 2.  
I n de pe n de nt D at a M o nit ori n g C o m mittee  
T he I D M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y d ata.  Me m bers of t he I D 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 I D M C will re vie w safet y 
da ta 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.  T he I D M C, base d o n 
t he nat ure, fre q ue n c y, a n d/ or se verit y of a n A E(s) 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 n ati o n.  A n I D M C c hart er will pr o vi de f ull 
g ui da n ce o n t he f u n cti o n a n d practices t o be f oll o we d b y t he I D M C.   
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 E C/I R B a n d re g ul at or y a ut h orities if re q uire d 
b y l oc al la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he s c o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B b ef ore i m ple me ntati o n of 
s uc h m o dificati o ns t o t he c o n d uct of t he st u d y.  If re q uire d b y l ocal la w, s u c 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 w e ver, Bi o ge n m a y, at a n y ti me, a m e n d t his pr ot oc ol t o eli mi nate a n a p pare nt i m me diate 
ha zar 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 C F m a y re q uir e si milar m o dificati o ns (see 
S ecti o ns 1 7. 2  a n d 1 7. 3 ). 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 6  
 
1 9. 4.  
Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 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 uir e d, t he re g ulat or y a ut h orities a n d E C/I R Bs 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 p y of t he st u d y s y n o psis i n acc or da n ce 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 b y a n y i nstit uti o nal re q uire me nts or l ocal la ws or re g ulati o ns.  Pri or t o 
pr ocee di n g wit h destr u cti o n of rec or ds, t he I n v esti gat or m ust n otif y Bi o ge n i n writi n g a n d 
recei v e writte n a ut h orizati o n 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 I n vesti gat or 
m ust  n otif y Bi o ge n of a n y c h a 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 v esti gat or lea v es 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 n e or m ore of t h e partici p ati n g St u d y I n v esti gat ors as a si g n at or y f or t he 
st u dy re p ort.  T his deter mi nati o n will be ma de b y se veral f act ors i ncl u di n g b ut n ot li mite d t o t he 
In v esti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of d esi g n, ma n a ge me nt, a n d/ or s u bje ct 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 ge n. 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 7  
 
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 di a g n osis of mil d c o g niti ve i m pair me nt d ue t o 
Alz hei mer's diseas e: 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 mer's Dise ase 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 Dis ease I nt er nati o nal ( A DI); 2 0 1 4. 
C h o w S, C ha n g M. A da pti ve Desi g n M et h o ds i n Cli nical Trials, Sec o n d E diti o n. Sec o n d E diti o n 
e d. B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1. 
D o o d y R S, T h o mas R G, Farl o w M, et al. P hase 3 trials of s ola nez u ma b f or mil d- t o- m o derate 
Alz hei mer's diseas e. N E n gl J Me d. 2 0 1 4; 3 7 0( 4): 3 1 1- 2 1; c orres p o n d e nce N E n gl J Me d. 
2 0 1 4; 3 7 0( 1 5): 1 4 5 9- 6 0. 
D u b ois B, Fel d ma n H H, J ac o va C, et al. Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n. La ncet Ne ur ol. 2 0 1 0; 9( 1 1): 1 1 1 8- 2 7. 
D u b ois B, Fel d ma n H H, J ac o va C, et al. A d va nci n g researc h dia g n ostic criteria f or Alz hei mer's 
disease: t he I W G- 2 criteria. La ncet N e ur ol. 2 0 1 4; 1 3( 6): 6 1 4- 2 9. 
Fa ga n T. Cre nez u ma b Disa p p oi nts i n P hase 2, Researc h ers Re mai n H o pef ul. C o nfere nce 
C o vera ge Seri es: Alz hei mer's Ass ociati o n I nter n ati o nal C o nfere nce ( A AI C) 2 0 1 4 [I nter n et]. 
Alzf or u m We b site. 2 0 1 4 J ul 2 2 [ cite d 2 0 1 4 Oct 0 4]. A vaila ble fr o m: 
htt p:// w w w.alzf or u m. or g/ ne ws/c o nfere nce-c o v era ge/ cre n ez u ma b- disa p p oi nts- p hase- 2-
researc hers-re mai n- h o pef ul. 
Har d y J, Sel k oe DJ. T he a m yl oi d h y p ot hesis of Al z hei mer's diseas e: 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 diseas e. N e 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.  
J ac 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 o cesses i n Alz hei mer's 
disease: a n u p dat e d h y p ot hetical m o del of d y na mi c bi o mar kers. La ncet Ne ur ol. 2 0 1 3; 1 2( 2): 2 0 7-
2 1 6. 
K of fie R M, Me yer- 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 ociat es wit h 
p osts y na ptic de nsities a n d c orrel ates wit h e x citat or y s y n a pse l oss near se nil e pla q ues. Pr oc N atl 
Aca d Sci U S A. 2 0 0 9; 1 0 6( 1 0): 4 0 1 2 -7.  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 8  
 
K uc hi b h otla K V, G ol d m a n S T, Lattar ul o C R, et al. A beta pla q ues le a d t o a berra nt r e 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 ma r- Si n g h S, Pirici D, Mc G o wa n E, et al. De ns e-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. 
Le n d er ki n g W R, Stee nr o d A, R ü dell K, et al. O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI 
a n d Pr o dr o mal Alz hei mer’s Diseas e: C o nte nt Vali dit y of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y S y m pt o ms of C o g niti ve Decli ne. A d va nces i n Alz hei mer’s Disease. 
2 0 1 4; 3: 1- 1 0. E p u b Marc h 2 0 1 4. 
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 nti a 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 d eli nes f or Alz hei mer's disease. Alz h ei mer's a n d De me ntia. 
2 0 1 1; 7( 3): 2 6 3 -2 6 9.  
Me yer- 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-bet a pla q ues i n a m o use m o del of Alz hei mer's dis ease. Nat ure. 2 0 0 8; 4 5 1( 7 1 7 9): 7 2 0 -4.  
M orris J C, Ble n n o w K, Fr oelic h L, et al. Har m o ni ze d dia g n ostic criteria f or Alz hei mer's disease: 
rec o m me n dati o ns. J I nter n Me d. 2 0 1 4; 2 7 5( 3): 2 0 4- 1 3. 
Ostr o w itz ki S, De pt ula D, T h urfjell L, et al. Mec h a nis m of a m yl oi d re m o val i n patie nts wit h 
Alz hei mer disease treate d wit h ga nte n er u ma b. Arc h Ne ur ol. 2 0 1 2; 6 9( 2): 1 9 8- 2 0 7. E p u b 2 0 1 1 Oct 
1 0. 
P feifer 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 n ce. 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 n e LI, H e p b ur n D L, et al. E x acer bati o n of c ere bral a m yl oi d a n gi o p at h y-
ass ociate d micr o h e m orr h a 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 osite d f or ms of a m yl oi d bet a. 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 y n a pses a n d ne urites i n a n Alz hei mer's diseas e m o use m o del. Brai n Res. 
2 0 0 9; 1 2 8 0: 1 7 8- 8 5. 
S perli n g R A, J ac k Jr C R, Blac k S E, et al. A m yl oi d-relate d i ma gi n g a b n or malities i n a m yl oi d-
m o dif yi n g t hera pe utic tri als: 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. P assi 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.  


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
8 9  
 
Wa hl u n d L O, Bar k h of F, Faze kas F, et al. A ne w rati n g scale f or a ge-relat e 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. 
Weller R O, S u bas h M, Prest o n S D, et al. Peri vasc ular drai na ge of a m yl oi d- beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a m yl oi d a n gi o pat h y a n d Alz hei mer's disease. Brai n Pat h ol. 
2 0 0 8; 1 8( 2): 2 5 3- 6 6. 
Wilc oc k D M, C olt o n C A. I m m u n ot hera p y, vasc ul ar 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 yl 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/ 0 2/ 2 7. 
 
 


Pr ot oc ol 2 2 1 A D 3 0 1 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
9 0  
 
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 h a ve rea d t he f ore g oi n g pr ot oc ol, “ A P hase 3 M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
P lace b o- C o ntr olle d, Parallel- Gr o u p St u d y t o E val uate t he Effi cac y a n d Safet y of A d uca n u ma b 
( BII B 0 3 7) i n S u bjects wit h Earl y Alz hei mer's Disease”, 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 bl e 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 h eir res p o nsi bilities a n d o bli gati o ns. 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or’s Si g n at ure  
  
  
  
Date 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or’s N a me ( Pri nt) 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
St u d y Site ( Pri nt) 
 
 
 






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T A B L E O F C O N T E N T S
1.
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 0
2.
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 1
3.
S Y N O P SI S ................................................................................................................. 1 4
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 7
4. 1.
St u d y  Sc he matic ......................................................................................................... 1 7
4. 2.
Sc he d ule of E ve nts ..................................................................................................... 1 8
4. 3.
A d diti o nal I nf or mati o n ...............................................................................................3 4
4. 3. 1.
Site Pers o n nel ............................................................................................................. 3 4
5.
I NT R O D U C TI O N ...................................................................................................... 3 6
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 3 7
5. 1. 1.
N o ncli nical E x perie nce ...............................................................................................3 7
5. 1. 2.
Cli nical E x perie nce..................................................................................................... 3 8
5. 2.
St u d y  Rati o nale........................................................................................................... 3 9
5. 3.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 3 9
5. 3. 1.
D osi n g Sc he me........................................................................................................... 4 0
5. 3. 1. 1.
Place b o -C o ntr olle d Peri o d .......................................................................................... 4 0
5. 3. 2.
D osi n g Sc he me M o dificati o n ..................................................................................... 4 1
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 4 2
6.
S T U D Y O BJ E C TI V E S A N D E N D P O I NT S ..............................................................4 3
6. 1.
Pri mar y  O bjecti ve a n d E n d p oi nt ................................................................................ 4 3
6. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts ......................................................................... 4 3
6. 3.
Tertiar y  O bjecti ves a n d E n d p oi nts ............................................................................. 4 3
6. 3. 1.
Tertiar y  O bjecti ves ..................................................................................................... 4 3
6. 3. 2.
Tertiar y  E n d p oi nts...................................................................................................... 4 4
6. 4.
L o n g -Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts ....................................................... 4 6
6. 4. 1.
O bjecti ves ...................................................................................................................4 6
6. 4. 2.
E n d p oi nts ....................................................................................................................4 6
7.
S T U D Y D E SI G N ....................................................................................................... 4 7
7. 1.
St u d y  O ver vie w..........................................................................................................4 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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. 2.
St u d y  S pecifics ........................................................................................................... 4 8
7. 2. 1.
D ose S us pe nsi o n, M o dificati o n, or Ter mi nati o n f or A RI A E ve nts ............................ 4 8
7. 2. 1. 1.
Dis p ositi o n of A RI A -E Cases ..................................................................................... 4 9
7. 2. 2.
Dis p ositi o n of A RI A -H Cases .................................................................................... 5 0
7. 2. 2. 1.
A RI A -H ( Micr o he m orr ha ge) ......................................................................................5 0
7. 2. 2. 2.
A RI A- H ( S u perficial Si der osis) ................................................................................. 5 3
7. 2. 2. 3.
A RI A - H ( Macr o he m orr ha ge)..................................................................................... 5 4
7. 2. 2. 4.
Dis p ositi o n of C oi nci de nt A RI A -H a n d A RI A- E Cases ............................................ 5 5
7. 2. 2. 5.
Res u m pti o n of St u d y  Treat me nt After S us pe nsi o n d ue t o A RI A............................... 5 5
7. 2. 2. 6.
Ma na ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI )............................................ 5 6
7. 2. 3.
I nf usi o n I nterr u pti o n................................................................................................... 5 7
7. 3.
O verall St u d y  D urati o n a n d F oll o w-U p ..................................................................... 5 7
7. 3. 1.
Scree ni n g .................................................................................................................... 5 8
7. 3. 2.
Treat me nt .................................................................................................................... 5 9
7. 3. 3.
F oll o w -U p ................................................................................................................... 5 9
7. 4.
St u d y  St o p pi n g R ules ................................................................................................. 5 9
7. 5.
E n d of St u d y ............................................................................................................... 5 9
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 6 0
8. 1.
I ncl usi o n Criteria........................................................................................................ 6 0
8. 2.
E xcl usi o n Criteria ....................................................................................................... 6 1
8. 3.
I ncl usi o n Criteria f or L o n g-Ter m E xte nsi o n Peri o d ................................................... 6 4
8. 4.
E xcl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d .................................................. 6 5
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I ON ............................ 6 6
9. 1.
Scree ni n g a n d E nr oll me nt ...........................................................................................6 6
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................6 6
9. 3.
Bli n di n g Pr oce d ures .................................................................................................... 6 6
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/ O R 
WI 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 ........................................... 6 8
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 6 8
1 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 6 9
1 1.
S T U D Y T R E A T M E N T U S E ..................................................................................... 7 0
1 1. 1.
Re gi me n ...................................................................................................................... 7 0


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1. 1. 1.
A d uca n u ma b ............................................................................................................... 7 0
1 1. 1. 2.
Place b o ........................................................................................................................ 7 0
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 7 0
1 1. 3.
Preca uti o ns .................................................................................................................. 7 0
1 1. 4.
C o m plia nce ................................................................................................................. 7 0
1 1. 5.
Pri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 7 0
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 7 0
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 7 1
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T her a p y .............................................................................. 7 1
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 7 1
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 7 2
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 ................................................................ 7 3
1 2. 1.
A d uca n u ma b ............................................................................................................... 7 3
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 7 3
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 7 4
1 2. 1. 3.
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 7 4
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 7 4
1 2. 2.
Place b o ........................................................................................................................ 7 4
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 7 4
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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ......................................................................................................... 7 5
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 7 5
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 7 5
1 3. 3.
P har mac o d y na mic Assess me nts ................................................................................. 7 5
1 3. 4.
A d diti o nal Assess me nts.............................................................................................. 7 6
7 6
1 3. 4. 2.
A p o E Ge n ot y pi n g .......................................................................................................7 6
7 7
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 7 7
1 4.
S A F E T Y A S S E S S M E N T S ................................ ........................................................7 8
1 4. 1.
Cli nical Safet y  Assess me nts....................................................................................... 7 8
1 4. 2.
La b orat or y  Safety Assess me nts ..................................................................................7 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 4. 3.
I m m u n o ge nicit y Assess me nts .................................................................................... 7 9
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 ................................................................................................. 8 0
1 5. 1.
Defi niti o ns.................................................................................................................. 8 0
1 5. 1. 1.
A d verse E ve nt ............................................................................................................. 8 0
1 5. 1. 2.
Seri o us A d verse E ve nt ................................................................................................ 8 0
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................ 8 1
1 5. 2.
Safet y  Classificati o ns.................................................................................................. 8 1
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ............................................................................. 8 1
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................ 8 2
1 5. 2. 3.
Se verit y  of E ve nts....................................................................................................... 8 2
1 5. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................8 2
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 8 2
1 5. 3. 1.
A d verse E ve nts ........................................................................................................... 8 2
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ............................................................................. 8 3
1 5. 3. 3.
Seri o us A d verse E ve nts ..............................................................................................8 3
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 8 3
1 5. 3. 4. 1.
Deat hs ......................................................................................................................... 8 4
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 8 4
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................8 4
1 5. 4. 1.
Pre g na nc y ................................................................................................................... 8 4
1 5. 4. 2.
O ver d ose ..................................................................................................................... 8 4
1 5. 4. 3.
Me dical E mer ge nc y .................................................................................................... 8 5
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 8 5
1 5. 5.
C o ntrace pti o n Re q uire me nts ...................................................................................... 8 5
1 5. 6.
Safe t y Res p o nsi bilities................................................................................................ 8 6
1 5. 6. 1.
T he I n vesti gat or .......................................................................................................... 8 6
1 5. 6. 2.
Bi o ge n ......................................................................................................................... 8 7
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 8
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 8 8
1 6. 2.
Efficac y  a n d P har mac o d yna mics ................................................................................8 8
1 6. 2. 1.
A nal y sis P o p ulati o n ....................................................................................................8 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6. 2. 2.
Met h o ds of A nal ys is................................................................................................... 8 8
1 6. 2. 2. 1.
Ge neral C o nsi derati o ns ...............................................................................................8 8
1 6. 2. 2. 2.
D ose Re gi me ns t o be E val uate d ................................................................................. 8 8
1 6. 2. 2. 3.
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts .............................................. 8 9
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y E n d p oi nt............................................................................... 9 0
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 9 0
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ....................................................................................... 9 0
1 6. 3.
P har mac o ki netics ........................................................................................................ 9 1
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 1
1 6. 3. 2.
Met h o d of A nal ys is..................................................................................................... 9 1
1 6. 4.
Safet y .......................................................................................................................... 9 1
1 6. 4. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 1
1 6. 4. 2.
Met h o ds of A nal ys is................................................................................................... 9 1
1 6. 4. 2. 1.
A d verse E ve nts ........................................................................................................... 9 1
1 6. 4. 2. 2.
Cli nical L a b orat or y Res ults........................................................................................ 9 2
1 6. 4. 2. 3.
Vital Si g ns .................................................................................................................. 9 2
1 6. 4. 2. 4.
E C G ............................................................................................................................ 9 2
1 6. 4. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 9 2
1 6. 5.
I m m u n o ge nicity Data ................................................................................................. 9 2
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 2
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................... 9 2
1 6. 6.
I nteri m A nalys es ......................................................................................................... 9 2
1 6. 6. 1.
I nteri m F utilit y A nal ysis ............................................................................................. 9 2
1 6. 6. 2.
I nteri m S u peri orit y A nal ysis.......................................................................................9 3
1 6. 7. 
Sa m ple Size C o nsi derati o ns ................................ .......................................................9 3
1 7.
E T HI C A L  R E Q UI R E M E N T S ...................................................................................9 4
1 7. 1.
Declarati o n of H elsi n ki ...............................................................................................9 4
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ........................................................... 9 4
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ...............................................................................9 4
1 7. 4.
S u bject Data Pr otecti o n ..............................................................................................9 5
1 7. 5.
C o m pe nsati o n f or I nj ur y .............................................................................................9 5


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 7. 6.
C o nflict of I nterest ...................................................................................................... 9 5
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 .............................................. 9 5
1 8.
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 9 6
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................... 9 6
1 8. 2.
Q ualit y  Ass ura nce....................................................................................................... 9 6
1 8. 3.
M o nit ori n g of t he St u d y ..............................................................................................9 6
1 8. 4.
St u d y  F u n di n g............................................................................................................. 9 6
1 8. 5.
P u blicati o ns ................................................................................................................. 9 6
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 7
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ................................................................................. 9 7
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ................................................................................. 9 7
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 9 7
1 9. 1. 3.
Electr o nic Data Ca pt ure ..............................................................................................9 7
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ..................................................... 9 7
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts...................................................................... 9 7
1 9. 1. 6.
Ne ur oc o g niti ve Assess me nts ...................................................................................... 9 8
1 9. 2.
St u d y  C o m mittees ....................................................................................................... 9 8
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................... 9 8
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee .................................................................. 9 8
1 9. 3.
C ha n ges t o Fi nal St u d y  Pr ot oc ol ................................................................................ 9 8
1 9. 4.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n ........................................................................................ 9 9
1 9. 5.
Rete nti o n of St u d y  Data..............................................................................................9 9
1 9. 6.
St u d y  Re p ort Si g nat or y...............................................................................................9 9
2 0.
R E F E R E N C E S ......................................................................................................... 1 0 0
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 ....................................... 1 0 3
LI S T O F T A B L E S
Ta ble 1:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8 ................. 1 8
Ta ble 2:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 2 2


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Ta ble 3:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -u p P h o ne Call Sc he d ule D uri n g 
t he Place b o-C o ntr olle d Peri o d ....................................................................................2 5
Ta ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4 ................................... 2 7
Ta ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 3 0
Ta ble 6:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he L o n g -Ter m E xte nsi o n ............................................................................... 3 3
Ta ble 7:
D osi n g Sc he me f or A d uca n u ma b b y Re gi me n ........................................................... 4 1
Ta ble 8:
Dis p ositi o n of A RI A -E Cases ..................................................................................... 4 9
Ta ble 9:
Dis p ositi o n of A RI A - H ( Micr o he m orr ha ge) Cases.................................................... 5 1
Ta ble 1 0:
Dis p ositi o n of A RI A -H ( S u perficial Si der osis) Cases ............................................... 5 3
Ta ble 1 1:
Res u m pti o n of St u d y  Treat me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A ............ 5 5
Ta ble 1 2:
D ose Gr o u p P o oli n g Strate g y  i n t he E ve nt of Treat me nt Gr o u p Ter mi nati o n........... 8 9
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n............................................................................................................... 1 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1.
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 5 0 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
 at 
Please refer t o t he St u d y  Refere nce Ma n ual
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 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
F U
F oll o w - u p
G C P
G o o d Cli nical Practice
H b A 1 c
gl yc os yl ate d he m o gl o bi n
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
h ealt h care pr ofessi o nal
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g
i m m u n o gl o b uli n 
I R
i nf or ma nt rate d
I RB
i nstit uti o nal re vie w b oar d
I T T
i nte nt-t o-treat
I V
i ntra ve n o us(ly)
I W G
I nter nati o nal W or ki n g Gr o u p
L T E
l o n g-ter m e xte nsi o n
L P
l u m bar p u nct ure
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 Re g ulat or y Acti vities
M M R M
M i xe d-m o del re peate d meas ures
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 P D Q - 2 0
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d versi o n
M RI
ma g netic res o na nce i ma gi n g
NI A
Nati o nal I nstit ute o n A gi n g
N PI - 1 0
Ne ur o ps yc hiatric I n ve nt or y - 1 0
P E T
p ositr o n e missi o n t o m o gra p h y
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
R B A N S
Re peata ble Batter y  f or Assess me nt of Ne ur o psyc h ol o gical 
Stat us
R N A
ri b o n ucleic aci d
S A B R
Safet y  a n d Be nefit-Ris k 
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
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 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
U V
u nsc he d ule d visit


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
3.
S Y N O P SI S
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
Pr ot oc ol Title:
A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he Efficac y a n d 
Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h Earl y
Alz hei mer's Disease
Versi o n N u m ber:
2. 0
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 I n dicati o n:
Alz hei mer’s Disease
St u d y Rati o nale:
T he p ur p ose of t his P hase 3 st u d y is t o assess t he efficac y a n d 
safet y of a d uca n u ma b c o m pare d wit h place b o i n s u bjects wit h 
earl y Alz hei mer’s Disease ( A D) , i ncl u di n g s u bjects wit h mil d 
c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a s u bset of mil d A D .  
A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of β -a m yl oi d ( A β), i ncl u di n g s ol u ble A β 
oli g o mers a n d de p osite d fi brillar A β .  I nteri m a nal yses of t he 
o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve 
de m o nstrate d tar get e n ga ge me nt, a p har mac o d y na mic effect o n 
a m yl oi d re d ucti o n, a n d a n effect o n t he Cli nical De me ntia Rati n g 
( C D R)-S u m of B o xes ( S B) a n d Mi ni -Me ntal State E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults al o n g 
wit h t he o bser ve d safet y a n d t olera bilit y pr ofile warra nt f urt her 
P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n 
s pa n ni n g t he earl y sta ges of t he A D c o ntin u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
(place b o -c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R-S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D .  
T he pri mar y e n d p oi nt t h at relates t o t his o bjecti ve is t he cha n ge 
fr o m baseli ne i n C D R -S B sc ore at Wee k 7 8.
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b 
as c o m pare d wit h place b o o n cli nical pr o gressi o n as 
meas ure d b y 

M M S E

C ha n ge fr o m baseli ne i n M M S E sc ore at Wee k
7 8

Alz hei mer’s Disease Assess me nt Scale -C o g niti ve 
S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3] 

C ha n ge fr o m baseli ne i n A D A S-C o g 1 3 at Wee k 7 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1

Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of 
Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt 
versi o n) [ A D C S -A D L -M CI] 

C ha n ge fr o m baseli ne i n A D C S -A D L -M CI
sc ore at 
Wee k
7 8
Tertiar y o bjecti ves of t his st u d y are liste d i n Secti o n 6. 3. 1 .  
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 .  
St u d y O bjecti ves a n d E n d p oi nts 
( D ose-Bli n d L o n g -Ter m  
E xte nsi o n peri o d of t he st u d y ):
T he o bjecti ves are 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 earl y A D, a n d 
t o e val uate t he l o n g-ter m efficac y of a d uca n u ma b treat me nt as 
meas ure d b y cli nical, ra di ol o gical a n d a d diti o nal assess me nts 
re p orte d b y t he s u bject a n d i nf or ma nt/care part ner.
E n d p oi nts f or t he l o n g-ter m e xte nsi o n (L T E ) peri o d of t he st u d y 
are liste d i n Secti o n 6. 4. 2 .  
St u d y Desi g n:
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p peri o d f oll o we d b y a n o pti o nal 
2 4- m o nt h d ose -bli n d, L T E peri o d
St u d y L ocati o n:
A p pr o xi matel y 1 5 0 sites gl o ball y
N u m ber of Pla n ne d S u bjects:
A p pr o xi matel y 1 3 5 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 earl y A D, i ncl u di n g 
s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a 
s ubset of mil d A D acc or di n g t o NI A -A A criteria .  S u bjects m ust 
be p ositi ve f or a m yl oi d pat h ol o g y as meas ure d b y a m yl oi d 
p ositr o n e missi o n t o m o gra p h y sca n .  S u bjects m ust be 5 0 t o 8 5 
years ol d, a n d a part fr o m t he cli nical dia g n osis of earl y A D, 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 .  S u bj ect 
e nr oll me nt will be m o nit ore d s o t hat a p pr o xi matel y 6 0 % t o 7 0 % 
a p oli p o pr otei n E 4 ( A p o E ε 4 ) carriers are e nr olle d .  E nr oll me nt 
will als o be m o ni t ore d, via i nteracti ve res p o nse tec h n ol o g y (I R T), 
s uc h t hat s u bjects wit h mil d A D re prese nt a s mall perce nta ge of 
t he t otal e nr olle d i n t he trial.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt Gr o u ps:
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d of t he st u d y a n d 
b ase d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d 
t o 1 of 3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o 
(a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o) as 
f oll o ws: 
A p o E ε 4 c arrier
     L o w  d ose ( 3 m g/ k g)
    Hi g h d ose ( 6 m g/ k g) 
     Pl ace b o 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
A p o E ε 4 n o n -c arrier
     L o w  d ose ( 6 m g/ k g) 
     Hi g h d ose ( 1 0 m g/ k g)
     Pl ace b o 
After c o m pleti o n of t he place b o -c o ntr olle d peri o d , s u bjects ma y 
e nter a 2 4 -m o nt h d ose -bli n d L T E st u d y d uri n g w hic h all s u bjects 
will recei ve a d uca n u ma b.  
D urati o n of Treat me nt a n d 
F oll o w U p:
St u d y d urati o n f or eac h s u bject partici pati n g i n t he place b o -
c o ntr olle d peri o d o nl y will be a p pr o xi matel y 1 0 2 wee ks ( u p t o a n 
8 -wee k scree ni n g peri o d, 7 6 wee ks of place b o or a d uca n u ma b
d osi n g, a n d 1 8 wee ks of f oll o w u p [ F U]).  
F or s u bjects w h o e nter t he o pti o nal L T E peri o d , t he t otal d urati o n 
will be a p pr o xi matel y 2 0 6 wee ks or 4 7 m o nt hs ( u p t o a n 8 -wee k 
scree ni n g peri o d, 7 6 wee ks of place b o or a d ucan u ma b d osi n g, 4 
wee ks of F U , 1 0 0 wee k s of d ose -bli n d a d uca n u ma b d osi n g, a n d 
1 8 wee ks of F U ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1
4. 1.
St u d y Sc he m atic
Fi g ure 1:
St u d y Desi g n
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve ; L T E = l o n g -ter m e xte nsi o n; R = ra n d o mizati o n date .
* S u bjects w h o are assi g ne d t o place b o d uri n g t he place b o -c o ntr olle d peri o d a n d are c o nti n ui n g i nt o t he L T E peri o d wi ll be ra n d o mize d i n a 1: 1 rati o t o hi g h a n d 
l o w d ose a d uca n u ma b treat me nt ( base d u p o n t heir A p o E ε 4 carrier stat us).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 8
4. 2.
Sc he d ule of E ve nts
T a ble 1:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8
St u d y Wee k
Scree ni n g 
(≤6 0 d a ys 
bef ore D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
I nitial Scree ni n g 
C o nse nt 2
X
F ull I nf or me d 
C o nse nt 3
X
Eli gi bilit y Criteria
X  
X  
X  
X 4
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
H b A 1c
X
HI V 5/ He patitis/
C oa g ulati o n
X
A p o E G e n ot y pi n g
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
Ser u m Pre g na nc y
Test 7
X
Uri ne Pre g na nc y 
Test 7
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 9
St u d y Wee k
Scree ni n g 
(≤6 0 d a ys 
bef ore D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 8
X
X  
X  
X  
X  
X  
X  
X
X  
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
Ra n d o mizati o n
X
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
A nti -
A d uca n u ma b A b 9
X
X
X
A d uca n u ma b 
C o nce ntrati o n 1 0
X 1 1
X 1 1
X 1 1
X  
X 1 1
X 1 1
X 1 1
X
A m yl oi d P E T 1 4
X
X
R B A N S
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
2 2
T a ble 2:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Tre at me nt or F oll o w- U p 
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
7 8 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
M e dic ati o n
9 4
( or 1 8 wee ks after fi n al 
d ose f or s u bjects w h o 
ter mi n ate tre atme nt 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
I nf or me d C o nse nt
X 3
Eli gi bilit y Criteria
X 2
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X
Uri ne Pre g na nc y Test 4
X  
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 5
X  
X  
X  
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
St u d y Treat me nt I nf usi o n
X  
X  
X  
X  
X  
X  
X
A nti - Ad uca n u ma b A b 6
X
X
X
A d uca n u ma b C o nce ntrati o n 7
X 8
X
X
A m yl oi d P E T 1 0
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 3: 
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -u p P h o ne C all Sc he d ule D uri n g t he Pl ace b o- C o ntr olle d Peri o d
St u d y Wee k
Scree ni n g
(≤6 0 d a ys 
bef ore D a y 1) 1
Pl ace b o -C o ntr olle d Peri o d
F U 2
1 
2 
6
1 0 
1 4 
1 8 
2 2 
2 6 
3 0 
4 2 
5 4 
7 8/
E O T
3
U nsc he d
-ule d 
Visit/ 
M RI f or 
A RI A 4
9 4
( or 1 8 
wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
disc o n -
ti n ue 
tre atme nt 
e arl y)
St u d y D a y
V 1  
V 2  
V 3
1
1 5
± 3
4 3
± 3
7 1
± 3
9 9
± 3
1 2 7
± 3
1 5 5
± 3
1 8 3
± 3
2 1 1
± 3
2 9 5
± 3
3 7 9
± 3
5 4 7
± 3
6 5 9
± 7
F oll o w -U p P h o ne Call 5
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 6
X
X
X
X  
X  
X  
X  
X  
X
A d uca n u ma b 
C o nce ntrati o n 7
X
X
X
X
M O C A
X
X
A RI A = a m yl oi d relate d i ma gi n g a b n or malities; E O T = E n d of Treat me nt ; F U = F oll o w -U p; L T E = l o n g -ter m e xte nsi 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; 
; V 1, V 2, V 3 = Scree ni n g Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3.
1 Brai n M RI ( V 2) w ill n ot be perf or me d u ntil t he s u bject has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1.  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 relate d 
t o P E T sca ns a n d s u bject t o S p o ns or a p pr o val.
2 S u bjects w h o c o m plete t he place b o -c o ntr olle d 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 U V isit at Wee k 9 4.  S u bjects wh o 
disc o nti n ue treat me nt or w it h dr a w fr o m t he st u d y earl y are t o ha ve a safet y F U V isit at 1 8 wee ks after t heir fi nal d ose.  T he o nl y e xce pti o n is a s u bject w h o 
disc o nti n ues treat me nt pre mat urel y a n d c o nti n ues o n st u d y f or at least 1 8 w ee ks after recei vi n g t he fi nal d ose.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
2 6
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y.  
S u bjects w h o wit h dra w  fr o m st u d y pre mat urel y are t o ret ur n t o t he site f or t he Wee k 7 8/ E O T Visit; f or s uc h s u bjects, t he site is t o c o ntact t he S p o ns or as s o o n 
as p ossi ble t o c o nfir m w het her t he efficac y assess me nts s pecifie d at t he Wee k 7 8/ E O T Visit are re q uire d.
4 If a s u bject res u mes treat me nt after A RI A, a n M RI will be perf or me d 2 wee ks ( ± 3 da ys) after t he sec o n d a d mi nistrat i o n of st u d y treat me nt at t he restarte d d ose 
or eac h i ncrease i n d ose if a n M RI is n ot sc he d ule d d uri n g t his peri o d (see Secti o n 7. 2. 2. 5 ).
5 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject w ill be at t he st u d y site f or cli nical assess me nts.
6 Arteria l s pi n la beli n g M RI a n d tas k free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
7 O ne sa m ple will be c ollecte d wit hi n 2 da ys after t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all p har mac o ki netic bl o o d sa m ples o n a 
s pecifie d case re p ort f or m.  N ote:  F or s u bjects w h o s us pe n d treat me nt d ue t o A RI A, o nl y 1 bl o o d sa m ple is re q uire d t o be c ollecte d at eac h s pecifie d visit 
d uri n g t he peri o d of d ose s us pe nsi o n; all ot her visits/assess me nts are re q uir e d t o be perf or me d.  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 n ce ntrati o n sa m ple will be c ollecte d at t he s u bject’s ne xt visit.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
Ra n d o mizati o n
X 1
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
Uri ne Pre g na nc y 
Test 2
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -
A d uca n u ma b A b 3
X
X
X
A d uca n u ma b 
C o nce ntrati o n 3
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
2 8
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
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
C D R
X  
X
X  
X  
X
M M S E
X  
X
X  
X  
X
A D A S -C o g 1 3
X  
X
X  
X  
X
A D C S -A D L -M CI
X  
X
X  
X  
X
N PI -1 0
X  
X
X  
X
E Q -5 D (I R-S) 
X  
X
X  
X
C- S S R S
X
X
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
C o nc o mita nt 
T hera p y a n d 
P r 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 D A S -C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale -C o g niti ve S u bscale ( 1 3 ite ms); A D C S -
A D L -M CI
= Alz hei mer's Disease C o o perati ve St u d y -Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n); C D R = Cli nical De me ntia 




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
3 0
T a ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Tre at me nt or F oll o w -U p
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
B o d y Wei g ht
X  
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
X
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -a d uca n u ma b 
A b 4
X
X
X
X
A d uca n u ma b 
C o nce ntrati o n 4
X
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
3 1
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
St u d y Dr u g 
I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X
A m yl oi d P E T 6
X
C D R
X  
X
X  
X
X
M M S E
X  
X
X  
X
X
A D A S -C o g 1 3
X  
X
X  
X
X
A D C S -A D L -M CI
X  
X
X  
X
X
N PI -1 0
X  
X
X
E Q -5 D (I R -S) 
X  
X
X
C- S S R S
X
X
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




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6:
Br ai n M RI , A RI A M a n a ge me nt , a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he L o n g -Ter m E xte nsi o n
St u d y Wee k
L o n g -Ter m E xte nsi o n
U nsc he d -
ule d V isit
f or A RI A1
F U 2
8 2 
8 6 
9 0 
9 4 
9 8 
1 0 2 
1 0 6 
1 1 0 
1 2 2 
1 3 4 
1 5 8
1 8 2 3
1 9 8
( or 1 8 wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
ter mi n ate 
tre atme nt 
e arl y)
St u d y D a y
5 7 5
± 5
6 0 3
± 5
6 3 1
± 5
6 5 9
± 5
6 8 7
± 5
7 1 5
± 5
7 4 3
± 5
7 7 1
± 5
8 5 5
± 5
9 3 9
± 5
1 1 0 7
± 5
1 2 7 5
± 5
1 3 8 7
± 7
F oll o w - Up 
P h o ne Call 4
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 5
X
X
X  
X  
X  
X  
X  
X
X
M O C A
X
A RI A = a m yl oi d relate d i ma gi n g a b n or malities; E O T = E n d of Treat me nt ; F U = f oll o w u p; L T E = l o n g-ter m e xte nsi 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.
1 If a s u bject res u mes treat me nt after A RI A, a n M RI will be perf or me d 2 wee ks ( ±3 da ys) after t he sec o n d a d mi nistrati o n of st u d y treat me nt at t he restarte d d ose 
or eac h i ncrease i n d ose if a n M RI is n ot sc he d ul e d d uri n g t his peri o d (see Secti o n 7. 2. 2. 5 ).
2 S 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 safet y F U V isit at Wee k 1 9 8.  S u bjects w h o 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 U V isit at 1 8 wee ks after t heir fi nal d ose.  T he o nl y e xce pti o n is a s u bject w h o disc o nti n ues treat me nt pre mat urel y a n d 
c o nti n ues o n st u d y f or at least 1 8 wee ks after recei vi n g t he fi nal d ose.
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y. 
S u bjects w h o wit h dra w  fr o m t he L T E peri o d pre mat urel y are t o ret ur n t o t he site f or t he Wee k 1 8 2/ E O T V isit; f or s uc h s u bjects, t he site is t o c o ntact t he 
S p o ns or as s o o n as p ossi ble t o c o nfir m w het her t he efficac y assess me nts s pecifie d at t he Wee k 1 8 2/ E O T V isit are re q uire d.
4 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject will be at t he st u d y site f or cli nical assess me nts.
5 Arterial- s pi n la beli n g M RI a n d tas k-free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n S u bjects wit h Earl y Alz hei mer's Disease  
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 4
4. 3.
A d diti o n al I nf or m ati o n
4. 3. 1.
Site Pers o n nel
A mi ni m u m of 3 se parate heat h care pr ofessi o nals ( H C Ps) are re q uire d:  
1.
A treati n g H C P (t he Pri nci pal I n vesti gat or [ PI ] or S u b -i n vesti gat or m a y  ser ve as a 
treati n g H C P w h o is res p o nsi ble f or t he f oll o wi n g:

A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y  1 a n d d uri n g 
ma na ge me nt of a m yl oi d-relate d i ma gi n g a b n or malities (A RI A) cases.

Ma na ge me nt of t he r o uti ne ne ur ol o gical care of t he s u bject.

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y) a n d treat me nt of a d verse e ve nts 
(A Es ).  

Re vie w of selecte d he mat ol o g y  a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y 
wit h hel d or per ma ne ntl y  disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
Secti o n 1 0. 1 .
2.
A n i n de pe n de nt rati n g H C P ( desi g nate d by t he PI of t he site) w h o is res p o nsi ble f or 
a d mi nisteri n g t he Cli nical De me ntia Rati n g ( C D R)
3.
A sec o n d i n de pe n de nt rati n g H C P ( desi g nate d by t he PI  of t he site) w h o will a d mi nister 
t he Alz hei mer’s Disease Assess me nt Scale - C o g niti ve S u bscale ( 1 3 ite ms) [A D A S -C o g
1 3] , Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of Dail y  Li vi n g I n ve nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [A D C S -A D L -M CI ], a n d t he Mi ni-Me ntal State 
E xa mi nati o n ( M M S E)
T he 2 i n de pe n de nt rati n g H C Ps 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 A Es, c o nc o mita nt t hera py , la b orat or y data, i ma gi n g 
data , or a n y ot her data t hat ha ve t he p ote ntial of re veali n g t he treat me nt assi g n me nt .  PI s ca n n ot 
ser ve as rati n g H C Ps. T he treati n g H C Ps m ust n ot disc uss A Es (e. g., A RI A) wit h t he 
i n de pe n de nt rati n g H C Ps.  
T o e ns ure c o nsiste nc y  acr oss sites, rati n g H C Ps m ust c o m plete t he sta n dar dize d st u d y -s pecific 
q ualificati o n pr ocess o n cli nical efficac y  assess me nt sc ori n g pri or t o a d mi nistrati o n of t he 
s pecific assess me nt at t heir site.  All sites s h o ul d atte m pt t o mai n tai n t he sa me rati n g H C P
t hr o u g h o ut t he st u dy f or s pecific assess me nts .  Eac h s u bject s h o ul d ha ve t he sa me rati n g H C P
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 dy.  If a rati n g H C P has t o be 
re place d, t he ne w rati n g H C P m ust u n der g o t he st u d y -s pecific q ualificati o n pr ocess pri or t o 
a d mi nistrati o n of t he assess me nt.
He mat ol o g y  a n d bl o o d c he mistr y data will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.  As wit h ot her la b orat or y  a n d cli nical i nf or mati o n, t hese data s h o ul d 
N O T be re vie we d b y t he rati n g H C Ps .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T he r oles of i n de pe n de nt raters a n d treati n g H C P are N O T i nterc han gea ble at t he s u bject le vel.  
I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc ha n gea ble at t he s u bject le vel.  If a rater has 
a d mi nistere d t he C D R t o a s u bject t he y  ma y n ot a d mi nister t he ot her ne ur oc o g niti ve assess me nts 
t o t hat s u bject at a n y p oi nt d uri n g t he st u d y.
A n u n bli n de d p har macist ( or a ut h orize d desi g nee) 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 t he st u d y bli n d.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
5.
I N T R O D U C TI O N
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i ncrease t o 1 3 5. 5 milli o n b y  2 0 5 0 
[ Alz hei mer's Disease I nter nati o nal 2 0 1 4].  
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 a n d 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 [Jac k 2 0 1 3].
Pat h ol o gicall y, A D 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 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra ne ur o nal ne ur ofi brillar y ta n gles c o m p ose d of 
h y per p h os p h or y late d ta u pr otei ns.  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 “a myl 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 dy a n d Sel k oe 2 0 0 2] .  
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n ha vi n g cate g orical sta ges .  E vi de nce s u g gests t he 
pat h o p h ysi ol o gical c ha n ges be gi n y ears 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].  
Re vis e d criteria f or t he cli nical dia g n osis of A D were p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) a n d t he Alz hei mer’s Ass ociati o n ( A A) [ Al bert 2 0 1 1; Mc K ha n n 2 0 1 1; S perli n g 
2 0 1 1] a n d t he Inter nati o nal W or ki n g Gr o u p (I W G)
[ D u b ois 2 0 1 0; D u b ois 2 0 1 4], a n d a gr o u p 
t hat i ncl u de d me m bers fr o m b ot h NI A- A A a n d I W G p u blis he d rec o m me n dati o ns t o har m o nize 
t he criteria [ M orris 2 0 1 4].  T hese criteria base t he dia g n osis of A D o n b ot h cli nical a n d 
bi ol o gical ele me nts, rec o g nizi n g t he e xiste nce of a n o n cli nical sta ge of t he disease b y acce pti n g
A D dia g n os es pri or t o si g ns of de me ntia usi n g A D bi o mar kers.
T he scie ntific c o m m u nit y  has s hifte d its f oc us t o tar get patie nts 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 patie nts are m ore li kel y t o be nefit fr o m a nti -a m yl oi d 
t hera py .  S u p p orti n g t his h y p ot hesis are res ults fr o m s ola nez u ma b a n d cre nez u ma b st u dies t hat 
ha ve s h o w n a tre n d i n sl o wi n g c o g niti ve decli ne i n mil d b ut n ot m o derate A D [ D o o d y 2 0 1 4; 
Fa ga n 2 0 1 4] .  
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 b y  re d uci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F) .  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s o l u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u blicati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h s ol u ble oli g o mers a n d a myl 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 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
calci u m h o me o stasis a n d ne ur o nal acti vit y, as well as re d ucti o n of o xi dati ve stress [ R oz kal ne 
2 0 0 9; S pires -J o nes 2 0 0 9].  Si milarl y , patie nts wit h A D w h o ge nerate d a nti-A β a nti b o dies after 
acti ve i m m u nizati o n wit h a g gre gate d A β( 4 2) s h o we d sl o wer rates of decli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [ H oc k 2 0 0 3].
5. 1.
Pr ofile of Pre vi o us E x perie nce W it h A d uc a n u m a b  
5. 1. 1.  
N o ncli nic al E x perie nce 
A d uca n u ma b is a u ni q ue h u ma n, a nti-A β m o n ocl o nal a nti b o d y  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 o r 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 .  
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 uble 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 m m u n o gl o b uli n (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 pr o perties si g nifica ntl y re d uce d 
a m yl 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, t hr o u g h a 
micr o glia -me diate d p ha g oc y tic mec ha nis m.  T hese data s u g gest a d uca n u ma b c o ul d pr o vi de 
be nefit b y re d uci n g pla q ue b ur de n .
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 gicall y 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 gic al 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].
Fi n di n gs c o nsiste nt wit h a m y l oi d pla q ues a n d vasc ular a myl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, i ncl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h t his m o del .  I n 
b ot h 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 wer e 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 o n of he m osi deri n i n Perls stai ne d 
brai n secti o ns of e ac 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 ad 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 nfla m mati o n w ere 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
See t he I n vesti gat or’s Br oc h ure (I B) f or detaile d i nf or mati o n o n n o ncli nical st u dies.
5. 1. 2.
Cli nic al E x perie nce
A d uca n u ma b has bee n e val uate d i n o ne c o m plete d si n gle asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d ose st u d y  (2 2 1 A D 1 0 3): 

St u d y  2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, st u d y 
of ad uca n u ma b i n s u bjects wit h mil d or m o derate A D .  
T he pri mar y  o bjecti ve was t o e val uate t he safety a n d t olera bilit y of a ra n ge of 
ad uca n u ma b d oses ( 0. 3 t o 6 0 m g/ k g) w he n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y  o bjecti ves were t o assess t he p har mac o ki netic ( P K) a n d 
i m m u n o ge nicity of ad uca n u ma b after si n gle -d ose a d mi nistrati o n .  
A si n gle d ose of a d uca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d .  
D ose -li miti n g A RI A ( 2 s u bjects wit h A RI A- E [e de ma] a n d 1 s u bject wit h A RIA- E
a n d A RI A-H [ micr o he m orr ha ge]) was o bser ve d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses bel o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near.

St u d y  2 2 1 A D1 0 3 is a n o n g oi n g ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d 
m ulti ple d ose st u d y  of ad uca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are 
a m yl oi d p ositi ve.  The st u d y  c o m prises a place b o-c o ntr olle d peri o d wit h s u bjects 
recei vi n g m o nt hl y d oses of ad uca n u ma b (fi xe d d oses of 1, 3, 6, or 1 0 m g/ k g, or 
titrati o n u p t o 6 m g/ k g) or place b o f or a ye ar f oll o we d b y a d ose -bli n d l o n g -ter m 
e xte nsi o n ( L T E ) peri o d wit h s u bjec ts recei vi n g m o nt hl y d oses of ad uca n u ma b .  
T he pri mar y  o bjecti ve of St u d y  2 2 1 A D 1 0 3 is t o e val uate t he safety a n d t olera bilit y of 
m ulti ple d oses of ad uca n u ma b a d mi nistere d m o nt hl y  as si n gle I V i nf usi o ns.  T he 
sec o n dar y o bjecti ves are t o assess t he effect of ad uca n u ma b o n cere bral a m y l oi d 
pla q ue c o nte nt as meas ure d b y  1 8F-fl or beta pir p ositr o n e missi o n t o m o gra p h y (P E T ), 
a n d t o e val uate t he P K a n d i m m u n o ge nicit y of ad uca n u ma b after m ulti ple -d ose 
a d mi nistrati o n .  E x pl orat or y  o bjecti ves i ncl u de assess me nt of t he effect of 
ad uca n u ma b o n t he cli nical pr o gressi o n of A D as meas ure d b y C D R -s u m of b o xes 
(S B ) a n d M M S E .  
T o date, A RI A has bee n t he m ost fre q ue nt A E re p orte d i n t he st u d y.  A RI A -E was 
ra di o gra p hicall y m o nit ore d b y ma g netic res o na nce i ma gi n g ( M RI ) a n d t y p icall y 
o bser ve d earl y i n treat me nt ( bet wee n 2 t o 5 d oses) .  I n m ost cases, A RI A-E res ol ve d 
4 t o 1 2 wee ks after o nset a n d A RI A -H was t y picall y sta ble 2 t o 4 wee ks after o nset.  
I nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose a n d A p oli p o p r otei n E4 
(A p o E ε 4) carria ge-de pe n de nt, es peciall y at t he hi g hest d oses (refer t o t he I B f or 
details o n e ve nts of A RI A) .  
Pr ot oc ol -defi ne d i nteri m a nal ys es ha ve de m o nstrate d a d ose - a n d ti me-de pe n de nt 
re d ucti o n of brai n a myl oi d b ur de n after 6 m o nt hs of d osi n g ( We e k 2 6), wit h 
statistical si g nifica nce ac hie ve d i n t he 3, 6, a n d 1 0 m g/ k g gr o u ps c o m pare d wit h 
place b o, a n d after 1 year of d osi n g ( Wee k 5 4), wit h statistical si g nifica nce ac hie ve d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
i n t he 3 a n d 1 0 m g/ k g gr o u ps c o m pare d wit h place b o (see c urre nt I B f or res ults of t he 
m ost rece nt i nteri m a nal ysis ).  T he res ults de m o nstrate tar get e n ga ge me nt (a m y l oi d 
pla q ues) a n d a p har mac o d y na mic effect ( d ose -de pe n de nt a m yl oi d re d ucti o n) .  I n 
a d diti o n res ults fr o m t he i nteri m a nal yses s h o we d a n effect at 1 year o n t he 
e x pl orat or y  e n d p oi nts C D R-S B a n d M M S E, s u g gesti n g a re d ucti o n i n t he pr o gressi o n 
of cli nical i m pair me nt f or a d uca n u ma b -treate d vers us place b o-treate d s u bjects.  At 
Wee k
5 4, a dj uste d mea n c ha n ge (i ncrease) fr o m baseli ne i n C D R- S B sc ore was 
s maller f or b ot h t he 3 a nd 1 0 m g/ k g gr o u ps c o m pare d wit h place b o, wit h statistical 
si g nifica nce ac hie ve d i n t he 1 0 m g/ k g gr o u p (see c urre nt I B f or res ults of t he m ost 
rece nt i nteri m a nalys is).  At Wee k 5 2, a dj uste d mea n c ha n ges ( decreases) i n M M S E 
sc ore fr o m baseli ne were statisticall y si g nifica nt i n t he 3 a n d 1 0 m g/ k g gr o u ps ( see 
c urre nt I B f or res ults of t he m ost rece nt i nteri m a nal ysis).  Refer t o t he I B f or details 
o n i nteri m a nal y ses res ults.
5. 2.
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safety of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D a n d a s u bset of mil d A D.  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y  t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β .  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 yer -L ue 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].  F or 
t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, w hile preser vi n g 
gl o bal f u ncti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.  
I nteri m a nalys es of t he o n g o i n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3 ) ha ve de m o nstrate d tar get 
e n ga ge me nt, a P D effect o n a m y l oi d re d ucti o n, a n d a n effect o n C D R-S B a n d M M S E s u g gesti ve 
of a re d ucti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b- treate d s u bjects.  T hese 
results al o n g wit h t he o bser ve d safet y a n d t olera bilit y  pr ofile warra nt t he f urt her P hase 3 
i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D 
c o nti n u u m.
5. 3.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
T he d osi n g re gi me n selecte d f or t his st u d y was base d o n t he P K a n d P D relati o ns hi p f or re m o val 
of brai n a m yl oi d a n d effect o n C D R -S B a n d M M S E o bser ve d i n St u d y  2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n safet y, t olera bilit y , a n d P K data fr o m st u dies 22 1 A D 1 0 1 (c o m plete) a n d 
2 2 1 A D 1 0 3 ( on g oi n g) .  
T he d ose - a n d ti me-de pe n de nt re d ucti o n of brai n a m y l oi d b ur de n o bser ve d wit h ad uca n u ma b 
treat me nt was statisticall y si g nifica nt at d oses of 3, 6 a n d 1 0 m g/ k g after 6 m o nt hs of d osi n g a n d 
at 3 a n d 1 0 m g/ k g after 1 2 m o nt hs of d osi n g ( see c urre nt I B f or res ults of t he m ost rece nt i nteri m 
a nal ys is).  T he effect o n mea n decrease fr o m baseli ne i n C D R - S B after 1 2 m o nt hs of d osi n g was 
o bser ve d at b ot h 3 a n d 1 0 m g/ k g (see c urre nt I B f or res ults of t he m ost rece nt i nteri m a nalys is), 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
wit h stati stical sig nifica nce ac hie ve d at 1 0 m g/ k g .  T he effect o n mea n decrease fr o m baseli ne i n 
M M S E sc ore was statisticall y  si g nifica nt at 3 a n d 1 0 m g/ k g.  T hese data i n dicate t hat 3 m g/ k g 
c o ul d be c o nsi dere d a n acce pta ble d ose f or P hase 3 st u dies; h o we ver, gi ve n t he d ose-de pe n de n t
nat ure of t hese o bser vati o ns, t he use of hi g her d oses ( 6 a n d 1 0 m g/ k g) c o ul d offer greater be nefit 
at acce pta ble ris k .  
A RI A has bee n i de ntifie d as a n e ve nt t hat ma y  occ ur wit h a nti-a m yl oi d tar geti n g dr u g ca n di dates 
a n d is c o nsi dere d a n e ve nt of s pecial i nterest i n t he a d uca n u ma b pr o gra m.  T o date, t he i nci de nce 
of A RI A has bee n o bser ve d t o be b ot h d ose a n d A p o E ε 4 carria ge de pe n de nt, es peciall y at t he 
hi g hest d oses .  I n a n eff ort t o ma xi mize t he d ose-de pe n de nt a m yl oi d re d ucti o n a n d eff ect o n 
C D R -S B a n d M M S E t hat ha ve bee n o bser ve d wit h d oses of 3 m g/ k g a n d hi g her w hile 
mai ntai ni n g A RI A i nci de nce, se verit y , a n d relate d disc o nti n uati o n rate wit hi n acce pta ble le vels, 
a titrati o n re gi me n will be e x pl ore d .  It has bee n s u g geste d t hat t he A RI A o bser ve d f oll o wi n g 
treat me nt wit h a myl oi d tar geti n g a ge nts ma y  be d ue, i n part, t o t he i nitial lar ge re m o val of 
a m yl oi d a n d s u bse q ue nt sat urati o n of peri vasc ular brai n a myl oi d cleara nce mec ha nis ms [ Weller 
2 0 0 8] .  Sl o w titrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o w er i nitial a m yl oi d re m o val, 
ye t tri g ger alter nati ve mec ha nis ms of a myl oi d cleara nce i ncl u di n g m o n ocl o nal 
a nti b o d y-de pe n de nt Fc -me diate d micr o glial cleara nce [ Ostr o witz ki 2 0 1 2] w hi c h w o ul d pre ve nt 
sat urati o n of a myl oi d cleara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is 
reac he d.  Si nce ad uca n u ma b -i n d uce d A RI A has bee n de m o nstrate d t o occ ur early d uri n g
treat me nt, wit h m ost cases occ urri n g wit hi n t he first 5 d oses, titrati o n of ad uca n u ma b f or u p t o 
6 d oses pri or t o reac hi n g t he tar get d ose ma y  res ult i n re d ucti o n of A RI A i nci de nce a n d se verit y.  
Gi ve n t he t olera bilit y  a n d a p pare nt efficac y of ad uca n u ma b s h o w n t o date, t he d oses t o be teste d 
usi n g a titrati o n re gi me n are 3 a n d 6 m g/ k g f or A p o E ε 4 carriers, a n d 6 a n d 1 0 m g/ k g f or A p o E 
ε 4 n o n-carriers.  Titrati o n will start at 1 m g/ k g a n d will escalate t o 3, 6 a n d 1 0 m g/ k g as detaile d 
bel o w .  
5. 3. 1.
D osi n g Sc he me
5. 3. 1. 1.
Pl ace b o -C o ntr olle d Peri o d
D oses will be a d mi nistere d a p pr o xi matel y  4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses) .  Base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d t o 1 of 
3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h 
d ose: place b o) as f oll o ws (Ta ble 7 a n d Fi g ure 1 ):
A p o E ε 4 C arrier

L o w d ose ( 3 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereafter

Hi g h d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter

Place b o  
Sali ne i nf u si o n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A p o E ε 4 N o n- C arrier

L o w d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter  

Hi g h d ose ( 1 0 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n
T a ble 7:
D osi n g Sc he me f or A d uc a n u m a b b y Re gi me n
D ose ( M o nt h)
1
2 
3 
4 
5 
6 
7 t o 2 0
Re gi m e n
D ose ( m g/ k g)
A p o E ε 4 ( +)
L o w D ose
1 
1 
3 
3 
3 
3 
3
Hi g h D ose
1 
1 
3 
3 
3 
3 
6
Pl ace b o
sali ne
A p o E ε 4 ( -)
L o w D ose
1 
1 
3 
3 
3 
3 
6
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0
Pl ace b o
sali ne
5. 3. 2.
D osi n g Sc he me M o dific ati o n
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will re vie w u n bli n de d safet y data, i ncl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d uca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter .
T he d osi n g sc he me ca n be m o difie d i n t he f oll o wi n g circ u msta nces: 

Safet y  a n d t olera bilit y of t he hi g h d ose 
If a ny of t he hi g h d ose s pr o p ose d ( 1 0 m g/ k g i n A p o E ε 4 n o n-carriers a n d 6 m g/ k g i n 
A p o E ε 4 carriers) is dee me d n ot acce pta ble, e nr oll me nt f or t he hi g h d ose gr o u p(s) 
will be ter mi nate d a n d s u bjects will n ot be re place d .  S u bjects w h o ha ve alrea d y bee n 
ra n d o mize d t o t he disc o nti n ue d d ose will be d o w n -d ose d t o t he ne xt a vaila ble d ose
acc or di n g t o t heir A p o E ε 4 carrier stat us .  Defi niti o n of l o w a n d hi g h d ose re gi me ns 
will be re vise d as descri be d i n Secti o n 1 6 .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

Be nefit of titrati o n 
A titrati o n sc he d ule has bee n i m ple me nt e d i n t his P hase 3 st u d y  a n d i n t he o n g oi n g 
m ulti ple -d ose St u d y  2 2 1 A D 1 0 3.  If, base d u p o n re vie w of t he data fr o m 
St u d y 2 2 1 A D 1 0 3, titrati o n is n ot dee me d be neficial , it will be eli mi nate d, a n d 
s u bse q ue ntl y e nr olle d s u bjects w h o are A p o E ε 4 carriers will recei ve a fi xe d d ose of 
3 or 6 m g/ k g a n d n o n -carriers will recei ve 6 or 1 0 m g/ k g .  
5. 3. 3.
L o n g - Ter m E xte nsi o n Peri o d
S u bjects w h o recei ve d 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 w h o e nter t he L T E 
peri o d will c o nti n ue t o recei ve t he sa me d ose of ad uca n u ma b t hat t he y were o n at t he e n d of t he 
place b o - c o ntr olled peri o d .  S u bjects w h o recei ve place b o d uri n g t he place b o-c o ntr olle d peri o d 
a n d w h o e nter t he L T E peri o d will be assi g ne d t o 1 of 2 treat me nt gr o u ps, base d u p o n t heir 
A p o E ε 4 carrier stat us, i n a 1: 1 r ati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose).  S u bjects 
will be d ose d usi n g t he sa me re gi me n descri be d f or t he place b o -c o ntr olle d peri o d (see Ta ble 7
a n d Fi g ure 1 ).  
A n y  m o dificati o ns t o t he d osi n g sc he me (i.e. ter mi nati o n of hi g h d ose gr o u ps a n d re place me nt of 
titrati o n wit h fi xe d d osi n g, as descri be d i n Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E
peri o d .  










Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
St u d y  2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p 
st u d y i n s u bjects wit h earl y A D, i ncl u di n g M CI d ue t o A D a n d a s u bset of mil d A D, f oll o we d b y 
a n o pti o nal 2 4- m o nt h d ose -bli n d L T E st u d y .  A p pr o xi matel y  1 3 5 0 s u bjects will be e nr olle d 
acr oss a p pr o xi matel y 1 5 0 ce nters gl o ball y .  T he pri mar y  st u d y o bjecti ve is t o e val uate t he 
efficac y of m o nt hly d oses of a d uca n u ma b o n t h e C D R-S B relati ve t o place b o .  Sec o n dar y  
o bjecti ves i ncl u de assess me nt of t he effect of m o nt hl y  d oses of a d uca n u ma b o n cli nical 
pr o gressi o n as c o m pare d t o place b o .  T he safet y of m o nt hl y  d oses of a d uca n u ma b will als o be 
e val uate d.
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y  e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a total of 2 0 d oses) .  S u bjects will be ra n d o mize d t o recei ve 
a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o i n a 1: 1: 1 rati o .  T he ra n d o mizati o n will 
be stratifie d b y site a n d A p o E ε 4 stat us (carrier or n o n-carrier).  S u bject e nr oll me nt will be 
m o nit ore d s o t hat a p pr o xi matel y 6 0% t o 7 0 % A p o E ε 4 carriers are e nr olle d .  E nr oll me nt will 
als o be m o nit ore d, via i nteracti ve res p o nse tec h n ol o g y (I RT), s uc h t hat s u bjects wit h mil d A D 
re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  
At t he e n d of t he d o u ble-bli n d , place b o -c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
e xte nsi o n e ntr y criteria ma y e nter a 2 4-m o nt h l o n g-ter m safet y a n d efficac y e xte nsi o n peri o d,
wit h all s u bjects recei vi n g a d uca n u ma b a p pr o xi matel y e ver y 4 wee ks (a t otal of 2 6 d o ses).  
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject o nl y partici pati n g i n t he place b o -
c o ntr olle d peri o d of t he st u d y  will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series of 
S cree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6- wee k 
place b o -c o ntr olle d treat me nt peri o d, a n d a safet y f oll o w - u p ( F U) peri o d of 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 eac h s u bject par tici pati n g i n t he place b o -c o ntr olle d 
peri o d a n d t he L T E peri o d will be u p t o a p pr o xi matel y  2 0 6 wee ks, i ncl u di n g a series of 
Scree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k place b o -
c o ntr olle d treat me nt peri o d, a 4- wee k F U peri o d, a 1 0 0 - wee k a d uca n u ma b d ose -bli n d treat me nt 
peri o d, a n d a safet y F U peri o d of a p pr o xi matel y  1 8 wee ks after t he fi nal d ose.  T he F U peri o d of 
1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half- life i n h u ma ns of 1 6 t o 2 4 da y s ( mea n 
a p pr o xi matel y 2 0 d a y s, base d o n res ults fr o m t he si n gle asce n di n g d ose st u d y [St u d y  
2 2 1 A D 1 0 1] ) a n d a ntici pate d brai n c o nce ntrati o ns of a d uca n u ma b of less t ha n o ne-t hir d t he E C5 0
(i n hi bit or y c o nce ntrati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or bi n di n g fi brillar 
a m yl oi d at 8 wee ks after t he last d ose .  
D uri n g t he p lace b o-co ntr olle d p eri o d, A p o E ε 4 carriers will recei ve place b o, a d uca n u ma b
3 m g/ k g, or a d uca n u ma b 6 m g/ k g w h ereas A p o E ε 4 n o n -carriers will recei ve place b o, 
a d uca n u ma b 6 m g / k g, or a d uca n u ma b 1 0 m g / k g.  A d uca n u ma b will be titrate d f or u p t o 6 d oses 
pri or t o reac hi n g t he tar get d ose as s h o w n i n Ta ble 7 a n d Fi g ure 1 .  S u bjects w h o recei ve d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
a d uca n u ma b i n t he pl ace b o-c o ntr olle d peri o d a n d w h o e nter t he L T E peri o d will recei ve t he 
sa me d ose of a d uca n u ma b t hat t he y recei ve d at t he e n d of t he p lace b o-co ntr olle d p eri o d ( u p t o 
6 m g/ k g a n d 1 0 m g / k g i n A p o E ε 4 carriers a n d n o n-carriers, res pecti vel y) .  S u bjects w h o 
recei ve d place b o d uri n g t he place b o-c o ntr olle d p eri o d a n d w h o e nter t he L T E peri o d will be 
assi g ne d t o treat me nt base d u p o n t heir A p o E ε 4 carrier stat us i n a 1: 1 rati o (a d uca n u ma b l o w 
d ose: a d uca n u ma b hi g h d ose) ; a d uca n u ma b will be titrate d f o r u p t o 6 d oses pri or t o reac hi n g t he 
tar get d ose f oll o wi n g t he sa me sc he d ule descri be d f or t he p lace b o-co ntr olle d p eri o d.  
See Secti o n 5. 3. 2 f or details of d osi n g sc he me m o dificati o n.  
I n di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d t o s u bjects w h o de vel o p A RI A .  See 
Secti o n 7. 2. 1 .
I n vesti gat ors, st u d y site staff (e xce pt f or t he desi g nate d u n bli n de d p har macist/ tec h nicia n), a n d 
st u d y s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he place b o -
c o ntr olle d peri o d.  D uri n g t he L T E peri o d , In vesti gat ors a n d s u bjects will re mai n bli n de d t o t he 
treat me nt assi g n me nt i n t he place b o-c o ntr olle d peri o d a n d t he a d uca n u ma b d ose f or t he L T E
peri o d .
7. 2.
St u d y S pecifics
7. 2. 1.  
D ose S us pe nsi o n, M o dific ati o n, or Ter mi n ati o n f or A RI A E ve nts
Disc o nti n u ati o n of D osi n g f or a Give n S u bject
T he ce ntral M RI rea di n g ce nter will re p ort i nci de nt cases of A RI A- E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he PI wit hi n a s pecifie d ti me after o bser vi n g t he fi n di n g o n M RI per t he i ma gi n g 
ma n ual p r oce d ures.  All cases of A RI A will be re vie we d b y  t he S p o ns or a n d t he PI ; decisi o ns o n 
d osi n g c o nti n uati o n, i nterr u pti o n, or disc o nti n uati o n will be base d o n cli nical s y m pt o ms, a n d t he 
M RI  i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C n otificati o n r ules will be o utli ne d i n t he 
I D M C c harter.  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 
(i ncl u di n g t he criteria t o be met f or t he c o nti n uati o n, s us pe nsi o n/res u m pti o n, or per ma ne nt 
disc o nti n uati o n of d osi n g d ue t o A RI A) are pr o vi de d i n Secti o ns 7. 2. 1. 1 a n d 7. 2. 2 .  D osi n g ma y 
als o be ter mi nate d at t he discreti o n of t he S p o ns or f or me dical reas 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.  In a d diti o n, g ui deli nes o n re u pitrati o n t o t he 
s u bject’s assi g ne d d ose after A RI A res ol ves are pr o vi de d i n Secti o n 7. 2. 2. 5.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7. 2. 1. 1.
Dis p ositi o n of A RI A -E C ases
T a ble 8 :
Dis p ositi o n of A RI A -E C ases
Cli nic al S y m pt o m 
Se verit y
A RI A -E Se verit y o n M RI ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
As y m pt o m atic 
C o nti n ue d osi n g at 
c urre nt d ose a n d 
sc he d ule
S us pe n d d osi n g. O nce A RI A -E res ol ves t he s u bject 
ma y res u me d osi n g at t he sa me d ose.  
Mil d
S us pe n d d osi n g.  O nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t he s u bject ma y 
res u me d osi n g at t he sa me d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y i m p ort a nt 
e ve nt ” o nl y 1
Seri o us, e xce pt f or 
“ ot her m e dic all y 
i mp ort a nt e ve nt ” 2
Disc o nti n ue D osi n g
1 “Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nific a 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. 3. 3 .
2 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 3. 3 .

S u bjects w h o de vel o p mi l d A RI A-E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 
d ose .  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d , i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
a p pr o xi matel y e ver y 
4 wee ks u ntil t he A RI A -E has res ol ve d per t he ce ntrall y rea d M RI.  T he S p o ns or ma y  
re q uire t hat t he s u bjects disc o nti n ue d osi n g or c o nti n ue d osi n g at a l o wer d ose le vel 
base d o n re vie w of safet y a n d M RI  data.

S u bjects w h o de vel o p m o der ate or se vere A RI A -E, per ce ntr al M RI re a di n g,
wit h 
n o cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
a p pr o xi matel y e ver y 
4 wee ks u ntil t he A RI A -E has res ol v e d per t he ce ntrall y rea d M RI.  If t he A RIA- E 
has res ol ve d a n d t he s u bjects re mai n as y m pt o matic, t he s u bjects ma y  res u me 
treat me nt at t he sa me d ose.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 
c o nsec uti ve d oses will be all o we d t o res u me treat me nt.  

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A -E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
i m p ort a nt e ve nt ” o nl y) cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will 
te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli ni c visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A 
a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A-E has res ol ve d per t he ce ntrall y  rea d 
M RI .  If t he A RI A-E has res ol ve d a n d t he cli nical s y m pt o ms ha ve res ol ve d, t he 
s u bject ma y  res u me treat me nt at t he sa me d ose.  O nl y s u bjects w h o ha ve n ot misse d 
m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me treat me nt.    

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ”) 
cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will per ma ne ntl y disc o nti n ue 
treat me nt.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A ap pr o xi matel y  e ver y 
4 wee ks u ntil t he A RI A -E has res ol ve d per ce ntrall y  rea d M RI.
See Secti o n 7. 2. 2. 5 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 2. 6 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 2.
Dis p ositi o n of A RI A -H C ases
7. 2. 2. 1.
A RI A -H ( Micr o he m orr h a ge)
I n t his st u dy, ne w i nci de nt micr o he m orr ha ges are defi ne d as ne w i nci de nt micr o he m orr ha ges 
t hat occ ur o n treat me nt a n d d o n ot i ncl u de micr o he m orr ha ges at baseli ne.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 9:
Dis p ositi o n of A RI A -H ( Micr o he m orr h a ge) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Micr o he m orr h a ges 1 ( Ce ntr al Re a d)
≥1 a n d ≤4
≥5 a n d ≤9
≥1 0
As y m pt o m atic
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble, t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt micr o he m orr ha ges = ne w i nci de nt micr o he m orr ha ges o n treat me nt; d oes n ot i ncl u de 
micr o he m orr ha ges at baseli ne.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nifi ca 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 as 
descri be d i n Secti o n 1 5. 3. 3 .
3 S A Es re q uiri n g pe r 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), 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/ or res ult i n 
persiste nt or si g nifica nt disa bilit y/i n ca 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. 3. 3 .
As y m pt o m atic A RI A -H ( Micr o he m orr h a ge) 

S u bjects w h o de vel o p a ≥1 a n d ≤4 ne w i nci de nt micr o he m orr h a ge (s) at a n y ti me 
d uri n g t he st u d y ma y c o nti n ue treat me nt at t he c urre nt d ose.

S u bjects w h o de vel o p ≥5 a n d ≤9 ne w i nci de nt micr o he m orr h a ges occ urri n g at a n y  
ti me d uri n g t he st u dy will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or 
a n M RI an d M O C A
e ver y 2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ge is c o nfir me d 
as sta ble per t he ce ntrall y rea d M RI.  A micr o he m orr ha ge is c o nsi dere d sta ble if it is 
u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he micr o he m orr ha ge is dee me d 
sta ble, s u bjects ma y res u me treat me nt at t he sa me d ose .  O nl y  s u bjects w h o ha ve n ot 
misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me treat me nt .  

S u bjects w h o de vel o p ≥1 0 ne w i nci de nt micr o he m orr h a ges d uri n g t he st u d y  will 
per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
visits f or assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d 
M O C A e ver y  2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ges are dee me d sta ble per 
ce ntrall y rea d M RI.
S y m pt o m atic A RI A - H ( Micr o he m orr h a ge)

S u bjects w h o de vel o p ≤9 ne w i nci de nt micr o he m orr h a ges a n d mil d, m o der ate, 
se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y [ Secti o n 1 5. 3. 3 ]) 
cli nic al s y m pt o ms wil l te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or 
a n M RI a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A - H ( micr o he m orr ha ge(s)) 
is c o nfir me d sta ble per t he ce ntrall y rea d M RI.  Micr o he m orr ha ges are c o nsi dere d 
sta ble if t he y are u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce A RI A-H 
( micr o he m orr ha ge) is dee me d sta ble a n d t he cli nical s ym p t o ms ha ve res ol ve d, t he 
s u bject ma y res u me treat me nt at t he sa me d ose.  O nl y s u bjects w h o ha ve n ot misse d 
m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti on 1 5. 3. 3 ]) cli nic al s y m pt o ms ass oci ate d wit h micr o he m orr h a ge(s) will 
per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A e ver y 
2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ge(s) is c o nfir me d sta ble per ce ntrall y  rea d 
M RI .  

S u bjects w h o de vel o p ≥1 0 ne w i nci de nt micr o he m orr h a ges , re gar dless of s ym pt o m 
se verity, d uri n g t he st u d y will per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d , i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
micr o he m orr ha ges are dee me d sta ble per ce ntrall y rea d M RI.  
See Secti o n 7. 2. 2. 5 f or details o n res u m pti o n of d osi n g w he n sus pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 2. 6 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7. 2. 2. 2.
A RI A -H ( S u perfici al Si der osis)
T a ble 1 0:
Dis p osi ti o n of A RI A-H ( S u perfici al S i der osis) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Are as of S u perfici al Si der osis 1 ( Ce ntr al Re a d)
1
2
> 2
As y m pt o m atic
C o nti n ue d osi n g at 
c urre nt d ose a n d sc he d ule
S us pe n d d osi n g .
Once A RI A -H 
is sta ble t he s u bject ma y res u me 
d osi n g at t he sa me d ose. 
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g .
Once A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose.  
M o der ate
Se vere 
Seri o us “ ot her 
me dic all y
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt s u perficial si der osis = ne w i nci de nt s u perficial si der osis o n treat me nt.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 as 
descri be d i n Secti o n 1 5. 3. 3 .
3 S A Es 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), 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/ 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. 3. 3 .
As y m pt o m atic A RI A -H ( S u perfici al S i der osis)

S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis) ma y  c o nti n ue treat me nt at t he c urre nt d ose, b ut m ust ha ve 
a n u nsc he d ule d visit f or a n M RI a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
s u perficial si der osis is c o nfir me d as sta ble per t he ce ntrally rea d M RI.  S u perficial 
si der osis is c o nsi dere d sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  

S u bjects w h o de vel o p 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d treat me nt , b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H 
(s u perficial si der osis) is c o nfir me d as sta ble per t he ce ntrall y rea d M RI.  S u perficial 
si der osis is c o nsi dere d sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
O nce t he s u perfici al si der osis is dee me d sta ble, t he s u bjects ma y  res u me treat me nt at 
t he sa me d ose.  O nly s u bjects w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses 
will be all o we d t o res u me treat me nt.  

S u bjects w h o de vel o p > 2 f oc al are as of he m osi der osis (s u perfici al si d er osis) 
occ urri n g at a n y ti me d uri n g t he st u d y m ust per ma ne ntl y disc o nti n ue treat me nt a n d 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H 
(s u perficial si der osis) is c o nfir me d as sta ble per t he ce ntrall y rea d M RI.  S u perficial 
si der osis is c o nsi dere d sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.   
S y m pt o m atic A RI A -H (s u perfici al si der osis)

S u bjects w h o de vel o p ≤2 ne w f oc al are a s of s u perfici al si der osis a n d mil d, 
m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y)
cli nical 
s ym pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  
a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H s u perficial si der osis is 
c o nfir me d sta ble per t he ce ntrall y rea d M RI.  S u perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he A RI A -H (s u perficial 
si der osis) is dee me d sta ble a n d t he cli nical sy m pt o ms ha ve res ol ve d, t he s u bjects ma y  
res ume treat me nt at t he sa me d ose.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 
c o nsec uti ve d oses will be all o we d t o res u me treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 3. 3] ) cli nic al s y m pt o ms ass oci ate d wit h A RI A -H (s u perfici al 
si der osis) will per ma ne ntl y  disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess me nts a n d i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  
a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d sta ble 
per ce ntrall y rea d M RI.

S u bjects w h o de vel o p > 2 ne w f oc al are as of s u perfici al si der osis re gar dless of 
cli nical s ym pt o m se verit y  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
s u perficial si der osis is c o nfir me d sta ble per ce ntrall y  rea d M RI.  
See Secti o n 7. 2. 2. 5 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 2. 6 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 2. 3.
A RI A -H ( M acr o he m orr h a ge)

S u bjects w h o de vel o p a n y ne w i nci de nt macr o he m orr ha ge, re gar dless of s ym pt o m 
se verity d uri n g t he st u d y,  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
u nsc he d ule d visit f or M RI a n d M O C A e ver y  2 wee ks ( ± 3 da ys) 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.
7. 2. 2. 4.
Dis p ositi o n of C oi nci de nt A RI A -H a n d A RI A -E C ases
S u bjects w h o de vel o p A RI A- H c oi nci de nt wit h A RI A- E at a n y ti me d uri n g t he st u d y  will f oll o w 
t he m ost restricti ve g ui deli nes. Pri or t o res u mi n g treat me nt, w here a p plica ble, A RI A -E m ust 
res ol ve, A RI A-H be dee me d sta ble, a n d t he s u bject m ust be as y m pt o matic.   F or e xa m ple, if a 
s u bject e x perie nces asy m pt o matic A RI A -H ( 1 -4 micr o he m orr ha ges) c oi nci de nt wit h A RI A- E 
assesse d as m o derate o n M RI  a n d acc o m pa nie d b y mil d cli nical sy m pt o ms, t he d ose s h o ul d be 
s us pe n de d per t he A RI A-E g ui deli nes s u m marize d i n Ta ble 1 1 .
7. 2. 2. 5.
Res u m pti o n of St u d y Tre at me nt After S us pe nsi o n d ue t o A RI A
7. 2. 2. 5. 1.
M RI M o nit ori n g
W he n treat me nt res u mes after a d ose s us pe nsi o n d ue t o A RI A, a n M RI a n d M O C A
will be 
perf or me d 2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of t he restarte d d ose if t he y d o n ot 
ha ve a sc he d ule d M RI  occ urri n g d uri n g t his peri o d.  In a d diti o n, if treat me nt was s us pe n de d 
d uri n g t he d ose titrati o n pri or t o t he s u bject reac hi n g t he ma xim u m assi g ne d d ose, a n M RI  a n d 
M O C A will be perf or me d
2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of eac h i ncrease i n 
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 ules of E ve nts ( Secti o n 4. 2 ).
7. 2. 2. 5. 2.
D osi n g U p o n Res u m pti o n of St u d y Tre at me nt
S u bjects w h o s us pe n d treat me nt d ue t o A RI A f or t he first ti me ma y res u me treat me nt at t he sa me 
d ose if t he y meet t he criteria as descri be d i n Secti o ns 7. 2. 1. 1 , 7. 2. 2 , a n d 7. 2. 2. 4. S u bjects w h o 
s us pe n d a n d t he n res u me d osi n g after ha vi n g alrea d y reac he d t heir assi g ne d t o p d ose le vel are t o 
c o nti n ue d osi n g at t hat d ose le vel.  H o we ver, if d osi n g is s us pe n de d d uri n g t he d ose titrati o n 
peri o d, t he s u bject ( 1) m ust recei ve at least 2 d oses at t he restart d ose bef ore titrati n g u p t o t he 
ne xt d os e le vel a n d ( 2) m ust c o m plete at least t he re q uire d n u m ber of d oses at t hat d ose le vel per 
t heir assi g ne d d osi n g re gi me n, as o utli ne d i n Ta ble 1 1 .  
T a ble 1 1 :
Res u m pti o n of St u d y Tre at me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A
D uri n g Titr ati o n
Assi g ne d D osi n g 
Re gi me n 
(M a xi m u m D ose )
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
A p o E ε 4 ( +)
L o w D ose ( 3 m g/ k g)
1 m g/ k g
1
2
Hi g h D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Assi g ne d D osi n g 
Re gi me n 
(M a xi m u m D ose )
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
A p o E ε 4 ( -)
L o w D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
7. 2. 2. 6.
M a n a ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI)
If t he s u bject has a sec o n d occ urre nce of A RI A (i.e., a sec o n d occ urre nce of A RI A- E or of 
A RI A- H, or A RI A -E a n d A RI A- H) t hat re q uires d ose s us pe nsi o n, after t he A R I A- E resol ves or 
sta bilizes, t he s u bject is t o res u me d osi n g at t he ne xt l o wer d ose a n d is t o recei ve 2 d oses at t hat 
d ose le vel (i.e., t he restart d ose) bef ore titrati n g u p t o t he ne xt hi g her d ose.  O nce d osi n g has 
res u me d, t he g ui deli nes o utli ne d i n Ta ble 1 1 a p pl y, u nless t he s u bject has re d uce d fr o m 1 m g / k g 
t o place b o.  I n t his case, t he s u bject will re mai n o n place b o f or t he d urati o n of t he place b o-
c o ntr olle d p orti o n of t he st u d y .  If a s u bject res u mes t reat ment after A RI A, a n M RI  a n d M O C A 
will be perf or me d 2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of t he restarte d d ose, a n d 
2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of eac h i ncrease i n d ose u nless t he s u bject has 
a sc he d ule d M RI d uri n g t his peri o d.  M RI s will ot her wise be perf or me d as i n dicate d i n t he 
Sc he d ules of E ve nts ( Secti o n 4. 2 ).
If t he s u bject e x perie nces a t hir d e pis o de of A RI A t hat re q uires d ose s us pe nsi o n, t he s u bject 
m ust disc o nti n ue st u d y  treat me nt.  S u bjects w h o 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 c o nti n ue all pr ot oc ol -re q uire d tests a n d assess me nts.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
S u bjects w h o de vel o p A RI A d uri n g t he place b o -c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d ose are eli gi ble t o e nter t he L T E peri o d a n d will recei ve t he l o west d ose 
t hat t he y ha ve t olerate d d uri ng t he place b o -c o ntr olle d peri o d.  A s u bject w h o is s witc he d t o 
place b o b ut re mai ns i n t he st u d y  ma y be titrate d t o a d uca n u ma b 1 m g / k g d uri n g t he L T E peri o d .
7. 2. 3. 
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 
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 Directi o ns f or Ha n dli n g a n d A d mi nistrati o n ( 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.
7. 3.
O v er all St u d y D ur ati o n a n d F oll o w -U p
T he st u d y  peri o d will c o nsist of scree ni n g, treat me nt, a n d F U .
T he d o u ble -bli n d , place b o -c o ntr olle d peri o d of t he st u d y will c o nsist of a n 8-wee k scree ni n g 
peri o d, a 7 6- wee k treat me nt peri o d , a n d a safet y F U peri o d of 1 8 wee ks after t he fi nal d ose .  
S u bje cts will ha ve a p pr o xi matel y 3 3 sc he d ule d cli nic visits d uri n g t he place b o -c o ntr olle d peri o d, 
a n d u p t o 8 tele p h o ne safet y  F U c o ntacts, as f oll o ws:

Scree ni n g Visits n o m ore t ha 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).  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 y s; 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 relate d t o P E T sca ns a n d s u bject 
t o S p o ns or a p pr o val.

2 0 o ut patie nt d osi n g visits.

8 tele p h o ne safet y F U c o ntacts a p pr o xi matel y 2 wee ks after eac h of t he first 8 d oses .

3 visits f or cli nical assess me nts .


2 visits f or a m y l oi d P E T sca n (i n a s u bset of s u bjects).


6 visits f or brai n M RI .

1 F U safety visit at Wee k 9 4 ( o nl y  f or s u bjects n ot e nteri n g t he L T E peri o d ) or 1 8 wee ks 
after last a d mi nistrati o n of st u d y  treat me nt f or t h ose s u bjects w h o wit h dr a w fr o m st u d y.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 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  4 0 a d diti o nal pla n ne d cli nic 
visits, a n d u p t o 8 tele p h o ne safet y F U c o ntacts, as f oll o ws:

2 6 o ut patie nt d osi n g visits .  

8 tele p h o ne safet y F U c o ntacts a p pr o xi matel y 2 wee ks after eac h of t he first 8 d oses .

4 visits f or cli nical assess me nts .


2 visit s f or a m yl oi d P E T sca n (i n a s u bset of s u bjects).


7 visits f or brai n M RI .  

1 F U safety visit .
S u bjects w h o ha ve a c ha n ge i n A D me dicati o n ( ot her t ha n st u d y treat me nt) d uri n g t he 
place b o - c o ntr olle d or L T E peri o d s h o ul d ha ve a n u nsc he d ule d visit; all cli nical assess me nts f or 
t he pri mar y a n d sec o n dar y e n d p oi nts s h o ul d be perf or me d pri or t o t he c ha n ge i n me dicati o n.  
S u bjects w h o e x perie nce A RI A d uri n g t he place b o -c o ntr olle d or L T E peri o d s h o ul d ha ve 
u nsc he d ule d vis its per t he g ui deli nes i n Secti o n 7. 2. 1 .
7. 3. 1.
Scree ni n g
D uri n g t he Scree ni n g Visit, u n der a se parate i nitial c o nse nt pr ocess, s u bjects ca n c o m plete t he 
ne ur oc o g niti ve scales ( C D R, M M S E, a n d t he Re peata ble Batter y  f or Assess me nt of 
Ne ur o ps yc h ol o gical Stat us [ R B A N S]) .  T his i nitial ne ur oc o g niti ve scree ni n g is i nte n de d t o 
re d uce t he b ur de n o n s u bjects a n d sites b y a v oi di n g u n necessar y testi n g if s u bjects d o n ot meet 
ke y  i ncl usi o n criteria.  If t he s u bject meets i ncl usi o n criteria f or t hese 3 scales, t he n t he f ull 
co 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 directl y t o t he f ull c o nse nt pr ocess, w hic h 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 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, M M S E a n d R B A N S) m ust 
be perf or me d at Scree ni n g Visit 1 .  T he A D A S -C o g 1 3, a n d A D C S -A D L -M CI  will be perf or me d 
at Scree ni n g Visit 2 wit hi n 2 0 da y s after Visit 1 a n d m ust N O T be perf or me d o n t he sa me da y as 
t he C D R, M M S E a n d R B A N S.  T he N PI -1 0 ca n be perf or me d at a n y ti me d uri n g Scree ni n g as 
l o n g as it is perf or me d after t he C D R (e. g., i ncl u di n g at Scree ni n g Visit 1).  All ot her c o g niti ve 
assess me nts 
 ma y be perf or me d at a ny ti me d uri n g Scree ni n g after 
eli gi bilit y is c o nfir me d d uri n g Scree ni n g Visit 1.  T he M RI  at Scree ni n g Visit 2 s h o ul d be d o ne 
o nl y  after t he 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 P E 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.  
S u bject eli gi bilit y  f or t he st u d y will be deter mi ne d n o m ore t ha n 6 0 da ys pri or t o st u d y e ntr 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 y s; 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 relate d t o P E T 
sca ns a n d s u bject t o S p o ns or a p pr o val.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
S u bjects w h o fail Scree ni n g will be per mitte d t o be rescree ne d o nce at t he S p o ns or’s discreti o n .  
S u bjects w h o fail Scree ni n g d ue t o P E T, M M S E, C D R, he patitis B or C res ults, or a b n or mal 
M RI  fi ndi n gs will n ot be all o we d t o re scree n.  
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 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 hese me dicatio ns has bee n sta bilize d f or t he re q uire d peri o d.  
7. 3. 2.
Tre at me nt
Eli gi ble s u bjects will re p ort t o t he st u d y  site t o recei ve st u d y treat me nt e ver y 4 wee ks f or 
7 6 wee ks ( 2 0 d oses).  All 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 will be 
eli gi ble t o e nter t he L T E peri o d a n d will recei ve st u d y treat me nt e ver y 4 wee ks f or a n a d diti o nal 
1 0 0 wee ks ( 2 6 d oses), wit h t he first d ose a d mi nistere d a p pr o xi matel y  4 wee ks after t he fi nal d ose 
i n t he place b o - c o ntr olle d peri o d of t he st u d y .
7. 3. 3.
F o ll o w- U p
All s u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d are t o ret ur n t o t he st u d y site 
a p pr o xi matel y 2 wee ks after t he fi nal d ose f or cli nical assess me nts.
S u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d a n d n ot e nteri n g t he L T E peri o d are t o 
ret ur n t o t he st u d y site f or an F U V isit at Wee k 9 4 ( 1 8 wee ks after t he last d ose).  T he fi nal st u d y  
visit f or t hese s u bjects will be Wee k 9 4.
S u bjects w h o partici pate i n t he L T E peri o d are t o ret ur n t o t he st u d y site t o recei ve t heir first 
L T E d ose a p pr o xi matel y 4 wee ks after t heir last d ose i n t he place b o -c o ntr olle d peri o d of t he 
st u d y.  A F U V isit will occ ur at Wee k 1 9 8 ( 1 8 wee ks after t he last L T E d ose ).  T he fi nal st u d y  
visit f or s u b jects partici pati n g i n t he L T E peri o d will be Wee k 1 9 8.
S u bjects w h o 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 c o nti n ue all pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil wit h dra wal of c o nse nt.  S u bjects are 
e nc o ura g e d t o ret ur n f or F U assess me nts 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, as are s u bjects w h o wit h dra w fr o m t he st u d y. 
7. 4.
St u d y St o p pi n g R ules
Bi o ge n m a 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.
D osi n g ma y  be ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e xcl usi vel y o n safety a n d t olera bilit y data or f oll o wi n g t he f utilit y a nal ys is, or at t he discreti o n of 
t he S p o ns or; t heref ore t here are n o st u dy -s pecific st o p pi n g r ules defi ne d i n t his pr ot oc ol.  
7. 5.
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 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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
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 foll o wi n g eli gi bilit y  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  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.
2.
A ge d 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 , please refer t o 
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 or m il d A D.
5.
M ust ha ve a p ositi ve a m y l oi d P E T sca 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 f or s u bjects n ot partici pati n g i n t he a m yl oi d P E T 
c o h ort.  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 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 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:

A C D R -Gl o bal Sc ore of 0. 5 .

A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair me nt (base d 
u p o n t he Dela y e d Me m or y In de x ( D MI) sc ore).

A n M M S E sc ore bet wee n 2 4
a n d 3 0 (i ncl usi ve).
7.
A part fr o m a cli nical dia g n osis of earl y 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  a n d Scree ni n g assess me nts.
8.
M ust c o nse nt t o a p oli p o pr otei n E ( 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 j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y  
be a vaila ble b y p h o ne t o p r o vi de i nf or mati o n t o t he I n vesti gat or a n d st u dy s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  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 t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
8. 2.
E xcl usi o n Criteri a
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 al 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 n t (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 yr 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 o-te m p oral 
de me ntia, hea d tra u ma).
2.
Cli nicall y  si g nifica nt ps yc hiatric ill ness (e. g., u nc o ntr olle d maj or de pressi o n, 
sc hiz o p hre nia, 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 ntrally rea d M RI) that s h o ws e vi de nce of a n y 
of t he f oll o wi n g:  

A cute 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) 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 y i 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).

Greater 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) .  

C ortical i nfarct ( defi ne d as > 1. 5 c m i n dia meter) .  

1 lac u nar i nfarct ( defi ne d as 1. 5 c m i n dia m eter) .

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 
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 safet y 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 In 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 
Ass 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 f i brillati o n) wit hi n 1 year pri or t o Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8.
Cli nicall y  si g nifica nt 1 2-lea d E C G a b n or malities, as deter mi ne d by t he I n vesti gat or.
9.
U nc o ntr olle d h y perte nsi o n defi ne d as : avera ge of 3 s y st 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/ 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 dy), or persiste nt S B P/ D B P rea di n gs > 1 8 0/ 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 t he S p o ns or:  

S u bjects wit h ca ncers i n re missi o n m ore t ha 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.  

S u bjec ts wit h pr ostate ca ncer i n sit u.
1 1. Hist or y  of seiz ure wit hi n 1 0 years pri or t o Scree ni n g.
1 2. I n dicatio n of i m paire d li ver f u ncti o n as s h o w n b y a n a b n or mal li ver f u ncti o n pr ofile at 
Scree ni n g (e. g., re peate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥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 urin g Scree ni n g.
1 6. Hist 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 ( HI V).
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  or he patitis B 
vir us ( defi ne d as p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g] or he patitis B c ore 
a nti b o d y [ H Bc A b]).  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 he patitis B s urface a nti b o d y I g G, a n d 
p ositi ve H Bc A b) are eli gi ble t o partici pate i n t he st u d y  ( U S Ce nters f or Disease C o ntr ol 
a n d Pre ve nti o n’s i nter pretati o n of t he he patitis B ser ol o g y  pa nel).
1 8. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns, or hist or y of hy p erse 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 (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n).
1 9. 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, 
w hic h 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Me dic ati o ns
2 0. 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 g niti 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 1. 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 ni n g Visit 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.
2 2. Use of me dicati o ns wit h platelet a nti -a g gre ga nt or a nti -c 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 3. Use of illicit narc otic me dicati o n.
2 4. 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 5. 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 A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 6. 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 wit hi n 1 2 m o nt hs of 
Scree ni n g 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  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- E d uri n g a pre vi o us disease -m o d if yi n g trial s h o ul d be 
e xcl u de d.  
2 8. Partici pati o n i n a pre vi o us st u d y  wit h a d uca n u ma b (s u bject is eli gi ble if he/s he di d n ot 
recei ve acti ve a d uca n u ma b).
St u dy Pr oce d ures
2 9. C o ntrai 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 0. 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 y perse 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 1. A ne gati ve P E T sca n res ult w it h a n y a myl oi d -tar geti n g li ga n d wit hi n 6 m o nt hs pri or t o
Scr ee ni n g.
3 2. 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.  
3 3. F or s u bjects w h o c o nse nt t o l u m bar p u nct ure (L P ), a n y c o ntrai n dicati o ns t o ha vi n g a LP 
(e. g., platelet c o u nt < 1 0 0, 0 0 0/ µ L, l u m bar s pi ne def or mit y).  A n y s y m pt o ms ca use d b y  or 
relate d t o t he o pti o nal L P d uri n g Scree ni n g m ust be res ol ve d pri or t o ra n d o mizati o n .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 u bjects ma y  still partici pate i n t he o verall st u d y e ve n if partici pati on i n t he o pti o nal L P 
p orti o n is c o ntrai n dicate d .  
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 will be per mitte d t o be 
rescree ne d o nce at t he S p o ns or’s discreti o n, exce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R, he patitis B or C, or a b n or mal M RI fi n di n gs .
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 of 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 L o n g-Ter m E xte nsi o n Peri o d
T o be eli gi ble t o p artici 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 7 8:
1.
S u bject m ust ha ve c o m plete d t he p lace b o-co ntr olle d p eri o d of t he st u d y i ncl u di n g t he
Wee k
7 8 Visit .  S u bject m ust ha ve ta ke n at least 1 4 d oses a n d n ot ha ve miss e d m ore t ha n 
4 c o nsec uti ve d oses .  S u bjects w h o d o n ot meet t hese criteria ca n e nter t he L T E peri o d 
o nl y  wit h S p o ns or’s a p pr o val.
2.
M M S E sc ore > 1 5 at t he Wee k 7 8 Visit.
3.
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 pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt ( or asse 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.
4.
Fe male s u bjec ts 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.
5.
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.
6.
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.
7.
Has o ne i nf or ma nt/care part ner w h o, i n t he I n vesti gat or’s j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y  
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  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 , 


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I nc.
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a n d t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .
8. 4.
E xcl usi o n Criter i a f or 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 at Wee k 7 8 t he y ha ve:
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.


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C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
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I nc.
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9.
E N R O L L M E N T , R E GI S T R A TI O N, A N D R A N D O MI Z A TI O N
9. 1.
Scree ni n g a n d E nr oll me nt
S u bjects ( or t heir le gally a ut h orize d re prese ntati ve, w here a p plica ble) 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 
ca n c o m plete t he ne ur oc o g niti ve scales ( C D R, M M S E a n d R B A N S) t o deter mi ne st u d y  
eli gi bilit y u n der a se parate 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 3 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 directl y t o t he f ull c o nse nt pr ocess w hic h 
w o ul d 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 (I C 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 .  
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 i nitiall y  c o nsi dere d f or 
i ncl usi o n i n this 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 y s; 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 relate d t o P E T sca n iss ues a n d s u bject t o S p o ns or a p pr o val.  If a s u bject is 
e xcl u de d fr o m t he st u d y, t he reas o ns f or e xcl usi o n will 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.  T he t otal st u d y  d urati o n f or eac h s u bject partici pati n g o nly 
i n t he place b o-c o ntr olle d peri o d will be a p pr o xi matel y  1 0 2 wee ks (a p pr o xi matel y a n 8-wee k 
scree ni n g p eri o d, 7 6 wee ks of place b o or a d uca n u ma b d osi n g, a n d 1 8 wee ks of F U ). 
9. 2.
R a n d o miz ati o n a n d Re gistr ati o n of S u bjects
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra n d o mize d o nl y after all 
baseli ne assess me nts ha ve bee n c o m plete d a n d t he In 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 .  N o s u bject ma y  be gi n treat me nt pri or t o assi g n me nt 
of a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y  s u bject i de ntificati o n 
n u m bers or ra n d o mizati o n sc he d ule assi g n me nts 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.  Re scree ne d s u bjects will be assi g ne d a ne w n u m ber.  
S u bjects will be ra n d o mize d t o recei ve a duca n u ma b l o w d ose: a d uca n u ma b hi g h d ose : place b o
i n a 1: 1 : 1 rati o.  T he ra n d o mizati o n will be stratifie d b y  site a n d A p o E ε 4 stat us (carrier or 
n o n- carrier), s o t hat a p pr o xi matel y 6 0% t o 7 0 % A p o E ε 4 carriers are e nr olle d .  E nr oll me nt will 
als o be m o nit ore d, via t he IR T, s uc h t hat t he p o p ulati o n of s u bjects wit h mil d A D re prese nts a 
s mall perce nta ge of t he t otal e nr olle d i n t he trial.  S u bjects w h o wit h dra w fr o m t he st u d y m a y  n ot 
be re place d.
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
T his st u d y  c o nsists of a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d peri o d, f oll o we d by a 
d ose - bli n de d L T E peri o d wit h all s u bjects recei vi n g a d uca n u ma b .  
F or t he d o u ble - bli n de d place b o - c o ntr olle d peri o d, all st u d y staff w h o c o n d uct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts .  T he rati n g H C Ps s h o ul d 


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I nc.
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re mai n bli n de d t o treat me nt assi g n me nt as well as s u bject care ma na ge me nt a n d o nl y ha ve access 
t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  As a 
place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are re q uire d t o ma na ge all 
as pects of st u d y treat me nt recei pt, dis pe nsi n g a n d pre parati o n.  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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d  
 or Bi o ge n safety staff.
F or t he L T E peri o d , t he d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d treati n g H C P 
s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nl y ha ve access t o t he i nf or mati o n 
necessar y  t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n t he st u d y
bli n d, it is i m perati ve t hat d ose i nf or mati o n is 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 bli n de d st u d y  tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
 or Bi o ge n safety staff .  


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Bi o ge n M A
I nc.
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1 0.
D I S C O N TI N U A TI O N O F ST U D Y T R E A T M E N T A N D/ O R
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:
o
A RI A- E acc o m pa nie d b y seri o us cli nical s y m pt o ms e xce pt f or “ ot her 
me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 8 .
o
S y m pt o matic A RI A -H ( m icr ohe m orr ha ges) wit h seri o us cli nical s y m pt o ms
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 9 .
o
S y m pt o matic A RI A -H (s u perficial si der osis) wit h or seri o us cli nical 
s ym pt o ms e xce pt f or “ ot her me dicall y i m p orta nt e ve nt” as defi ne d i n 
Ta ble 1 0 .
o
A RI A- H wit h ≥1 0 micr o he m orr ha ges a n d/or > 2 f ocal areas of s u perficial 
si der osis.  
o
A n y  ne w i nci de nt macr o he m orr ha ge .
o
A t hir d rec urre nce of A RI A after rec halle n ge t hat re q uires d ose s us pe nsi o n
See Secti o n 7. 2. 1 f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d ucti o n d ue t o 
A RI A- E or A RI A -H.

T he s u bject bec o mes pre g na nt .  St u d y  treat me nt m ust be disco nti n ue d i m me diatel y  
a n d pre g na nc y m ust be re p orte d 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.

T he s u bject e x perie nces a me dical e mer ge nc y  t hat necessitates per ma ne nt 
dis c 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.  

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 vesti gat or f or me dical reas o ns.

At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce.
T he reas o n f or disc o nti n uati o n of st u d y  treat me nt m ust be rec or de d i n t he s u bject’s case re p ort 
f or m (C R F ).
A s u bject w h o disc o nti n ue s treat me nt is to re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil t he s u bject wit h dra w s c o nse nt.  T he site 


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I nc.
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is t o c o ntact t he S p o ns or as s o o n as p ossi ble after disc o nti n uati o n t o c o nfir m w het her t he 
efficac y assess me nts o utli ne d f or t he E O T Visit i n Secti o n 4. 2 nee d t o be perf or me d.  
1 0. 2.
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:

Deat h .

Wi t h dra wal of c o nse nt .

L ost t o f oll o w - u p.
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 s h o ul d 
c o m plete t he E O T Visit after t he reas o n f or wit h dra wal is i de ntifie d .  F or s uc h s u bject s, t he site 
is t o c o ntact t he S p o ns or as s o o n as p ossi ble after wit h dra wal t o c o nfir m w het her t he efficac y 
assess me nts o utli ne d f or t his visit i n Secti o n 4. 2 nee d t o be perf or me d.  T hese s u bjects are als o t o 
ret ur n t o t he site f or a F U Visit 1 8 wee ks after recei vi n g t heir last d ose of st u d y  treat me nt.  


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I nc.
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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 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 .  
Please see Secti o n 4. 2 ( Sc he d ule of E ve nts) f or t he st u d y treat me nt i nf usi o n sc he d ule d uri n g t he 
p lace b o-co ntr olle d a n d L T E p eri o ds of t he st u d y.
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 treatme nt.
1 1. 1. 1.
A d uc a n u m a b   
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.  
1 1. 1. 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.
1 1. 2.
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule
Refer t o Secti o n 7. 2. 1 ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 3 (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at least 2 1 da ys a part.  If t he d osi n g i nter val ca n n ot be met, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y t he st u d y me dical m o nit or .
1 1. 3.
Prec a uti o ns
N ot a p plica ble .
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.
Pri or a n d 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 
t he F U Visit ( Wee k 9 4 or Wee k 1 9 8) or E O T Visit .
N o pre me dicati o n (e. g., a nti-aller g y dr u gs, a nti p yr 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 with t he st u d y  me dical m o nit or i n a d va nce.


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I nc.
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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 are all o we d 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 .  

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, are all o we d 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 t hat t he y sta y on 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 are all o we d d uri n g t he st u d y.  
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 .
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 nti -a g gre ga nt or a nti-c 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 dicati 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).  L o cal 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 m a y  be per mitte d at t he S p o ns or ’s dis creti 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 
(see all o we d c o nc o mita nt t hera py a b o ve ) a n d a v oi d starti n g a ny 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, as it 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 or of a ny 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 b y  t he I n vesti gat or 
an 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, wit h t he e xce pti o n of me dicati o ns use d t o treat A Es, w hic h w o ul d n ot res ult i n 
a ut o matic wit h dra wal .  T he S p o ns or 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 v isit f or a c ha n ge i n A D me dicati o n, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he 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 t he F U or E O T V isit, u nless 
t he s u bjects is bei n g f oll o we d f or st u dy -relate d t o xicit y.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 ure s 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, a ll re g ulat or y re q uire me nts re gar di n g p ostst u d y access will be met.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 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° 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 ye d f or m ore t ha n 2 h o urs, t he n it s h o ul d be ke pt at 2° 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 ye d f or m ore t ha n 2 4 h o urs, it m ust be 
disca r 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
(or its desi g nee ), 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 pers o n nel 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 od 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 dy treat me nt is t he res p o nsi bilit y of t he I n vesti gat or.  T he st u d y  site m ust 
mai ntai n acc urate rec or ds de m o nstrati n g dates a n d a m o u nt of st u d y  treat me nt recei ve d, t o w h o m 
dis pe nse d (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 ment acci de ntall y or 
deli beratel y destr o ye d.  
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  treat me nt 
acc o u nta bilit y.  B y  t he e n d of t he st u d y rec o nciliati o n m ust be ma de bet wee n t he a m o u nt of 
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 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 
T he place b o ( 0. 9 % sterile s o di u m c hl ori de f or i njecti o n) will be pr o vi de d b y  t he site i n t he f or m 
of 1 0 0 ml sali ne I V ba gs.  
1 2. 3.
A d diti o n al Pr ot oc ol -Desi g n ate d Pr o d ucts
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.
T o c o nfir m a m yl oi d pat h ol o g y  at Scree ni n g, P E T sca ns 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 ur ace q™ (
1 8F- fl or beta be n).  F or t h ose 
s u bjects partici pati n g i n t he a m yl oi d P E T s u bst u d y , Scree ni n g a n d F U sca ns m ust be perf or me d 
usi n g A m y vi d.  F or s u bjects partici pati n g i n t he P E T s u bst u d y  i n Ja pa n, Viza m yl (1 8F-
fl ute met o m ol) will be use d.  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 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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
P H A R M A C O D Y N A MI C A S S E S S M E N T S
Refer t o Secti o n 4. 2 f or t he ti mi n g of assess me nts.
1 3. 1.
Cli nic al Effic ac y Assess me nts
T he f oll o wi n g cli nic al assess me nts will be perf or me d t o e val uate t he efficac y  of a d uca n u ma b: 

C D R

M M S E

A D A S -C o g 1 3

A D C S -A D L -M CI

N PI - 1 0
It is rec o m me n de d t hat cli nical assess me nts be perf or me d at t he sa me ti me of da y f or s u bjects 
d uri n g t heir st u d y visits .  
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s daily acti vities a n d c o g niti ve ca pa bilities .  
T he rec o m me n de d or der of a d mi nistrati o n of t he cli nical assess me nts is descri be d i n t he St u d y  
Refe re nce G ui de.  
1 3. 2.
P h ar m ac o k i netic Assess me nts
Ser u m c o nce ntrati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y .  
1 3. 3.
P h ar m ac o d y n a mic Assess me nts
T he f oll o wi n g tests will be perf or me d t o assess t he p har mac o d y na mic pr o perties of a d uca n u ma b:

Serial meas ure me nt of a m y l oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y am y l oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects partici pati n g i n 
t he a m yl oi d P E T c o h ort ).  
O nl y  sites wit h ca pa bilities of perf or mi n g 1 8F- fl or beta pir P E T will be all o we d t o 
perf or m t his assess me nt .  I nvesti gat or partici pati o n i n t his part of t he st u d y is o pti o nal 
a n d c o nti n ge nt u p o n a p pr o val b y  his/ her et hics c o m mittee ( E C) or i nstit uti o nal re vie w 
b oar d (I R B) .  If t he I n vesti gat or is n ot partici pati n g or t he test is n ot a p pr o ve d b y 
his/ her E C/I R B, t he rele va nt secti o n of t he I C F will n ot be a p plica ble t o t hat site .
S u bject partici pati o n i n t his part of t he st u d y  is o pti o nal at partici pati n g sites.  
I nf or me d c o nse nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a se parate pr oce d ural ma n ual f or P E T.  A p pr o xi matel y 
4 0 0 s u bjects are e x pecte d t o partici pate i n t he a m yl oi d P E T s u bst u d y.  






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
1 4.
S A F E T Y A S S E S S M E N T S
See Secti o n 4. 2 f or t he ti mi n g of 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 m o nit ori n g.

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.

Ne ur ol o gical e xa mi nati o n .

Vital si g ns (b o d y  te m perat ure, heart rate, S B P, D B P, a n d res pirat or y rate).

1 2- lea d E C G.

Brai n M RI.

C o nc o mita nt me dicati o n, t hera p y a n d pr oce d ure m o nit ori n g.   

M O C A (f or A RI A m o nit ori n g a n d ma na ge me nt).  

C ol u m bia S uici de Se verit y  Rati n g Scale.  
1 4. 2.
L a b or at or y S afet y Assess me nts
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 .

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, A L T, A S T, lactate de h y dr o ge nase, 
ga m ma -gl uta m y l-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 vity, 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 mal).

Ser u m a n d uri ne pre g na nc y  test f or 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 In vest i gat or’s discreti o n after 
c o nsi derati o n of ris k fact ors ), H b A1c, a n d alc o h ol/ dr u g scree n at Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 4. 3.
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a nti -a d uca n u ma b 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).  C o nfir me d a nti dr u g a nti b o d y-p ositi ve sa m ples will be teste d f or t he 
prese nce of a nti -a d uca n u ma b ne utralizi n g a nti b o dies usi n g a vali date d assa y .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 5.
S A F E T Y D E FI NI TI O N S, R E C O R D I 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 m ust be gi ve n 
t he na mes a n d tele p h o ne n u m bers of st u d y 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 necessaril y  ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal 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 uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct .
Deter mi nati o n of w het her a n a b n or mal la b ora t or y val ue 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 .  Alt h o u g h a b n or mal la b orat or y  val ues are ty picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or a n S A E .

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y.

A la b orat or y  a b n or malit y t hat t he In vesti gat or c o nsi ders t o be cli nicall y si g nifica nt .
Pre -treat me nt n o nseri o us A Es t hat occ ur wit hi n 4 8 h o urs after recei pt of a li ga n d will be 
ca pt ure d b y t he sites o n t he A E f or m.  
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:

R es ults i n deat h .

In 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 o s pitalizati o n.

R es ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y.

R es ults i n a c o n ge nital a n o mal y / birt h defect.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A n S A E ma y  als o be a n y ot her me dically i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he 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 oce d ure or r o uti nely 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 pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.
o
If a 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 u nless 
o ne of t he re q uire me nts i n S ecti 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 hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 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 .






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e mail a c o m plete d S A E f or m.  Refer t o t he 
St u d y  Refere nce G ui de f or c o u ntr y-s pecific 
 fa x n u m bers or e mail 
1 5. 3. 4. 1.
De at h s
Deat h is a n o utc o me of a n e ve nt .  T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F .  All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt .  T he I n vesti gat or s h o ul d ma ke e ver y  eff ort t o o btai n a n d se n d 
deat h certificates a n d a ut o ps y re p orts t o 
.  T he ter m d eat h s h o ul d be 
re p orte d as a n S A E o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d by t he I n vesti gat or or Bi o ge n t o be relate d t o t he st u d y treat me nt a d mi nistere d.
A p pr o priate pers o n nel i n Bi o ge n Safet y  a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y  re p orti n g.  Bi o ge n or desi g nee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y  a ge ncies acc or di n g t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n.
1 5. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 5. 4. 1.
Pre g n a nc y
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y a n d 
f or 2 4 wee ks after t heir l ast d ose of st u d y tre at me nt.  If a fe male 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 di ately.
T he I n vesti gat or m ust re p o rt a pre g na nc y  occ urri n g i n a fe male s u bject b y  fa xi n g t he a p pr o priate 
f or m t o 
wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he 
pre g na nc y  at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u d y refere nce ma n ual.  T he 
I n vesti gat or or st u dy site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
 
  
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 gi ve n 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 descri be d i n 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 
 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
 e ve n if t he o ver d ose d oes 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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.
8 5
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 
 
.  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, st u d y 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
2 4- h o ur e mer ge nc y  me dical s u p p ort n u m ber.  Refer t o t he St u d y  
Refere nce G ui de’s Official 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 vise 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, n 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.
1 5. 5.
C o ntr ace pti o n Re q uire me nts
F or t he p ur p oses of t his st u d y, w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h y si ol o gically ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns:

P ost me n o pa usal

1 2 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 or 6 wee ks aft er s ur gical bilateral o o p h orect o m y  wit h or wit h o ut 
h y sterect o my.

P ost h y sterect o m y.

Fe male s ur gical steril izati o n (e. g., bilateral t u bal li gati o n).
F or t he p ur p oses of t his st u d y , hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g:

F or fe males of c hil d beari n g p ote ntial:

Esta blis he d use of oral, i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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8 6

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne s y ste m

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 occl 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.

Male se x ual part ners u n der we nt 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:

Vasect o m y wit h ne gati ve se me n a nal ys is at F U .

Use of c o n d o ms wit h s per mici de.

Fe male se x ual part ner s w h o u n der we nt s ur gical sterilizati o n (e. g., bilateral t u bal 
ligati o n), are p ost me n o pa usal, are p ost -h y sterect o m y, or are usi n g hi g hl y effecti ve 
c o ntrace ptio n as liste d a b o ve f or fe male s u bjects.
F or males a n d fe males 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 life style of 
t he s u bject, ca n be c o nsi dere d a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he I n vesti gat or w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n 
of t he cli nical trial.  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot he r mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d acce pta ble met h o ds of 
c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 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 t he f oll o wi n g:

M o ni t or a n d rec or d all A Es, i ncl u di n g S A Es, re gar dless of t he se verit y or relati o ns hi p 
t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g n a ncies a n d F U o n t he o utc o me of t he pre g na nc y  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 S A B R ( or desi g nee) wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

P urs ue S A E F U i nf or mati o n acti vel y a n d persiste ntl y .  F U inf or mati o n m ust be 
re p orte d t o Bi o ge n S A B R ( or desi g nee) wit hi n 2 4 h o urs of t he st u d y  site staff 
bec o mi n g a ware of ne w i nf or mati o n.

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E F U 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.

Re p ort S A Es t o l ocal E C /IR Bs , 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 st u d y site acti vati o n a n d s u bject e nr oll me nt, t he C li nical M o nit or 
is 
res p o nsi ble f or re vie wi n g wit h st u d y 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 ( or desi g nee) is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C /IR B s, 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 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
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 .
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 [ S D], 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.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al ysis P o p ul ati o n
T he i nte nt -t o-treat (I T T) 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 st u d y treat me nt (a d uca n u ma b or place b o), will be use d f or t he efficac y 
a nal ys es.  F or eac h e n d p oi nt, a d diti o nal c o n diti o ns ma y  a p pl y t o t he defi niti o n of t he p o p ulati o n 
f or t he a nal ysis.  S u bjects will be a nal y ze d i n t he gr o u ps t o w hic h t he y were ra n d o mize d.  
1 6. 2. 2.
Met h o ds of A n al ysis
1 6. 2. 2. 1.
Ge ner al C o nsi der ati o ns
S u m mar y  statistics will be prese nte d.  F or c o nti n u o us e n d p oi nts, s u m mar y  statistics will 
ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, sta n dar d de viati o n, me dia n, a n d ra n ge .  
F or cate g orical e n d p oi nts, t his will ge nerall y  i ncl u de: n u m ber of s u bjects ra n d o mize d or d ose d, 
n u m ber wit h data, a n d t he perce nt of t h ose wit h data i n ea c h cate g or y.  Statistical testi n g f or 
efficac y e n d p oi nts will be ma de bet wee n eac h a d uca n u ma b re gi me n a n d place b o.  All statistical 
tests will be 2-si de d.
1 6. 2. 2. 2.
D ose Re gi me ns t o be E v al u ate d
T he f oll o wi n g d ose re gi me n s of a d uca n u ma b as c o m pare d wit h place b o will be e val uate d :

A d uca n u ma b hi g h -d ose re gi me n ( 6 m g/ k g i n A p o E ε 4 carriers a n d 1 0 m g / k g i n 
A p o E ε 4 n o n carriers).

A d uca n u ma b 6 m g / k g d ose re gi me n ( 6 m g / k g i n A p o E ε 4 carriers a n d
A p o E ε 4 n o n-carriers) .

A d uca n u ma b l o w-d ose re gi me n ( 3 m g/ k g i n A p o E ε 4 carriers a n d 6 m g / k g i n 
A p o E ε 4 n o n- carriers) .  
I n t he e ve nt t hat t he pr o p ose d ma xi m u m d ose ( 1 0 m g/ k g i n A p o E ε 4 n o n-carriers or 6 m g/ k g i n 
A p o E ε 4 carriers) is ter mi nate d after t he start of t he st u d y  ( Secti o n 5. 3. 2 ) t he defi niti o n of 
a d uca n u ma b hi g h d ose re gi me n a n d a d uca n u ma b l o w d ose re gi me n will be m o difie d as s h o w n i n 
Ta ble 1 2 .  T he d osi n g m o dificati o n will be e ntirel y base d o n i nteri m a nal ys is of o utc o mes t hat
are i n de pe n de nt of, a n d u ni nf or mati ve a b o ut, t he treat me nt-relate d efficac y effect.  C o ntr ol of 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
T y pe I err or rate is t h us mai ntai ne d wit h o ut a statistical a dj ust me nt f or s uc h a da ptati o ns[ C h o w 
a n d C ha n g 2 0 1 1] .
T a ble 1 2:
D ose Gr o u p P o oli n g S tr ate g y i n t he E ve nt of Tre at me nt Gr o u p Ter mi n ati o n
Tre at me nt gr o u p(s) Ter mi n ate d
Defi niti o ns of Re vise d P o ole d Tre at me nt 
Gr o u ps f or C o m p aris o n
A p o E ε 4 carrier hi g h-d ose g r o u p ( 6 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 1 0 m g/ k g
A p o E ε 4 n o n -carrier h i g h- dose g r o u p ( 1 0 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 6 m g/ k g a n d 
n o n -carrier 6 m g/ k g
A p o E ε 4 carrier  h i gh -d ose g r o u p ( 6 m g/ k g) 
A N D
A p o E ε 4 n o n -carrier h i g h-d ose g r o u p ( 1 0 m g/ k g) 
A p o E ε 4 carrier 3 m g/ k g a n d n o n -carrier 
6 m g/ k g
1 6. 2. 2. 3.
C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I  err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y  e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws: a d uca n u ma b hi g h -d ose re gi me n vers us place b o, a d uca n u ma b 6 m g/ k g re gi me n vers us 
place b o, a n d a d uca n u ma b l o w -d ose re gi me n vers us place b o .  I n t he e ve nt of a d o si n g 
m o dificati o n (see Ta ble 1 2 ), t he first c o m paris o n is t he a d uca n u ma b hi g h -d ose re gi me n vers us 
place b o a n d t he sec o n d c o m paris o n is t he a d uca n u ma b l o w-d ose re gi me n vers us place b o .  If t he 
first c o m paris o n is statisticall y si g nifica nt ( p ≤0. 0 5) , t he n t he sec o n d c o m paris o n will als o be 
ma de at t he 0. 0 5 α le vel.  If t he sec o n d c o m paris o n is statisticall y si gnifica nt ( p ≤0. 0 5), t he n t he 
t hir d c o m paris o n will als o be ma de at t he 0. 0 5 α le vel.  H o we ver, all c o m paris o ns after t he i nitial 
c o m paris o n with p > 0. 0 5 will n ot be c o nsi dere d statisticall y  si g nifica nt.
Sec o n dar y  e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  I n or der t o 
c o ntr ol f or a T ype I err or f or t he sec o n dar y  e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be use d a n d will i ncl u de b ot h t he or der of t he sec o n dar y  e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y  e n d p oi nts, a se q ue ntial (cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T y pe I err or rate d ue t o m ulti ple 
treat me nt c o m paris o ns.  If statistical si g nifica nce is n ot ac hie ve d f or o ne, t w o or all t hree 
c o m paris o ns, all e n d p oi nt(s) of a l o wer ra n k will n ot be c o nsi dere d statisticall y  si g nifica nt f or 1, 
2, or all 3 c o m paris o ns, res pecti v el y.  
D ue t o a c urre nt lac k of scie ntific c o nse ns us i n t he A D fiel d o n w hic h bi o mar ker(s) mi g ht be 
m ost a p pr o priate, t he selecti o n of t he bi o mar kers a n d met h o d ol o g y  f or c o ntr ol of T ype I err or 
will be pre -s pecifie d i n t he statistical a nalys is pla n ( S A P). Ot her wise, t here will be n o m ulti ple 
c o m paris o n a dj ust me nts f or t he tertiar y  e n d p oi nts.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6. 2. 2. 4.
A n al ysis of t he Pri m ar y E n d p oi nt
T he p o p ulati o n f or t he pri mar y  e n d p oi nt a nalys is will be s u bjects i n t he I T T p o p ulati o n wit h a 
baseli ne a n d at least o ne p ost- baseli ne C D R -S B sc ore .  A mi xe d m o del re peate d meas ures 
( M M R M) m o del will be use d as t he pri mar y a nalysis t o a nal y ze c ha n ge fr o m baseli ne C D R -S B 
usi n g fi xe d effects of treat me nt, ti me, treat me nt- b y -ti me i nteracti o n, baseli ne C D R -S B, baseli ne 
C D R -S B b y  ti me, baseli ne M M S E , a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5.
A n al ysis of t he Sec o n d ar y E n d p oi nts
1 6. 2. 2. 5. 1. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n M M S E 
T he p o p ulati o n f or t he a nal ysis will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least 
o ne p ost -baseli ne M M S E val ue .  A M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m baseli ne M M S E usi n g fi xe d effects of treat me nt, ti me, treat me nt -b y -ti me 
i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y  ti me i nteracti o n a n d baseli ne A p o E ε 4
stat us 
1 6. 2. 2. 5. 2. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D A S -C o g 1 3
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D A S -C o g 1 3 sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m baseli ne A D A S -C o g 1 3 usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D A S-C o g 1 3, baseli ne A D A S -C o g 1 3 b y  ti me 
i nteracti o n; baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5. 3. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D C S -A D L -M CI
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D C S -A D L -M CI sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nal ysis 
t o a nal yze c ha n ge fr o m baseli ne A D C S -A D L -M CI
usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D C S -A D L -M CI,
baseli ne A D C S -A D L -M CI b y  ti me 
i nteracti o n; baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 6.
Terti ar y E n d p oi nts A n al ysis
1 6. 2. 2. 6. 1. Pl ace b o - Co ntr olle d P eri o d
W here a p pr o priate, a M M R M m o del will be use d as t he pri mar y  a nalys is t o a nal yze c ha n ge fr o m 
baseli ne usi n g fi xe d effects of treat me nt, ti me, treat me nt b y  ti me i nteracti o n, baseli ne val ue, 
baseli ne val ue b y ti me i nteracti o n, baseli ne M M S E a n d baseli ne A p o E ε 4 stat us.
Ot her wise, a n a nal ys is of c o varia nce or its n o n-para metric e q ui vale nt ma y  be use d t o a nalyz e 
t hese e x pl orat or y e n d p oi nts.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
1 6. 2. 2. 6. 2. L o n g -Ter m E xte nsi o n Peri o d
T he a d diti o nal e n d p oi nts f or t he L T E peri o d are c ha n ge fr o m baseli ne o ver t he p lace b o-
c o ntr olle d a n d L T E peri o ds of t he st u d y .  A nal ys es will be prese nte d b y treat me nt gr o u p i n t he 
place b o -c o ntr olle d peri o d usi n g t he place b o -c o ntr olle d peri o d baseli ne.  Details of t he a nal ys es 
will be pre -s pecifie d i n t he S A P .  
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 p o p ulati o n f or P K a nal y sis is defi ne d as all s u bjects w h o were ra n d o mize d, were d ose d with 
st u d y treat me nt, 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 p o p ulati o n P K c haracteristics of a d uca n u ma b will be deter mi ne d b y n o nli near mi xe d effects 
a p pr oac h .  C o variates t hat mi g ht i nfl ue nce t he dis p ositi o n of a d uca n u ma b (e. g., b o d y wei g ht, 
a ge, se x, i m m u n o ge nicit y, A p o E ε 4 stat us) will be e val uate d a n d t he p ote ntial e x p os ure-res p o nse 
relati o ns hi ps will be e x pl ore d.
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 recei ve d at least 1 d ose of st u d y  treat me nt 
(i ncl u di n g place b o a n d 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 si g ns will be 
e val uate d f or safet y.
1 6. 4. 2. 1.
A d vers e 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 dy 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 ps, 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 place b o-c ontr olle d peri o d a n d o ver t he 2 4- m o nt h 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 ystem or ga n class as 
well as f or preferre d ter ms wit hi n eac h s ys te 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 ( Me d D R A).  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
1 6. 4. 2. 2.
Cli nic al L a b or at or y Res ults
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 nalys is 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 bas eli 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 cate g 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 h a 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 .  
1 6. 4. 2. 3.
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n cli nicall y rele va nt a b n or malities.
1 6. 4. 2. 4.
E C G
T he n u m ber a n d perce nta ge of s u bjects wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or 
a b n or mal A E) will be s u m marize d b y  treat me nt gr o u p.  
1 6. 4. 2. 5.
C ol u m bi a S uici de Se verit y R ati n g Sc ale
T he C ol u m bia S uici de Se verit y Rati n g Scale 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 ulati 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 nicity.  
1 6. 5. 2.
Met h o ds of A n al ysis
A nti- a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.
1 6. 6.
I nteri m A n al yses
1 6. 6. 1.
I nteri m F utilit y A n al ysis
A n i nteri m a nal ys is f or f utilit y of t he pri mar y e n d p oi nt will occ ur after a p pr o xi matel y  5 0 % of t he 
s u bjects ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m f utilit y a nalys is.  T his i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he I D M C ma y  rec o m me n d ter mi nati n g 
t he st u d y f or f utilit y if it is e vi de nt t hat t he efficac y of a d uca n u ma b is u nli kel y t o be ac hie ve d.  
T he f utilit y  criteria will be disc usse d i n detail i n t he S A P.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 6. 6. 2. 
I nteri m S u peri orit y A n al ysis
A n i nteri m a nal ys is f or s u peri orit y m a y  be perf or me d after a p pr o xi matel y  5 0 % of t he su bjects 
ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d) .  T he La n -De M ets met h o d wit h O’ Brie n -
Fle mi n g st o p pi n g b o u n dar y  f or efficac y will be use d.  I n or der t o mai ntai n t he treat me nt bli n d i n 
t he e ve nt of t his i nteri m a nalys is, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be 
i n v ol ve d i n t he c o n d uct of t he st u d y after u n bli n di n g will perf or m t he i nteri m s u peri orit y
a nal ys is.  T he i n de pe n de nt gr o u p will prese nt t he u n bli n de d i nteri m a nal y sis t o t he ID M C .  T he 
ai m of t his i nteri m a nal ysis is t o all o w t he p ossi bilit y t o de m o nstrate treat me nt effect early.  T he 
a nal ys is will be disc usse d i n detail i n t he S A P.
1 6. 7.
S a m ple Size C o nsi der ati o ns
T he st u d y ’s sa m ple size is base d, i n part, o n res ults fr o m a pr ot oc ol-s pecifie d i nteri m a nal ys is 
fr o m St u d y 2 2 1 A D 1 0 3 w hic h i ncl u de d 1 year data fr o m 1, 3 a n d 1 0 m g/ k g treat me nt gr o u ps.
A sa m ple size of 4 5 0 s u bjects per treat me nt gr o u p will ha ve a p pr o xi matel y  9 0 % p o wer t o detect 
a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne C D R- S B at Wee k 7 8 bet wee n t he 
2 treat me nt gr o u ps.  T his p o wer calc ulati o n is base d o n a 2 -si de d t-test ass u mi n g e q ual varia nce 
wit h a fi nal si g nifica nce le vel of 0. 0 5, a S D of 1. 9 2 a n d a dr o p- o ut rate of 3 0 % .  T he S D esti mate 
of 1. 9 2 f or Wee k 7 8 reflects a 3 9 % i ncrease o ver t he S D fr o m t he pr ot oc ol-s pecifie d i nteri m 
a nal ys is of 1-ye ar data.
T he ass u me d tr ue mea n differe nce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d ucti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o me a n c ha n ge is esti mate d t o be 2.
T he sa m ple size ma y  be reassesse d i n a bli n de d ma n ner a p pr o xi matel y 3 m o nt hs bef ore 
e nr oll me nt is c o m plete if at least 1 5 % of t he data are a vaila ble o n t he pri mar y  e n d p oi nt.  At t his
i nteri m ti me-p oi nt, t he S D f or t he pri mar y e n d p oi nt will be esti mate d base d o n t he bli n de d data .  
T he sa m ple size ma y  be i ncrease d if t he S D is esti mate d t o be m ore t ha n a p pr o xi matel y 2. 0 7.  I n 
a d diti o n, t he sa m ple size c o ul d be i ncrease d usi n g e xter nal cli nical trial res ults t hat bec o me 
a vaila ble after t he start of t he st u d y .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
1 7.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n ,  
 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 nfere nce o n Har m o nisati o n (IC 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 ulati o 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 perience, i n acc or da nce wit h 
a p plica ble I C H a n d G C P g ui deli nes .  T he I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y -relate d d uties ha ve bee n dele gate d.
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 /I nstit uti o n al Re vie w B o ar d
T he I n vesti gat or m ust o btai n E C/I R B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y  
d oc u me nts pri or t o starti n g t he st u d y.  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 E C.  A c o p y  of t he ap 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 gree me nt of t he rele va nt E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) 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 C/I R B a p pr o val, w hic h s pecificall y  i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y .  Pr ot oc ol a me n d me nts 
will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he E C/I R B at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he E C/IR B a n d Bi o ge n .
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 gally a ut h orize d re prese ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns .  S u bjects ca n c o m plete t he ne ur oc o g niti ve scales 
( C D R, M M S E a n d R B A N S) as a n i nitial scree ni n g u n der a se parate c o nse nt process .  If t he 
s u bject meets i ncl usi o n criteria f or t hese 3 scales, t he f ull c o nse nt pr ocess m ust be c o m plete d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 a n d will be use d d uri n g 
a nal ys is 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 , care gi ver a n d/ or le gall y 
a ut h orize d re prese ntati ve.  T he si g ne d a n d date d I C F will be retai ne d wit h t he st u d y  rec or ds.  
L ocal re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal ( wet 
si g nat ure) a n d c o pies of t he si g ne d a n d date d I CFs.
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 b y l ocal la w (e. g., Pr otecte d Healt h I nf or mati o n
aut h orizati o n i n N ort h A merica).
T he s u bject will n ot be i de ntifie d b y  na me i n t he C R F or i n a n y st u d y re p orts a nd t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n , its part ner(s) a n d desi g nee(s), E C/I R Bs , 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.
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. T hese data ma y  be use d i n t he 
a nal ys is of t he safet y, efficac y, a n d/ or p har mac o ki netic pr ofile of t he st u d y  treat me nt. It is 
u n k n o w n if t he p ote nc y  or effects of t he st u d y treat me nt are i nfl ue nce d b y race or et h nicit y.  
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 vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
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 pat e 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 u lati o ns.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 bjects 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 Ass ur a nce
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 uth orities ma y  wis h t o perf or m o nsite a u dits.  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 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.
T he Cli nical M o nit or(s) will visit t he I n vesti gat or(s) 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.
D uri n g t hese visits, C R Fs a n d s u p p orti n g 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 .  
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 de li nes t o 
e ns ure pr ot oc ol a d here nce, q ualit y  of data, 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.
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 ndi 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 ntract(s) 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.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
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 raters 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.
1 9. 2.
St u d y C o m mittees
1 9. 2. 1.
A d vis or y C o m mittee
A n a d vis or y  c o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u dy 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y  c o m mittee will meet 
peri o dicall y t o m o nit or s u bject accr ual a n d o versee st u d y  c o n d uct , i ncl u di n g a d visi n g o n st u dy 
desi g n a n d e xec uti o n .  T he a d vis or y  c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g t he st u d y .  
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x perts i n Alz hei mer’s disease .  
Bi o ge n will des i gnate o ne of t he partici pati n g e xter nal e x perts t o be t he c hair pers o n of t he 
a d vis or y c o m mittee.
1 9. 2. 2.
I n de pe n de nt D at a M o nit ori n g C o m mittee 
T he ID M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y  data.  Me m bers of t he ID M C 
will n ot be all o we d t o par tici pate as i n vesti gat ors i n t his st u d y.  T he ID 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 .  T he ID M C, base d o n 
t he nat ure, fre q ue nc y, a n d/ or se verity of a n A E(s) 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.  A n I D 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 I D M C .  
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 E C/I R B a n d re g ulat or y a ut h orities if re q uire d 
b y  l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B bef ore i m ple me ntati o n of 
s uc h m o dificati o ns t o t he c on d uct of t he st u d y.  If re q uire d by l ocal la w, s uc h m o dificati o ns m ust 
als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o i m ple me ntati o n .
H o we ver, Bi o ge n m a 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 bje ct.  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 m a y  re q uire si milar m o dificati o ns (see 
Secti o ns 1 7. 2 a n d 1 7. 3 ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
1 9. 4.
Et hics C o m mittee /I nstit uti o n al Re view B o ar d 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 aut h orities a n d E C/I R Bs 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 nt i 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 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 ves ti 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 o n 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 off site facilit y or tra nsfer of o w ners hi p if t he In 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 St u d y  In 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 d e b y se veral fact ors i ncl u di n g b ut n ot li mite d t o t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or 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 ge n .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
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 mer'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.
C h o w S, C ha n g M .  A da pti ve Desi g n Met h o ds i n Cli nical Trials, Sec o n d E diti o n.  Sec o n d 
E diti o n e d .  B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1.
D o o d y  R S, T h o mas R G, Farl o w M, et al.  P hase 3 trials of s ola nez u ma b f or mil d -t o-m o derate 
Alz hei mer's disease .  N E n gl J Me d .  2 0 1 4; 3 7 0( 4): 3 1 1 -2 1; c orres p o n de nce N E n gl J Me d .  
2 0 1 4; 3 7 0( 1 5): 1 4 5 9 -6 0.
D u b ois B, Fel d ma n H H, Jac o va C, et al .  Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n.  La ncet Ne ur ol .  2 0 1 0; 9( 1 1): 1 1 1 8 -2 7.
D u b ois B, Fel d ma n H H, Jac o va C, et al .  A d va nci n g r esearc h dia g n ostic criteria f or Alz hei mer's 
disease: t he I W G -2 criteria .  La ncet Ne ur ol .  2 0 1 4; 1 3( 6): 6 1 4 - 2 9.
Fa ga n T .  Cre nez u ma b Disa p p oi nts i n P hase 2, Researc hers Re mai n H o pef ul .  C o nfere nce 
C o vera ge Series: Alz hei mer's Ass ociati o n I nter nati o nal C o nfere nce ( A AI C) 2 0 1 4 [I nter net] .  
Alzf or u m We b site .  2 0 1 4 J ul 2 2 [cite d 2 0 1 4 Oct 0 4] .  A vaila ble fr o m: 
htt p:// w w w.alzf or u m. or g/ ne ws/c o nfe re nce-c o vera ge/cre nez u ma b -disa p p oi nts -p hase - 2-
researc hers-re mai n-h o pef ul .
Har d y J , Sel k oe DJ.  T he a m y l 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 n ietz 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 ys i 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.
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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
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 
n et 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 .
Le n der ki n g W R, Stee nr o d A, R ü dell K, et al .  O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI  
a n d Pr o dr o mal Alz hei mer’s Disease: C o nte nt Vali dit y  of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y Sy m pt o ms of C o g niti ve Decli ne .  A d va nces i n Alz hei mer’s 
Disease .  2 0 1 4; 3: 1 -1 0.  E p u b Marc h 2 0 1 4.
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 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 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.
M orris J C, Ble n n o w K, Fr oelic h L, et al .  Har m o nize d dia g n ostic criteria f or Alz hei mer's 
disease: rec o m me n dati o ns .  J Inter n Me d .  2 0 1 4; 2 7 5( 3): 2 0 4 - 1 3.
Ostr o witz ki S, De pt ula D, T h urfjell L, et al .  Mec ha nis m of a m y l oi d re m o val i n patie nts wit h
Alz hei mer disease treate d wit h ga nte ner u ma b .  Arc h Ne ur ol .  2 0 1 2; 6 9( 2): 1 9 8 - 2 0 7.  E p u b 2 0 1 1 
Oct 1 0.
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 osite d f or ms of a m yl 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.
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 ML,  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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
Wa hl u n d L O, Bar k h of F, Faze kas F, et 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.
Weller R O, S u bas h M, Prest o n S D, et al .  Peri vasc ular drai na ge of a myl oi d -beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a myl oi d a n gi o pat h y  a n d Alz hei mer's disease.  Brai n Pat h ol .  
2 0 0 8; 1 8( 2): 2 5 3 - 6 6.
Wilc oc k D M, C olt o n C A .  I mm 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 s tr 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/ 0 2/ 2 7.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 3
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 3 M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b
(BII B 0 3 7 ) i n S u bjects wit h Earl y Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T A B L E O F C O N T E N T S
1.
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 0
2.
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 1
3.
S Y N O P SI S ................................................................................................................. 1 4
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 7
4. 1.
St u d y  Sc he matic ......................................................................................................... 1 7
4. 2.
Sc he d ule of E ve nts ..................................................................................................... 1 8
4. 3.
A d diti o nal I nf or mati o n ...............................................................................................3 5
4. 3. 1.
Site Pers o n nel ............................................................................................................. 3 5
5.
I NT R O D U C TI O N ...................................................................................................... 3 7
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 3 8
5. 1. 1.
N o ncli nical E x perie n ce ...............................................................................................3 8
5. 1. 2.
Cli nical E x perie nce..................................................................................................... 3 9
5. 2.
St u d y  Rati o nale........................................................................................................... 4 0
5. 3.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 4 0
5. 3. 1.
D osi n g Sc he me ........................................................................................................... 4 1
5. 3. 1. 1.
Place b o -C o ntr olle d Peri o d .......................................................................................... 4 1
5. 3. 2.
D osi n g Sc he me M o dificati o n ..................................................................................... 4 2
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 4 3
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 ..............................................................4 4
6. 1.
Pri mar y  O bjecti ve a n d E n d p oi nt ................................................................................ 4 4
6. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts ......................................................................... 4 4
6. 3.
Tertiar y  O bjecti ves a n d E n d p oi nts ............................................................................. 4 4
6. 3. 1.
Tertiar y  O bjecti ves ..................................................................................................... 4 4
6. 3. 2.
Tertiar y  E n d p oi nts......................................................................................................4 5
6. 4.
L o n g -Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts .......................................................4 7
6. 4. 1.
O bjecti ves ...................................................................................................................4 7
6. 4. 2.
E n d p oi nts ....................................................................................................................4 7
7.
S T U D Y D E SI G N ....................................................................................................... 4 8
7. 1.
St u d y  O ver vie w..........................................................................................................4 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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. 2.
St u d y  S pecifics ........................................................................................................... 4 9
7. 2. 1.
D ose S us pe nsi o n, M o dificati o n, or Ter mi nati o n f or A RI A E ve nts ............................ 4 9
7. 2. 1. 1.
Dis p ositi o n of A RI A -E Cases ..................................................................................... 5 0
7. 2. 1. 2.
A RI A -H ( Micr o he m orr ha ge) ...................................................................................... 5 1
7. 2. 1. 3.
A RI A - H ( S u perficial Si der osis) ................................................................................. 5 4
7. 2. 1. 4.
A RI A - H ( Macr o he m orr ha ge)..................................................................................... 5 6
7. 2. 1. 5.
Dis p ositi o n of C oi nci de nt A RI A -H a n d A RI A -E Cases ............................................ 5 6
7. 2. 1. 6.
Res u m pti o n of St u d y  Treat me nt After S us pe nsi o n d ue t o A RI A............................... 5 6
7. 2. 1. 7.
Ma na ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI )............................................ 5 7
7. 2. 2.
I nf usi o n I nterr u pti o n................................................................................................... 5 8
7. 3.
O verall St u d y  D urati o n a n d F oll o w-U p ..................................................................... 5 8
7. 3. 1.
Scree ni n g .................................................................................................................... 5 9
7. 3. 2.
Treat me nt .................................................................................................................... 6 0
7. 3. 3.
F oll o w -U p ................................................................................................................... 6 0
7. 4.
St u d y  St o p pi n g R ules ................................................................................................. 6 1
7. 5.
E n d of St u d y ............................................................................................................... 6 1
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 6 2
8. 1.
I ncl usi o n Criteria........................................................................................................ 6 2
8. 2.
E xcl usi o n Criteria ....................................................................................................... 6 3
8. 3.
I ncl usi o n Criteria f or L o n g-Ter m E xte nsi o n Peri o d ................................................... 6 6
8. 4.
E xcl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d .................................................. 6 7
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I ON ............................ 6 8
9. 1.
Scree ni n g a n d E nr oll me nt ........................................................................................... 6 8
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................6 8
9. 3.
Bli n di n g Pr oce d ures ....................................................................................................6 8
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/ O R 
WI 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 ........................................... 7 0
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 7 0
1 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 7 1
1 1.
S T U D Y T R E A T M E N T U S E ..................................................................................... 7 2
1 1. 1.
Re gi me n ......................................................................................................................7 2
1 1. 1. 1.
A d uca n u ma b ...............................................................................................................7 2


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1. 1. 2.
Place b o ........................................................................................................................ 7 2
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 7 2
1 1. 3.
Preca uti o ns .................................................................................................................. 7 2
1 1. 4.
C o m plia nce ................................................................................................................. 7 2
1 1. 5.
Pri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 7 2
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 7 2
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 7 3
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T her a p y .............................................................................. 7 3
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 7 3
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 7 4
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 ................................................................ 7 5
1 2. 1.
A d uca n u ma b ............................................................................................................... 7 5
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 7 5
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 7 6
1 2. 1. 3.
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 7 6
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 7 6
1 2. 2.
Place b o ........................................................................................................................ 7 6
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 7 6
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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ......................................................................................................... 7 7
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 7 7
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 7 7
1 3. 3.
P har mac o d y na mic Assess me nts ................................................................................. 7 7
1 3. 4.
A d diti o nal Assess me nts.............................................................................................. 7 8
7 8
1 3. 4. 2.
A p o E Ge n ot y pi n g ....................................................................................................... 7 8
7 9
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 7 9
1 4.
S A F E T Y A S S E S S M E N T S ................................ ........................................................8 0
1 4. 1.
Cli nical Safet y  Assess me nts....................................................................................... 8 0
1 4. 2.
La b orat or y  Safety Assess me nts .................................................................................. 8 0
1 4. 3.
I m m u n o ge nicity Assess me nts .................................................................................... 8 1


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 ................................................................................................. 8 2
1 5. 1.
Defi niti o ns.................................................................................................................. 8 2
1 5. 1. 1.
A d verse E ve nt ............................................................................................................. 8 2
1 5. 1. 2.
Seri o us A d verse E ve nt ................................................................................................ 8 2
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................ 8 3
1 5. 2.
Safet y  Classificati o ns.................................................................................................. 8 3
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ............................................................................. 8 3
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................ 8 4
1 5. 2. 3.
Se verit y  of E ve nts....................................................................................................... 8 4
1 5. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................8 4
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 8 4
1 5. 3. 1.
A d verse E ve nts ........................................................................................................... 8 4
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ............................................................................. 8 5
1 5. 3. 3.
Seri o us A d verse E ve nts ..............................................................................................8 5
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 8 5
1 5. 3. 4. 1.
Deat hs ......................................................................................................................... 8 6
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 8 6
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................8 6
1 5. 4. 1.
Pre g na nc y ................................................................................................................... 8 6
1 5. 4. 2.
O ver d ose ..................................................................................................................... 8 6
1 5. 4. 3.
Me dical E mer ge nc y .................................................................................................... 8 7
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 8 7
1 5. 5.
C o ntrace pti o n Re q uire me nts ...................................................................................... 8 7
1 5. 6.
Safe t y Res p o nsi bilities................................................................................................ 8 8
1 5. 6. 1.
T he I n vesti gat or .......................................................................................................... 8 8
1 5. 6. 2.
Bi o ge n .........................................................................................................................8 9
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 ........... 9 0
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 9 0
1 6. 2.
Efficac y  a n d P har mac o d yna mics ................................................................................9 0
1 6. 2. 1.
A nal y sis P o p ulati o n ....................................................................................................9 0
1 6. 2. 2.
Met h o ds of A nal ys is...................................................................................................9 0


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6. 2. 2. 1.
Ge neral C o nsi derati o ns ...............................................................................................9 0
1 6. 2. 2. 2.
D ose Re gi me ns t o be E val uate d ................................................................................. 9 0
1 6. 2. 2. 3.
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts .............................................. 9 1
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y E n d p oi nt............................................................................... 9 2
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 9 2
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ....................................................................................... 9 2
1 6. 3.
P har mac o ki netics ........................................................................................................ 9 3
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 3
1 6. 3. 2.
Met h o d of A nal ys is..................................................................................................... 9 3
1 6. 4.
Safet y .......................................................................................................................... 9 3
1 6. 4. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 3
1 6. 4. 2.
Met h o ds of A nal ys is................................................................................................... 9 3
1 6. 4. 2. 1.
A d verse E ve nts ........................................................................................................... 9 3
1 6. 4. 2. 2.
Cli nical L a b orat or y Res ults........................................................................................ 9 4
1 6. 4. 2. 3.
Vital Si g ns .................................................................................................................. 9 4
1 6. 4. 2. 4.
E C G ............................................................................................................................ 9 4
1 6. 4. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 9 4
1 6. 5.
I m m u n o ge nicity Data ................................................................................................. 9 4
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 4
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................... 9 4
1 6. 6.
I nteri m A nalys es ......................................................................................................... 9 4
1 6. 6. 1.
I nteri m F utilit y A nal ysis ............................................................................................. 9 4
1 6. 6. 2.
I nteri m S u peri orit y A nal ysis....................................................................................... 9 5
1 6. 7.
Sa m ple Size C o nsi derati o ns ................................ .......................................................9 5
1 7.
E T HI C A L  R E Q UI R E M E N T S ...................................................................................9 6
1 7. 1.
Declarati o n of H elsi n ki ...............................................................................................9 6
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ...........................................................9 6
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ............................................................................... 9 6
1 7. 4.
S u bject Data Pr otecti o n ..............................................................................................9 7
1 7. 5.
C o m pe nsati o n f or I nj ur y .............................................................................................9 7
1 7. 6.
C o nflict of I nterest ......................................................................................................9 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 7. 7.
Re gistrati o n of St u d y a n d Discl os ure of St u d y Res ults .............................................. 9 7
1 8.
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 9 8
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................... 9 8
1 8. 2.
Q ualit y  Ass ura nce....................................................................................................... 9 8
1 8. 3.
M o nit ori n g of t he St u d y ..............................................................................................9 8
1 8. 4.
St u d y  F u n di n g............................................................................................................. 9 8
1 8. 5.
P u blicati o ns ................................................................................................................. 9 8
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 9
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ................................................................................. 9 9
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ................................................................................. 9 9
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 9 9
1 9. 1. 3.
Electr o nic Data Ca pt ure ..............................................................................................9 9
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ..................................................... 9 9
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts...................................................................... 9 9
1 9. 1. 6.
Ne ur oc o g niti ve Assess me nts .................................................................................... 1 0 0
1 9. 2.
St u d y  C o m mittees ..................................................................................................... 1 0 0
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................. 1 0 0
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee ................................................................ 1 0 0
1 9. 3.
C ha n ges t o Fi nal St u d y  Pr ot oc ol .............................................................................. 1 0 0
1 9. 4.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n ...................................................................................... 1 0 1
1 9. 5.
Rete nti o n of St u d y  Data............................................................................................ 1 0 1
1 9. 6.
St u d y  Re p ort Si g nat or y.............................................................................................1 0 1
2 0.
R E F E R E N C E S ......................................................................................................... 1 0 2
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 ....................................... 1 0 5
LI S T O F T A B L E S
Ta ble 1:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8 ................. 1 8
Ta ble 2:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 2 2
Ta ble 3:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -u p P h o ne Call Sc he d u le D uri n g 
t he Place b o-C o ntr olle d Peri o d .................................................................................... 2 5


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Ta ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4 ................................... 2 7
Ta ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 3 0
Ta ble 6:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he L o n g -Ter m E xte nsi o n ............................................................................... 3 3
Ta ble 7:
D osi n g Sc he me f or A d uca n u ma b b y Re gi me n ........................................................... 4 2
Ta ble 8:
Dis p ositi o n of A RI A -E Cases ..................................................................................... 5 0
Ta ble 9:
Dis p ositi o n of A RI A - H ( Micr o he m orr ha ge) Cases.................................................... 5 2
Ta ble 1 0:
Dis p ositi o n of A RI A -H ( S u perficial Si der osis) Cases ............................................... 5 4
Ta ble 1 1:
Res u m pti o n of St u d y  Treat me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titrati o n .......................................................................................................... 5 7
Ta ble 1 2:
D ose Gr o u p P o oli n g Strate g y  i n t he E ve nt of Treat me nt Gr o u p Ter mi nati o n........... 9 1
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n............................................................................................................... 1 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1.
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 5 0 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
 at 
Please refer t o t he St u d y  Refere nce Ma n ual
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 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
E Q -5 D ( S R)
E ur o Q ol healt h stat us meas ure, s u bject self-re p orte d
F U
F oll o w - u p
G C P
G o o d Cli nical Practice
H b A 1 c
gl yc os yl ate d he m o gl o bi n
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
h ealt h care pr ofessi o nal
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g
i m m u n o gl o b uli n 
I R
i nf or ma nt rate d
I RB
i nstit uti o nal re vie w b oar d
I T T
i nte nt-t o-treat
I V
i ntra ve n o us(ly)
I W G
I nter nati o nal W or ki n g Gr o u p
L T E
l o n g-ter m e xte nsi o n
L P
l u m bar p u nct ure
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 Re g ulat or y Acti vities
M M R M
M i xe d-m o del re peate d meas ures
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 P D Q - 2 0
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d versi o n
M RI
ma g netic res o na nce i ma gi n g
NI A
Nati o nal I nstit ute o n A gi n g
N PI - 1 0
Ne ur o ps yc hiatric I n ve nt or y - 1 0
P E T
p ositr o n e missi o n t o m o gra p h y
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
R B A N S
Re peata ble Batter y  f or Assess me nt of Ne ur o psyc h ol o gical 
Stat us
R N A
ri b o n ucleic aci d
S A B R
Safet y  a n d Be nefit-Ris k 
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T E A E
treat me nt-e mer ge nt a d verse e ve nt
U V
u nsc he d ule d visit


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
3.
S Y N O P SI S
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
Pr ot oc ol Title:
A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he Efficac y a n d 
Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h Earl y
Alz hei mer's Disease
Versi o n N u m ber:
3. 0
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 I n dicati o n:
Alz hei mer’s Disease
St u d y Rati o nale:
T he p ur p ose of t his P hase 3 st u d y is t o assess t he efficac y a n d 
safet y of a d uca n u ma b c o m pare d wit h place b o i n s u bjects wit h 
earl y Alz hei mer’s Disease ( A D) , i ncl u di n g s u bjects wit h mil d 
c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a s u bset of mil d A D .  
A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of β -a m yl oi d ( A β), i ncl u di n g s ol u ble A β 
oli g o mers a n d de p osite d fi brillar A β .  I nteri m a nal yses of t he 
o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve 
de m o nstrate d tar get e n ga ge me nt, a p har mac o d y na mic effect o n 
a m yl oi d re d ucti o n, a n d a n effect o n t he Cli nical De me ntia Rati n g 
( C D R)-S u m of B o xes ( S B) a n d Mi ni -Me ntal State E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults al o n g 
wit h t he o bser ve d safet y a n d t olera bilit y pr ofile warra nt f urt her 
P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n 
s pa n ni n g t he earl y sta ges of t he A D c o ntin u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
(place b o -c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R-S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D .  
T he pri mar y e n d p oi nt t h at relates t o t his o bjecti ve is t he cha n ge 
fr o m baseli ne i n C D R -S B sc ore at Wee k 7 8.
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b as 
c o m pare d wit h place b o o n cli nical pr o gressi o n as 
meas ure d b y

M M S E
- C ha n ge fr o m baseli ne i n M M S E sc ore at Wee k
7 8

Alz hei mer’s Disease Assess me nt Scale -C o g niti ve 
S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3] 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
- C ha n ge fr o m baseli ne i n A D A S -C o g 1 3 at Wee k 7 8

Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of 
Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt 
versi o n) [ A D C S -A D L -M CI] 
- C ha n ge fr o m baseli ne i n A D C S -A D L -M CI
sc ore at
Wee k
7 8
Tertiar y o bjecti ves of t his st u d y are liste d i n Secti o n 6. 3. 1 .  
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 .  
St u d y O bjecti ves a n d E n d p oi nts 
( D ose-Bli n d L o n g -Ter m  
E xte nsi o n peri o d of t he st u d y ):
T he o bjecti ves are 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 earl y A D, a n d 
t o e val uate t he l o n g-ter m efficac y of a d uca n u ma b treat me nt as 
meas ure d b y cli nical, ra di ol o gical a n d a d diti o nal assess me nts 
re p orte d b y t he s u bject a n d i nf or ma nt/care part ner.
E n d p oi nts f or t he l o n g-ter m e xte nsi o n (L T E ) peri o d of t he st u d y 
are liste d i n Secti o n 6. 4. 2 .  
St u d y Desi g n:
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p peri o d f oll o we d b y a n o pti o nal 
2 4- m o nt h d ose -bli n d, L T E peri o d
St u d y L ocati o n:
A p pr o xi matel y 1 5 0 sites gl o ball y
N u m ber of Pla n ne d S u bjects:
A p pr o xi matel y 1 3 5 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 earl y A D, i ncl u di n g 
s u bjects wit h mil d c o g n iti ve i m pair me nt ( M CI) d ue t o A D a n d a 
s u bset of mil d A D acc or di n g t o NI A -A A criteria .  S u bjects m ust 
be p ositi ve f or a m yl oi d pat h ol o g y as meas ure d b y a m yl oi d 
p ositr o n e missi o n t o m o gra p h y sca n .  S u bjects m ust be 5 0 t o 8 5 
years ol d, a n d a part fr o m t he cli nical dia g n osis of earl y A D, 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 .  S u bj ect 
e nr oll me nt will be m o nit ore d s o t hat a p pr o xi matel y 6 0 % t o 7 0 % 
a p oli p o pr otei n E 4 ( A p o E ε 4 ) carriers are e nr olle d .  E nr oll me nt 
will als o be m o nit ore d, via i nteracti ve res p o nse tec h n ol o g y (I R T), 
s uc h t hat s u bjects wit h mil d A D re prese nt a s mall perce nta ge of 
t he t otal e nr olle d i n t he trial.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt Gr o u ps:
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d of t he st u d y a n d 
b ase d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d 
t o 1 of 3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o 
(a d uca nu ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o) as 
f oll o ws: 
A p o E ε 4 c arrier
     L o w  d ose ( 3 m g/ k g)
     Hi g h d ose ( 6 m g/ k g) 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
     Pl ace b o 
A p o E ε 4 n o n -c arrier
     L o w  d ose ( 6 m g/ k g) 
     Hi g h d ose ( 1 0 m g/ k g)
     Pl ace b o 
After c o m pleti o n of t he place b o -c o ntr olle d peri o d , s u bjects ma y 
e nter a 2 4 -m o nt h d ose -bli n d L T E st u d y d uri n g w hic h all s u bjects 
will recei ve a d uca n u ma b .  
D urati o n of Treat me nt a n d 
F oll o w U p:
St u d y d urati o n f or eac h s u bject partici pati n g i n t he place b o -
c o ntr olle d peri o d o nl y wil l be a p pro xi matel y 1 0 2 wee ks ( u p t o a n 
8- wee k scree ni n g peri o d, 7 6 wee ks of place b o or a d uca n u ma b
d osi n g, a n d 1 8 wee ks of f oll o w u p [ F U]).  
F or s u bjects w h o e nter t he o pti o nal L T E peri o d , t he t otal d urati o n 
will be a p pr o xi matel y 2 0 6 wee ks or 4 7 m o nt hs ( u p t o a n 8-wee k 
scree ni n g peri o d, 7 6 wee ks of place b o or a d ucan u ma b d osi n g, 4 
wee ks of F U , 1 0 0 wee ks of d ose -bli n d a d uca n u ma b d osi n g, a n d 
1 8 wee ks of F U ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1
4. 1.
St u d y Sc he m atic
Fi g ure 1:
St u d y Desi g n
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve ; L T E = l o n g -ter m e xte nsi o n; R = ra n d o mizati o n date .
* S u bjects w h o are assi g ne d t o place b o d uri n g t he place b o -c o ntr olle d peri o d a n d are c o nti n ui n g i nt o t he L T E peri o d wi ll be ra n d o mize d i n a 1: 1 rati o t o hi g h a n d 
l o w d ose a d uca n u ma b treat me nt ( base d u p o n t heir A p o E ε 4 carrier stat us).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
4. 2.
Sc he d ule of E ve nts
T a ble 1:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8
St u d y Wee k
Scree ni n g 
(≤6 0 d a ys 
bef ore D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
I nitial Scree ni n g 
C o nse nt 2 ( o pti o nal)
X
F ull I nf or me d 
C o nse nt 3
X
Eli gi bilit y Criteria
X  
X  
X  
X 4
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
H b A 1c
X
HI V 5/ He patitis/
C oa g ulati o n
X
A p o E G e n ot y pi n g
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
Ser u m Pre g na nc y
Test 7
X
Uri ne Pre g na nc y 
Test 7
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
St u d y Wee k
Scree ni n g 
(≤6 0 d a ys 
bef ore D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 8
X
X  
X  
X  
X  
X  
X  
X
X  
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
Ra n d o mizati o n
X
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
A nti -
A d uca n u ma b A b 9
X
X
X
A d uca n u ma b 
C o nce ntrati o n 1 0
X 1 1
X 1 1
X 1 1
X  
X 1 1
X 1 1
X 1 1
X
A m yl oi d P E T 1 4
X
X
R B A N S
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 2:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Tre at me nt or F oll o w -U p 
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
7 8 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
M e dic ati o n
9 4
( or 1 8 wee ks after fi n al 
d ose f or s u bjects w h o 
ter mi n ate tre atme nt 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
I nf or me d C o nse nt
X 3
Eli gi bilit y Criteria
X 3
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X
Uri ne Pre g na nc y Test 4
X  
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 5
X  
X  
X  
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
St u d y Treat me nt I nf usi o n
X  
X  
X  
X  
X  
X  
X
A nti - Ad uca n u ma b A b 6
X
X
X
A d uca n u ma b C o nce ntrati o n 7
X 8
X
X
A m yl oi d P E T 1 0
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 3: 
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -u p P h o ne C all Sc he d ule D uri n g t he Pl ace b o -C o ntr olle d Peri o d
St u d y Wee k
Scree ni n g
(≤6 0 d a ys 
bef ore D a y 1) 1
Pl ace b o -C o ntr olle d Peri o d
F U 2
1 
2 
6
1 0 
1 4 
1 8 
2 2 
2 6 
3 0 
4 2 
5 4 
7 8 /
E O T
3
U nsc he d
-ule d 
Visit/ 
M RI f or 
A RI A 4
9 4
( or 1 8 
wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
disc o n -
ti n ue 
tre atme nt 
e arl y)
St u d y D a y
V 1  
V 2  
V 3
1
1 5
± 3
4 3
± 3
7 1
± 3
9 9
± 3
1 2 7
± 3
1 5 5
± 3
1 8 3
± 3
2 1 1
± 3
2 9 5
± 3
3 7 9
± 3
5 4 7
± 3
6 5 9
± 7
F oll o w -U p P h o ne Call 5
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 6
X
X
X
X  
X  
X  
X  
X  
X
A d uca n u ma b 
C o nce ntrati o n 7
X
X
X
X  
X
M O C A
X
X
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 -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 -
he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt ; F U = F oll o w -U p; L T E = l o n g -ter m e xte nsi o n; M O C A = M o ntreal C o g niti ve Assess me nt; 
M RI
= ma g netic re s o na nce i ma gi n g; P K = p har mac o ki netic;
; V 1, V 2, V 3 = Scree ni n g Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3.
1 Brai n M RI ( V 2) w ill n ot be perf or me d u ntil t he s u bject has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1.  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 relate d 
t o P E T sca ns a n d s u bject t o S p o ns or a p pr o val.
2 S u bj ects w h o c o m plete t he place b o -c o ntr olle d 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 U V isit at Wee k 9 4.  S u bjects wh o 
disc o nti n ue treat me nt or w it h dr a w fr o m t he st u d y earl y are t o ha ve a safet y F U V isit at 1 8 wee ks after t heir fi nal d ose.  T he o nl y e xce pti o n is a s u bject w h o 
disc o nti n ues treat me nt pre mat urel y a n d c o nti n ues o n st u d y f or at least 1 8 w ee ks after recei vi n g t he fi nal d ose.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y.  
S u bjects w h o wit h dra w  fr o m st u d y pre mat urel y are t o ret ur n t o t he site f or t he Wee k 7 8/ E O T Visit; f or s uc h s u bjects, t he site is t o c o ntact t he S p o ns or as s o o n 
as p ossi ble t o c o nfir m w het her t he efficac y assess me nts s pecifie d at t he Wee k 7 8/ E O T Visit are re q uire d.
4 F or t he fre q ue nc y of re q uire d brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f or s u bjects w h o de vel o p A RI A -E a n d/ or A RI A - H, see Secti o ns 7. 2. 1. 1 t o 
7. 2. 1. 5 .  F or t he fre q ue nc y of brai n M RI, M O C A, P K , a n d bi o mar ker assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  
F or ma na ge me nt of rec urre nt A RI A , see Secti o n 7. 2. 1. 7 .  
5 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject w ill be at t he st u d y site f or cli nical assess me nts.
6 Arterial s pi n la beli n g M RI a n d tas k free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
7 O ne sa m ple will be c ollecte d wit hi n 2 da ys after t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f o r all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
Ra n d o mizati o n
X 1
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
Uri ne Pre g na nc y 
Test 2
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -
A d uca n u ma b A b 3
X
X
X
A d uca n u ma b 
C o nce ntrati o n 3
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
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
A m yl oi d P E T 5
X
C D R
X
X  
X
M M S E
X
X  
X
A D A S -C o g 1 3
X
X  
X
A D C S -A D L -M CI
X
X  
X
N PI -1 0
X
X
E Q -5 D (I R-S)
X
X
C- S S R S
X
X
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
C o nc o mita nt 
T hera p y a n d 
P r 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 D A S -C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale -C o g niti ve S u bscale ( 1 3 ite ms); 
A D C S -A D L -M CI
= Alz hei mer's Disease C o o perati ve St u d y -Acti vi ties of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n);
 
 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; 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
E C G = electr ocar di o gra m; 
; E Q-5 D (I R -S) = E Q -5 D, 
i nf or ma nt re p orte d o n s u bject; 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;  N PI -1 0 = Ne ur o ps yc hiatric I n ve nt or y -1 0 ; 
P E T = p ositr o n e m issi 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.
1 S u bjects w h o were i n t he place b o gr o u p d uri n g t he place b o -c o ntr olle d peri o d will be ra n d o mize d t o a d uca n u ma b hi g h a n d l o w d ose ( 1: 1 rati o).
2 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
 
5 O nl y f or s u bjects w h o partici pate i n t he a m yl oi d P E T c o h ort.
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Tre at me nt or F oll o w -U p
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
B o d y Wei g ht
X  
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
X
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -a d uca n u ma b 
A b 4
X
X
X
X
A d uca n u ma b 
C o nce ntrati o n 4
X
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
St u d y Dr u g 
I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X
A m yl oi d P E T 6
X
C D R
X
X  
X
X
M M S E
X
X  
X
X
A D A S -C o g 1 3
X
X  
X
X
A D C S -A D L -M CI
X
X  
X
X
N PI -1 0
X
X
E Q -5 D (I R -S) 
X
X
C- S S R S
X
X
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
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




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6:
Br ai n M RI , A RI A M a n a ge me nt , a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he L o n g -Ter m E xte nsi o n
St u d y Wee k
L o n g -Ter m E xte nsi o n
U nsc he d -
ule d V isit
f or A RI A1
F U 2
8 2 
8 6 
9 0 
9 4 
9 8 
1 0 2 
1 0 6 
1 1 0 
1 2 2 
1 3 4 
1 5 8
1 8 2 3
1 9 8
( or 1 8 wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
ter mi n ate 
tre atme nt 
e arl y)
St u d y D a y
5 7 5
± 5
6 0 3
± 5
6 3 1
± 5
6 5 9
± 5
6 8 7
± 5
7 1 5
± 5
7 4 3
± 5
7 7 1
± 5
8 5 5
± 5
9 3 9
± 5
1 1 0 7
± 5
1 2 7 5
± 5
1 3 8 7
± 7
F oll o w - Up 
P h o ne Call 4
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 5
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 6
X
M O C A
X
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 -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 -
he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt ; F U = f oll o w u p; L T E = l o n g-ter m e xte nsi 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 K = p har mac o ki netic.
1 F or t he fre q ue nc y of re q uire d brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f or s u bjects w h o de vel o p A RI A-E a n d/ or A RI A - H, see Secti o ns 7. 2. 1. 1 t o 
7. 2. 1. 5 .  F or t he fre q ue nc y of brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  
F or ma na ge me nt of rec urre nt A RI A , see Secti o n 7. 2. 1. 7 .  
2 S 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 safet y F U V isit at Wee k 1 9 8.  S u bjects w h o 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 U V isit at 1 8 wee ks after t heir fi nal d ose .  T he o nl y e xce pti o n is a s u bject w h o disc o nti n ues treat me nt pre mat urel y a n d 
c o nti n ues o n st u d y f or at least 1 8 wee ks after recei vi n g t he fi nal d ose.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y. 
S u bjects w h o wit h dra w  fr o m t he L T E peri o d pre mat urel y are t o ret ur n t o t he site f or t he Wee k 1 8 2/ E O T V isit; f or s uc h s u bjects, t he site is t o c o ntact t he 
S p o ns or as s o o n as p ossi ble t o c o nfir m w het her t he efficac y assess me nts s pecifie d at t he Wee k 1 8 2/ E O T V isit are re q uire d.
4 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject w ill be at t he st u d y site f or cli nical assess me nts.
5 Arterial- s pi n la beli n g M RI a n d tas k-free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites
6 O ne sa m ple will be c olle cte d wit hi n 2 da ys after t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n S u bjects wit h Earl y Alz hei mer's Disease  
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
4. 3.
A d diti o n al I nf or m ati o n
4. 3. 1.
Site Pers o n nel
A mi ni m u m of 3 se parate heat h care pr ofessi o nals ( H C Ps) are re q uire d:  
1.
A treati n g H C P (t he Pri nci pal I n vesti gat or [ PI ] or S u b -i n vesti gat or m a y  ser ve as a 
treati n g H C P ) w h o is res p o nsi ble f or t he f oll o wi n g:

A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y  1 a n d d uri n g 
ma na ge me nt of a m yl oi d-relate d i ma gi n g a b n or malities (A RI A) cases.

Ma na ge me nt of t he r o uti ne ne ur ol o gical care of t he s u bject.

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y) a n d treat me nt of a d verse e ve nts 
(A Es ).  

Re vie w of selecte d he mat ol o g y  a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y 
wit h hel d or per ma ne ntl y  disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
Secti o n 1 0. 1 .
2.
A n i n de pe n de nt rati n g H C P ( desi g nate d by t he PI of t he site) w h o is res p o nsi ble f or 
a dmi nisteri n g t he Cli nical De me ntia Rati n g ( C D R)
3.
A sec o n d i n de pe n de nt rati n g H C P ( desi g nate d by t he PI  of t he site) w h o will a d mi nister 
t he Alz hei mer’s Disease Assess me nt Scale - C o g niti ve S u bscale ( 1 3 ite ms) [A D A S -C o g
1 3] , Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of Dail y  Li vi n g I n ve nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [A D C S -A D L -M CI ], a n d t he Mi ni-Me ntal State 
E xa mi nati o n ( M M S E)
T he 2 i n de pe n de nt rati n g H C Ps 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 A Es, c o nc o mita nt t hera py , la b orat or y data, i ma gi n g 
data , or a n y ot her data t hat ha ve t he p ote ntial of re veali n g t he treat me nt assi g n me nt .  T he 2 
i n de pe n de nt rati n g H C Ps m ust n ot s hare a ny i nf or mati o n a b o ut s u bjects.  PIs ca n n ot ser ve as 
rati n g H C Ps .
T he treati n g H C Ps m ust n ot disc uss A Es (e. g., A RI A) wit h t he i n de pe n de nt rati n g 
H C Ps.  
T o e ns ure c o nsiste nc y  acr oss sites, rati n g H C Ps m ust c o m plete t he sta n dar dize d st u d y -s pecific 
q ualificati o n pr ocess o n cli nical efficac y  assess me nt sc ori n g pri or t o a d mi nistrati o n of t he 
s pecific assess me nt at t heir site.  All sites s h o ul d atte m pt t o mai ntai n t he sa me rati n g H C P
t hr o u g h o ut t he st u dy f or s pecific assess me nts .  Eac h s u bject s h o ul d ha ve t he sa me rati n g H C P
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 dy.  If a rati n g H C P has t o be 
re place d, t he ne w rati n g H C P m ust u n der g o t he st u d y -s pecific q ualificati o n pr ocess pri or t o 
a d mi nistrati o n of t he assess me nt.
He mat ol o g y  a n d bl o o d c he mistr y data will be se nt t o the i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.  As wit h ot her la b orat or y  a n d cli nical i nf or mati o n, t hese data s h o ul d 
N O T be re vie we d b y t he rati n g H C Ps .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T he r oles of i n de pe n de nt raters a n d treati n g H C P are N O T i nterc han gea ble at t he s u bjec t le vel.  
I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc ha n gea ble at t he s u bject le vel.  If a rater has 
a d mi nistere d t he C D R t o a s u bject t he y  ma y n ot a d mi nister t he ot her ne ur oc o g niti ve assess me nts 
t o t hat s u bject at a n y p oi nt d uri n g t he st u d y.
A n u n bli n de d p har macist ( or a ut h orize d desi g nee) 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 t he st u d y bli n d.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
5.
I N T R O D U C TI O N
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i ncrease t o 1 3 5. 5 milli o n b y  2 0 5 0 
[ Alz hei mer's Disease I nter nati o nal 2 0 1 4].  
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 a n d 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 [Jac k 2 0 1 3].
Pat h ol o gicall y, A D 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 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra ne ur o nal ne ur ofi brillar y ta n gles c o m p ose d of 
h y per p h os p h or y late d ta u pr otei ns.  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 “a myl 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 dy a n d Sel k oe 2 0 0 2] .  
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n ha vi n g cate g orical sta ges .  E vi de nce s u g gests t he 
pat h o p h ysi ol o gical c ha n ges be gi n y ears 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].  
Re vis e d criteria f or t he cli nical dia g n osis of A D were p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) a n d t he Alz hei mer’s Ass ociati o n ( A A) [ Al bert 2 0 1 1; Mc K ha n n 2 0 1 1; S perli n g 
2 0 1 1] a n d t he Inter nati o nal W or ki n g Gr o u p (I W G)
[ D u b ois 2 0 1 0; D u b ois 2 0 1 4], a n d a gr o u p 
t hat i ncl u de d me m bers fr o m b ot h NI A- A A a n d I W G p u blis he d rec o m me n dati o ns t o har m o nize 
t he criteria [ M orris 2 0 1 4].  T hese criteria base t he dia g n osis of A D o n b ot h cli nical a n d 
bi ol o gical ele me nts, rec o g nizi n g t he e xiste nce of a n o n cli nical sta ge of t he disease b y acce pti n g
A D dia g n os es pri or t o si g ns of de me ntia usi n g A D bi o mar kers.
T he scie ntific c o m m u nit y  has s hifte d its f oc us t o tar get patie nts 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 patie nts are m ore li kel y t o be nefit fr o m a nti -a m yl oi d 
t hera py .  S u p p orti n g t his h y p ot hesis are res ults fr o m s ola nez u ma b a n d cre nez u ma b st u dies t hat 
ha ve s h o w n a tre n d i n sl o wi n g c o g niti ve decli ne i n mil d b ut n ot m o derate A D [ D o o d y 2 0 1 4; 
Fa ga n 2 0 1 4] .  
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 b y  re d uci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F) .  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s o l u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u blicati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h s ol u ble oli g o mers a n d a myl 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 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
calci u m h o me o stasis a n d ne ur o nal acti vit y, as well as re d ucti o n of o xi dati ve stress [ R oz kal ne 
2 0 0 9; S pires -J o nes 2 0 0 9].  Si milarl y , patie nts wit h A D w h o ge nerate d a nti-A β a nti b o dies after 
acti ve i m m u nizati o n wit h a g gre gate d A β( 4 2) s h o we d sl o wer rates of decli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [ H oc k 2 0 0 3].
5. 1.
Pr ofile of Pre vi o us E x perie nce W it h A d uc a n u m a b  
5. 1. 1.  
N o ncli nic al E x perie nce 
A d uca n u ma b is a u ni q ue h u ma n, a nti-A β m o n ocl o nal a nti b o d y  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 o r 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 .  
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 uble 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 m m u n o gl o b uli n (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 pr o perties si g nifica ntl y re d uce d 
a m yl 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, t hr o u g h a 
micr o glia -me diate d p ha g oc y tic mec ha nis m.  T hese data s u g gest a d uca n u ma b c o ul d pr o vi de 
be nefit b y re d uci n g pla q ue b ur de n .
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 gicall y 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 gic al 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].
Fi n di n gs c o nsiste nt wit h a m y l oi d pla q ues a n d vasc ular a myl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, i ncl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h t his m o del .  I n 
b ot h 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 wer e 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 o n of he m osi deri n i n Perls stai ne d 
brai n secti o ns of e ac 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 ad 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 nfla m mati o n w ere 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
See t he I n vesti gat or’s Br oc h ure (I B) f or detaile d i nf or mati o n o n n o ncli nical st u dies.
5. 1. 2.
Cli nic al E x perie nce
A d uca n u ma b has bee n e val uate d i n o ne c o m plete d si n gle asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d ose st u d y  (2 2 1 A D 1 0 3): 

St u d y  2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, st u d y 
of ad uca n u ma b i n s u bjects wit h mil d or m o derate A D .  
T he pri mar y  o bjecti ve was t o e val uate t he safety a n d t olera bilit y of a ra n ge of 
ad uca n u ma b d oses ( 0. 3 t o 6 0 m g/ k g) w he n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y  o bjecti ves were t o assess t he p har mac o ki netic ( P K) a n d 
i m m u n o ge nicity of ad uca n u ma b after si n gle -d ose a d mi nistrati o n .  
A si n gle d ose of a d uca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d .  
D ose -li miti n g A RI A ( 2 s u bjects wit h A RI A- E [e de ma] a n d 1 s u bject wit h A RIA- E
a n d A RI A-H [ micr o he m orr ha ge]) was o bser ve d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses bel o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near.

St u d y  2 2 1 A D1 0 3 is a n o n g oi n g ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d 
m ulti ple d ose st u d y  of ad uca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are 
a m yl oi d p ositi ve.  The st u d y  c o m prises a place b o-c o ntr olle d peri o d wit h s u bjects 
recei vi n g m o nt hl y d oses of ad uca n u ma b (fi xe d d oses of 1, 3, 6, or 1 0 m g/ k g, or 
titrati o n u p t o 6 m g/ k g) or place b o f or a ye ar f oll o we d b y a d ose -bli n d l o n g -ter m 
e xte nsi o n ( L T E ) peri o d wit h s u bjec ts recei vi n g m o nt hl y d oses of ad uca n u ma b .  
T he pri mar y  o bjecti ve of St u d y  2 2 1 A D 1 0 3 is t o e val uate t he safety a n d t olera bilit y of 
m ulti ple d oses of ad uca n u ma b a d mi nistere d m o nt hl y  as si n gle I V i nf usi o ns.  T he 
sec o n dar y o bjecti ves are t o assess t he effect of ad uca n u ma b o n cere bral a m y l oi d 
pla q ue c o nte nt as meas ure d b y  1 8F-fl or beta pir p ositr o n e missi o n t o m o gra p h y (P E T ), 
a n d t o e val uate t he P K a n d i m m u n o ge nicit y of ad uca n u ma b after m ulti ple -d ose 
a d mi nistrati o n .  E x pl orat or y  o bjecti ves i ncl u de assess me nt of t he effect of 
ad uca n u ma b o n t he cli nical pr o gressi o n of A D as meas ure d b y C D R -s u m of b o xes 
(S B ) a n d M M S E .  
T o date, A RI A has bee n t he m ost fre q ue nt A E re p orte d i n t he st u d y.  A RI A -E was 
ra di o gra p hicall y m o nit ore d b y ma g netic res o na nce i ma gi n g ( M RI ) a n d t y p icall y 
o bser ve d earl y i n treat me nt ( bet wee n 2 t o 5 d oses) .  I n m ost cases, A RI A-E res ol ve d 
4 t o 1 2 wee ks after o nset a n d A RI A -H was t y picall y sta ble 2 t o 4 wee ks after o nset.  
I nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose a n d A p oli p o p r otei n E4 
(A p o E ε 4) carria ge-de pe n de nt, es peciall y at t he hi g hest d oses (refer t o t he I B f or 
details o n e ve nts of A RI A) .  
Pr ot oc ol -defi ne d i nteri m a nal ys es ha ve de m o nstrate d a d ose - a n d ti me-de pe n de nt 
re d ucti o n of brai n a myl oi d b ur de n after 6 m o nt hs of d osi n g ( We e k 2 6), wit h 
statistical si g nifica nce ac hie ve d i n t he 3, 6, a n d 1 0 m g/ k g gr o u ps c o m pare d wit h 
place b o, a n d after 1 year of d osi n g ( Wee k 5 4), wit h statistical si g nifica nce ac hie ve d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
i n t he 3 a n d 1 0 m g/ k g gr o u ps c o m pare d wit h place b o (see c urre nt I B f or res ults of t he 
m ost rece nt i nteri m a nal ysis ).  T he res ults de m o nstrate tar get e n ga ge me nt (a m y l oi d 
pla q ues) a n d a p har mac o d y na mic effect ( d ose -de pe n de nt a m yl oi d re d ucti o n) .  I n 
a d diti o n res ults fr o m t he i nteri m a nal yses s h o we d a n effect at 1 year o n t he 
e x pl orat or y  e n d p oi nts C D R-S B a n d M M S E, s u g gesti n g a re d ucti o n i n t he pr o gressi o n 
of cli nical i m pair me nt f or a d uca n u ma b -treate d vers us place b o-treate d s u bjects.  At 
Wee k
5 4, a dj uste d mea n c ha n ge (i ncrease) fr o m baseli ne i n C D R- S B sc ore was 
s maller f or b ot h t he 3 a nd 1 0 m g/ k g gr o u ps c o m pare d wit h place b o, wit h statistical 
si g nifica nce ac hie ve d i n t he 1 0 m g/ k g gr o u p (see c urre nt I B f or res ults of t he m ost 
rece nt i nteri m a nalys is).  At Wee k 5 2, a dj uste d mea n c ha n ges ( decreases) i n M M S E 
sc ore fr o m baseli ne were statisticall y si g nifica nt i n t he 3 a n d 1 0 m g/ k g gr o u ps ( see 
c urre nt I B f or res ults of t he m ost rece nt i nteri m a nal ysis).  Refer t o t he I B f or details 
o n i nteri m a nal y ses res ults.
5. 2.
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safety of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D a n d a s u bset of mil d A D.  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y  t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β .  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 yer -L ue 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].  F or 
t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, w hile preser vi n g 
gl o bal f u ncti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.  
I nteri m a nalys es of t he o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3 ) ha ve de m o nstrate d tar get 
e n ga ge me nt, a P D effect o n a m y l oi d re d ucti o n, a n d a n effect o n C D R-S B a n d M M S E s u g gesti ve 
of a re d ucti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b- treate d s u bjects.  T hese 
res ults al o n g wit h t he o bser ve d safety a n d t olera bilit y  pr ofile warra nt t he f urt her P hase 3 
i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D 
c o nti n u u m.
5. 3.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
T he d osi n g re gi me n selecte d f or t his st u d y  was base d o n t he P K a n d P D relati o ns hi p f or re m o val 
of brai n a m yl oi d a n d effect o n C D R -S B a n d M M S E o bser ve d i n St u d y  2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n safet y, t olera bilit y , a n d P K data fr o m st u dies 22 1 A D 1 0 1 (c o m p lete) a n d 
2 2 1 A D 1 0 3 ( o n g oi n g).  
T he d ose - a n d ti me-de pe n de nt re d ucti o n of brai n a m y l oi d b ur de n o bser ve d wit h ad uca n u ma b 
treat me nt was statisticall y si g nifica nt at d oses of 3, 6 a n d 1 0 m g/ k g after 6 m o nt hs of d osi n g a n d 
at 3 a n d 1 0 m g/ k g after 1 2 m o nt hs of d osi n g (see c urre nt I B f or res ults of t he m ost rece nt i nteri m 
a nal ys is).  T he effect o n mea n decrease fr o m baseli ne i n C D R - S B after 1 2 m o nt hs of d osi n g was 
o bser ve d at b ot h 3 a n d 1 0 m g/ k g (see c urre nt I B f or res ults of t he m ost rece nt i nteri m a nalys is), 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
wi t h statistical sig nifica nce ac hie ve d at 1 0 m g/ k g .  T he effect o n mea n decrease fr o m baseli ne i n 
M M S E sc ore was statisticall y  si g nifica nt at 3 a n d 1 0 m g/ k g.  T hese data i n dicate t hat 3 m g/ k g 
c o ul d be c o nsi dere d a n acce pta ble d ose f or P hase 3 st u dies; h o we ve r, gi ve n t he d ose-de pe n de n t
nat ure of t hese o bser vati o ns, t he use of hi g her d oses ( 6 a n d 1 0 m g/ k g) c o ul d offer greater be nefit 
at acce pta ble ris k .  
A RI A has bee n i de ntifie d as a n e ve nt t hat ma y  occ ur wit h a nti-a m yl oi d tar geti n g dr u g ca n di dates 
a n d is c o nsi dere d a n e ve nt of s pecial i nterest i n t he a d uca n u ma b pr o gra m.  T o date, t he i nci de nce 
of A RI A has bee n o bser ve d t o be b ot h d ose a n d A p o E ε 4 carria ge de pe n de nt, es peciall y at t he 
hi g hest d oses .  I n a n eff ort t o ma xi mize t he d ose-de pe n de nt a m yl oi d re d ucti o n a n d effect o n 
C D R -S B a n d M M S E t hat ha ve bee n o bser ve d wit h d oses of 3 m g/ k g a n d hi g her w hile 
mai ntai ni n g A RI A i nci de nce, se verit y , a n d relate d disc o nti n uati o n rate wit hi n acce pta ble le vels, 
a titrati o n re gi me n will be e x pl ore d .  It has bee n s u g geste d t hat t he A RI A o bser ve d f oll o wi n g 
treat me nt wit h a myl oi d tar geti n g a ge nts ma y  be d ue, i n part, t o t he i nitial lar ge re m o val of 
a m yl oi d a n d s u bse q ue nt sat urati o n of peri vasc ular brai n a myl oi d cleara nce mec ha nis ms [ Weller 
2 0 0 8] .  Sl o w titrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o wer i nitial a m yl oi d re m o val, 
ye t tri g ger alter nati ve mec ha nis ms of a myl oi d cleara nce i ncl u di n g m o n ocl o nal 
a nti b o d y-de pe n de nt Fc -me diate d micr o glial cleara nce [ Ostr o witz ki 2 0 1 2] w hic h w o ul d pre ve nt 
sat urati o n of a myl oi d cleara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is 
reac he d.  Si nce ad uca n u ma b -i n d uce d A RI A has bee n de m o nstrate d t o occ ur early d uri n g
treat me nt, wit h m ost cases occ urri n g wit hi n t he first 5 d oses, titrati o n of ad uca n u ma b f or u p t o 
6 d oses pri or t o reac hi n g t he tar get d ose ma y  res ult i n re d ucti o n of A RI A i nci de nce a n d se verit y.  
Gi ve n t he t olera bilit y  a n d a p pare nt efficac y of ad uca n u ma b s h o w n t o date, t he d oses t o be teste d 
usi n g a titrati o n re gi me n are 3 a n d 6 m g/ k g f or A p o E ε 4 carriers, a n d 6 a n d 1 0 m g/ k g f or A p o E 
ε 4 n o n-carriers.  Titrati o n will start at 1 m g/ k g a n d will escalate t o 3, 6 a n d 1 0 m g/ k g as detaile d 
bel o w .  
5. 3. 1.
D osi n g Sc he me
5. 3. 1. 1.
Pl ace b o -C o ntr olle d Peri o d
D oses will be a d mi nistere d a p pr o xi matel y 4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses) .  Base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d t o 1 of 
3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h 
d ose: place b o) as f oll o ws (Ta ble 7 a n d Fi g ure 1 ):
A p o E ε 4 C arrier

L o w d ose ( 3 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereafter

Hi g h d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter

Place b o  
Sali ne i nf u si o n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A p o E ε 4 N o n- C arrier

L o w d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter  

Hi g h d ose ( 1 0 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n
T a ble 7:
D osi n g Sc he me f or A d uc a n u m a b b y Re gi me n
D ose ( M o nt h)
1
2 
3 
4 
5 
6 
7 t o 2 0
Re gi m e n
D ose ( m g/ k g)
A p o E ε 4 ( +)
L o w D ose
1 
1 
3 
3 
3 
3 
3
Hi g h D ose
1 
1 
3 
3 
3 
3 
6
Pl ace b o
sali ne
A p o E ε 4 ( -)
L o w D ose
1 
1 
3 
3 
3 
3 
6
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0
Pl ace b o
sali ne
5. 3. 2.
D osi n g Sc he me M o dific ati o n
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will re vie w u n bli n de d safet y data, i ncl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d uca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter .
T he d osi n g sc he me ca n be m o difie d i n t he f oll o wi n g circ u msta nces: 

Safet y  a n d t olera bilit y of t he hi g h d ose 
If a ny of t he hi g h d ose s pr o p ose d ( 1 0 m g/ k g i n A p o E ε 4 n o n-carriers a n d 6 m g/ k g i n 
A p o E ε 4 carriers) is dee me d n ot acce pta ble, e nr oll me nt f or t he hi g h d ose gr o u p(s) 
will be ter mi nate d a n d s u bjects will n ot be re place d .  S u bjects w h o ha ve alrea d y bee n 
ra n d o mize d t o t he disc o nti n ue d d ose will be d o w n -d ose d t o t he ne xt a vaila ble d ose
acc or di n g t o t heir A p o E ε 4 carrier stat us .  Defi niti o n of l o w a n d hi g h d ose re gi me ns 
will be re vise d as descri be d i n Secti o n 1 6 .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

Be nefit of titrati o n 
A titrati o n sc he d ule has bee n i m ple me nt e d i n t his P hase 3 st u d y  a n d i n t he o n g oi n g 
m ulti ple -d ose St u d y  2 2 1 A D 1 0 3.  If, base d u p o n re vie w of t he data fr o m 
St u d y 2 2 1 A D 1 0 3, titrati o n is n ot dee me d be neficial , it will be eli mi nate d, a n d 
s u bse q ue ntl y e nr olle d s u bjects w h o are A p o E ε 4 carriers will recei ve a fi xe d d ose of 
3 or 6 m g/ k g a n d n o n -carriers will recei ve 6 or 1 0 m g/ k g .  
5. 3. 3.
L o n g - Ter m E xte nsi o n Peri o d
S u bjects w h o recei ve d 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 w h o e nter t he L T E 
peri o d will c o nti n ue t o recei ve t he sa me d ose of ad uca n u ma b t hat t he y were o n at t he e n d of t he 
place b o - c o ntr olled peri o d .  S u bjects w h o recei ve place b o d uri n g t he place b o-c o ntr olle d peri o d 
a n d w h o e nter t he L T E peri o d will be assi g ne d t o 1 of 2 treat me nt gr o u ps, base d u p o n t heir 
A p o E ε 4 carrier stat us, i n a 1: 1 r ati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose).  S u bjects 
will be d ose d usi n g t he sa me re gi me n descri be d f or t he place b o -c o ntr olle d peri o d (see Ta ble 7
a n d Fi g ure 1 ).  
A n y  m o dificati o ns t o t he d osi n g sc he me (i.e. ter mi nati o n of hi g h d ose gr o u ps a n d re place me nt of 
titrati o n wit h fi xe d d osi n g, as descri be d i n Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E
peri o d .  










Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
St u d y  2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p 
st u d y i n s u bjects wit h earl y A D, i ncl u di n g M CI d ue t o A D a n d a s u bset of mil d A D, f oll o we d b y 
a n o pti o nal 2 4- m o nt h d ose -bli n d L T E st u d y .  A p pr o xi matel y  1 3 5 0 s u bjects will be e nr olle d 
acr oss a p pr o xi matel y 1 5 0 ce nters gl o ball y .  T he pri mar y  st u d y o bjecti ve is t o e val uate t he 
efficac y of m o nt hly d oses of a d uca n u ma b o n t h e C D R-S B relati ve t o place b o .  Sec o n dar y  
o bjecti ves i ncl u de assess me nt of t he effect of m o nt hl y  d oses of a d uca n u ma b o n cli nical 
pr o gressi o n as c o m pare d t o place b o .  T he safet y of m o nt hl y  d oses of a d uca n u ma b will als o be 
e val uate d.
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y  e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a t otal of 2 0 d oses).  S u bjects will be ra n d o mize d t o recei ve 
a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o i n a 1: 1: 1 rati o .  T he ra n d o mizati o n will 
be stratifie d b y site a n d A p o E ε 4 stat us (carrier or n o n-carrier).  S u bject e nr oll me nt will be 
m o nit ore d s o t hat a p pr o xi matel y 6 0% t o 7 0 % A p o E ε 4 carriers are e nr olle d .  E nr oll me nt will 
als o be m o nit ore d, via i nteracti ve res p o nse tec h n ol o g y (I RT), s uc h t hat s u bjects wit h mil d A D 
re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  
At t he e n d of t he d o u ble -bli n d , place b o -c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
e xte nsi o n e ntr y criteria ma y e nter a 2 4-m o nt h l o n g-ter m safet y a n d efficac y e xte nsi o n peri o d,
wit h all s u bjects recei vi n g a d uca n u ma b a p pr o xi matel y e ver y 4 wee ks (a t otal of 2 6 d oses).  
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject o nl y partici pati n g i n t he place b o -
c o ntr olle d peri o d of t he st u d y  will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series of 
S cree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a n d a safet y f oll o w - u p ( F U) peri o d of 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 eac h s u bject partici pati n g i n t he place b o -c o ntr olle d 
peri o d a n d t he L T E peri o d will be u p t o a p pr o xi matel y  2 0 6 wee ks, i ncl u di n g a series of 
Scree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k place b o -
c o ntr olle d treat me nt peri o d, a 4- wee k F U peri o d, a 1 0 0 - wee k a d uca n u ma b d ose -bli n d treat me nt 
peri o d, a n d a safet y F U peri o d of a p pr o xi matel y  1 8 wee ks after t he fi nal d ose.  T he F U peri o d of 
1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half- life i n h u ma ns of 1 6 t o 2 4 da y s ( mea n 
a p pr oxi matel y  2 0 d a y s, base d o n res ults fr o m t he si n gle asce n di n g d ose st u d y [St u d y  
2 2 1 A D 1 0 1] ) a n d a ntici pate d brai n c o nce ntrati o ns of a d uca n u ma b of less t ha n o ne-t hir d t he E C5 0
(i n hi bit or y c o nce ntrati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or bi n din g fi brillar 
a m yl oi d at 8 wee ks after t he last d ose .  
D uri n g t he p lace b o-co ntr olle d p eri o d, A p o E ε 4 carriers will recei ve place b o, a d uca n u ma b
3 m g/ k g, or a d uca n u ma b 6 m g/ k g w h ereas A p o E ε 4 n o n -carriers will recei ve place b o, 
a d uca n u ma b 6 m g / k g, or a d uca n u ma b 1 0 m g / k g.  A d uca n u ma b will be titrate d f or u p t o 6 d oses 
pri or t o reac hi n g t he tar get d ose as s h o w n i n Ta ble 7 a n d Fi g ure 1 .  S u bjects w h o recei ve d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 w h o e nter t he L T E peri o d will recei ve t he 
sa me d ose of a d uca n u ma b t hat t he y recei ve d at t he e n d of t he p lace b o-co ntr olle d p eri o d ( u p t o 
6 m g/ k g a n d 1 0 m g / k g i n A p o E ε 4 carriers a n d n o n-carriers, res pecti vel y) .  S u bjects w h o 
recei ve d place b o d uri n g t he place b o-c o ntr olle d p eri o d a n d w h o e nter t he L T E peri o d will be 
assi g ne d t o treat me nt base d u p o n t heir A p o E ε 4 carrier stat us i n a 1: 1 rati o (a d uca n u ma b l o w 
d ose: a d uca n u ma b hi g h d ose) ; a d uca n u ma b will be titrate d f or u p t o 6 d oses pri or t o reac hi n g t he 
tar get d ose f oll o wi n g the sa me sc he d ule descri be d f or t he p lace b o-co ntr olle d p eri o d.  
See Secti o n 5. 3. 2 f or details of d osi n g sc he me m o dificati o n.  
I n di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d t o s u bjects w h o de vel o p A RI A .  See 
Secti o n 7. 2. 1 .
I n vesti gat ors, st u d y site staff (e xce pt f or t he desi g nate d u n bli n de d p har macist/ tec h nicia n), a n d 
st u d y s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he place b o -
c o ntr olle d peri o d .  D uri n g t he L T E peri o d , In vesti gat ors a n d s u bjects will re mai n bli n de d t o t he 
treat me nt assi g n me nt i n t he place b o-c o ntr olle d peri o d a n d t he a d uca n u ma b d ose f or t he L T E
peri o d .
7. 2.
St u d y S pecifics
7. 2. 1.  
D ose S us pe nsi o n, M o dific ati o n, or Ter mi n ati o n f or A RI A E ve nts
Disc o nti n u ati o n of D osi n g f or a Give n S u bject
T he ce ntral M RI rea di n g ce nter will re p ort i nci de nt cases of A RI A- E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he PI wit hi n a s pecifie d ti me after o bser vi n g t he fi n di n g o n M RI per t he i ma gi n g 
ma n ual pr oce d ures .  All cases of A RI A will be re vie we d b y  t he S p o ns or a n d t he PI ; decisi o ns o n 
d osi n g c o nti n uati o n, i nterr u pti o n, or disc o nti n uati o n will be base d o n cli nical s y m pt o ms, a n d t he 
M RI  i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C n otificati o n r ules will be o utli ne d i n t he 
I D M C c harter.  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 
(i ncl u di n g t he criteria t o be met f or t he c o nti n uati o n, s us pe nsi o n/res u m pti o n, per ma ne nt 
disc o nti n uati o n of d osi n g d ue t o A RI A, res u m pti o n of d osi n g after d ose s us pe nsi o n d ue t o A RI A
[i ncl u di n g r ules f or titrati n g u p t o t he assi g ne d d ose], a n d ma na ge me nt of rec urre nt A RI A) are 
pr o vi de d i n t he f oll o wi n g s u bsecti o ns.  D osi n g ma y als o be ter mi nate d at t he discreti o n of t he 
S p o ns or f or me dical reas o ns. See Sect i 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7. 2. 1. 1.
Dis p ositi o n of A RI A -E C ases
T a ble 8:
Dis p ositi o n of A RI A -E C ases
Cli nic al S y m pt o m 
Se verit y
A RI A -E Se verit y o n M RI ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
As y m pt o m atic 
C o nti n ue d osi n g at 
c urre nt d ose a n d 
sc he d ule
S us pe n d d osi n g. O nce A RI A -E res ol ves t he s u bject 
ma y res u me d osi n g at t he sa me d ose.  
Mil d
S us pe n d d osi n g.  O nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t he s u bject ma y 
res u me d osi n g at t he sa me d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y i m p ort a nt 
e ve nt ” o nl y 1
Seri o us, e xce pt f or 
“ ot her m e dic all y 
i mp ort a nt e ve nt ” 2
Disc o nti n ue D osi n g
1 “Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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. 3. 3 .
2 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 3. 3 .

S u bjects w h o de vel o p mi l d A RI A-E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 
d ose .  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d , i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
as well as bi o mar ker a n d 
P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A- E has res ol ve d per
t he ce ntrall y rea d M RI .  T he S p o ns or ma y  re q uire t hat t he s u bjects disc o nti n ue d osi n g 
or c o nti n ue d osi n g at a l o wer d ose le vel base d o n re vie w of safet y a n d M RI data.

S u bjects w h o de vel o p m o der ate or se vere A RI A -E, per ce ntr al M RI re a di n g,
wit h 
n o cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
as well as bi o mar ker a n d 
P K sa m ple c ollecti o n a p pr o xi mate l y e ver y 4 wee ks u ntil t he A RI A- E has res ol v e d per
t he ce ntrall y rea d M RI .  If t he A RI A-E has res ol ve d a n d t he s u bjects re mai n 
as ym pt o matic, t he s u bjects ma y  res u me treat me nt at t he sa me d ose.  O nly s u bjects 
w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me 
treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y 
i m p ort a nt e ve nt ” o nl y) cli nic al s y m pt o ms at a n y ti me d uri n g t he st ud y  will 
te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as 
well as bi o mar ker a n d P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he 
A RI A- E has res ol ve d per t he ce ntrall y rea d M RI.  If t he A RI A -E has res ol ve d a n d t he 
cli nical s ym pt o ms ha ve res ol ve d, t he s u bject ma y  res u me treat me nt at t he sa me d ose.  
O nl y  s u bjects w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o 
res u me treat me nt.    

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ”) 
cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will per ma ne ntl y disc o nti n ue 
treat me nt.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d,
i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A as well as bi o mar ker 
a n d P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A -E has 
res ol ve d per ce ntrall y rea d M RI.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 2.
A RI A -H ( Micr o he m orr h a ge)
I n t his st u dy, ne w i nci de nt micr o he m orr ha g es are defi ne d as ne w i nci de nt micr o he m orr ha ges 
t hat occ ur o n treat me nt a n d d o n ot i ncl u de micr o he m orr ha ges at baseli ne.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 9:
Dis p ositi o n of A RI A -H ( Micr o he m orr h a ge) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Mi cr o he morr h a ges 1 ( Ce ntr al Re a d)
≥1 a n d ≤4
≥5 a n d ≤9
≥1 0
As y m pt o m atic
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble, t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt micr o he m orr ha ges = ne w i nci de nt micr o he m orr ha ges o n treat me nt; d oes n ot i ncl u de 
micr o he m orr ha ges at baseli ne.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 pi talizati 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 as 
descri be d i n Secti o n 1 5. 3. 3 .
3 S A Es 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), 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/ 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. 3. 3 .
As y m pt o m atic A RI A -H ( Micr o he m orr h a ge) 

S u bjects w h o de vel o p a ≥1 a n d ≤4 ne w i nci de nt micr o he m orr h a ge (s) at a n y ti me 
d uri n g t he st u d y ma y co nti n ue treat me nt at t he c urre nt d ose.

S u bjects w h o de vel o p ≥5 a n d ≤9 ne w i nci de nt micr o he m orr h a ges occ urri n g at a n y  
ti me d uri n g t he st u dy will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or 
a n M RI a n d M O C A
as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks 
( ± 3 da ys) u ntil t he micr o he m orr ha ge is c o nfir me d as sta ble per t he ce ntrall y rea d 
M RI .  A micr o he m orr ha ge is c o nsi dere d sta ble if it is u nc ha n ge d 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 2 
wee ks ( ± 3 da ys) later.  O nce t he micr o he m orr ha ge is dee me d sta ble, s u bjects ma y  
res u me treat me nt at t he sa me d o se.  O nl y s u bjects w h o ha ve n ot misse d m ore t ha n 4 
c o nsec uti ve d oses will be all o we d t o res u me treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

S u bjects w h o de vel o p ≥1 0 ne w i nci de nt micr o he m orr h a ges d uri n g t he st u d y  will 
per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic 
visits f or assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d 
M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil 
t he micr o he m orr ha ges are dee me d sta ble per ce ntrall y rea d M RI.
S y m pt o m atic A RI A - H ( Micr o he m orr h a ge)

S u bjects w h o de vel o p ≤9 ne w i nci de nt micr o he m orr h a ges a n d mil d, m o der ate, 
se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y [ Secti o n 1 5. 3. 3 ]) 
cli nic al s y m pt o ms will te m p oraril y s us pe n d treat me nt, b ut s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or 
a n M RI a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks 
( ± 3 da ys) u ntil t he A RI A -H ( mic r o he m orr ha ge(s)) is c o nfir me d sta ble per t he 
ce ntrall y rea d M RI.  Micr o he m orr ha ges are c o nsi dere d sta ble if t he y  are u nc ha n ge d 
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 2 wee ks ( ± 3 da ys) later.  O nce A RI A-H ( micr o he m orr ha ge) is dee me d 
sta ble a n d t he cli nical sy m pt o ms ha ve res ol ve d, t he s u bject ma y  res u me treat me nt at 
t he sa me d ose.  O nly s u bjects w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses 
will be all o we d t o res u me treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 3. 3 ]) cli nic al s y m pt o ms ass oci ate d wit h micr o he m orr h a ge(s) will 
per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as 
well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
micr o he m orr ha ge(s) is c o nfir me d sta ble per ce ntrall y  rea d M RI.  

S u bjects w h o de vel o p ≥1 0 ne w i nci de nt micr o he m orr h a ges , re gar dless of s ym pt o m 
se verit y, d uri n g t he st u d y will per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks (± 3 da y s) u ntil t he micr o he m orr ha ges are dee me d sta ble per 
ce ntrall y rea d M RI.  
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
7. 2. 1. 3.
A RI A -H ( S u perfici al Si der osis)
T a ble 1 0:
Dis p osi ti o n of A RI A-H ( S u perfici al S i der osis) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Are as of S u perfici al Si der osis 1 ( Ce ntr al Re a d)
1
2
> 2
As y m pt o m atic
C o nti n ue d osi n g at 
c urre nt d ose a n d sc he d ule
S us pe n d d osi n g .
Once A RI A -H 
is sta ble t he s u bject ma y res u me 
d osi n g at t he sa me d ose. 
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g .
Once A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose.  
M o der ate
Se vere 
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt s u perficial si der osis = ne w i nci de nt s u perficial si der osis o n treat me nt.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nifi ca 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 as 
descri be d i n Secti o n 1 5. 3. 3 .
3 S A Es re q uiri n g pe r 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), 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/ or res ult i n 
persiste nt or si g nifica nt disa bilit y/i n ca 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. 3. 3 .
As y m pt o m atic A RI A -H ( S u perfici al S i der osis)

S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis) ma y  c o nti n ue treat me nt at t he c urre nt d ose, b ut m ust ha ve 
a n u nsc he d ule d visit f or a n M RI a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d as 
sta ble per t he ce ntrally rea d M RI .  S u perficial si der osis is c o nsi dere d sta ble if it is 
u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  

S u bjects w h o de vel o p 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d treat me nt , b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A- H (s u perficial si der osis) is 
c o nfir me d as sta ble per t he ce ntrall y  rea d M RI.  S u perficial si der osis is c o nsi dere d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he s u perficial si der osis 
is dee me d sta ble, t he s u bjects ma y res u me treat me nt at t he sa me d ose.  O nl y s u bjects 
w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o res u me 
treat me nt.  

S u bjects w h o de vel o p > 2 f oc al are as of he m osi der osis ( s u perfici al si der osis) 
occ urri n g at a n y ti me d uri n g t he st u d y m ust per ma ne ntl y disc o nti n ue treat me nt a n d 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H (s u perficial si der osis) is 
c o nfir me d as sta ble per t he ce ntrall y  rea d M RI.  S u perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.   
S y m pt o m atic A RI A -H (s u perfici al si der osis)

S u bjects w h o de vel o p ≤2 ne w f oc al are a s of s u perfici al si der osis a n d mil d, 
m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y)
cli nical 
s ym pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  
a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys)
u nt il t he A RIA- H s u perficial si der osis is c o nfir me d sta ble per t he ce ntrally rea d M RI.  
S u perficial si der osis is c o nsi dere d sta ble if it is u nc ha n ge d bet wee n 2 c o nsec uti ve 
M RI s 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 2 wee ks ( ± 3 da ys)
later.  O nce t he A RI A - H (s u perficial si der osis) is dee me d sta ble a n d t he cli nical 
s ym pt o ms ha ve res ol ve d, t he s u bjects ma y  res u me treat me nt at t he sa me d ose.  O nl y 
s u bjects w h o ha ve n ot misse d m ore t ha n 4 c o nsec uti ve d oses will be all o we d t o 
res u me treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 3. 3 ]) cli nic al s y m pt o ms ass oci ate d wit h A RI A -H (s u perfici al 
si der osis) will per ma ne ntl y  disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess m e nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI 
a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) 
u ntil t he s u perficial si der osis is c o nfir me d sta ble per ce ntrall y rea d M RI.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

S u bjects w h o de vel o p > 2 ne w f oc al are as o f s u perfici al si der osis re gar dless of 
cli nical s ym pt o m se verit y  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d sta ble 
per ce ntrall y rea d M RI.  
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 4.
A RI A -H ( M acr o he m orr h a ge)

S u bjects w h o de vel o p a n y ne w i nci de nt macr o he m orr ha ge, re gar dless of s ym pt o m 
se verity d uri n g t he st u d y,  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc h e d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or M RI a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n
e ver y 2 wee ks ( ± 3 da ys) 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.
7. 2. 1. 5.
Dis p ositi o n of C oi nci de nt A RI A -H a n d A RI A -E C ases
S u bjects w h o de vel o p A RI A- H c oi nci de nt wit h A RI A- E at a n y ti me d uri n g t he st u d y  will f oll o w 
t he m ost restricti ve g ui deli nes. Pri or t o res u mi n g treat me nt, w here a p plica ble, A RI A- E m ust 
res ol ve, A RI A-H m ust be dee me d sta ble , a n d t he s u bject m ust be as ym pt o matic.   F or e xa m ple, if 
a s u bject e x perie nces as y m pt o matic A RI A -H ( 1 -4 micr o he m orr ha ges) c oi nci de nt wit h A RI A -E 
assesse d as m o derate o n M RI  a n d acc o m pa nie d b y mil d cli nical s ym pt o ms, t he d ose s h o ul d be 
s us pe n de d per t he A RIA- E g ui deli nes s u m marize d i n Ta ble 1 1 .
7. 2. 1. 6.
Res u m pti o n of St u d y Tre at me nt After S us pe nsi o n d ue t o A RI A
7. 2. 1. 6. 1.
M RI M o nit ori n g
W he n treat me nt res u mes after a d ose s us pe nsi o n d ue t o A RI A, a n M RI a n d M O C A
will be 
perf or me d as well as bi o mar ker a n d P K sa m ple c ollecti o n 2 wee ks ( ± 3 da ys) after t he sec o n d 
a d mi nistrati o n o f t he restarte d d ose if t he y d o n ot ha ve a sc he d ule d MRI  occ urri n g d uri n g t his 
peri o d .  I n a d diti o n, if treat me nt was s us pe n de d d uri n g t he d ose titrati o n pri or t o t he s u bject 
reac hi n g t he ma xi m u m assi g ne d d ose, a n M RI  a n d M O C A will be perf or me d as well as 
bi o mar ker a n d P K sa m ple c ollecte d 2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of eac h 
i ncrease i n d ose.  M RIs will ot her wise be perf or me d as i n dicate d i n t he Sc he d ules of E ve nts 
( Secti o n 4. 2 ).
7. 2. 1. 6. 2.
D osi n g U p o n Res u m pti o n of St u d y Tre at me nt
S u bjects w h o s us pe n d treat me nt d ue t o A RI A f or t he first ti me ma y res u me treat me nt at t he sa me 
d ose if t he y meet t he criteria as descri be d i n Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5 . S u bjects w h o s us pe n d 
a n d t he n res u me d osi n g after ha vi n g alrea d y reac he d t heir assi g ne d t o p d ose le vel are t o c o nti n ue 
d osi n g at t hat d ose le vel.  H o we ver, if d osi n g is s us pe n de d d uri n g t he d ose titrati o n peri o d, t he 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
s u bject ( 1) m ust recei ve at least 2 d oses at t he restart d ose bef ore titrati n g u p t o t he ne xt d ose 
le vel a n d ( 2) m ust c o m plete at least t he re q uire d n u m ber of d oses at t hat d ose le vel per t heir 
assi g ne d d osi n g re gi me n, as o utli ne d i n Ta ble 1 1 .  
T a ble 1 1:  
Res u m pti o n of St u d y Tre at me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A
D uri n g Titr ati o n
Assi g ne d D osi n g 
Re gi me n 
(M a xi m u m D ose )
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
A p o E ε 4 ( +)
L o w D ose ( 3 m g/ k g)
1 m g/ k g
1
2
Hi g h D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
A p o E ε 4 ( -)
L o w D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
7. 2. 1. 7.
M a n a ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI)
If t he s u bject has a sec o n d occ urre nce of A RI A (i.e., a sec o n d occ urre nce of A RI A- E or of 
A RI A- H, or A RI A -E a n d A RI A- H) t hat re q uires d ose s us pe nsi o n, after t he A R I A- E resol ves or 
sta bilizes, t he s u bject is t o res u me d osi n g at t he ne xt l o wer d ose a n d is t o recei ve 2 d oses at t hat 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
d ose le vel (i.e., t he restart d ose) bef ore titrati n g u p t o t he ne xt hi g her d ose.  O nce d osi n g has 
res u me d, t he g ui deli nes o utli ne d i n Ta ble 1 1 a p pl y, u nless t he s u bject has re d uce d fr o m 1 m g / k g 
t o place b o.  I n t his case, t he s u bject will re mai n o n place b o f or t he d urati o n of t he place b o-
c o ntr olle d p orti o n of t he st u d y .  If a s u bject res u mes t reat me nt after A RI A, a n M RI a n d M O C A 
will be perf or me d as well as bi o mar ker a n d P K sa m ple c ollecti o n 2 wee ks ( ± 3 da y s) after t he 
sec o n d a d mi nistrati o n of t he restarte d d ose, a n d 2 wee ks ( ± 3 da y s) after t he sec o n d 
a d mi nistrati o n of eac h i ncrease i n d ose u nless t he s u bject has a sc he d ule d M RI  d uri n g t his 
peri o d.  M RI s will ot her wise be perf or me d as i n dicate d i n t he Sc he d ules of E ve nts ( Secti o n 4. 2 ).
If t he s u bject e x perie nces a t hir d e pis o de of A RI A t hat re q uires d ose s us pe nsi o n, t he s u bject 
m ust disc o nti n ue st u d y  treat me nt.  S u bjects w h o 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 c o nti n ue all pr ot oc ol -re q uire d tests a n d assess me nts.  
S u bjects w h o de vel o p A RI A d uri n g t he place b o -c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d ose are eli gi ble t o e nter t he L T E peri o d a n d will recei ve t he l o west d ose 
t hat t he y ha ve t olerate d d uri ng t he place b o -c o ntr olle d peri o d.  A s u bject w h o is s witc he d t o 
place b o b ut re mai ns i n t he st u d y  may be titrate d t o a d uca n u ma b 1 m g / k g d uri n g t he L T E peri o d .
7. 2. 2. 
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 
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 nt i n ue d if n ot c o m plete d wit hi n 3 h o urs.  
Refer t o 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 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.
7. 3.
O v er all St u d y D ur ati o n a n d F oll o w -U p
T he st u d y  peri o d will c o nsist of scree ni n g, treat me nt, a n d F U .
T he d o u ble -bli n d , place b o -c o ntr olle d peri o d of t he st u d y will c o nsist of a n 8-wee k scree ni n g 
peri o d, a 7 6- wee k treat me nt peri o d , a n d a safet y F U peri o d of 1 8 wee ks after t he fi nal d ose .  
S u bjects will ha ve a p pr o xi matel y  3 2 sc he d ule d cli nic visits d uri n g t he place b o -c o ntr olle d peri o d, 
a n d u p t o 8 tele p h o ne safet y  F U c o ntacts, as f oll o ws:

Scree ni n g Visits n o m ore t ha n 6 0 da y s bef ore t he first d ose of st u d y treat me nt o n 
D a y 1 ( visits will be c o n d ucte d o n m ulti ple da ys).  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 relate d t o P E T 
sca ns a n d s u bject t o S p o ns or a p pr o val.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
S u bject s ma y als o pr ocee d directl y t o t he f ull c o nse nt pr ocess, w hic h 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 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, M M S E a n d R B A N S) m ust 
be perf or me d at Scree ni n g Visit 1 .  T he A D A S -C o g 1 3 a n d A D C S -A D L -M CI  will be perf or me d 
at Scree ni n g Visit 2 wit hi n 2 0 da y s after Visit 1 a n d m ust N O T be perf or me d o n t he sa me da y as 
t he C D R, M M S E a n d R B A N S.  T he N PI -1 0 ca n be perf or me d at a n y ti me d uri n g Scree ni n g as 
l o n g as it is perf or me d after t he C D R (e. g., i ncl u di n g at Scree ni n g Visit 1).  All ot her c o g niti ve 
assess me nts 
 ma y be perf or me d at a ny ti me d uri n g Scree ni n g after 
eli gi bilit y is c o nfir me d d uri n g Scree ni n g Visit 1.  T he M RI  at Scree ni n g Visit 2 s h o ul d be d o ne 
o nl y  after t he 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 P E 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.  
S u bject eli gi bilit y  f or t he st u d y will be deter mi ne d n o m ore t ha n 6 0 da ys pri or t o st u d y e ntr 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 relate d t o P E T 
sca ns a n d s u bject t o S p o ns or a p pr o val.
S u bjects w h o fail Scree ni n g will be per mitte d t o be rescree ne d o nce at t he S p o ns or’s discreti o n .  
S u bjects w h o fail Scree ni n g d ue t o P E T, M M S E, C D R, he patitis B or C res ults, or a b n or mal 
M RI  fi ndi n gs will n ot be all o we d t o re scree n.  
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 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 nin g Visit 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.  
7. 3. 2.
Tre at me nt
Eli gi ble s u bjects will re p ort t o t he st u d y  site t o recei ve st u d y treat me nt e ver y 4 wee ks f or 
7 6 wee ks ( 2 0 d oses).  All 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 will be 
eli gi ble t o e nter t he L T E peri o d a n d will recei ve st u d y treat me nt e ver y 4 wee ks f or a n a d diti o nal 
1 0 0 wee ks ( 2 6 d oses), wit h t he first d ose a d mi nistere d a p pr o xi matel y  4 wee ks after t he fi nal d ose 
i n t he place b o - c o ntr olle d peri o d of t he st u d y .
7. 3. 3.
F o ll o w- U p
All s u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d are t o ret ur n t o t he st u d y site 
a p pr o xi matel y 2 wee ks after t he fi nal d ose f or cli nical assess me nts.
S u bjects partici pati n g i n t he place b o - c o ntr olle d peri o d a n d n ot e nteri n g t he L T E peri o d are t o 
ret ur n t o t he st u d y site f or an F U V isit at Wee k 9 4 ( 1 8 wee ks after t he last d ose).  T he fi nal st u d y  
visit f or t hese s u bjects will be Wee k 9 4.
S u bjects w h o partici pate i n t he L T E peri o d are t o ret ur n t o t he st u d y site t o recei ve t heir first 
L T E d ose a p pr o xi matel y 4 wee ks after t heir last d ose i n t he place b o -c o ntr olle d peri o d of t he 
st u d y.  A F U V isit will occ ur at Wee k 1 9 8 ( 1 8 wee ks after t he last L T E d ose ).  T he fi nal st u d y  
visit f or s u b jects partici pati n g i n t he L T E peri o d will be Wee k 1 9 8.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
S u bjects w h o 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 c o nti n ue all pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil wit h dra wal of c o nse nt.  S u bjects are 
e nc o ura ge d t o ret ur n f or F U assess me nts 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, as are s u bjects w h o wit h dra w fr o m t he st u d y. 
7. 4.
St u d y St o p pi n g R ules
Bi o ge n m a 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.
D osi n g ma y  be ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e xcl usi vel y o n safety a n d t olera bilit y data or f oll o wi n g t he f utilit y a nal ys is, or at t he discreti o n of 
t he S p o ns or; t heref ore t here are n o st u dy -s pecific st o p pi n g r ules defi ne d i n t his pr ot oc ol.  
7. 5.
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 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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
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 foll o wi n g eli gi bilit y  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  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.
2.
A ge d 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 , please refer t o 
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 or m il d A D.
5.
M ust ha ve a p ositi ve a m y l oi d P E T sca 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 f or s u bjects n ot partici pati n g i n t he a m yl oi d P E T 
c o h ort.  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 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 o r M CI
d ue t o A D or mil d A D 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:

A C D R -Gl o bal Sc ore of 0. 5 .

A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair me nt (base d 
u p o n t he Dela y e d Me m or y In de x ( D MI) sc ore).

A n M M S E sc ore bet wee n 2 4
a n d 3 0 (i ncl usi ve).
7.
A part fr o m a cli nical dia g n osis of earl y 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  a n d Scree ni n g assess me nts.
8.
M ust c o nse nt t o a p oli p o pr otei n E ( 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 j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  A n i nf or ma nt/care part ner s h o ul d be a vaila ble f or t he d uratio n of t he st u d y , 
a n d t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8. 2.
E xcl usi o n Criteri a
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 oint s pecifie d i n t he i n di vi d ual criteri o n liste d:
Me dic al 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 yr 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 o-te m p oral 
de me ntia, hea d tra u ma).
2.
Cli nicall y  si g nifica nt ps yc hiatric ill ness (e. g., u nc o ntr olle d maj or de pressi o n, 
sc hiz o p hre nia, 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 ntrally 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) 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 y i 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).

Greater 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) .  

C ortical i nfarct ( defi ne d as > 1. 5 c m i n dia meter) .  

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 
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 safet y 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 In 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 
Ass 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8.
Cli nicall y  si g nifica nt 1 2-lea d E C G a b n or malities, as deter mi ne d by t he I n vesti gat or.
9.
U nc o ntr olle d h y pert e nsi o n defi ne d as : avera ge of 3 s y st 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/ 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 dy), or persiste nt S B P/ D B P rea di n gs > 1 8 0/ 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 t he S p o ns or:  

S u bjects wit h ca ncers i n re missi o n m ore t ha 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.  

S u bjec ts wit h pr ostate ca ncer i n sit u.
1 1. Hist or y  of seiz ure wit hi n 1 0 years pri or t o Scree ni n g.
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 (e. g., re peate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥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 his t 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. Hist 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 ( HI V).
1 7. Hist or y  of or p ositi ve test res ult at Scree ni n g f or he pa titis C vir us a nti b o d y or he patitis B 
vir us ( defi ne d as p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g] or he patitis B c ore 
a nti b o d y [ H Bc A b]).  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 he patitis B s urface a nti b o d y Ig G, a n d 
p ositi ve H Bc A b) are eli gi ble t o partici pate i n t he st u d y  ( U S Ce nters f or Disease C o ntr ol 
a n d Pre ve nti o n’s i nter pretati o n of t he he patitis B ser ol o g y  pa nel).
1 8. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns, or hist or y of h y p erse 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 (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n).
1 9. 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, 
w hic h 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 safety or i nterfere wit h 
t he st u d y assess me nts.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
Me dic ati o ns
2 0. 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 g niti 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 1. 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 ni n g Visit 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 pe zil, 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.
2 2. Use of me dicati o ns wit h platelet a nti -a g gre ga nt or a nti -c oa g ula nt pr o perties (t he use of 
as piri n at a pr o p h yl actic dose [ ≤3 2 5 m g dail y ] is all o we d).
2 3. Use of illicit narc otic me dicati o n.
2 4. 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 5. 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 A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 6. Parti ci 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 wit hi n 1 2 m o nt hs of 
Scree ni n g 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  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 - E d uri n g a pre vi o us disease -m o d if yi n g trial s h o ul d be 
e xcl u de d.  
2 8. Partici pati o n i n a pre vi o us st u d y  wit h a d uca n u ma b (s u bject is eli gi ble if he/s he di d n ot 
recei ve acti ve a d uca n u ma b).
St u dy Pr oce d ures
2 9. C o ntrai 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 0. 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 1. A ne gati ve P E T sca n res ult w it h a n y a myl 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 2. 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6
3 3. F or s u bjects w h o c o nse nt t o l u m bar p u nct ure (L P ), a n y c o ntrai n dicati o ns t o ha vi n g a LP 
(e. g., platelet c o u nt < 1 0 0, 0 0 0/ µ L, l u m bar s pi ne def or mit y).  A n y s y m pt o ms ca use d b y  or 
relate d t o t he o pti o nal L P d uri n g Scree ni n g m ust be res ol ve d pri or t o ra n d o mizati o n .  
S u bjects ma y  still partici pate i n t he o verall st u d y e ve n if partici pati o n i n t he o pti o nal LP 
p orti o n is c o ntrai n dicate d .  
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 will be per mitte d t o be 
rescree ne d o nce at t he S p o ns or’s discreti o n, e xce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R, he patitis B or C, or a b n or mal M RI fi n di n gs .
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 of 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 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 7 8:
1.
S u bject m ust ha ve c o m plete d t he p lace b o-co ntr olle d p eri o d of t he st u d y i ncl u di n g t he
Wee k
7 8 Visit .  S u bject m ust ha ve ta ke n at least 1 4 d oses a n d n ot ha ve misse d m ore t ha n 
4 c o nsec uti ve d oses .  S u bjects w h o d o n ot meet t hese criteria ca n e nter t he L T E peri o d 
o nl y  wit h S p o ns or’s a p pr o val.
2.
M M S E sc ore > 1 5 at t he Wee k 7 8 Visit.
3.
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 pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt ( or asse 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.
4.
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.
5.
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.
6.
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.
7.
Has o ne i nf or ma nt/care part ner w h o , i n t he I n vesti gat or’s j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  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 t he u se of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .
8. 4.
E xcl usi o n Criteri a f or 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 at Wee k 7 8 t he y ha ve:
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 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
9.
E N R O L L M E N T , R E GI S T R ATI O N, A N D R A N D O MI Z A TI O N
9. 1.
Scree ni n g a n d E nr oll me nt
S u bjects ( or t heir le gally a ut h orize d re prese ntati ve, w here a p plica ble) 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 
ca n c o m plete t he ne ur oc o g niti ve scales ( C D R, M M S E a n d R B A N S) 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 3 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 
w hic h w o ul d all o w t he a d mi ni strati 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 .  
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 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 y s; 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 relate d t o P E T sca n iss ues a n d s u bject t o S p o ns or a p pr o val.  If a s u bject is 
e xcl u de d fr o m t he st u d y, t he reas o ns f or e xcl usi o n will 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.  T he t otal st u d y  d urati o n f or eac h s u bject partici pati n g o nly 
i n t he place b o-c o ntr olle d peri o d will be a p pr o xi matel y  1 0 2 wee ks (a p pr o xi matel y a n 8-wee k 
scree ni n g p eri o d, 7 6 wee ks of place b o or a d uca n u ma b d osi n g, a n d 1 8 wee ks of F U ). 
9. 2.
R a n d o miz ati o n a n d Re gistr ati o n of S u bjects
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra n d o mize d o nl y after all 
baseli ne assess me nts ha ve bee n c o m plete d a n d t he In 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 .  N o s u bject ma y  be gi n treat me nt pri or t o assi g n me nt 
of a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y  s u bject i de ntificati o n 
n u m bers or ra n d o mizati o n sc he d ule assi g n me nts 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.  Re screene d s u bjects will be assi g ne d a ne w n u m ber .  
S u bjects will be ra n d o mize d t o recei ve a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose : place b o
i n a 1: 1 : 1 rati o.  T he ra n d o mizati o n will be stratifie d b y  site a n d A p o E ε 4 stat us (carrier or 
n o n- carrier), s o t hat a p pr o xi matel y 6 0% t o 7 0 % A p o E ε 4 carriers are e nr olle d .  E nr oll me nt will 
als o be m o nit ore d, via t he IR T, s uc h t hat t he p o p ulati o n of s u bjects wit h mil d A D re prese nts a 
s mall perce nta ge of t he t otal e nr olle d i n t he trial.  S u bjects w h o wit h dra w fr o m t he st ud y m a y  n ot 
be re place d.
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
T his st u d y  c o nsists of a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d peri o d, f oll o we d by a 
d ose - bli n de d L T E peri o d wit h all s u bjects recei vi n g a d uca n u ma b .  
F or t he d o u ble - bli n de d place b o - c o ntr olle d peri o d, all st u d y staff w h o c o n d uct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts .  T he rati n g H C Ps s h o ul d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
re mai n bli n de d t o treat me nt assi g n me nt as well as s u bject care ma na ge me nt a n d o nl y ha ve access 
t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  As a 
place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are re q uire d t o ma na ge all 
as pects of st u d y treat me nt recei pt, dis pe nsi n g a n d pre parati o n.  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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
 or Bi o ge n safety staff.
F or t he L T E peri o d , t he d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d tr eati n g H C P 
s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nl y ha ve access t o t he i nf or mati o n 
necessar y  t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n t he st u d y
bli n d, it is i m perati ve t hat d ose i nf or mati o n is 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 bli n de d st u d y  tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
or Bi o ge n safety staff .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
1 0.
D I S C O N TI N U A TI O N O F ST U D Y T R E A T M E N T A N D/ O R
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:

A RI A- E acc o m pa nie d b y seri o us cli nical s y m pt o ms e xce pt f or “ ot her me dicall y 
i m p orta nt e ve nt” as defi ne d i n Ta ble 8 .

S y m pt o matic A RI A -H ( m icr ohe m orr ha ges) wit h seri o us cli nical s y m pt o ms
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 9 .

S y m pt o matic A RI A -H (s u perficial si der osis) wit h or seri o us cli nical s y m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 1 0 .

A RI A - H wit h ≥1 0 micr o he m orr ha ges a n d/or > 2 f ocal areas of s u perficial 
si der osis.  

A n y  ne w i nci de nt macr o he m orr ha ge.

A t hir d rec urre nce of A RI A after rec halle n ge t hat re q uires d ose s us pe nsi o n
See Secti o n 7. 2. 1 f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d ucti o n d ue t o 
A RI A- E or A RI A -H.

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 
a n d pre g na nc y m ust be re p orte d 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.

T he s u bject e x perie nces a me dical e mer ge nc y t hat necessitates per ma ne nt 
dis c 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.  

T he s u bjec t 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 vesti gat or f or me dical reas o ns.

At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce.
T he reas o n f or disc o nti n uati o n of st u d y  treat me nt m ust be rec or de d i n t he s u bject’s cas e re p ort 
f or m (C R F ).
A s u bject w h o disc o nti n ue s treat me nt is t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil t he s u bject wit h dra w s c o nse nt.  T he site 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
is t o c o ntact t he S p o ns or as s o o n as p ossi ble after disc o nti n uati o n t o c o nfir m w het her t he 
efficac y assess me nts o utli ne d f or t he E O T Visit i n Secti o n 4. 2 nee d t o be perf or me d.  
1 0. 2.
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 o r 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 ws c o nse nt.

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 S p o ns or .
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 s h o ul d 
c o m plete t he E O T Visit after t he reas o n f or wit h dra wal is i de ntifie d .  F or s uc h s u bjects, t he site 
is t o c o ntact t he S p o ns or as s o o n as p ossi ble after wit h dra wal t o c o nfir m w het her t he efficac y  
assess me nts o utli ne d f or t his visit i n Secti o n 4. 2 nee d t o be perf or me d.  T hese s u bjects are als o t o 
ret ur n t o t he site f or a F U Visit 1 8 wee ks after recei vi n g t heir last d ose of st u d y  treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 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 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 .  
Please see Secti o n 4. 2 ( Sc he d ule of E ve nts) f or t he st u d y treat me nt i nf usi o n sc he d ule d uri n g t he 
p lace b o-co ntr olle d a n d L T E p eri o ds of t he st u d y.
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   
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.  
1 1. 1. 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.
1 1. 2.
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule
Refer t o Secti o n 7. 2. 1 ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 2 (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at least 2 1 da ys a part.  If t he d osi n g i nter val ca n n ot be met, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y t he st u d y me dical m o nit or .
1 1. 3.
Prec a uti o ns
N ot a p plica ble .
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.
Pri or a n d 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 bjec t’s fi nal cli nic visit (i ncl u di n g t he F U Visit).
N o pre me dicati o n (e. g., a nti-aller g y dr u gs, a nti p yr 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 are all o we d 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 .  

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, are all o we d 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 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 are all o we d d uri n g t he st u d y.  
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 .
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 nt i-a g gre ga nt or a nti-c 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 dicati 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).  L o cal 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 m a y  be per mitte d at t he S p o ns or ’s dis creti 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 n str 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 
(see all o we d c o nc o mita nt t hera py a b o ve ) a n d a v oi d starti n g a ny 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, as it 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 or of a ny 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 b y  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, wit h t he e xce pti o n of me dicati o ns use d t o treat A Es, w hic h w o ul d n ot res ult i n 
a ut o matic wit h dra wal .  T he S p o ns or 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 v isit f or a c ha n ge i n A D me dicati o n, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he 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 psy, p h ys ical 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 F U visit), u nless t he s u bjects is bei n g f oll o we d f or st u dy -relate d t o xicit y.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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, a ll re g ulat or y re q uire me nts re gar di n g p ostst u d y access will be met.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6
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° 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 ye d f or m ore t ha n 2 h o urs, t he n it s h o ul d be ke pt at 2° 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 ye 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 ui re 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
(or its desi g nee ), 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 pers o n nel 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 nt 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.  
U nles s 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 treat me nt 
acc o u nta bilit y.  B y  t he e n d of t he st u d y rec o nciliati o n m ust be ma de bet wee n t he a m o u nt of 
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 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 
T he place b o ( 0. 9 % sterile s o di u m c hl ori de f or i njecti o n) will be pr o vi de d b y  t he site i n t he f or m 
of 1 0 0 ml sali ne I V ba gs .  
1 2. 3.
A d diti o n al Pr ot oc ol -Desi g n ate d Pr o d ucts
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.
T o c o nfir m a m yl oi d pat h ol o g y  at Scree ni n g, P E T sca ns 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 t h ose 
s u bjects partici pati n g i n t he a m yl oi d P E T s u bst u d y , Scree ni n g a n d F U sca ns m ust be perf or me d 
usi n g A m y vi d.  F or s u bjects partici pati n g i n t he P E T s u bst u d y i n Ja pa n, Viza m yl (1 8F-
fl ute met o m ol) will be use d.  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 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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
P H A R M A C O D Y N A MI C A S S E S S M E N T S
Refer t o Secti o n 4. 2 f or t he ti mi n g of assess me nts.
1 3. 1.
Cli nic al Effic ac 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 efficac y of a d uca n u ma b: 

C D R

M M S E

A D A S -C o g 1 3

A D C S -A D L -M CI

N PI - 1 0
It is rec o m me n de d t hat cli nical assess me nts be perf or me d at t he sa me ti me of da y f or s u bjects 
d uri n g t heir st u d y visits .  
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s daily acti vities a n d c o g niti ve ca pa bilities .  
T he rec o m me n de d or der of a d mi nistrati o n of t he cli nical assess me nts is descri be d i n t he St u d y  
Refere nce G ui de .  
1 3. 2.
P h ar m ac o k i netic Assess me nts
Ser u m c o nce ntrati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y .  
1 3. 3.
P h ar m ac o d y n a mic Assess me nts
T he f oll o wi n g tests will be perf or me d t o assess t he p har mac o d y na mic pr o perties of a d uca n u ma b:

Serial meas ure me nt of a m y l oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y am y l oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects partici pati n g i n 
t he a m yl oi d P E T c o h ort ).  
O nl y  sites wit h ca pa bilities of perf or mi n g 1 8F- fl or beta pir P E T will be all o we d t o 
perf or m t his assess me nt .  I nvesti gat or partici pati o n i n t his part of t he st u d y is o pti o nal 
a n d c o nti n ge nt u p o n a p pr o val b y  his/ her et hics c o m mittee ( E C) or i nstit uti o nal re vie w 
b oar d (I R B) .  If t he I n vesti gat or is n ot partici pati n g or t he test is n ot a p pr o ve d b y 
his/ her E C/I R B, t he rele va nt sec ti o n of t he I C F will n ot be a p plica ble t o t hat site.
S u bject partici pati o n i n t his part of t he st u d y  is o pti o nal at partici pati n g sites.  
I nf or me d c o nse nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a se parate pr oce d u ral ma n ual f or P E T.  A p pr o xi matel y 
4 0 0 s u bjects are e x pecte d t o partici pate i n t he a m yl oi d P E T s u bst u d y.  






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 4.
S A F E T Y A S S E S S M E N T S
See Secti o n 4. 2 f or t he ti mi n g of 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 m o nit ori n g.

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.

Ne ur ol o gical e xa mi nati o n.

Vital si g ns (b o d y  te m perat ure, heart rate, S B P, D B P, a n d res pirat or y rate).

1 2- lea d E C G.

Brai n M RI.

C o nc o mita nt me dicati o n, t hera p y a n d pr oce d ure m o nit ori n g.   

M O C A (f or A RI A m o nit ori n g a n d ma na ge me nt).  

C ol u m bia S uici de Se verit y  Rati n g Scale.  
1 4. 2.
L a b or at or y S afet y Assess me nts
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 .

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, A L T, A S T, lactate de h y dr o ge nase, 
ga m ma -gl uta m y l-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 .

Ur i nal ysis:  c ol or, s pecific gra vity, 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 mal).

Ser u m a n d uri ne pre g na nc y  test f or 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 In vesti gat or’s discreti o n after 
c o nsi derati o n of ris k fact ors ), H b A1c, a n d alc o h ol/ dr u g scree n at Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 4. 3.
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a nti -a d uca n u ma b 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).  C o nfir me d a nti dr u g a nti b o d y-p ositi ve sa m ples will be teste d f or t he 
prese nce of a nti -a d uca n u ma b ne utralizi n g a nti b o dies usi n g a vali date d assa y .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 5.
S A F E T Y D E FI NI TI O N S, R E C O R D I 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 u l 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 m ust be gi ve n 
t he na mes a n d tele p h o ne n u m bers of st u d y 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 necessaril y  ha ve a ca usal relati o ns hi p 
wit h t his treat me nt .  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal 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 uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct .
Deter mi nati o n of w het her a n a b n or mal la b orat or y  val ue 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 .  Alt h o u g h a b n or mal la b orat or y  val ues are ty picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or a n S A E .

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y.

A la b orat or y  a b n or malit y t hat t he In vesti gat or c o nsi ders t o be cli nicall y si g nifica nt .
P re-treat me nt, n o nseri o us A Es t hat occ ur wit hi n 4 8 h o urs after recei pt of a li ga n d will be 
ca pt ure d b y t he sites o n t he A E f or m.  
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:

R es ults i n deat h .

In 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.

R es ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y.

R es ults i n a c o n ge nital a n o mal y / birt h defect.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A n S A E ma y  als o be a n y ot her me dically i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he s u bject or ma y re q uire i nter ve nti o n t o pre vent 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 on.)
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 oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he 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 pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.

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 u nless o ne 
of t he re q uire me nts i n S ecti 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 hi p of t he e ve nt t o st u d y treat me nt as defi ne d i n Secti o n 1 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 .






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e mail a c o m plete d S A E f or m.  Refer t o t he 
St u d y  Refere nce G ui de f or c o u ntr y-s pecific 
 fa x n u m bers or e mail 
1 5. 3. 4. 1.
De at h s
Deat h is a n o utc o me of a n e ve nt .  T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F .  All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt .  T he I n vesti gat or s h o ul d ma ke e ver y  eff ort t o o btai n a n d se n d 
deat h certificates a n d a ut o ps y re p orts t o 
.  T he ter m d eat h s h o ul d be 
re p orte d as a n S A E o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d by t he I n vesti gat or or Bi o ge n t o be relate d t o t he st u d y treat me nt a d mi nistere d.
A p pr o priate pers o n nel i n Bi o ge n Safet y  a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y  re p orti n g.  Bi o ge n or desi g nee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y a ge ncies acc or di n g t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n.
1 5. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 5. 4. 1.
Pre g n a nc y
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y a n d 
f or 2 4 wee ks after t heir l ast d ose of st u d y tre at me nt.  If a fe male 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 di ately.
T he I n vesti gat or m ust re p ort a pre g na nc y  occ urri n g i n a fe male s u bject b y  fa xi n g t he a p pr o priate 
f or m t o 
wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he 
pre g na nc y  at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u d y refere nce ma n ual.  T he 
I n vesti gat or or st u dy site staff m ust re p ort t he o utc o me of t he pre g na nc y  t o 
 
.  
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 ny d ose of st u d y treat me nt gi ve n 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 descri be d i n 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 
 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 
 e ve n if t he o ver d ose d oes 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 must 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 
 
  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, st u d y 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
 2 4-h o ur e mer ge nc y  me dical s u p p ort n u m ber.  Refer t o t he St u d y 
Refere nce G ui de’s Official 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 vise d n ot t o di v ul ge t he s u bject’s treat me nt assi g n me n t 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, n 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.
1 5. 5.
C o ntr ace pti o n Re q uire me nts
F or t he p ur p oses of t his st u d y , w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h y si ol o gically ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns:

P ost me n o pa usal

1 2 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 or 6 wee ks after s ur gical bilateral o o p h orect o m y wit h o r wit h o ut 
h y sterect o my.

P ost h y sterect o m y.

Fe male s ur gical steril izati o n (e. g., bilateral t u bal li gati o n).
F or t he p ur p oses of t his st u d y , hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g:

F or fe males of c hil d beari n g p ote ntial:

Esta blis he d use of oral, i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne s y ste m

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 occl 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.

Male se x ual part ners u n der we nt 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:

Vasect o m y wit h ne gati ve se me n a nal ys is at F U .

Use of c o n d o ms wit h s per mici de.

Fe male se x ual part ner s w h o u n der we nt s ur gical sterilizati o n (e. g., bilateral t u bal 
li gati o n), are p ost me n o pa usal, are p ost -h y sterect o m y, or are usi n g hi g hl y effecti ve 
c o ntrace ptio n as liste d a b o ve f or fe male s u bjects.
F or males a n d fe males 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 a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he I n vesti gat or w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n 
of t he cli nical trial.  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d acce pta ble met h o ds of 
c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 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 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, re gar dless of t he se verit y or relati o ns hi p 
t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g na ncies a n d F U o n t he o utc o me of t he pre g na nc y  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 S A B R ( or desi g nee) wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9

P urs ue S A E F U i nf or mati o n acti vel y a n d persiste ntl y.  F U inf or mati o n m ust be 
re p orte d to Bi o ge n S A B R ( or desi g nee) wit hi n 2 4 h o urs of t he st u d y  site staff 
bec o mi n g a ware of ne w i nf or mati o n.

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E F U 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.

Re p ort S A Es t o l ocal E C /IR Bs , 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 st u d y site acti vati o n a n d s u bject e nr oll me nt, t he C li nical M o nit or ( 
) is 
res p o nsi ble f or re vie wi n g wit h st u d y 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 ( or desi g nee) is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C /IR B s, 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 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
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 .
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 [ S D], 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.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al ysis P o p ul ati o n
T he i nte nt -t o-treat (I T T) 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 st u d y treat me nt (a d uca n u ma b or place b o), will be use d f or t he efficac y 
a nal ys es.  F or eac h e n d p oi nt, a d diti o nal c o n diti o ns ma y  a p pl y t o t he defi niti o n of t he p o p ulati o n 
f or t he a nal ysis.  S u bjects will be a nal y ze d i n t he gr o u ps t o w hic h t he y were ra n d o mize d.  
1 6. 2. 2.
Met h o ds of A n al ysis
1 6. 2. 2. 1.
Ge ner al C o nsi der ati o ns
S u m mar y  statistics will be prese nte d.  F or c o nti n u o us e n d p oi nts, s u m mar y  statistics will 
ge nerall y i ncl u de: n u m ber of s u bjects wit h data, me a n, sta n dar d de viati o n, me dia n, a n d ra n ge .  
F or cate g orical e n d p oi nts, t his will ge nerall y  i ncl u de: n u m ber of s u bjects ra n d o mize d or d ose d, 
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 .  Statistical testi n g f or 
efficac y e n d p oi nts will be ma de bet wee n eac h a d uca n u ma b re gi me n a n d place b o.  All statistical 
tests will be 2-si de d.
1 6. 2. 2. 2.
D ose Re gi me ns t o be E v al u ate d
T he f oll o wi n g d ose re gi me n s of a d uca n u ma b as c o m pare d wit h place b o will be e val uate d :

A d uca n u ma b hi g h -d ose re gi me n ( 6 m g/ k g i n A p o E ε 4 carriers a n d 1 0 m g / k g i n 
A p o E ε 4 n o n carriers).

A d uca n u ma b 6 m g / k g d ose re gi me n ( 6 m g / k g i n A p o E ε 4 carriers a n d
A p o E ε 4 n o n-carriers) .

A d uca n u ma b l o w-d ose re gi me n ( 3 m g/ k g i n A p o E ε 4 carriers a n d 6 m g / k g i n 
A p o E ε 4 n o n- carriers) .  
I n t he e ve nt t hat t he pr o p ose d ma xi m u m d ose ( 1 0 m g/ k g i n A p o E ε 4 n o n -carriers or 6 m g/ k g i n 
A p o E ε 4 carriers) is ter mi nate d after t he start of t he st u d y  ( Secti o n 5. 3. 2 ) t he defi niti o n of 
a d uca n u ma b hi g h d ose re gi me n a n d a d uca n u ma b l o w d ose re gi me n will be m o difie d as s h o w n i n 
Ta ble 1 2 .  T he d osi n g m o dificati o n will be e ntirel y base d o n i nteri m a nal ys is of o utc o mes t hat
are i n de pe n de nt of, a n d u ni nf or mati ve a b o ut, t he treat me nt-relate d efficac y effect.  C o ntr ol of 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
T y pe I err or rate is t h us mai ntai ne d wit h o ut a statistical a dj ust me nt f or s uc h a da ptati o ns[ C h o w 
a n d C ha n g 2 0 1 1] .
T a ble 1 2:
D ose Gr o u p P o oli n g Str ate g y i n t he E ve nt of Tre at me nt Gr o u p Ter mi n ati o n
Tre at me nt gr o u p(s) Ter mi n ate d
Defi niti o ns of Re vise d P o ole d Tre at me nt 
Gr o u ps f or C o m p aris o n
A p o E ε 4 carrier hi g h-d ose g r o u p ( 6 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 1 0 m g/ k g
A p o E ε 4 n o n -carrier h i g h- dose g r o u p ( 1 0 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 6 m g/ k g a n d 
n o n -carrier 6 m g/ k g
A p o E ε 4 carrier h i gh -d ose g r o u p ( 6 m g/ k g) 
A N D
A p o E ε 4 n o n -carrier h i g h-d ose g r o u p ( 1 0 m g/ k g) 
A p o E ε 4 carrier 3 m g/ k g a n d n o n- carrier 
6 m g/ k g
1 6. 2. 2. 3.
C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I  err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y  e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws: a d uca n u ma b hi g h -d ose re gi me n vers us place b o, a d uca n u ma b 6 m g/ k g re gi me n vers us 
place b o, a n d a d uca n u ma b l o w -d ose re gi me n vers us place b o .  I n t he e ve nt of a d osi n g 
m o dificati o n (see Ta ble 1 2 ), t he first c o m paris o n is t he a d uca n u ma b hi g h -d ose re gi me n vers us 
place b o a n d t he sec o n d c o m paris o n is t he a d uca n u ma b l o w-d ose re gi me n vers us place b o .  If t he 
first c o m paris o n is statisticall y si g nifica nt ( p ≤0. 0 5) , t he n t he sec o n d c o m paris o n will als o be
ma de at t he 0. 0 5 α le vel.  If t he sec o n d c o m paris o n is statisticall y si gnifica nt ( p ≤0. 0 5), t he n t he 
t hir d c o m paris o n will als o be ma de at t he 0. 0 5 α le vel.  H o we ver, all c o m paris o ns after t he i nitial 
c o m paris o n wit h p > 0. 0 5 will n ot be c o nsi dere d statist icall y si g nifica nt.
Sec o n dar y  e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  I n or der t o 
c o ntr ol f or a T ype I err or f or t he sec o n dar y  e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be use d a n d will i ncl u de b ot h t he or der of t he sec o n dar y e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y  e n d p oi nts, a se q ue ntial (cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T y pe I err or rate d ue t o m ulti ple 
treat me nt c o mparis o ns .  If statistical si g nifica nce is n ot ac hie ve d f or o ne, t w o or all t hree 
c o m paris o ns, all e n d p oi nt(s) of a l o wer ra n k will n ot be c o nsi dere d statisticall y  si g nifica nt f or 1, 
2, or all 3 c o m paris o ns, res pecti vel y.  
D ue t o a c urre nt lac k of scie ntific c o nse ns us i n t he A D fiel d o n w hic h bi o mar ker(s) mi g ht be 
m ost a p pr o priate, t he selecti o n of t he bi o mar kers a n d met h o d ol o g y  f or c o ntr ol of T ype I err or 
will be pre -s pecifie d i n t he statistical a nalys is pla n ( S A P).  Ot her wise, t here will be n o m ul ti ple 
c o m paris o n a dj ust me nts f or t he tertiar y  e n d p oi nts.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
1 6. 2. 2. 4.
A n al ysis of t he Pri m ar y E n d p oi nt
T he p o p ulati o n f or t he pri mar y  e n d p oi nt a nalys is will be s u bjects i n t he I T T p o p ulati o n wit h a 
baseli ne a n d at least o ne p ost- baseli ne C D R -S B sc ore .  A mi xe d m o del re peate d meas ures 
( M M R M) m o del will be use d as t he pri mar y a nalysis t o a nal y ze c ha n ge fr o m baseli ne C D R -S B 
usi n g fi xe d effects of treat me nt, ti me, treat me nt -b y -ti me i nteracti o n, baseli ne C D R -S B, baseli ne 
C D R -S B b y  ti me, baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5.
A n al ysis of t he Sec o n d ar y E n d p oi nts
1 6. 2. 2. 5. 1. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n M M S E 
T he p o p ulati o n f or t he a nal ysis will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least 
o ne p ost -baseli ne M M S E val ue .  A M M R M m o del will be use d as t he pri mar y a nal ys is t o 
a nal yz e c ha n ge fr o m baseli ne M M S E usi n g fi xe d effects of treat me nt, ti me, treat me nt -b y -ti me 
i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y  ti me i nteracti o n a n d baseli ne A p o E ε 4
stat us 
1 6. 2. 2. 5. 2. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D A S -C o g 1 3
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D A S -C o g 1 3 sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m baseli ne A D A S -C o g 1 3 usi n g fi xe d effects of treat me nt, ti me, 
treat ment -b y -ti me i nteracti o n, baseli ne A D A S-C o g 1 3, baseli ne A D A S -C o g 1 3 b y  ti me 
i nteracti o n; baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5. 3. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D C S -A D L -M CI
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D C S -A D L -M CI sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nal ysis 
t o a nal yze c ha n ge fr o m baseli ne A D C S -A D L -M CI
usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D C S-A D L -M CI,
baseli ne A D C S -A D L -M CI b y  ti me 
i nteracti o n; baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 6.
Terti ar y E n d p oi nts A n al ysis
1 6. 2. 2. 6. 1. Pl ace b o - Co ntr olle d P eri o d
W here a p pr o priate, a M M R M m o del will be use d as t he pri mar y  a nalys is t o a nal yze c ha n ge fr o m 
baseli ne usi n g fi xe d e ffects of treat me nt, ti me, treat me nt b y ti me i nteracti o n, baseli ne val ue, 
baseli ne val ue b y ti me i nteracti o n, baseli ne M M S E a n d baseli ne A p o E ε 4 stat us.
Ot her wise, a n a nal ys is of c o varia nce or its n o n-para metric e q ui vale nt ma y  be use d t o a nalyz e 
t hese e x plorat or y  e n d p oi nts.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 6. 2. 2. 6. 2. L o n g -Ter m E xte nsi o n Peri o d
T he a d diti o nal e n d p oi nts f or t he L T E peri o d are c ha n ge fr o m baseli ne o ver t he p lace b o-
c o ntr olle d a n d L T E peri o ds of t he st u d y .  A nal ys es will be prese nte d b y treat me nt gr o u p i n t he 
place b o -c o ntr olle d peri o d usi n g t he place b o -c o ntr olle d peri o d baseli ne.  Details of t he a nal ys es 
will be pre -s pecifie d i n t he S A P .  
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 p o p ulati o n f or P K a nal y sis 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 
st u d y treat me nt, 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 p o p ulati o n P K c haracteristics of a d uca n u ma b will be deter mi ne d b y n o nli near mi xe d effects 
a p pr oac h .  C o variates t hat mi g ht i nfl ue nce t he dis p ositi o n of a d uca n u ma b (e. g., b o d y wei g ht, 
a ge, se x, i m m u n o ge nicit y, A p o E ε 4 stat us) will be e val uate d a n d t he p ote ntial e x p os ure-res p o nse 
relati o ns hi ps will be e x pl ore d.
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 recei ve d at least 1 d ose of st u d y treat me nt 
(i ncl u di n g place b o a n d 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 si g 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 dy 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 ps, 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 place b o-c ontr olle d peri o d a n d o ver t he 2 4- m o nt h 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 yste m or ga n class as 
well as f or preferre d ter ms wit hi n eac h s ys te 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 ( Me d D R A).  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
1 6. 4. 2. 2.
Cli nic al L a b or at or y Res ults
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 nalys is 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 
for 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 cate g 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 .  
1 6. 4. 2. 3.
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n cli nicall y rele va nt a b n or malities.
1 6. 4. 2. 4.
E C G
T he n u m ber a n d perce nta ge of s u bjects wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or 
a b n or mal A E) will be s u m marize d b y  treat me nt gr o u p.  
1 6. 4. 2. 5.
C ol u m bi a S uici de Se verit y R ati n g Sc ale
T he C ol u m bia S uici de Se verit y Rati n g Scale 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 ulati 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 nicity.  
1 6. 5. 2.
Met h o ds of A n al ysis
A nti- a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.
1 6. 6.
I nteri m A n al yses
1 6. 6. 1.
I nteri m F utilit y A n al ysis
A n i nteri m a nal ys is f or f utilit y of t he pri mar y  e n d p oi nt will occ ur after a p pr o xi matel y  5 0 % of t he 
s u bjects ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m f utilit y a nal ys is.  T his i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he I D M C ma y  rec o m me n d ter mi nati n g 
t he st u d y f or f utilit y if it is e vi de nt t hat t he efficac y of a d uca n u ma b is u nli kel y t o be ac hie ve d.  
T he f utilit y  criteria will be disc usse d i n detail i n t he S A P.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 6. 6. 2. 
I nteri m S u peri orit y A n al ysis
A n i nteri m a nal ys is f or s u peri orit y m a y  be perf or me d after a p pr o xi matel y  5 0 % of t he s u bjects 
ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n u e d).  T he La n -De M ets met h o d wit h O’ Brie n -
Fle mi n g st o p pi n g b o u n dar y  f or efficac y will be use d.  I n or der t o mai ntai n t he treat me nt bli n d i n 
t he e ve nt of t his i nteri m a nalys is, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be 
i n v ol ve d i n t he c o n d uct of t he st u d y after u n bli n di n g will perf or m t he i nteri m s u peri orit y
a nal ys is.  T he i n de pe n de nt gr o u p will prese nt t he u n bli n de d i nteri m a nal y sis t o t he ID M C .  T he 
ai m of t his i nteri m a nal ysis is t o all o w t he p ossi bilit y t o de m o nstrate treat me nt effect early.  T he 
a nal ys is will be disc usse d i n detail i n t he S A P.
1 6. 7.
S a m ple Size C o nsi der ati o ns
T he st u d y ’s sa m ple size is base d, i n part, o n res ults fr o m a pr ot oc ol-s pecifie d i nteri m a nal ys is 
fr o m St u d y 2 2 1 A D 1 0 3 w hic h i ncl u de d 1 year data fr o m 1, 3 a n d 1 0 m g/ k g treat me nt gr o u ps.
A sa m ple size of 4 5 0 s u bjects per treat me nt gr o u p will ha ve a p pr o xi matel y  9 0 % p o wer t o detect 
a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne C D R- S B at Wee k 7 8 bet wee n t he 
2 treat me nt gr o u ps.  T his p o wer calc ulati o n is base d o n a 2 -si de d t-test ass u mi n g e q ual varia nce 
wit h a fi nal si g nifica nce le vel of 0. 0 5, a S D of 1. 9 2 a n d a dr o p- o ut rate of 3 0 % .  T he S D esti mate 
of 1. 9 2 f or Wee k 7 8 reflects a 3 9 % i ncrease o ver t he S D fr o m t he pr ot oc ol-s pecifie d i nteri m 
a nal ys is of 1-ye ar data.
T he ass u me d tr ue mea n differe nce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d ucti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o me a n c ha n ge is esti mate d t o be 2.
T he sa m ple size ma y  be reassesse d i n a bli n de d ma n ner a p pr o xi matel y 3 m o nt hs bef ore 
e nr oll me nt is c o m plete if at least 1 5 % of t he data are a vaila ble o n t he pri mar y  e n d p oi nt.  At t his
i nteri m ti me-p oi nt, t he S D f or t he pri mar y e n d p oi nt will be esti mate d base d o n t he bli n de d data .  
T he sa m ple size ma y  be i ncrease d if t he S D is esti mate d t o be m ore t ha n a p pr o xi matel y 2. 0 7.  I n 
a d diti o n, t he sa m ple size c o ul d be i ncrease d usi n g e xter nal cli nical trial res ults t hat bec o me 
a vaila ble after t he start of t he st u d y .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 7.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n , 
, 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 nfere nce o n Har m o nisati o n (IC 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 ulati o 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 perience, i n acc or da nce wit h 
a p plica ble I C H a n d G C P g ui deli nes .  T he I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y -relate d d uties ha ve bee n dele gate d.
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 /I nstit uti o n al Re vie w B o ar d
T he I n vesti gat or m ust o btai n E C/I R B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y  
d oc u me nts pri or t o starti n g t he st u d y.  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 E C.  A c o p y  of t he ap 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 gree me nt of t he rele va nt E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) 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 C/I R B a p pr o val, w hic h s pecificall y  i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y .  Pr ot oc ol a me n d me nts 
will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he E C/I R B at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he E C/IR B a n d Bi o ge n .
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 gally a ut h orize d re prese ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns .  S u bjects ca n c o m plete t he ne ur oc o g niti ve scales 
( C D R, M M S E a n d R B A N S) as a n i nitial o pti o nal scree 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 3 scales, t he f ull c o nse nt pr ocess m ust be c o m plete d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 gall y 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 / or et h nicit y will be c ollecte d a n d will be use d 
d uri n g a nal ys is of st u d y res ults (o nl y  i n c o u ntries w here per mitte d b y l ocal la w/re g ulati o n).
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 , care gi ver a n d/ or le gall y 
a ut h orize d re prese ntati ve.  T he si g ne d a n d date d I C F will be retai ne d wit h t he st u d y  rec or ds.  
L ocal re g ul ati 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 CFs.
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 o r t o a n y testi n g u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts, ca n di dates 
m ust als o pr o vi de all a ut h orizati o ns re q uire d b y l ocal la w (e. g., Pr otecte d Healt h I nf or mati o n
aut h orizati o n i n N ort h A merica).
T he s u bject will n ot be i de ntifie d b y na me i n t he C R F or i n a n y st u d y re p orts a n d t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n , its part ner(s) a n d desi g nee(s), E C/I R Bs , 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.
D uri n g t he st u d y , s u bjects’ race a n d/ or et h nicit y will be c ollecte d ( o nly i n c o u ntries w here 
per mitte d b y  l ocal la w/re g ulati o n). T hese data ma y  be use d i n t he a nalys is of t he safety, 
efficac y, a n d/or p har mac o ki netic pr ofile of t he st u d y  treat me nt. It is u n k n o w n if t he p ote nc y  or 
effects of t he st u d y treat me nt are i nfl ue nce d b y race or et h nicit y.  
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 vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
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 pat e 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 u lati o ns.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
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 bjects 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 Ass ur a nce
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 uth orities ma y  wis h t o perf or m o nsite a u dits.  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 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.
T he Cli nical M o nit or(s) will visit t he I n vesti gat or(s) at r e 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.
D uri n g t hese visits, C R Fs a n d s u p p orti n g 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 .  
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 pr ot oc ol a d here nce, q ualit y of data, 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.
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 ntract(s) 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.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
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 raters 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 ojec t-s pecific pla ns.
1 9. 2.
St u d y C o m mittees
1 9. 2. 1.
A d vis or y C o m mittee
A n a d vis or y  c o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u dy 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y  c o m mittee will meet 
peri o dicall y t o m o nit or s u bject accr ual a n d o versee st u d y  c o n d uct, i ncl u di n g a d visi n g o n st u dy 
desi g n a n d e xec uti o n .  T he a d vis or y  c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g t he st u d y .  
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x p erts i n Alz hei mer’s disease .  
Bi o ge n will desi g nate o ne of t he partici pati n g e xter nal e x perts t o be t he c hair pers o n of t he 
a d vis or y c o m mittee.
1 9. 2. 2.
I n de pe n de nt D at a M o nit ori n g C o m mittee 
T he ID M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y  data.  Me m bers of t he ID 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 ID 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 .  T he ID M C, base d o n 
t he nat ure, fre q ue nc y, a n d/ or se verity of a n A E (s) ma y rec o m me n d pr ot oc ol mo 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.  A n I D 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 I D M C .  
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 E C/I R B a n d re g ulat or y  a ut h orities if re q uire d 
b y  l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B 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 dy .  If re q uire d by l ocal la w, s uc h m o dificati o ns m ust 
als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o i m ple me ntati o n .
H o we ver, Bi o ge n m a 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 m a y  re q uire si milar m o dificati o ns (see 
Secti o ns 1 7. 2 a n d 1 7. 3 ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
1 9. 4.
Et hics C o m mittee /I nstit uti o n al Re vie w B o ar d 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 aut h orities a n d E C/I R Bs 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 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 o n 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 off site facilit y or tra nsfer of o w ners hi p if t he In 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 St u d y  In 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 d e b y se veral fact ors i ncl u di n g b ut n ot li mite d t o t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or 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 ge n .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
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 mer'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.
C h o w S, C ha n g M .  A da pti ve Desi g n Met h o ds i n Cli nical Trials, Sec o n d E diti o n .  Sec o n d 
E diti o n e d .  B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1.
D o o d y  R S, T h o mas R G, Farl o w M, et al.  P hase 3 trials of s ola nez u ma b f or mil d -t o-m o derate 
Alz hei mer 's disease.  N E n gl J Me d .  2 0 1 4; 3 7 0( 4): 3 1 1 -2 1; c orres p o n de nce N E n gl J Me d .  
2 0 1 4; 3 7 0( 1 5): 1 4 5 9 -6 0.
D u b ois B, Fel d ma n H H, Jac o va C, et al .  Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n.  La ncet Ne ur ol .  2 0 1 0; 9( 1 1): 1 1 1 8 -2 7.
D u b ois B, Fel d ma n H H, Jac o va C, et al .  A d va nci n g researc h dia g n ostic criteria f or Alz hei mer's 
disease: t he I W G -2 criteria .  La ncet Ne ur ol .  2 0 1 4; 1 3( 6): 6 1 4 - 2 9.
Fa ga n T .  Cre nez u ma b Disa p p oi nts i n P hase 2, Researc hers Re mai n H o pef ul .  C o nfere nce 
C o vera ge Series: Alz h ei mer's Ass ociati o n I nter nati o nal C o nfere nce ( A AI C) 2 0 1 4 [I nter net] .  
Alzf or u m We b site .  2 0 1 4 J ul 2 2 [cite d 2 0 1 4 Oct 0 4] .  A vaila ble fr o m: 
htt p:// w w w.alzf or u m. or g/ ne ws/c o nfere nce- c o vera ge/cre nez u ma b -disa p p oi nts -p hase - 2-
researc hers-re mai n-h o pef ul .
Har d y J , Sel k oe DJ.  T he a m yl oi d h y p 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 ys i 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.
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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 3
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.
Le n der ki n g W R, Stee nr o d A, R ü dell K, et al .  O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI  
a n d Pr o dr o mal Alz hei mer’s Disease: C o nte nt Vali dit y of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y Sy m pt o ms of C o g niti ve Decli ne .  A d va nces i n Alz hei mer’s 
Disease .  2 0 1 4; 3: 1 -1 0.  E p u b Marc h 2 0 1 4.
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 di a g n osis of de me ntia 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 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.
M orris J C, Ble n n o w K, Fr oelic h L, et al .  Har m o nize d dia g n ostic criteria f or Alz hei mer's 
disea se: rec o m me n dati o ns.  J Inter n Me d .  2 0 1 4; 2 7 5( 3): 2 0 4 - 1 3.
Ostr o witz ki S, De pt ula D, T h urfjell L, et al .  Mec ha nis m of a m y l oi d re m o val i n patie nts wit h 
Alz hei mer disease treate d wit h ga nte ner u ma b .  Arc h Ne ur ol .  2 0 1 2; 6 9( 2): 1 9 8 - 2 0 7.  E p u b 2 0 1 1 
Oct 1 0.
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 osite d f or ms of a m yl 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 gl e 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.
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 herape 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
Wa hl u n d L O, Bar k h of F, Faze kas F, et 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.
Weller R O, S u bas h M, Prest o n S D, et al .  Peri vasc ular drai na ge of a myl oi d -beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a myl oi d a n gi o pat h y  a n d Alz hei mer's disease.  Brai n Pat h ol .  
2 0 0 8; 1 8( 2): 2 5 3 - 6 6.
Wilc oc k D M, C olt o n C A .  I mm 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/ 0 2/ 2 7.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 3 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 5
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 3 M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b
(BII B 0 3 7 ) i n S u bjects wit h Earl y Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T A B L E O F C O N T E N T S
1.
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 0
2.
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 1
3.
S Y N O P SI S ................................................................................................................. 1 4
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 7
4. 1.
St u d y  Sc he matic ......................................................................................................... 1 7
4. 2.
Sc he d ule of E ve nts ..................................................................................................... 1 8
4. 3.
A d diti o nal I nf or mati o n ...............................................................................................3 5
4. 3. 1.
Site Pers o n nel ............................................................................................................. 3 5
5.
I NT R O D U C TI O N ...................................................................................................... 3 7
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 3 8
5. 1. 1.
N o ncli nical E x perie nce ...............................................................................................3 8
5. 1. 2.
Cli nical E x perie nce ..................................................................................................... 3 9
5. 2.
St u d y  Rati o nale........................................................................................................... 4 0
5. 3.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 4 1
5. 3. 1.
D osi n g Sc he me........................................................................................................... 4 2
5. 3. 1. 1.
Pla ce b o-C o ntr olle d Peri o d .......................................................................................... 4 2
5. 3. 2.
D osi n g Sc he me M o dificati o n ..................................................................................... 4 3
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 4 3
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 ..............................................................4 5
6. 1.
Pri mar y  O bjecti ve a n d E n d p oi nt ................................................................................ 4 5
6. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts ......................................................................... 4 5
6. 3.
Tertiar y  O bjecti ves a n d E n d p oi nts ............................................................................. 4 5
6. 3. 1.
Tertiar y  O bjecti ves .....................................................................................................4 5
6. 3. 2.
Tertiar y  E n d p oi nts......................................................................................................4 6
6. 4.
L o n g -Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts .......................................................4 7
6. 4. 1.
O bjecti ves ................................................................................................................... 4 7
6. 4. 2.
E n d p oi nts ....................................................................................................................4 8
7.
S T U D Y D E SI G N .......................................................................................................4 9
7. 1.
St u d y  O ver vie w..........................................................................................................4 9
7. 2.
St u d y  S pecifics ...........................................................................................................5 0


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4
7. 2. 1.
D ose S us pe nsi o n, M o dificati o n, or Ter mi nati o n f or A RI A E ve nts ............................ 5 0
7. 2. 1. 1.
A RI A -E Cases ............................................................................................................ 5 1
7. 2. 1. 2.
A RI A -H ( Micr o he m orr ha ge) ...................................................................................... 5 2
7. 2. 1. 3.
A RI A -H ( S u perficial S i der osis) ................................................................................. 5 5
7. 2. 1. 4.
A RI A - H ( Macr o he m orr ha ge)..................................................................................... 5 7
7. 2. 1. 5.
C oi nci de nt A RI A -H a n d A RI A- E Cases .................................................................... 5 7
7. 2. 1. 6.
Res u m pti o n of St u d y  Treat me nt After S us pe nsi o n d ue t o A RI A............................... 5 7
7. 2. 1. 7.
Ma na ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI )............................................ 5 9
7. 2. 2.
I nf usi o n I nterr u pti o n................................................................................................... 5 9
7. 3.
O verall St u d y  D urati o n a n d F oll o w-U p ..................................................................... 5 9
7. 3. 1.
Scree ni n g .................................................................................................................... 6 0
7. 3. 2.
Treat me nt .................................................................................................................... 6 1
7. 3. 3.
F oll o w -U p ................................................................................................................... 6 1
7. 4.
St u d y  St o p pi n g R ules ................................................................................................. 6 2
7. 5.
E n d of St u d y ............................................................................................................... 6 2
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 6 3
8. 1.
I ncl usi o n Criteria........................................................................................................ 6 3
8. 2.
E xcl usi o n Criteria ....................................................................................................... 6 4
8. 3.
I ncl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d ................................................... 6 7
8. 4.
E xcl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d .................................................. 6 8
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I ON ............................ 6 9
9. 1.
Scree ni n g a n d E nr oll me nt ........................................................................................... 6 9
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................6 9
9. 3.
Bli n di n g Pr oce d ures ....................................................................................................6 9
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/ O R 
WI 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 ........................................... 7 1
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 7 1
1 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 7 2
1 1.
S T U D Y T R E A T M E N T U S E ..................................................................................... 7 3
1 1. 1.
Re gi me n ......................................................................................................................7 3
1 1. 1. 1.
A d uca n u ma b ...............................................................................................................7 3
1 1. 1. 2.
Place b o ........................................................................................................................7 3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 7 3
1 1. 3.
Preca uti o ns .................................................................................................................. 7 3
1 1. 4.
C o m plia nce ................................................................................................................. 7 3
1 1. 5.
Pri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 7 3
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 7 3
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 7 4
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T hera p y .............................................................................. 7 4
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 7 4
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 7 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 ................................................................ 7 6
1 2. 1.
A d uca n u ma b ............................................................................................................... 7 6
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 7 6
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 7 6
1 2. 1. 3.
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 7 7
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 7 7
1 2. 2.
Place b o ........................................................................................................................ 7 7
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 7 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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ......................................................................................................... 7 8
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 7 8
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 7 8
1 3. 3.
P har mac o d y na mic Assess me nts ................................................................................. 7 8
1 3. 4.
A d diti o nal Assess me nts.............................................................................................. 7 9
7 9
1 3. 4. 2.
A p o E Ge n ot y pi n g .......................................................................................................7 9
8 0
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 8 0
1 3. 5.
F ut ure Scie ntific Researc h Assess me nts .................................................................... 8 0
1 4.
S A F E T Y A S S E S S M E N T S ................................ ........................................................8 2
1 4. 1.
Cli nical Safet y  Assess me nts....................................................................................... 8 2
1 4. 2.
La b orat or y  Safety Assess me nts .................................................................................. 8 2
1 4. 3.
I m m u n o ge nicity Assess me nts .................................................................................... 8 3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6
1 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 .................................................................................................8 4
1 5. 1.  
Defi niti o ns.................................................................................................................. 8 4
1 5. 1. 1.
A d verse E ve nt ............................................................................................................. 8 4
1 5. 1. 2.
Seri o us A d verse E ve nt ................................................................................................ 8 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................ 8 5
1 5. 2.
Safet y  Classificati o ns.................................................................................................. 8 5
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ............................................................................. 8 5
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................ 8 6
1 5. 2. 3.
Se verit y  of E ve nts....................................................................................................... 8 6
1 5. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................8 6
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 8 6
1 5. 3. 1.
A d verse E ve nts ........................................................................................................... 8 6
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ............................................................................. 8 7
1 5. 3. 3.
Seri o us A d verse E ve nts ..............................................................................................8 7
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 8 7
1 5. 3. 4. 1.
Deat hs ......................................................................................................................... 8 8
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 8 8
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................8 8
1 5. 4. 1.
Pre g na nc y ................................................................................................................... 8 8
1 5. 4. 2.
O ver d ose ..................................................................................................................... 8 8
1 5. 4. 3.
Me dical E mer ge nc y .................................................................................................... 8 9
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 8 9
1 5. 5.
C o ntrace pti o n Re q uire me nts ...................................................................................... 8 9
1 5. 6.
Safe t y Res p o nsi bilities................................................................................................ 9 0
1 5. 6. 1.
T he I n vesti gat or .......................................................................................................... 9 0
1 5. 6. 2.
Bi o ge n .........................................................................................................................9 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 ........... 9 2
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 9 2
1 6. 2.
Efficac y  a n d P har mac o d yna mics ................................................................................9 2
1 6. 2. 1.
A nal y sis P o p ulati o n ....................................................................................................9 2
1 6. 2. 2.
Met h o ds of A nal ys is...................................................................................................9 2


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7
1 6. 2. 2. 1.
Ge neral C o nsi derati o ns ...............................................................................................9 2
1 6. 2. 2. 2.
D ose Re gi me ns t o be E val uate d ................................................................................. 9 2
1 6. 2. 2. 3.
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts .............................................. 9 3
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y E n d p oi nt............................................................................... 9 3
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 9 4
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ....................................................................................... 9 4
1 6. 3.
P har mac o ki netics ........................................................................................................ 9 4
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 4
1 6. 3. 2.
Met h o d of A nal ys is..................................................................................................... 9 5
1 6. 4.
Safet y .......................................................................................................................... 9 5
1 6. 4. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 5
1 6. 4. 2.
Met h o ds of A nal ys is................................................................................................... 9 5
1 6. 4. 2. 1.
A d verse E ve nts ........................................................................................................... 9 5
1 6. 4. 2. 2.
Cli nical L a b orat or y Res ults........................................................................................ 9 5
1 6. 4. 2. 3.
Vital Si g ns .................................................................................................................. 9 5
1 6. 4. 2. 4.
E C G ............................................................................................................................ 9 5
1 6. 4. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 9 6
1 6. 5.
I m m u n o ge nicity Data ................................................................................................. 9 6
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 6
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................... 9 6
1 6. 6.
I nteri m A nalys es ......................................................................................................... 9 6
1 6. 6. 1.
I nteri m F utilit y A nal ysis ............................................................................................. 9 6
1 6. 6. 2.
I nteri m S u peri orit y A nal ysis....................................................................................... 9 6
1 6. 7.
Sa m ple Size C o nsi derati o ns ................................ .......................................................9 6
1 7.
E T HI C A L  R E Q UI R E M E N T S ...................................................................................9 8
1 7. 1.
Declarati o n of Helsi n ki ...............................................................................................9 8
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ...........................................................9 8
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ............................................................................... 9 8
1 7. 4.
S u bject Data Pr otecti o n ..............................................................................................9 9
1 7. 5.
C o m pe nsati o n f or I nj ur y .............................................................................................9 9
1 7. 6.
C o nflict of I nterest ......................................................................................................9 9
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 .............................................. 9 9


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
8
1 8.
A D MI NI S T R A TI V E P R O C E D U R E S ..................................................................... 1 0 0
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................. 1 0 0
1 8. 2.
Q ualit y  Ass ura nce..................................................................................................... 1 0 0
1 8. 3.
M o nit ori n g of t he St u d y ............................................................................................ 1 0 0
1 8. 4.
St u d y  F u n di n g........................................................................................................... 1 0 0
1 8. 5.
P u blicati o ns ............................................................................................................... 1 0 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...................... 1 0 1
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ............................................................................... 1 0 1
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ............................................................................... 1 0 1
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................. 1 0 1
1 9. 1. 3.
Electr o nic Data Ca pt ure ............................................................................................ 1 0 1
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ................................................... 1 0 1
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts.................................................................... 1 0 1
1 9. 1. 6.
Ne ur oc o g niti ve Assess me nts .................................................................................... 1 0 1
1 9. 2.
S t u d y C o m mittees..................................................................................................... 1 0 2
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................. 1 0 2
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee ................................................................ 1 0 2
1 9. 3.
C ha n ges t o Fi nal St u d y  Pr ot oc ol .............................................................................. 1 0 2
1 9. 4.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n ...................................................................................... 1 0 2
1 9. 5.
Rete nti o n of St u d y  Data............................................................................................ 1 0 3
1 9. 6.
St u d y  Re p ort Si g nat or y.............................................................................................1 0 3
2 0.
R E F E R E N C E S ......................................................................................................... 1 0 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 ....................................... 1 0 6
LI S T O F T A B L E S
Ta ble 1:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8 ................. 1 8
Ta ble 2:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 2 2
Ta ble 3:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -u p P h o ne Call Sc he d u le D uri n g 
t he Place b o-C o ntr olle d Peri o d .................................................................................... 2 5
Ta ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4 ................................... 2 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
9
Ta ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 3 0
Ta ble 6:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he L o n g -Ter m E xte nsi o n ............................................................................... 3 3
Ta ble 7:
D osi n g Sc he me f or A d uca n u ma b b y Re gi me n ........................................................... 4 3
Ta ble 8:
Dis p ositi o n of A RI A -E Cases ..................................................................................... 5 1
Ta ble 9:
Dis p ositi o n of A RI A - H ( Micr o he m orr ha ge) Cases.................................................... 5 3
Ta ble 1 0:
Dis p ositi o n of A RI A -H ( S u perficial Si der osis) Cases ............................................... 5 5
Ta ble 1 1:
Res u m pti o n of St u d y  Treat me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titrati o n .......................................................................................................... 5 8
Ta ble 1 2:
D ose Gr o u p P o oli n g Strate g y  i n t he E ve nt of Treat me nt Gr o u p Ter mi nati o n........... 9 3
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n............................................................................................................... 1 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 0
1.
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 5 0 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
 at 
Please refer t o t he St u d y  Refere nce Ma n ual
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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 2
F U
F oll o w - u p
G C P
G o o d Cli nical Practice
H b A 1 c
gl yc os yl ate d he m o gl o bi n
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
h ealt h care pr ofessi o nal
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g
i m m u n o gl o b uli n 
I R
i nf or ma nt rate d
I RB
i nstit uti o nal re vie w b oar d
I T T
i nte nt-t o-treat
I V
i ntra ve n o us(ly)
I W G
I nter nati o nal W or ki n g Gr o u p
L T E
l o n g-ter m e xte nsi o n
L P
l u m bar p u nct ure
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 Re g ulat or y Acti vities
M M R M
M i xe d-m o del re peate d meas ures
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 P D Q - 2 0
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d versi o n
M RI
ma g netic res o na nce i ma gi n g
NI A
Nati o nal I nstit ute o n A gi n g
N PI - 1 0
Ne ur o ps yc hiatric I n ve nt or y - 1 0
P B M C
Peri p heral bl o o d m o n o n uclear cells
P D
p har mac o d y n a mic
P E T
p ositr o n e missi o n t o m o gra p h y
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
R B A N S
Re peata ble Batter y  f or Assess me nt of Ne ur o ps yc h ol o gical 
Stat us
R N A
ri b o n ucleic aci d
S A B R
Safet y  a n d Be nefit-Ris k 
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 4
3.
S Y N O P SI S
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
Pr ot oc ol Title:
A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he Efficac y a n d 
Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h Earl y
Alz hei mer's Disease
Versi o n N u m ber:
4. 0
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 I n dicati o n:
Alz hei mer’s Disease
St u d y Rati o nale:
T he p ur p ose of t his P hase 3 st u d y is t o assess t he efficac y a n d 
safet y of a d uca n u ma b c o m pare d wit h place b o i n s u bjects wit h 
earl y Alz hei mer’s Disease ( A D) , i ncl u di n g s u bjects wit h mil d 
c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a s u bset of mil d A D .  
A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of β -a m yl oi d ( A β), i ncl u di n g s ol u ble A β 
oli g o mers a n d de p osite d fi brillar A β .  I nteri m a nal yses of t he 
o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve 
de m o nstrate d tar get e n ga ge me nt, a p har mac o d y na mic effect o n 
a m yl oi d re d ucti o n, a n d a n effect o n t he Cli nical De me ntia Rati n g 
( C D R)-S u m of B o xes ( S B) a n d Mi ni -Me ntal State E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults al o n g 
wit h t he o bser ve d safet y a n d t olera bilit y pr ofile warra nt f urt her 
P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n 
s pa n ni n g t he earl y sta ges of t he A D c o nti n u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
(place b o -c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R-S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D .  
T he pri mar y e n d p oi nt t h at relates t o t his o bjecti ve is t he cha n ge 
fr o m baseli ne i n C D R -S B sc ore at Wee k 7 8.
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b as 
c o m pare d wit h place b o o n cli nical pr o gressi o n as 
meas ure d b y

M M S E
- C ha n ge fr o m baseli ne i n M M S E sc ore at Wee k
7 8

Alz hei mer’s Disease Assess me nt Scale -C o g niti ve 
S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3] 
- C ha n ge fr o m baseli ne i n A D A S -C o g 1 3 at Wee k 7 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 5
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1

Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of 
Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt 
versi o n) [ A D C S -A D L -M CI] 
- C ha n ge fr o m baseli ne i n A D C S -A D L -M CI
sc ore at
Wee k
7 8
Tertiar y o bjecti ves of t his st u d y ar e liste d i n Secti o n 6. 3. 1 .  
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 .  
St u d y O bjecti ves a n d E n d p oi nts 
( D ose-Bli n d L o n g -Ter m  
E xte nsi o n peri o d of t he st u d y ):
T he o bjecti ves are 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 earl y A D, a n d 
t o e val uate t he l o n g-ter m efficac y of a d uca n u ma b treat me nt as 
meas ure d b y cli nical, ra di ol o gical a n d a d diti o nal assess me nts 
re p orte d b y t he s u bject a n d i nf or ma nt/care part ner.
E n d p oi nts f or t he l o n g-ter m e xte nsi o n (L T E ) peri o d of t he st u d y 
are liste d i n Secti o n 6. 4. 2 .  
St u d y Desi g n:
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p peri o d f oll o we d b y a n o pti o nal 
2 4- m o nt h d ose -bli n d, L T E peri o d
St u d y L ocati o n:
A p pr o xi matel y 1 5 0 sites gl o ball y
N u m ber of Pla n ne d S u bjects:
A p pr o xi matel y 1 3 5 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 earl y A D, i ncl u di n g 
s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d u e t o A D a n d a 
s u bset of mil d A D acc or di n g t o NI A -A A criteria .  S u bjects m ust 
be p ositi ve f or a m yl oi d pat h ol o g y as meas ure d b y a m yl oi d 
p ositr o n e missi o n t o m o gra p h y sca n .  S u bjects m ust be 5 0 t o 8 5 
years ol d, a n d a part fr o m t he cli nical dia g n osis of earl y A D , 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 .  T he rati o of 
a p oli p o pr otei n ε 4 ( A p o E ε 4 ) carriers t o n o n -carriers i n t he st u d y 
p o p ulati o n will reflect t he distri b uti o n i n t he br oa der A D 
p o p ulati o n .  E nr oll me nt will als o be m o nit ore d, via i nteracti ve 
res p o nse tec h n ol o g y (I R T), s uc h t hat s u bjects wit h mil d A D 
re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt Gr o u ps:
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d of t he st u d y a n d 
b ase d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d 
t o 1 of 3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o 
(a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o) as 
f oll o ws:
A p o E ε 4 c arrier
     L o w  d ose ( 3 m g/ k g)
     Hi g h d ose ( 1 0 m g/ k g) 
     Pl ace b o 
A p o E ε 4 n o n -c arrier


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 6
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
     L o w  d ose ( 6 m g/ k g) 
     Hi g h d ose ( 1 0 m g/ k g)
     Pl ace b o 
After c o m pleti o n of t he place b o -c o ntr olle d peri o d , s u bjects ma y 
e nter a 2 4 -m o nt h d ose -bli n d L T E st u d y d uri n g w hic h all s u bjects 
will recei ve a d uca n u ma b .  
D urati o n of Treat me nt a n d 
F oll o w U p:
St u d y d urati o n f or eac h s u bject partici pati n g i n t he place b o -
c o ntr olle d peri o d o nl y will be a p pr o xi matel y 1 0 2 wee ks ( u p t o a n 
8- wee k scree ni n g peri o d , 7 6 wee ks of place b o or a d uca n u ma b
d osi n g, a n d 1 8 wee ks of f oll o w u p [ F U]).  
F or s u bjects w h o e nter t he o pti o nal L T E peri o d , t he t otal d urati o n 
will be a p pr o xi matel y 2 0 6 wee ks or 4 7 m o nt hs ( u p t o a n 8 -wee k 
scree ni n g peri o d, 7 6 wee ks of place b o or ad uca n u ma b d osi n g, 4 
wee ks of F U , 1 0 0 wee ks of d ose -bli n d a d uca n u ma b d osi n g, a n d 
1 8 wee ks of F U ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1
4. 1.
St u d y Sc he m atic
Fi g ure 1:
St u d y Desi g n
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve ; L T E = l o n g -ter m e xte nsi o n; R = ra n d o mizati o n date .
* S u bjects w h o are assi g ne d t o place b o d uri n g t he place b o -c o ntr olle d peri o d a n d are c o nti n ui n g i nt o t he L T E peri o d wi ll be ra n d o mize d i n a 1: 1 rati o t o hi g h a n d 
l o w d ose a d uca n u ma b treat me nt ( base d u p o n t heir A p o E ε 4 carrier stat us).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
4. 2.
Sc he d ule of E ve nts
T a ble 1:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8
St u d y Wee k
Scree ni n g ( ≤ 
6 0 d a ys bef ore 
D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
I nitial Scree ni n g 
C o nse nt 2 ( o pti o nal)
X
F ull I nf or me d 
C o nse nt 3
X
Eli gi bilit y Criteria
X  
X  
X  
X 4
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
H b A 1c
X
HI V 5/ He patitis/
C oa g ulati o n
X
A p o E G e n ot y pi n g
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
Ser u m Pre g na nc y
Test 7
X
Uri ne Pre g na nc y 
Test 7
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
St u d y Wee k
Scree ni n g ( ≤ 
6 0 d a ys bef ore 
D a y 1 )1
W k 
1, 
D a y 
1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 8
X
X  
X  
X  
X  
X  
X  
X
X  
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
Ra n d o mizati o n
X
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
A nti -
A d uca n u ma b A b 9
X
X
X
A d uca n u ma b 
C o nce ntrati o n 1 0
X 1 1
X 1 1
X 1 1
X  
X 1 1
X 1 1
X 1 1
X
P B M C C ollecti o n
X
X  
X
X
X
A m yl oi d P E T 1 4
X
X
R B A N S
X
C D R 
X
X
X
M M S E
X
X
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 2:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Tre at me nt or F oll o w -U p 
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
7 8 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
M e dic ati o n
9 4
( or 1 8 wee ks after fi n al 
d ose f or s u bjects w h o 
ter mi n ate tre atme nt 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
I nf or me d C o nse nt
X 3
Eli gi bilit y Criteria
X 3
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X
Uri ne Pre g na nc y Test 4
X  
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 5
X  
X  
X  
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
St u d y Treat me nt I nf usi o n
X  
X  
X  
X  
X  
X  
X
A nti - Ad uca n u ma b A b 6
X
X
X
A d uca n u ma b C o nce ntrati o n 7
X 8
X
X
X
P B M C C ollecti o n
X
X
X
A m yl oi d P E T 1 0
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 3: 
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -u p P h o ne C all Sc he d ule D uri n g t he Pl ace b o - Co ntr olle d Peri o d
St u d y Wee k
Scree ni n g
(≤ 6 0 d a ys 
bef ore D a y 1) 1
Pl ace b o -C o ntr olle d Peri o d
F U 2
1 
2 
6
1 0 
1 4 
1 8 
2 2 
2 6 
3 0 
4 2 
5 4 
6 6 
7 8 /
E O T 3
U nsc he d -
ule d Visit/ 
M RI f or 
A RI A 4
9 4
( or 1 8 
wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
disc o n -
ti n ue 
tre atme nt 
e arl y)
St u d y D a y
V 1  
V 2  
V 3
1
1 5
± 3
4 3
± 3
7 1
± 3
9 9
± 3
1 2 7
± 3
1 5 5
± 3
1 8 3
± 3
2 1 1
± 3
2 9 5
± 3
3 7 9
± 3
4 6 3 ±
3
5 4 7
± 3
6 5 9
± 7
F oll o w -U p P h o ne Call 5
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 6
X
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 7
X
X
X
X 8
X
M O C A
X
X
P B M C c ollecti o n 9
X 8
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 -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 -
he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt ; F U = F oll o w -U p; L T E = l o n g -ter m e xte nsi 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 B M C = peri p heral bl o o d m o n o n uclear cells; P K = p har mac o ki netic; 
; V 1, V 2, V 3 = Scree ni n g 
Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3.
1 Brai n M RI ( V 2) w ill n ot be perf or me d u ntil t he s u bject has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1.  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 relate d 
t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.
2 S u bjects w h o c o m plete t he place b o -c o ntr olle d 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 U V isit at Wee k 9 4.  S u bjects w h o 
disc o nti n ue treat me nt or w it h dr a w fr o m t he st u d y earl y are t o ha ve a safet y F U V isit at 1 8 wee ks after t heir fi nal d ose.  T he o nl y e xce pti o n is a s u bject w h o 
disc o nti n ues treat me nt pre mat urel y a n d c o nti n ues o n st u d y f or at least 1 8 wee ks after recei vi n g t he fi nal d ose.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
3S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y per t he 
sc he d ule of e ve nts.  S u bjects w h o wit h dra w  fr o m 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 V isit; f or s uc h s u bjects, efficac y assess me nts s pecifie d 
at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt wit hi n 3 m o nt hs of t he pre vi o us efficac y asse ss me nt visit a n d n o si g nifica nt c ha n ges i n 
c o g niti ve stat us are s us pecte d b y t he I n vesti gat or; T he site s h o ul d n otif y t he s p o ns or i n s uc h cases.  
4 F or t he fre q ue nc y of re q uire d brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f or s u bjects w h o de vel o p A RI A -E a n d/ or A RI A -H , see Secti o ns 7. 2. 1. 1 t o 
7. 2. 1. 5 .  F or t he fre q ue nc y of brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  
F or ma na ge me nt of rec urre nt A RI A , see Secti o n 7. 2. 1. 7 .  
5 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject w ill be at t he st u d y site f or cli nical assess me nts.
6 Arterial s pi n la beli n g M RI a n d tas k free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
7 O ne sa m ple will be c ollecte d wit hi n ± 2 d a y s of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.  
8 O nl y at t he first u nsc he d ule d visit f or A RI A m o nit ori n g per e pis o de
9


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
Ra n d o mizati o n
X 1
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
Uri ne Pre g na nc y 
Test 2
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -
A d uca n u ma b A b 3
X
X
X
P B M C c ollecti o n
X
X
A d uca n u ma b 
C o nce ntrati o n 3
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  
X




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
2 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
 
5 O nl y f or s u bjects w h o partici pate i n t he a m yl oi d P E T s u bst u d y .  A m yl oi d P E T ma y be sc he d ule d w it hi n a wi n d o w of ± 7 da ys .  
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Tre at me nt or F oll o w -U p
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
B o d y Wei g ht
X  
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
X
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -a d uca n u ma b 
A b 4
X
X
X
P B M C c ollecti o n
X
X
X
A d uca n u ma b 
C o nce ntrati o n 4
X
X
X
X
St u d y Dr u g 
I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E OT) 2
U V f or a 
C h a n ge i n 
A D 
M e dic a-
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
A m yl oi d P E T 6
X
C D R
X
X  
X
X
M M S E
X
X  
X
X
A D A S -C o g 1 3
X
X  
X
X
A D C S -A D L -M CI
X
X  
X
X
N PI -1 0
X
X
E Q -5 D (I R -S) 
X
X
C- S S R S
X
X
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
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 D A S -C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale -C o g niti ve S u bscale ( 1 3 ite ms); 
A D C S -A D L -M CI
= Alz hei mer's Disease C o o perati ve St u d y -Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n); 
 
; 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; 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
E C G = electr ocar di o gra m; 
; E Q-5 D (I R -S) = E Q -5 D, 
i nf or ma nt re p orte d o n s u bject; E O T = E n d of Treat me nt; F U = F oll o w-U p; L T E = l o n g -ter m e xte nsi o n; M MS E = Mi ni -Me ntal State E xa mi nati o n; N PI -1 0 = 
Ne ur o ps yc hiatric I n ve nt or y -1 0; P B M C = peri p heral bl o o d m o n o n uclear cells ; 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.
1 S 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 safet y F U V isit at Wee k 1 9 8.  S u bjects w h o 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 U V isit at 1 8 wee ks after t heir fi nal d ose .  T he o nl y e xce pti o n is a s u bject w h o disc o nti n ues treat me nt pre mat urel y a n d 
c o nti n ues o n st u d y f or at least 1 8 wee ks after recei vi n g t he fi nal d ose.
2 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he stu d y per 
t he sc he d ule of e ve nts.  S u bjects w h o wit h dra w  fr o m t he L T E peri o d pre mat urel y are t o ret ur n t o t he site f or t he E O T V isit; f or s uc h s u bjects, efficac y 
assess me nts s pecifie d at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt w it hi n 3 m o nt hs of t he pre vi o us efficac y assess me nt visit a n d n o 
si g nifica nt c ha n ges i n c o g niti ve stat us are s us pecte d b y t he I n vesti gat or; T he site s h o ul d n otif y t he S p o ns or i n s uc h cases .  
3 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
 
 
6 O nl y f or s u bjects w h o partici pate i n t he a m yl oi d P E T s u bst u d y A m yl oi d P E T ma y be sc he d ule d w it hi n a wi n d o w of ± 7 da ys .  
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6:
Br ai n M RI , A RI A M a n a ge me nt , a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he L o n g -Ter m E xte nsi o n
St u d y Wee k
L o n g -Ter m E xte nsi o n
U nsc he d -
ule d V isit
f or A RI A1
F U 2
8 2 
8 6 
9 0 
9 4 
9 8 
1 0 2 
1 0 6 
1 1 0 
1 2 2 
1 3 4 
1 5 8
1 8 2 3
1 9 8
( or 1 8 wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
ter mi n ate 
tre atme nt 
e arl y)
St u d y D a y
5 7 5
± 5
6 0 3
± 5
6 3 1
± 5
6 5 9
± 5
6 8 7
± 5
7 1 5
± 5
7 4 3
± 5
7 7 1
± 5
8 5 5
± 5
9 3 9
± 5
1 1 0 7
± 5
1 2 7 5
± 5
1 3 8 7
± 7
F oll o w - Up 
P h o ne Call 4
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 5
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 6
X 7
M O C A
X
P B M C 
c ollecti o n 8
X 7
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 -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 -
he m orr ha ge or s u perficial si der osis ; E O T = E n d of Treat me nt ; F U = f oll o w u p; L T E = l o n g-ter m e xte nsi 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 B M C = peri p heral bl o o d m o n o n uclear cells; P K = p har mac o ki netic; 
.
1 F or t he fre q ue nc y of re q uire d brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f or s u bjects w h o de vel o p A RI A -E a n d/ or A RI A - H, see Secti o ns 7. 2. 1. 1 t o 
7. 2. 1. 5 .  F or t he fre q ue nc y of brai n M RI, M O C A, P K, a n d bi o mar ker assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  
F or ma na ge me nt of rec urre nt A RI A , see Secti o n 7. 2. 1. 7 .  
2 S 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 safet y F U V isit at Wee k 1 9 8.  S u bjects w h o 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 U V isit at 1 8 wee ks after t heir fi nal d ose .  T he o nl y e xce pti o n is a s u bject w h o disc o nti n ues treat me nt pre mat urel y a n d 
c o nti n ues o n st u d y f or at least 1 8 wee ks after recei vi n g t he fi nal d ose.
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts u ntil t he e n d of t he st u d y per 
t he sc he d ule of e vents .  S u bjects w h o wit h dra w  fr o m t he L T E peri o d pre mat urel y are t o ret ur n t o t he site f or t he Wee k E O T V isit; f or s uc h s u bjects, efficac y 




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n S u bjects wit h Earl y Alz hei mer's Disease  
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
4. 3.
A d diti o n al I nf or m ati o n
4. 3. 1.
Site Pers o n nel
A mi ni m u m of 3 se parate heat h care pr ofessi o nals ( H C Ps) are re q uire d:  
1.
A treati n g H C P (t he Pri nci pal I n vesti gat or [ PI ] or S u b -i n vesti gat or m a y  ser ve as a 
treati n g H C P ) w h o is res p o nsi ble f or t he f oll o wi n g:

A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y  1 a n d d uri n g 
ma na ge me nt of a m yl oi d-relate d i ma gi n g a b n or malities (A RI A) cases.

Ma na ge me nt of r o uti ne ne ur ol o gical care of t he s u bject.

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y ) a n d treat me nt of a d verse e ve nts 
(A Es ).  

Re vie w of selecte d he mat ol o g y  a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y 
wit h hel d or per ma ne ntl y  disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
Secti o n 1 0. 1 .  
2.
A n i n de pe n de nt rati n g H C P ( desi g nate d by t he PI of t he site) w h o is res p o nsi ble f or 
a d mi nisteri n g t he Cli nical De me ntia Rati n g ( C D R)
3.
A sec o n d i n de pe n de nt rati n g H C P ( desi g nate d by t he PI  of t he site) w h o will a d mi nister 
t he Alz hei mer’s Disease Assess me nt Scale - C o g niti ve S u bscale ( 1 3 ite ms) [A D A S -C o g
1 3] , Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of Dail y  Li vi n g I n ve nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [A D C S -A D L -M CI ], a n d t he Mi ni-Me ntal Sta te 
E xa mi nati o n ( M M S E)
T he 2 i n de pe n de nt rati n g H C Ps 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 A Es, c o nc o mita nt t hera py , la b orat or y data, i ma gi n g 
data , or a n y ot her data t hat ha ve t he p ote ntial of r e veali n g t he treat me nt assi g n me nt .  T he 2 
i n de pe n de nt rati n g H C Ps m ust n ot s hare a ny i nf or mati o n a b o ut s u bjects .  PIs ca n n ot ser ve as 
rati n g H C Ps.  T he treati n g H C Ps m ust n ot disc uss A Es (e. g., A RI A) wit h t he i n de pe n de nt rati n g 
H C Ps .  
T o e ns ure c o nsiste nc y acr oss sites, rati n g H C Ps m ust c o m plete t he sta n dar dize d st u d y -s pecific 
q ualificati o n pr ocess o n cli nical efficac y  assess me nt sc ori n g pri or t o a d mi nistrati o n of t he 
s pecific assess me nt at t heir site.  All sites m ust atte m pt t o mai ntai n t he sa me rati n g H C P
t hr o u g h o ut t he st u dy f or s pecific assess me nts 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 sa me rati n g H C P 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 o nl y  c o n d uct assess me nts i n place of t he 
pri mar y  rater 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 rati n g H C P has t o be re place d, t he ne w rati n g H C P m ust u n der g o t he 
st u d y-s pecific q ualificati o n pr ocess pri or t o a d mi nistrati o n of t he assess me nt.
He mat ol o g y  a n d bl o o d c he mistr y data will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.  As wit h ot her la b orat or y  a n d cli nical i nf or mati o n, t hese data s h o ul d 
N O T be re vie we d b y t he rati n g H C Ps .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T he r oles of i n de pe n de nt raters a n d treati n g H C P are N O T i nterc han gea ble at t he s u bject le vel.  
I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc ha n gea ble at t he s u bject le vel .  If a rater has 
a d mi nistere d t he C D R t o a s u bject t he y ma y n ot a d mi nister t he ot her ne ur oc o g niti ve assess me nts 
t o t hat s u bject at a n y p oi nt d uri n g t he st u d y.
A n u n bli n de d p har macist ( or a ut h orize d desi g nee) 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 n ta 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 t he st u d y bli n d.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
5.
I N T R O D U C TI O N
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i ncrease t o 1 3 5. 5 milli o n b y  2 0 5 0 
[Alz hei mer's Disease I nter nati o nal 2 0 1 4].  
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 a n d be ha vi oral dist ur b a 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 [Jac k 2 0 1 3].
Pat h ol o gicall y, A D is defi ne d b y t he prese nce i n t he bra i n of e xtracell ular ne uritic pla q ues 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra ne ur o nal ne ur ofi brillar y ta n gles c o m p ose d of 
h y per p h os p h or y late d ta u pr otei ns.  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 r e 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 “a myl 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 ].  
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t h a n ha vi n g cate g orical sta ges .  E vi de nce s u g gests t he 
pat h o p h y si ol o gical c ha n ges be gi n years 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].  
Re vise d criteria f or t he cli nical dia g n osis of A D were p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) a n d t he Alz hei mer’s Ass ociati o n ( A A) [Al bert 2 0 1 1 ; Mc K ha n n 2 0 1 1 ; S perli n g 
2 0 1 1] a n d t he Inter nati o nal W or ki n g Gr o u p (I W G)
[D u b ois 2 0 1 0 ; D u b ois 2 0 1 4 ], a n d a gr o u p 
t hat i ncl u de d me m bers fr o m b ot h NI A- A A a n d I W G p u blis he d rec o m me n dati o ns t o har m o nize 
t he criteria [M orris 2 0 1 4 ].  T hese criteria base t he dia g n osis of A D o n b ot h cli nical a n d 
bi ol o gical ele me nts, rec o g nizi n g t he e xiste nce of a n o n cli nical sta ge of t he disease b y acce pti n g
A D dia g n os es pri or t o si g ns of de me ntia usi n g A D bi o mar kers.
T he scie ntific c o m m u nit y has s hifte d its f oc us t o tar get patie nts 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 patie nts are m ore li kel y t o be nefit fr o m a nti -a m yl oi d 
t hera py.  
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 b y  re d uci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F) .  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β .  Earlier 
p u blicati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h s ol u ble oli g o mers a n d a myl 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 [R oz kal ne 
2 0 0 9 ; S pires -J o nes 2 0 0 9].  Si milarl y , patie nts wit h A D w h o ge nerate d a nti-A β a nti b o dies after 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
acti ve i m m u nizati o n wit h a g gre gate d A β( 4 2) s h o we d sl o wer rates of decli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [H oc k 2 0 0 3 ].
5. 1.
Pr ofile of Pre vi o us E x perie nce W it h A d uc a n u m a b  
5. 1. 1.  
N o ncli nic al E x perie nce 
A d uca n u ma b is a u ni q ue h u ma n , a nti-A β m o n ocl o nal a nti b o d y  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 .  
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 m m u n o gl o b uli n (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 pr o perties si g nifica ntl y re d uce d 
a m yl oi d pla q ue b ur de n i n t he brai ns of a ge d T g 25 7 6 mice, a m o use m o del of A D, t hr o u g h a 
micr o glia -me diate d p ha g oc y tic mec ha nis m.  T hese data s u g gest a d uca n u ma b c o ul d pr o vi de 
be nefit b y re d uci n g pla q ue b ur de n .
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 
stu dies a n d i n c y n 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 gicall y 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 gic al 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 ].
Fi n di n gs c o nsiste nt wit h a m y l oi d pla q ues a n d vasc ular a myl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, i ncl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h t his m o del .  I n 
b ot h st u dies, re pea te 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 .  The 
e val uati o n of micr o he m orr ha ge, c haracterize d b y  q ua ntificati o n 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 ad uca n u ma b treat me nt i n eit her st u d y .  The i nci de nce a n d se verit y of 
he m orr ha ge or cere bral vasc ular i nfla m mati o n w ere 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.  
See t he I n vesti gat or’s Br oc h ure (I B) f or detaile d i nf or mati o n o n n o ncli nical st u dies.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
5. 1. 2.
Cli nic al E x perie nce
A d uca n u ma b has b ee n e val uate d i n o ne c o m plete d si n gle asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 3): 

St u d y  2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, st u d y 
of ad uca n u ma b i n s u bjects wit h mil d or m o derate A D .  
T he pri mar y  o bjecti ve was t o e val uate t he safety a n d t olera bilit y of a ra n ge of 
ad uca n u ma b d oses ( 0. 3 t o 6 0 m g/ k g) w he n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y  o bjecti ves were t o assess t he p har mac o ki netic ( P K) a n d 
i m m u n o ge nicity of ad uca n u ma b after si n gle -d ose a d mi nistrati o n .  
A si n gle d ose of a d uca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d.  
D ose -li miti n g A RI A ( 2 s u bjects wit h A RI A- E [e de ma] a n d 1 s u bject wit h A RIA- E
a n d A RI A-H [ micr o he m orr ha g e]) was o bser ve d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses bel o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near.

St u d y  2 2 1 A D1 0 3 is a n o n g oi n g ra n d o mize d, d o u ble-bli n d, pl ace b o-c o ntr olle d 
m ulti ple d ose st u d y  of a d uca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are 
a m yl oi d p ositi ve.  T he st u d y  c o m prises a place b o-c o ntr olle d peri o d wit h s u bjects 
recei vi n g m o nt hl y d oses of ad uca n u ma b (fi xe d d oses of 1, 3, 6, or 1 0 m g/ k g, or
titrati o n u p t o 1 0 m g/ k g) or p lace b o f or a ye ar f oll o we d b y a d ose -bli n d l o n g -ter m 
e xte nsi o n ( L T E ) peri o d wit h s u bjects recei vi n g m o nt hl y d oses of ad uca n u ma b .  N ote:  
T he fi xe d- d ose c o h orts e nr olle d b ot h A p o E ε 4 carriers a n d n o n -carriers w hile t he
titrati o n c o h ort is c o m prise d of A p o E ε 4 carriers o nl y .
T he pri mar y  o bjecti ve of St u d y  2 2 1 A D 1 0 3 is t o e val uate t he safety a n d t olera bilit y of 
m ulti ple d oses of ad uca n u ma b a d mi nistere d m o nt hl y  as si n gle I V i nf usi o ns.  T he 
sec o n dar y o bjecti ves are t o assess t he effect of ad uca n u ma b o n cere bral a m y l oi d 
pla q ue c o nte nt as meas ure d b y  1 8F -fl or beta pir p ositr o n e missi o n t o m o gra p h y (P E T ), 
a n d t o e val uate t he P K a n d i m m u n o ge nicit y of ad uca n u ma b after m ulti ple -d ose 
a d mi nistrati o n .  E x pl orat or y  o bjecti ves i ncl u de assess me nt of t he effect of 
ad uca n u ma b o n t he cli nical pr o gressi o n of A D as meas ure d b y 
C D R -s u m of b o xes (S B ) a n d M M S E .  
T o date, t he i nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose - a n d A p o E ε 4 
carria ge-de pe n de nt, es pec iall y at t he hi g hest d oses w he n a d mi nistere d as a fi xe d d ose .  
A RI A- E was ra di o gra p hicall y  m o nit ore d b y ma g netic res o na nce i ma gi n g ( M RI ) a n d 
t ypicall y o bser ve d earl y i n treat me nt ( bet wee n 2 t o 5 d oses).  I n m ost cases, A RIA- E 
res ol ve d 4 t o 1 2 wee ks after onset a n d A RI A -H was t y picall y  sta ble 2 t o 4 wee ks 
after o nset.  I nci de nce of A RIA has bee n o bser ve d t o be b ot h d ose a n d 
A p oli p o p r otei n E 4 (A p o E ε 4) carria ge -de pe n de nt, es peciall y at t he hi g hest d oses .  
T he i nci de nce of A RI A -E a p peare d t o be l o wer i n t he gr o u p recei vi n g titrati o n t o 
1 0 m g/ k g (c o m prisi n g A p o E ε 4 carriers o nl y; 8/ 2 3[ 3 5 %] ) t ha n i n carriers i n t he 
6 m g/ k g a n d 1 0 m g / k g fi xe d-d ose gr o u ps ( 9/ 2 1 [ 4 3 %] a n d 1 1/ 2 0 [ 5 5 %] , res pecti vel y).  
T he i nci de nce of A RI A i n A p o E ε 4 carriers w h o were titrat e d u p t o 6 m g/ k g( 2 d oses 
of 3 m g/ k g, t he n 6 m g/ k g) was 1 5 % ( 2/ 1 3), wit h a n o verall rate of 1 1 % ( 2/ 1 9) as n o 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A p o E ε 4 n o n -carriers ( 0/ 6) e x perie nce d A RI A .  Of n ote, a m o n g t he 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 bs er ve d at t he 3 a n d 
6 m g/ k g d oses, bef ore t he y  reac he d 1 0 m g / k g.  Als o, 1 3 ( of 2 3, 5 7 %) s u bjects i n t he 
titrati o n ar m ha ve bee n titrate d t o 1 0 m g/ k g , a n d of t hese 1 2 c o nti n ue d treat me nt a n d 
recei ve d at least 1 0 d oses of 1 0 m g/ k g ; n o ne of t hese s u bjects e x perie nce d A RIA- E or 
A RI A- H.  F urt her m ore , A RIA -E e ve nts w he n t he y  occ urre d (i n t he titrati o n gr o u p) 
ha ve bee n eit her as y m pt o matic or ass ociate d wit h mil d s y m pt o ms t hat res ol ve d, a n d 
m ost s u bjects w h o ha d A RI A- E c o nti n ue d treat me nt ( 6/ 8; 7 5 %) c o m pare d wit h o nl y  
3 6 % ( 4/ 1 1) of carriers i n t he fi xe d -d ose 1 0 m g/ k g ar m (refer t o t he I B f or details o n 
e ve nts of A RI A) .  
Pr ot oc ol -s pecifie d i nteri m a nal yses of t he o n g oi n g m ulti ple-asce n di n g d ose 
S t u d y 2 2 1 A D 1 0 3 ha ve de m o nstrate d e n ga ge me nt of a d uca n u ma b wit h a m yl oi d 
pla q ues, a p har mac o d y n a mic (P D ) effect o n a m yl oi d re d ucti o n, a n d a n effect o n 
C D R -S B a n d M M S E s u g gesti ve of a sl o wi n g of cli nical decli ne i n 
a d uca n u ma b -treate d s u bjects.  T he d ose - a n d ti me -de pe n de nt re d ucti o n of brai n A β 
b ur de n o bser ve d wit h a d uca n u ma b treat me nt was statisticall y si g nifica nt at d oses of 
3, 6, a n d 1 0 m g/ k g after 6 a n d 1 2 m o nt hs of d osi n g , as well as wit h 1 m g/ k g a n d 
titrati o n fr o m 1 t o 1 0 m g/ k g after 1 2 m o nt hs of d osi n g.  O ver t he first ye ar of t he L T E 
( 2 4 m o nt hs of d osi n g), f urt her d ose-de pe n de nt re d ucti o ns i n cere bral A β were 
o bser ve d .  T he res ults de m o nstrate tar get e n ga ge me nt (a m y l oi d pla q ues) a n d a P D
effect ( d ose -de pe n de nt a m y l oi d re d ucti o n).  
I n a d diti o n res ults fr o m t he i nteri m a nalys es s h o we d a n effect at 1 year o n t he 
e x pl orat or y e n d p oi nts C D R -S B a n d M M S E (at fi xe d d oses of 1 m g/ k g, 3 m g/ k g, 6 
m g/ k g a n d 1 0 m g/ k g c o m pare d wit h place b o) , s u g gesti n g a re d ucti o n i n t he 
pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b- treate d vers us place b o-treate d 
s u bjects. I n t he m ost rece nt i nterim a nal y sis, ge nerall y c o nsiste nt treat me nt 
differe nces were see n f or t he fi xe d - d ose c o h orts, a n d i n t he titrati o n gr o u p, effects o n 
t he C D R-S B a n d M M S E after 1 ye ar were ge nerall y c o nsiste nt wit h t he fi xe d -d ose 
res ults.  C o m pare d wit h place b o, a dj uste d mea n c ha n ges fr o m baseli ne t o Wee k 5 4 i n 
C D R -S B sc ores fa v ore d all a d uca n u ma b d ose re gi me ns teste d, wit h treat me nt 
differe nces of 0. 5 p oi nts or greater fa v ori n g a d uca n u ma b at d oses of 3, 6, a n d 1 0 
m g/ k g a n d titrati o n t o 1 0 m g/ k g, a n d statistical si g nifica nce see n i n t he 1 0 m g/ k g a n d 
t he titrati o n gr o u ps.  O n t he M M S E, a dj uste d mea n decreases fr o m baseli ne t o 
Wee k
5 2 were s u g geste d a cli nicall y mea ni n gf ul be nefit i n t he 3 a n d 1 0 m g/ k g gr o u ps 
a n d t he titrati o n gr o u p a n d were si g nifica ntl y  l o wer i n t he 1 0 m g/ k g gr o u p.  
F urt her m ore, res ults fr o m t he L T E f or t he fi xe d -d ose re gi me ns ha ve de m o nstrate d 
c o nti n ue d sl o wi n g of cli nical decli ne i n s u bjects c o nti n ui n g o n a d uca n u ma b
c o m pare d wit h s u bjects w h o s witc he d fr o m place b o t o a d uca n u ma b i n t he L T E .  
Refer t o t he I B f or details o n i nteri m a nal yses res ults.
5. 2.
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safety of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D a n d a s ubset of mil d A D .  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y  t hat rec o g nizes 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β .  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 o t o xic 
[K offie 2 0 0 9 ; K uc hi b h otla 2 0 0 8 ; M e y er -L ue 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 ormalizati 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].  F or 
t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, w hile preser vi n g 
gl o bal f u ncti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.  
I nteri m a nalys es of t he o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3 ) ha ve de m o nstrate d tar ge t 
e n ga ge me nt, a P D effect o n a m y l oi d re d ucti o n, a n d a n effect o n C D R-S B a n d M M S E s u g gesti ve 
of a re d ucti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b- treate d s u bjects.  T hese 
res ults al o n g wit h t he o bser ve d safety a n d t olera bilit y  pr ofile warra nt t he f urt her P hase 3 
i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D 
c o nti n u u m.
5. 3.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
T he d osi n g re gi me n selecte d f or t his st u d y  was base d o n t he P K a n d P D relati o ns hi p f or re mo val 
of brai n a m yl oi d a n d effect o n C D R -S B a n d M M S E o bser ve d i n St u d y  2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n safet y, t olera bilit y , a n d P K data fr o m st u dies 22 1 A D 1 0 1 (c o m plete) a n d 
2 2 1 A D 1 0 3 ( o n g oi n g).  
T he d ose - a n d ti me-de pe n de nt re d ucti o n of brai n a m y l oi d b ur de n o bser ve d wit h a d uca n u ma b 
treat me nt i n St u d y 2 2 1 A D 1 0 3 was statisticall y si g nifica nt at d oses of 3, 6 a n d 1 0 m g/ k g after 6 
m o nt hs of d osi n g , a n d at 3, 6, a n d 1 0 m g/ k g as well as wit h titrati o n t o 1 0 m g/ k g after 1 2 m o nt hs 
of d osi n g.  O n t he e x pl orat or y  e n d p oi nts of C D R-S B a n d M M S E c ha n ges fr o m baseli ne , a d ose-
de pe n de nt sl o wi n g of cli nical decli ne was o bser ve d f or a d uca n u ma b vers us place b o after 1 ye ar 
of treat me nt .  C o m pare d wit h place b o, a dj uste d mea n c ha n ges fr o m baseli ne t o Wee k 5 4 f or 
C D R -S B fa v ore d all t he a d uca n u ma b d ose gr o u ps teste d, wit h treat me nt differe nces of 0. 5 p oi nts 
or greater at fi xe d d oses of a d uca n u ma b 3, 6, a n d 1 0 m g/ k g a n d als o wit h titrati o n t o 1 0 m g/ k g.  
O n t he M M S E, a dj uste d mea n decreases fr o m baseli ne t o Wee k 5 2 were s maller i n all d ose 
gr o u ps t ha n i n t he place b o gr o u p .  Of n ote, o n t he C D R -S B, t he p oi nt esti mate f or t he titrati o n 
gr o u p (c o m prisi n g A p o E ε 4 carriers o nly) was ge nerall y si milar t o t hat f or t he 1 0 m g/ k g gr o u p 
a n d si g nifica ntl y l o wer t ha n place b o i n b ot h t h ose gr o u ps; o n t he M M S E, t he p oi nt esti mate f or 
t he titrati o n gr o u p is ge nerally si milar t o t hat i n t he 1 0 m g/ k g gr o u p ( w hic h s h o we d si g nifica ntl y  
less decli ne t ha n place b o) a n d t he 3 m g/ k g gr o u p.  
T o date, t he i nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose - a n d A p o E ε 4 
carria ge-de pe n de nt, es peciall y  at t he hi g hest d oses w he n a d mi nistere d as a fi xe d d ose .  H o we ver , 
t he i nci de nce of A RI A -E , as well as disc o nti n uati o ns fr o m treat me nt d ue t o A RIA- E, i n s u bjects 
recei vi n g a d uca n u ma b titrate d t o 1 0 m g/ k g ( A p o E ε 4 carriers o nly) a p pear t o be re d uce d ( 8/ 2 3 
[ 3 5 %]) c o m pare d wit h fi xe d d oses of a d uca n u ma b at 6 m g/ k g ( 9/ 2 1[ 4 3 %]) a n d 1 0 m g/ k g
( 1 1/ 2 0[ 5 5 %]).  F urt her m ore, a m o n g t h ose s u bjects ra n d o mize d t o recei ve a d uca n u ma b titrate d t o 
1 0 m g/ k g, A RI A -E occ urre d o nl y  at t he 3 m g / k g a n d 6 m g/ k g d ose le vels .  A ls o, 1 3 ( of 2 3, 5 7 %) 
s u bjects i n t he titrati o n ar m ha ve bee n titrate d t o 1 0 m g/ k g , a n d of t hese 1 2 c o nti n ue d treat me nt 
a n d recei ve d at least 1 0 d oses of 1 0 m g/ k g ; n o ne of t hese s u bjects e x perie nce d A RI A-E or 
A RI A- H..  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
I n a n eff ort t o ma xi mize t he d ose-de pe n de nt a m yl oi d re d ucti o n a n d effect o n C D R -S B a n d 
M M S E t hat ha ve bee n o bser ve d wit h d oses of 3 m g/ k g a n d hi g her w hile mai ntai ni n g A RI A 
i nci dence, se verit y, a n d relate d disc o nti n uati o n rate wit hi n acce pta ble le vels, a titrati o n re gi me n 
will be e x pl ore d i n t his st u d y.  It has bee n s u g geste d t hat t he A RI A o bser ve d f oll o wi n g treat me nt 
wit h a m y l oi d tar geti n g a ge nts ma y be d ue, i n part, t o t he i nitial lar ge re m o val of a myl oi d a n d 
s u bse q ue nt sat urati o n of peri vasc ular brai n a m yl oi d cleara nce mec ha nis ms [ Weller 2 0 0 8].  
T itrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o wer i nitial a m yl oi d re m o val, yet tri g ger 
alter nati ve mec ha nis ms of a m yl oi d cleara nce i ncl u di n g m o n ocl o nal a nti b o d y -de pe n de nt Fc -
me diate d micr o glial cleara nce [Ostr o witz ki 2 0 1 2 ] w hic h w o ul d pre ve nt sat urati o n of a m yl oi d 
cleara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is reac he d .  Si nce 
ad uca n u ma b -i n d uce d A RI A has bee n de m o nstrate d t o occ ur early d uri n g treat me nt, wit h m ost 
cases occ urri n g wit hi n t he first 5 d oses, titrati o n of a d uca n u ma b f or u p t o 6 d oses pri or t o 
reac hi n g t he tar get d ose ma y res ult i n re d ucti o n of A RI A i nci de nce a n d se verit y.  
Gi ve n t he t olera bilit y  a n d a p pare nt efficac y of ad uca n u ma b s h o w n t o date, t he d oses t o be teste d 
usi n g a titrati o n re gi me n are 3 a n d 1 0 m g / k g f or A p o E ε 4 carriers, a n d 6 a n d 1 0 m g/ k g f or A p o E 
ε 4 n o n-carriers.  Titrati o n will start at 1 m g/ k g a n d will escal ate t o 3, 6 a n d 1 0 m g/ k g as detaile d 
bel o w .  
5. 3. 1.
D osi n g Sc he me
5. 3. 1. 1.
Pl ace b o -C o ntr olle d Peri o d
D oses will be a d mi nistere d a p pr o xi matel y  4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses) .  Base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assig ne d t o 1 of 
3 treat me nt gr o u ps ( 4 5 0 s u bjects eac h) i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h 
d ose: place b o) as f oll o ws (Ta ble 7 a n d Fi g ure 1 ):
A p o E ε 4 C arrier

L o w d ose ( 3 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereafter

Hi g h d ose ( 1 0 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n
A p o E ε 4 N o n- C arrier

L o w d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter  

Hi g h d ose ( 1 0 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

Place b o  
Sali ne i nf usi o n
T a ble 7:
D osi n g Sc he me f or A d uc a n u m a b b y Re gi me n
D ose ( M o nt h)
1
2 
3 
4 
5 
6 
7 t o 2 0
Re gi m e n
D ose ( m g/ k g)
A p o E ε 4 ( +)
L o w D ose
1 
1 
3 
3 
3 
3 
3
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0 1
Pl ace b o
sali ne
A p o E ε 4 ( -)
L o w D ose
1 
1 
3 
3 
3 
3 
6
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0
Pl ace b o
sali ne
1 1 0 m g/ k g is t he tar get d ose f or all A p o E e 4 carriers assi g ne d t o t he a d uca n u ma b hi g h -d ose re gi me n .  S u bjects
e nr olle d u n der pre vi o us versi o ns of t he pr ot oc ol a n d assi g ne d t o t he pre vi o us hi g h-d o se re gi me n of 6 m g/ k g will 
be titrate d t o 1 0 m g/ k g u p o n recei pt of at least 2 d oses at 6 m g/ k g.  
5. 3. 2.
D osi n g Sc he me M o dific ati o n
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will re vie w u n bli n de d safet y data, i ncl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d uca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter .
T he d osi n g sc he me ca n be m o difie d i n t he f oll o wi n g circ u msta nces: 

Safet y  a n d t olera bilit y of t he hi g h d ose 
If t he hi g h d ose ( 1 0 m g/ k g) is dee me d n ot acce pta ble, e nr oll me nt f or t he hi g h d ose 
gr o u p(s) will be ter mi nate d a n d s u bjects will n ot be re place d .  S u bjects w h o ha ve 
alrea d y bee n ra n d o mize d t o t he disc o nti n ue d d ose will be d o w n -d ose d t o t he ne xt 
a vaila ble d ose acc or di n g t o t heir A p o E ε 4 carrier stat us.  Defi niti o n of l o w a n d hi g h -
d ose re gi me ns will be re vise d as descri be d i n Secti o n 1 6 .  
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d
S u bjects w h o recei ve d 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 w h o e nter t he L T E 
peri o d will mai ntai n t he d osi n g s c he me o utli ne d i n t he pr ot oc ol at t he ti me of tra nsiti o n fr o m t he 
P C peri o d t o t he L T E peri o d (e. g. s u bjects w h o are o n sta ble d osi n g i n t he P C peri o d will 
c o nti n ue o n t he sa me d ose, s u bjects w h o are o n a titrati o n re gi me n d uri n g t he tra nsiti o n will 
c o nti n ue t o titrate i nt o t he L T E peri o d a n d s u bjects w h o c o m plete t he P C peri o d u n der pr ot oc ol 
versi o ns 1 -3 a n d are assi g ne d t o t he hi g h d ose a d uca n u ma b treat me nt gr o u p ma y  u p titrate t o 1 0 
m g/ k g i n t he L T E) .  S u bjects w h o recei ve place b o d uri n g t he place b o-c o ntr olle d peri o d a n d w h o 
e nter t he L T E peri o d will be assi g ne d t o 1 of 2 treat me nt gr o u ps, base d u p o n t heir A p o E ε 4 
carrier stat us, i n a 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose) .  S u bjects wi ll be 
d ose d usi n g t he sa me re gi me n descri be d f or t he place b o -c o ntr olle d peri o d (see Ta ble 7 a n d 
Fi g ure 1 ).  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A p o E ε 4 carrier s u bjects w h o are e nr olle d i n t he L T E a n d ra n d o mize d t o t he hi g h-d ose gr o u p
pri or t o i m ple me ntati o n of versi o n 4 of t he pr ot oc ol wil l be all o we d t o titrate t o 1 0 m g/ k g.  A n y  
m o dificati o ns t o t he d osi n g sc he me (i.e .  ter mi nati o n of hi g h- d ose gr o u p, as descri be d i n 
Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E peri o d .  










Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
St u d y  2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p 
st u d y i n s u bjects wit h earl y A D, i ncl u di n g M CI d ue t o A D a n d a s u bset of mil d A D, f oll o we d b y 
a n o pti o nal 2 4- m o nt h d ose -bli n d L T E st u d y .  A p pr o xi matel y  1 3 5 0 s u bjects will be e nr olle d 
acr oss a p pr o xi matel y 1 5 0 ce nters gl o ball y .  T he pri mar y  st u d y o bjecti ve is t o e val uate t he 
efficac y of m o nt hly d oses of a d uca n u ma b o n t h e C D R-S B relati ve t o place b o .  Sec o n dar y  
o bjecti ves i ncl u de assess me nt of t he effect of m o nt hl y  d oses of a d uca n u ma b o n cli nical 
pr o gressi o n as c o m pare d t o place b o .  T he safet y of m o nt hl y  d oses of a d uca n u ma b will als o be 
e val uate d.
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y  e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a t otal of 2 0 d oses).  S u bjects will be ra n d o mize d t o recei ve 
a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o i n a 1: 1: 1 rati o .  T he ra n d o mizati o n will 
be stratifie d b y s ite a n d A p o E ε 4 stat us (carrier or n o n-carrier).  T he rati o of A p o E ε 4 carriers t o 
n o n- carriers i n t he st u d y p o p ulati o n will reflect t he distri b uti o n i n t he br oa der A D p o p ulati o n .  
E nr oll me nt will als o be m o nit ore d , via i nteracti ve res p o nse tec h n ol o g y (I R T), s uc h t hat s u bjects 
wit h mil d A D re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  
At t he e n d of t he d o u ble -bli n d , place b o -c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
e xte nsi o n e ntr y criteria ma y e nter a 2 4-m o nt h l o n g-ter m safet y a n d efficac y e xte nsi o n peri o d,
wit h all s u bjects recei vi n g a d uca n u ma b a p pr o xi matel y e ver y 4 wee ks (a t otal of 2 6 d oses).  
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject o nl y partici pati n g i n t he 
place b o - c o ntr olle d peri o d of t he st u d y  will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series 
of S cree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6- wee k 
place b o -c o ntr olle d treat me nt peri o d, a n d a safet y f oll o w - u p ( F U) peri o d of 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 eac h s u bject partici pati n g i n t he place b o -c o ntr olle d 
peri o d a n d t he L T E peri o d will be u p t o a p pr o xi matel y  2 0 6 wee ks, i ncl u di n g a series of 
Scree ni n g v isits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a 4- wee k F U peri o d, a 1 0 0 -wee k a d uca n u ma b d ose -bli n d
treat me nt peri o d, a n d a safety F U peri o d of a p pr o xi matel y  1 8 wee ks after t he fi nal d ose.  T he 
F U peri o d of 1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half- life i n h u ma ns of 1 6 t o 
2 4 da y s ( mea n a p pr o xi matel y 2 0 d a y s, base d o n res ults fr o m t he si n gle asce n di n g d ose st u d y
[St u d y  2 2 1 A D 1 0 1] ) a n d a ntici pate d brai n c o nce ntrati o ns of a d uca n u ma b of less t ha n o ne-t hir d 
t he E C5 0 (i n hibit or y  c o nce ntrati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or bi n di n g 
fi brillar a myl oi d at 8 wee ks after t he last d ose .  
D uri n g t he p lace b o-co ntr olle d p eri o d, A p o E ε 4 carriers will recei ve place b o, 
a d uca n u ma b 3 m g / k g, or a d uca n u ma b 1 0 m g / k g w hereas A p o E ε 4 n o n -carriers will recei ve 
place b o, a d uca n u ma b 6 m g/ k g, or a d uca n u ma b 1 0 m g/ k g .  A d uca n u ma b will be titrate d f or u p t o
6 d oses pri or t o reac hi n g t he tar get d ose as s h o w n i n Ta ble 7 a n d Fi g ure 1 .  N ote: 1 0 m g/ k g is t he 
tar get d ose f or all A p o E ε 4 carriers i n t he hi g h d ose gr o u p.  A p o E ε 4 carriers w h o are e nr olle d i n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
t he hi g h d ose gr o u p recei vi n g 6 m g/ k g m ust ha ve recei ve d 2 or m ore d oses at 6 m g/ k g pri or t o 
bei n g titrate d u p t o 1 0 m g/ k g .  S u bjects w h o recei ve d place b o d uri n g t he place b o-co ntr oll e d 
p eri o d a n d w h o e nter t he L T E peri o d will be assi g ne d t o treat me nt base d u p o n t heir A p o E ε 4 
carrier stat us i n a 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose); a d uca n u ma b will be 
titrate d f or u p t o 6 d oses pri or t o reac hi n g t he tar get d ose f oll o wi n g t he sa me sc he d ule descri be d 
f or t he p lace b o-co ntr olle d p eri o d.  
See Secti o n 5. 3. 2 f or details of d osi n g sc he me m o dificati o n.  
I n di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d i n s u bjects w h o de vel o p A RI A .  See
Secti o n 7. 2. 1 .  .
I n vesti gat ors, st u d y site staff (e xce pt f or t he desi g nate d u n bli n de d p har macist/ tec h nicia n), a n d 
st u d y s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he place b o -
c o ntr olle d peri o d .  D uri n g t he L T E peri o d , In vesti gat ors a n d s u bjects will re mai n bli n de d t o t he 
treat me nt assi g n me nt i n t he place b o-c o ntr olle d peri o d a n d t he a d uca n u ma b d ose f or t he L T E
peri o d .
7. 2.
St u d y S pecifics
7. 2. 1.  
D ose S us pe nsi o n, M o dific ati o n, or Ter mi n ati o n f or A RI A E ve nts
Disc o nti n u ati o n of D osi n g f or a Give n S u bjec t
T he ce ntral M RI rea di n g ce nter will re p ort i nci de nt cases of A RI A- E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he PI wit hi n a s pecifie d ti me after o bser vi n g t he fi n di n g o n M RI per t he i ma gi n g 
ma n ual pr oce d ures .  All cases of A RI A will be re vie we d b y  t he S p o ns or a n d t he PI ; decisi o ns o n 
d osi n g c o nti n uati o n, i nterr u pti o n, or disc o nti n uati o n will be base d o n cli nical s y m pt o ms, a n d t he 
M RI  i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C n otificati o n r ules will be o utli ne d i n t he 
I D M C c harter.  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 
(i ncl u di n g t he criteria t o be met f or t he c o nti n uati o n, s us pe nsi o n/res u m pti o n, per ma ne nt 
disc o nti n uati o n of d osi n g d ue t o A RI A, res u m pti o n of d osi n g after d ose s us pe nsi o n d ue t o A RI A
[i ncl u di n g r ules f or titrati n g u p t o t he assi g ne d d ose], a n d ma na ge me nt of rec urre nt A RI A) are 
pr o vi de d i n t he f oll o wi n g s u bsecti o ns.  D osi n g ma y als o be ter mi nate d at t he discreti o n of t he 
S p o ns or f or me dical reas 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7. 2. 1. 1.
A RI A -E C ases
T a ble 8:
Dis p ositi o n of A RI A -E C ases
Cli nic al S y m pt o m 
Se verit y
A RI A -E Se verit y o n M RI ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
As y m pt o m atic 
C o nti n ue d osi n g at 
c urre nt d ose a n d 
sc he d ule
S us pe n d d osi n g .  O nce A RI A -E res ol ves t he s u bject 
ma y res u me d osi n g at t he sa me d ose .  
Mil d
S us pe n d d osi n g .  O nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t he s u bject ma y 
res u me d osi n g at t he sa me d ose .  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y i m p ort a nt 
e ve nt ” o nl y 1
Seri o us, e xce pt f or 
“ ot her m e dic all y 
i mp ort a nt e ve nt ” 2
Disc o nti n ue D osi n g
1 “Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nific a 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. 2 .
2 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 2 .

S u bjects w h o de vel o p mi l d A RI A-E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 
d ose .  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d , i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
as well as bi o mar ker a n d 
P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A- E has res ol ve d per
t he ce ntrall y rea d M RI .  T he S p o ns or ma y  re q uire t hat t he s u bjects disc o nti n ue d osi n g 
or c o nti n ue d osi n g at a l o wer d ose le vel base d o n re vie w of safet y a n d M RI data.

S u bjects w h o de vel o p m o der ate or se vere A RI A -E, per ce ntr al M RI re a di n g,
wit h 
n o cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A
as well as bi o mar ker a n d 
P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A- E has res ol v e d per
t he ce ntrall y rea d M RI .  If t he A RI A-E has res ol ve d a n d t he s u bjects re mai n 
as ym pt o matic, t he s u bjects ma y  res u me treat me nt at t he sa me d ose.  S u bjects w h o 
ha ve misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A wil l n ot be all o we d t o 
res u me treat me nt.  

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
i m p ort a nt e ve nt ” o nl y) cli nic al s y m pt o ms at a n y ti me d uri n g t he st u dy will 
te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as 
well as bi o mar ker a n d P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he 
A RI A- E has res ol ve d per t he ce ntrall y rea d M RI .  If t he A RI A-E has res ol ve d a n d t he 
cli nical s ym pt o ms ha ve res ol ve d, t he s u bject ma y  res u me treat me nt at t he sa me d ose.  
S u bjects w h o ha ve misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be 
all o we d t o res u me treat me nt .  

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ”) 
cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will per ma ne ntl y disc o nti n ue 
treat me nt.  S u bje cts s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d ,
i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A as well as bi o mar ker 
a n d P K sa m ple c ollecti o n a p pr o xi matel y e ver y 4 wee ks u ntil t he A RI A -E has 
res ol ve d per ce ntrall y rea d M RI.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 2.
A RI A -H ( Micr o he m orr h a ge)
I n t his st u dy, ne w i nci de nt micr o he m orr ha ges are defi ne d as ne w i nci de nt micr o he m orr ha ges 
t hat occ ur o n treat me nt a n d d o n ot i ncl u de micr o he m orr ha ges at baseli ne.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 9:
Dis p ositi o n of A RI A -H ( Micr o he m orr h a ge) C ases
Cli nic al 
S y m pt o m  
Se verit y
N e w I nci de nt Micr o he morr h a ges 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
≥ 1 a n d ≤ 4
≥ 5 a n d ≤ 9
≥ 1 0
As y m pt o m atic
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule
S us pe n d d osi n g .  O nce A RI A -H 
is sta ble, t he s u bject ma y res u me 
d osi n g at t he sa me d ose .  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g .  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose .  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt micr o he m orr ha ges = ne w i nci de nt micr o he m orr ha ges o n treat me nt; d oes n ot i ncl u de 
micr o he m orr ha ges at baseli ne.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nifi ca 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es re q uiri n g pe r 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), 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/ or res ult i n 
persiste nt or si g nifica nt disa bilit y/i n ca 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. 2 .
As y m pt o m atic A RI A -H ( Micr o he m orr h a ge) 

S u bjects w h o de vel o p a ≥ 1 a n d ≤ 4 ne w i nci de nt micr o he m orr h a ge (s) [ mil d] at 
a n y ti me d uri n g t he st u d y ma y c o nti n ue treat me nt at t he c urre nt d ose.

S u bjects w h o de vel o p ≥ 5 a n d ≤ 9 ne w i nci de nt micr o he m orr h a ges [ m o der ate]
occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A
as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ge is c o nfir me d as sta ble 
per t he ce ntrall y rea d M RI .  A micr o he m orr ha ge is c o nsi dere d sta ble if it is 
u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he micr o he m orr ha ge is dee me d 
sta ble, s u bjects ma y res u me treat me nt at t he sa me d ose .  S u bjects w h o ha ve misse d 
m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be all o we d t o res u me treat me nt .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4

S u bjects w h o de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges [se vere] d uri n g t he 
st u d y will per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or 
a n M RI a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks 
( ± 3 da ys) u ntil t he micr o he m orr ha ges are dee me d sta ble per ce ntrall y rea d M RI .
S y m pt o m atic A RI A - H ( Micr o he m orr h a ge)

S u bjects w h o de vel o p ≤ 9 ne w i nci de nt micr o he m orr h a ges ( mil d or m o der ate)
a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ul e d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H ( micr o he m orr ha ge(s ) is 
c o nfir me d sta ble per t he ce ntrall y rea d M RI .  Mic r o he m orr ha ges are c o nsi dere d 
sta ble if t he y are u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce A RI A -H 
( micr o he m orr ha ge) is dee me d sta ble a n d t he cli nical s ym pt o ms ha ve res ol ve d, t he 
s u bject ma y res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve misse d m ore t ha n 
4 c o nsec uti ve d oses d ue t o A RI A will n ot be all o we d t o res u me treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h micr o he m orr h a ge(s) will 
per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A as 
well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
micr o he m orr ha ge(s) is c o nfir me d sta ble per ce ntrall y  rea d M RI.  

S u bjects w h o de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges (se vere), re gar dless of 
s ym pt o m se verit y, d uri n g t he st u d y will per ma ne ntl y  disc o nti n ue treat me nt.  S u bjects 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ges are dee me d sta ble per 
ce ntrall y rea d M RI .  
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
7. 2. 1. 3.
A RI A -H ( S u perfici al Si der osis)
T a ble 1 0:
Dis p osi ti o n of A RI A-H ( S u perfici al S i der osis) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Are as of S u perfici al Si der osis 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
1
2
> 2
As y m pt o m atic
C o nti n ue d osi n g at 
c urre nt d ose a n d sc he d ule
S us pe n d d osi n g .  O nce A RI A -H 
is sta ble t he s u bject ma y res u me 
d osi n g at t he sa me d ose .  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g .  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me
d ose .  
M o der ate
Se vere 
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt s u perficial si der osis = ne w i nci de nt s u perficial si der osis o n treat me nt.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 nifi ca 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es re q uiri n g pe r 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), 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/ or res ult i n 
persiste nt or si g nifica nt disa bilit y/i n ca 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. 2 .
As y m pt o m atic A RI A -H ( S u perfici al S i der osis)

S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis)[ mil d] ma y  c o nti n ue treat me nt at t he c urre nt d ose, b ut 
m ust ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K 
sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d 
as sta ble per t he ce ntrall y rea d M RI.  S u p erficial si der osis is c o nsi dere d sta ble if it is 
u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  

S u bjects w h o de vel o p 2 f oc al are as of he m osi der osis (s u perfici al 
si der osis)[ m o der ate] occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d 
P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A- H (s u perficial 
si der osis) is c o nfir me d as sta ble per t he ce ntrally rea d M RI .  S u perficial si der osis is 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
c o nsi dere d sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he s u perficial 
si der osis is dee me d sta ble, t he s u bjects ma y res u me treat me nt at t he sa me d ose.  
S u bjects w h o ha ve misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be 
all o we d t o res u me treat me nt.  

S u bjects w h o de vel o p > 2 f oc al are as of he m osi der osis (s u perfici al 
si der osis)[se vere] occ urri n g at a n y  ti me d uri n g t he st u d y m ust per ma ne ntl y 
disc o nti n ue treat me nt a n d s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts 
a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A as well as
bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H 
(s u perficial si der osis) is c o nfir me d as sta ble per t he ce ntrall y rea d M RI.  S u perficial 
si der osis is c o nsi dere d sta ble if it is u nc ha n ge d 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 orme d 2 wee ks ( ± 3 da ys) later.  
S y m pt o m atic A RI A -H (s u perfici al si der osis)

S u bjects w h o de vel o p ≤ 2 ne w f oc al are a s of s u perfici al si der osis ( mil d or 
m o der ate) a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt 
e ve nt ” o nl y) cli nical s y m pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H s u pe rficial si der osis is 
c o nfir me d sta ble per t he ce ntrall y rea d M RI .  S u perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  O nce t he A RI A -H (s u perficial 
si der osis) is dee me d sta ble a n d t he cli nical sy m pt o ms ha ve res ol ve d, t he s u bjects ma y  
res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve misse d m ore t ha n 4 
c o nsec uti ve d oses d ue t o A RIA will n ot be all o we d t o res u me treat me nt .  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h A RI A -H (s u perfici al 
si der osis) will per ma ne ntl y  disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess me nts a n d , i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI 
a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n e ver y 2 wee ks ( ± 3 da ys) 
u ntil t he s u perficial si der osis is c o nfir me d sta ble per ce ntrall y rea d M RI.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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

S u bjects w h o de vel o p > 2 ne w f oc al are as of s u perfic i al si der osis (se vere)
re gar dless of cli nical sy m pt o m se verit y  will per ma ne ntl y disc o nti n ue treat me nt, b ut 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A as well as bi o mar ker a n d P K sa m ple 
c ollecti o n e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d sta ble 
per ce ntrall y rea d M RI .  
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 4.
A RI A -H ( M acr o he m orr h a ge)

S u bjects w h o de vel o p a n y ne w i nci de nt macr o he m orr ha ge, re gar dless of s ym pt o m 
se verity d uri n g t he st u d y,  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or M RI a n d M O C A as well as bi o mar ker a n d P K sa m ple c ollecti o n
e ver y 2 wee ks ( ± 3 da ys) 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.  
7. 2. 1. 5.  
C oi nci de nt A RI A- H a n d A RI A -E C ases
S u bjects w h o de vel o p A RI A- H c oi nci de nt wit h A RI A- E at a n y ti me d uri n g t he st u d y  will f oll o w 
t he m ost restricti ve g ui deli nes.  Pri or t o res u mi n g treat me nt, w here a p plica ble, A RI A-E m ust 
res ol ve, A RI A-H m ust be dee me d sta ble, a n d t he s u bject m ust be as y m pt o matic .  F or e xa m ple, if 
a s u bject e x perie nces as y m pt o matic A RI A -H ( 1 -4 micr o he m orr ha ges) c oi nci de nt wit h A RI A -E 
assesse d as m o derate o n M RI  a n d acc o m pa nie d b y mil d cli nical s ym pt o ms, t he d ose s h o ul d be 
s us pe n de d per t he A RI A-E g ui deli nes s u m marize d i n Ta ble 8 .  
7. 2. 1. 6.
Res u m pti o n of St u d y Tre at me nt After S us pe nsi o n d ue t o A RI A
7. 2. 1. 6. 1.
M RI M o nit ori n g
W he n treat me nt res u mes after a d ose s us pe nsi o n d ue t o A RI A, a n M RI a n d M O C A
will be 
perf or me d as well as bi o mar ker a n d P K sa m ple c ollecti o n 2 wee ks ( ± 3 da ys) after t he sec o n d 
a d mi nistrati o n o f t he restarte d d ose.  I n a d diti o n, if treat me nt was s us pe n de d d uri n g t he d ose 
titrati o n pri or t o t he s u bject reac hi n g t he ma xi m u m assi g ne d d ose, a n MRI  a n d M O C A will be 
perf or me d as well as bi o mar ker a n d P K sa m ple c ollecte d 2 wee ks ( ± 3 da ys) 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
(titrati o n peri o d of 6 d oses a n d a fi nal M RI after t he sec o n d d ose at 1 0 m g/ k g) t o mai ntai n st u d y 
bli n di n g , n ot c o u nti n g u nsc he d ule d M RI visits f or m o nit ori n g of A RI A .  M RI s will ot her wise be 
perf or me d as i n dicate d i n t he Sc he d ules of E ve nts ( Secti o n 4. 2 ).
7. 2. 1. 6. 2.
D osi n g U p o n Res u m pti o n of St u d y Tre at me nt
S u bjects w h o s us pe n d treat me nt d ue t o A RI A f or t he first ti me ma y res u me treat me nt at t he sa me 
d ose if t he y meet t he criteria as descri be d i n Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5 .  S u bjects w h o s us pe n d 
a n d t he n res u me d osi n g after ha vi n g alrea d y reac he d t heir assi g ne d t o p d ose le vel are t o c o nti n ue 
d osi n g at t hat d ose le vel .  H o we ver, if d osi n g is s us pe n de d pri or t o a s u bject reac hi n g t heir 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
assi g ne d t o p d ose le vel , t he s u bject ( 1) m ust recei ve at least 2 d oses at t he restart d ose bef ore 
titrati n g u p t o t he ne xt d ose le vel a n d ( 2 ) m ust c o m plete at least t he re q uire d n u m ber of d oses at 
t hat d ose le vel per t heir assi g ne d d osi n g re gi me n, as o utli ne d i n t he ri g ht c ol u m n of Ta ble 1 1 .  
T a ble 1 1:
Res u m pti o n of St u d y Tre at me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A
D uri n g Titr ati o n
Assi g ne d D osi n g 
Re gi me n 
(M a xi m u m D ose )
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses at 
C urre nt D ose Le vel 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
A p o E ε 4 ( +)
L o w D ose ( 3 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
A p o E ε 4 ( -)
L o w D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
7. 2. 1. 7.
M a n a ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI)
If t he s u bject has a sec o n d occ urre nce of A RI A (i.e., a sec o n d occ urre nce of A RI A- E or of 
A RI A- H, or A RI A -E a n d A RI A- H) t hat re q uires d ose s us pe nsi o n, after t he A R I A- E resol ves or 
sta bilizes, t he s u bject is t o res u me d osi n g at t he ne xt l o wer d ose a n d is t o recei ve 2 d oses at t hat 
d ose le vel (i.e., t he restart d ose) bef ore titrati n g u p t o t he ne xt hi g her d ose .  O nce d osi n g has 
res u me d, t he g ui deli nes o utli ne d i n Ta ble 1 1 a p pl y, u nless t he s u bject has re d uce d fr o m 1 m g / k g 
t o place b o.  I n t his case, t he s u bject will re mai n o n place b o f or t he d urati o n of t he 
place b o -c o ntr olle d p orti o n of t he st u d y .  If a s u bject res u mes t reat me nt after A RI A, a n M RI a n d 
M O C A will be perf or me d as well as bi o mar ker a n d P K sa m ple c ollecti o n 2 wee ks ( ± 3 da y s) 
after t he sec o n d a d mi nistrati o n of t he restarte d d ose, a n d 2 wee ks ( ± 3 da y s) after e ver y sec o n d 
d ose u ntil t he c o m ple ti o n of titrati o n, wit h all s u bjects ass u me d t o be titrati n g t o 1 0 m g/ k g (6
d oses) t o mai ntai n st u d y  bli n di n 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 ules of E ve nts ( Secti o n 4. 2 ).
If t he s u bject e x perie nces a t hir d e pis o de of A RI A t hat re q uires d ose s us pe nsi o n, t he s u bject 
m ust disc o nti n ue st u d y  treat me nt.  S u bjects w h o 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 c o nti n ue all pr ot oc ol -re q uire d tests a n d assess me nts.  
S u bjects w h o de vel o p A RI A d uri n g t he place b o -c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d ose are eli gi ble t o e nter t he L T E peri o d a n d will mai ntai n t he d osi n g 
sc he me fr o m t he place b o-c o ntr olle d peri o d i nt o t he L T E, w hic h ma y i ncl u de a c o nti n uati o n o n 
t he sa me d ose or c o m pleti o n of titrati o n i nt o t he L T E peri o d.  A s u bject w h o is d ose -re d uce d t o 
place b o b ut re mai ns i n t he st u d y  ma y be titrate d t o a d uca n u ma b 1 m g / k g d uri n g t he L T E peri o d .
7. 2. 2. 
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 
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 Directi o ns f or Ha n dli n g a n d A d mi nistrati o n ( 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.
7. 3.
O v er all St u d y D ur ati o n a n d F oll o w -U p
T he st u d y  peri o d will c o nsist of scree ni n g, treat me nt, a n d F U .
T he d o u ble -bli n d , place b o -c o ntr olle d peri o d of t he st u d y will c o nsist of a n 8-wee k scree ni n g 
peri o d, a 7 6- wee k treat me nt peri o d , a n d a safet y F U peri o d of 1 8 wee ks after t he fi nal d ose .  
S u bjects will ha ve a p pr o xi matel y  3 2 sc he d ule d cli nic visits d uri n g t he place b o -c o ntr olle d peri o d, 
a n d u p t o 8 tele p h o ne safet y  F U c o ntacts, as f oll o ws:




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1
Ne ur o ps yc h ol o gical Stat us [ R B A N S]) a n d A p o E ge n ot y pi n g .  T his i nitial ne ur oc o g niti ve 
scree ni n g is i nte n de d t o re d uce t he b ur de n o n s u bjects a n d sites by a v oi di n g u n necessar y  testi n g 
if s u bjects d o n ot meet ke y i ncl usi o n criteria.  If t he s u bject meets i ncl usi o n criteria f or t hese 3 
scales, t he n 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 directl y t o t he f ull c o nse nt pr ocess, w hic h 
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 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, M M S E a n d R B A N S) m ust 
be perf or me d at Scree ni n g Visit 1 .  T o e ns ure t he st u d y  p o p ulati o n is reflecti ve of t he br oa der 
A D p o p ulati o n, wit h b ot h A p o E ε 4 carriers a n d n o n-carriers e nr olle d, A p o E ge n ot y pi n g ma y  be 
perf or me d at Visit 1 pri or t o ot her scree ni n g assess me nts.  T he A D A S -C o g 1 3 a n d A D C S -A D L -
M CI  will be perf or me d at Scree ni n g Visit 2 wit hi n 2 0 da y s after Visit 1 a n d m ust N O T be 
perf or me d o n t he sa me da y as t he C D R, M M S E a n d R B A N S .  T he N PI -1 0 ca n be perf or me d at 
a n y ti me d uri n g Scree ni n g as l o n g as it is perf or me d after t he C D R (e. g., i ncl u di n g at Scree ni n g 
Visit 1) .  All ot her c o g niti ve assess me nts 
 ma y be perf or me d at a ny 
ti me d uri n g Scree ni n g after eli gi bilit y is c o nfir me d d uri n g Scree ni n g Visit 1.  T he M RI  at 
Scree ni n g Visit 2 s h o ul d be d o ne o nl y after t he s u bject eli gi bilit y base d o n cli nic al 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 P E 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.  
S u bject eli gi bilit y  f or t he st u d y will be deter mi ne d n o m ore t ha n 6 0 da ys pri or t o st ud y  e ntr 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 relate d t o P E T 
sca ns a n d is s u bject t o S p o ns or a p pr o val.
S u bjects w h o fail Scree ni n g will be per mitte d t o be rescree ne d o nce at t he S p o ns or’s discreti o n .  
S u bjects w h o fail Scree ni n g d ue t o P E T, M M S E, C D R, he patitis B or C res ults, or a b n or mal 
M RI  fi ndi n gs will n ot be all o we d t o re scree n.  
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 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 hese me dicati o ns has bee n sta bilize d f or t he re q uire d peri o d.  
7. 3. 2.
Tre at me nt
Eli gi ble s u bjects will re p ort t o t he st u d y  site t o recei ve st u d y treat me nt e ver y 4 wee ks f or 
7 6 wee ks ( 2 0 d oses).  All 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 crite ria will be 
eli gi ble t o e nter t he L T E peri o d a n d will recei ve st u d y treat me nt e ver y 4 wee ks f or a n a d diti o nal 
1 0 0 wee ks ( 2 6 d oses), wit h t he first d ose a d mi nistere d a p pr o xi matel y  4 wee ks after t he fi nal d ose 
i n t he place b o - c o ntr olle d peri o d of t he st u d y .
7. 3. 3.
F o ll o w- U p
All s u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d are t o ret ur n t o t he st u d y site 
a p pr o xi matel y 2 wee ks after t he fi nal d ose f or cli nical assess me nts.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
S u bjects partici pati n g i n t he place b o - c o ntr olle d peri o d a n d n ot e nteri n g t he L T E peri o d are t o 
ret ur n t o t he st u d y site f or an F U V isit at Wee k 9 4 ( 1 8 wee ks after t he last d ose).  T he fi nal st u d y  
visit f or t hese s u bjects will be Wee k 9 4.
S u bjects w h o partici pate i n t he L T E peri o d are t o ret ur n t o t he st u d y site t o recei ve t heir first 
L T E d ose a p pr o xi matel y 4 wee ks after t heir last d ose i n t he place b o -c o ntr olle d peri o d of t he 
st u d y.  A F U V isit will occ ur at Wee k 1 9 8 ( 1 8 wee ks after t he last L T E d ose ).  T he fi nal st u d y  
visit f or s u bjects partici pati n g i n t he L T E peri o d will be Wee k 1 9 8.
S u bjects w h o 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 c o nti n ue all pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil wit h dra wal of c o nse nt.  S u bjects w h o 
wit h dra w fr o m t he st u d y are e nc o ura ge d t o ret ur n f or F U assess me nts 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.  
7. 4.
St u d y St o p pi n g R ules
Bi o ge n m a 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.
D osi n g ma y  be ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e xcl usi vel y o n safety a n d t olera bilit y data or f oll o wi n g t he f utilit y  a nalys is, or at t he discreti o n of 
t he S p o ns or; t heref ore t here are n o st u d y-s pecific st o p pi n g r ules defi ne d i n t his pr ot oc ol.  
7. 5.
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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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
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 foll o wi n g eli gi bilit y 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  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.
2.
A ge d 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 p ti 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 , please refer t o 
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 d eficits
ot her t ha n M CI or m il d A D.
5.
M ust ha ve a p ositi ve a m y l oi d P E T sca 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 f or s u bjects n ot partici pati n g i n t he a m yl oi d P E T 
s u bst u d y.  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 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 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:

A C D R -Gl o bal Sc ore of 0. 5 .

A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair me nt (base d 
u p o n t he Dela y e d Me m or y In de x ( D MI) sc ore).  

A n M M S E sc ore bet wee n 2 4 a n d 3 0 (i ncl usi ve).
7.
A part fr o m a cli nical dia g n osis of earl y 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  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 j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  A n i nf or ma nt/care part ner s h o ul d be a vaila ble f or t he d uratio n of t he st u d y , 
a n d t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8. 2.
E xcl usi o n Criteri a
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 oint s pecifie d i n t he i n di vi d ual criteri o n liste d:
Me dic al 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 m e 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 yr 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 o-te m p oral 
de me ntia, hea d tra u ma).
2.
Cli nicall y  si g nifica nt u nsta ble ps y c hiatric ill ness (e. g., u nc o ntr olle d ma j 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 ntrally 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) 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 y i 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).

Greater 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) .  

C ortical i nfarct ( defi ne d as > 1. 5 c m i n dia meter) .  

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 
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 safet y 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 In 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 y ocar dial i nfarcti o n, c hr o nic heart fail ure ( Ne w Y or k Heart 
Ass 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8.
Cli nicall y  si g nifica nt 1 2-lea d E C G a b n or malities, as deter mi ne d by t he I n vesti gat or.
9.
U nc o ntr olle d h y perte nsi o n defi ne d as : avera ge of 3 s y st 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/ 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 m its 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 dy), or persiste nt S B P/ D B P rea di n gs > 1 8 0/ 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 t he S p o ns or:  

S u bjects wit h ca ncers i n re missi o n m ore t ha 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 bjec ts 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.
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 (e. g., re peate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥ 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 Sc ree 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. Hist 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 ( HI V).
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 or he patitis B 
vir us ( defi ne d as p ositi ve f or b ot h he patitis B s urface a nti ge n A N D he patitis B c ore 
a nti b o d y).
1 8. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns, or hist or y of hy p erse 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 (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n).
1 9. 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, 
w hic h 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


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6
2 0. 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 g niti 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 1. 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 ni n g Visit 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 for at least 8 wee ks pri or t o Scree ni n g Visit 1.
2 2. Use of me dicati o ns wit h platelet a nti -a g gre ga nt or a nti -c 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 3. Use of illicit narc otic me dicati o n.
2 4. 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 5. 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 A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 6. 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 wit hi n 1 2 m o nt hs of 
Scree ni n g 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  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- E d uri n g a pre vi o us disease -m o d if yi n g trial s h o ul d be 
e xcl u de d.  
2 8. Partici pati o n i n a pre vi o us st u d y  wit h a d uca n u ma b (s u bject is eli gi ble if he/s he di d n ot 
recei ve acti ve a d uca n u ma b).
St u dy Pr oce d ures
2 9. C o ntrai 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 0. 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 y perse 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 1. A ne gati ve P E T sca n res ult w it h a n y a myl oi d -tar geti n g li ga n d wit hi n 6 m o nt hs pri or t o
Scr ee ni n g.
3 2. 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.  
3 3. F or s u bjects w h o c o nse nt t o l u m bar p u nct ure (L P ), a n y c o ntrai n dicati o ns t o ha vi n g a LP 
(e. g., platelet c o u nt < 1 0 0, 0 0 0/ µ L , l u m bar s pi ne def or mit y).  A n y s y m pt o ms ca use d b y or 
relate d t o t he o pti o nal L P d uri n g Scree ni n g m ust be res ol ve d pri or t o ra n d o mizati o n .  
S u bjects ma y  still partici pate i n t he o verall st u d y e ve n if partici patio n i n t he o pti o nal L P 
p orti o n is c o ntrai n dicate d .  
Ot hers


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 will be per mitte d t o be 
rescree ne d o nce at t he S p o ns or’s discreti o n, e xce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R, he patitis B or C, or a b n or mal M RI fi n di n gs .
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 of 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 L o n g-Ter m E xte nsi o n Peri o d
T o be eli gi ble t o p artici 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 7 8:
1.
S u bject m ust ha ve c o m plete d t he p lace b o-co ntr olle d p eri o d of t he st u d y i ncl u di n g t he
Wee k
7 8 Visit .  S u bject m ust ha ve ta ke n at least 1 4 d oses a n d n ot ha ve miss e d m ore t ha n 
4 c o nsec uti ve d oses , re gar dless of t he reas o n.  S u bjects w h o d o n ot meet t hese criteria 
ca n e nter t he L T E peri o d o nl y  wit h S p o ns or’s a p pr o val.
2.
M M S E sc ore > 1 0 at t he Wee k 7 8 Visit.
3.
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 pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt ( or asse 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.
4.
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.
5.
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.
6.
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.
7.
Has o ne i nf or ma nt/care part ner w h o, i n t he I n vesti gat or’s j u d g me nt, 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y  
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n .  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 t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
8. 4.
E xcl usi o n Criteri a f or 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 at Wee k 7 8 t he y ha ve:
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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
9.
E N R O L L M E N T , R E GI S T R A TI O N, A N D R A N D O MI Z A TI O N
9. 1.
Scree ni n g a n d E nr oll me nt
S u bjects ( or t heir le gally a ut h orize d re prese ntati ve, w here a p plica ble) 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 
ca n c o m plete t he ne ur oc o g niti ve scales ( C D R, M M S E a n d R B A N S) a n d A p o E ge n o t ypi 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 3 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 directl y t o t he f ull 
c o nse nt pr ocess w hic h w o ul d 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 (I C 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 o e ns ure t he st u d y  p o p ulati o n is reflecti ve of t he br oa der A D p o p ulati o n, wit h b ot h 
A p o E ε 4 carriers a n d n o n -carriers e nr olle d, A p o E ge n ot y pi n g ma y  be perf or me d at Visit 1 pri or 
t o ot her scree ni n g assess me nts.  
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 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 y s; 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 relate d t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.  If a s u bject is e xcl u de d 
fr o m t he st u d y, t he reas o ns f or e xcl usi o n will 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.  T he t otal st u d y  d urati o n f or eac h s u bject partici pati n g o nly i n t he 
place b o -c o ntr olle d peri o d will be a p pr o xi matel y  1 0 2 wee ks (a p pr o xi matel y a n 8- wee k scree ni n g 
p eri o d, 7 6 wee ks of place b o or a d uca n u ma b d osi n g, a n d 1 8 wee ks of F U ).  
9. 2.
R a n d o miz ati o n a n d Re gistr ati o n of S u bjects
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra n d o mize d o nl y after all 
baseli ne assess me nts ha ve bee n c o m plete d a n d t he In 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 .  N o s u bject ma y  be gi n treat me nt pri or t o assi g n me nt 
of a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y  s u bject i de ntificati o n 
n u m bers or ra n d o mizati o n sc he d ule assi g n me nts 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.  Re screene d s u bjects will be assi g ne d a ne w n u m ber .  
S u bjects will be ra n d o mize d t o recei ve a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose : place b o
i n a 1: 1 : 1 rati o.  T he ra n d o mizati o n will be stratifie d b y  site a n d A p o E ε 4 stat us (carrier or 
n o n- carrier).  E nr oll me nt will be m o nit ore d , via t he IR T, s uc h t hat t he p o p ulati o n of s u bjects 
wit h mil d A D re prese nts a s mall perce nta ge of t he t otal e nr olle d i n t he trial .  S u bjects w h o 
wit h dra w fr o m t he st u d y ma y  n ot be re place d.
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
T his st u d y  c o nsists of a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d peri o d, f oll o we d by a 
d ose - bli n de d L T E peri o d wit h all s u bjects recei vi n g a d uca n u ma b .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
F or t he d o u ble - bli n de d place b o - c o ntr olle d peri o d, all st u d y staff w h o c o n d uct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts .  T he rati n g H C Ps s h o ul d 
re mai n bli n de d t o treat me nt assi g n me nt as well as s u bject care ma na ge me nt a n d o nl y ha ve access 
t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  As a 
place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are re q uire d t o ma na ge all 
as pects of st u d y treat me nt recei pt, dis pe nsi n g a n d pre parati o n.  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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d  
 or Bi o ge n safety staff.
F or t he L T E peri o d , t he d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d treati n g H C P 
s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nly ha ve access t o t he i nf or mati o n 
necessar y  t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n t he st u d y
bli n d, it is i m perati ve t hat d ose i nf or mati o n is 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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
 or Bi o ge n safety staff .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 0.
D I S C O N TI N U A TI O N O F ST U D Y T R E A T M E N T A N D/ O R
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:

A RI A- E acc o m pa nie d b y seri o us cli nical s y m pt o ms e xce pt f or “ ot her me dicall y 
i m p orta nt e ve nt” as defi ne d i n Ta ble 8 .

S y m pt o matic A RI A -H ( m icr ohe m orr ha ges) wit h seri o us cli nical s y m pt o ms
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 9 .

S y m pt o matic A RI A -H (s u perficial si der osis) wit h or seri o us cli nical sy m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 1 0 .

A RI A - H wit h ≥ 1 0 micr o he m orr ha ges a n d/or > 2 f ocal areas of s u perficial 
si der osis.  

A n y  ne w i nci de nt macr o he m orr ha ge.

A t hir d rec urre nce of A RI A after rec halle n ge t hat re q uires d ose s us pe nsi o n
See Secti o n 7. 2. 1 f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d ucti o n d ue t o 
A RI A- E or A RI A -H.

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 
a n d pre g na nc y m ust be re p orte d 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.

T he s u bject e x perie nces a me dical e mer ge nc y  t hat necessitates per ma ne nt 
dis c 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.  

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 vesti gat or f or me dical reas o ns.

At t he discre ti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce.
T he reas o n f or disc o nti n uati o n of st u d y  treat me nt m ust be rec or de d i n t he s u bject’s case re p ort 
f or m (C R F ).
A s u bject w h o disc o nti n ue s treat me nt is t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uire d
tests a n d assess me nts u ntil t he e n d of t he st u d y per t he sc he d ule of e ve nts or u ntil t he s u bject
wit h dra w s c o nse nt .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0. 2.
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 ws c o nse nt.

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 S p o ns or .
N ote: A s u bject w h o disc o nti n ue s 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 hey c o nti n ue t o atte n d cli nic visits a n d 
c o m plete all assess me nts .  
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 s h o ul d 
c o m plete t he E O T Visit after t he reas o n f or wit h dra wal is i de ntifie d .  For s uc h s u bjects, efficac y 
assess me nts s pecifie d at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt 
wit hi n 3 m o nt hs of t he pre vi o us efficac y  assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve 
stat us are s us pecte d by t he I n vesti gat or; T he site s h o ul d n otif y t he s p o ns or i n s uc h cases .  
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 F U Visit 1 8 wee ks 
after recei vi n g t heir last d ose of st u d y  treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 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 .  
Please see Secti o n 4. 2 ( Sc he d ule of E ve nts) f or t he st u d y treat me nt i nf usi o n sc he d ule d uri n g t he 
p lace b o-co ntr olle d a n d L T E p eri o ds of t he st u d y.
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   
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.  
1 1. 1. 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.
1 1. 2.
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule
Refer t o Secti o n 7. 2. 1 ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 2 (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at least 2 1 da ys a part.  If t he d osi n g i nter val ca n n ot be met, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y t he st u d y me dical m o nit or .
1 1. 3.
Prec a uti o ns
N ot a p plica ble .
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 by u n bli n de d site staff.
1 1. 5.
Pri or a n d 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 F U Visit).
N o pre me dicati o n (e. g., a nti-aller g y dr u gs, a nti p yr 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 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 are all o we d 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 .  

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, are all o we d 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 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 are all o we d d uri n g t he st u d y.  
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 .
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 nti -a g gre ga nt or a nti-c 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 dicati 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).  L o cal 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 m a y  be per mitte d at t he S p o ns or ’s dis creti 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 
(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 ny 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, as it 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 or of a ny 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 b y  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 w o ul d n ot res ult i n a ut o matic wit h dra wal .  T he 
S p o ns or 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 v isit f or a c ha n ge i n A D me dicati o n, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he c ha n ge i n 
me d icati 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 F U visit), u nless t he s u bjects is bei n g f oll o we d f or st u d y-relate d t o xicit y.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 nefic ial, all re g ulat or y re q uire me nts re gar di n g p ostst u d y access will be met.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
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 ye d f or m ore t ha n 2 h o urs, t he n it s h o ul d be ke pt at 2° 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 ye 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
(or its desi g nee ), 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 pers o n nel 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 nt 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.  
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  treat me nt 
acc o u nta bilit y.  B y  t he e n d of t he st u d y rec o nciliat i 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 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 
T he place b o ( 0. 9 % sterile s o di u m c hl ori de f or i njecti o n) will be pr o vi de d b y  t he site i n t he f or m 
of 1 0 0 ml sali ne I V ba gs .  
1 2. 3.
A d diti o n al Pr ot oc ol -Desi g n ate d Pr o d ucts
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.
T o c o nfir m a m yl oi d pat h ol o g y  at Scree ni n g, P E T sca ns 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 t h ose 
s u bjects partici pati n g i n t he a m yl oi d P E T s u bst u d y , Scree ni n g a n d F U sca ns m ust be perf or me d 
usi n g A m y vi d a n d for s u bjects partici pati n g i n t he P E T s u bst u d y i n Ja pa n, Viza m yl (1 8F-
fl ute met o m ol) ma y  als o be use d .  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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
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
P H A R M A C O D Y N A MI C A S S E S S M E N T S
Refer t o Secti o n 4. 2 f or t he ti mi n g of assess me nts.
1 3. 1.
Cli nic al Effic ac 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 efficac y  of a d uca n u ma b: 

C D R

M M S E

A D A S -C o g 1 3

A D C S -A D L -M CI

N PI -1 0
It is rec o m me n de d t hat cli nical assess me nts be perf or me d at t he sa me ti me of da y f or s u bjects 
d uri n g t heir st u d y visits .  
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s daily acti vities a n d c o g niti ve ca pa bilities .  
T he rec o m me n de d or der of a d mi nistrati o n of t he cli nical assess me nts is descri be d i n t he St u d y  
Refere nce G ui de .  
1 3. 2.
P h ar m ac o k i netic Assess me nts
Ser u m c o nce ntrati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y .  
1 3. 3.
P h ar m ac o d y n a mic Assess me nts
T he f oll o wi n g tests will be perf or me d t o assess t he P D pr o perties of a d uca n u ma b:

Serial meas ure me nt of a m y l oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y am y l oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects partici pati n g i n 
t he a m yl oi d P E T c o h ort ).  
O nl y  sites wit h ca pa bilities of perf or mi n g 1 8F- fl or beta pir P E T will be all o we d t o 
perf or m t his assess me nt .  I nvesti gat or partici pati o n i n t his part of t he st u d y is o pti o nal 
a n d c o nti n ge nt u p o n a p pr o val b y  his/ her et hics c o m mittee ( E C) or i nstit uti o nal re vie w 
b oar d (I R B) .  If t he I n vesti gat or is n ot partici pati n g or t he test is n ot a p pr o ve d b y 
his/ her E C/I R B, t he rele va nt secti o n of t he I C F will n ot be a p plica ble t o t hat site .
S u bject partici pati o n i n t his p art of t he st u d y is o pti o nal at partici pati n g sites.  
I nf or me d c o nse nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a se parate pr oce d ural ma n ual f or P E T.  A p pr o xi matel y 
4 0 0 s u bjects are e x pecte d t o partici pate i n t he am y l oi d P E T s u bst u d y.  








Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4.
S A F E T Y A S S E S S M E N T S
See Secti o n 4. 2 f or t he ti mi n g of 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 m o nit ori n g.

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.

Ne ur ol o gical e xa mi nati o n .

Vital si g ns (b o d y  te m perat ure, heart rate, S B P, D B P, a n d res pirat or y rate).

1 2- lea d E C G.

Brai n M RI.

C o nc o mita nt me dicati o n, t hera p y a n d pr oce d ure m o nit ori n g .  

M O C A (f or A RI A m o nit ori n g a n d ma na ge me nt).  

C ol u m bia S uici de Se verit y  Rati n g Scale.  
1 4. 2.
L a b or at or y S afet y Assess me nts
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 b s ol ute 
ne utr o p hil c o u nt .

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, A L T, A S T, lactate de h y dr o ge nase, 
ga m ma -gl uta m y l-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 vity, 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 mal).

Ser u m a n d uri ne pre g na nc y  test f or 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 ), H b A1c, a n d alc o h ol/ dr u g scree n at Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4. 3.
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a nti -a d uca n u ma b 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).  C o nfir me d a nti dr u g a nti b o d y-p ositi ve sa m ples will be teste d f or t he 
prese nce of a nti -a d uca n u ma b ne utralizi n g a nti b o dies usi n g a vali date d assa y .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 5.
S A F E T Y D E FI NI TI O N S, R E C O R D I 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 b ject.  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 m ust be gi ve n 
t he na mes a n d tele p h o ne n u m bers of st u d y site staff f or re p orti n g A Es a n d me dical emer 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 necessaril y  ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal 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 uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct .
Deter mi nati o n of w het her a n a b n or mal la b orat or y  val ue 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 .  Alt h o u g h a b n or mal la b orat or y  val ues are ty picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or a n S A E.

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y.

A la b orat or y  a b n or malit y t hat t he In vesti gat or c o nsi ders t o be cli nicall y si g nifica nt.
P re-treat me nt, n o nseri o us A Es t hat occ ur wit hi n 4 8 h o urs after recei pt of a li ga n d will be 
ca pt ure d b y t he sites o n t he A E f or m .  
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:

R es ults i n deat h .

In 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.

R e 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 .

R es ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y.

R es ults i n a c o n ge nital a n o mal y / birt h defect.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
A n S A E ma y  als o be a n y ot her me dically i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he 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 h e 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 oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he 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 pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.

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 u nless o ne 
of t he re q uire me nts i n S ecti 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 hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 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 .






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e mail a c o m plete d S A E f or m.  Refer t o t he 
St u d y  Refere nce G ui de f or c o untr y -s pecific 
 fa x n u m bers or e mail 
1 5. 3. 4. 1.
De at h s
Deat h is a n o utc o me of a n e ve nt .  T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F .  All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt .  T he I n vesti gat or s h o ul d ma ke e ver y  eff ort t o o btai n a n d se n d 
deat h certificates a n d a ut o ps y re p orts t o 
.  T he ter m d eat h s h o ul d be 
re p orte d as a n S A E o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d by t he I n vesti gat or or Bi o ge n t o be relate d t o t he st u d y treat me nt a d mi nistere d.
A p pr o priate pers o n nel i n Bi o ge n Safet y  a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y  re p orti n g.  Bi o ge n or desi g nee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y  a ge ncies acc or di n g t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n.
1 5. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 5. 4. 1.
Pre g n a nc y
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y a n d 
f or 2 4 wee ks after t heir l ast d ose of st u d y tre at me nt.  If a fe male 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 di ately.
T he I n vesti gat or m ust re p ort a pre g na nc y  occ urri n g i n a fe male s u bject b y  fa xi n g t he a p pr o priate 
f or m t o 
wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he 
pre g na nc y  at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u d y refere nce ma n ual.  T he 
I n vesti gat or or st u dy site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
 
  
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 gi ve n 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 descri be d i n 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 
 wit hi n 2 4 h o ur s 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 
 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 
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
).  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, st u d y 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
 2 4-h o ur e mer ge nc y  me dical s u p p ort n u m ber.  Refer t o t he St u d y  
Refere nce G ui de’s Official 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 gn 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 vise 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, n 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.
1 5. 5.
C o ntr ace pti o n Re q uire me nts
F or t he p ur p oses of t his st u d y , w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h y si ol o gically ca pa ble of bec o mi n g pre g na nt, U N L E S S t h e y  meet o ne of t he f oll o wi n g 
c o n diti o ns:

P ost me n o pa usal

1 2 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 or 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 my.

P ost h y sterect o m y.

Fe male s ur gical st erilizati o n (e. g., bilateral t u bal li gati o n).
F or t he p ur p oses of t his st u d y , hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g:

F or fe males of c hil d beari n g p ote ntial:

Esta blis he d use of oral, i njecte d, or i m pla nte d h or m o nal met h o ds of
c o ntrace pti o n.

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne s y ste m

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 occl 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 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
s u p p osit or y.  T he use of barrier c o ntrace pti ves s h o ul d al wa y s be s u p ple me nte d 
wit h t he use of a s per mici de.

Male se x ual part ners u n der we nt 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:

Vasect o m y wit h ne gati ve se me n a nal ys is at F U .

Use of c o n d o ms wit h s per mici de.

Fe male se x ual part ner s w h o u n der we nt s ur gical sterilizati o n (e. g., bilateral t u bal 
li gati o n), are p ost me n o pa usal, are p ost -h y sterect o m y, or are usi n g hi g hl y effecti ve 
c o ntrace ptio n as liste d a b o ve f or fe male s u bjects.
F or males a n d fe males 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 a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he In 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 trial .  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d acce pta ble met h o ds of 
c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 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 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, re gar dless of t he se verit y  or relati o ns hi p 
t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g na ncies a n d F U o n t he o utc o me of t he pre g na nc y  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 S A B R ( or desi g nee) wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.

P urs ue S A E F U i nf or mati o n acti vel y a n d persiste ntl y.  F U inf or mati o n m ust be 
re p orte d t o Bi o ge n S A B R ( or desi g nee) wit hi n 2 4 h o urs of t he st u d y  site staff 
bec o mi n g a ware of ne w i nf or mati o n.

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E F U 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 1

Re p ort S A Es t o l ocal E C /IR Bs , as re q uire d by 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 st u d y site acti vati o n a n d s u bject e nr oll me nt, t he C li nical M o nit or ( 
) is 
res p o nsi ble f or re vie wi n g wit h st u d y 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 ( or desi g nee) is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C /IR B s, 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 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
1 6.
S T A TI S T I 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 .
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 [ S D], 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.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al ysis P o p ul ati o n
T he i nte nt -t o-treat (I T T) 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 st u d y treat me nt (a d uca n u ma b or place b o), will be use d f or t he efficac y 
a nal ys es.  F or eac h e n d p oi nt, a d diti o nal c o n diti o ns ma y  a p pl y t o t he defi niti o n of t he p o p ulati o n 
f or t he a nal ysis.  S u bjects will be a nal y ze d i n t he gr o u ps t o w hic h t he y were ra n d o mize d.  
1 6. 2. 2.
Met h o ds of A n al ysis
1 6. 2. 2. 1.
Ge ner al C o nsi der ati o ns
S u m mar y  statistics will be prese nte d.  F or c o nti n u o us e n d p oi nts, s u m mar y  statistics will 
ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, sta n dar d de viati o n, me dia n, a n d ra n ge .  
F or cate g oric al e n d p oi nts, t his will ge nerall y i ncl u de: n u m ber of s u bjects ra n d o mize d or d ose d, 
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 .  Statistical testi n g f or 
efficac y e n d p oi nts will be ma de bet wee n eac h a d uca n u ma b re gi me n a n d place b o. All statistical 
tests will be 2-si de d.
1 6. 2. 2. 2.
D ose Re gi me ns t o be E v al u ate d
T he f oll o wi n g d ose re gi me n s of a d uca n u ma b as c o m pare d wit h place b o will be e val uate d :

A d uca n u ma b hi g h -d ose re gi me n ( 1 0 m g/ k g i n A p o E ε 4 [i ncl u di n g 6 m g/ k g f or 
s u bjects e nr olle d u n der pr ot oc ol versi o n 1-3 w h o d o n ot ha ve t he o p p ort u nit y  t o 
u ptitrate t o 1 0 m g/ k g pri or t o c o m pleti n g Wee k 7 8 of t he st u d y ] a n d 1 0 m g / k g i n 
A p o E ε 4 n o n carriers).

A d uca n u ma b l o w-d ose re gi me n ( 3 m g/ k g i n A p o E ε 4 carriers a n d 6 m g / k g i n 
A p o E ε 4 n o n- carriers) .  
I n t he e ve nt t hat t he ma xi m u m d ose ( 1 0 m g/ k g) is ter mi nate d after t he start of t he st u d y 
(Secti o n 5. 3. 2 ) t he defi niti o n of a d uca n u ma b hi g h d ose re gi me n a n d a d uca n u ma b l o w d ose 
re gi me n will be m o difie d as s h o w n i n Ta ble 1 2 .  T he d osi n g m o dificati o n will be e nt irel y base d 
o n i nteri m a nal y sis of o utc o mes t hat are i n de pe n de nt of, a n d u ni nf or mati ve a b o ut, t he treat me nt-
relate d efficac y effect.  C o ntr ol of T y pe I err or rate is t h us mai ntai ne d wit h o ut a statistical 
a dj ust me nt f or s uc h a da ptati o ns [C h o w a n d C ha n g 2 0 1 1 ].


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T a ble 1 2:
D ose Gr o u p P o oli n g Str ate g y i n t he E ve nt of Tre at me nt Gr o u p Ter mi n ati o n
Tre at me nt Gr o u p (s) Ter mi n ate d
Defi niti o ns of Re vise d P o ole d Tre at me nt 
Gr o u ps f or C o m p aris o n
A p o E ε 4 carrier hi g h-d ose g r o u p (1 0 m g / k g)
[i ncl u di n g 6 m g/ k g f or s u bjects e nr olle d u n der pr ot oc ol 
versi o n 1 - 3 w h o d o n ot ha ve t he o p p ort u nit y t o u ptitrate 
t o 1 0 mg/ k g pri or t o c o m pleti n g Wee k 7 8 of t he st u d y]
L o w: A p o E ε 4 carrier 3 m g/ k g a n d
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 1 0 m g/ k g
A p o E ε 4 n o n -carrier h i g h- dose g r o u p ( 1 0 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 1 0 m g/ k g a n d 
n o n- carrier 6 m g/ k g
A p o E ε 4 carrier h i gh -d ose g r o u p ( 1 0 m g / k g) 
A N D
A p o E ε 4 n o n -carrier h i g h-d ose g r o u p ( 1 0 m g/ k g) 
A p o E ε 4 carrier 3 m g/ k g a n d n o n -carrier 
6 m g/ k g
1 6. 2. 2. 3.
C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I  err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y  e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws: a d uca n u ma b hi g h -d ose re gi me n vers us place b o a n d a d uca n u ma b l o w -d ose re gi me n 
vers us place b o .  All c o m paris o ns after t he i nitial c o m paris o n wit h p > 0. 0 5 will n ot be c o nsi dere d 
statisticall y si g nifica nt.
Sec o n dar y  e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  I n order t o 
c o ntr ol f or a T ype I err or f or t he sec o n dar y  e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be use d a n d will i ncl u de b ot h t he or der of t he sec o n dar y  e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y  e n d p oi nts, a seq ue n tial (cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T y pe I err or rate d ue t o m ulti ple 
treat me nt c o m paris o ns.  If statistical si g nifica nce is n ot ac hie ve d f or 1 or 2 c o m paris o ns , all 
e n d p oi nt(s) of a l o wer r a n k will n ot be c o nsi dere d statisticall y  si g nifica nt f or 1 or 2 , res pecti vely .  
D ue t o a c urre nt lac k of scie ntific c o nse ns us i n t he A D fiel d o n w hic h bi o mar ker(s) mi g ht be 
m ost a p pr o priate, t he selecti o n of t he bi o mar kers a n d met h o d ol o g y  f or c o ntr ol of T ype I err or 
will be pre -s pecifie d i n t he statistical a nalys is pla n ( S A P).  Ot her wise, t here will be n o m ulti ple 
c o m paris o n a dj ust me nts f or t he tertiar y e n d p oi nts.  
1 6. 2. 2. 4.
A n al ysis of t he Pri m ar y E n d p oi nt
T he p o p ulati o n f or t he pri mar y  e n d p oi nt a nalys is will be s u bjects i n t he I T T p o p ulati o n wit h a 
baseli ne a n d at least o ne p ost- baseli ne C D R -S B sc ore .  A mi xe d m o del re peate d meas ures 
( M M R M) m o del will be use d as t he pri mar y  a nalysis t o a nal y ze c ha n ge fr o m baseli ne C D R -S B 
usi n g fi xe d effects of treat me nt, ti me, treat me nt- b y -ti me i nteracti o n, baseli ne C D R -S B, baseli ne 
C D R -S B b y  ti me, baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
1 6. 2. 2. 5.
A n al ysis of t he Sec o n d ar y E n d p oi nts
1 6. 2. 2. 5. 1. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n M M S E 
T he p o p ulati o n f or t he a nal ysis will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least 
o ne p ost -baseli ne M M S E val ue .  A M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m bas eli ne M M S E usi n g fi xe d effects of treat me nt, ti me, treat me nt -b y -ti me 
i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y  ti me i nteracti o n a n d baseli ne A p o E ε 4
stat us 
1 6. 2. 2. 5. 2. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D A S -C o g 1 3
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D A S -C o g 1 3 sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m baseli ne A D A S -C o g 1 3 usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D AS -C o g 1 3, baseli ne A D A S -C o g 1 3 b y  ti me 
i nteracti o n; baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5. 3. C h a n ge F r o m B aseli ne t o Wee k 7 8 i n A D C S -A D L -M CI
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D C S -A D L -M CI sc ore .  A n M M R M m o del will be use d as t he pri mar y  a nal ysis 
t o a nal yze c ha n ge fr o m baseli ne A D C S -A D L -M CI
usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D C S-A D L -M CI,
baseli ne A D C S -A D L -M CI b y  ti me 
i nteracti o n; baseli ne M MS E , a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 6.
Terti ar y E n d p oi nts A n al ysis
1 6. 2. 2. 6. 1. Pl ace b o - Co ntr olle d P eri o d
W here a p pr o priate, a M M R M m o del will be use d as t he pri mar y  a nalys is t o a nal yze c ha n ge fr o m 
baseli ne usi n g fi xe d effects of treat me nt, ti me, treat me nt b y  ti me i nteracti o n, baseli ne val ue, 
baseli ne val ue b y ti me i nteracti o n, baseli ne M M S E a n d baseli ne A p o E ε 4 stat us.
Ot her wise, a n a nal ys is of c o varia nce or its n o n-para metric e q ui vale nt ma y  be use d t o a nalyz e 
t hese e x pl orat or y e n d p oi nts.
1 6. 2. 2. 6. 2. L o n g -Ter m E xte nsi o n Peri o d
T he a d diti o nal e n d p oi nts f or t he L T E peri o d are c ha n ge fr o m baseli ne o ver t he p lace b o-
c o ntr olle d a n d L T E peri o ds of t he st u d y .  A nal ys es will be prese nte d b y treat me nt gr o u p i n t he 
place b o -c o ntr olle d peri o d usi n g t he place b o -c o ntr olle d peri o d baseli ne.  Details of t he a nal ys es 
will be pre -s pecifie d i n t he S A P .  
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 p o p ulati o n f or P K a nal y sis 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 
st u d y treat me nt, 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 6. 3. 2.
Met h o d of A n al ysis
T he p o p ulati o n P K c haracteristics of a d uca n u ma b will be deter mi ne d b y n o nli near mi xe d effects 
a p pr oac h .  C o variates t hat mi g ht i nfl ue nce t he dis p ositi o n of a d uca n u ma b (e. g., b o d y wei g ht, 
a ge, se x, i m m u n o ge nicit y, A p o E ε 4 stat us) will be e val uate d a n d t he p ote ntial e x p os ure-res p o nse 
relati o ns hi ps will be e x pl ore d.
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 recei ve d at least 1 d ose of st u d y  treat me nt 
(i ncl u di n g place b o a n d 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 si g 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 ment, 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 ps, 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 place b o-c ontr olle d peri o d a n d o ver t he 2 4 -m o nt h 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 yste m or ga n class as 
well as f or preferre d ter ms wit hi n eac h s ys te 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 ( Me d D R A).  
1 6. 4. 2. 2.
Cli nic al L a b or at or y Res ults
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 nalys is 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 cate g orize d 
base d o n c o m m o n t o xicit y criteria gra de wil l 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 .  
1 6. 4. 2. 3.
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n cli nicall y rele va nt a b n or malities.
1 6. 4. 2. 4.
E C G
T he n u m ber a n d perce nta ge of s u bjects wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or 
a b n or mal A E) will be s u m marize d b y  treat me nt gr o u p.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
1 6. 4. 2. 5.
C ol u m bi a S uici de Se verit y R ati n g Sc ale
T he C ol u m bia S uici de Se verit y Rati n g Scale 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 ulati 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 nicity.  
1 6. 5. 2.
Met h o ds of A n al ysis
A nti- a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.
1 6. 6.
I nteri m A n al yses
1 6. 6. 1.
I nteri m F utilit y A n al ysis
A n i nteri m a nal ys is f or f utilit y of t he pri mar y e n d p oi nt will occ ur after a p pr o xi matel y  5 0 % of t he 
s u bjects ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m f utilit y a nalys is.  T his i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he I D M C ma y  rec o m me n d ter mi nati n g 
t he st u d y f or f utilit y if it is e vi de nt t hat t he efficac y of a d uca n u ma b is u nli kel y t o be ac hie ve d.  
T he f utilit y  criteria will be disc usse d i n detail i n t he S A P.
1 6. 6. 2.
I nteri m S u peri orit y A n al ysis
A n i nteri m a nal ys is f or s u peri orit y m a y  be perf or me d after a p pr o xi matel y  5 0 % of t he s u bjects 
ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d) .  T he O’ Brie n -Fle mi n g b o u n dar y  a p pr oac h 
will be use d f or t he a nal ysis .  I n or der t o mai ntai n t he treat me nt bli n d i n t he e ve nt of t his i nteri m 
a nal ys is, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m s u peri orit y a nal ys is.  T he i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he ai m of t his i nteri m a nal y sis is t o all o w 
t he p ossi bilit y t o de m o nstrate treat me nt effect earl y.  T he a nal ys is will be disc usse d i n detail i n 
t he S A P.
1 6. 7.
S a m ple Size C o nsi der ati o ns
T he st u d y ’s sa m ple size is base d, i n part, o n res ults fr o m a pr ot oc ol-s pecifie d i nteri m a nalys is 
fr o m St u d y 2 2 1 A D 1 0 3 w hic h i ncl u de d 1 year data fr o m 1, 3 a n d 1 0 m g/ k g treat me nt gr o u ps.
A sa m ple size of 4 5 0 s u bjects per treat me nt gr o u p will ha ve a p pr o xi matel y  9 0 % p o wer t o detect 
a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne C D R-S B at Wee k 7 8 bet wee n t he 
2 treat me nt gr o u ps.  T his p o wer calc ulati o n is base d o n a 2 -si de d t-test ass u mi n g e q ual varia nce 
wit h a fi nal si g nifica nce le vel of 0. 0 5, a S D of 1. 9 2 a n d a dr o p- o ut rate of 3 0 % .  T he S D esti mate 
of 1. 9 2 f or Wee k 7 8 reflects a 3 9 % i ncrease o ver t he S D fr o m t he pr ot oc ol-s pecifie d i nteri m 
a nal ys is of 1-ye ar data.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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
T he ass u me d tr ue mea n differe nce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d ucti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o mea n c ha n ge is esti mate d t o be 2.
T he sa m ple size ma y  be reassesse d i n a bli n de d ma n ner a p pr o xi matel y 3 m o nt hs bef ore 
e nr oll me nt is c o m plete if at least 1 5 % of t he data are a vaila ble o n t he pri mar y  e n d p oi nt.  At t his
i nteri m ti me-p oi nt, t he S D f or t he pri mar y e n d p oi nt will be esti mate d base d o n t he bli n de d data .  
T he sa m ple size ma y  be i ncrease d if t he S D is esti mate d t o be m ore t ha n a p pr o xi matel y 2. 0 7.  I n 
a d diti o n, t he sa m ple size c o ul d be i ncrease d usi n g e xter nal c li nical trial res ults t hat bec o me 
a vaila ble after t he start of t he st u d y .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 8
1 7.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n ,  
 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 nfere nce o n Har m o nisati o n (IC 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 ulati o 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 ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y -relate d d uties ha ve bee n dele gate d.
1 7. 1.
Dec l ar ati o n of Helsi n ki
T his st u d y  will be perf or me d i n ali g n me nt wit h t he et hical pri nci ples o utli ne d i n t he Declarati o n 
of Helsi n ki .
1 7. 2.
Et hics C o m mittee /I nstit uti o n al Re vie w B o ar d
T he I n vesti gat or m ust o btai n E C/I R B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y  
d oc u me nts pri or t o starti n g t he st u d y.  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 E C.  A c o p y  of t he a p pr o ve d IC 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 gree me nt of t he rele va nt E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) 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 C/I R B a p pr o val, w hic h s pecificall y  i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y.  Pr ot oc ol a me n d me nts 
will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he E C/I R B at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he E C/IR B a n d Bi o ge n .
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 prese ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns .  S u bjects ca n c o m plete t he ne ur oc o g niti ve scales 
( C D R, M M S E a n d R B A N S) as a n i nitial o pti o nal scree 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 3 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 directl y 
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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 9
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 / or et h nicit y will be c ollecte d a n d will be use d 
d uri n g a nal ys is of st u d y res ults ( o nl y i n c o u ntries w here per mitte d b y l ocal la w/re g ulati o n).
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 , care gi ver a n d/ or le gall y 
a ut h orize d re prese ntati ve.  T he si g ne d a n d dated I C F will be retai ne d wit h t he st u d y  rec or ds.  
L ocal re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal ( wet 
si g nat ure) a n d c o pies of t he si g ne d a n d date d I CFs.
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 b y l ocal la w (e. g., Pr otecte d Healt h I nf or mati o n
aut h orizat i o n i n N ort h A merica).
T he s u bject will n ot be i de ntifie d b y  na me i n t he C R F or i n a n y st u d y re p orts a n d t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n , its part ner(s) a n d desi g nee(s), E C/I R Bs , a n d 
vari o us g o ver n me nt healt h a ge ncies ma y  i nspect 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.
D uri n g t he st u d y , s u bjects’ race a n d/ or et h nicit y will be c ollecte d ( o nly i n c o u ntries w here 
per mitte d b y  l ocal la w/re g ulati o n).  T hese data ma y  be use d i n t he a nalys is of t he safety , 
efficac y, a n d/ or p har mac o ki netic pr ofile of t he st u d y  treat me nt.  It is u n k n o w n if t he p ote nc y  or 
effects of t he st u d y treat me nt are i nfl ue nce d b y race or et h nicit y.  
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 vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
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 pat e 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 u lati o ns.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 0
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 bjects 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 d etaile 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 Ass ur a nce
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 uth orities ma y  wis h t o perf or m o nsite a u dits.  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 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’ medical hist ories.
T he Cli nical M o nit or(s) will visit t he I n vesti gat or(s) 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.
D uri n g t hese visits, C R Fs a n d s u p p orti n g d oc u me ntati o n relate d t o t he st u d y will be re vie we d 
a nd a n y discre pa ncies or o missi o ns will be res ol ve d .  
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 pr ot oc ol a d here nce, q ualit y of data, 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.
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 ntract(s) 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.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 2
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.
1 9. 2.
St u d y C o m mittees
1 9. 2. 1.
A d vis or y C o m mittee
A n a d vis or y  c o m mittee will be f or med t o pr o vi de scie ntific a n d me dical directi o n f or t he st u d y 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y  c o m mittee will meet 
peri o dicall y t o m o nit or s u bject accr ual a n d o versee st u d y  c o n d uct, i ncl u di n g a d visi n g o n st u dy 
desi g n a n d e xec uti o n .  T he a d vis or y  c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g t he st u d y .  
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x perts i n Alz hei mer’s disease .  
Bi o ge n will desi g nate o ne of t he partici pati n g e xter nal e x pert s t o be t he c hair pers o n of t he 
a d vis or y c o m mittee.
1 9. 2. 2.
I n de pe n de nt D at a M o nit ori n g C o m mittee 
T he ID M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y  data.  Me m bers of t he ID 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 ID 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 .  T he ID M C, base d o n 
t he nat ure, fre q ue nc y, a n d/ or se verity of a n A E(s) 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 minati o n .  A n I D 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 I D M C .  
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 E C/I R B a n d re g ulat or y  a ut h orities if re q uire d 
b y  l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B 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 dy .  If re q uire d by l ocal la w, s uc h m o dificati o ns m ust 
als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o i m ple me ntati o n .
H o we ver, Bi o ge n m a 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 horities 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 m a y  re q uire si milar m o dificati o ns (see 
Secti o ns 1 7. 2 a n d 1 7. 3 ).
1 9. 4.
Et hics C o m mittee /I nstit uti o n al Re vie w B o ar d 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 aut h orities a n d E C/I R Bs 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 3
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 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 o n 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 off site facilit y or tra nsfer of o w ners hi p if t he In vesti g at 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 St u d y  In 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 d e b y se veral fact ors i ncl u di n g b ut n ot li mite d t o t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or 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 ge n .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 4
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 mer'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.
C h o w S, C ha n g M. A da pti ve Desi g n Met h o ds i n Cli nical Trials, Sec o n d E diti o n. Sec o n d E diti o n 
e d. B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1.
D u b ois B, Fel d ma n H H, Jac o va C, et al. Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n. La ncet Ne ur ol. 2 0 1 0; 9( 1 1): 1 1 1 8- 2 7.
D u b ois B, Fel d ma n H H, Jac o va C, et al. A d va nci n g researc h dia g n ostic criteria f or Alz hei mer's 
disease: t he I W G -2 criteria. La ncet Ne ur ol. 2 0 1 4; 1 3( 6): 6 1 4 - 2 9.
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.
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 nea r 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 k s. 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.
Le n der ki n g W R, Stee nr o d A, R ü dell K, et al. O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI  
a n d Pr o dr o mal Alz hei mer’s Disease: C o nte nt Vali dit y  of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y Sy m pt o ms of C o g niti ve Decli ne. A d va nces i n Alz hei mer’ s Disease. 
2 0 1 4; 3: 1 -1 0. E p u b Marc h 2 0 1 4.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 5
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 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 A lz 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.
M orris J C , Ble n n o w K, Fr oelic h L, et al. Har m o nize d dia g n ostic criteria f or Alz hei mer's disease: 
rec o m me n dati o ns. J Inter n Me d. 2 0 1 4; 2 7 5( 3): 2 0 4 - 1 3.
Ostr o witz ki S, De pt ula D, T h urfjell L, et al. Mec ha nis m of a m y l oi d re m o val i n patie nts wit h 
Alz hei mer disease treate d wit h ga nte ner u ma b. Arc h Ne ur ol. 2 0 1 2; 6 9( 2): 1 9 8- 2 0 7. E p u b 2 0 1 1 Oct 
1 0.
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 osite d f or ms of a m yl 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.
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 un 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, et 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 00 1; 3 2( 6): 1 3 1 8 - 2 2.
Weller R O, S u bas h M, Prest o n S D, et al. Peri vasc ular drai na ge of a m yl oi d -beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a myl oi d a n gi o pat h y  a n d Alz hei mer's disease. Brai n Pat h ol. 
2 0 0 8; 1 8( 2): 2 5 3 - 6 6.
Wilc oc k D M, C olt o n C A. I m m u n ot h era 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/ 0 2/ 2 7.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 4 . 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
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 6
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 3 M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b
(BII B 0 3 7 ) i n S u bjects wit h Earl y Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
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Bi o ge n M A I nc.
3
T A B L E O F C O N T E N T S
1.
S P O N S O R I NF O R M A TI O N ..................................................................................... 1 0
2.
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 1
3.
S Y N O P SI S ................................................................................................................. 1 4
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 7
4. 1.
St u d y  Sc he matic ......................................................................................................... 1 7
4. 2.
Sc he d ule of E ve nts ..................................................................................................... 1 8
4. 3.
A d diti o nal I nf or mati o n ...............................................................................................3 6
4. 3. 1.
Site Pers o n nel ............................................................................................................. 3 6
5.
I NT R O D U C TI O N ...................................................................................................... 3 8
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 3 9
5. 1. 1.
N o ncli nical E x perie nce ...............................................................................................3 9
5. 1. 2.
Cli nical E x perie nce..................................................................................................... 4 0
5. 2.
St u d y  Rati o nale...........................................................................................................4 1
5. 3.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 4 2
5. 3. 1.
D osi n g Sc he me........................................................................................................... 4 3
5. 3. 1. 1.
Place b o -C o ntr olle d Peri o d .......................................................................................... 4 3
5. 3. 2.
D osi n g Sc he me M o dificati o n ..................................................................................... 4 4
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 4 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 ..............................................................4 6
6. 1.
Pri mar y  O bjecti ve a n d E n d p oi nt ................................................................................ 4 6
6. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts ......................................................................... 4 6
6. 3.
Tertiar y  O bjecti ves a n d E n d p oi nts ............................................................................. 4 6
6. 3. 1.
Tertiar y  O bjecti ves ..................................................................................................... 4 6
6. 3. 2.
Tertiar y  E n d p oi nts......................................................................................................4 7
6. 4.
A d diti o nal E x pl orat or y  O bjecti ves a n d E n d p oi nts.....................................................4 7
6. 4. 1.
A d diti o nal E x pl orat or y  O bjecti ves............................................................................. 4 7
6. 4. 2.
A d di ti o nal E x pl orat or y E n d p oi nts..............................................................................4 8
6. 5.
L o n g -Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts .......................................................4 9
6. 5. 1.
Tertiar y  LT E O bjecti ves................................ .............................................................4 9
6. 5. 2.
Tertiar y  LT E E n d p oi nts ..............................................................................................4 9


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Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4
6. 5. 3.
A d diti o nal E x pl orat or y  LT E O bjecti ve ...................................................................... 4 9
6. 5. 4.
A d diti o nal E x pl orat or y  LT E E n d p oi nts ...................................................................... 4 9
7.
S T U D Y D E SI G N ....................................................................................................... 5 1
7. 1.
St u d y  O ver vie w .......................................................................................................... 5 1
7. 2.
St u d y  S pecifics ........................................................................................................... 5 2
7. 2. 1.
D ose S us pe nsi o n, M o dificati o n, or Ter mi nati o n f or A RI A E ve nts ............................ 5 2
7. 2. 1. 1.
A RI A -E Cases ............................................................................................................ 5 3
7. 2. 1. 2.
A RI A -H ( Micr o he m orr ha ge) ...................................................................................... 5 4
7. 2. 1. 3.
A RI A - H ( S u perficial Si der osis) ................................................................................. 5 7
7. 2. 1. 4.
A RI A - H ( Macr o he m orr ha ge)..................................................................................... 5 9
7. 2. 1. 5.
C oi nci de nt A RI A -H a n d A RI A- E Cases .................................................................... 5 9
7. 2. 1. 6.
Res u m pti o n of St u d y  Treat me nt After S us pe nsi o n d ue t o A RI A............................... 5 9
7. 2. 1. 7.
Ma na ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI )............................................ 6 0
7. 2. 2.
I nf usi o n I nterr u pti o n................................................................................................... 6 1
7. 3.
O verall St u d y  D urati o n a n d F oll o w-U p ..................................................................... 6 1
7. 3. 1.
Scree ni n g .................................................................................................................... 6 2
7. 3. 2.
Treat me nt .................................................................................................................... 6 3
7. 3. 3.
F oll o w -U p ................................................................................................................... 6 3
7. 4.
St u d y  St o p pi n g R ules ................................................................................................. 6 4
7. 5.
E n d of St u d y ............................................................................................................... 6 4
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 6 5
8. 1.
I ncl usi o n Criteria........................................................................................................ 6 5
8. 2.
E xcl usi o n Criteria ....................................................................................................... 6 6
8. 3.
I ncl usi o n Criteria f or L o n g-Ter m E xte nsi o n Peri o d ...................................................6 9
8. 4.
E xcl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d .................................................. 7 0
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I ON ............................ 7 1
9. 1.
Scree ni n g a n d E nr oll me nt ........................................................................................... 7 1
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................7 1
9. 3.
Bli n di n g Pr oce d ures .................................................................................................... 7 1
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/ O R 
WI 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 ........................................... 7 3
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 7 3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5
1 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 7 4
1 1.
S T U D Y T R E A T M E N T U S E .....................................................................................7 5
1 1. 1.
Re gi me n ...................................................................................................................... 7 5
1 1. 1. 1.
A d uca n u ma b ............................................................................................................... 7 5
1 1. 1. 2.
Place b o ........................................................................................................................ 7 5
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 7 5
1 1. 3.
Preca uti o ns .................................................................................................................. 7 5
1 1. 4.
C o m plia nce ................................................................................................................. 7 5
1 1. 5.
Pri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 7 5
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 7 5
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 7 6
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T hera p y .............................................................................. 7 6
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 7 6
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 7 7
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 ................................................................ 7 8
1 2. 1.
A d uca n u ma b ............................................................................................................... 7 8
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 7 8
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 7 9
1 2. 1. 3.
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 7 9
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 7 9
1 2. 2.
Place b o ........................................................................................................................ 7 9
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 7 9
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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ......................................................................................................... 8 1
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 8 1
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 8 1
1 3. 3.
P har mac o d y na mic Assess me nts ................................................................................. 8 1
1 3. 4.
A d diti o nal Assess me nts.............................................................................................. 8 2
8 2
1 3. 4. 2.
A p o E Ge n ot y pi n g .......................................................................................................8 3
8 3
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 8 3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6
1 3. 5. 
F ut ure Scie ntific Researc h Assess me nts .................................................................... 8 4
1 4.
S A F E T Y A S S E S S M E N T S ........................................................................................ 8 5
1 4. 1.
Cli nical Safet y  Assess me nts....................................................................................... 8 5
1 4. 2.
La b orat or y  Safety Assess me nts .................................................................................. 8 5
1 4. 3.
I m m u n o ge nicity Assess me nts .................................................................................... 8 6
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 ................................................................................................. 8 7
1 5. 1.
Defi niti o ns.................................................................................................................. 8 7
1 5. 1. 1.
A d verse E ve nt ............................................................................................................. 8 7
1 5. 1. 2.
Seri o us A d verse E ve nt ................................................................................................ 8 7
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................ 8 8
1 5. 2.
Safet y  Classificati o ns.................................................................................................. 8 8
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ............................................................................. 8 8
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................ 8 9
1 5. 2. 3.
Se verit y  of E ve nts....................................................................................................... 8 9
1 5. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................8 9
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 8 9
1 5. 3. 1.
A d verse E ve nts ........................................................................................................... 8 9
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ............................................................................. 9 0
1 5. 3. 3.
Seri o us A d verse E ve nts ..............................................................................................9 0
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 9 0
1 5. 3. 4. 1.
Deat hs ......................................................................................................................... 9 1
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 9 1
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................9 1
1 5. 4. 1.
Pre g na nc y ................................................................................................................... 9 1
1 5. 4. 2.
O ver d ose ..................................................................................................................... 9 1
1 5. 4. 3.
Me dical E mer ge nc y ....................................................................................................9 2
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 9 2
1 5. 5.
C o ntrace pti o n Re q uire me nts ................................ ......................................................9 2
1 5. 6.
Safet y  Res p o nsi bilities................................................................................................ 9 3
1 5. 6. 1.
T he I n vesti gat or .......................................................................................................... 9 3
1 5. 6. 2.
Bi o ge n ......................................................................................................................... 9 4


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7
1 6.
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 ........... 9 5
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 9 5
1 6. 2.
Efficac y  a n d P har mac o d yna mics ................................................................................ 9 5
1 6. 2. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 5
1 6. 2. 2.
Met h o ds of A nal ys is................................................................................................... 9 5
1 6. 2. 2. 1.
Ge neral C o nsi derati o ns............................................................................................... 9 5
1 6. 2. 2. 2.
A d uca n u ma b D oses t o be E val uate d .......................................................................... 9 5
1 6. 2. 2. 3.
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts .............................................. 9 6
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y  E n d p oi nt............................................................................... 9 6
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 9 6
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ....................................................................................... 9 7
1 6. 3.
P har mac o ki netics ........................................................................................................ 9 7
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 7
1 6. 3. 2.
Met h o d of A nal ys is..................................................................................................... 9 7
1 6. 4.
A d diti o nal E x pl orat or y  A nal yses ............................................................................... 9 8
1 6. 5.
Safet y .......................................................................................................................... 9 8
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 8
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................... 9 8
1 6. 5. 2. 1.
A d verse E ve nts ........................................................................................................... 9 8
1 6. 5. 2. 2.
Cli nical L a b orat or y Res ults........................................................................................ 9 8
1 6. 5. 2. 3.
Vital Si g ns .................................................................................................................. 9 8
1 6. 5. 2. 4.
E C G ............................................................................................................................ 9 8
1 6. 5. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 9 8
1 6. 6.
I m m u n o ge nicity Data .................................................................................................9 9
1 6. 6. 1.
A nal y sis P o p ulati o n ....................................................................................................9 9
1 6. 6. 2.
Met h o ds of A nal ys is...................................................................................................9 9
1 6. 7.
I nteri m A nalys es .........................................................................................................9 9
1 6. 7. 1.
I nteri m F utilit y A nal ysis............................................................................................. 9 9
1 6. 7. 2.
I nteri m S u peri orit y A nal ysis.......................................................................................9 9
1 6. 8. 
Sa m ple Size C o nsi derati o ns ................................ .......................................................9 9
1 7.
E T HI C A L  R E Q UI R E M E N T S .................................................................................1 0 1
1 7. 1.
Declarati o n of Helsi n ki .............................................................................................1 0 1


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
8
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ......................................................... 1 0 1
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ............................................................................. 1 0 1
1 7. 4.
S u bject Data Pr otecti o n ............................................................................................ 1 0 2
1 7. 5.
C o m pe nsati o n f or I nj ur y ........................................................................................... 1 0 2
1 7. 6.
C o nflict of I nterest .................................................................................................... 1 0 2
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 ............................................ 1 0 2
1 8.
A D MI NI S T R A TI V E P R O C E D U R E S ..................................................................... 1 0 3
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................. 1 0 3
1 8. 2.
Q ualit y  Ass ura nce..................................................................................................... 1 0 3
1 8. 3.
M o nit ori n g of t he St u d y ............................................................................................ 1 0 3
1 8. 4.
St u d y  F u n di n g........................................................................................................... 1 0 3
1 8. 5.
P u blicati o ns ............................................................................................................... 1 0 3
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 0 4
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ............................................................................... 1 0 4
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ............................................................................... 1 0 4
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................. 1 0 4
1 9. 1. 3.
Electr o nic Data Ca pt ure ............................................................................................ 1 0 4
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ................................................... 1 0 4
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts.................................................................... 1 0 4
1 9. 1. 6.
Ne ur oc o g niti ve Assess me nts .................................................................................... 1 0 4
1 9. 2.
St u d y  C o m mittees..................................................................................................... 1 0 5
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................. 1 0 5
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee ................................................................ 1 0 5
1 9. 3.
C ha n ges t o F i nal St u d y Pr ot oc ol ..............................................................................1 0 5
1 9. 4.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n...................................................................................... 1 0 5
1 9. 5.
Rete nti o n of St u d y  Data............................................................................................1 0 6
1 9. 6.
St u d y  Re p ort Si g nat or y.............................................................................................1 0 6
2 0.
R E F E R E N C E S .........................................................................................................1 0 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 ....................................... 1 0 9


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
LI S T O F T A B L E S
Ta ble 1:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8 ................. 1 8
Ta ble 2:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 2 2
Ta ble 3:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he Place b o -C o ntr olle d Peri o d ........................................................................ 2 5
Ta ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4 ................................... 2 7
Ta ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 3 0
Ta ble 6:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he L o n g -Ter m E xte nsi o n ............................................................................... 3 4
Ta ble 7:
D osi n g Sc he me f or A d uca n u m a b b y Treat me nt Gr o u p a n d A p o E ε 4 Carrier 
Stat us ........................................................................................................................... 4 4
Ta ble 8:
Dis p ositi o n of A RI A- E Cases .....................................................................................5 3
Ta ble 9:
Dis p ositi o n of A RI A- H ( Micr o he m orr ha ge) Cases.................................................... 5 5
Ta ble 1 0:
Dis p ositi o n of A RI A -H ( S u perficial Si der osis) Cases ............................................... 5 7
Ta ble 1 1:
Res u m pti o n of St u d y  Treat me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titrati o n .......................................................................................................... 6 0
Ta ble 1 2:
Treat me nt Gr o u ps i n t he E ve nt of Hi g h D ose Gr o u p Ter mi nati o n ............................ 9 6
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n............................................................................................................... 1 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 0
1.
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 h i 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
 at 
Please refer t o t he St u d y Refere nce Ma n ual 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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 1
2.
LI S T O F A B B R E VI A TI O N S
1 2 F 6 A
rec o m bi na nt, h u ma n a nti- β-a m yl oi d i m m u n o gl o b uli n G 1
m o n ocl o nal a nti b o d y  wit h a n a mi n o aci d se q ue nce i de ntical t o 
a d uca n u ma b, pr o d uce d i n a differe nt C hi nese ha mster o var y  
cell li ne
A β
β- a m yl oi d ( pe pti de deri ve d fr o m me m bra ne b o u n d a m yl oi d 
prec urs or pr otei n)
A A
Alz hei mer’s Ass ociati o n
A D
Alz hei mer’s disease
A D A
a nti dr u g a nti b o d y
A D A S -C o g 1 3
Alz hei mer’s Disease Assess me nt Scale -C o g niti ve S u bscale 
( 1 3 ite ms)
A D C S -A D L -M CI
Alz hei mer’s Disease C o o perati ve St u d y  - Acti vities of Dail y  
Li vi n g I n ve nt or y  ( Mil d C o g niti ve I m pair me nt versi o n)
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A p o E
a p oli p o pr otei n E
A p o E ε 4 
a p oli p o pr otei n E 4
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-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- he m orr ha ge or s u perficial 
si der osis
A S T
as partate a mi n otra nsferase
C D R
Cli nical De me ntia Rati n g 
C D R -S B
Cli nical De me ntia Rati n g s u m of b o xes
c h 1 2 F 6 A
m uri ne I g G 2a c hi meric versi o n of 1 2 F 6 A or a d uca n u ma b 
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 
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
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E D C
electr o nic data ca pt ure
E O T
E n d of Treat me nt
E Q - 5 D
E ur o Q ol healt h stat us meas ure
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 2
E Q -5 D (I R -S)
E ur o Q ol healt h stat us meas ure, i nf or ma nt re p orte d o n s u bject
E Q -5 D ( S R)
E ur o Q ol healt h stat us meas ure, s u bject self- re p orte d
F U
foll o w - u p
G C P
G o o d Cli nical Practice
H b A 1 c
gl yc os yl ate d he m o gl o bi n
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
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g
i m m u n o gl o b uli n 
I R
i nf or ma nt rate d
I RB
i nstit uti o nal re vie w b oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
I T T
i nte nt-t o-treat
I V
i ntra ve n o us(ly)
I W G
I nter nati o nal W or ki n g Gr o u p
L T E
l o n g-ter m e xte nsi o n
L P
l u m bar p u nct ure
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 Re g ulat or y Acti vities
M M R M
m i xe d-m o del re peate d meas ures
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 P D Q - 2 0
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d versi o n
M RI
ma g netic res o na nce i ma gi n g
NI A
Nati o nal I nstit ute o n A gi n g
NI A- A A
Nati o nal I nstit ute o n A gi n g ( NI A) at Nati o nal I nstit utes of 
Healt h ( NI H) a n d t he Alz hei mer’ s Ass ociati o n ( A A)
N PI - 1 0
Ne ur o ps yc hiatric I n ve nt or y - 1 0
P B M C
peri p heral bl o o d m o n o n uclear cells
P D
p har mac o d y n a mic(s)
P E T
p ositr o n e missi o n t o m o gra p h y
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
R B A N S
Re peata ble Batter y  f or Assess me nt of Ne ur o psyc h ol o gical 
Stat us
R N A
ri b o n ucleic aci d
S A B R
Safet y  a n d Be nefit-Ris k 
S A E
seri o us a d verse e ve nt


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 4
3.
S Y N O P SI S
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
Pr ot oc ol Title:
A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he 
Efficac y a n d Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h 
Earl y Alz hei mer ’s Disease
Versi o n N u m ber:
5. 0
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 I n dicati o n:
Alz hei mer’s Disease
St u d y Rati o nale:
T he p ur p ose of t his P hase 3 st u d y is t o assess t he efficac y a n d 
safet y of a d uca n u ma b c o m pare d wit h place b o i n s u bjects wit h 
earl y Alz hei mer’s Disease ( A D), i ncl u di n g s u bjects wit h mil d 
c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a s u bset of mil d A D.  
A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of β -a m yl oi d ( A β), i ncl u di n g s ol u ble A β 
oli g o mers a n d de p osite d fi brillar A β.  I nteri m a nal yses of t he 
o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve 
de m o nstrate d tar get e n ga ge me nt, a p har mac o d y na mic effect o n 
a m yl oi d re d ucti o n, a n d a n effect o n t he Cli nical De me ntia Rati n g 
( C D R)-su m  of b o xes ( S B) a n d Mi ni-Me ntal State E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults,
al o n g wit h t he o bser ve d safet y a n d t olera bilit y pr ofile , warra nt 
f urt her P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt 
p o p ulati o n s pa n ni n g t he earl y sta ges o f t he A D c o nti n u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
( place b o-c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R-S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D.  
T he pri mar y e n d p oi nt t hat relates t o t his o bjecti ve is t he c ha n ge 
fr o m baseli ne i n C D R-S B sc ore at Wee k 7 8.
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b as 
c o m pare d wit h place b o o n cli nical pr o gressi o n as meas ure d b y


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 5
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1

M M S E
- C ha n ge fr o m baseli ne i n M M S E sc ore at Wee k 7 8

Alz hei mer’s Disease Assess me nt Scale -C o g niti ve 
S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3] 
- C ha n ge fr o m baseli ne i n A D A S -C o g 1 3 at Wee k 7 8

Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of 
Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt 
versi o n) [ A D C S -A D L -M CI] 
- C ha n ge fr o m base li ne i n A D C S-A D L -M CI  sc ore at
Wee k
7 8
Tertiar y o bjecti ves of t his st u d y are liste d i n Secti o n 6. 3. 1 .  
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 . 
A d diti o nal e x pl orat or y o bjecti ves a n d e n d p oi nts are liste d i n 
Secti o n 6. 4 .  
St u d y O bjecti ves a n d E n d p oi nts 
( D ose-Bli n d L o n g -Ter m  
E xte nsi o n peri o d of t he st u d y):
T he o bjecti ves are 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 earl y A D, a n d 
t o e val uate t he l o n g-ter m efficac y of a d uca n u ma b treat me nt as 
meas ure d b y cli nical, ra di ol o gical , a n d healt h -o utc o mes 
assess me nts.
E n d p oi nts f or t he l o n g -ter m e xte nsi o n ( L T E) peri o d of t he st u d y 
are liste d i n Secti o n 6. 5 .  
St u d y Desi g n:
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p peri o d f oll o we d b y a n o pti o nal 
2 4- m o nt h d ose -bli n d, L T E peri o d
St u d y L ocati o n:
A p pr o xi matel y 1 5 0 sites gl o ball y
N u m ber of Pla n ne d S u bjects:
A p pr o xi matel y 1 3 5 0 s u bjects will be e nr olle d
N ote:  I n t he e ve nt t hat a pres pecifie d, bli n de d sa m ple size 
re-esti mati o n is perf or me d, t he sa m ple size ma y be i ncrease d b ut 
will n ot e xcee d 1 7 6 4 s u bjects.
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 earl y A D, i ncl u di n g 
s u bjects wit h M CI d ue t o A D a n d a s u bset of mil d A D acc or di n g 
t o Nati o nal I nstit ute o n A gi n g ( NI A) at t he Nati o nal I nstit ut es of 
Healt h ( NI H) a n d t he Alz hei mer ’s Ass ociati o n (NI A -A A ) criteria.  
S u bjects m ust be p ositi ve f or a m yl oi d pat h ol o g y as meas ure d b y 
a m yl oi d p ositr o n e missi o n t o m o gra p h y sca n.  S u bjects m ust be 5 0 
t o 8 5 years ol d, a n d a part fr o m t he cli nical dia g n osis of earl y A D, 
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, 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 6
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
base d o n me dical hist or y a n d t he scree ni n g assess me nts.  T he 
rati o of a p oli p o pr otei n E 4 ( A p o E ε 4) carriers t o n o n-carriers i n 
t he st u d y p o p ulati o n will ge nerall y reflect t he distri b uti o n i n t he 
br oa der A D p o p ulati o n.  E nr oll me nt will als o be m o nit ore d, via 
i nteracti ve res p o nse tec h n ol o g y, s uc h t hat s u bjects wit h mil d A D 
re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt Gr o u ps:
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d of t he st u d y a n d 
base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d 
t o 1 of 3 treat me nt gr o u ps i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose: 
a d uca n u ma b hi g h d ose: place b o) as f oll o ws: 
A p o E ε 4 c arrier
    L o w  d ose ( 3 m g/ k g)
     Hi g h d ose ( 1 0 m g/ k g) 
     Pl ace b o 
A p o E ε 4 n o n -c arrier
     L o w  d ose ( 6 m g/ k g) 
     Hi g h d ose ( 1 0 m g/ k g)
     Pl ace b o 
After c o m pleti o n of t he place b o -c o ntr olle d peri o d, s u bjects ma y 
e nter a 2 4 -m o nt h d ose -bli n d L T E st u d y d uri n g w hic h all s u bjects 
will recei ve a d uca n u ma b.  
D urati o n of Treat me nt a n d 
F oll o w U p:
St u d y d urati o n f or eac h s u bject partici pati n g i n t he 
place b o -c o ntr olle d peri o d o nl y will be a p pr o xi matel y 1 0 2 wee ks 
( u p t o a n 8-wee k scree ni n g peri o d, 7 6 wee ks of place b o or
a d uca n u ma b d osi n g, a n d 1 8 wee ks of f oll o w-u p [ F U]).  
F or s u bjects w h o e nter t he o pti o nal L T E peri o d, t he t otal st u d y 
d urati o n will be a p pr o xi matel y 2 0 6 wee ks or 4 7 m o nt hs ( u p t o a n 
8- wee k scree ni n g peri o d, 7 6 wee ks of place b o or a d uca n u ma b 
d osi n g, a n d 4 wee ks of F U , pl us a n o pti o nal L T E peri o d i ncl u di n g 
1 0 0 wee ks of d ose -bli n d a d uca n u ma b d osi n g a n d 1 8 wee ks of 
F U).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1
4. 1.
St u d y Sc he m atic
Fi g ure 1:
St u d y Desi g n 
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve; L T E = l o n g -ter m e xte nsi o n; P = place b o; R = ra n d o mizati o n date.
* S u bjects w h o are assi g ne d t o place b o d uri n g t he place b o -c o ntr olle d peri o d a n d are c o nti n ui n g i nt o t he L T E peri o d w ill be ra n d o mize d i n a 1: 1 rati o t o hi g h a n d 
l o w d ose a d uca n u ma b treat me nt ( base d u p o n t heir A p o E ε 4 carrier stat us).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
4. 2.
Sc he d ule of E ve nts
T a ble 1:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8
St u d y Wee k
Scree ni n g 
( ≤6 0 d a ys 
bef ore 
D a y 1) 1
W k 1, 
D a y 1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
I nitial Scree ni n g 
C o nse nt 2 ( o pti o nal)
X
F ull I nf or me d 
C o nse nt 3
X
Eli gi bilit y Criteria
X  
X  
X
X 4
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
H b A 1c
X
HI V 5 / He patitis/
C oa g ulati o n
X
A p o E Ge n ot y pi n g
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
Ser u m Pre g na nc y 
Test 7
X
Uri ne Pre g na nc y 
Test 7
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
Scree ni n g 
( ≤6 0 d a ys 
bef ore 
D a y 1) 1
W k 1, 
D a y 1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G  
X
X
X
Vital Si g ns 8
X
X  
X  
X  
X  
X  
X  
X
X  
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
Ra n d o mizati o n
X
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
A nti -A d uca n u ma b 
A b 9
X
X
X
A d uca n u ma b 
C o nce ntrati o n 1 0
X 1 1
X 1 1
X 1 1
X
X 1 1
X 1 1
X 1 1
X
P B M C C ollecti o n
X
X  
X
X
X
A m yl oi d P E T 1 4
X
X
R B A N S
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 2:
Pl ace b o - C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Tre at me nt or F oll o w-U p 
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
7 8 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
Me dic ati o n
9 4
( or 1 8 wee ks after fi n al 
d ose f or s u bjects w h o 
ter mi n ate tre atme nt 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
I nf or me d C o nse nt
X 3
Eli gi bilit y Criteria
X 3
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X
Uri ne Pre g na nc y Test 4
X  
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns 5
X  
X  
X  
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
St u d y Treat me nt I nf usi o n
X  
X  
X  
X  
X  
X  
X
A nti -A d uca n u ma b A b 6
X
X
X
A d uca n u ma b C o nce ntrati o n 7
X 8
X
X
X
P B M C C ollecti o n
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
7 8 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
Me dic ati o n
9 4
( or 1 8 wee ks after fi n al 
d ose f or s u bjects w h o 
ter mi n ate tre atme nt 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
A m yl oi d P E T 1 0
X
C D R 
X
X
X
X
M M S E
X
X
X
X
A D C S -A D L -M CI
X
X
X
X
A D A S -C o g 1 3
X
X
X
X
N PI -1 0
X
X
E Q -5 D ( S R) 
X
X
E Q -5 D (I R -S)
X
X
m P D Q -2 0
X
X
C- S S R S
X
X
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
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




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 3:
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he Pl ace b o- C o ntr olle d Peri o d
St u d y Wee k
Scree ni n g
(≤ 6 0 d a ys 
bef ore D a y 1) 1
Pl ace b o -C o ntr olle d Peri o d
F U 2
1 
2 
6
1 0 
1 4 
1 8 
2 2 
2 6 
3 0 
4 2 
5 4 
6 6 
7 8/
E O T 3
U nsc he d -
ule d Visit/ 
M RI f or 
A RI A 4
9 4
( or 1 8 
wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
disc o n -
ti n ue 
tre atme nt 
e arl y)
St u d y D a y
V 1  
V 2  
V 3
1
1 5
± 3
4 3
± 3
7 1
± 3
9 9
± 3
1 2 7
± 3
1 5 5
± 3
1 8 3
± 3
2 1 1
± 3
2 9 5
± 3
3 7 9
± 3
4 6 3 ±
3
5 4 7
± 3
6 5 9
± 7
F oll o w -U p P h o ne Call 5
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 6
X
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 7
X
X
X
X
X
M O C A
X
X
P B M C c ollecti o n 8
X
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-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-
he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt; F U = F oll o w -U p; L T E = l o n g -ter m e xte nsi 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 B M C = peri p heral bl o o d m o n o n uclear cells; P K = p har mac o ki netic; 
; V 1, V 2, V 3 = Scree ni n g 
Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
1 Brai n M RI ( V 2) w ill n ot be perf or me d u ntil t he s u bject has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1.  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 relate d 
t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.
2 S u bjects w h o c o m plete t he place b o -c o ntr olle d 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 U Visit at Wee k 9 4.  S u bjects w h o 
disc o nti n ue treat me nt or w it h dr a w fr o m t he st u d y earl y are t o ha ve a safet y F U Visit at 1 8 wee ks after t heir fi nal d ose.  T he o nl y e xce pti o n is a s u bject w h o 
disc o nti n ues treat me nt pre mat urel y a n d c o nti n ues o n st u d y f or at least 1 8 w ee ks after recei vi n g t he fi nal d ose.
3S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re quire d tests a n d assess me nts u ntil t he e n d of t he st u d y per t he 
sc he d ule of e ve nts.  S u bjects w h o wit h dra w fr o m 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; f or s uc h s u bjects, efficac y assess me nts s pecifie d 
at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt wit hi n 3 m o nt hs of t he pre vi o us efficac y assess me nt visit a n d n o si g nifica nt c ha n ges i n
c o g niti ve stat us are s us pecte d b y t he I n vesti gat or; T he site s h o ul d n otif y t he s p o ns or i n s uc h cases.  
4 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g per 
e pis o de o nl y. F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 . F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 . 
5 P h o ne visit ma y be perf or me d i n per s o n if t he s u bject will be at t he st u d y site f or cli nical assess me nts.
6 Arterial s pi n la beli n g M RI a n d tas k free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
7 O ne sa m ple will be c ollecte d wit hi n ± 2 d a y s of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 4:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
Ra n d o mizati o n
X 1
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
Uri ne Pre g na nc y 
Test 2
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -
A d uca n u ma b A b 3
X
X
X
P B M C c ollecti o n
X
X
A d uca n u ma b 
C o nce ntrati o n 3
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 8
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
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
A m yl oi d P E T 5
X
C D R
X
X  
X
M M S E
X
X  
X
A D A S -C o g 1 3
X
X  
X
A D C S -A D L -M CI
X
X  
X
N PI -1 0
X
X
E Q -5 D (I R -S)
X
X
C- S S R S
X
X
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
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




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 5:
L o n g -Ter m E xte nsi o n Sc he d ule Fr o m Wee k 1 3 6 t o E n d of Tre at me nt or F oll o w -U p
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
Me dic a -
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
B o d y Wei g ht
X  
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
X
P h ysical 
E xa mi nati o n
X
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -a d uca n u ma b 
A b 4
X
X
X
P B M C c ollecti o n
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
F U 1
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0
1 8 2 
( E O T)2
U V f or a 
C h a n ge i n 
A D 
Me dic a -
ti o n
1 9 8
( or 1 8 wee ks 
after fi n al d ose 
f or s u bjects 
w h o ter m i n ate 
tre atme nt 
e arl y)
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
1 3 8 7
± 7
A d uca n u ma b 
C o nce ntrati o n 4
X
X
X
X
St u d y Dr u g 
I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X
A m yl oi d P E T 6
X
C D R
X
X  
X
X
M M S E
X
X  
X
X
A D A S -C o g 1 3
X
X  
X
X
A D C S -A D L -M CI
X
X  
X
X
N PI -1 0
X
X
E Q -5 D (I R -S) 
X
X
C- S S R S
X
X




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
T a ble 6: 
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he L o n g -Ter m E xte nsi o n
St u d y Wee k
L o n g -Ter m E xte nsi o n
U nsc he d -
ule d Visit 
f or A RI A
1
F U 2
8 0 
8 2 
8 6 
9 0 
9 4 
9 8 
1 0 2 
1 0 6 
1 1 0 
1 2 2 
1 3 4 
1 5 8
1 8 2 3
1 9 8
( or 1 8 
wee ks 
after fi n al 
d ose f or 
s u bjects 
w h o 
ter mi n ate 
tre atme nt 
e arl y)
St u d y D a y
5 6 1
± 5
5 7 5
± 5
6 0 3
± 5
6 3 1
± 5
6 5 9
± 5
6 8 7
± 5
7 1 5
± 5
7 4 3
± 5
7 7 1
± 5
8 5 5
± 5
9 3 9
± 5
1 1 0 7
± 5
1 2 7 5
± 5
1 3 8 7
± 7
F oll o w -U p 
P h o ne Call 4
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 5
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 6
X
M O C A
X
X
P B M C 
c ollecti o n 7
X
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-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-
he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt; F U = F oll o w - Up; L T E = l o n g -ter m e xte nsi o n; M O C A = M ontreal C o g niti ve Assess me nt; 
M RI
= ma g netic res o na nce i ma gi n g; P B M C = peri p heral bl o o d m o n o n uclear cells; P K = p har mac o ki netic; 
.
1 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c olle cti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g per 
e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .  




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n S u bjects wit h Earl y Alz hei mer’s Disease  
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
4. 3.
A d diti o n al I nf or m ati o n
4. 3. 1.
Site Pers o n nel
A mi ni m u m of 3 se parate heat h care pr ofessi o nals ( H C Ps) are re q uire d:  
1.
A treati n g H C P (t he Pri nci pal I n vesti gat or [ PI ] or S u b-i n vesti gat or ma y ser ve as a 
treati n g H C P) w h o is res p o nsi ble f or t he f oll o wi n g:

A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y  1, Wee k 8 0, 
a n d d uri n g ma na ge me nt of a m yl oi d-relate d i ma gi n g a b n or malities ( A RI A) cases.

Ma na ge me nt of r o uti ne ne ur ol o gical care of
t he s u bject.

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y ) a n d treat me nt of a d verse e ve nts 
( A Es).  

Re vie w of selecte d he mat ol o g y  a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y 
wit h hel d or per ma ne ntl y  disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
Secti o n 1 0. 1 .  
2.
A n i n de pe n de nt rati n g H C P ( desi g nate d b y t he PI of t he site) w h o is res p o nsi ble f or 
a d mi nisteri n g t he Cli nical De me ntia Rati n g ( C D R) 
3.
A sec o n d i n de pe n de nt rati n g H C P ( d esi g nate d b y t he PI  of t he site) w h o will a d mi nister 
t he Alz hei mer’s Disease Assess me nt Scale-C o g niti ve S u bscale ( 1 3 ite ms) [ A D A S- C o g 
1 3], Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of Dail y  Li vi n g I n ve nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [ A D C S-A D L -M CI], a n d t he Mi ni -Me ntal State 
E xa mi nati o n ( M M S E)
T he 2 i n de pe n de nt rati n g H C Ps 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 A Es, c o nc o mita nt t hera p y, la b orat or y data, i ma gi n g 
data, or a n y ot her data t hat ha ve t he p ote ntial of re veali n g t he treat me nt assi g n me nt.  T he 
2 i n de pe n de nt rati n g H C Ps m ust n ot s hare a n y i nf or mati o n a b o ut s u bjects.  PIs ca n n ot ser ve as 
rati n g H C Ps.  T he treati n g H C Ps m ust n ot disc uss A Es (e. g., A RI A) wit h t he i n de pe n de nt rati n g 
H C Ps.  
T o e ns ure c o nsiste nc y  acr oss sites, rati n g H C Ps m ust c o m plete t he sta n dar dize d st u d y-s pecific 
q ualificati o n pr ocess o n cli nical efficac y  assess me nt sc ori n g pri or t o a d mi nistrati o n of t he 
s pecific assess me nt at t heir site.  All sites m ust atte mpt t o mai ntai n t he sa me rati n g H C P 
t hr o u g h o ut t he st u dy f or s pecific assess me nts 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 sa me rati n g H C P 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 o nl y  c o n d uct assess me nts i n place of t he 
pri mar y  rater 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 rati n g H C P has t o be re place d, t he ne w rati n g H C P m ust u n der g o t he 
stu 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.
He mat ol o g y  a n d bl o o d c he mistr y data will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.  As wit h ot her la b orat or y  a n d cli nical i nf or mati o n, t hese data s h o ul d 
N O T be re vie we d b y t he rati n g H C Ps.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T he r oles of i n de pe n de nt raters a n d treati n g H C P are N O T i nterc ha n gea ble at t he s u bject le vel.  
I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc ha n gea ble at t he s u bject le vel.  If a rater has 
a d mi nistere d t he C D R t o a s u bject, t he y ma y n ot a d mi nister t he ot her ne ur oc o g niti ve 
assess me nts t o t hat s u bject at a n y p oi nt d uri n g t he st u d y .
A n u n bli n de d p har macist ( or a ut h orize d desi g nee) 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 bil it 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 t he st u d y bli n d.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
5.
I N T R O D U C TI O N 
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i nc rease t o 1 3 5. 5 milli o n b y 2 0 5 0 
[Alz hei mer's Disease I nter nati o nal 2 0 1 4].  
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 a n d 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 [Jac k 2 0 1 3].
Pat h ol o gicall y, A D 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 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra ne ur o nal ne ur ofi brillar y ta ngles c o m p ose d of 
h y per p h os p h or y late d ta u pr otei ns.  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 y n 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 “a myl 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 ].  
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n ha vi n g cate g orical sta ges.  E vi de nce s u g gests t he 
pat h o p h ysi ol o gical c ha n ges be gi n y ears 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].  
Re vise d criteria f or t he cli nical dia g n osis of A D wer e p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) at t he Nati o nal Instit utes of Healt h ( NI H) a n d t he Alz hei mer’s Ass ociati o n ( A A) 
[Al bert 2 0 1 1 ; Mc K ha n n 2 0 1 1 ; S perli n g 2 0 1 1 ] a n d t he Inter nati o nal W or ki n g Gr o u p (I W G) 
[ D u b ois 2 0 1 0; D u b ois 2 0 1 4 ], a n d a gr o u p t hat i ncl u de d me m bers fr o m b ot h NI A -A A a n d I W G 
p u blis he d rec o m me n dati o ns t o har m o nize t he criteria [M orris 2 0 1 4 ].  T hese criteria base t he 
dia g n osis of A D o n b ot h cli nic al a n d bi ol o gical ele me nts, rec o g nizi n g t he e xiste nce of a 
n o ncli nical sta ge of t he disease b y acce pti n g A D dia g n oses pri or t o si g ns of de me ntia usi n g A D 
bi o mar kers.
T he scie ntific c o m m u nit y  has s hifte d its f oc us t o tar get patie nts 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 patie nts are m ore li kel y t o be nefit fr o m a nti -a m yl oi d 
t hera py.  
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 on.  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 b y  re d uci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F).  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y  t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u blicati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h s ol u ble olig 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 nor 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 [R oz kal ne 
2 0 0 9 ; S pires -J o nes 2 0 0 9].  Si milarl y , patie nts wit h A D w h o ge nerate d a nti-A β a nti b o dies after 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
acti ve i m m u nizati o n wit h a g gre gate d A β( 4 2) s h o we d sl o wer rates of decli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [H oc k 2 0 0 3 ].
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uc a n u m a b  
5. 1. 1.  
N o ncli nic al E x perie nce 
A d uca n u ma b is a u ni q ue 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  
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 gregate d A β.  
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 pr o perties t o a d uca n u ma b ( BII B 0 3 7) si g nifica ntly re d uce d 
a m yl 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, t hr o u g h a 
micr o glia -me diate d p ha g oc y tic mec ha nism.  T hese data s u g gest a d uca n u ma b c o ul d pr o vi de 
be nefit b y re d uci n g pla q ue b ur de n.
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 76 m o use is 
c o nsi dere d t he pri mar y  p har mac ol o gicall y 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 de ri 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 ].
Fi n di n gs c o nsiste nt wit h a m y l oi d pla q ues a n d vasc ular a myl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, i ncl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h this m o del.  I n 
b ot h 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 o n 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 nu ma b treat me nt i n eit her st u d y .  T he i nci de nce a n d se verity of 
he m orr ha ge or cere bral vasc ular i nfla 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.  
See t he I n vesti gat or’s Br oc h ure (I B) f or detaile d i nf or mati o n o n n o ncli nical st u dies.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
5. 1. 2.
Cl i nic al E x perie nce
A d uca n u ma b has bee n e val uate d i n o ne c o m plete d si n gle asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 3): 

St u d y  2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, st u d y 
of a d uca n u m a b i n s u bjects wit h mil d or m o derate A D.  
T he pri mar y  o bjecti ve was t o e val uate t he safety a n d t olera bilit y of a ra n ge of 
a d uca n u ma b d oses ( 0. 3 t o 6 0 m g/ k g) w he n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y o bjecti ves were t o assess the p har mac o ki netic ( P K) a n d 
i m m u n o ge nicity of a d uca n u ma b after si n gle -d ose a d mi nistrati o n.  
A si n gle d ose of a d uca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d.  
D ose -li miti n g A RI A ( 2 s u bjects wit h A RI A-E [e de ma] a n d 1 s u bject wit h A RI A- E 
a n d A RI A -H [ micr o he m orr ha ge]) was o bser ve d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses bel o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near.

St u d y  2 2 1 A D 1 0 3 is a n o n g oi n g ra n d omize d, d o u ble -bli n d, place b o -c o ntr olle d 
m ulti ple d ose st u d y  of a d uca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are 
a m yl oi d p ositi ve.  T he st u d y c o m prises a place b o-c o ntr olle d peri o d wit h s u bjects 
recei vi n g m o nt hl y d oses of a d uca n u ma b (fi xe d d oses of 1, 3, 6, or 1 0 m g/ k g, or 
titrati o n u p t o 1 0 m g/ k g) or place b o f or a ye ar f oll o we d b y a d ose -bli n d l o n g -ter m 
e xte nsi o n ( LT E) peri o d wit h s u bjects recei vi n g m o nt hl y  d oses of a d uca n u ma b.  N ote:  
T he fi xe d- d ose c o h orts e nr olle d b ot h a p oli p o pr otei n E 4 (A p o E ε 4 ) carriers a n d 
n o n- carriers w hile t he titrati o n c o h ort is c o m prise d of A p o E ε 4 carriers o nl y.
T he pri mar y  o bjecti ve of St u d y 2 2 1 A D 1 0 3 is t o e val uate t he safety a n d t olera bilit y of 
m ulti ple d oses of a d uca n u ma b a d mi nistere d m o nt hl y  as si n gle I V i nf usi o ns.  T he 
sec o n dar y o bjecti ves are t o assess t he effect of a d uca n u ma b o n cere bral a m y l oi d 
pla q ue c o nte nt as meas ure d b y  1 8F-fl or beta pir p ositr o n e missi o n t o m o gra p h y  ( P E T), 
a n d t o e val uate t he P K a n d i m m u n o ge nicit y of a d uca n u ma b after m ulti ple -d ose 
a d mi nistrati o n. E x pl orat or y  o bjecti ves i ncl u de assess me nt of t he effect of 
a d uca n u ma b o n t he cli nical pr o gressi o n of A D as meas ure d b y 
C D R -s u m of b o xes ( S B) a n d M M S E.  
T o date, t he i nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose - a n d A p o E ε 4 
carria ge-de pe n de nt, es pe ciall y at t he hi g hest d oses w he n a d mi nistere d as a fi xe d d ose.  
A RI A- E was ra di o gra p hicall y  m o nit ore d by m a g netic res o na nce i ma gi n g ( M RI) a n d 
t ypicall y o bser ve d earl y i n treat me nt ( bet wee n 2 t o 5 d oses).  I n m ost cases, A RI A- E 
res ol ve d 4 t o 1 2 wee ks after o nset a n d A RI A -H was t y picall y  sta ble 2 t o 4 wee ks 
after o nset.  T he i nci de nce of A RI A -E a p peare d t o be l o wer i n t he gr o u p recei vi n g 
titrati o n t o 1 0 m g/ k g (c o m prisi n g A p o E ε 4 carriers o nl y ; 8/ 2 3 [ 3 5 %]) t ha n i n carriers 
i n t he 6 m g/ k g a n d 1 0 m g / k g fi xe d- d ose gr o u ps ( 9/ 2 1 [ 4 3 %] a n d 1 1/ 2 0 [ 5 5 %], 
res pecti vely).  T he i nci de nce of A RI A i n A p o E ε 4 carriers w h o were titrate d u p t o 
6 m g/ k g ( 2 d oses of 3 m g/ k g, t he n 6 m g/ k g) was 1 5 % ( 2/ 1 3), wit h a n o verall rate of 
1 1 % ( 2/ 1 9) as n o A p o E ε 4 n o n -carriers ( 0/ 6) e x perie nc e d A RI A.  Of n ote, a m o n g t he 
s u bjects recei vi n g titrati o n t o 1 0 m g/ k g w h o ha d A RIA- E, t he a b n or malities were 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
o bser ve d at t he 3 a n d 6 m g/ k g d oses, bef ore t he y reac he d 1 0 m g / k g.  Als o, 1 3 ( of 2 3, 
5 7 %) s u bjects i n t he titrati o n ar m ha ve bee n titrate d t o 1 0 m g / k g, a n d of t hese,
1 2 c o nti n ue d treat me nt a n d recei ve d at least 1 0 d oses of 1 0 m g/ k g; n o ne of t hese 
s u bjects e x perie nce d A RI A-E or A RI A -H.   F urt her m ore, A RI A -E e ve nts w he n t he y  
occ urre d (i n t he titrati o n gr o u p) ha ve bee n eit her as y m pt o matic or ass ociate d w it h 
mil d s y m pt o ms t hat res ol ve d, a n d m ost s u bjects w h o ha d A RI A -E c o nti n ue d 
treat me nt ( 6/ 8; 7 5 %) c o m pare d wit h o nl y 3 6 % ( 4/ 1 1) of carriers i n t he fi xe d-d ose 
1 0 m g/ k g ar m (refer t o t he I B f or details o n e ve nts of A RI A).  
Pr ot oc ol -s pecifie d i nteri m a nal yses of t he o n g oi n g m ulti ple -asce n di n g d ose 
St u d y 2 2 1 A D 1 0 3 ha ve de m o nstrate d e n ga ge me nt of a d uca n u ma b wit h a m yl oi d 
pla q ues, a p har mac o d y n a mic ( P D) effect o n a m yl oi d re d ucti o n, a n d a n effect o n 
C D R -S B a n d M M S E s u g gesti ve of a sl o wi n g of cli nical decli ne i n 
a d uca n u ma b -treate d s u bjects.  T he d ose- a n d ti me -de pe n de nt re d ucti o n of brai n A β 
b ur de n o bser ve d wit h a d uca n u ma b treat me nt was statisticall y  si g nifica nt at d oses of 
3, 6, a n d 1 0 m g/ k g after 6 a n d 1 2 m o nt hs of d osi n g, as well as wit h 1 m g/ k g a n d 
titrati o n fr o m 1 t o 1 0 m g/ k g after 1 2 m o nt hs of d osi n g.  O ver t he first ye ar of t he L T E 
(2 4 m o nt hs of d osi n g), f urt her d ose -de pe n de nt re d ucti o ns i n cere bral A β were 
o bser ve d.  T he res ults de m o nstrate tar get e n ga ge me nt (a m y l oi d pla q ues) a n d a P D 
effect ( d ose -de pe n de nt a m y l oi d re d ucti o n).  
I n a d diti o n, res ults fr o m t he i nteri m a nalys es s h o we d a n effect at 1 year o n t he 
e x pl orat or y e n d p oi nts C D R- S B a n d M M S E (at fi xe d d oses of 1 m g/ k g, 3 m g/ k g, 
6 m g/ k g a n d 1 0 m g/ k g c o m pare d wit h place b o), s u g gesti n g a re d ucti o n i n t he 
pr o gre ssi o n of cli nical i m pair me nt f or a d uca n u ma b-treate d vers us place b o-treate d 
s u bjects.  I n t he m ost rece nt i nteri m a nalys is, ge nerall y c o nsiste nt treat me nt 
differe nces were see n f or t he fi xe d - d ose c o h orts, a n d i n t he titrati o n gr o u p, effects o n 
t he C D R-S B a n d M M S E after 1 ye ar were ge nerall y c o nsiste nt wit h t he fi xe d -d ose 
res ults.  C o m pare d wit h place b o, a dj uste d mea n c ha n ges fr o m baseli ne t o Wee k 5 4 i n 
C D R -S B sc ores fa v ore d all a d uca n u ma b d ose re gi me ns teste d, wit h treat me nt 
differe nces of 0. 5 p oi nts or grea ter fa v ori n g a d uca n u ma b at d oses of 3, 6, a n d 
1 0 m g/ k g a n d titrati o n t o 1 0 m g/ k g, a n d statistical si g nifica nce see n i n t he 1 0 m g/ k g 
a n d t he titrati o n gr o u ps.  O n t he M M S E, a dj uste d mea n decreases fr o m baseli ne t o 
Wee k
5 2 s u g geste d a cli nicall y mea ni n gf ul b e nefit i n t he 3 a n d 1 0 m g/ k g gr o u ps a n d 
t he titrati o n gr o u p a n d were si g nifica ntly l o wer i n t he 1 0 m g/ k g gr o u p .  F urt her m ore, 
res ults fr o m t he L T E f or t he fi xe d- d ose re gi me ns ha ve de m o nstrate d c o nti n ue d 
sl o wi n g of t he cli nical decli ne i n s u bjects c o nti n ui ng o n a d uca n u ma b c o m pare d wit h 
s u bjects w h o s witc he d fr o m place b o t o a d uca n u ma b i n t he L T E.  Refer t o t he I B f or 
details o n i nteri m a nal y ses res ults.
5. 2.
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safet y of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D a n d a s u bset of mil d A D.  A d uca n u ma b is a h u ma n I g G 1 m o n ocl o nal a nti b o d y t hat 
rec o g nizes a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osited fi brillar A β.  
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 y l oi d pla q ues are 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
ne ur ot o xic [K offie 2 0 0 9 ; K uc hi b h otla 2 0 0 8 ; Me yer -L ue 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].  F or t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, 
w hile preser vi n g gl o bal f u ncti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.  
I nteri m a nalys es of t he o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) ha ve de m o nstrate d tar get 
e n ga ge me nt, a P D effect o n a m yl oi d re d ucti o n, a n d a n effect o n C D R-S B a n d M M S E s u g gesti ve 
of a re d ucti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b -treate d s u bjects.  T hese 
res ults, al o n g wit h t he o bser ve d safet y a n d t olera bilit y  pr ofile, warra nt t he f urt her P hase 3 
i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he early sta ges of t he A D 
c o nti n u u m.
5. 3.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
T he d osi n g re gi me n selecte d f or t his st u d y  was base d o n t he P K a n d P D relati o ns hi p f or re m o val 
of brai n a m y l oi d a n d effect o n C D R-S B a n d M M S E o bser ve d i n St u d y  2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n safet y, t olera bilit y , a n d P K data fr o m st u dies 2 2 1 A D 1 0 1 (c o m plete) a n d 
2 2 1 A D 1 0 3 ( o n g oi n g).  
T he d ose - a n d ti me-de pe n de nt re d ucti o n of brai n a m y l oi d b ur de n o bser ve d wit h a d uca n u ma b 
treat me nt i n St u d y 2 2 1 A D 1 0 3 was statisticall y si g nifica nt at d oses of 3, 6, a n d 1 0 m g/ k g after 
6 m o nt hs of d osi n g, a n d at 3, 6, a n d 1 0 m g/ k g as well as wit h titrati o n t o 1 0 m g/ k g after 
1 2 m o nt hs of d osi n g.  O n t he e x pl orat or y  e n d p oi nts of C D R-S B a n d M M S E c ha n ges fr o m 
baseli ne, a d ose -de pe n de nt sl o wi n g of cli nical decli ne was o bser ve d f or a d uca n u ma b vers us 
place b o after 1 ye ar of treat me nt.  C o m pare d wit h place b o, a dj uste d mea n c ha n ges fr o m baseli ne 
t o Wee k 5 4 f or C D R-S B fa v ore d all t he a d uca n u ma b d ose gr o u ps teste d, wit h treat me nt 
differe nces of 0. 5 p oi nts or greater at fi xe d d oses of a d uca n u ma b 3, 6, a n d 1 0 m g/ k g a n d als o 
wit h titrati o n t o 1 0 m g/ k g.  O n t he M M S E, a dj uste d mea n decreases fr o m baseli ne t o Wee k 5 2 
were s maller i n all d ose gr o u ps t ha n i n t he place b o gr o u p.  Of n ote, o n t he C D R - S B, t he p oi nt 
esti mate f or t he titrati o n gr o u p (c o m prisi n g A p o E ε 4 carriers o nl y) was ge nerall y si milar t o t hat 
f or t he 1 0 m g/ k g gr o u p a n d si g nifica ntly l o wer t ha n place b o i n b ot h t h ose gr o u ps; o n t he M M S E, 
t he p oi nt esti mate f or t he titrati o n gr o u p is ge nerall y  si milar t o t hat i n t he 1 0 m g/ k g gr o u p ( w hic h 
s h o we d si g nifica ntl y less decli ne t ha n place b o) a n d t he 3 m g/ k g gr o u p.  
T o date, t he i nci de nce of A RI A has bee n o bser ve d t o be b ot h d ose - a n d A p o E ε 4 
carria ge-de pe n de nt, es peciall y  at t he hi g hest d oses w he n a d mi nistere d as a fi xe d d ose. H o we ver, 
t he i nci de nce of A RI A-E, as well as disc o nti n uati o ns fr o m treat me nt d ue t o A RI A- E, i n s u bjects 
recei vi n g a d uca n u ma b titrate d t o 1 0 m g/ k g ( A p o E ε 4 carriers o nly) a p pear t o be re d uce d ( 8/ 2 3 
[ 3 5 %]) c o m pare d wit h fi xe d d oses of a d uca n u ma b at 6 m g/ k g ( 9/ 2 1 [ 4 3 %]) a n d 1 0 m g/ k g 
( 1 1/ 2 0 [ 5 5 %]). F urt her m ore, a m o n g t h ose s u bjects ra n d o mize d t o recei ve a d uca n u ma b titrate d t o 
1 0 m g/ k g, A RI A -E occ urre d o nl y  at t he 3 m g/ k g a n d 6 m g/ k g d ose le vels. Als o, 1 3 ( of 2 3, 5 7 %) 
s u bjects i n t he titrati o n ar m ha ve bee n titrate d t o 1 0 m g/ k g, a n d of t hese, 1 2 c o nti n ue d treat me nt 
a n d recei ve d at least 1 0 d oses of 1 0 m g/ k g; n o ne of t hese s u bjects e x perie nce d A RI A -E or 
A RI A- H.
I n a n eff ort t o ma xi mize t he d ose-de pe n de nt a m yl oi d re d ucti o n a n d effect o n C D R -S B a n d 
M M S E t hat ha ve bee n o bser ve d wit h d oses of 3 m g/ k g a n d hi g her w hile mai ntai ni n g A RI A 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
i nci dence, se verit y, a n d relate d disc o nti n uati o n rate wit hi n acce pta ble le vels, a titrati o n re gi me n 
will be e x pl ore d i n t his st u d y.  It has bee n s u g geste d t hat t he A RI A o bser ve d f oll o wi n g treat me nt 
wit h a m y l oi d tar geti n g a ge nts ma y be d ue, i n part, t o t he i nitial lar ge re m o val of a myl oi d a n d 
s u bse q ue nt sat urati o n of peri vasc ular brai n a m yl oi d cleara nce mec ha nis ms [ Weller 2 0 0 8].  
Titrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o wer i nitial a m y l oi d re m o val, yet tri g ger 
alter nati ve mec ha nis ms of a m yl oi d cleara nce i ncl u di n g m o n ocl o nal a nti b o d y- de pe n de nt 
Fc -me diate d micr o glial cleara nce [Ostr o witz ki 2 0 1 2 ], w hic h w o ul d pre ve nt sat urati o n of 
a m yl oi d cleara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is reac he d.  
Si nce a d uca n u ma b -i n d uce d A RI A has bee n de m o nstrate d t o occ ur earl y d uri n g treat me nt, wit h 
m ost cases occ urri n g wit hi n t he first 5 d oses, titrati o n of a d uca n u ma b f or u p t o 6 d oses pr i or t o 
reac hi n g t he tar get d ose ma y res ult i n re d ucti o n of A RI A i nci de nce a n d se verit y.  
Gi ve n t he t olera bilit y  a n d a p pare nt efficac y of a d uca n u ma b s h o w n t o date, t he d oses t o be teste d 
usi n g a titrati o n re gi me n are 3 a n d 1 0 m g/ k g f or A p o E ε 4 carriers, a n d 6 a n d 1 0 m g/ k g f or A p o E 
ε 4 n o n-carriers.  Titrati o n will start at 1 m g/ k g a n d will escalate t o 3, 6, a n d 1 0 m g/ k g as detaile d 
bel o w.  
5. 3. 1.
D osi n g Sc he me
5. 3. 1. 1.
Pl ace b o -C o ntr olle d Peri o d
D oses will be a d mi nistere d a p pr o xi matel y  4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses). Base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d t o 1 of 
3 treat me nt gr o u ps (a p pr o xi matel y 4 5 0 s u bjects eac h [ N ote:  I n t he e ve nt a pres pecifie d bli n de d, 
sa m ple size re-esti mati o n is perf or me d, t he sa m ple size ma y  be i ncrease d b ut will n ot e xcee d 
5 8 8 s u bjects per treat me nt gr o u p]) i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose:a d uca n u ma b hi g h 
d ose: place b o) as f oll o ws ( Ta ble 7 a n d Fi g ure 1 ):
A p o E ε 4 C arrier

L o w d ose ( 3 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereaf ter

Hi g h d ose ( 1 0 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n
A p o E ε 4 N o n -C arrier

L o w d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter  

Hi g h d ose ( 1 0 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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

Place b o  
Sali ne i nf usi o n
T a ble 7 :
D osi n g Sc he me f or A d uc a n u m a b b y Tre at me nt Gr o u p a n d A p o E ε 4 C arrier 
St at us
D ose ( M o nt h)
1
2 
3 
4 
5 
6
7 t o 2 0
Tre at m e nt Gr o u p
D ose ( m g/ k g)
A p o E ε 4 ( +)
L o w D ose
1 
1 
3 
3 
3 
3 
3
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0 1
Pl ace b o
sali ne
A p o E ε 4 ( -)
L o w D ose
1 
1 
3 
3 
3 
3 
6
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0
Pl ace b o
sali ne
1 1 0 m g/ k g is t he tar get d ose f or all A p o E e 4 carriers assi g ne d t o t he a d uca n u ma b hi g h -d ose gr o u p .  S u bjects 
e nr olle d u n der pre vi o us versi o ns of t he pr ot oc ol a n d assi g ne d t o t he pre vi o us hi g h -d ose of 6 m g/ k g will be titrate d 
t o 1 0 m g/ k g u p o n recei pt of at least 2 d oses at 6 m g/ k g.  
5. 3. 2.
D osi n g Sc he me M o dific ati o n
A n i n de pe n de nt data m o nit ori n g c o m mittee ( I DM C) will re vie w u n bli n de d safet y data, i ncl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d uca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter.
T he d osi n g sc he me ca n be m o di fie d i n t he f oll o wi n g circ u msta nces: 

Safet y  a n d t olera bilit y of t he hi g h d ose 
If t he hi g h d ose ( 1 0 m g/ k g) is dee me d n ot acce pta ble, e nr oll me nt f or t he hi g h-d ose 
gr o u p(s) will be ter mi nate d a n d s u bjects will n ot be re place d. S u bjects w h o ha ve 
alrea d y bee n ra n d o mize d t o t he disc o nti n ue d d ose will be d o w n-d ose d t o t he ne xt 
a vaila ble d ose acc or di n g t o t heir A p o E ε 4 carrier stat us. Defi niti o n of l o w a n d 
hi g h -d ose gr o u ps will be re vise d as descri be d i n Secti o n 1 6 . 
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d
S u bjects w h o recei v e d 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 w h o e nter t he L T E 
peri o d will mai ntai n t he d osi n g sc he me o utli ne d i n t he pr ot oc ol at t he ti me of tra nsiti o n fr o m t he 
place b o -c o ntr olle d peri o d t o t he L T E peri o d (e. g. s u bjects w h o are o n sta ble d osi n g i n t he 
place b o -c o ntr olle d peri o d will c o nti n ue o n t he sa me d ose, s u bjects w h o are o n a titrati o n re gi me n 
d uri n g t he tra nsiti o n will c o nti n ue t o titrate i nt o t he L T E peri o d a n d s u bjects w h o c o m plete t he 
place b o -c o ntr olle d peri o d u n der pr ot oc ol versi o ns 1 t o 3 a n d are assi g ne d t o t he hi g h d ose 
a d uca n u ma b treat me nt gr o u p ma y  u p titrate t o 1 0 m g/ k g i n t he L T E). S u bjects w h o recei ve 
place b o d uri n g t he place b o-c o ntr olle d peri o d a n d w h o e nter t he L T E peri o d will be assi g ne d t o 
1 of 2 treat me nt gr o u ps, base d u p o n t heir A p o E ε 4 carrier stat us, i n a 1: 1 rati o (a d uca n u ma b l o w 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
d ose: a d uca n u ma b hi g h d ose). S u bjects will be d ose d usi n g t he sa me re gi me n descri be d f or t he 
place b o -c o ntr olle d peri o d (see Ta ble 7 a n d Fi g ure 1 ). 
A p o E ε 4 carrier s u bjects w h o are e nr olle d i n t he L T E a n d ra n d o mize d t o t he hi g h -d ose gr o u p 
pri or t o i m ple me ntati o n of versi o n 4 of t he pr ot oc ol will be all o we d t o titrate t o 1 0 m g/ k g.  A n y  
m o dificati o ns t o t he d osi n g sc he me (i.e. ter mi nati o n of hi g h - d ose gr o u p, as descri be d i n 
Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E peri o d .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
6.
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
6. 1.
Pri m ar y O bjecti ve a n d E n d p oi nt
T he pri mar y  o bjecti ve of t he st u d y is t o e val uate t he efficac y of m o nt hl y d oses of a d uca n u ma b i n
sl o wi n g c o g niti ve a n d f u ncti o nal i m pair me nt as meas ure d by c ha n ges i n t he C D R-S B sc ore as 
c o m pare d wit h place b o i n s u bjects wit h earl y A D.
T he pri mar y  e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n C D R-S B sc ore at 
Wee k
7 8.
6. 2.
Sec o n d ar y O b jecti ves a n d E n d p oi nts
A sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d wit h 
place b o o n cli nical pr o gressi o n as meas ure d b y t he M M S E.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n M M S E sc ore at 
Wee k
7 8.
A n ot her sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gressi o n as meas ure d b y  A D A S-C o g 1 3.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D A S -C o g 1 3 
sc ore at Wee k 7 8.
A n ot her sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gressi o n as meas ure d b y  A D C S-A D L -M CI.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D C S - AD L -
M CI  sc ore at Wee k 7 8.
6. 3.
Terti ar y O bjecti ves a n d E n d p oi nts
6. 3. 1.
Terti ar y O bjecti ves
Safet y  a n d T olera bilit y

T o assess t he safety a n d t olera bilit y of m o nt hl y d oses of a d uca n u ma b.  

T o assess t he i m m u n o ge nicit y of a d uca n u ma b.  
Bi o mar ker /Efficac y / Healt h O utc o mes

T o assess t he effect of a d uca n u ma b o n cere bral a m y l oi d pla q ue c o nte nt as meas ure d 
b y  a myl oi d P E T i ma gi n g (i n a s u bset of a p pr o xi matel y  4 0 0 s u bjects).

T o assess t he effect of a d uca n u ma b o n be ha vi or as meas ure d b y t he Ne ur o ps yc hiatric 
I n ve nt or y-1 0 ( N PI -1 0).

T o assess t he effect of a d uca n u ma b o n s u bject healt h stat us, meas ure d b y E ur o Q ol 
healt h stat us meas ures ( E Q - 5 D [i nf or ma nt-rate d a n d s u bject self-re p orte d]).










Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
St u d y  2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, parallel -gr o u p 
P hase 3 st u d y  i n s u bjects wit h early A D, i ncl u di n g M CI d ue t o A D a n d a s u bset of mil d A D, 
f oll o we d by a n o pti o nal 2 4 -m o nt h d ose -bli n d L T E st u d y . A p pr o xi matel y  1 3 5 0 s u bjects ( or, i n 
t he e ve nt t hat a pres pecifie d, bli n de d sa m ple size re -esti mati o n is perf or me d, ma y  be i ncrease d 
b ut will n ot e xcee d 1 7 6 4 s u bjects, see Secti o n 1 6. 8 ) will be e nr olle d acr oss a p pr o xi matel y 
1 5 0 ce nters gl o ball y. T he pri mar y  st u d y o bjecti ve is t o e val uate t he efficac y of m o nt hly d oses of 
a d uca n u ma b o n t he C D R -S B relati ve t o p lace b o. Sec o n dar y o bjecti ves i ncl u de assess me nt of t he 
effect of m o nt hl y d oses of a d uca n u ma b o n cli nical pr o gressi o n as c o m pare d t o place b o. T he 
safety of m o nt hl y d oses of a d uca n u ma b will als o be e val uate d.
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y  e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a t otal of 2 0 d oses).  S u bjects will be ra n d o mize d t o recei ve 
a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o i n a 1: 1: 1 rati o.  T he ra n d o mizati o n will 
be stratifie d b y site a n d A p o E ε 4 st at us (carrier or n o n -carrier).  T he rati o of A p o E ε 4 carriers t o 
n o n- carriers i n t he st u d y p o p ulati o n will ge nerall y reflect t he distri b uti o n i n t he br oa der A D 
p o p ulati o n.  E nr oll me nt will als o be m o nit ore d, via i nteracti ve res p o nse tec h n ol o g y (I R T), s uc h 
t hat s u bjects wit h mil d A D re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  
At t he e n d of t he d o u ble -bli n d, place b o -c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
e xte nsi o n e ntr y criteria ma y e nter a 2 4-m o nt h l o n g -ter m safet y a n d efficac y e xte nsi o n peri o d, 
wit h all s u bjects recei vi n g a d uca n u ma b a p pr o xi matel y  e ver y 4 wee ks (a t otal of 2 6 d oses).  
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject o nl y partici pati n g i n t he 
place b o -c o ntr olle d peri o d of t he st u d y  will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series 
of scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a n d a safet y f oll o w -u p ( F U) peri o d of 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 eac h s u bject partici pati n g i n t he place b o-c o ntr olle d 
peri o d a n d t he L T E peri o d will be u p t o a p pr o xi matel y  2 0 6 wee ks, i ncl u di n g a series of 
scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a 4 -wee k F U peri o d, a 1 0 0 -wee k a d uca n u ma b d ose -bli n d 
treat me nt peri o d, a n d a safety F U peri o d of 1 8 wee ks after t he fi nal d ose.  T he F U peri o d of 
1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half -life i n h u ma ns of 1 6 t o 2 4 da y s ( mea n 
a p pr o xi matel y 2 0 d a y s, base d o n res ults fr o m t he si n gle asce n di n g d ose st u d y [ St u d y 
2 2 1 A D 1 0 1]) a n d a ntici pate d brai n c o nce ntrati o ns of a d uca n u ma b of less t ha n o ne -t hir d t he E C5 0
(i n hi bit or y c o ncentrati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or bi n di n g fi brillar 
a m yl oi d at 8 wee ks after t he last d ose.  
D uri n g t he place b o -c o ntr olle d peri o d, A p o E ε 4 carriers will recei ve place b o, 
a d uca n u ma b 3 m g / k g, or a d uca n u ma b 1 0 m g/ k g w hereas A p o E ε 4 n o n-carriers will recei ve 
place b o, a d uca n u ma b 6 m g/ k g, or a d uca n u ma b 1 0 m g/ k g.  A d uca n u ma b will be titrate d f or u p t o 
6 d oses pri or t o reac hi n g t he tar get d ose as s h o w n i n Ta ble 7 a n d Fi g ure 1 .  N ote: 1 0 m g/ k g is t he 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
tar get d ose f or all A p o E ε 4 carriers i n t he hi g h-d ose gr o u p.  A p o E ε 4 carriers w h o are e nr olle d i n 
t he hi g h-d ose gr o u p recei vi n g 6 m g/ k g m ust ha ve recei ve d 2 or m ore d oses at 6 m g/ k g pri or t o 
bei n g titrate d u p t o 1 0 m g/ k g.  S u bjects w h o recei ve d place b o d uri n g t he place b o -c o ntr olle d 
peri o d a n d w h o e nter t he L T E peri o d will be assi g ne d t o treat me nt base d u p o n t heir A p o E ε 4 
carrier stat us i n a 1: 1 rati o (a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose); a d uca n u ma b will be 
titrate d f or u p t o 6 d oses pri or t o reac hi n g t he tar get d ose f oll o wi n g t he sa me sc he d ule descri be d 
f or t he place b o-c o ntr olle d peri o d.  
See Secti o n 5. 3. 2 f or details of d osi n g sc he me m o dificati o n.  
I n di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d i n s u bjects w h o de vel o p A RI A.  See
Secti o n 7. 2. 1 .
I n vesti gat ors, st u d y site staff (e xce pt f or t he desi g nate d u n bli n de d p har macist/tec h nicia n), a n d 
st u d y s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he 
place b o - c o ntr olle d peri o d.  D uri n g t he L T E peri o d, I n vesti gat ors a n d s u bjects will re mai n 
bli n de d t o t he t reat me nt assi g n me nt i n t he place b o-c o ntr olle d peri o d a n d t he a d uca n u ma b d ose 
f or t he L T E peri o d.
7. 2.
St u d y S pecifics
7. 2. 1.  
D ose S us pe nsi o n, M o dific ati o n, or Ter mi n ati o n f or A RI A E ve nts
Disc o nti n u ati o n of D osi n g f or a Give n S u bject
T he ce ntral M RI  rea di n g ce nter will re p ort i nci de nt cases of A RI A-E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he PI  wit hi n a s pecifie d ti me after o bser vi n g t he fi n di n g o n M RI per t he i ma gi n g 
ma n ual pr oce d ures.  All cases of A RI A will be re vie we d b y t he S p o ns or a n d t he PI ; decisi o ns o n 
d osi n g c o nt i n uati o n, i nterr u pti o n, or disc o nti n uati o n will be base d o n cli nical s ym pt o ms, a n d t he 
M RI  i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C n otificati o n r ules will be o utli ne d i n t he 
I D M C c harter.  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 
(i ncl u di n g t he criteria t o be met f or t he c o nti n uati o n, s us pe nsi o n/res u m pti o n, per ma ne nt 
disc o nti n uati o n of d osi n g d ue t o A RI A, res u m pti o n of d osi n g after d ose s us pe nsi o n d ue t o A RI A 
[i ncl u di n g r ules f or titrati n g u p t o t he assi g ne d d ose], an d ma na ge me nt of rec urre nt A RI A) are 
pr o vi de d i n t he f oll o wi n g s u bsecti o ns.  D osi n g ma y als o be ter mi nate d at t he discreti o n of t he 
S p o ns or f or me dical reas 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7. 2. 1. 1.
A RI A -E C as es
T a ble 8:
Dis p ositi o n of A RI A -E C ases
Cli nic al S y m pt o m 
Se verit y
A RI A -E Se verit y o n M RI ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
As y m pt o m atic 
C o nti n ue d osi n g at 
c urre nt d ose a n d 
sc he d ule
S us pe n d d osi n g.  O nce A RI A -E res ol ves t he s u bject 
ma y res u me d osi n g at t he sa me d ose.  
Mil d
S us pe n d d osi n g.  O nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t he s u bject ma y 
res u me d osi n g at t he sa me d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y i m p ort a nt 
e ve nt ” o nl y 1
Seri o us, e xce pt f or 
“ ot her m e dic all y 
i mp ort a nt e ve nt ” 2
Disc o nti n ue D osi n g
1 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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. 2 .
2 S A Es 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), 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/ 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. 2 .

S u bje cts w h o de vel o p mi l d A RI A-E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 
d ose.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 
4 wee ks u ntil t he A RI A -E has res ol ve d per t he ce ntrall y  rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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.  T he S p o n s or ma y re q uire t hat t he s u bjects 
disc o nti n ue d osi n g or c o nti n ue d osi n g at a l o wer d ose le vel base d o n re vie w of safet y 
a n d M RI data.

S u bjects w h o de vel o p m o der ate or se vere A RI A -E, per ce ntr al M RI re a di n g, wit h 
n o cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A a p pr o xi matel y e ver y 
4 wee ks u ntil t he A RI A -E has res ol ve d per t he ce ntrall y  rea d M RI. I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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. If t he A RI A-E has res ol ve d a n d t he s u bjects re mai n 
as ym pt o matic (i n t he I n vesti gat or’s o pi ni o n), t he s u bjects ma y  res u me treat me nt at 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
t he sa me d ose.  S u bjects w h o ha ve misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o 
A RI A will n ot be all o we d t o res u me treat me nt.  

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y 
i m p ort a nt e ve nt ” o nl y) cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will 
te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A 
ap pr o xi matel y  e ver y 4 wee ks u ntil t he A RI A-E has res ol ve d per t he ce ntrall y  rea d 
M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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.  If t he A RI A -E has res ol ve d a n d t he 
cli nical s y m pt o ms ha ve res ol ve d (i n t he In vesti gat or’s o pi ni o n), t he s u bject ma y  
res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve misse d m ore t ha n 
4 c o nsec uti ve d oses d ue t o A RIA will n ot be all o we d t o res u me treat me nt.  

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A-E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ”) 
cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will per ma ne ntl y disc o nti n ue 
treat me nt.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, 
i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A a p pr o xi matel y e ver y 
4 wee ks u ntil t he A RI A -E has res ol ve d per ce ntrall y  rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C sa m ples will be c ollecte d at t he first u nsc he d ule d visit 
f oll o win g a n e pis o de of A RI A.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 2.
A RI A -H ( Micr o he m orr h a ge)
I n t his st u dy, ne w i nci de nt micr o he m orr ha ges are defi ne d as ne w i nci de nt micr o he m orr ha ges 
t hat occ ur o n treat me nt a n d d o n ot i ncl u de micr o he m orr ha ges at baseli ne.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 a ble 9:
Dis p ositi o n of A RI A - H ( Micr o he m orr h a ge) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Micr o he m orr h a ges 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
≥ 1 a n d ≤ 4
≥ 5 a n d ≤ 9
≥ 1 0
As y m pt o m atic
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble, t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me 
d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt micr o he m orr ha ges = ne w i nci de nt micr o he m orr hages o n treat me nt; d oes n ot i ncl u de 
micr o he m orr ha ges at baseli ne.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 o l 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 2 .
As y m pt o m atic A RI A -H ( Micr o he m orr h a ge) 

S u bjects w h o de vel o p a ≥ 1 a n d ≤ 4 ne w i nci de nt micr o he m orr h a ge(s) [ mil d] at 
a n y ti me d uri n g t he st u d y ma y c o nti n ue treat me nt at t he c urre nt d ose.

S u bjects w h o de vel o p ≥ 5 a n d ≤ 9 ne w i nci de nt micr o he m orr h a ges [ m o der ate]
occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
micr o he m orr ha ge is c o nfir me d as sta ble per t he ce ntrall y  rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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.  A micr o he m orr ha ge is c o nsi dere d sta ble if it is 
u nc ha n ge d bet wee n 2 c o nsec uti ve M RI s 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 2 wee ks ( ± 3 da ys) later.  O nce t he micr o he m orr ha ge is dee me d 
sta ble, s u bjects ma y res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve misse d 
m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be all o we d t o res u me treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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

S u bjects w h o de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges [se vere] d uri n g t he 
st u d y will per ma ne ntl y disc o nti n ue treat me nt.  S u bjects s h o ul d c o m plete all 
sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsche d ule d visit f or 
a n M RI a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ges are dee me d 
sta ble per ce ntrally rea d M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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 y m p t o m atic A RI A- H ( Micr o he m orr h a ge)

S u bjects w h o de vel o p ≤ 9 ne w i nci de nt micr o he m orr h a ges ( mil d or m o der ate) 
a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H 
( micr o he m orr ha ge(s) is c o nfir me d sta ble per t he ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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.  Micr o he m orr ha ges are c o nsi dere d sta ble if t he y  are 
u nc ha n ge d 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 2 wee ks ( ± 3 da y s) later.  O nce A RIA- H ( micr o he m orr ha ge) is 
dee me d sta ble a n d t he cli nical s y m pt o ms ha ve res ol ve d (i n t he In vesti gat or’s 
o pi ni o n), t he s u bject ma y res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve 
misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be all o we d t o res u me 
treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h micr o he m orr h a ge(s) will 
per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 
2 wee ks ( ± 3 da ys) u ntil t he micr o he m orr ha ge(s) is c o nfir me d sta ble per ce ntrall y  rea d 
M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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 de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges (se vere) , re gar dless of 
s ym pt o m se verit y, d uri n g t he st u d y will per ma ne ntl y  disc o nti n ue treat me nt.  S u bjects 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
micr o he m orr ha ges are dee me d sta ble per ce ntrall y rea d M RI.  I n a d diti o n, bi o mar ker, 
P K, a n d P B M C sa m ples will be c o llecte 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.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7. 2. 1. 3.
A RI A -H ( S u perfici al Si der osis)
T a ble 1 0:
Dis p ositi o n of A RI A - H ( S u perfici al Si der osis) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Are as of S u perfici al Si der osis 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
1
2
> 2
As y m pt o m atic
C o nti n ue d osi n g at 
c urre nt d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me 
d ose.  
M o der ate
Se vere 
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt s u perficial si der osis = ne w i nci de nt s u perficial si der osis o n treat me nt.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose s us pe nsi o n i nc l 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es 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 ar e life -t hreate ni n g (i n t he o pi ni o n 
of t he I n vesti gat or), 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/ 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 Se cti o n 1 5. 1. 2 .
As y m pt o m atic A RI A -H ( S u perfici al Si der osis)

S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis) [ mil d] ma y  c o nti n ue treat me nt at t he c urre nt d ose, b ut 
m ust ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil 
t he s u perficial si der osis is c o nfir me d as sta ble per t he ce ntrally rea d M RI.  I n 
a d diti o n, bi o mar ker, P K, a n d P B M C 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 perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  

S u bjects w h o de vel o p 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
[ m o der ate] occ urri n g at a n y  ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys)
u ntil t he A RI A- H (s u per ficial si der osis) is c o nfir me d as sta ble per t he ce ntrall y rea d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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 perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d bet wee n 2 c o nsec uti ve M RI s 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 2 wee ks ( ± 3 da ys) later.  O nce t he s u perficial si der osis 
is dee me d sta ble, t he s u bjects ma y res u me treat me nt at t he sa me d ose.  S u bjects w h o 
ha ve misse d m ore t ha n 4 c o nse c uti ve d oses d ue t o A RIA will n ot be all o we d t o 
res u me treat me nt.  

S u bjects w h o de vel o p > 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
[se vere] occ urri n g at a n y ti me d uri n g t he st u d y  m ust per ma ne ntly disc o nti n ue 
treat me nt a n d s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys)
u ntil t he A RI A- H (s u perficial si der osis) is c o nfir me d as sta ble per t he ce ntrall y  rea d 
M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B MC 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 perficial si der osis is c o nsi dere d 
sta ble if it is u nc ha n ge d 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 2 wee ks ( ± 3 da ys) later.  
S y m pt o m atic A RI A -H (s u perfici al si der osis)

S u bjects w h o de vel o p ≤ 2 ne w f oc al are as of s u perfici al si der osis ( mil d or 
m o der ate) a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt 
e ve nt ” o nl y) cli nical s y m pt o ms will te m p oraril y  s us pen d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he A RI A -H 
s u perficial si der osis is c o nfir me d sta ble per t he ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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 perficial si der osis is c o nsi dere d sta ble if it is 
u nc ha n ge d 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 2 wee ks ( ± 3 da y s) later.  O nce t he A RI A- H (s u perficial si der osis) is 
dee me d sta ble a n d t he cli nical s y m pt o ms ha ve res ol ve d (i n t he In vesti gat or’s 
o pi ni o n), t he s u bjects ma y res u me treat me nt at t he sa me d ose.  S u bjects w h o ha ve 
misse d m ore t ha n 4 c o nsec uti ve d oses d ue t o A RI A will n ot be all o we d t o res u me 
treat me nt.  

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h A RI A-H (s u perfici al 
si der osis) will per ma ne ntl y  disc onti n ue treat me nt, b ut s h o ul d c o m plete all sc he d ule d 
cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  
a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he s u perficial si der osis is c o nfir me d sta ble 
per ce ntrall y rea d M RI.  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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 de vel o p > 2 ne w f oc al are as of s u perfici al si der osis (se vere) 
re gar dless of cli nical sy m pt o m se verit y  will per ma ne ntl y disco nti n ue treat me nt, b ut 
s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 2 wee ks ( ± 3 da ys) u ntil t he 
s u perficial si der osis is c o nfir me d sta ble per ce ntrall y  rea d M RI.  I n a d diti o n, 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
bi o mar ker, P K, a n d P B M C 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.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 4.
A RI A -H ( M acr o he m orr h a ge)

S u bjects w h o de vel o p a n y ne w i nci de nt macr o he m orr ha ge, re gar dless of s y m pt o m 
se verity d uri n g t he st u d y,  will per ma ne ntl y disc o nti n ue treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli n ic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or M RI a n d M O C A e ver y  2 wee ks ( ± 3 da ys) 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.  I n a d diti o n, bi o mar ker, 
P K, a n d P B M C sa m ples will be c ollecte d at t he firs t u nsc he d ule d visit f oll o wi n g a n 
e pis o de of A RI A -H ( macr o he m orr ha ge).
7. 2. 1. 5.  
C oi nci de nt A RI A- H a n d A RI A -E C ases
S u bjects w h o de vel o p A RI A- H c oi nci de nt wit h A RI A- E at a n y ti me d uri n g t he st u d y  will f oll o w 
t he m ost restricti ve g ui deli nes.  Pri or t o res u mi n g treat ment, w here a p plica ble, A RI A -E m ust 
res ol ve, A RI A-H m ust be dee me d sta ble, a n d t he s u bject m ust be as y m pt o matic.  F or e xa m ple, if 
a s u bject e x perie nces as y m pt o matic A RI A- H ( 1 -4 micr o he m orr ha ges) c oi nci de nt wit h A RI A -E 
assesse d as m o derate o n M RI  a n d acc o m pa nie d b y mil d cli nical s ym pt o ms, t he d ose s h o ul d be 
s us pe n de d per t he A RI A-E g ui deli nes s u m marize d i n Ta ble 8 .  I n a d diti o n, u nsc he d ule d visits 
s h o ul d occ ur as descri be d i n Secti o n 7. 2. 1. 1 t hr o u g h Secti o n 7. 2. 1. 4 .
7. 2. 1. 6.
Res u m pti o n of St u d y Tre at me nt After S us pe nsi o n d ue t o A RI A
7. 2. 1. 6. 1.
M RI M o nit ori n g
W he n treat me nt res u mes after a d ose s us pe nsi o n d ue t o A RI A, a n M RI a n d M O C A will be 
perf or me d 2 wee ks ( ± 3 da y s) after t he sec o n d a d mi nistrati o n of t he restarte d d ose.  I n a d diti o n, if 
treat me nt was s us pe n de d d uri n g t he d ose titrati o n pri or t o t he s u bject reac hi n g t he ma xi m u m 
assi g ne d d ose, a n M RI a n d M O C A will be perf or me d 2 wee ks ( ± 3 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 
(titrati o n perio d of 6 d oses a n d a fi nal M RI after t he sec o n d d ose at 1 0 m g/ k g) t o mai ntai n st u d y  
bli n di n g, n ot c o u nti n g u nsc he d ule d M RI visits f or m o nit ori n g of A RI A.  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 E ve nts ( Secti o n 4. 2 ).
7. 2. 1. 6. 2.
D osi n g U p o n Res u m pti o n of St u d y Tre at me nt
S u bjects w h o s us pe n d treat me nt d ue t o A RI A f or t he first ti me ma y  res u me treat me nt at t he sa me 
d ose if t he y meet t he criteria as descri be d i n Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5.   S u bjects w h o s us pe n d 
a n d t he n res u me d osi n g after ha vi n g alrea d y reac he d t heir assi g ne d t o p d ose le vel are t o c o nti n ue 
d osi n g at t hat d ose le vel. H o we ver, if d osi n g is s us pe n de d pri or t o a s u bject reac hi n g t heir 
assi g ne d t o p d ose le vel, t he s u bject ( 1) m u st recei ve at least 2 d oses at t he restart d ose bef ore 
titrati n g u p t o t he ne xt d ose le vel a n d ( 2) m ust c o m plete at least t he re q uire d n u m ber of d oses at 
t hat d ose le vel per t heir assi g ne d treat me nt gr o u p, as o utli ne d i n t he ri g ht c ol u m n of Ta ble 1 1 . 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a bl e 1 1:
Res u m pti o n of St u d y Tre at me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titr ati o n
Assi g ne d Tre at me nt 
Gr o u p
( M a xi m u m D ose)
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses at 
C u rre nt D ose Le vel 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
A p o E ε 4 ( +)
L o w D ose ( 3 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
A p o E ε 4 ( -)
L o w D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
7. 2. 1. 7.
M a n a ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI)
If t he s u bject has a sec o n d occ urre nce of A RI A (i.e., a sec o n d occ urre nce of A RI A -E or of 
A RI A- H, or A RI A -E a n d A RI A- H) t hat re q uires d ose s us pe nsi o n ( per criteria i n Secti o n 7. 2. 1. 1 , 
Secti o n 7. 2. 1. 2 , a n d Secti o n 7. 2. 1. 3 ), after t he A RI A-E res ol ves or sta bilizes, t he s u bject is t o 
res u me d osi n g at t he ne xt l o wer d ose a n d is t o recei ve 2 d oses at t hat d ose le vel (i.e., t he restart 
d ose) bef ore titrati n g u p t o t he ne xt hi g her d ose.  O nce d osi n g has res u me d, t he g ui deli nes 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
o utli ne d i n Ta ble 1 1 a p pl y, u nless t he s u bject has re d uce d fr o m 1 m g/ k g t o place b o.  I n t his case, 
t he s u bject will re mai n o n place b o f or t he d urati o n of t he place b o-c o ntr olle d p orti o n of t he st u d y .  
If a s u bject res u mes treat me nt after A RI A, a n M RI a n d M O C A will be perf or me d 2 w ee ks 
( ± 3 d a y s) after t he sec o n d a d mi nistrati o n of t he restarte d d ose, a n d 2 wee ks ( ± 3 da y s) after e ver y 
sec o n d d ose u ntil t he c o m pleti o n of titrati o n, wit h all s u bjects ass u me d t o be titrati n g t o 1 0 
m g/ k g ( 6 d oses) t o mai ntai n st u d y  bli n di n g.  M RIs will other wise be perf or me d as i n dicate d i n 
t he Sc he d ule of E ve nts ( Secti o n 4. 2 ).
If t he s u bject e x perie nces a t hir d e pis o de of A RI A t hat re q uires d ose s us pe nsi o n (i.e., after 
e x perie nci n g 2 pri or e pis o des of A RI A meeti n g t he criteria f or d ose s us pe nsi o n [see 
Sec ti o n 7. 2. 1. 1 , Secti o n 7. 2. 1. 2 , a n d Secti o n 7. 2. 1. 3 ]), t he s u bject m ust disc o nti n ue st u d y 
treat me nt.  S u bjects w h o 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 c o nti n ue all 
pr ot oc ol -re q uire d tests a n d assess me nts. 
S u bjects w h o de vel o p A RI A d uri n g t he place b o -c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d ose are eli gi ble t o e nter t he L T E peri o d a n d will mai ntai n t he d osi n g 
sc he me fr o m t he place b o-c o ntr olle d peri o d i nt o t he L T E, w hic h ma y  i ncl u de a c o nti n uati o n o n 
t he sa me d ose or co m pleti o n of titrati o n i nt o t he L T E peri o d.  A s u bject w h o is d ose -re d uce d t o 
place b o b ut re mai ns i n t he st u d y  ma y be titrate d t o a d uca n u ma b 1 m g / k g d uri n g t he L T E peri o d.
7. 2. 2. 
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 
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 h e Directi o ns f or Ha n dli n g a n d A d mi nistrati o n ( 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.
7. 3.
O ver all St u d y D ur ati o n a n d F oll o w -U p
T he st u d y  peri o d will c o nsist of S cree ni n g, treat me nt, a n d F U.
T he d o u ble -bli n d, place b o -c o ntr olle d peri o d of t he st u d y  will c o nsist of a n 8-wee k scree ni n g 
peri o d, a 7 6 - wee k treat me nt peri o d, a n d a safety F U peri o d of 1 8 wee ks after t he fi nal d ose.  
S u bjects will ha ve a p pr o xi matel y  3 2 sc he d ule d clinic visits d uri n g t he place b o -c o ntr olle d peri o d, 
a n d u p t o 8 tele p h o ne safet y  F U c o ntacts, as f oll o ws:

Scree ni n g Visits n o m ore t ha n 6 0 da y s bef ore t he first d ose of st u d y treat me nt o n 
D a y 1 ( visits will be c o n d ucte d o n m ulti ple da y s).  It is rec o m me n de d that 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 






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d a n d n ot e nteri n g t he L T E peri o d are t o 
ret ur n t o t he st u d y site f or a n F U Visit at Wee k 9 4 ( 1 8 wee ks after t he l ast d ose).  T he fi nal st u d y  
visit f or t hese s u bjects will be Wee k 9 4.
S u bjects w h o partici pate i n t he L T E peri o d are t o ret ur n t o t he st u d y  site t o recei ve t heir first 
L T E d ose a p pr o xi matel y  4 wee ks after t heir last d ose i n t he place b o-c o ntr olle d peri o d of t he 
st u d y.  A F U Visit will occ ur at Wee k 1 9 8 ( 1 8 wee ks after t he last L T E d ose).  T he fi nal st u d y 
visit f or s u bjects partici pati n g i n t he L T E peri o d will be Wee k 1 9 8.
S u bjects w h o 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 c o nti n ue all pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y or u ntil wit h dra wal of c o nse nt.  S u bjects w h o 
wit h dra w fr o m t he st u d y are e nc o ura ge d t o ret ur n f or F U assess me nts 1 8 wee ks after t heir last 
d ose of st u d y  treat me nt.  
7. 4.
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.
D osi n g ma y  be ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e xcl usi vel y o n safety a n d t olera bilit y data or f oll o wi n g t he f utilit y a nalys is, or at t he discreti o n of 
t he S p o ns or; t heref ore, t here are n o st u dy- s pecific st o p pi ng r ules defi ne d i n t his pr ot oc ol.  
7. 5.
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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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
T o be eli gi ble t o partici pate i n t his st u d y , ca n di dates m ust meet t he f oll o wi n g eli gi bilit y criteria 
at Scree ni n g 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  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.
2.
A ge d 5 0 t o 8 5 y ears 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 , please refer t o 
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 or mil d A D.
5.
M ust ha ve a p ositi ve
a m yl oi d P E T sca 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 f or s u bjects n ot partici pati n g i n t he a m yl oi d P E T 
s u bst u d y.  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 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 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:

A C D R g l o bal sc ore of 0. 5.

A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair me nt ( base d 
u p o n t he Dela y e d Me m or y In de x sc ore).  

A n M M S E sc ore bet wee n 2 4 a n d 3 0 (i ncl usi ve).
7.
A part fr o m a cli nical dia g n osis of earl y 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  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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
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 vest i gat or a n d st u d y s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n.  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 t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6
8. 2.
E xcl usi o n Criteri a
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 al 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 o-te 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 doc 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).

Greater 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).  

C ortica l i nfarct ( defi ne d as > 1. 5 c m i n dia meter).  

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 
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 safet y 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 oag 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 
Ass 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 E C G a b n or malities, as deter mi ne d by t he I n 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 yperte 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 t he S p o ns or:  

S u bjects wit h ca ncers i n re missi o n m ore t ha n 5 ye ars pri or t o Scree ni n g.

S u bjects wit h a hist or y  of excise 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.
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 b y a n a b n or mal li ver f u ncti o n pr ofile at 
Scree ni n g (e. g., re peate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥ 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 ng.
1 6. Hist 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 ( HI V).
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 or he patitis B 
vir us ( defi ne d as p ositi ve f or b ot h he patitis B s urface a nti ge n A N D he patitis B c ore
a nti b o d y).
1 8. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns, or hist or y of hy p erse 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 (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
1 9. 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, 
w hic h 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 0. 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 og niti 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 1. 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 ni n g Visit 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.
2 2. Use of me dicati o ns wit h platelet a nti -a g gr e ga nt or a nti-c 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 3. Use of illicit narc otic me dicati o n.
2 4. 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 5. 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 A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 6. 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 wit hi n 1 2 m o nt hs of 
Scree ni n g 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  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- E 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 8. Partici pati o n i n a pre vi o us st u d y wit h a d uca n u ma b (s u bject is eli gi ble if he/s he di d n ot 
recei ve acti ve a d uca n u ma b).
St u dy Pr oce d ures
2 9. C o ntrai 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 0. 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 magi n g a ge nt, fail ure t o partici pate i n a n d c o m pl y wit h pre vi o us P E T 
sca ns).
3 1. A ne gati ve P E T sca n res ult w it h a n y a myl 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 2. 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 n i 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
3 3. F or s u bjects w h o c o nse nt t o L P, a n y  c o ntrai n dicati o ns t o ha vi n g a L P (e. g., platelet c o u nt 
< 1 0 0, 0 0 0/ µ L , l u m bar s pi ne def or mity).  A n y s y m pt o ms ca use d b y or relate d t o t he 
o pti o nal L P d uri n g Scree ni n g m ust be res ol ve d pri or t o ra n d o mizati o n.  S u bjects ma y  still 
partici pate i n t he o verall st u d y e ve n if partici pati o n i n t he o pti o nal L P p orti o n is 
c o ntrai n dicate d.  
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 will be per mitte d t o be 
rescree ne d o nce at t he S p o ns or’s discreti o n, e xce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R gl o bal sc ore > 0. 5, he patitis B or C, or a b n or mal M RI  fi n di n gs. ( S u bjects w h o fail 
S cree ni n g d ue t o a C D R gl o bal sc ore of 0 ma y  be rescree ne d; s uc h s u bjects will be 
all o we d t o re peat t he scree ni n g C D R assess me nt after 6 m o nt hs.)
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 of 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 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 7 8:
1.
S u bject m ust ha ve c o m plete d t he place b o -c o ntr olle d peri o d of t he st u d y i ncl u di n g t he 
Wee k
7 8 Visit.  S u bject m ust ha ve ta ke n at least 1 4 d oses a n d n ot ha ve misse d m ore t ha n 
4 c o nsec uti ve d oses, re gar dless of t he reas o n.  S u bjects w h o d o n ot meet t hese criteria 
ca n e nter t he L T E peri o d o nl y wit h S p o ns or’s a p pr o val.
2.
T he s u bject ( or t he s u bje ct’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 pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt ( or asse 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 oca l s u bject pri vac y re g ulati o ns.
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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0
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 ve sti gat or a n d st u d y staff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n.  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 t he use of t he sa me i nf or ma nt/care pa rt ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d.
8. 4.
E xcl usi o n Criteri a f or 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 at Wee k 7 8 t he y ha ve:
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 ormalit 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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I O N
9. 1.
Scree ni n g a n d E nr oll me nt
S u bjects ( or t heir le gall y a ut h orize d re prese ntati ve, w here a p plica ble) 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 
ca n c o m plete t he ne ur oc o g niti ve scales ( C D R, M M S E a n d R B A N S) a n d A p o E ge n ot y pi n g t o 
deter m i 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 3 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 also pr ocee d directl y  t o t he f ull 
c o nse nt pr ocess w hic h w o ul d 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 (I C 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.  A p o E ge n oty pi n g ma y  be perf or me d at Visit 1 pri or t o ot her scree ni n g assess me nts.
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 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 d a 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 relate d t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.  If a s u bject is e xcl u de d 
fr o m t he st u d y, t he reas o ns f or e xcl usi o n will 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.  T he t otal st u d y  d urati o n f or eac h s u bject partici pati n g o nly i n t he 
place b o -c o ntr olle d peri o d will be a p pr o xi matel y  1 0 2 wee ks (a p pr o xi matel y a n 8-wee k scree ni n g 
peri o d, 7 6 wee ks of place b o or a d uca n u m a b d osi n g, a n d 1 8 wee ks of F U ).  
9. 2.
R a n d o miz ati o n a n d Re gistr ati o n of S u bjects
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra n d o mize d o nl y after all 
baseli ne assess me nts ha ve bee n c o m plete d a n d t he In 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 .  N o s u bject ma y be gi n treat me nt pri or t o assi g n me nt 
of a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y  s u bject i de ntificati o n 
n u m bers or ra n d o mizati o n sc he d ule assi g n me nts t hat are assi g n e 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.  Rescree ne d s u bjects will be assi g ne d a ne w n u m ber.  
S u bjects will be ra n d o mize d t o recei ve a d uca n u ma b l o w d ose: a d uca n u ma b hi g h d ose: place b o 
i n a 1: 1: 1 rati o.  T he ra n d o mizati o n will be stratifie d b y site a n d A p o E ε 4 stat us (carrier or 
n o n- carrier).  E nr oll me nt will be m o nit ore d, via t he I R T, s uc h t hat t he p o p ulati o n of s u bjects 
wit h mil d A D re prese nts a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  S u bjects w h o 
wit h dra w fr o m t he st u d y ma y  n ot be re place d.
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
T his st u d y  c o nsists of a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d peri o d, f oll o we d b y a 
d ose -bli n de d L T E peri o d wit h all s u bjects recei vi n g a d uca n u ma b.  
F or t he d o u ble -bli n de d place b o -c o ntr olle d peri o d, all st u d y  staff w h o c o n d uct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts.  T he rati n g H C Ps s h o ul d 
re mai n bli n de d t o treat me nt assi g n me nt as well as s u bject care ma na ge me nt a n d o nl y  ha ve access 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  As a 
place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are re q uire d t o ma na ge all 
as pects of st u d y treat me nt recei pt, dis pe nsi n g, a n d pre parati o n.  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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
 or Bi o ge n safet y staff.
F or t he L T E peri o d , t he d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d treati n g H C P 
s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nl y ha ve access t o t he i nf or mati o n 
necessar y  t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n t he st u d y  
bli n d, it is i m perati ve t hat d ose i nf or mati o n is n ot s hare d wit h t h e s u bjects, t heir fa milies, or a n y 
me m ber of t he bli n de d st u d y  tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
 or Bi o ge n safety s taff.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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/ O R 
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:

A RI A- E acc o m pa nie d b y seri o us cli nical s y m pt o ms e xce pt f or “ ot her me dicall y  
i m p orta nt e ve nt” as defi ne d i n Ta ble 8 .

S y m pt o matic A RI A -H ( micr o he m orr ha ges) wit h seri o us cli nical s y m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 9 .

S y m pt o matic A RI A -H (s u perficial si der osis) wit h or seri o us cli nical s y m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 1 0 .

A RI A - H wit h ≥ 1 0 micr o he m orr ha ges a n d/ or > 2 f ocal areas of s u perficial 
si der osis.  

A n y  ne w i nci de nt macr o he m orr ha ge.

A t hir d e pis o de of A RI A after rec halle n ge t hat re q uires s us pe nsi o n (i.e., after 
e x perie nci n g 2 pri or e pis o des of A RI A meeti n g t he criteria f or d ose s us pe nsi o n 
(see Secti o n 7. 2. 1. 1 , Secti o n 7. 2. 1. 2 , a n d Secti o n 7. 2. 1. 3 ).
See Secti o n 7. 2. 1 f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d ucti o n d ue t o 
A RI A- E or A RI A -H.

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 
a n d pre g na nc y m ust be re p orte d 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.

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.  

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 vesti gat or f or me dical reas o ns.

At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce .
T he reas o n f or disc o nti n uati o n of st u d y  treat me nt m ust be rec or de d i n t he s u bject’s case re p ort 
f or m ( C R F).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
A s u bject w h o disc o nti n ues treat me nt is t o re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol-re q uire d 
tests a n d assess me nts u ntil t he e n d of t he st u d y per t he sc he d ule of e ve nts or u ntil t he s u bject 
wit h dra ws c o nse nt .  
1 0. 2.
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 ws c o nse nt.

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 S p o ns or.
N ote: A s u bject w h o 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 all assess me nts.  
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 s h o ul d 
c o m plete t he E O T Visit after t he reas o n f or wit h dra wal is i de ntifie d.  For s uc h s u bjects, efficac y  
assess me nts s pecifie d at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt 
wit hi n 3 m o nt hs of t he pre vi o us efficac y  assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve 
status are s us pecte d b y t he I n vesti gat or; T he site s h o ul d n otif y t he s p o ns or i n s uc h cases.  
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 F U Visit 1 8 wee ks 
after recei vi n g t heir last d ose of st u d y  treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 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.  
Please see Secti o n 4. 2 ( Sc he d ule of E ve nts) f or t he st u d y treat me nt i nf usi o n sc he d ule d uri n g t he 
place b o -c o ntr olle d a n d L T E peri o ds of t he st u d y.
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  
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.  
1 1. 1. 2.
Pl ace 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 dy 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
Refer t o Secti o n 7. 2. 1 ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 2 (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at least 2 1 da y s a part.  If t he d osi n g i nter val ca n n ot be met, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y t he st u d y me dical m o nit or.
1 1. 3.
Prec a uti o ns
N ot a p plica ble.
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.
Pri or a n d 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 F U 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6
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 are all o we d 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.  

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 n e pezil, ri vasti g mi ne, 
gala nta mi ne, tacri ne, a n d me ma nti ne, are all o we d 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 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 are all o we d d uri n g t he st u d y.  
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 ys pri or t o a n y 
d osi n g visit a n d f or 1 0 da ys after a d osi n g visit.
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 nti -a g gre ga nt or a nti-c 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 dicati 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 m a y  be per mitte d at t he S p o ns or’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 nt i n ue t he me dicati o ns t hat t he y were recei vi n g at e nr oll me nt 
(see all o we d c o nc o mita nt t hera py 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, as it 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 or of a ny 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 b y 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 w o ul d n ot res ult i n a ut o matic wit h dra wal.  T he 
S p o ns or 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, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he 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 ur e 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 F U visit) , u nless t he s u bjects is bei n g f oll o we d f or st u d y-relate d t o xicit y.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 re g ulat or y  re q uire me nts re gar di n g p ostst u d y access will be met.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 dr u g it s h o ul d n ot be use d.  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 2 h o urs, t he n i t 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 
( or its desi g nee), 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 pers o n nel 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 nt 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.  
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 s t u d y treat me nt 
acc o u nta bilit y.  B y t he e n d of t he st u d y rec o nciliati o n m ust be ma de bet wee n t he a m o u nt of 
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 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 
T he place b o ( 0. 9 % sterile s o di u m c hl ori de f or i njecti o n) will be pr o vi de d b y  t he site i n t he f or m 
of 1 0 0 m L sali ne I V ba gs.  
1 2. 3.
A d diti o n al Pr ot oc ol -Desi g n ate d Pr o d ucts
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.
T o c o nfir m a m yl oi d pat h ol o g y  at Scree ni n g, P E T sca ns will be perf or me d usi n g A my vi d ™ 
(1 8F- fl or beta pir), Viza myl ™ ( 1 8F- fl ute met o m ol), or Ne urace q ™ (1 8F- fl or beta be n).  F or t h ose 
s u bjects partici pati n g i n t he a m yl oi d P E T s u bst u d y , Scree ni n g a n d F U sca ns m ust be perf or me d 
usi n g A m y vi d a n d f or s u bjects partici pati n g i n t he P E T s u bst u d y i n Ja pa n, Viza m yl 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
(1 8F- fl ute met o m ol) ma y als o be use d.  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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 
P H A R M A C O D Y N A MI C A S S E S S M E N T S
Refer t o Secti o n 4. 2 f or t he ti mi n g of assess me nts.
1 3. 1.
Cli nic al Effic ac 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 efficac y  of a d uca n u ma b: 

C D R 

M M S E

A D A S -C o g 1 3

A D C S -A D L -M CI

N PI - 1 0
It is rec o m me n de d t hat clinical assess me nts be perf or me d at t he sa me ti me of da y  f or s u bjects 
d uri n g t heir st u d y visits.  
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s daily acti vities a n d c o g niti ve ca pa bilities.  
T he rec o m me n de d or der of a d mi nistrati o n of t he cli nical assess me nts is descri be d i n t he St u d y  
Refere nce G ui de.  
1 3. 2.
P h ar m ac o k i netic Assess me nts
Ser u m c o nce ntrati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y .  
1 3. 3.
P h ar m ac o d y n a mic Assess me nts
T he f oll o wi n g tests will be perf or me d t o assess t he P D pr o perties of a d uca n u ma b:

Serial meas ure me nt of a m y l oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y a m yl oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects partici pati n g i n 
t he a m yl oi d P E T c oh ort).  
O nl y  sites wit h ca pa bilities of perf or mi n g 1 8F- fl or beta pir P E T will be all o we d t o 
perf or m t his assess me nt.  I n vesti gat or partici pati o n i n t his part of t he st u d y is o pti o nal 
a n d c o nti n ge nt u p o n a p pr o val b y  his/ her et hics c o m mittee ( E C) or i nstit utio nal re vie w 
b oar d (I R B).  If t he I n vesti gat or is n ot partici pati n g or t he test is n ot a p pr o ve d b y  
his/ her E C/I R B, t he rele va nt secti o n of t he I C F will n ot be a p plica ble t o t hat site.
S u bject partici pati o n i n t his part of t he st u d y  is o pti o nal at partici pati n g sites.  
I nf or me d c o nse nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a se parate pr oce d ural ma n ual f or P E T.  A p pr o xi matel y 
4 0 0 s u bjects are e x pecte d t o partici pate i n t he a m yl oi d P E T s u bst u d y.  








Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
1 4.
S A F E T Y A S S E S S M E N T S
See Secti o n 4. 2 f or t he ti mi n g of 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 m o nit ori n g.

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.

Ne ur ol o gical e xa mi nati o n.

Vital si g ns ( b o d y te m perat ure, heart rate, S B P, D B P, a n d res pirat or y  rate).

1 2- lea d E C G.

Brai n M RI.

C o nc o mita nt me dicati o n, t hera p y , a n d pr oce d ure m o nit ori n g.  

M O C A (f or A RI A m o nit ori n g a n d ma na ge me nt).  

C ol u m bia S uici de Se verit y  Rati n g Scale ( C-S S R S) .  
1 4. 2.
L a b or at or y S afet y Assess me nts
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.

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, A L T, A S T, lactate de h y dr o ge nase, 
ga m ma -gl uta m y l-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 vity, 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 mal).

Ser u m a n d uri ne pre g na nc y  test f or 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 nclu 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), H b A 1c, a n d alc o h ol/ dr u g scree n at Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4. 3.
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a nti -a d uca n u ma b will be deter mi ne d usi n g a vali date d assa y .  A sta n dar d 
3- tier a nti dru 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).  It is pla n ne d t hat c o nfir me d A D A -p ositi ve sa m ples m a y be e val uate d f or t he 
prese nce of a nti -a d uca n u ma b ne utralizi n g a nti b o dies usi n g a vali date d assa y .  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 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 m ust be gi ve n 
t he na mes a n d tele p h o ne n u m bers of st u d y 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 necessaril y  ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal 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 uct, w het her or n ot relate d t o t he me di ci 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 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.  Alt h o u g h a b n or mal la b orat or y val ues are t y picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or a n S A E.

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y.

A la b orat or y a b n or malit y t hat t he I n vesti g at or c o nsi ders t o be cli nicall y si g nifica nt.
Pre -treat me nt, n o nseri o us A Es t hat occ ur wit hi n 4 8 h o urs after recei pt of a li ga n d will be 
ca pt ure d b y t he sites o n t he A E f or m.  
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.

Res ults i n a c o n ge nital a n o mal y / birt h defect.


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8 8
A n S A E ma y  als o be a n y ot her me dically i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he 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 v e 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 oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he 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 pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.

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 u nless 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 hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 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 .






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
T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e mail a c o m plete d S A E f or m.  Refer t o t he 
St u d y  Refere nce G ui de f or c o u ntr y -s pecific 
 fa x n u m bers or e mail 
1 5. 3. 4. 1.
De at hs
Deat h is a n o utc o me of a n e ve nt.  T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F.  All ca uses of deat h m ust be r e p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt.  T he I n vesti gat or s h o ul d ma ke e ver y  eff ort t o o btai n a n d se n d 
deat h certificates a n d a ut o ps y  re p orts t o 
.  T he ter m deat h s h o ul d be 
re p orte d as a n S A E o nly if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d by t he I n vesti gat or or Bi o ge n t o be relate d t o t he stu d y  treat me nt a d mi nistere d.
A p pr o priate pers o n nel i n Bi o ge n Safet y  a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y  re p orti n g.  Bi o ge n or desi g nee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y  a ge ncies acc or di ng t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n.
1 5. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 5. 4. 1.
Pre g n a nc y
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y a n d 
f or 2 4 wee ks after t heir l ast d ose of st u d y tre at me nt.  If a fe male 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 di ately.
T he I n vesti gat or m ust re p ort a pre g na nc y  occ urri n g i n a fe male s u bject b y fa xi n g t he a p pr o priate 
f or m t o 
 wit hi n 2 4 h o urs of t he st u d y site staff bec o mi n g a ware of t he 
pre g na nc y  at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u dy refere nce ma n ual.  T he 
I n vesti gat or or st u dy site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
 
.  
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 ncepti 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 gi ve n 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 descri be d i n 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 
 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 
 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 


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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 
 
).  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, st u d y 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 
 e mer ge nc y me dical s u p p ort n u m ber.  Refer t o t he St u d y 
Refere nce G ui de’s Official 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 vise 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, n 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.
1 5. 5.
C o ntr ace pti o n Re q uire me nts
F or t he p ur p oses of t his st u d y, w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h y si ol o gically ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns:

P ost me n o pa usal

1 2 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 or 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 my.

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).
F or t he p ur p oses of t his st u d y , hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g:

F or fe males of c hil d beari n g p ote ntial:

Esta blis he d use of oral, i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n.

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne s y ste m


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
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 occl 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.

Male se x ual part ners u n der we nt s ur gical sterilizat i 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:

Vasect o m y wit h ne gati ve se me n a nal ys is at F U.

Use of c o n d o ms wit h s per mici de.

Fe male se x ual part ners w h o u n der we nt s ur gical sterilizati o n (e. g., bilat eral t u bal 
li gati o n), are p ost me n o pa usal, are p ost-h y sterect o m y, or are usi n g hi g hl y effecti ve 
c o ntrace pti o n as liste d a b o ve f or fe male s u bjects.
F or males a n d fe males 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 a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he I n vesti gat or w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n 
of t he cli nical trial.  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d acce pta ble met h o ds of 
c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 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 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, re gar dless of t he se verit y  or relati o ns hi p 
t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d r ec or d all pre g na ncies a n d F U o n t he o utc o me of t he pre g na nc y  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 S A B R ( or desi g nee) wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.

P urs ue S A E F U i nf or mati o n acti vel y a n d persiste ntl y.  F U i nf or mati o n m ust be 
re p orte d t o Bi o ge n S A B R ( or desi g nee) wit hi n 2 4 h o urs of t he st u d y site staff 
bec o mi n g a ware of ne w i nf or mati o n.


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
E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or d s.

P urs ue A E F U 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.

Re p ort S A Es t o l ocal E C/I R Bs, 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 st u d y site acti vati o n a n d s u bject e nr oll me nt, t h e Cli nical M o nit or ( 
) is 
res p o nsi ble f or re vie wi n g wit h st u d y 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 ( or desi g nee) is t o n otif y  all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C/I R Bs, 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.


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9 5
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 .
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 [ S D], 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.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al y sis P o p ul ati o n
T he i nte nt -t o-treat (I T T) 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 st u d y treat me nt (a d uca n u ma b or place b o), will be use d f or t he efficac y 
a nal ys es.  F or eac h e n d p oi nt, a d diti o nal c o n diti o ns ma y  a p pl y t o t he defi niti o n of t he p o p ulati o n 
f or t he a nal ysis.  S u bjects will be a nal yze d i n t he gr o u ps t o w hic h t he y were ra n d o mize d.  
1 6. 2. 2.
Met h o ds of A n al ysis
1 6. 2. 2. 1.
Ge ner al C o nsi der ati o ns
S u m mar y  statistics will be prese nte d. F or c o nti n u o us e n d p oi nts, s u m mar y statistics will 
ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, sta n dar d de viati o n, me dia n, a n d ra n ge.  
F or cate g orical e n d p oi nts, t his will ge nerall y  i ncl u de: n u m ber of s u bjects ra n d o mize d or d ose d, 
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.  Statistical testi n g f or 
efficac y e n d p oi nts will be ma de bet wee n eac h a d uca n u ma b d ose ( hi g h a n d l o w) a n d place b o.  
All statistical tests will be 2 -si de d.
1 6. 2. 2. 2.
A d uc a n u m a b D oses t o be E v al u ate d
T he f oll o wi n g a d uca n u ma b d oses as c o m pare d wit h place b o will be e val uate d:

A d uca n u ma b hi g h -d ose ( 1 0 m g/ k g i n A p o E ε 4 [i ncl u di n g 6 m g/ k g f or s u bjects 
e nr olle d u n der pr ot oc ol versi o n 1- 3 w h o d o n ot ha ve t he o p p ort u nit y  t o u ptitrate t o 
1 0 m g/ k g pri or t o c o m pleti n g Wee k 7 8 of t he st u d y ] a n d 1 0 m g/ k g i n 
A p o E ε 4 n o n-carriers).

A d uca n u ma b l o w -d ose ( 3 m g/ k g i n A p o E ε 4 carriers a n d 6 m g/ k g i n 
A p o E ε 4 n o n-carriers). 
I n t he e ve nt t hat t he ma xi m u m d ose ( 1 0 m g/ k g) is ter mi nate d after t he start of t he st u d y 
( Secti o n 5. 3. 2 ) t he defi niti o n of a d uca n u ma b hi g h d ose a n d a d uca n u ma b l o w d ose will be 
m o difie d as s h o w n i n Ta ble 1 2 .  T he d osi n g m o dificati o n will be e ntirely base d o n i nteri m 
a nal ys is of o utc o mes t hat are i n de pe n de nt of, a n d u ni nf or mati ve a b o ut, t he treat me nt-relate d 
efficac y effect.  C o ntr ol of T ype I err or rate is t h us mai ntai ne d wit h o ut a statistical a dj ust me nt 
f or s uc h a da ptati o ns [C h o w a n d C ha n g 2 0 1 1 ].


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 1 2:
Tre at me nt Gr o u p s i n t he E ve nt of Hi g h D ose Gr o u p Ter mi n ati o n
Hi g h D ose Gr o u p(s) Ter mi n ate d
Defi niti o ns of Re vise d Tre at me nt 
( L o w/ Hi g h D ose) Gr o u ps f or C o m p aris o n
A p o E ε 4 carrier hi g h -d ose gr o u p ( 1 0 m g/ k g) 
[i ncl u di n g 6 m g/ k g f or s u bjects e nr olle d u n der pr ot oc ol 
versi o n 1 -3 w h o d o n ot ha ve t he o p p ort u nit y t o u ptitrate 
t o 1 0 m g/ k g pri or t o c o m pleti n g Wee k 7 8 of t he st u d y]
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g / k g
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 1 0 m g/ k g
A p o E ε 4 n o n -carrier hi g h -d ose gr o u p ( 1 0 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 1 0 m g/ k g a n d 
n o n- carrier 6 m g/ k g
A p o E ε 4 carrier hi g h - d ose gr o u p ( 1 0 mg/ k g) 
A N D
A p o E ε 4 n o n -carrier hi g h -d ose gr o u p ( 1 0 m g/ k g) 
A p o E ε 4 carrier 3 m g/ k g a n d n o n- carrier 
6 m g/ k g
1 6. 2. 2. 3.
C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I  err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y  e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws: a d uca n u ma b hi g h -d ose vers us place b o a n d a d uca n u ma b l o w - dose vers us place b o.  All 
c o m paris o ns after t he i nitial c o m paris o n wit h p > 0. 0 5 will n ot be c o nsi dere d statisticall y  
si g nifica nt.
Sec o n dar y  e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  In or der t o 
c o ntr ol f or a T ype I err or f or t h e sec o n dar y e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be use d a n d will i ncl u de b ot h t he or der of t he sec o n dar y e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y e n d p oi nts, a se q ue ntial (cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T ype I err or rate d ue t o m ulti ple 
treat me nt c o m paris o ns.  If statistical si g nifica nce is n ot ac hie ve d f or 1 or 2 c o m paris o ns, all 
e n d p oi nt(s) of a l o wer ra n k will n ot be c o nsi dere d statisticall y si g nifica nt f or 1 or 2, res pecti vely.  
1 6. 2. 2. 4.
A n al ysis of t he Pri m ar y E n d p oi nt
T he p o p ulati o n f or t he pri mar y  e n d p oi nt a nalys is will be s u bjects i n t he I T T p o p ulati o n wit h a 
baseli ne a n d at least o ne p ost- baseli ne C D R - S B sc ore.  A mi xe d m o del re peate d meas ures 
( M M R M) m o del will be use d as t he pri mar y a nalysis t o a nal y ze c ha n ge fr o m baseli ne C D R -S B 
usi n g fi xe d effects of treat me nt, ti me, treat me nt- b y -ti me i nteracti o n, baseli ne C D R-S B, baseli ne 
C D R -S B b y  ti me, baseli ne M M S E, a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5.
A n al ysis o f t he Sec o n d ar y E n d p oi nts
1 6. 2. 2. 5. 1. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n M M S E 
T he p o p ulati o n f or t he a nal ysis will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least 
o ne p ost -baseli ne M M S E val ue.  A M M R M m o del will be use d as t he pri mar y  a nalys is t o 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
a nal y ze c ha n ge fr o m baseli ne M M S E usi n g fi xe d effects of treat me nt, ti me, treat me nt -b y -ti me 
i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y ti me i nteracti o n a n d baseli ne A p o E ε 4 
stat us 
1 6. 2. 2. 5. 2. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n A D A S -C o g 1 3
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost -baseli ne A D A S - C o g 1 3 sc ore.  A n M M R M m o del will be use d as t he pri mar y  a nalys is t o 
a nal yz e c ha n ge fr o m baseli ne A D A S -C o g 1 3 usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D A S- C o g 1 3, baseli ne A D A S-C o g 1 3 b y  ti me 
i nteracti o n, baseli ne M M S E , a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 5. 3. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n A D C S -A D L -M CI
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n wit h a baseli ne a n d at least o ne 
p ost - baseli ne A D C S-A D L -M CI sc ore.  A n
M M R M m o del will be use d as t he pri mar y  a nal ysis 
t o a nal yze c ha n ge fr o m baseli ne A D C S -A D L -M CI usi n g fi xe d effects of treat me nt, ti me, 
treat me nt-b y -ti me i nteracti o n, baseli ne A D C S-A D L -M CI, baseli ne A D C S -A D L -M CI b y  ti me 
i nteracti o n, baseli ne M M S E , a n d baseli ne A p o E ε 4 stat us.
1 6. 2. 2. 6.
Terti ar y E n d p oi nts A n al ysis
1 6. 2. 2. 6. 1. Pl ace b o -C o ntr olle d Peri o d
W here a p pr o priate, a n M M R M m o del will be use d as t he pri mar y  a nalys is t o a nal yze c ha n ge 
fr o m baseli ne usi n g fi xe d effects of treat me nt, ti me, treat me nt by ti me i nteracti o n, baseli ne 
val ue, baseli ne val ue b y t i me i nteracti o n, baseli ne M M S E a n d baseli ne A p o E ε 4 stat us.
Ot her wise , a n a nal ys is of c o varia nce ma y be use d t o a nal yze t hese e x pl orat or y e n d p oi nts or 
descri pti ve s u m mar y  statistics ma y be prese nte d.
1 6. 2. 2. 6. 2. L o n g -Ter m E xte nsi o n Peri o d
T he e n d p oi nts f or t he L T E peri o d are c ha n ge fr o m baseli ne o ver t he place b o -c o ntr olle d a n d L T E 
peri o ds of t he st u d y.  A nal yses will be prese nte d b y  treat me nt gr o u p i n t he place b o-c o ntr olle d 
peri o d usi n g t he place b o -c o ntr olle d peri o d baseli ne.  Details of t he a nal ys es will be pres pecifie d 
i n t he statistical a nal ysis pla n (S A P ).  
1 6. 3.
P h ar m ac o k i netics
1 6. 3. 1.
A n a l ysis P o p ul ati o n
T he p o p ulati o n f or P K a nal y sis 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 
st u d y treat me nt, 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 meter s of a d uca n u ma b will be s u m marize d descri pti vel y.   




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
1 6. 6.
I m m u n o ge nicit y D at a
1 6. 6. 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 ulati 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 nicity.  
1 6. 6. 2.
Met h o ds of A n al ysis
A nti- a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.
1 6. 7.
I nteri m A n al yses
1 6. 7. 1.
I nteri m F utilit y A n al ysis
A n i nteri m a nal ys is f or f utilit y of t he pri mar y e n d p oi nt will occ ur after a p pr o xi matel y  5 0 % of t he 
s u bjects ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m f utilit y a nalys is.  T his i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he I D M C ma y rec o m me n d ter mi nati n g 
t he st u d y f or f utilit y if it is e vi de nt t hat t he efficac y of a d uca n u ma b is u nli kel y t o be ac hie ve d.  
T he f utilit y  criteria will be disc usse d i n detail i n t he S A P.
1 6. 7. 2. 
I nteri m S u peri orit y A n al ysis
A n i nteri m a nal ys is f or s u peri orit y m a y be perf or me d after a p pr o xi matel y 5 0 % of t he s u bjects 
ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  T he O’ Brie n -Fle mi n g b o u n dar y  a p pr oac h 
will be use d f or t he a nal ysis.  I n or der t o mai ntai n t he treat me nt bli n d i n t he e ve nt of t his i nteri m 
a nal ys is, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m s u peri orit y a nalys is.  T he i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he ai m of t his i nteri m a nal ysis is t o all o w 
t he p ossi bilit y t o de m o nstrate treat me nt effect earl y.  T he a nalys is will be disc usse d i n detail i n 
t he S A P.
1 6. 8.
S a m ple Size C o nsi der ati o ns
T he st u d y ’s sa m ple size is base d, i n part, o n res ults fr o m a pr ot oc ol-s pecifie d i nteri m a nalys is 
fr o m St u d y 22 1 A D 1 0 3 , w hic h i ncl u de d 1 -ye ar data fr o m 1, 3 , a n d 1 0 m g/ k g treat me nt gr o u ps.
A sa m ple size of 4 5 0 s u bjects per treat me nt gr o u p will ha ve a p pr o xi matel y  9 0 % p o wer t o detect 
a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne C D R- S B at Wee k 7 8 bet wee n t he 
2 treat me nt gr o u ps.  T his p o wer calc ulati o n is base d o n a 2- si de d t-test ass u mi n g e q ual varia nce 
wit h a fi nal si g nifica nce le vel of 0. 0 5, a n S D of 1. 9 2 , a n d a dr o p-o ut rate of 3 0 %.  T he S D 
esti mate of 1. 9 2 f or Wee k 7 8 reflects a 3 9 % i ncrease o ver t he S D fr o m t he pr ot oc ol -s pecifie d 
i nteri m a nal ysis of 1-year data.
T he ass u me d tr ue mea n differe nce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d ucti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o mea n c ha n ge is es ti mate d t o be 2.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0
T he sa m ple size f or t his st u d y  (a n d f or t he i de nticall y desi g ne d St u d y 2 2 1 A D 3 0 2) ma y be 
reassesse d i n a bli n de d ma n ner a p pr o xi matel y 3 m o nt hs bef ore e nr oll me nt is c o m plete if at least 
1 0 % of t he data are a vaila ble o n t he pri mar y  e n d p oi nt fr o m eac h st u dy.  At t his i nteri m 
ti me p oi nt, t he S D f or t he pri mar y e n d p oi nt will be esti mate d base d o n t he p o ole d bli n de d data 
(i.e., treat me nt gr o u ps c o m bi ne d) fr o m St u dies 2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2.  T he sa m ple size ma y 
be i ncrease d if t he S D is esti mate d t o be m ore t ha n a p pr o xi matel y  2. 0 7 t o ass ure a de q uate p o wer 
f or detecti n g a treat me nt effect.  I n a d diti o n, t he sa m ple size c o ul d be i ncrease d usi n g e xter nal 
cli nical trial res ults t hat bec o me a vaila ble after t he start of t he st u d y.  Base d o n t his reassess me nt, 
t he sa m ple size ma y be i ncrease d b y u p t o a p pr o xi matel y 3 0 % a n d t he re vise d sa m ple size f or 
eac h st u d y will n ot e xcee d 1 7 6 4 s u bjects ( or 5 8 8 s u bjects per gr o u p). 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
1 7.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n,  
, 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 ulati o 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 ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y-relate d d uties ha ve bee n dele gate d.
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/I nstit uti o n al Re vie w B o ar d
T he I n vesti gat o r m ust o btai n E C/IR B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y  
d oc u me nts pri or t o starti n g t he st u d y.  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 E C.  A c o p y  of t he a p pr o ve d IC 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 gree me nt of t he rele va nt E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) 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 C/I R B a p pr o val, w hic h s pecificall y  i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y .  Pr ot oc ol a me n d me nts 
will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he E C/I R B at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he E C/IR B a n d Bi o ge n.
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 prese ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns.  S u b jects ca n c o m plete t he ne ur oc o g niti ve scales 
( C D R, M M S E, a n d R B A N S) as well as A p o E ge n ot ypi n g as a n i nitial o pti o nal scree 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 3 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 2
S u bjects ma y  als o pr ocee d directl y 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 p ate 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/ or et h nicit y will be c ollecte d a n d will be use d 
d uri n g a nal ys is of st u d y res ults ( o nl y i n c o u ntries w here per mitte d b y l ocal la w/re g ulati o n).
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, care gi ver a n d/ or le gall y 
a ut h orize d re prese ntati ve.  T he si g ne d a n d date d I C F will be retai ne d wit h t he st u d y  rec or ds.  
L ocal re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal ( wet 
si g nat ure) a n d c o pies of t he si g ne d a n d date d I CFs.
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 b y 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).
T he s u bject will n ot be i de ntifie d b y  na me i n t he C R F or i n a n y st u d y re p orts a n d t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n, its part ner(s) a n d desi g nee(s), E C/I R Bs, 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.
D uri n g t he st u d y, s u bjects’ race a n d/ or et h nicit y  will be c ollecte d ( o nly i n c o u ntries w here 
per mitte d b y  l ocal la w/re g ulati o n).  T hese data ma y be use d i n t he a nalys is of t he safety, 
efficac y, a n d/ or p har mac o ki netic pr ofile of t he st u d y treat me nt.  It is u n k n o w n if t he p ote nc y or 
effects of t he st u d y treat me nt are i nfl ue nce d b y race or et h nicit y.  
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 vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
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 stu 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 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 3
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 bjects 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 Ass ur a nce
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.  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 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.
T he Cli nical M o nit or(s) will visit t he I n vesti gat or(s) 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.
D uri n g t hese visits, C R Fs a n d s u p p orti n g 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.  
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 pr ot oc ol a d here nce, q ualit y of data, 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.
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 ntract(s) bet wee n t he i nstit uti o n, I n 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 .




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 5
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.
1 9. 2.
St u d y C o m mittees
1 9. 2. 1.
A d vis or y C o m mittee
A n a d vis or y  c o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u dy 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y c o m mittee will meet 
peri o dicall y t o m o nit or s u bject accr ual a n d o versee st u d y c o n d uct, i ncl u di n g a d visi n g o n st u d y 
desi g n a n d e xec uti o n.  T he a d vis or y  c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g t he st u d y.  
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x perts i n Alz hei mer’s disease.  
Bi o ge n will desi g nate o ne of t he partici pati n g e xter nal e x perts t o be t he c hair pers o n of t he 
a d vis or y c o m mittee.
1 9. 2. 2.
I n de pe n de nt D at a M o nit ori n g C o m mittee 
T he I D M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y data.  Me m bers of t he I D M C 
will n ot be all o we d t o partici pate as In vesti gat ors i n t his st u d y .  T he I D 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.  T he I D M C, base d o n 
t he nat ure, fre q ue nc y, a n d/ or se verity of a n A E(s) 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.  A n ID 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 I D M C.  
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 E C/I R B a n d re g ulat or y  a ut h orities if re q uire d 
b y  l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B 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 dy.  If re q uire d b y l ocal la w, s uc h m o dificati o ns m ust 
als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o i m ple me ntati o n.
H o we ver, 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 IC F ma y  re q uire si milar m o dificati o ns (see 
Secti o ns 1 7. 2 a n d 1 7. 3 ).
1 9. 4.
Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 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 E C/IR Bs 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.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6
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 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 horizati o n 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 the 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 St u d y  In vesti gat ors as a si g nat or y  f or t he 
st u d y re p ort.  T his deter mi nati o n will be ma de b y se veral fact ors i ncl u di n g b ut n ot li mite d t o t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or 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 ge n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 7
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 mer'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.
C h o w S, C ha n g M. A da pti ve Desi g n Met h o ds i n Cli nical Trials, Sec o n d E diti o n. Sec o n d E diti o n 
e d. B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1.
D u b ois B, Fel d ma n H H, Jac o va C, et al. Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n. La ncet Ne ur ol. 2 0 1 0; 9( 1 1): 1 1 1 8- 2 7.
D u b ois B, Fel d ma n H H, Jac o va C, et al. A d va nci n g researc h dia g n ostic criteria f o r Alz hei mer's 
disease: t he I W G -2 criteria. La ncet Ne ur ol. 2 0 1 4; 1 3( 6): 6 1 4 - 2 9.
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 ni etz 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.
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.
Le n der ki n g W R, Stee nr o d A, R ü dell K, et al. O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI  
a n d Pr o dr o mal Alz hei mer’s Disease: C o nte nt Vali dit y  of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y Sy m pt o ms of C o g niti ve Decli ne. A d va nces i n Alz hei mer’s Disease. 
2 0 1 4; 3: 1 -1 0. E p u b Marc h 2 0 1 4.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 8
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 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 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.
M orris J C, Ble n n o w K, Fr oelic h L, et al. Har m o nize d dia g n ostic criteria f or Alz hei mer's disease: 
rec o m me n dati o ns. J Inter n Me d. 2 0 1 4; 2 7 5( 3): 2 0 4 - 1 3.
Ostr o witz ki S, De pt ula D, T h urfjell L, et al. Mec ha nis m of a m y l oi d re m o val i n patie nts wit h 
Alz hei mer disease treate d wit h ga nte n er u ma b. Arc h Ne ur ol. 2 0 1 2; 6 9( 2): 1 9 8 -2 0 7. E p u b 2 0 1 1 Oct 
1 0.
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 xace r bati o n of cere bral a m yl 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 osite d f or ms of a m yl 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 n e 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.
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 gin g a b n or malities i n a m y l 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, et 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.
Wel ler R O, S u bas h M, Prest o n S D, et al. Peri vasc ular drai na ge of a myl oi d -beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a myl oi d a n gi o pat h y  a n d Alz hei mer's disease. Brai n Pat h ol. 
2 0 0 8; 1 8( 2): 2 5 3 - 6 6.
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/ 0 2/ 2 7.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
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 3 M ultice nter, Ra n d o mize d, D o u ble-Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b
( BII B 0 3 7) i n S u bjects wit h Earl y Alz hei mer's Disease”, 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 an d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 nsent of 
Bi o ge n M A  I nc.
3
T A B L E O F C O N T E N T S
1.
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 0
2.
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 1
3.
S Y N O P SI S ................................................................................................................. 1 4
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 
2 2 1 A D 3 0 1 ................................................................................................................... 1 7
4. 1.
St u d y  Sc he matic ......................................................................................................... 1 7
4. 2.
Sc he d ule of E ve nts ..................................................................................................... 1 9
4. 3.
A d diti o nal I nf or mati o n ...............................................................................................5 0
4. 3. 1.
Site Pers o n nel ............................................................................................................. 5 0
5.
I NT R O D U C TI O N ...................................................................................................... 5 2
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 5 3
5. 1. 1.
N o ncli nical E x perie nce ...............................................................................................5 3
5. 1. 2.
Cli nical E x perie nce ..................................................................................................... 5 4
5. 2.
St u d y  Rati o nale........................................................................................................... 5 6
5. 3.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................ 5 6
5. 3. 1.
D osi n g Sc he me........................................................................................................... 5 7
5. 3. 1. 1.
Place b o -C o ntr olle d Peri o d .......................................................................................... 5 7
5. 3. 2.
D osi n g Sc he me M o dificati o n ..................................................................................... 5 8
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 5 9
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 ..............................................................6 0
6. 1.
Pri mar y  O bjecti ve a n d E n d p oi nt ................................................................................ 6 0
6. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts ......................................................................... 6 0
6. 3.
Tertiar y  O bjecti ves a n d E n d p oi nts ............................................................................. 6 0
6. 3. 1.
Tertiar y  O bjecti ves .....................................................................................................6 0
6. 3. 2.
Tertiar y  E n d p oi nts......................................................................................................6 1
6. 4.
A d diti o nal E x pl orat or y  O bjecti ves a n d E n d p oi nts.....................................................6 1
6. 4. 1.
A d diti o nal E x pl orat or y  O bjecti ves............................................................................. 6 1
6. 4. 2.
A d diti o nal E x pl orat or y  E n d p oi nts..............................................................................6 2
6. 5.
L o n g -Ter m E xte nsi o n O bjecti ves a n d E n d p oi nts .......................................................6 3
6. 5. 1.
Tertiar y  LT E O bjecti ves................................ .............................................................6 3
6. 5. 2.
Tertiar y  LT E E n d p oi nts ..............................................................................................6 3


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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. 5. 3.
A d diti o nal E x pl orat or y  LT E O bjecti ve ...................................................................... 6 3
6. 5. 4.
A d diti o nal E x pl orat or y  LT E E n d p oi nts ...................................................................... 6 3
7.
S T U D Y D E SI G N ....................................................................................................... 6 5
7. 1.
St u d y  O ver vie w.......................................................................................................... 6 5
7. 2.
St u d y  S pecifics ........................................................................................................... 6 6
7. 2. 1.
D ose S us pe nsi o n, M o dificati o n, or Ter mi nati o n f or A RI A E ve nts ............................ 6 6
7. 2. 1. 1.
A RI A -E Cases ............................................................................................................ 6 7
7. 2. 1. 2.
A RI A -H ( Micr o he m orr ha ge) ...................................................................................... 6 8
7. 2. 1. 3.
A RI A - H ( S u perficial Si der osis) ................................................................................. 7 1
7. 2. 1. 4.
A RI A - H ( Macr o he m orr ha ge)..................................................................................... 7 3
7. 2. 1. 5.
C oi nci de nt A RI A -H a n d A RI A- E Cases .................................................................... 7 3
7. 2. 1. 6.
Res u m pti o n of St u d y  Treat me nt After S us pe nsi o n d ue t o A RI A............................... 7 3
7. 2. 1. 7.
Ma na ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI )............................................ 7 5
7. 2. 2.
I nf usi o n I nterr u pti o n................................................................................................... 7 6
7. 3.
O verall St u d y  D urati o n a n d F oll o w-U p ..................................................................... 7 6
7. 3. 1.
Scree ni n g .................................................................................................................... 7 7
7. 3. 2.
Treat me nt .................................................................................................................... 7 8
7. 3. 3.
F oll o w -U p ................................................................................................................... 7 8
7. 4.
St u d y  St o p pi n g R ules ................................................................................................. 7 9
7. 5.
E n d of St u d y ............................................................................................................... 7 9
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 8 0
8. 1.
I ncl usi o n Criteria........................................................................................................ 8 0
8. 2.
E xcl usi o n Criteria ....................................................................................................... 8 1
8. 3.
I ncl usi o n Criteria f or L o n g-Ter m E xte nsi o n Peri o d ...................................................8 4
8. 4.
E xcl usi o n Criteria f or L o n g -Ter m E xte nsi o n Peri o d ..................................................8 5
9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I ON ............................ 8 6
9. 1.
Scree ni n g a n d E nr oll me nt ........................................................................................... 8 6
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................8 6
9. 3.
Bli n di n g Pr oce d ures .................................................................................................... 8 7
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/ O R 
WI 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 ........................................... 8 8
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ...........................................................................8 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 8 9
1 1.
S T U D Y T R E A T M E N T U S E ..................................................................................... 9 0
1 1. 1.
Re gi me n ...................................................................................................................... 9 0
1 1. 1. 1.
A d uca n u ma b ............................................................................................................... 9 0
1 1. 1. 2.
Place b o ........................................................................................................................ 9 0
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 9 0
1 1. 3.
Preca uti o ns .................................................................................................................. 9 0
1 1. 4.
C o m plia nce ................................................................................................................. 9 0
1 1. 5.
Pri or a n d C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................ 9 0
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 9 0
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 9 1
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T hera p y .............................................................................. 9 1
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 9 1
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 9 2
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 ................................................................ 9 3
1 2. 1.
A d uca n u ma b ............................................................................................................... 9 3
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 9 3
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 9 4
1 2. 1. 3.
A d uca n u m a b Ha n dli n g a n d Dis p osal ......................................................................... 9 4
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 9 4
1 2. 2.
Place b o ........................................................................................................................ 9 4
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 9 4
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 P H A R M A C O D Y N A MI C 
A S S E S S M E N T S .........................................................................................................9 6
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 9 6
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 9 6
1 3. 3.
P har mac o d y na mic Assess me nts .................................................................................9 6
1 3. 4.  
A d diti o nal Assess me nts.............................................................................................. 9 7
9 7
1 3. 4. 2.
A p o E Ge n ot y pi n g .......................................................................................................9 8
9 8
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 9 8


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
9 9
1 4. 
S A F E T Y A S S E S S M E N T S ...................................................................................... 1 0 0
1 4. 1.
Cli nical Safet y  Assess me nts..................................................................................... 1 0 0
1 4. 2.
La b orat or y  Safety Assess me nts ................................................................................ 1 0 0
1 4. 3.
I m m u n o ge nicity Assess me nts .................................................................................. 1 0 1
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 ...............................................................................................1 0 2
1 5. 1.
Defi niti o ns................................................................................................................ 1 0 2
1 5. 1. 1.
A d verse E ve nt ........................................................................................................... 1 0 2
1 5. 1. 2.
Seri o us A d verse E ve nt ..............................................................................................1 0 2
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.............. 1 0 3
1 5. 2.
Safet y  Classificati o ns................................................................................................ 1 0 3
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ........................................................................... 1 0 3
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt..............................................................1 0 4
1 5. 2. 3.
Se verit y  of E ve nts..................................................................................................... 1 0 4
1 5. 2. 4.
E x pecte d ness of E ve nts ............................................................................................ 1 0 4
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts ............................................................................ 1 0 4
1 5. 3. 1.
A d verse E ve nts ......................................................................................................... 1 0 4
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ........................................................................... 1 0 5
1 5. 3. 3.
Seri o us A d verse E ve nts ............................................................................................ 1 0 5
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts..................................................... 1 0 5
1 5. 3. 4. 1.
Deat hs ....................................................................................................................... 1 0 6
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns .................................................. 1 0 6
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns .............................................................1 0 6
1 5. 4. 1.
Pre g na nc y ................................................................................................................. 1 0 6
1 5. 4. 2.
O ver d ose ...................................................................................................................1 0 6
1 5. 4. 3.
Me dical E mer ge nc y ..................................................................................................1 0 7
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ......................................................................... 1 0 7
1 5. 5.
C o ntrace pti o n Re q uire me nts ................................ ....................................................1 0 7
1 5. 6.
Safet y Res p o nsi bilities ..............................................................................................1 0 8
1 5. 6. 1.
T he I n vesti gat or ........................................................................................................ 1 0 8
1 5. 6. 2.
Bi o ge n ....................................................................................................................... 1 0 9


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 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 ......... 1 1 0
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................. 1 1 0
1 6. 2.
Efficac y  a n d P har mac o d yna mics .............................................................................. 1 1 0
1 6. 2. 1.
A nal y sis P o p ulati o n .................................................................................................. 1 1 0
1 6. 2. 2.
Met h o ds of A nal ys is................................................................................................. 1 1 0
1 6. 2. 2. 1.
Ge neral C o nsi derati o ns .............................................................................................1 1 0
1 6. 2. 2. 2.
A d uca n u ma b D oses t o be E val uate d ........................................................................ 1 1 0
1 6. 2. 2. 3.
C o nsi derati o ns f or M ulti ple C o m paris o n A dj ust me nts ............................................ 1 1 1
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y E n d p oi nt............................................................................. 1 1 1
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts....................................................................... 1 1 2
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ..................................................................................... 1 1 2
1 6. 3.
P har mac o ki netics ...................................................................................................... 1 1 3
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................. 1 1 3
1 6. 3. 2.
Met h o d of A nal ys is................................................................................................... 1 1 3
1 6. 4.
A d diti o nal E x pl orat or y  A nal yses ............................................................................. 1 1 3
1 6. 5.
Safet y ........................................................................................................................ 1 1 3
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................. 1 1 3
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................. 1 1 3
1 6. 5. 2. 1.
A d verse E ve nts ......................................................................................................... 1 1 3
1 6. 5. 2. 2.
Cli nical L a b orat or y Res ults...................................................................................... 1 1 4
1 6. 5. 2. 3.
Vital Si g ns ................................................................................................................ 1 1 4
1 6. 5. 2. 4.
E C G .......................................................................................................................... 1 1 4
1 6. 5. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................. 1 1 4
1 6. 6.
I m m u n o ge nicity Data ...............................................................................................1 1 4
1 6. 6. 1.
A nal y sis P o p ulati o n ..................................................................................................1 1 4
1 6. 6. 2.
Met h o ds of A nal ys is.................................................................................................1 1 4
1 6. 7.
I nteri m A nalys es .......................................................................................................1 1 4
1 6. 7. 1.
I nteri m F utilit y A nal ysis ........................................................................................... 1 1 4
1 6. 7. 2.
I nteri m S u peri orit y A nal ysis.....................................................................................1 1 5
1 6. 8. 
Sa m ple Size C o nsi derati o ns ................................ .....................................................1 1 5
1 7.
E T HI C A L  R E Q UI R E M E N T S .................................................................................1 1 6


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 7. 1.
Declarati o n of Helsi n ki .............................................................................................1 1 6
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ......................................................... 1 1 6
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ............................................................................. 1 1 6
1 7. 4.
S u bject Data Pr otecti o n ............................................................................................ 1 1 7
1 7. 5.
C o m pe nsati o n f or I nj ur y ........................................................................................... 1 1 7
1 7. 6.
C o nflict o f Interest .................................................................................................... 1 1 7
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 ............................................ 1 1 7
1 8.
A D MI NI S T R A TI V E P R O C E D U R E S ..................................................................... 1 1 8
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................. 1 1 8
1 8. 2.
Q ualit y  Ass ura nce..................................................................................................... 1 1 8
1 8. 3.
M o nit ori n g of t he St u d y ............................................................................................ 1 1 8
1 8. 4.
St u d y  F u n di n g........................................................................................................... 1 1 8
1 8. 5.
P u blicati o ns ............................................................................................................... 1 1 8
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 1 9
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ............................................................................... 1 1 9
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ............................................................................... 1 1 9
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................. 1 1 9
1 9. 1. 3.
Electr o nic Data Ca pt ure ............................................................................................ 1 1 9
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ................................................... 1 1 9
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts.................................................................... 1 1 9
1 9. 1. 6.
Ne ur oc o g niti ve Assess me nts .................................................................................... 1 2 0
1 9. 2.
St u d y  C o m mittees..................................................................................................... 1 2 0
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................. 1 2 0
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee ................................................................ 1 2 0
1 9. 3.
C ha n ges t o Fi nal St u d y  Pr ot oc ol ..............................................................................1 2 0
1 9. 4.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n...................................................................................... 1 2 1
1 9. 5.
Rete nti o n of St u d y  Data............................................................................................ 1 2 1
1 9. 6.
St u d y  Re p ort Si g nat or y.............................................................................................1 2 1
2 0.
R E F E R E N C E S .........................................................................................................1 2 2
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 .......................................1 2 4


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 nsent of 
Bi o ge n M A  I nc.
9
LI S T O F T A B L E S
Ta ble 1:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8 ................. 1 9
Ta ble 2:
Place b o -C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Treat me nt or 
F oll o w -U p ................................................................................................................... 2 3
Ta ble 3:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule 
D uri n g t he Place b o -C o ntr olle d Peri o d ........................................................................ 2 7
Ta ble 4:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4 ....................... 2 9
Ta ble 5:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 1 3 6 t o Wee k 1 8 2 ..................... 3 2
Ta ble 6:
Brai n M RI, A RI A Ma na ge me nt, a n d F oll o w -U p P h o ne Call Sc he d ule Fr o m 
Wee ks
8 0 t o 1 8 2 of t he L o n g -Ter m E xte nsi o n Peri o d ............................................... 3 5
Ta ble 7:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 1 8 4 t o Wee k 2 3 4 ..................... 3 6
Ta ble 8:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 2 3 6 t o Wee k 2 8 6 ..................... 3 8
Ta ble 9:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 2 8 8 t o t he E n d of 
Treat me nt or F oll o w -U p ............................................................................................. 4 0
Ta ble 1 0:
S u bjects W h o Disc o nti n ue St u d y  Treat me nt b ut Re mai n i n t he St u d y –
Place b o -C o ntr olle d Peri o d .......................................................................................... 4 4
Ta ble 1 1:
S u bjects W h o Disc o nti n ue St u d y  Treat me nt b ut Re mai n i n t he St u d y –
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 4 7
Ta ble 1 2:
D osi n g Sc he me f or A d uca n u ma b b y  Treat me nt Gr o u p a n d A p o E ε 4 Carrier 
Stat us ........................................................................................................................... 5 8
Ta ble 1 3:
Dis p ositi o n of A RI A- E Cases .....................................................................................6 7
Ta ble 1 4:
Dis p ositi o n of A RI A- H ( Micr o he m orr ha ge) Cases.................................................... 6 9
Ta ble 1 5:
Dis p ositi o n of A RI A -H ( S u perficial Si der osis) Cases ............................................... 7 1
Ta ble 1 6:
Res u m pti o n of St u d y  Treat me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titrati o n .......................................................................................................... 7 4
Ta ble 1 7:
Treat me nt Gr o u ps i n t he E ve nt of Hi g h D ose Gr o u p Ter mi nati o n .......................... 1 1 1
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n............................................................................................................... 1 7


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
1.
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 h i 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
at 
Please refer t o t he St u d y Refere nce Ma n ual 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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
2.
LI S T O F A B B R E VI A TI O N S
1 2 F 6 A
rec o m bi na nt, h u ma n a nti- β-a m yl oi d i m m u n o gl o b uli n G 1
m o n ocl o nal a nti b o d y  wit h a n a mi n o aci d se q ue nce i de ntical t o 
a d uca n u ma b, pr o d uce d i n a differe nt C hi nese ha mster o var y  
cell li ne
A β
β- a m yl oi d ( pe pti de deri ve d fr o m me m bra ne b o u n d a m yl oi d 
prec urs or pr otei n)
A A
Alz hei mer’s Ass ociati o n
A D
Alz hei mer’s dise ase
A D A
a nti dr u g a nti b o d y
A D A S -C o g 1 3
Alz hei mer’s Disease Assess me nt Scale -C o g niti ve S u bscale 
( 1 3 ite ms)
A D C S -A D L -M CI
Alz hei mer’s Disease C o o perati ve St u d y  - Acti vities of Dail y  
Li vi n g I n ve nt or y  ( Mil d C o g niti ve I m pair me nt versi o n)
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A p o E
a p oli p o pr otei n E
A p o E ε 4 
a p oli p o pr otei n E 4
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-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- he m orr ha ge or s u perficial 
si der osis
A S T
as partate a mi n otra nsferase
C D R
Cli nical De me ntia Rati n g 
C D R -S B
Cli nical De me ntia Rati n g s u m of b o xes
c h 1 2 F 6 A
m uri ne I g G 2a c hi meric versi o n of 1 2 F 6 A or a d uc a n u ma b 
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 F
cere br os pi nal fl ui d
C- S S R S
C ol u m bia S uici de Se verit y  Rati n g Scale 
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
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E D C
electr o nic data ca pt ure
E O T
E n d of Treat me nt
E Q - 5 D
E ur o Q ol healt h stat us meas ure
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
E Q -5 D (I R -S)
E ur o Q ol healt h stat us meas ure, i nf or ma nt re p orte d o n s u bject
E Q -5 D ( S R)
E ur o Q ol healt h stat us meas ure, s u bject self- re p orte d
F U
foll o w - u p
G C P
G o o d Cli nical Practice
H b A 1 c
gl yc os yl ate d he m o gl o bi n
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
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I CF
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g
i m m u n o gl o b uli n 
I R
i nf or ma nt rate d
I RB
i nstit uti o nal re vie w b oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
I T T
i nte nt-t o-treat
I V
i ntra ve n o us(ly)
I W G
I nter nati o nal W or ki n g Gr o u p
L T E
l o n g-ter m e xte nsi o n
L P
l u m bar p u nct ure
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 Re g ulat or y Acti vities
M M R M
m i xe d-m o del re peate d meas ures
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 P D Q - 2 0
Percei ve d Deficits Q uesti o n naire -2 0 m o difie d versi o n
M RI
ma g netic res o na nce i ma gi n g
NI A
Nati o nal I nstit ute o n A gi n g
NI A- A A
Nati o nal I nstit ute o n A gi n g ( NI A) at Nati o nal I nstit utes of 
Healt h ( NI H) a n d t he Alz hei mer’ s Ass ociati o n ( A A)
N PI - 1 0
Ne ur o ps yc hiatric I n ve nt or y - 1 0
P B M C
peri p heral bl o o d m o n o n uclear cells
P D
p har mac o d y n a mic(s)
P E T
p ositr o n e missi o n t o m o gra p h y
PI
Pri nci pal I nvesti gat or
P K
p har mac o ki netic(s)
R B A N S
Re peata ble Batter y  f or Assess me nt of Ne ur o psyc h ol o gical 
Stat us
R N A
ri b o n ucleic aci d
S A B R
Safet y  a n d Be nefit-Ris k 


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
3.
S Y N O P SI S
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
Pr ot oc ol Title:
A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y t o E val uate t he 
Efficac y a n d Safet y of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h 
Earl y Alz hei mer ’s Disease
Versi o n N u m ber:
6. 0
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 I n dicati o n:
Alz hei mer’s Disease
St u d y Rati o nale:
T he p ur p ose of t his P hase 3 st u d y is t o assess t he efficac y a n d 
safet y of a d uca n u ma b c o m pare d wit h place b o i n s u bjects wit h 
earl y Alz hei mer’s Disease ( A D), i ncl u di n g s u bjects wit h mil d 
c o g niti ve i m pair me nt ( M CI) d ue t o A D a n d a s u bset of mil d A D.  
A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y t hat rec o g nizes 
a g gre gate d f or ms of β -a m yl oi d ( A β), i ncl u di n g s ol u ble A β 
oli g o mers a n d de p osite d fi brillar A β.  I nteri m a nal yses of t he 
o n g oi n g m ulti ple d ose st u d y ( St u d y 2 2 1 A D 1 0 3) h a ve 
de m o nstrate d tar get e n ga ge me nt, a p har mac o d y na mic effect o n 
a m yl oi d re d ucti o n, a n d a n effect o n t he Cli nical De me ntia Rati n g 
( C D R)-s u m of b o xes ( S B) a n d Mi ni-Me ntal State E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults,
al o n g wit h t he o bser ve d safet y a n d t olera bilit y pr ofile , warra nt 
f urt her P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt 
p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D c o nti n u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
( place b o-c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R- S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D.  
T he pri mar y e n d p oi nt t hat relates t o t his o bjecti ve is t he c ha n ge 
fr o m baseli ne i n C D R-S B sc ore at Wee k 7 8.
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 assess t he effect of m o nt hl y d oses of a d uca n u ma b as 


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
c o m pare d wit h place b o o n cli nical pr o gressi o n as meas ure d b y

M M S E
- C ha n ge fr o m baseli ne i n M M S E sc ore at Wee k 7 8

Alz hei mer’s Disease Assess me nt Scale -C o g niti ve 
S u bscale ( 1 3 ite ms) [ A D A S -C o g 1 3] 
- C ha n ge fr o m baseli ne i n A D A S -C o g 1 3 at Wee k 7 8

Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of 
Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt 
versi o n) [ A D C S -A D L -M CI] 
- C ha n ge fr o m base li ne i n A D C S-A D L -M CI  sc ore at
Wee k
7 8
Tertiar y o bjecti ves of t his st u d y are liste d i n Secti o n 6. 3. 1 .  
Tertiar y e n d p oi nts of t his st u d y are liste d i n Secti o n 6. 3. 2 . 
A d diti o nal e x pl orat or y o bjecti ves a n d e n d p oi nts are liste d i n 
Secti o n 6. 4 .  
St u d y O bjecti ves a n d E n d p oi nts 
( D ose-Bli n d L o n g -Ter m  
E xte nsi o n peri o d of t he st u d y):
T he o bjecti ves are 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 earl y A D, a n d 
t o e val uate t he l o n g-ter m efficac y of a d uca n u ma b treat me nt as 
meas ure d b y cli nical, ra di ol o gical , a n d healt h -o utc o mes 
assess me nts .
E n d p oi nts f or t he l o n g -ter m e xte nsi o n ( L T E) peri o d of t he st u d y 
are liste d i n Secti o n 6. 5 .  
St u d y Desi g n:
M ultice nter, ra n d o mize d st u d y wit h a n 1 8 -m o nt h d o u ble -bli n d, 
place b o -c o ntr olle d, parallel -gr o u p peri o d f oll o we d b y a n o pti o nal 
u p t o 5- year , d ose -bli n d, L T E peri o d
St u d y L ocati o n:
A p pr o xi matel y 1 5 0 sites gl o ball y
N u m ber of Pla n ne d S u bjects:
A p pr o xi matel y 1 6 0 5 s u bjects are pla n ne d t o 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 earl y A D, i ncl u di n g 
s u bjects wit h M CI d ue t o A D a n d a s u bset of mil d A D acc or di n g 
t o Nati o nal I nstit ute o n A gi n g ( NI A) at t he Nati o nal I nstit utes of 
Healt h ( NI H) a n d t he Alz hei mer’s Ass ociati o n ( NI A -A A) criteri a.  
S u bjects m ust be p ositi ve f or a m yl oi d pat h ol o g y as meas ure d b y 
a m yl oi d p ositr o n e missi o n t o m o gra p h y sca n.  S u bjects m ust be 5 0 
t o 8 5 years ol d, a n d a part fr o m t he cli nical dia g n osis of earl y A D, 
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.  T he 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 1
rati o of a p oli p o pr otei n E 4 ( A p o E ε 4) carriers t o n o n-carriers i n 
t he st u d y p o p ulati o n will ge nerall y reflect t he distri b uti o n i n t he 
br oa der A D p o p ulati o n.  E nr oll me nt will als o be m o nit ore d, via 
i nteracti ve res p o nse tec h n ol o g y, s uc h t hat s u bjects wit h mil d A D 
re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt Gr o u ps:
F or t he 1 8 -m o nt h place b o -c o ntr olle d peri o d of t he st u d y a n d 
base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d 
t o 1 of 3 treat me nt gr o u ps i n a 1: 1: 1 rati o (a d uca n u ma b l o w d ose: 
a d uca n u ma b hi g h d ose: place b o) as f oll o ws: 
A p o E ε 4 c arrier
    L o w  d ose ( 3 m g/ k g)
     Hi g h d ose ( 1 0 m g/ k g) 
     Pl ace b o 
A p o E ε 4 n o n -c arrier
     L o w  d ose ( 6 m g/ k g) 
     Hi g h d ose ( 1 0 m g/ k g)
     Pl ace b o 
After c o m pleti o n of t he place b o -c o ntr olle d peri o d, s u bjects ma y 
e nter a d ose -bli n d L T E st u d y d uri n g w hic h all s u bjects will 
recei ve a d uca n u ma b f or u p t o 5 years.  
D urati o n of Treat me nt a n d 
F oll o w U p:
St u d y d urati o n f or eac h s u bject partici pati n g i n t he 
place b o -c o ntr olle d peri o d o nl y will be a p pr o xi matel y 1 0 2 wee ks 
( u p t o a n 8-wee k scree ni n g peri o d, 7 6 wee ks of p lace b o or 
a d uca n u ma b d osi n g, a n d 1 8 wee ks of f oll o w-u p [ F U]).  
F or s u bjects w h o e nter t he o pti o nal L T E peri o d, t he t otal st u d y 
d urati o n will var y a n d be u p t o a p pr o xi matel y 3 6 2 wee ks or 
8 3 m o nt hs ( u p t o a n 8 -wee k scree ni n g peri o d, 7 6 wee ks of 
place b o or a d uca n u ma b d osi n g, a n d 4 wee ks of F U , pl us a n 
o pti o nal L T E peri o d i ncl u di n g 2 5 6 wee ks of d ose -bli n d 
a d uca n u ma b d osi n g a n d 1 8 wee ks of F U).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F E V E N T S F O R S T U D Y 2 2 1 A D 3 0 1
4. 1.
St u d y Sc he m atic
Fi g ure 1:
St u d y Desi g n
A p o E ε 4 +/ - = a p oli p o pr otei n E 4 p ositi ve/ ne gati ve; F U = f oll o w -u p; P = place b o; R = ra n d o mizati o n date.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
* S u bjects w h o are assi g ne d t o place b o d uri n g t he place b o -c o ntr olle d peri o d are ra n d o mize d i n a 1: 1 rati o t o hi g h a n d l o w d ose a d uca n u ma b treat me nt ( base d 
u p o n t heir A p o E ε 4 carrier stat us) f or t he l o n g -ter m e xte nsi o n peri o d o n St u d y Da y 1 .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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. 2.
Sc he d ule of E ve nts
T a ble 1:
Pl ace b o -C o ntr olle d Peri o d Sc he d ule Fr o m Scree ni n g T hr o u g h Wee k 4 8
St u d y Wee k
Scree ni n g 
( ≤6 0 d a ys 
bef ore
D a y 1) 1
W k 1, 
D a y 1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
I nitial Scree ni n g 
C o nse nt 2 ( o pti o nal)
X
F ull I nf or me d 
C o nse nt 3
X
Eli gi bilit y Criteria
X  
X  
X
X 4
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
H b A 1c
X
HI V 5 / He patitis/
C oa g ulati o n
X
A p o E Ge n ot y pi n g
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
Ser u m Pr e g na nc y 
Test 7
X
Uri ne Pre g na nc y Test 7
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
P h ysical E xa mi nati o n
X
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
Scree ni n g 
( ≤6 0 d a ys 
bef ore
D a y 1) 1
W k 1, 
D a y 1
4 
8
1 2 
1 6 
2 0 
2 4 
2 6 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
V 1  
V 2  
V 3
1
2 9
± 3
5 7
± 3
8 5
± 3
1 1 3
± 3
1 4 1
± 3
1 6 9
± 3
1 8 3
± 3
1 9 7
± 3
2 2 5
± 3
2 5 3
± 3
2 8 1
± 3
3 0 9
± 3
3 3 7
± 3
Ne ur ol o g ical 
E xa mi nati o n
X
X
X
X
1 2 -lea d P a per E C G
X
X
X
Vital Si g ns 8
X
X  
X  
X  
X  
X  
X  
X
X  
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
Ra n d o miz ati o n
X 9
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
A nti -A d u ca n u ma b 
A b 1 0
X
X
X
A d uca n u m a b 
C o nce ntrati o n 1 1
X 1 2
X 1 2
X 1 2
X
X 1 2
X 1 2
X 1 2
X
P B M C C ollecti o n
X
X  
X
X
X
A m yl oi d P E T 1 5
X
X
R B A N S
X
C D R 
X
X
X






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 2:
Pl ace b o - C o ntr olle d Peri o d Sc he d ule Fr o m Wee k 5 0 t o E n d of Tre at me nt or F oll o w-U p 
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6
7 8 ( E O T) 2
U V f or a 
C h a n ge i n 
A D 
Me dic ati o n
9 4
( or 1 8 w ks 
after fi n al 
d ose f or 
s u bjects 
w h o D C T 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
I nf or me d 
C o nse nt
X 3
Eli gi bilit y 
Criteria
X 3
B o d y Wei g ht
X
X
X
X
X
X
X
X
Uri ne 
Pre g na nc y 
Test 4
X
X
X
X
X
X
X
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
X
Vital Si g ns 5
X
X
X
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
St u d y 
Treat me nt 
I nf usi o n
X
X
X
X
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
F U 1
5 0 
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6
7 8 ( E O T) 2
U V f or a 
C h a n ge i n 
A D 
Me dic ati o n
9 4
( or 1 8 w ks 
after fi n al 
d ose f or 
s u bjects 
w h o D C T 
e arl y)
St u d y D a y
3 5 1 ± 3
3 6 5 ± 3
3 9 3 ± 3
4 2 1 ± 3
4 4 9 ± 3
4 7 7 ± 3
5 0 5 ± 3
5 3 3 ± 3
5 4 7 ± 3
6 5 9 ± 7
A nti -
A d uca n u ma b 
A b 6
X
X
X
A d uca n u ma b 
C o nce ntrati o n 7
X 8
X
X
X
P B M C 
C ollecti o n
X
X
X
A m yl oi d 
P E T 1 0
X
C D R
X
X
X
X
M M S E
X
X
X
X
A D C S -A D L 
M CI
X
X
X
X
A D A S -C o g 1 3
X
X
X
X
N PI -1 0
X
X
E Q -5 D ( S R)
X
X




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
disc o nti n ues treat me nt wit hi n 3 m o nt hs of t he pre vi o us efficac y assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve stat us are s us pecte d b y t he 
I n vesti gat or.  T he site s h o ul d n otif y t he S p o ns or i n s uc h cases.
3 O nl y f or s u bjects e nte ri n g t he l o n g-ter m e xte nsi o n peri o d.
4 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y (see Secti o n 1 5. 5 ).
5 Vital 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 will b e m eas 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.
6 Sa m ple c ollecti o n f or a nti -a d uca n u ma b a nti b o d y will be perf or me d pri or t o st u d y treat me nt i nf usi o n ( w here a p plica ble).
7 Bl 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.
8 O ne a d diti o nal bl o o d sa m ple f or a d uca n u ma b c o nce ntrati o n will be c ollecte d bet w ee n 1 0 a n d 6 0 mi n utes after c o m pleti o n of t he i nf usi o n a n d li ne fl us h.  N ote:  
F or s u bjects w h o s us pe n d treat me nt d ue t o A RI A, o nl y 1 bl o o d sa m ple is re q uire d t o be c ollecte d at eac h s pecifie d visit d uri n g t he peri o d of d ose s us pe nsi o n; 
all ot her visits/assess me nts are re q uire d t o be perf or me d.
9 Sa m ple will be c ollecte d pri or t o i nf usi o n ( w here a p plica ble).
1 0 A m yl oi d P E T at Wee k 7 8 w ill o nl y be c o n d ucte d i n selecte d sites f or s u bjects w h o are partici pati n g i n t he a m yl oi d P E T s u bst u d y a n d ma y be sc he dule d w it hi n 
a wi n d o w of ± 7 da ys.
 
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 3:
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -U p P h o ne C all Sc he d ule D uri n g t he Pl ace b o -C o ntr olle d Peri o d
St u d y Wee k
Scree ni n g
(≤ 6 0 d a ys 
bef ore D a y 1) 1
Pl ace b o -C o ntr olle d Peri o d
F U 2
1 
2 
6
1 0 
1 4 
1 8 
2 2 
2 6 
3 0 
4 2 
5 4 
6 6 
7 8/
E O T 3
U nsc he d -
ule d Visit/ 
M RI f or 
A RI A 4
9 4
( or 1 8 w k s 
after fi n al 
d ose f or 
s u bjects w h o 
D C T e arl y)
St u d y D a y
V 1  
V 2  
V 3
1
1 5
± 3
4 3
± 3
7 1
± 3
9 9
± 3
1 2 7
± 3
1 5 5
± 3
1 8 3
± 3
2 1 1
± 3
2 9 5
± 3
3 7 9
± 3
4 6 3
± 3
5 4 7
± 3
6 5 9
± 7
F oll o w -U p 
P h o ne Call 5
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 6
X
X
X
X  
X  
X  
X  
X  
X
X
A d uca n u ma b 
C o nce ntrati o n 7
X
X
X
X
X
M O C A
X
X
P B M C 
C ollecti o n 8
X
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-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-he m orr ha ge or s u perficial si der osis; D C T = disc o nti n ue treat me nt; E O T = E n d of Treat me nt; F U = F oll o w -U p; L T E = l o n g -ter m e xte nsi 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 B M C = peri p heral bl o o d m o n o n uclear cells; P K = p ha r mac o ki netic; 
; V 1, V 2, V 3 = Scree ni n g Visit 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 3; wks = wee k s.
1 Brai n M RI ( V 2) w ill n ot be perf or me d u ntil t he s u bject has met t he eli gi bilit y criteria a n d has acce pta ble la b orat or y tests fr o m V 1.  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 relate d 
t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.
2 S u bjects w h o c o mplete t he place b o -c o ntr olle d 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 U Visit at Wee k 9 4.  S u bjects w h o 
disc o nti n ue treat me nt or w it h dr a w fr o m t he st u d y earl y are t o ha ve a safet y F U Visit at 1 8 wee ks after t heir fi nal d ose.
3 S u bjects w h o disc o nti n ue treat me nt pre mat urel y are t o re mai n i n t he st u d y, atte n d a F U Visit 1 8 we e ks after t he fi nal d ose, a n d i m me diatel y c o nti n ue 
pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 , a n d T a ble 1 1 ) u ntil t he e n d of t he st u d y per t he sc he d ule of e ve nts.  (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 we e 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.  S u bjects w h o w it h dra w fr o m st u d y pre mat urel y are 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
2 8
t o ret ur n t o t he site f or a n E O T Visit; f or s uc h s u bjects, efficac y assess me nts s pecifie d at t he E O T visit are n ot re q uire d if t he s u bject disc o nti n ues treat me nt 
wit hi n 3 m o nt hs of t he pre vi o us efficac y assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve stat us are s us pecte d b y t he
I n vesti gat or; T he site s h o ul d n otif y 
t he s p o ns or i n s uc h cases.
4 F or t he fre q ue nc y of re q uire d b rai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A-E a n d/ or 
A RI A -H, see Secti o n 7. 2. 1. 1 t o Secti o n 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g 
per e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
5 P h o ne visit ma y be perf or me d i n per s o n if t he s u bject will be at t he st u d y site f or cli nical assess me nts.
6 Arterial s pi n la beli n g M RI a n d tas k -free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
7 O ne sa m ple will be c ollecte d wit hi n ± 2 da ys of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.
8 Sa m ple ma y be c ollecte d ± 2 da ys of t he M RI visit at t he sa me ti me as sa m ple c ollecti o n f or a d uca n u ma b c o nce ntrati o n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4:
L o n g -Ter m E xte nsi o n Peri o d S c he d ule Fr o m Wee k 8 0 t o Wee k 1 3 4
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
B o d y Wei g ht
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
Uri ne 
Pre g na nc y 
Test 1
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X
P h ysical 
E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per 
E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
X  
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
A nti -
A d uca n u ma b 
A b 2
X
X
X
P B M C
C ollecti o n
X
X
A d uca n u ma b 
C o nce ntrati o n 2
X
X
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
8 0 
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4 
1 0 6 
1 0 8 
1 1 2 
1 1 6 
1 2 0 
1 2 4 
1 2 8 
1 3 2 
1 3 4
U V f or a 
C h a n ge 
i n A D 
Me dic a -
ti o n
St u d y D a y
5 6 1
± 5
5 8 9
± 5
6 1 7
± 5
6 4 5
± 5
6 7 3
± 5
7 0 1
± 5
7 2 9
± 5
7 4 3
± 5
7 5 7
± 5
7 8 5
± 5
8 1 3
± 5
8 4 1
± 5
8 6 9
± 5
8 9 7
± 5
9 2 5
± 5
9 3 9
± 5
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
A m yl oi d P E T 4
X
C D R
X
X  
X
M M S E
X
X  
X
A D A S -C o g 1 3
X
X  
X
A D C S -A D L -
M CI
X
X  
X
N PI -1 0
X
X
E Q -5 D (I R -S)
X
X
C- S S R S
X
X
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
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




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 5:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 1 3 6 t o Wee k 1 8 2
St u d y Wee k
1 3 6 
1 4 0 
1 4 4 
1 4 8 
1 5 2 
1 5 6 
1 6 0 
1 6 2 
1 6 4 
1 6 8 
1 7 2 
1 7 6 
1 8 0 
1 8 2
U V f or a 
C h a n ge i n 
A D Me dic a-
ti o n
St u d y D a y
9 5 3
± 5
9 8 1
± 5
1 0 0 9
± 5
1 0 3 7
± 5
1 0 6 5
± 5
1 0 9 3
± 5
1 1 2 1
± 5
1 1 3 5 
± 5
1 1 4 9
± 5
1 1 7 7
± 5
1 2 0 5
± 5
1 2 3 3
± 5
1 2 6 1
± 5
1 2 7 5
± 5
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 1
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X
X  
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
A nti - Ad uca n u ma b 
A b 2
X
X
P B M C C o llecti o n
X
X
A d uca n u ma b 
C o nce ntrati o n 2
X
X
X
St u d y Dr u g I nf usi o n
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X
A m yl oi d P E T 4
X




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 6:
Br ai n M RI, A RI A M a n a ge me nt, a n d F oll o w -U p P h o ne C all Sc he d ule Fr o m Wee ks 8 0 t o 1 8 2 of t he L o n g -Ter m 
E xte nsi o n Peri o d
St u d y Wee k
L o n g -Ter m E xte nsi o n
U nsc he d ule d 
Visit f or A RI A 1
8 0 
8 2 
8 6 
9 0 
9 4 
9 8 
1 0 2 
1 0 6 
1 1 0 
1 2 2 
1 3 4 
1 5 8 
1 8 2
St u d y D a y
5 6 1
± 5
5 7 5
± 5
6 0 3
± 5
6 3 1
± 5
6 5 9
± 5
6 8 7
± 5
7 1 5
± 5
7 4 3
± 5
7 7 1
± 5
8 5 5
± 5
9 3 9
± 5
1 1 0 7
± 5
1 2 7 5
± 5
F oll o w -U p 
P h o ne Call 2
X  
X  
X  
X  
X  
X  
X  
X
Brai n M RI 3
X
X
X  
X  
X  
X  
X
X 3
A d uca n u ma b 
C o nce ntrati o n 4
X
M O C A
X
X
P B M C 
C ollecti o n 5
X
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-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-he m orr ha ge or s u perficial si der osis; E O T = E n d of Treat me nt; L T E = l o n g -ter m e xte nsi 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 B M C = peri p heral bl o o d m o n o n uclear cells; P K = p har mac o ki netic;
.
1 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o n 7. 2. 1. 1 t o Secti o n 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g 
per e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
2 P h o ne visit ma y be perf or me d i n pers o n if t he s u bject w ill be at t he st u d y site f or cli nical assess me nts.
3 Arterial- s pi n la beli n g M RI a n d tas k-free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites, a n d will n ot be perf or med at a n y visit after W ee k 1 8 2.
4 O ne sa m ple will be c ollecte d wit hi n ± 2 da ys of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.
5 Sa m ple ma y be c ollecte d wit hi n ± 2 da ys of t he M RI visit at t he sa me ti me as sa m ple c ollecti o n f or a d uca n u ma b c o nce ntrati o n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 7:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 1 8 4 t o Wee k 2 3 4
St u d y Wee k
1 8 4 
1 8 8 
1 9 2 
1 9 6 
2 0 0 
2 0 4 
2 0 8 
2 1 2 
2 1 6 
2 2 0 
2 2 4 
2 2 8 
2 3 2
U V f or 
A RI A 1
St u d y D a y
1 2 8 9
± 5
1 3 1 7
± 5
1 3 4 5
± 5
1 3 7 3
± 5
1 4 0 1
± 5
1 4 2 9
± 5
1 4 5 7
± 5
1 4 8 5
± 5
1 5 1 3
± 5
1 5 4 1
± 5
1 5 6 9
± 5
1 5 9 7
± 5
1 6 2 5
± 5
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 2
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P h ysical E xa mi nati o n
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
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
P B M C C olle cti o n
X 3
A d uca n u ma b 
C o nce ntrati o n
X 4
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
X  
X
C D R
X
M M S E
X
A D A S -C o g 1 3
X
A D C S -A D L -M CI
X
E Q -5 D -(I R-S)
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
1 8 4 
1 8 8 
1 9 2 
1 9 6 
2 0 0 
2 0 4 
2 0 8 
2 1 2 
2 1 6 
2 2 0 
2 2 4 
2 2 8 
2 3 2
U V f or 
A RI A 1
St u d y D a y
1 2 8 9
± 5
1 3 1 7
± 5
1 3 4 5
± 5
1 3 7 3
± 5
1 4 0 1
± 5
1 4 2 9
± 5
1 4 5 7
± 5
1 4 8 5
± 5
1 5 1 3
± 5
1 5 4 1
± 5
1 5 6 9
± 5
1 5 9 7
± 5
1 6 2 5
± 5
M O C A
X
C- S S R S
X
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
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 D = Alz hei mer’s disease; A E = a d verse e ve nt; A D A S -C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale C o g niti ve S u bscale ( 1 3 ite ms); 
A D C S -A D L -M CI
= Alz hei mer ’s Disease C o o perati ve St u d y Acti vities of Dail y Li vi n g I n ve nt or y ( Mil d C o g niti ve I m pair me nt versi o n); 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-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 he m orr ha ge or s u perficial 
si der osis; C D R = Cli nical De me ntia Rati n g scale; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; 
 
; E Q-5 D (I R -S) = E Q -5 D, i nf or ma nt re p orte d o n s u bject; 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 = m a g netic res o na nce i ma gi n g; P B M C = peri p heral bl o o d m o n o n uclear cells; 
P K = p har mac o ki netic; 
; S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit.
1 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o n 7. 2. 1. 1   t o Secti o n 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g 
per e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
2 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
3 Sa m ple ma y be c ollec te d wit hi n ± 2 da ys of t he M RI visit at t he sa me ti me as sa m ple c ollecti o n f or a d uca n u ma b c o nce ntrati o n.
4 O ne sa m ple will be c ollecte d wit hi n ± 2 da ys of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 8:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 2 3 6 t o Wee k 2 8 6
St u d y Wee k
2 3 6 
2 4 0 
2 4 4 
2 4 8 
2 5 2 
2 5 6 
2 6 0 
2 6 4 
2 6 8 
2 7 2 
2 7 6 
2 8 0 
2 8 4
U V f or 
A RI A 1
St u d y D a y
1 6 5 3
± 5
1 6 8 1
± 5
1 7 0 9
± 5
1 7 3 7
± 5
1 7 6 5
± 5
1 7 9 3
± 5
1 8 2 1
± 5
1 8 4 9
± 5
1 8 7 7
± 5
1 9 0 5
± 5
1 9 3 3
± 5
1 9 6 1
± 5
1 9 8 9
± 5
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 2
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P h ysical E xa mi nati o n
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
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
P B M C C ollecti o n
X 3
A d uca n u ma b 
C o nce ntrati o n
X 4
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
X  
X
A m yl oi d P E T 5
X
C D R
X
M M S E
X
A D A S -C o g 1 3
X
A D C S -A D L -M CI
X
E Q -5 D -(I R-S)
X


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
2 3 6 
2 4 0 
2 4 4 
2 4 8 
2 5 2 
2 5 6 
2 6 0 
2 6 4 
2 6 8 
2 7 2 
2 7 6 
2 8 0 
2 8 4
U V f or 
A RI A 1
St u d y D a y
1 6 5 3
± 5
1 6 8 1
± 5
1 7 0 9
± 5
1 7 3 7
± 5
1 7 6 5
± 5
1 7 9 3
± 5
1 8 2 1
± 5
1 8 4 9
± 5
1 8 7 7
± 5
1 9 0 5
± 5
1 9 3 3
± 5
1 9 6 1
± 5
1 9 8 9
± 5
M O C A
X
C- S S R S
X
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
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 D = Alz hei mer’s disease; A E = a d verse e ve nt; A D A S -C o g 1 3 = Alz hei mer’s Disease Assess me nt Scale C o g niti ve S u bscale ( 1 3 ite ms); 
A D C S -A D L -M CI
= Alz hei mer’s Disease C o o perati ve St u d y Acti vities of Dail y Li vi n g I n ve nt or y  ( Mil d C o g niti ve I m pair me nt versi o n); 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-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 he m orr ha ge or s u perficial 
si der osis; C D R = Cli nical De me ntia Rati n g scale; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; 
 
 E Q-5 D (I R -S) = E Q -5 D, i nf or ma nt re p orte d o n s u bject;  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 B M C = peri p heral bl o o d m o n o n uclear cells; P E T = p ositr o n 
e missi o n t o m o gra p h y; P K = p har mac o ki netic; 
; S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit.
1 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o n 7. 2. 1. 1   t o Secti o n 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g 
per e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
2 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
3 Sa m ple ma y be c ollecte d wit hi n ± 2 da ys of t he M RI visit at t he sa me ti me as sa m ple c ollecti o n f or a d uca n u ma b c o nce ntrati o n.
4 O ne sa m ple will be c ollecte d wit hi n ± 2 da ys of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.
5 O nl y f or s u bjects w h o partici pate i n t he a m yl oi d P E T s u bst u d y.  A m yl oi d P E T ma y be sc he d ule d w it hi n a wi n d o w of ± 7 da ys.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 9:
L o n g -Ter m E xte nsi o n Peri o d Sc he d ule Fr o m Wee k 2 8 8 t o t he E n d of Tre at me nt or F oll o w-U p
St u d y Wee k
F U 1
2 8 8 
2 9 2 
2 9 6 
3 0 0 
3 0 4 
3 0 8 
3 1 2 
3 1 6 
3 2 0 
3 2 4 
3 2 8 
3 3 2 
3 3 6 
3 3 8
E O T 2
U V f or 
A RI A 3
3 5 4
( or 1 8 wks
after fi n al 
d ose f or 
s u bjects 
w h o D C T 
e arl y)
St u d y D a y
2 0 1 7
± 5
2 0 4 5
± 5
2 0 7 3
± 5
2 1 0 1
± 5
2 1 2 9
± 5
2 1 5 7
± 5
2 1 8 5
± 5
2 2 1 3
± 5
2 2 4 1
± 5
2 2 6 9
± 5
2 2 9 7
± 5
2 3 2 5
± 5
2 3 5 3
± 5
2 3 6 7
± 5
2 4 7 9
± 7
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 4
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
P h ysical E xa mi nati o n
X
X
X
Ne ur ol o gical 
E xa mi nati o n
X
X
X
1 2 -lea d Pa per E C G
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
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
A nti - Ad uca n u ma b A b
X
X
P B M C C ollecti o n
X 5
X 6
X
A d uca n u ma b 
C o nce ntrati o n
X
X 7
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


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
St u d y Wee k
F U 1
2 8 8 
2 9 2 
2 9 6 
3 0 0 
3 0 4 
3 0 8 
3 1 2 
3 1 6 
3 2 0 
3 2 4 
3 2 8 
3 3 2 
3 3 6 
3 3 8
E O T 2
U V f or 
A RI A 3
3 5 4
( or 1 8 wks
after fi n al 
d ose f or 
s u bjects 
w h o D C T 
e arl y)
St u d y D a y
2 0 1 7
± 5
2 0 4 5
± 5
2 0 7 3
± 5
2 1 0 1
± 5
2 1 2 9
± 5
2 1 5 7
± 5
2 1 8 5
± 5
2 2 1 3
± 5
2 2 4 1
± 5
2 2 6 9
± 5
2 2 9 7
± 5
2 3 2 5
± 5
2 3 5 3
± 5
2 3 6 7
± 5
2 4 7 9
± 7
Brai n M RI
X 9
X
X 9
A m yl oi d P E T 1 0
X
C D R
X
X
M M S E
X
X
A D A S -C o g 1 3
X
X
A D C S -A D L -M CI
X
X
N PI -1 0
X 5
E Q -5 D -(I R-S)
X
M O C A
X
C- S S R S
X
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
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






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 1 0: 
S u bjects W h o Disc o nti n ue St u d y Tre at me nt b ut Re m ai n i n t he St u d y – Pl ace b o -C o ntr olle d Peri o d
St u d y Wee k
Pl ace b o -C o ntr olle d Peri o d 1
1 2
2 4
2 6
4 8
5 0
7 2
7 8
( E O T)2
U V f or 
A RI A 3
St u d y D a y
8 5 ± 3
1 6 9 ± 3
1 8 3 ± 3
3 3 7 ± 3
3 5 1 ± 3
5 0 5 ± 3
5 4 7 ± 3
I nf or me d C o nse nt
X 4
B o d y Wei g ht
X
X
X
X
Eli gi bilit y Criteria
X 4
P h ysical E xa mi nati o n
X
X
X
X
X
Ne ur ol o gical E xa mi nati o n
X
X
X
X
X
1 2 -lea d Pa per E C G
X
X
X
X
Vital Si g ns
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
P B M C C ollecti o n
X 5
A d uca n u ma b C o nce ntrati o n
X 6
Brai n M RI 7
X
X
A m yl oi d P E T 8
X
X
C D R
X
X
X
M M S E
X
X
X
A D A S -C o g 1 3
X
X
X
A D C S -A D L -M CI
X
X
X




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
2 S u bjects w h o wit h dra w  fr o m 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; f or s uc h s u bjects, efficac y assess me nts s pecifie d at t he E O T Visit are 
n ot re q uire d if t he s u bject disc o nti n ues treat me nt wit hi n 3 m o nt hs of t he pre vi o us efficac y assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve stat us are 
s us pecte d b y t he I n vesti gat or.  T he site s h o ul d n otif y t he S p o ns or i n s uc h cases.
3 F or t he fre q ue nc y of re q uire d brai n M RI a n d M O C A assess me nts, a n d P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n f or s u bjects w h o de vel o p A RI A -E a n d/ or 
A RI A -H, see Secti o n 7. 2. 1. 1   t o Secti o n 7. 2. 1. 5 .  T his i ncl u des P K, bi o mar ker, a n d P B M C sa m ple c ollecti o n at t he first u nsc he d ule d visit f or A RI A m o nit ori n g 
per e pis o de o nl y.  F or t he fre q ue nc y of brai n M RI a n d M O C A assess me nts f oll o wi n g res ol uti o n of A RI A a n d res u m pti o n of d osi n g, see Secti o n 7. 2. 1. 6 .  F or 
m a na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
4 O nl y f or s u bjects e nteri n g t he l o n g -ter m e xte nsi o n peri o d.
5 Sa m ple ma y be c ollecte d wit hi n ± 2 da ys of t he M RI visit at t he sa me ti me as sa m ple c ollecti o n f or a d uca n u ma b c o nce ntrati o n.
6 O ne sa m ple will b e c ollecte d wit hi n ± 2 da ys of t he M RI visit.  E xact c ollecti o n date a n d ti me will be ca pt ure d f or all P K bl o o d sa m ples o n a s pecifie d case 
re p ort f or m.
7 Arterial s pi n la beli n g M RI a n d tas k -free f u ncti o nal M RI will be perf or me d o nl y at a s u bset of sites.
8 O nl y f or s u bjects w h o partici pate i n t he a m yl oi d P E T s u bst u d y.  A m yl oi d P E T ma y be sc he d ule d w it hi n a wi n d o w of ± 7 da ys.
 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
T a ble 1 1:
S u bjects W h o Disc o nti n ue St u d y Tre at me nt b ut Re m ai n i n t he St u d y – L o n g -Ter m E xte nsi o n Peri o d
St u d y Wee k
L T E Peri o d 1
9 2 
1 0 4 
1 0 6 
1 2 8 
1 3 4 
1 5 2 
1 6 2 
1 7 6 
1 8 2 
2 0 8 
2 3 2 
2 6 0 
2 8 4 
3 1 2 
3 3 8
( E O T)2
U V f or 
A RI A 3
St u d y D a y
6 4 5
± 5
7 2 9
± 5
7 4 3
± 5
8 9 7
± 5
9 3 9
± 5
1 0 6 5
± 5
1 1 3 5
± 5
1 2 3 3
± 5
1 2 7 5
± 5
1 4 5 7
± 5
1 6 2 5
± 5
1 8 2 1
± 5
1 9 8 9
± 5
2 1 8 5
± 5
2 3 6 7
± 5
B o d y Wei g ht
X  
X
X
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  
X  
X  
X  
X
Ne ur ol o gical E xa mi nati o n  
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
Vital Si g ns
X  
X
X
X
X  
X  
X  
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
X
P B M C C ollecti o n
X 5
A d uca n u ma b C o nce ntrati o n
X 6
Brai n M RI 7
X
X
X
X
X 7
X
A m yl oi d P E T 8
X
X
X
C D R
X
X
X
X
X
X
X
M M S E
X
X
X
X
X
X
X
A D A S -C o g 1 3
X
X
X
X
X
X
X
A D C S -A D L -M CI
X
X
X
X
X
X
X
N PI -1 0
X
X
X
X
X 4






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
4. 3.
A d diti o n al I nf or m ati o n
4. 3. 1.
Site Pers o n nel
A mi ni m u m of 3 se parate heat h care pr ofessi o nals ( H C Ps) are re q uire d:  
1.
A treati n g H C P (t he Pri nci pal I n vesti gat or [ PI ] or S u b-i n vesti gat or ma y ser ve as a 
treati n g H C P) w h o is res p o nsi ble f or t he f oll o wi n g:

A d mi nistrati o n of M o ntreal C o g niti ve Assess me nt ( M O C A) at Da y  1, Wee k 8 0, 
a n d d uri n g ma na ge me nt of a m yl oi d-relate d i ma gi n g a b n or malities ( A RI A) cases.

Ma na ge me nt of r o uti ne ne ur ol o gical care of t he s u bject.

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y ) a n d treat me nt of a d verse e ve nts 
( A Es).  

Re vie w of selecte d he mat ol o g y a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y 
wit h hel d or per ma ne ntl y  disc o nti n ue d acc or di n g t o t he criteria detaile d i n 
Secti o n 1 0. 1 .
2.
A n i n de pe n de nt rati n g H C P ( desi g nate d by t he PI of t he site) w h o is res p o nsi ble f or 
a d mi nisteri n g t he Cli nical De me ntia Rati n g ( C D R) 
3.
A sec o n d i n de pe n de nt rati n g H C P ( desi g nate d b y t he PI  of t he site) w h o will a d mi nister 
t he Alz hei mer’s Disease Assess me nt Scale- C o g niti ve S u bscale ( 1 3 ite ms) [ A D A S-C o g 
1 3], Alz hei mer’s Disease C o o perati ve St u d y -Acti vities of Dail y  Li vi n g I n ve nt or y ( Mil d 
C o g niti ve I m pair me nt versi o n) [ A D C S-A D L -M CI], a n d t he Mi ni -Me ntal State 
E xa mi nati o n ( M M S E)
T he 2 i n de pe n de nt rati n g H C Ps 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 A Es, c o nc o mita nt t hera p y, la b orat or y data, i ma gi n g 
data, or a n y ot her data t hat ha ve t he p ote ntial of re veali n g t he treat me nt assi g n me nt.  T he 
2 i n de pe n de nt rati n g H C Ps m ust n ot s hare a n y i nf or mati o n a b o ut s u bjects.  PIs ca n n ot ser ve as 
rati n g H C Ps.  T he treati n g H C Ps m ust n ot disc uss A Es (e. g., A RI A) wit h t he i n de pe n de nt rati n g 
H C Ps.  
T o e ns ure c o nsiste nc y  acr oss sites, rati n g H C Ps m ust c o m plete t he sta n dar dize d st u d y-s pecific 
q ualifi cati o n pr ocess o n cli nical efficac y assess me nt sc ori n g pri or t o a d mi nistrati o n of t he 
s pecific assess me nt at t heir site.  All sites m ust atte m pt t o mai ntai n t he sa me rati n g H C P 
t hr o u g h o ut t he st u dy f or s pecific assess me nts i n a n atte m pt t o re mai n c o nsiste n t.  Eac h s u bject 
s h o ul d ha ve t he sa me rati n g H C P 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 o nl y  c o n d uct assess me nts i n place of t he 
pri mar y  rater 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 rati n g H C P has t o be re place d, t he ne w rati n g H C P m ust u n der g o t he 
st u d y-s pecific q ualificati o n pr ocess pri or t o a d mi nistrati o n of t he assess me nt.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
He mat ol o g y  a n d bl o o d c he mistr y data will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.  As wit h ot her la b orat or y  a n d cli nical i nf or mati o n, t hese data s h o ul d 
N O T be re vie we d b y t he rati n g H C Ps.  
T he r oles of i n de pe n de nt raters a n d treati n g H C P are N O T i nterc ha n ge a ble at t he s u bject le vel.  
I n a d diti o n, t he 2 i n de pe n de nt raters are n ot i nterc ha n gea ble at t he s u bject le vel.  If a rater has 
a d mi nistere d t he C D R t o a s u bject , t he y ma y n ot a d mi nister t he ot her ne ur oc o g niti ve 
assess me nts t o t hat s u bject at a n y p oi nt d ur i n g t he st u d y.
A n u n bli n de d p har macist ( or a ut h orize d desi g nee) 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 t he st u d y bli n d.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
5.
I N T R O D U C TI O N 
Alz hei mer’s disease ( A D) 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 3, t here were 4 4. 4 milli o n 
pe o ple li vi n g wit h de me ntia w orl d wi de a n d t hat t his fi g ure will i nc rease t o 1 3 5. 5 milli o n b y 2 0 5 0 
[Alz hei mer's Disease I nter nati o nal 2 0 1 4].  
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 a n d 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 [Jac k 2 0 1 3].
Pat h ol o gical l y, A D 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 
c o ntai ni n g β- a m yl oi d ( A β) pe pti de a n d i ntra ne ur o nal ne ur ofi brillar y ta n gles c o m p ose d of 
h y per p h os p h or y late d ta u pr otei ns.  T he pat h o ge nesis of t hese pla q ues a n d ta n gles a n d h ow t he y  
c o ntri b ute t o t he cli nical s y n 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 “a myl 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 uct i 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 ].  
T he c urre nt vie w of A D, t he disease pr ocess a n d its cli nical ma nifestati o ns, is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n ha vi n g cate g orical sta ges.  E vi de nce s u g gests t he 
pat h o p h ysi ol o gical c ha n ges be gi n y ears 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].  
Re vise d criteria f or t he cli nical dia g n osis of A D were p u blis he d b y t he Nati o nal I nstit ute o n 
A gi n g ( NI A) at t he Nati o nal Instit utes of Healt h ( NI H) a n d t he Alz hei mer’s Ass ociati o n ( A A) 
[Al bert 2 0 1 1 ; Mc K ha n n 2 0 1 1 ; S perli n g 2 0 1 1 ] a n d t he Inter nati o nal W or ki n g Gr o u p (I W G) 
[ D u b ois 2 0 1 0; D u b ois 2 0 1 4 ], a n d a gr o u p t hat i ncl u de d me m bers fr o m b ot h NI A -A A a n d I W G 
p u b lis he d rec o m me n dati o ns t o har m o nize t he criteria [M orris 2 0 1 4 ].  T hese criteria base t he 
dia g n osis of A D o n b ot h cli nical a n d bi ol o gical ele me nts, rec o g nizi n g t he e xiste nce of a 
n o ncli nical sta ge of t he disease by acce pti n g A D dia g n oses pri or t o si g ns of de me ntia usi n g A D 
bi o mar kers.
T he scie ntific c o m m u nit y has s hifte d its f oc us t o tar get patie nts 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 patie nts are m ore li kel y t o be nefit fr o m a nti -a m yl oi d 
t hera py.  
T here are c urre ntl y  n o t hera pies t hat m o dif y t he c ourse 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 b y  re d uci n g eit her s ol u ble or i ns ol u ble f or ms of A β i n t he brai n a n d 
cere br os pi nal fl ui d ( C S F).  A d uca n u ma b is a h u ma n m o n ocl o nal a nti b o d y  t hat rec o g nizes 
a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  Earlier 
p u blicati o ns ha ve re p orte d o n res ults t hat de m o nstrate d i n t he brai n of a n a ni mal m o del of A D 
t hat b ot h s ol u ble oli g o mers a n d a myl 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 [R oz kal ne 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
2 0 0 9 ; S pires -J o nes 2 0 0 9].  Si milarl y , patie nts wit h A D w h o ge nerate d a nti-A β a nti b o dies after 
acti ve i m m u nizati o n wit h a g gre gate d A β( 4 2) s h o we d sl o wer rates of decli ne of c o g niti ve 
f u ncti o n a n d acti vities of dail y li vi n g [H oc k 2 0 0 3 ].
5. 1.
Pr ofile of Pre vi o us E x perie nce Wit h A d uc a n u m a b
5. 1. 1.
N o ncli nic al E x peri e nce 
A d uca n u ma b is a u ni q ue 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  
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.  
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 pr o perties t o a d uca n u ma b ( BII B 0 3 7) si g nifica ntly re d uce d 
a m yl 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, t hr o u g h a 
micr o glia -me diate d p ha g oc y tic mec ha nis m.  T hese data s u g gest a d uca n u ma b c o ul d pr o vi de 
be nefit b y re d uci n g pla q ue b ur de n.
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 gicall y 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 ].
Fi n di n gs c o nsiste nt wit h a m y l oi d pla q ues a n d vasc ular a myl oi d were i de ntifie d i n t he brai n 
secti o ns of a ni mals i n all gr o u ps, incl u di n g t he c o ntr ol gr o u p, as e x pecte d wit h t his m o del.  I n 
b ot h 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/c ere 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 o n 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 nfla 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.  
See t he I n vesti gat or’s Br oc h ure (I B) f or de taile d i nf or mati o n o n n o ncli nical st u dies.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
5. 1. 2.
Cli nic al E x perie nce
A d uca n u ma b has bee n e val uate d i n o ne c o m plete d si n gle asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 1) a n d 
o ne o n g oi n g m ulti ple asce n di n g d ose st u d y  ( 2 2 1 A D 1 0 3): 

St u d y  2 2 1 A D 1 0 1 was a P hase 1, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, st u d y 
of a d uca n u ma b i n s u bjects wit h mil d or m o derate A D.  
T he pri mar y  o bjecti ve was t o e val uate t he safety a n d t olera bilit y of a ra n ge of 
a d uca n u ma b d oses ( 0. 3 t o 6 0 m g/ k g) w he n a d mi nistere d as si n gle i ntra ve n o us (I V) 
i nf usi o ns.  T he sec o n dar y o bjecti ves were t o assess t he p har mac o ki netic ( P K) a n d 
i m m u n o ge nicity of a d uca n u ma b after si n gle -d ose a d mi nistrati o n.  
A si n gle d ose of a d uca n u ma b u p t o 3 0 m g/ k g was de m o nstrate d t o be well t olerate d.  
D ose -li miti n g A RI A ( 2 s u bjects wit h A RI A -E [e de ma] a n d 1 s u bject wit h A RI A- E 
a n d A RI A-H [ micr o he m orr ha ge]) was o bser ve d i n t he 6 0 m g/ k g d ose gr o u p res ulti n g 
i n ter mi nati o n of f urt her d osi n g i n t hat c o h ort; n o cases of A RI A were o bser ve d at 
si n gle d oses bel o w 6 0 m g/ k g.  T he P K pr ofile was d ose li near.

St u d y  2 2 1 A D 1 0 3 is a n o n g oi n g ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d 
m ulti ple d ose st u d y  of a d uca n u ma b i n s u bjects wit h pr o dr o mal or mil d A D w h o are 
a m yl oi d p ositi ve.  T he st u d y c o m prises a place b o-c o ntr olle d peri o d wit h s u bjects 
recei vi n g m o nt hl y  d oses of a d uca n u ma b (fi xe d d oses of 1, 3, 6, or 1 0 m g/ k g, or 
titrati o n u p t o 1 0 m g/ k g) or place b o f or a ye ar f oll o we d b y a d ose -bli n d l o n g -ter m 
e xte nsi o n ( LT E) peri o d wit h s u bjects recei vi n g m o nt hl y  d oses of a d uca n u ma b.  N ote:  
T he fi xe d- d ose c o h or ts e nr olle d b ot h a p oli p o pr otei n E 4 (A p o E ε 4 ) carriers a n d 
n o n- carriers w hile t he titrati o n c o h ort is c o m prise d of A p o E ε 4 carriers o nl y.
T he pri mar y  o bjecti ve of St u d y 2 2 1 A D 1 0 3 is t o e val uate t he safety a n d t olera bilit y of 
m ulti ple d oses of a d uca n u ma b a d mi nistere d m o nt hl y as si n gle I V i nf usi o ns.  T he 
sec o n dar y o bjecti ves are t o assess t he effect of a d uca n u ma b o n cere bral a m y l oi d 
pla q ue c o nte nt as meas ure d b y  1 8F-fl or beta pir p ositr o n e missi o n t o m o gra p h y  ( P E T), 
a n d t o e val uate t he P K a n d i m m u n o ge nicit y of a d uca n u ma b after m ulti ple -d ose 
a d mi nistrati o n.  E x pl orat or y o bjecti ves i ncl u de assess me nt of t he effect of 
a d uca n u ma b o n t he cli nical pr o gressi o n of A D as meas ure d b y 
C D R -s u m of b o xes ( S B) a n d M M S E.  
I n t he m ost rece nt i nteri m a nal ysis (2 5 M a y  2 0 1 7), t he i nci de nce of A RI A has bee n 
o bser ve d t o be b ot h d ose - a n d A p o E ε 4 carria ge - de pe n de nt, es pecially at t he hi g hest 
d oses w he n a d mi nistere d as a fi xe d d ose .  A RI A-E was ra di o gra p hicall y m o nit ore d 
b y  ma g netic res o na nce i ma gi n g ( M RI) a n d ty picall y o bser ve d earl y i n treat me nt 
( bet wee n 2 t o 5 d oses).  I n m ost cases, A RI A-E res ol ve d 4 t o 1 2 wee ks after o nset 
a n d A RI A-H was t y picall y sta ble 2 t o 4 wee ks after o nset.  I n t he place b o-c o ntr olle d 
peri o d, t he i nci de nce of A RI A- E a p peare d t o be l o wer i n t he gr o u p recei vi n g titrati o n 
t o 1 0 m g/ k g (c o m prisi n g A p o E ε 4 carriers o nl y;  8/ 2 3 [ 3 5 %]) t ha n i n carriers i n t he 
6 m g/ k g a n d 1 0 m g / k g fi xe d- d ose gr o u ps ( 9/ 2 1 [ 4 3 %] a n d 1 1/ 2 0 [ 5 5 %], res pecti vel y).  
Of n ote, a m o n g t he 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 h e 
a b n or malities were o bser ve d at t he 3 a n d 6 m g/ k g d ose le vels, bef ore t he y reac he d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
1 0 m g/ k g.  Als o, 1 3 ( of 2 3, 5 7 %) s u bjects i n t he titrati o n ar m ha ve bee n titrate d t o 
1 0 m g/ k g, a n d of t hese , 1 2 c o nti n ue d treat me nt a n d recei ve d at least 1 7 d oses of 
1 0 m g/ k g; n o ne of t hese s u bjects e x perie nce d A RI A -E or A RI A -H.   F urt her m ore, 
A RI A- E e ve nts w he n t he y  occ urre d (i n t he titrati o n gr o u p) ha ve bee n eit her 
as ym pt o matic or ass ociate d wit h mil d s y m pt o ms t hat res ol ve d, a n d m ost s u bjects w h o 
ha d A RI A -E c o nti n ue d treat me nt ( 6/ 8; 7 5 %) c o m pare d wit h o nly 3 6 % ( 4/ 1 1) of 
carriers i n t he fi xe d -d ose 1 0 m g/ k g ar m (refer t o t he I B f or details o n e ve nts of 
A RI A).  In t he L T E peri o d, t he i nci de nce of A RI A-E i n A p o E ε 4 carriers w h o were 
titrate d u p t o 6 m g/ k g ( 2 d oses of 3 m g/ k g, t he n 6 m g/ k g) was 2 3 % ( 3/ 1 3), wit h a n 
o verall rate of 1 6 % ( 3/ 1 9) as n o A p o E ε 4 n o n -carriers ( 0/ 6) e x perie nce d A RIA- E.
Pr ot oc ol -s pecifie d i nteri m a nal yses of t he o n g oi n g m ulti ple-asce n di n g d ose 
St u d y 2 2 1 A D 1 0 3 ha ve de m o nstrate d e n ga ge me nt of a d uca n u ma b w it h a myl oi d 
pla q ues, a p har mac o d y n a mic ( P D) effect o n a m yl oi d re d ucti o n, a n d a n effect o n 
C D R -S B a n d M M S E s u g gesti ve of a sl o wi n g of cli nical decli ne i n 
a d uca n u ma b -treate d s u bjects.  T he d ose- a n d ti me -de pe n de nt re d ucti o n of brai n A β 
b ur de n o bser ve d wit h a d uca n u ma b treat me nt was statisticall y  si g nifica nt at d oses of 
3, 6, a n d 1 0 m g/ k g after 6 a n d 1 2 m o nt hs of d osi n g, as well as wit h 1 m g/ k g a n d 
titrati o n fr o m 1 t o 1 0 m g/ k g after 1 2 m o nt hs of d osi n g.  Furt her d ose -de pe n de nt 
re d ucti o ns i n brai n A β were o bser v e d f or u p t o 3 6 m o nt hs.  S u bjects w h o s witc he d 
fr o m place b o t o a d uca n u ma b i n t he LT E peri o d sa w a re d ucti o n i n brai n A β si milar t o 
t hat see n by s u bjects w h o recei ve d a d uca n u ma b i n t he place b o -c o ntr olle d peri o d.  
T he res ults de m o nstrate tar get e n ga ge me nt (a myl oi d pla q ues) a n d a P D effect 
( d ose-de pe n de nt a m yl oi d re d ucti o n).  
I n a d diti o n, res ults fr o m t he i nteri m a nalys es s h o we d a n effect at 1 year o n t he 
e x pl orat or y e n d p oi nts C D R- S B a n d M M S E (at fi xe d d oses of 1 m g/ k g, 3 m g/ k g, 
6 m g/ k g a n d 1 0 m g/ k g c o m pare d wit h place b o), s u g gesti n g a re d ucti o n i n t he 
pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b- treate d vers us place b o-treate d 
s u bjects.  F urt her m ore , ge nerall y c o nsiste nt treat me nt differe nces were see n f or t he 
fi xe d-d ose c o h orts, a n d i n t he titrati o n gr o u p, effects o n t he C D R -S B a n d M M S E 
after 1 ye ar were ge nerall y c o nsiste nt wit h t he fi xe d -d ose res ults.  C o m pare d wit h 
place b o, a dj uste d mea n c ha n ges fr o m baseli ne t o Wee k 5 4 i n C D R -S B sc ores fa v ore d 
all a d uca n u ma b d ose re gi me ns teste d, wit h treat me nt differe nces of 0. 5 p oi nts or 
greater fa v ori n g a d uca n u ma b at d oses of 3, 6, a n d 1 0 m g/ k g a n d titrati o n t o 1 0 m g/ k g, 
a n d statistical si g nifica nce see n i n t he 1 0 m g / k g a n d titrati o n gr o u ps.  O n t he M M S E, 
a dj uste d mea n decreases fr o m baseli ne t o Wee k 5 2 s u g geste d a cli nicall y mea ni n gf ul 
be nefit i n t he 3 a n d 1 0 m g / k g gr o u ps a n d t he titrati o n gr o u p a n d were si g nifica ntl y 
l o wer t ha n place b o i n t he 1 0 m g/ k g gr o u p .  F urt her m ore, C D R -S B a n d M M S E data 
s u g geste d a cli nical be nefit i n t h ose c o nti n ui n g o n a d uca n u ma b u p t o 3 ye ars 
c o m pare d wit h t h ose w h o s witc he d fr o m place b o t o a d uca n u ma b i n t he L T E peri o d .  
Refer t o t he I B f or details o n i nteri m a nal y ses res ults.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
5. 2.
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he efficac y a n d safet y of a d uca n u ma b c o m pare d wit h 
place b o i n s u bjects wit h earl y A D i ncl u di n g s u bjects wit h mil d c o g niti ve i m pair me nt ( M CI) d ue 
t o A D a n d a s u bset of mil d A D.  A d uca n u ma b is a h u ma n I g G 1 m o n ocl o nal a nti b o d y t hat 
rec o g nizes a g gre gate d f or ms of A β, i ncl u di n g s ol u ble A β oli g o mers a n d de p osite d fi brillar A β.  
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 y l 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 yer -L ue 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].  F or t his reas o n, treat me nt wit h a d uca n u ma b is e x pecte d t o sl o w pr o gressi o n of A D, 
w hile preser vi n g gl o bal f u ncti o n l o n ger, w he n c o m pare d wit h u ntreate d s u bjects.  
I nteri m a nalys es of t he o n g oi n g m ulti ple d ose st u d y  ( St u d y 2 2 1 A D 1 0 3) ha ve de m o nstrate d tar get 
e n ga ge me nt, a P D effect o n a m y l oi d re d ucti o n, a n d a n effect o n C D R-S B a n d M M S E s u g gesti ve 
of a re d ucti o n i n t he pr o gressi o n of cli nical i m pair me nt f or a d uca n u ma b -treate d s u bjects.  T hese 
res ults, al o n g wit h t he o bser ve d safet y a n d t olera bilit y  pr ofile, warra nt t he f urt her P hase 3 
i n vesti gati o n of a d uca n u ma b i n a patie nt p o p ulati o n s pa n ni n g t he early sta ges of t he A D 
c o nti n u u m.
5. 3.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
T he d osi n g re gi me n selecte d f or t his st u d y  was base d o n t he P K a n d P D relati o ns hi p f or re m o val 
of brai n a m yl oi d a n d effect o n C D R -S B a n d M M S E o bser ve d i n St u d y  2 2 1 A D 1 0 3 i nteri m 
a nal ys es a n d o n safet y, t olera bilit y , a n d P K data fr o m st u dies 2 2 1 A D 1 0 1 (c o m plete) a n d 
2 2 1 A D 1 0 3 ( o n g oi n g).  
T he d ose - a n d ti me-de pe n de nt re d ucti o n of brai n a m y l oi d b ur de n o bser ve d wit h a d uca n u ma b 
treat me nt i n St u d y 2 2 1 A D 1 0 3 was statisticall y si g nifica nt at d oses of 3, 6, a n d 1 0 m g/ k g after 
6 m o nt hs of d osi n g, a n d at 3, 6, a n d 1 0 m g/ k g as well as wit h titrati o n t o 1 0 m g/ k g after 
1 2 m o nt hs of d osi n g.  O n t he e x pl orat or y  e n d p oi nts of C D R-S B a n d M M S E c ha n ges fr o m 
baseli ne, a d ose -de pe n de nt sl o wi n g of cli nical decli ne was o bser ve d f or a d uca n u ma b vers us 
place b o after 1 ye ar of treat me nt.  C o m pare d wit h place b o, a dj uste d mea n c ha n ges fr o m baseli ne 
t o Wee k 5 4 f or C D R-S B fa v ore d all t he a d uca n u ma b d ose gr o u ps teste d, wit h treat me nt 
differe nces of 0. 5 p oi nts or greater at fi xe d d oses of a d uca n u ma b 3, 6, a n d 1 0 m g/ k g a n d als o 
wit h titrati o n t o 1 0 m g/ k g.  O n t he M M S E, a dj uste d mea n decreases fr o m baseli ne t o Wee k 5 2 
were s maller i n all d ose gr o u ps t ha n i n t he place b o gr o u p.  Of n ote, o n t he C D R - S B, t he p oi nt 
esti mate f or t he titrati o n gr o u p (c o m prisi n g A p o E ε 4 carriers o nl y) was ge nerall y si milar t o t hat 
f or t he 1 0 m g/ k g gr o u p a n d si g nifica ntly l o wer t ha n place b o i n b ot h t h ose gr o u ps; o n t he M M S E, 
t he p oi nt esti mate f or t he titrati o n gr o u p is ge nerall y si milar t o t hat i n t he 1 0 m g/ k g gr o u p ( w hic h 
s h o we d si g nifica ntl y less decli ne t ha n place b o) a n d t he 3 m g/ k g gr o u p.  
I n t he m ost rece nt i nteri m a nal ysis ( 2 5 Ma y 2 0 1 7), t he i nci de nce of A RI A has bee n o bser ve d t o 
be b ot h d ose- a n d A p o E ε 4 carria ge -de pe n de nt, es peciall y at t he hi g hest d oses w he n 
a d mi nistere d as a fi xe d d ose. H o we ver, t he i nci de nce of A RI A -E, as well as disc o nti n uati o ns 
fr o m treat me nt d ue t o A RIA- E, i n s u bjects recei vi n g a d uca n u ma b titrate d t o 1 0 m g/ k g ( A p o E ε 4 
carriers o nl y) a p pear t o be re d uce d ( 8/ 2 3 [ 3 5 %]) c o m pare d wit h fi xe d d oses of a d uca n u ma b at 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
6 m g/ k g ( 9/ 2 1 [ 4 3 %]) a n d 1 0 m g/ k g ( 1 1/ 2 0 [ 5 5 %]). F urt her m ore, a m o n g t h ose s u bjects 
ra n d o mize d t o recei ve a d uca n u ma b titrate d t o 1 0 m g/ k g, A RI A-E occ urre d o nl y  at t he 3 m g/ k g 
a n d 6 m g/ k g d ose le vels. Als o, 1 3 ( of 2 3, 5 7 %) s u bjects i n t he titrati o n ar m ha ve bee n t itrate d t o 
1 0 m g/ k g, a n d of t hese , 1 2 c o nti n ue d treat me nt a n d recei ve d at least 1 7 d oses of 1 0 m g/ k g; n o ne 
of t hese s u bjects e x perie nce d A RI A -E or A RI A -H.
I n a n eff ort t o ma xi mize t he d ose-de pe n de nt a m yl oi d re d ucti o n a n d effect o n C D R -S B a n d 
M M S E t hat ha ve bee n o bser ve d wit h d oses of 3 m g/ k g a n d hi g her w hile mai ntai ni n g A RI A 
i nci dence, se verit y, a n d relate d disc o nti n uati o n rate wit hi n acce pta ble le vels, a titrati o n re gi me n 
will be e x pl ore d i n t his st u d y .  It has bee n s u g geste d t hat t he A RI A o bser ve d f oll o wi n g treat me nt 
wit h a m y l oi d tar geti n g a ge nts ma y be d ue, i n part, t o t he i nitial lar ge re m o val of a myl oi d a n d 
s u bse q ue nt sat urati o n of peri vasc ular brai n a m yl oi d cleara nce mec ha nis ms [ Weller 2 0 0 8].  
Titrati o n t o t he tar get d ose is e x pecte d t o res ult i n sl o wer i nitial a m yl oi d re m o val, yet tri g ger 
alter nati ve mec ha nis ms of a m yl oi d cleara nce i ncl u di n g m o n ocl o nal a nti b o d y- de pe n de nt 
Fc -me diate d micr o glial cleara nce [Ostr o witz ki 2 0 1 2 ], w hic h w o ul d pre ve nt sat urati o n of 
a m yl oi d cleara nce a n d s u bse q ue nt A RI A d uri n g titrati o n a n d o nce t he tar get d ose is reac he d.  
Si nc e a d uca n u ma b -i n d uce d A RI A has bee n de m o nstrate d t o occ ur earl y d uri n g treat me nt, wit h 
m ost cases occ urri n g wit hi n t he first 5 d oses, titrati o n of a d uca n u ma b f or u p t o 6 d oses pri or t o 
reac hi n g t he tar get d ose ma y res ult i n re d ucti o n of A RI A i nci de nce a n d se verit y.  
Gi ve n t he t olera bilit y  a n d a p pare nt efficac y of a d uca n u ma b s h o w n, t he d oses t o be teste d usi n g a 
titrati o n re gi me n are 3 a n d 1 0 m g/ k g f or A p o E ε 4 carriers, a n d 6 a n d 1 0 m g/ k g f or A p o E ε 4 
n o n- carriers.  Titrati o n will start at 1 m g/ k g a n d will es calate t o 3, 6 , a n d 1 0 m g/ k g as detaile d 
bel o w.  
5. 3. 1.
D osi n g Sc he me
5. 3. 1. 1.
Pl ace b o -C o ntr olle d Peri o d
D oses will be a d mi nistere d a p pr o xi matel y  4 wee ks a part, o ver a p pr o xi matel y 7 6 wee ks (a t otal 
of 2 0 d oses). Base d u p o n t heir A p o E ε 4 carrier stat us, s u bjects will be assi g ne d t o 1 of 
3 treat me nt gr o u ps (a p pr o xi matel y 5 3 5 s u bjects eac h [see Secti o n 1 6. 8 ]) i n a 1: 1: 1 rati o 
(a d uca n u ma b l o w d ose:a d uca n u ma b hi g h d ose: place b o) as f oll o ws ( Ta ble 1 2 a n d Fi g ure 1 ):
A p o E ε 4 C arrier

L o w d ose ( 3 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g t hereafter

Hi g h d ose ( 1 0 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
A p o E ε 4 N o n -C arrier

L o w d ose ( 6 m g/ k g) 
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 4 d oses, a n d 6 m g/ k g t hereafter  

Hi g h d ose ( 1 0 m g/ k g)
1 m g/ k g f or t he first 2 d oses, 3 m g/ k g f or t he ne xt 2 d oses, 6 m g/ k g f or t he ne xt 
2 d oses, a n d 1 0 m g/ k g t hereafter

Place b o  
Sali ne i nf usi o n
T a ble 1 2:
D osi n g Sc he me f or A d uc a n u m a b b y Tre at me nt Gr o u p a n d A p o E ε 4 C arrier 
St at us
D ose ( M o nt h)
1
2 
3 
4 
5 
6
7 t o 2 0
Tre at m e nt Gr o u p
D ose ( m g/ k g)
A p o E ε 4 ( +)
L o w D ose
1 
1 
3 
3 
3 
3 
3
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0 1
Pl ace b o
sali ne
A p o E ε 4 ( -)
L o w D ose
1 
1 
3 
3 
3 
3 
6
Hi g h D ose
1 
1 
3 
3 
6 
6
1 0
Pl ace b o
sali ne
1 1 0 m g/ k g is t he tar get d ose f or all A p o E 4 carriers assi g ne d t o t he a d uca n u ma b hi g h -d ose gr o u p .  S u bjects 
e nr olle d u n der pr ot oc ol versi o ns pri or t o Versi o n 4 a n d assi g ne d t o t he pre vi o us hi g h -d ose of 6 m g/ k g will be 
titrate d t o 1 0 m g/ k g u p o n recei pt of at least 2 d oses at 6 m g/ k g.  
5. 3. 2.
D osi n g Sc he me M o dific ati o n
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will re vie w u n bli n de d safet y data, i ncl u di n g 
seri o us A Es ( S A Es) a n d i nci de nt cases of A RI A, fr o m all o n g oi n g a d uca n u ma b st u dies (e. g., 
St u dies 2 2 1 A D 1 0 3, 2 2 1 A D 1 0 4, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) as descri be d i n t he I D M C c harter.
T he d osi n g sc he me ca n be m o difie d i n t he f oll o wi n g circ u msta nces: 

Safet y  a n d t olera bilit y of t he hi g h d ose 
If t he hi g h d ose ( 1 0 m g/ k g) is dee me d n ot acce pta ble, e nr oll me nt f or t he hi g h-d ose 
gr o u p(s) will be ter mi nate d a n d s u bjects will n ot be re place d.   S u bjects w h o ha ve 
alrea d y bee n ra n d o mize d t o t he disc o nti n ue d d ose will be d o w n -d ose d t o t he ne xt 
a vaila ble d ose acc or di n g t o t heir A p o E ε 4 carrier stat us. Defi niti o n of l o w a n d 
hi g h -d ose gr o u ps will be re vise d as descri be d i n Secti o n 1 6 . 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
5. 3. 3.
L o n g -Ter m E xte nsi o n Peri o d
S u bjects w h o recei ve d 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 w h o e nter t he L T E 
peri o d will mai ntai n t he d osi n g sc he me o utli ne d i n t he pr ot oc ol at t he ti me of tra nsiti o n fr o m t he 
place b o -c o ntr olle d peri o d t o t he L T E peri o d (e. g. , s u bjects w h o are o n sta ble d osi n g i n t he 
place b o -c o ntr olle d peri o d will c o nti n ue o n t he sa me d ose, s u bjects w h o are o n a titrati o n re gi me n 
d uri n g t he tra nsiti o n will c o nti n ue t o titrate i nt o t he L T E peri o d a n d s u bjects w h o c o m plete t he 
place b o -c o ntr olle d peri o d u n der pr ot oc ol versi o ns pri or t o Versi o n 4 a n d are assi g ne d t o t he hi g h 
d ose a d uca n u ma b treat me nt gr o u p ma y  u p titrate t o 1 0 m g/ k g i n t he L T E). S u bjects ra n d o mize d 
t o place b o at t he start of t he place b o-c o ntr olle d peri o d ( St u d y Da y 1) will als o be ra n d o mize d t o 
recei ve d ose -bli n de d a d uca n u ma b (l o w d ose: hi g h d ose, 1: 1 rati o ) f or t he L T E peri o d . 
R a n d o mizati o n will be stratifie d b y s u bject A p o E ε 4 carrier stat us. S u bjects will be d ose d usi n g 
t he sa me re gi me n descri be d f or t he place b o-c o ntr olle d p eri o d (see Ta ble 1 2 a n d Fi g ure 1 ). 
A n y  m o dificati o ns t o t he d osi n g sc he me (i.e., ter mi nati o n of hi g h-d ose gr o u p, as descri be d i n 
Secti o n 5. 3. 2 ) will als o be i m ple me nte d i n t he L T E peri o d .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
6.
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
6. 1.
Pri m ar y O bjecti ve a n d E n d p oi nt
T he p ri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of m o nt hl y d oses of a d uca n u ma b i n 
sl o wi n g c o g niti ve a n d f u ncti o nal i m pair me nt as meas ure d by c ha n ges i n t he C D R-S B sc ore as 
c o m pare d wit h place b o i n s u bjects wit h earl y A D.
T he pri mar y  e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n C D R-S B sc ore at 
Wee k
7 8.
6. 2.
Sec o n d ar y O bjecti ves a n d E n d p oi nts
A sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d wit h 
place b o o n cli nical pr o gressi o n as meas ure d b y t he M M S E.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n M M S E sc ore at 
Wee k
7 8.
A n ot her sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gress i o n as meas ure d b y A D A S-C o g 1 3.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D A S -C o g 1 3 
sc ore at Wee k 7 8.
A n ot her sec o n dar y  o bjecti ve is t o assess t he effect of m o nt hl y  d oses of a d uca n u ma b as c o m pare d 
wit h place b o o n cli nical pr o gressi o n as meas ure d b y  A D C S-A D L -M CI.

T he e n d p oi nt t hat relates t o t his o bjecti ve is c ha n ge fr o m baseli ne i n A D C S -A D L -
M CI  sc ore at Wee k 7 8.
6. 3.
Terti ar y O bjecti ves a n d E n d p oi nts
6. 3. 1.
Terti ar y O bjecti ves
Safet y  a n d T olera bilit y

T o assess t he safety a n d t olera bilit y of m o nt hl y d oses of a d uca n u ma b.  

T o assess t he i m m u n o ge nicit y of a d uca n u ma b.  
Bi o mar ker /Efficac y / Healt h O utc o mes

T o assess t he effect of a d uca n u ma b o n cere bral a m y l oi d pla q ue c o nte nt as meas ure d 
b y  a myl oi d P E T i ma gi n g (i n a s u bset of a p pr o xi matel y  4 0 0 s ubjects).

T o assess t he effect of a d uca n u ma b o n be ha vi or as meas ure d b y t he Ne ur o ps yc hiatric 
I n ve nt or y-1 0 ( N PI -1 0).

T o assess t he effect of a d uca n u ma b o n s u bject healt h stat us, meas ure d b y E ur o Q ol 
healt h stat us meas ures ( E Q - 5 D [i nf or ma nt-rate d a n d s u bject self-re p orte d]).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1

T o assess t he effect of a d uca n u ma b o n s u bject self- re p orte d c o g niti ve f u ncti o n, 
meas ure d b y t he m o difie d Percei ve d Deficits Q uesti o n naire -2 0 ( m P D Q -2 0) 
[Le n der ki n g 2 0 1 4 ].

T o assess t he c orrelati o n bet wee n pri mar y  e n d p oi nt a n d cere bral a m yl oi d pla q ue 
c o nte nt as meas ure d b y P E T i ma gi n g.   
P har mac o ki netics

T o c ollect a n d c haracterize t he P K para meters of a d uca n u ma b i n ser u m.
6. 3. 2.
Terti ar y E n d p oi nts
Safet y  a n d T olera bilit y

I nci de nce of all A Es a n d S A Es.

Brai n M RI fi n di n gs i ncl u di n g i nci de nce of A RI A -E a n d A RI A -H.

Cli nical la b orat or y  s hifts i n re p orte d val ues.

Cli nicall y  si g nifica nt c ha n ges i n vital si g n meas ure me nts a n d electr ocar di o gra ms 
( E C Gs).

I nci de nce of a nti -a d uca n u ma b a nti b o dies i n ser u m.  
Bi o mar kers/ Efficac y / Healt h O utc o mes

C ha n ge fr o m baseli ne i n a m yl oi d P E T si g nal at Wee k 2 6 (i n a s u bset of sites a n d 
s u bjects).

C ha n ge fr o m baseli ne i n a m y l oi d P E T si g nal at Wee k 7 8 (i n a s u bset of sites a n d 
s u bjects).

C ha n ge fr o m baseli ne i n N PI -1 0 sc ore at Wee k 7 8.

C ha n ge fr o m baseli ne i n s u bject self -re p orte d E Q-5 D i n de x sc ore at Wee k 7 8.

C ha n ge fr o m baseli ne i n i nf or ma nt -rate d s u bject E Q-5 D i n de x sc ore at Wee k 7 8.

C ha n ge fr o m baseli ne i n m P D Q- 2 0 at Wee k 7 8.

C orrelati o n bet wee n t he pri mar y e n d p oi nt a n d cere bral a myl oi d pla q ue c o nte nt as 
meas ure d b y P E T i ma gi n g o ver ti me.
P har mac o ki netics

Ser u m c o nce ntrati o ns a n d P K para meters of a d uca n u ma b.
6. 4.
A d diti o n al E x pl or at or y O bjecti ves a n d E n d p oi nts
6. 4. 1.
A d diti o n al E x pl or at or y O bjecti ves








Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
St u d y  2 2 1 A D 3 0 1 is a m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, parallel -gr o u p 
P hase 3 st u d y  i n s u bjects wit h early A D, i ncl u di n g M CI d ue t o A D a n d a s u bset of mil d A D, 
f oll o we d by a n o pti o nal d ose - bli n de d L T E peri o d of u p t o 5 ye ars. A p pr o xi matel y  1 6 0 5 s u bjects 
(see Secti o n 1 6. 8 ) will be e nr olle d acr oss a p pr o xi matel y 1 5 0 ce nters gl o ball y.  T he pri mar y st u d y 
o bjecti ve is t o e val uate t he efficac y  of m o nt hl y d oses of a d uca n u ma b o n t he C D R-S B relati ve t o 
place b o. Sec o n dar y  o bjecti ves i ncl u de assess me nt of t he effect of m o nt hly d oses of a d uca n u ma b 
o n cli nical pr o gressi o n as c o m pare d t o place b o. T he safet y of m o nt hl y d oses of a d uca n u ma b 
will als o be e val uate d.
S u bjects will recei ve i nf usi o ns of a d uca n u ma b or place b o a p pr o xi matel y  e ver y 4 wee ks f or 
a p pr o xi matel y 1 8 m o nt hs (a t otal of 2 0 d oses).  S u bjects will be ra n d o mize d t o recei ve 
a d uca n u ma b l o w d ose:a d uca n u ma b hi g h d ose: place b o i n a 1: 1: 1 rati o.  T he ra n d o mizati o n will 
be stratifie d b y site a n d A p o E ε 4 stat us (ca rrier or n o n-carrier).  T he rati o of A p o E ε 4 carriers t o 
n o n- carriers i n t he st u d y p o p ulati o n will ge nerall y reflect t he distri b uti o n i n t he br oa der A D 
p o p ulati o n.  E nr oll me nt will als o be m o nit ore d, via i nteracti ve res p o nse tec h n ol o g y (I R T), s uc h 
t hat s u bjects wit h mil d A D re prese nt a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  
At t he e n d of t he d o u ble -bli n d, place b o -c o ntr olle d treat me nt peri o d, s u bjects w h o meet t he 
e xte nsi o n e ntr y criteria ma y e nter a l o n g-ter m safet y a n d efficac y e xte nsi o n peri o d, wit h all 
s u bjects recei vi n g a d uca n u ma b a p pr o xi matel y e ver y 4 wee ks ( u p t o a t otal of 6 5 d oses o ver 
5 ye ars).  T he E O T V isit will occ ur at Wee k 3 3 8 , or w he n t he last s u bject has ha d his or her 
Wee k 1 8 2 Visit, w hic he ver occ urs first.
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject o nl y partici pati n g i n t he 
place b o -c o ntr olle d peri o d of t he st u d y  will be u p t o a p pr o xi matel y 1 0 2 wee ks, i ncl u di n g a series 
of scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a n d a safet y f oll o w -u p ( F U) peri o d of 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 eac h s u bject partici pati n g i n t he place b o-c o ntr olle d 
peri o d a n d t he L T E peri o d will var y  a n d be u p t o a p pr o xi matel y  3 6 2 wee ks, i ncl u di n g a series of 
scree ni n g visits wit hi n 8 wee ks bef ore a d mi nistrati o n of t he first d ose, a 7 6 -wee k 
place b o -c o ntr olle d treat me nt peri o d, a 4 -wee k F U peri o d, a 2 5 6- wee k a d uca n u ma b d ose -bli n d 
treat me nt peri o d, a n d a safety F U peri o d of 1 8 wee ks after t he fi nal d ose.  T he F U peri o d of 
1 8 wee ks is base d o n a n esti mate d mea n eli mi nati o n half- life i n h u ma ns of 1 6 t o 2 4 da y s ( mea n 
a p pr o xi matel y 2 0 d a y s, base d o n res ults fr o m t he si n gle asce n di n g d ose st u d y [ St u d y 
2 2 1 A D 1 0 1]) a n d a nti ci pate d brai n c o nce ntrati o ns of a d uca n u ma b of less t ha n o ne -t hir d t he E C5 0
(i n hi bit or y c o nce ntrati o n at 5 0 % of t he ma xi m u m o bser ve d bi ol o gic effect) f or bi n di n g fi brillar 
a m yl oi d at 8 wee ks after t he last d ose.  
D uri n g t he place b o -c o ntr olle d peri o d, A p o E ε 4 carriers will recei ve place b o, 
a d uca n u ma b 3 m g / k g, or a d uca n u ma b 1 0 m g/ k g w hereas A p o E ε 4 n o n-carriers will recei ve 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6
place b o, a d uca n u ma b 6 m g/ k g, or a d uca n u ma b 1 0 m g/ k g.  A d uca n u ma b will be titrate d f or u p t o 
6 d oses pri or t o reac hi n g t he tar get d ose as s h o w n i n Ta ble 1 2 a n d Fi g ure 1 .  N ote: As of 
Pr ot oc ol Versi o n 4, 1 0 m g/ k g is t he tar get d ose f or all A p o E ε 4 carriers i n t he hi g h -d ose gr o u p.  
A p o E ε 4 carriers w h o were ra n d o ml y assi g ne d t o t he hi g h-d ose gr o u p w he n t he tar get d ose was 
6 m g/ k g ( u n der pr ot ocol versi o ns pri or t o Versi o n 4) m ust ha ve recei ve d 2 or m ore d oses at 
6 m g/ k g pri or t o bei n g titrate d u p t o 1 0 m g/ k g.  S u bjects w h o recei ve d place b o d uri n g t he 
place b o - c o ntr olle d peri o d will be assi g ne d t o treat me nt base d u p o n t heir A p o E ε 4 carrier stat us 
i n a 1: 1 rati o (a d uca n u ma b l o w d ose:a d uca n u ma b hi g h d ose) f or t he L T E peri o d, a n d
a d uca n u ma b will be titrate d f or u p t o 6 d oses pri or t o reac hi n g t he tar get d ose f oll o wi n g t he sa me 
sc he d ule descri be d f or t he place b o-c o ntr olle d peri o d.
See Secti o n 5. 3. 2 f or details of d osi n g sc he me m o dificati o n.  
I n di vi d ual d ose a dj ust me nts ma y als o be i m ple me nte d i n s u bjects w h o de vel o p A RI A.  See
Secti o n 7. 2. 1 .
I n vesti gat ors, st u d y site staff (e xce pt f or t he desi g nate d u n bli n de d p har macist/tec h nicia n), a n d 
st u d y s u bjects will be bli n de d t o t he s u bjects’ ra n d o mize d treat me nt assi g n me nt f or t he 
place b o - c o ntr olle d peri o d.  D uri n g t he L T E peri o d, I n vesti gat ors a n d s u bjects will re mai n 
bli n de d t o t he treat me nt assi g n me nt i n t he place b o- c o ntr olle d peri o d a n d t he a d uca n u ma b d ose 
f or t he L T E peri o d.
7. 2.
St u d y S pecifics
7. 2. 1.  
D ose S us pe nsi o n, M o dific ati o n, or Ter mi n ati o n f or A RI A E ve nts
Disc o nti n u ati o n of D osi n g f or a Give n S u bject
T he ce ntral M RI  rea di n g ce nter will re p ort i nci de nt cases of A RI A-E a n d A RI A- H t o b ot h t he 
S p o ns or a n d t he P I wit hi n a s pecifie d ti me after o bser vi n g t he fi n di n g o n M RI per t he i ma gi n g 
ma n ual pr oce d ures.  All cases of A RI A will be re vie we d b y t he S p o ns or a n d t he PI ; decisi o ns o n 
d osi n g c o nti n uati o n, i nterr u pti o n, or disc o nti n uati o n will be base d o n cli nical s y m p t o ms, a n d t he 
M RI  i nf or mati o n pr o vi de d b y t he ce ntral rea der.  I D M C n otificati o n r ules will be o utli ne d i n t he 
I D M C c harter.  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 
(i ncl u di n g t he criteria t o be met f or t he c o nti n uati o n, s us pe nsi o n/res u m pti o n, per ma ne nt 
disc o nti n uati o n of d osi n g d ue t o A RI A, res u m pti o n of d osi n g after d ose s us pe nsi o n d ue t o A RI A 
[i ncl u di n g r ules f or titrati n g u p t o t he assi g ne d d ose], a n d ma na ge me nt of rec urre nt A RI A) are 
pr o vi de d i n t he f oll o wi n g s u bsecti o n s.  D osi n g ma y als o be ter mi nate d at t he discreti o n of t he 
S p o ns or f or me dical reas 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7. 2. 1. 1.
A RI A -E C ases
T a ble 1 3:
Dis p ositi o n of A RI A - E C ases
Cli nic al S y m pt o m 
Se verit y
A RI A -E Se verit y o n M RI ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
As y m pt o m atic 
C o nti n ue d osi n g at 
c urre nt d ose a n d 
sc he d ule
S us pe n d d osi n g.  O nce A RI A -E res ol ves t he s u bject 
ma y res u me d osi n g at t he sa me d ose.  
Mil d
S us pe n d d osi n g.  O nce A RI A -E a n d cli nical s y m pt o ms res ol ve, t he s u bject ma y 
res u me d osi n g at t he sa me d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y i m p ort a nt 
e ve nt ” o nl y 1
Seri o us, e xce pt f or 
“ ot her m e dic all y 
i mp ort a nt e ve nt ” 2
Disc o nti n ue D osi n g
1 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 preve 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. 2 .
2 S A Es 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), 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/ 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. 2 .

S u bjects w h o de vel o p mi l d A RI A-E, per ce ntr al M RI re a di n g, wit h n o cli nic al 
s y m pt o ms at a n y ti me d uri n g t he st u d y ma y c o nti n ue i n t he st u d y at t heir c urre nt 
d ose.  S u bjects s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s)
u ntil t he A RI A- E has res ol ve d per t he ce ntrally rea d M RI .  I n a d diti o n, bi o mar ker, 
P K, a n d P B M C 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.  T he S p o ns or ma y re q uire t hat t he s u bjects disc o nti n ue d osi n g or 
c o nti n ue d osi n g at a l o wer d ose le vel base d o n re vie w of safet y a n d M RI data.

S u bjects w h o de vel o p m o der ate or se vere A RI A -E, per ce ntr al M RI re a di n g, wit h 
n o cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s) 
u ntil t he A RI A- E has res ol ve d per t he ce ntrall y rea d M RI .  I n a d diti o n, bi o mar ker, 
P K, a n d P B M C 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. If t he A RIA- E has res ol ve d a n d t he s u bjects re mai n as y m pt o matic 
(i n t he In vesti gat or’s o pi ni o n), t he s u bjects ma y  res u me treat me nt at t he sa me d ose.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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

S u bjects w h o de vel o p mi l d, m o der ate, or se vere A RI A- E, per ce ntr al M RI 
re a di n g, acc o m p a nie d b y mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y 
i m p ort a nt e ve nt ” o nl y) cli nic al s y m pt o ms at a n y ti me d uri n g t he st u d y will 
te m p orarily s us pe n d treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or 
assess me nts a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 
4 wee ks ( ±5 d a y s) u ntil t he A RI A -E has res ol ve d per t he ce ntrall y rea d M RI .  I n 
a d diti o n, b i o mar ker, P K, a n d P B M C 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.  If t he A RI A -E has res ol ve d a n d t he 
cli nical s ym pt o ms ha ve res ol ve d (i n t he In vesti gat or’s o pi ni o n), t he s u bjec t ma y 
res u me treat me nt at t he sa me d ose.  

S u bjects w h o de vel o p mil d, m o derate, or se vere A RI A- E, per ce ntral M RI  rea di n g, 
acc o m pa nie d b y seri o us (e xce pt “ ot her me dicall y i m p orta nt e ve nt”) cli nical 
s ym pt o ms at a n y  ti me d uri n g t he st u d y will per ma ne ntl y disc o nti n ue treat me nt b ut 
re mai n i n st u d y.  S u bjects s h o ul d c o m plete a F U Visit 1 8 wee ks after t he fi nal d ose, 
pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 ,
a n d Ta ble 1 1 ), a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A 
e ver y 4 wee ks ( ±5 d a y s) u ntil t he A RI A- E has res ol ve d per ce ntrall y rea d M RI .  I n 
a d diti o n, bi o mar ker, P K, a n d P B M C 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.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.
7. 2. 1. 2.
A RI A -H ( Micr o he m orr h a ge)
I n t his st u dy, ne w i nci de nt micr o he m orr ha ges are defi ne d as ne w i nci de nt mic r o he m orr ha ges 
t hat occ ur o n treat me nt a n d d o n ot i ncl u de micr o he m orr ha ges at baseli ne.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9
T a ble 1 4:
Dis p ositi o n of A RI A - H ( Micr o he m orr h a ge) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Micr o he m orr h a ges 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
≥ 1 a n d ≤ 4
≥ 5 a n d ≤ 9
≥ 1 0
As y m pt o m atic
C o nti n ue d osi n g at c urre nt 
d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble, t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me 
d ose.  
M o der ate
Se vere
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt micr o he m orr ha ges = ne w i nci de nt micr o he m orr hages o n treat me nt; d oes n ot i ncl u de 
micr o he m orr ha ges at baseli ne.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 o l 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 2 .
As y m pt o m atic A RI A -H ( Micr o he m orr h a ge) 

S u bjects w h o de vel o p a ≥ 1 a n d ≤ 4 ne w i nci de nt micr o he m orr h a ge(s) [ mil d] at 
a n y ti me d uri n g t he st u d y ma y c o nti n ue treat me nt at t he c urre nt d ose.

S u bjects w h o de vel o p ≥ 5 a n d ≤ 9 ne w i nci de nt micr o he m orr h a ges [ m o der ate]
occ urri n g at a n y ti me d uri n g t he st u d y will te m p oraril y s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d di ti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ± 5 d a y s) u ntil t he 
micr o he m orr ha ge is c o nfir me d as sta ble per t he ce ntrall y  rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C sa m ples will be c ollecte d at t he first u nsc he d ule d visit 
f oll o wi ng a n e pis o de of A RI A.  A micr o he m orr ha ge is c o nsi dere d sta ble if t here is 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 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 d a y s) later.  O nce t he micr o he m orr ha ge is dee me d sta ble, s u bjects ma y  
res u me treat me nt at t he sa me d ose.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0

S u bjects w h o de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges [se vere] d uri n g t he 
st u d y will per ma ne ntl y disc o nti n ue treat me nt b ut re mai n i n st u d y .  S u bjects s h o ul d 
c o m plete a F U Visit 1 8 wee ks after t he fi nal d ose, pr ot oc ol -re q uire d tests a n d 
assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ), a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ± 5 d a y s)
u ntil t he micr o he m orr ha ges are dee me d sta ble per ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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 y m pt o m atic A RI A -H ( Micr o he m orr h a ge)

S u bjects w h o de vel o p ≤ 9 ne w i nci de nt micr o he m orr h a ges ( mil d or m o der ate) 
a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt e ve nt ” o nl y 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s) u ntil t he A RI A -H 
( micr o he m orr ha ge(s) is c o nfir me d sta ble per t he ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C sa m ples will be c ollecte d at t he first u nsc he d u le d visit 
f oll o wi n g a n e pis o de of A RIA.  Micr o he m orr ha ges are c o nsi dere d sta ble if t here is 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 d a y s) later.  O nce A RI A- H ( micr o he m orr ha ge) is dee me d sta ble a n d t he 
cli nical s ym pt o ms ha ve res ol ve d (i n t he In vesti gat or’s o pi ni o n), t he s u bject ma y  
res u me treat me nt at t he sa me d ose.

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m port a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h micr o he m orr h a ge(s) will 
per ma ne ntl y disc o nti n ue treat me nt b ut re mai n i n st u d y .  S u bjects s h o ul d c o m plete a 
F U Visit 1 8 wee ks after t he fi nal d ose, pr ot oc ol -re q uire d tests a n d assess me nts at a 
s u bset of t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ), a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s) u ntil t he 
micr o he m orr ha ge(s) is c o nfir me d sta ble per ce ntrall y  rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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 de vel o p ≥ 1 0 ne w i nci de nt micr o he m orr h a ges (se vere) , re gar dless of 
s ym pt o m se verit y, d uri n g t he st u d y will per ma ne ntl y  disc o nti n ue treat me nt b ut 
re mai n i n st u d y.  S u bjects s h o ul d c o m plete a F U V isit 1 8 wee ks after t he fi nal d ose, 
pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0
a n d Ta ble 1 1 ), a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A 
e ver y 4 wee ks ( ±5 d a y s) u ntil t he micr o he m orr ha ges are dee me d sta ble per ce ntrall y 
rea d M RI.  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A RI A.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7. 2. 1. 3.
A RI A -H ( S u perfici al Si der osis)
T a ble 1 5:
Dis p os iti o n of A RI A- H ( S u perfici al Si der osis) C ases
Cli nic al 
S y m pt o m  
Se verit y
Ne w I nci de nt Are as of S u perfici al Si der osis 1 ( Ce ntr al Re a d)
Mil d
M o der ate
Se vere
1
2
> 2
As y m pt o m atic
C o nti n ue d osi n g at 
c urre nt d ose a n d sc he d ule
S us pe n d d osi n g.  O nce A RI A -H 
is sta ble t he s u bject ma y res u me 
d osi n g at t he sa me d ose.  
Disc o nti n ue d osi n g
Mil d
S us pe n d d osi n g.  O nce A RI A -H sta bilizes a n d cli nical 
s y m pt o ms res ol ve, t he s u bject ma y res u me d osi n g at t he sa me 
d ose.  
M o der ate
Se vere 
Seri o us “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” o nl y 2
Seri o us, e xce pt 
f or “ ot her 
me dic all y 
i mp ort a nt 
e ve nt ” 3
Disc o nti n ue d osi n g
1 N e w  i nci de nt s u perficial si der osis = ne w i nci de nt s u perficial si der osis o n treat me nt.
2 “ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d ose 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 as 
descri be d i n Secti o n 1 5. 1. 2 .
3 S A Es 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), 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/ or res ult i n 
persiste nt or si g nific a 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. 2 .
As y m pt o m atic A RI A -H ( S u perfici al Si der osis)

S u bjects w h o de vel o p a si n gle i nci de nt f oc al are a of he m osi der osis (als o referre d 
t o as s u perfici al si der osis) [ mil d] ma y  c o nti n ue treat me nt at t he c urre nt d ose, b ut 
m ust ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 da y s) u ntil 
t he s u perficial si der osis is c o nfir me d as sta ble per t he ce ntrally rea d M RI.  I n 
a d diti o n, bi o mar ker, P K, a n d P B M C sa m ples wil l 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 perficial si der osis is c o nsi dere d 
sta ble if t here is 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 nit ial detecti o n M RI a n d t he 
M RI  perf or me d 4 wee ks ( ±5 d a y s) later.  

S u bjects w h o de vel o p 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
[ m o der ate] occ urri n g at a n y  ti me d uri n g t he st u d y will te m p oraril y s us pe n d 
treat me nt, b ut s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts a n d, i n 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s)
u ntil t he A RI A -H (s u perficia l si der osis) is c o nfir me d as sta ble per t he ce ntrall y rea d 
M RI .  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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.  O nce t he s u perficial si der osis is 
dee me d sta ble, t he s u bjects ma y  res u me treat me nt at t he sa me d ose. 

S u bjects w h o de vel o p > 2 f oc al are as of he m osi der osis (s u perfici al si der osis)
[se vere] occ urri n g at a n y ti me d uri n g t he st u d y  m ust per ma ne ntly disc o nti n ue 
treat me nt b ut re mai n i n st u d y . S u bjects s h o ul d c o m plete a F U V isit 1 8 wee ks after 
t he fi nal d ose, pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits 
(see Ta ble 1 0 a n d Ta ble 1 1 ), a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI 
a n d M O C A e ver y 4 wee ks ( ±5 d a y s) u ntil t he A RI A -H (s u perficial si der osis) is 
c o nfir me d as sta ble per t he ce ntrall y  rea d M RI.  I n a d diti o n, bi o mar ker, P K, a n d 
P B M C 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 y m pt o m atic A RI A -H (s u perfici al si der osis)

S u bjects w h o de vel o p ≤ 2 ne w f oc al are as of s u perfici al si der osis ( mil d or 
m o der ate) a n d mil d, m o der ate, se vere, or seri o us ( “ ot her me dic all y i m p ort a nt 
e ve nt ” o nl y) cli nical s y m pt o ms will te m p oraril y  s us pe n d treat me nt, b ut s h o ul d 
c o m plete all sc he d ule d cli nic visit s f or assess me nts a n d, i n a d diti o n, ha ve a n 
u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s) u ntil t he A RI A -H 
s u perficial si der osis is c o nfir me d sta ble per t he ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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 perficial si der osis is c o nsi dere d sta ble if t here is 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 d a y s) later.  O nce t he A RI A - H (s u perficial si der osis) is dee me d sta ble 
a n d t he cli nical s y m pt o ms ha ve res ol ve d (i n t he In vesti gat or’s o pi ni o n), t he s u bjects 
ma y res u me treat me nt at t he sa me d ose.

S u bjects w h o e x perie nce seri o us (e xce pt “ ot her me dic all y i m p ort a nt e ve nt ” 
[ Secti o n 1 5. 1. 2 ]) cli nic al s y m pt o ms ass oci ate d wit h A RI A-H (s u perfici al 
si der osis) will per ma ne ntl y  disc o nti n ue treat me nt b ut re mai n i n st u d y .  Su bjects
s h o ul d c o m plete a F U V isit 1 8 wee ks after t he fi nal d ose, pr ot oc ol -re q uire d tests a n d 
assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ), a n d, i n 
a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI  a n d M O C A e ver y 4 wee ks ( ±5 d a y s) 
u ntil t he s u perficial si der osis is c o nfir me d sta ble per ce ntrall y rea d M RI.  I n a d diti o n, 
bi o mar ker, P K, a n d P B M C 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 de vel o p > 2 ne w f oc al are as of s u perfici al si der osis (se vere) 
re gar dless of cli nical sy m pt o m se verit y  will per ma ne ntl y disc o nti n ue treat me nt b ut 
re mai n i n st u d y. S u bjects s h o ul d c o m plete a F U V isit 1 8 wee ks after t he fi nal d ose, 
pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0
a n d Ta ble 1 1 ), a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or a n M RI a n d M O C A 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
e ver y 4 wee ks ( ±5 d a y s) u ntil t he s u perficial si der osis is c o nfir me d sta ble per 
ce ntrall y rea d M RI.  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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.
See Secti o n 7. 2. 1. 6 f or details o n res u m pti o n of d osi n g w he n s us pe nsi o n occ urs d uri n g t he 
titrati o n peri o d a n d Secti o n 7. 2. 1. 7 f or g ui deli nes o n res u mi n g d osi n g after a rec urre nce of 
A R I A.
7. 2. 1. 4.
A RI A -H ( M acr o he m orr h a ge)
S u bjects 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 s ym pt o m se verit y d uri n g t he st u d y, will per ma ne ntl y  disc o nti n ue 
treat me nt, b ut re mai n i n st u d y.  S u bjects s h o uld c o m plete a F U V isit 1 8 wee ks after t he fi nal 
d ose, pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 a n d
Ta ble 1 1 ) a n d, i n a d diti o n, ha ve a n u nsc he d ule d visit f or M RI  a n d M O C A e ver y 4 wee ks 
( ±5 d a y s) u ntil t he macr o hem 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 t here is 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 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.  I n a d diti o n, bi o mar ker, P K, a n d P B M C 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 -H 
( macr o he m orr ha ge).
7. 2. 1. 5.  
C oi nci de nt A RI A- H a n d A RI A -E C ases
S u bjects w h o de vel o p A RI A- H c oi nci de nt wit h A RI A- E at a n y ti me d uri n g t he st u d y  will f oll o w 
t he m ost restricti ve g ui deli nes.  Pri or t o res u mi n g treat me nt, w here a p plica ble, A RI A-E m ust 
res ol ve, A RI A-H m ust be dee me d sta ble, a n d t he s u bject m ust be as y m pt o m atic.  F or e xa m ple, if 
a s u bject e x perie nces as y m pt o matic A RI A- H ( 1 -4 micr o he m orr ha ges) c oi nci de nt wit h A RI A -E 
assesse d as m o derate o n M RI  a n d acc o m pa nie d b y mil d cli nical s ym pt o ms, t he d ose s h o ul d be 
s us pe n de d per t he A RI A-E g ui deli nes s u m marize d i n Ta ble 1 3 .  I n a d diti o n, u nsc he d ule d visits 
s h o ul d occ ur as descri be d i n Secti o n 7. 2. 1. 1 t hr o u g h Secti o n 7. 2. 1. 4 .
7. 2. 1. 6.
Res u m pti o n of St u d y Tre at me nt After S us pe nsi o n d ue t o A RI A
7. 2. 1. 6. 1.
M RI M o nit ori n g
W he n treat me nt res u mes after a d ose s us pe nsi o n d ue t o A RI A, a n M RI a n d M O C A will be 
perf or me d 2 wee ks ( ± 5 d a y s) after t he sec o n d a d mi nistrati o n of t he restarte d d ose.  I n a d diti o n, if 
treat me nt was s us pe n de d d uri n g t he d ose titrati o n pri or t o t he s u bject reac hi n g t he ma xi m u m 
assi g ne d d ose, a n M RI a n d M O C A will be perf or me d 2 wee ks ( ± 5 d a 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 
(titrati o n peri o d of 6 d oses a n d a fi nal M RI after t he sec o n d d ose at 1 0 m g/ k g) t o mai ntai n st u dy 
bli n di n g, n ot c o u nti n g u nsc he d ule d M RI visits f or m o nit ori n g of A RI A.  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 E ve nts ( Secti o n 4. 2 ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
7. 2. 1. 6. 2.
D osi n g U p o n Res u m pti o n of St u d y Tre at me nt
S u bjects w h o s us pe n d treat me nt d ue t o A RI A ma y res u me treat me nt at t he sa me d ose if th e y  
meet t he criteria a s descri be d i n Secti o ns 7. 2. 1. 1 t o 7. 2. 1. 5.   S u bjects w h o s us pe n d a n d t he n 
res u me d osi n g after ha vi n g alrea dy reac he d t heir assi g ne d t o p d ose le vel are t o c o nti n ue d osi n g 
at t hat d ose le vel. H o we ver, if d osi n g is s us pe n de d pri or t o a s u bject reac hi n g t heir assi g ne d t o p 
d ose le vel, t he s u bject ( 1) m ust recei ve at least 2 d oses at t he restart d ose bef ore titrati n g u p t o 
t he ne xt d ose le vel a n d ( 2) m ust c o m plete at least t he re q uire d n u m ber of d oses at t hat d ose le vel 
per t heir assi g ne d treat me nt gr o u p, as o utli ne d i n t he ri g ht c ol u m n of Ta ble 1 6 . 
T a ble 1 6:
Res u m pti o n of St u d y Tre at me nt F oll o wi n g D ose S us pe nsi o n D ue t o A RI A 
D uri n g Titr ati o n
Assi g ne d Tre at me nt 
Gr o u p
( M a xi m u m D ose)
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses at 
C urre nt D ose Le vel 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
A p o E ε 4 ( +)
L o w D ose ( 3 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2
6 m g/ k g
1
2
6 m g/ k g
2
2
A p o E ε 4 ( -)
L o w D ose ( 6 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
3
3 m g/ k g
2
2
3 m g/ k g
3
2
3 m g/ k g
4
2
Hi g h D ose ( 1 0 m g/ k g)
1 m g/ k g
1
2
1 m g/ k g
2
2
3 m g/ k g
1
2
3 m g/ k g
2
2


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
Assi g ne d Tre at me nt 
Gr o u p
( M a xi m u m D ose)
D ose Le vel at W hic h 
A RI A Occ urre d
N u m ber of D oses Pri or 
t o A RI A
N u m ber of D oses at 
C urre nt D ose Le vel 
Nee de d Bef ore G oi n g 
t o t he Ne xt Hi g her 
D ose
6 m g/ k g
1
2
6 m g/ k g
2
2
7. 2. 1. 7.
M a n a ge me nt After Rec urre nt A RI A ( D osi n g a n d M RI)
If t he s u bject has m ore t ha n o ne occ urre nce of A RI A (i.e., a sec o n d or a n y a d diti o nal
occ urre nce s of A RI A -E or of A RI A -H, or A RI A -E a n d A RI A - H) t hat re q uires d ose s us pe nsi o n
( per criteria i n Secti o n 7. 2. 1 . 1, Secti o n 7. 2. 1. 2 , a n d Secti o n 7. 2. 1. 3 ), after t he A RI A resol ves or 
sta bilizes, t he s u bject is t o res u me d osi n g at t he sa me d ose as t hat descri be d i n Secti o n 7. 2. 1. 6. 2 .  
O nce d osi n g has res u me d, t he g ui deli nes o utli ne d i n Ta ble 1 6 a p pl y.  If a s u bject res u mes 
treat me nt after A RI A, a n M RI a n d M O 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 t he restarte d d ose, a n d 2 wee ks ( ± 5 da y s) after e ver y sec o n d d ose u ntil t he 
c o m pleti o n of titrati o n, wit h all s u bject s ass u me d t o be titrati n g t o 1 0 m g / k g ( 6 d oses) t o 
mai ntai n st u d y  bli n di n g.  M RIs will ot her wise be perf or me d as i n dicate d i n t he Sc he d ule of 
E ve nts ( Secti o n 4. 2 ).
S u bjects w h o de vel o p A RI A d uri n g t he place b o -c o ntr olle d peri o d b ut c o nti n ue or res u me 
treat me nt at a n acti ve d ose are eli gi ble t o e nter t he L T E peri o d a n d will mai ntai n t he d osi n g 
sc he me fr o m t he place b o-c o ntr olle d peri o d i nt o t he L T E, w hic h ma y  i ncl u de a c o nti n uati o n o n 
t he sa me d ose or c o m pleti o n of titrati o n i nt o t he L T E peri o d.
F or s u bjects w h o disc o nti n ue d treat me nt d ue t o a t hir d A RI A e ve nt t hat re q uire d d ose s us pe nsi o n 
u n der a pre vi o us versi o n of t he pr ot oc ol a n d re mai ne d o n t he st u d y: t hese s u bjects will n ot 
res u me d osi n g.
F or s u bjects w h o res u me d d osi n g at t he ne xt l o wer d ose after rec urr e nt A RI A u n der a pre vi o us 
versi o n of t he pr ot oc ol a n d ha ve n o t titrate d t o t heir tar get d ose: t hese s u bjects will c o nti n ue 
d osi n g (i.e., recei ve 2 d oses at t hat d ose le vel bef ore titrati n g u p t o t he ne xt hi g her d ose).
F or s u bjects w h o d ose -re d uce d t o placeb o after rec urre nt A RI A u n der a pre vi o us versi o n of t he 
pr ot oc ol a n d re mai ne d i n t he st u d y: t hese s u bjects ca n res u me d osi n g d uri n g t he L T E peri o d a n d 
will be titrate d u p t o his or her ra n d o ml y assi g ne d d ose usi n g t he sa me re gi me n as t hat descri be d 
f or t he place b o -c o ntr olle d peri o d (see Ta ble 1 2 a n d Fi g ure 1 ). 
F or s u bjects w h o d ose -re d uce d t o place b o after rec urre nt A RI A a n d t he n res u me d d osi n g at 
a d uca n u ma b 1 m g/ k g d uri n g t he L T E peri o d u n der a pre vi o us versi o n of t he pr ot oc ol: t hese 
s u bjects ca n be titrate d u p t o his or her ra n d o mly assi g ne d d ose usi n g t he sa me re gi me n as t hat 
descri be d f or t he place b o -c o ntr olle d peri o d (see Ta ble 1 2 a n d Fi g ure 1 ).
F or s u bjects w h o ha d d ose s us pe nsi o n d ue t o a rec urre nt A RI A e ve nt pri or t o t he i m ple me ntati o n 
of Pr ot oc ol Versi o n 6. 0 t hat di d n ot res ol ve or sta bilize u ntil after t he i m ple me ntati o n of Pr ot oc ol 
Versi o n 6. 0 : t hese s u bjects are t o res u me d osi n g at t he sa me d ose as t hat descri be d i n 
Secti o n 7. 2. 1. 6. 2 .






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 8
  
T he M RI  at Scree ni n g Visit 2 s h o ul d be d o ne o nl y after t he 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 P E 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. 
S u bject eli gi bilit y  f or t he st u d y will be deter mi ne d n o m ore t ha n 6 0 da ys pri or t o st u d y e ntr 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 relate d t o P E T 
sca ns a n d is s u bject t o S p o ns or a p pr o val.
S u bjects w h o fail Scree ni n g will be per mitte d t o be rescree ne d o nce a t t he S p o ns or’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 > 0. 5, 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 of t he i nitial e val uati o n.
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 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 hese me dicati o ns has bee n sta bilize d f or t he re q uire d peri o d.  
7. 3. 2.
Tre at me nt
Eli gi ble s u bjects will re p ort t o t he st u d y  site t o recei ve st u d y treat me nt e ver y 4 wee ks f or 
7 6 wee ks ( 2 0 d oses).  All 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 will be 
eli gi ble t o e nter t he L T E peri o d a n d will recei ve st u d y treat me nt e very 4 wee ks f or u p t o a n 
a d diti o nal 2 5 6 wee ks ( 6 5 d oses), wit h t he first d ose a d mi nistere d a p pr o xi matel y  4 wee ks after 
t he fi nal d ose i n t he place b o-c o ntr olle d peri o d of t he st u d y.  Su bjects will c o nti n ue treat me nt 
o nce e ver y  4 wee ks, u ntil Wee k
3 3 6, or u nti l t he last s u bject has ha d his or her Wee k 1 82 Visit, 
w hic he ver occ urs first .
7. 3. 3.
F oll o w -U p
All s u bjects partici pati n g i n t he place b o -c o ntr olle d peri o d are t o ret ur n t o t he st u d y  site 
a p pr o xi matel y 2 wee ks after t he fi nal d ose f or cli nical assess me nts.
S u bject s partici pati n g i n t he place b o-c o ntr olle d peri o d a n d n ot e nteri n g t he L T E peri o d are t o 
ret ur n t o t he st u d y site f or a F U Visit at Wee k 9 4 ( 1 8 wee ks after t he last place b o -c o ntr olle d 
peri o d d ose).  T he fi nal st u d y  visit f or t hese s u bjects will be Wee k 9 4.
S u bjects w h o partici pate i n t he L T E peri o d are t o ret ur n t o t he st u d y  site t o recei ve t heir first 
L T E d ose a p pr o xi matel y  4 wee ks after t heir last d ose i n t he place b o-c o ntr olle d peri o d of t he 
st u d y.  A F U Visit will occ ur 1 8 wee ks after t he last LT E peri o d d ose.  T he ti mi n g of t he fi nal 
st u d y visit f or s u bjects partici pati n g i n t he L T E peri o d will var y , si nce the E O T V isit f or a 
s u bject w h o partici pates i n t he LT E peri o d will oc c ur at Wee k 3 3 8, or w he n t he last s u bject has 
ha d his or her Wee k 1 8 2 Visit, w hic he ver occ urs first .
S u bjects w h o disc o nti n ue treat me nt are t o re mai n i n t he st u d y , atte n d a F U V isit 1 8 wee ks after 
t he fi nal d ose, a n d i m me diatel y c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ) u ntil t he e n d of t he st u d y  or u ntil wit h dra wal of 
c o nse nt.  S u bjects w h o wit h dra w fr o m t he st u d y are e nc o ura ge d t o ret ur n f or F U assess me nts 
1 8 wee ks after t heir last d ose of s t u d y treat me nt.
7. 4.
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.
D osi n g ma y  be ter mi nate d b y t he S p o ns or at t he rec o m me n dati o n of t he I D M C, base d 
e xcl usi vel y o n safety a n d t olera bilit y data or f oll o wi n g t he f utilit y a nalys is, or at t he discreti o n of 
t he S p o ns or; t heref ore, t here are n o st u dy -s pecific st o p pi n g r ules defi ne d i n t his pr ot oc ol.  
7. 5.
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.   T he E O T V isit f or a s u bject w h o c o nti n ues i n t he 
st u d y will occ ur at Wee k 3 3 8, or w he n t he last s u bject has ha d his or her Wee k 1 8 2 Visit, 
w hic he ver occ urs first.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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
T o be eli gi ble t o partici pate i n t his st u d y , ca n di dates m ust meet t he f oll o wi n g eli gi bilit y criteria 
at Scree ni n g 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  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 nd 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.
2.
A ge d 5 0 t o 8 5 y ears 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 , please refer t o 
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 or mil d A D.
5.
M ust ha ve a p ositi ve a m y l oi d P E T sca 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 f or s u bjects n ot partici pati n g i n t h e a m yl oi d P E T 
s u bst u d y.  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 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 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:

A C D R gl o bal sc ore of 0. 5.

A n R B A N S sc ore of 8 5 or l o wer i n dicati ve of o bjecti ve c o g niti ve i m pair me nt ( base d 
u p o n t he Dela y e d Me m or y In de x sc ore).  

A n M M S E sc ore bet wee n 2 4 a n d 3 0 (i ncl usi ve).
7.
A part fr o m a cli nical dia g n osis of earl y 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  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 pa rt 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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
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 d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n.  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 , 
an d t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
8. 2.
E xcl usi o n Criteri a
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 al 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 nc e a b use, vita mi n B 1 2 deficie nc y, a b n or mal t h yr 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 o-te 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).

Greater 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).  

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 define 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 
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 safet y 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 
Ass 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 Scre e ni n g.
8.
Cli nicall y  si g nifica nt 1 2-lea d E C G a b n or malities, as deter mi ne d by t he I n 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 ( b l 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 t he S p o ns or:  

S u bjects wit h ca ncers i n re missi o n m ore t ha n 5 ye ars 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.
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 (e. g., re peate d val ues of as partate a mi n otra nsferase [ A S T] a n d ala ni ne 
a mi n otra nsferase [ A L T] ≥ 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 S cree 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. Hist 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 ( HI V).
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 or he pati tis B 
vir us ( defi ne d as p ositi ve f or b ot h he patitis B s urface a nti ge n A N D he patitis B c ore 
a nti b o d y).
1 8. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns, or hist or y of hy p erse 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 (refer t o t he I B f or i nf or mati o n o n t he 
cli nical f or m ulati o n).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9. 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, 
w hic h 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 0. 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 g niti 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 1. 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 ni n g Visit 1 a n d d uri n g S cree ni n g u p t o St u d y  D a 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 S creen i n g u p t o St u d y D a y 1.
2 2. Use of me dicati o ns wit h platelet a nti -a g gre ga nt or a nti -c 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 3. Use of illicit narc otic me dicati o n.
2 4. 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 5. 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 A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 6. 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 wit hi n 1 2 m o nt hs of 
Scree ni n g 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  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- E 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 8. Partici pati o n i n a pre vi o us st u d y  wit h a d uca n u ma b (s u bject is eli gi ble if he/s he di d n ot 
recei ve acti ve a d uca n u ma b).
St u dy Pr oce d ures
2 9. C o ntrai 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 0. 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 1. A ne gati ve P E T sca n res ult wit h a n y a myl 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 2. 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
3 3. F o r s u bjects w h o c o nse nt t o LP, a n y  c o ntrai n dicati o ns t o ha vi n g a L P (e. g., platelet c o u nt 
< 1 0 0, 0 0 0/ µ L , l u m bar s pi ne def or mity).  A n y s y m pt o ms ca use d b y or relate d t o t he 
o pti o nal L P d uri n g Scree ni n g m ust be res ol ve d pri or t o ra n d o mizati o n ( Da y 1).  S u bjects
ma y  still partici pate i n t he o verall st u d y e ve n if partici pati o n i n t he o pti o nal LP p orti o n is 
c o ntrai n dicate d.  
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 will be per mitte d t o be 
rescree ne d o nce at t he S p o ns or’s discreti o n, e xce pt t h ose w h o fail d ue t o P E T, M M S E, 
C D R gl o bal sc ore > 0. 5, he patitis B or C, or a b n or mal M RI  fi n di n gs. ( S u bjects w h o fail 
Scree ni n g d ue t o a C D R gl o bal sc ore of 0 ma y  be rescree ne d; s uc h s u bjects will be 
all o we d t o re peat t he scree ni n g C D R assess me nt after 6 m o nt hs.)
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 of 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 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 7 8:
1.
S u bject m ust ha ve c o m plete d t he place b o -c o ntr olle d peri o d of t he st u d y i ncl u di n g t he 
Wee k
7 8 Visit.  S u bject m ust ha ve ta ke n at least 1 4 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 ose was s us pe n de d d ue t o A RI A ( See 
Secti o n 7. 2. 1 ).  S u bjects w h o d o n ot meet t hese criteria m a y  e nter t he L T E peri o d o nl y 
wit h S p o ns or’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 pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt ( or asse 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.
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 h e 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.


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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 c o g niti ve a n d f u ncti o nal a bilities.  T he i nf or ma nt/care part ner m ust mi ni mall y 
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 s taff a b o ut t he 
s u bject a n d a grees t o atte n d i n pers o n cli nic visits t hat re q uire part ner i n p ut f or scale 
c o m pleti o n.  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 t he use of t he sa me i nf or ma nt/care part ner f or t he d urati o n of t he st u d y is 
e nc o ura ge d.
8. 4.
E xcl usi o n Criteri a f or 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 at Wee k 7 8 t he y ha ve:
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.


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9.
E N R O L L M E N T, R E GI S T R A TI O N, A N D R A N D O MI Z A T I O N
9. 1.
Scree ni n g a n d E nr oll me nt
S u bjects ( or t heir le gall y a ut h orize d re presentati ve, w here a p plica ble) 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 
ca n c o m plete t he ne ur oc o g niti ve scales ( C D R, M M S E a n d R B A N S) 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 3 scales the 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 directl y t o t he f ull 
c o nse nt pr ocess w hic h w o ul d 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 (I C 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.  A p o E ge n oty pi n g ma y be perf or me d at Visit 1 pri or t o ot her scree ni n g assess me nts.
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 i n itiall 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 y s; 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 relate d t o P E T sca ns a n d is s u bject t o S p o ns or a p pr o val.  If a s u bject is e xcl u de d 
fr o m t he st u d y, t he reas o ns f or e xcl usi o n will 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.  T he t otal st u d y  d urati o n f or eac h s u bject partici pati n g o nly i n t he 
place b o -c o ntr olle d peri o d will be a p pr o xi matel y 1 0 2 wee ks (a p pr o xi matel y a n 8-wee k scree ni n g 
peri o d, 7 6 wee ks of place b o or a d uca n u ma b d osi n g, a n d 1 8 wee ks of F U ).  
9. 2.
R a n d o miz ati o n a n d Re gistr ati o n of S u bjects
S u bjects will be re gistere d at t he Scree ni n g Visit a n d ra nd o mize d o nl y  after all 
baseli ne assess me nts ha ve bee n c o m plete d a n d t he In 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 .  N o s u bject ma y be gi n treat me nt pri or t o assi g n me nt 
of a u ni q ue i de ntificati o n n u m ber (re gistrati o n) a n d ra n d o mizati o n.  A n y  s u bject i de ntificati o n 
n u m bers or ra n d o mizati o n sc he d ule assi g n me nts 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.  Rescree ne d s u bjects will be assi g ne d a ne w n u m ber.  
S u bjects wil l be ra n d o mize d t o recei ve a d uca n u ma b l o w d ose:a d uca n u ma b hi g h d ose: place b o i n 
a 1: 1: 1 rati o.  T he ra n d o mizati o n will be stratifie d b y  site a n d A p o E ε 4 stat us (carrier or 
n o n -carrier).  S u bjects ra n d o mize d t o place b o at t he start of t he place b o- c o ntr olle d peri o d will 
als o be ra n d o mize d t o recei ve d ose -bli n de d a d uca n u ma b (l o w d ose: hi g h d ose, 1: 1 rati o) f or t he 
L T E peri o d a n d r a n d o mizati o n will be stratifie d b y s u bject A p o E ε 4 carrier stat us.  Treat me nt 
gr o u p assi g n me nts f or t he place b o -c o ntr olle d peri o d a n d t he L T E peri o d will be assi g ne d at 
St u d y  D a y 1.  E nr oll me nt will be m o nit ore d, via t he I R T, s uc h t hat t he p o p ulati o n of s u bjects 
wit h mil d A D re prese nts a s mall perce nta ge of t he t otal e nr olle d i n t he trial.  S u bjects w h o 
wit h dra w fr o m t he st u d y ma y  n ot be re place d.
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.


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9. 3.
Bli n di n g Pr oce d ures
T his st u d y  c o nsists of a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d peri o d, f oll o we d b y a 
d ose -bli n de d L T E peri o d wit h all s u bjects recei vi n g a d uca n u ma b.  
F or t he d o u ble -bli n de d place b o -c o ntr olle d peri o d, all st u d y  staff w h o c o n d uct s u bject 
assess me nts will be bli n de d t o t he s u bject treat me nt assi g n me nts.  T he rati n g H C Ps s h o ul d 
re mai n bli n de d t o treat me nt assi g n me nt as well as s u bject care ma na ge me nt a n d o nl y ha ve access 
t o t he i nf or mati o n necessar y t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  As a 
place b o matc h is n ot pr o vi de d f or t he st u d y, u n bli n de d p har mac y staff are re q uire d t o ma na ge all 
as pects of st u d y treat me nt recei pt, dis pe nsi n g, a n d pre parati o n.  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 nme 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 bli n de d st u d y tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y  m o nit or, a n d t he 
u n bli n de d 
or Bi o ge n safet y staff.
F or t he L T E peri o d , t he d ose i nf or mati o n m ust re mai n restricte d.  T he rati n g a n d treati n g H C P 
s h o ul d re mai n bli n de d t o treat me nt assi g n me nt a n d o nl y ha ve access t o t he i nf or mati o n 
necessar y  t o carr y o ut t heir res p o nsi bilities as detaile d i n Secti o n 4. 3. 1 .  T o mai ntai n t he st u d y  
bli n d, it is i m perati ve t hat d ose i nf or mati o n is 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 bli n de d st u d y  tea m, eit her at t he st u d y site or at Bi o ge n or its re prese ntati ves, 
e xce pt t he u n bli n de d p har macist ( or desi g nee), t he u n bli n de d p har mac y m o nit or, a n d t he 
u n bli n de d 
or Bi o ge n safet y staff.  


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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/ O R 
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 pe r 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:

A RI A- E acc o m pa nie d b y seri o us cli nical s y m pt o ms e xce pt f or “ ot her me dicall y  
i m p orta nt e ve nt” as defi ne d i n Ta ble 1 3 .

S y m pt o matic A RI A -H ( micr o he m orr ha ges) wit h seri o us cli nical s y m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 1 4 .

S y m pt o matic A RI A -H (s u perficial si der osis) wit h or seri o us cli nical s y m pt o ms 
e xce pt f or “ ot her me dicall y  i m p orta nt e ve nt” as defi ne d i n Ta ble 1 5 .

A RI A - H wit h ≥ 1 0 micr o he m orr ha ges a n d/ or > 2 f ocal areas of s u perficial 
si der osis.  

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).
See Secti o n 7. 2. 1 f or f ull details re gar di n g disc o nti n uati o n a n d d ose re d ucti o n d ue t o 
A RI A -E or A RI A -H.

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 
a n d pre g na nc y m ust be re p orte d 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 bj ect wit h dra ws c o nse nt t o c o nti n ue st u d y  treat me nt.

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 r es 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 vesti gat or f or me dical reas o ns.

At t he discreti o n of t he I n vesti gat or or S p o ns o r f or n o nc o m plia nce.
T he reas o n f or disc o nti n uati o n of st u d y  treat me nt m ust be rec or de d i n t he s u bject’s case re p ort 
f or m ( C R F).
A s u bject w h o disc o nti n ues treat me nt is t o re mai n i n t he st u d y, atte n d a F U V isit 1 8 wee ks after 
t he fi nal d ose, a n d i m me diatel y c o nti n ue pr ot oc ol -re q uire d tests a n d assess me nts at a s u bset of 
t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ) u ntil t he e n d of t he st u d y  per t he sc he d ule of e ve nts 
or u ntil t he s u bject wit h dra ws c o nse nt .  


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1 0. 2.
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 ws c o nse nt.

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 S p o ns or.
N ote:
A s u bject w h o disc o nti n u es 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.  T he s u bject is t o re mai n i n t he st u d y, a n d
c o nti n ue wit h a F U Visit 1 8 wee ks after t he fi nal d ose, a n d pr ot oc ol -re q uire d tests a n d 
assess me nts at a s u bset of t he cli nic visits (see Ta ble 1 0 a n d Ta ble 1 1 ) u ntil t he e n d of t he st u d y  
or u ntil t he s u bject wit h dra ws c o nse nt .  
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 s h o ul d 
c o m plete t he E O T Visit after t he reas o n f or wit h dra wal is i de ntifie d.  F or s uc h s u bjects, efficac y  
assess me nts s pecifie d at t he E O T V isit are n ot re q uire d if t he su bject disc o nti n ues treat me nt 
wit hi n 3 m o nt hs of t he pre vi o us efficac y  assess me nt visit a n d n o si g nifica nt c ha n ges i n c o g niti ve 
stat us are s us pecte d by t he I n vesti gat or; T he site s h o ul d n otif y t he s p o ns or i n s uc h cases.  
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 F U Visit 1 8 wee ks 
after recei vi n g t heir last d ose of st u d y  treat me nt.  


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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 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.  
Please see Secti o n 4. 2 ( Sc he d ule of E ve nts) f or t he st u d y treat me nt i nf usi o n sc he d ule d uri n g t he 
place b o -c o ntr olle d an d L T E peri o ds of t he st u d y .
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  
T he S p o ns or will pr o vi de a d uca n u ma b t o st u d y sites.  
1 1. 1. 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.
1 1. 2.
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule
Refer t o Secti o n 7. 2. 1 ( d ose s us pe nsi o n) a n d Secti o n 7. 2. 2 (i nf usi o n i nterr u pti o n).  D oses s h o ul d 
be a d mi nistere d at least 2 1 da y s a part.  If t he d osi n g i nter val ca n n ot be met, t he d ose 
a d mi nistrati o n s h o ul d be assesse d b y t he st u d y me dical m o nit or.
1 1. 3.
Prec a uti o ns
N ot a p plica ble.
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.
Pri or a n d 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 F U 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.


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
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 are all o we d 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, are all o we d 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 are all o we d d uri n g t he st u d y.  
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 ys pri or t o a n y 
d osi n g visit a n d f or 1 0 da ys after a d osi n g visit.
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 nti -a g gre ga nt or a nti-c 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 dicati 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 o i 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 m a y  be per mitte d at t he S p o ns or’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, as it 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 In vesti gat or 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 b y 
t he In 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 w o ul d n ot res ult i n a ut o matic 
per ma ne nt st u 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 
req uires c o nti n ue d use of a disall o we d t hera p y , t he s u bject m ust per ma ne ntl y disc o nti n ue st u d y 
treat me nt.  T he S p o ns or 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, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he 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 mea s ure me nt, r o uti ne c ol o n osc o p y, bacterial c ult ures) 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 2
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 F U V isit), u nless t he s u bjects is bei n g f oll o we d f or st u dy- 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 m a 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 re g ulat or y  re q uire me nts re gar di n g p ostst u d y access will be met.




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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
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 dr u g it s h o ul d n ot be use d.  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 nis trati o n of t he pre pare d a d uca n u ma b is dela ye 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 
( or its desi g nee), 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 pers o n nel 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 o f 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 nt of st u d y  treat me nt recei ve d, t o wh 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.  
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  treat me nt 
acc o u nta bilit y.  B y t he e n d of t he st ud 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 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 
T he place b o ( 0. 9 % sterile s o di u m c hl ori de f or i nj ecti o n) will be pr o vi de d b y t he site i n t he f or m 
of 1 0 0 m L sali ne I V ba gs.  
1 2. 3.
A d diti o n al Pr ot oc ol -Desi g n ate d Pr o d ucts
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.
T o c o nfir m a m yl oi d pat h ol o g y  at Scree ni n g, P E T sca ns will be perf or me d usi n g A m y vi d ™ 
(1 8F- fl or beta pir), Viza myl ™ ( 1 8F- fl ute met o m ol), or Ne urace q ™ (1 8F- fl or beta be n).  F or t h ose 
s u bjects partici pati n g i n t he a m yl oi d P E T s u bst u d y , Scree ni n g a n d F U sca ns m ust be perf or me d 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
usi n g A m y vi d a n d f or s u bjects partici pati n g i n t he P E T s u bst u d y i n Ja pa n, Viza m yl 
(1 8F -fl ute met o m ol) ma y als o be use d.  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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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
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 
P H A R M A C O D Y N A MI C A S S E S S M E N T S
Refer t o Secti o n 4. 2 f or t he ti mi n g of assess me nts.
1 3. 1.
Cli nic al Effic ac 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 efficac y  of a d uca n u ma b: 

C D R 

M M S E

A D A S -C o g 1 3

A D C S -A D L -M CI

N PI - 1 0
It is rec o m me n de d t hat cli nical assess me nts be perf or me d at t he sa me ti me of da y f or s u bjects 
d uri n g t heir st u d y visits.  
S o me tests will re q uire t he i nf or ma nt/care part ner t o partici pate a n d a ns wer q uesti o ns re gar di n g 
t he s u bject’s daily acti vities a n d c o g niti ve ca pa bilities.  
T he rec o m me n de d or der of a d mi nistrati o n of t he cli nical assess me nts is descri be d i n t he St u d y  
Refere nce G ui de.  
1 3. 2.
P h ar m ac o k i netic Assess me nts
Ser u m c o nce ntrati o ns of a d uca n u ma b will be meas ure d usi n g a vali date d assa y .  
1 3. 3.
P h ar m ac o d y n a mic Assess me nts
T he f oll o wi n g tests will be perf or me d t o assess t he P D pr o perties of a d uca n u ma b:

Serial meas ure me nt of a m y l oi d pla q ue b ur de n i n certai n areas of t he brai n as 
meas ure d b y a m yl oi d P E T (i n a s u bset of a p pr o xi matel y 4 0 0 s u bjects partici pati n g i n 
t he a m yl oi d P E T c o h ort).  
O nl y  sites wit h ca pa bilities of perf or mi n g 1 8F- fl or beta pir P E T will be all o we d t o 
perf or m t his assess me nt.  I n vesti gat or partici pati o n i n t his part of t he st u d y is o pti o nal 
a n d c o nti n ge nt u p o n a p pr o val b y  his/ her et hics c o m mittee ( E C) or i nstit uti o nal re vie w 
b oar d (I R B).  If t he I n vesti gat or is n ot partici pati n g or t he tes t is n ot a p pr o ve d b y 
his/ her E C/I R B, t he rele va nt secti o n of t he I C F will n ot be a p plica ble t o t hat site.
S u bject partici pati o n i n t his part of t he st u d y  is o pti o nal at partici pati n g sites.  
I nf or me d c o nse nt m ust be rec or de d i n t he C R F.  Detaile d P E T sca n ni n g pr ot oc ols 
will be descri be d i n a se parate pr oce d ural ma n ual f or P E T.  A p pr o xi matel y 
4 0 0 s u bjects are e x pecte d t o partici pate i n t he a m yl oi d P E T s u bst u d y.  








Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0
1 4.
S A F E T Y A S S E S S M E N T S
See Secti o n 4. 2 f or t he ti mi n g of 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 m o nit ori n g.

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.

Ne ur ol o gical e xa mi nati o n.

Vital si g ns ( b o dy te m perat ure, heart rate, S B P, D B P, a n d res pirat or y  rate).

1 2- lea d E C G.

Brai n M RI.

C o nc o mita nt me dicati o n, t hera p y , a n d pr oce d ure m o nit ori n g.  

M O C A (f or A RI A m o nit ori n g a n d ma na ge me nt).  

C ol u m bia S uici de Se verit y  Rati n g Scale ( C-S S R S) .  
1 4. 2.
L a b or at or y S afet y Assess me nts
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.

Bl o o d c he mistr y:  t ot al 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, A L T, A S T, lactate de h y dr o ge nase, 
ga m ma -gl uta m y l-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.

Ur i nal ysis:  c ol or, s pecific gra vity, 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 mal).

Ser u m a n d uri ne pre g na nc y  test f or 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), H b A 1c, a n d alc o h ol/ dr u g scree n at Scree ni n g.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
1 4. 3.
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a nti -a d uca n u ma b 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 dy ( 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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 2
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 represe ntati ve m ust be gi ve n 
t he na mes a n d tele p h o ne n u m bers of st u d y 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 necessaril y  ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal 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 uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct .
Deter mi nati o n of w het her a n a b n or mal la b orat or y  val ue 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.  Alt h o u g h a b n or mal la b ora t or y val ues are ty picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or a n S A E.

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera py.

A la b orat or y a b n or malit y t hat t he I n vesti gat or c o nsi ders t o be cli nicall y si g nifica nt.
Pre -treat me nt, n o nseri o us A Es t hat occ ur wit hi n 4 8 h o urs after recei pt of a li ga n d will be 
ca pt ure d b y t he sites o n t he A E f or m.  
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.

Res ults i n a c o n ge nital a n o mal y / birt h defect.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 3
A n S A E ma y als o be a n y ot her me dicall y i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he 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 oc e 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 on 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 oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he 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 pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital ad missi o n.

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 u nless 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 hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 5. 2. 2 .

T he se verit y of t he e ve nt as d efi ne d i n Secti o n 1 5. 2. 3 .






Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e mai l a c o m plete d S A E f or m.  Refer t o t he 
St u d y  Refere nce G ui de f or c o u ntr y-s pecific 
 fa x n u m bers or e mail 
1 5. 3. 4. 1.
De at hs
Deat h is a n o utc o me of a n e ve nt.  T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F.  All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt.  T he I n vesti gat or s h o ul d ma ke e ver y  eff ort t o o btai n a n d se n d 
deat h certificates a n d a ut o ps y re p orts t o 
.  T he ter m deat h s h oul d be 
re p orte d as a n S A E o nly if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d by t he I n vesti gat or or Bi o ge n t o be relate d t o t he st u d y treat me nt a d mi nistere d.
A p pr o priate pers o n nel i n Bi o ge n Safet y  a n d Be nefit Ris k ( S A B R) will u n bli n d S U S A Rs f or t he 
p ur p ose of re g ulat or y  re p orti n g.  Bi o ge n or desi g nee will s u b mit S U S A Rs (i n bli n de d or 
u n bli n de d fas hi o n) t o re g ulat or y a ge ncies acc or di n g t o l ocal la w.  Bi o ge n or desi g nee will s u b mit 
S U S A Rs t o I n vesti gat ors i n a bli n de d fas hi o n.
1 5. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 5. 4. 1.
Pre g n a nc y
S u bjects s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he s t u d y a n d 
f or 2 4 wee ks after t heir l ast d ose of st u d y tre at me nt.  If a fe male 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 di ately.
T he I n vesti gat or m ust re p ort a pre g na nc y  occ urri n g i n a fe male s u bject b y fa xi n g t he a p pr o priate 
f or m to 
wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he 
pre g na nc y  at t he S A E re p orti n g fa x n u m ber pr o vi de d i n t he st u d y refere nce ma n ual.  T he 
I n vesti gat or or st u d y site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
 
.  
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 gi ve n 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 descri be d i n 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 on a n O ver d ose f or m 
a n d fa xe d t o 
 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 
 e ve n if t he o ver d ose d oes 


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 7
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 
.  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, st u d y 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 
2 4- h o ur e mer ge nc y  me dical s u p p ort n u m ber.  Refer t o the St u d y  
Refere nce G ui de’s Official 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 vise 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, n 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.
1 5. 5.
C o ntr ace pti o n Re q uire me nts
F or t he p ur p oses of t his st u d y , w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h y si ol o gicall y ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns:

P ost me n o pa usal

1 2 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 or 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).
F or t he p ur p oses of t his st u d y , hi g hl y effecti ve c o ntrace pti o n is defi ne d as use of 1 of t he 
f oll o wi n g:

F or fe males of c hil d beari n g p ote ntial:

Esta blis he d use of oral , i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n.

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne s y ste m


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 8

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 occl 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.

Male se x ual part ners u n der we nt 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:

Vasect o m y wit h ne gati ve se me n a nal ys is at F U.

Use of c o n d o ms wit h s per mici de.

Fe male se x ual part ners w h o u n der we nt s ur gical sterilizati o n (e. g., bilateral t u bal 
li gati o n), are p ost me n o pa usal, are p ost-h y sterect o m y, or are usi n g hi g hl y  effecti ve 
c o ntrace pti o n as liste d a b o ve f or fe male s u bjects.
F or males a n d fe males 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 a n acce pta ble met h o d of c o ntrace pti o n base d o n t he 
e val uati o n of t he I n vesti gat or w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n 
of t he cli nical trial.  Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d a cce pta ble met h o ds of 
c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 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 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, re gar dless of t he se veri t y or relati o ns hi p 
t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g na ncies a n d F U o n t he o utc o me of t he pre g na nc y 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 ( or desi g nee) wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.

P urs ue S A E F U i nf or mati o n acti vel y  a n d persiste ntl y.  F U i nf or mati o n m ust be 
re p orte d t o Bi o ge n ( or desi g nee) wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g 
a ware of ne w i nf or mati o n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 9

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E F U 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.

Re p ort S A Es t o l ocal E C/I R Bs, 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 st u d y site acti vati o n a n d s u bject e nr oll me nt, t he Cli nical M o nit or (
) is 
res p o nsi ble f or re vie wi n g wit h st u d y 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 ( or desi g nee) is t o n otif y  all a p pr o priate re g ulat or y a ut h orities, ce ntral 
E C/I R Bs, 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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0
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 .
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 [ S D], 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.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al ysis P o p ul ati o n
T he i nte nt -t o-treat (I T T) 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 st u d y treat me nt (a d uca n u ma b or place b o), will be use d f or t he efficac y 
a nal ys es.  S u bjects will be a nal yz e d i n t he gr o u ps t o w hic h t he y  were ra n d o mize d.  
1 6. 2. 2.
Met h o ds of A n al ysis
1 6. 2. 2. 1.
Ge ner al C o nsi der ati o ns
S u m mar y  statistics will be prese nte d. F or c o nti n u o us e n d p oi nts, s u m mar y  statistics will 
ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, sta n dar d de viati o n, me dia n, a n d ra n ge.  
F or cate g orical e n d p oi nts, t his will ge nerall y i ncl u de: n u m ber of s u bjects ra n d o mize d or d ose d, 
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 .  Statistical testi n g f or 
efficac y e n d p oi nts will be ma de bet wee n eac h a d uca n u ma b d ose ( hi g h a n d l o w) a n d place b o.  
All statistical tests will be 2 -si de d.
1 6. 2. 2. 2.
A d uc a n u m a b D oses t o be E v al u ate d
T he f oll o wi n g a d uca n u ma b d oses as c o m pare d wit h place b o will be e val uate d:

A d uca n u ma b hi g h -d ose ( 1 0 m g/ k g i n A p o E ε 4 [i ncl u di n g 6 m g/ k g f or s u bjects 
e nr olle d u n der pr ot oc ol v ersi o ns pri or t o Versi o n 4 w h o d o n ot ha ve t he o p p ort u nit y  
t o u ptitrate t o 1 0 m g/ k g pri or t o c o m pleti n g Wee k 7 8 of t he st u d y ] a n d 1 0 m g/ k g i n 
A p o E ε 4 n o n-carriers).

A d uca n u ma b l o w -d ose ( 3 m g/ k g i n A p o E ε 4 carriers a n d 6 m g/ k g i n 
A p o E ε 4 n o n-carriers). 
I n t he e ve nt t hat t he ma xi m u m d ose ( 1 0 m g/ k g) is ter mi nate d after t he start of t he st u d y 
( Secti o n 5. 3. 2 ) t he defi niti o n of a d uca n u ma b hi g h d ose a n d a d uca n u ma b l o w d ose will be 
m o difie d as s h o w n i n Ta ble 1 7 .  T he d osi n g m o dificati o n will be e ntirely base d o n i nteri m 
a nal ys is of o utc o mes t hat are i n de pe n de nt of, a n d u ni nf or mati ve a b o ut, t he treat me nt-relate d 
efficac y effect.  C o ntr ol of T ype I err or rate is t h us mai ntai ne d wit h o ut a statistical a dj ust me nt 
f or s uc h a da ptati o ns [C h o w a n d C ha n g 2 0 1 1 ].


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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
T a ble 1 7:
Tre at me nt Gr o u p s i n t he E ve nt of Hi g h D ose Gr o u p Ter mi n ati o n
Hi g h D o se Gr o u p(s) Ter mi n ate d
Defi niti o ns of Re vise d Tre at me nt 
( L o w/ Hi g h D ose) Gr o u ps f or C o m p aris o n
A p o E ε 4 carrier hi g h -d ose gr o u p ( 1 0 m g/ k g) 
[i ncl u di n g 6 m g/ k g f or s u bjects e nr olle d u n der versi o ns 
pri or t o Versi o n 4 w h o d o n ot ha ve t he o p p ort u nit y t o 
u ptitrat e t o 1 0 m g/ k g pri or t o c o m pleti n g Wee k 7 8 of 
t he st u d y]
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 1 0 m g/ k g
A p o E ε 4 n o n -carrier hi g h -d ose gr o u p ( 1 0 m g/ k g)
L o w: A p o E ε 4 carrier 3 m g/ k g a n d 
n o n- carrier 6 m g/ k g
Hi g h: A p o E ε 4 carrier 1 0 m g/ k g a n d 
n o n- carrier 6 m g/ k g
A p o E ε 4 carrier hi g h -d ose gr o u p ( 1 0 m g/ k g) 
A N D
A p o E ε 4 n o n -carrier hi g h -d ose gr o u p ( 1 0 m g/ k g) 
A p o E ε 4 carrier 3 m g/ k g a n d n o n- carrier 
6 m g/ k g
1 6. 2. 2. 3.
C o nsi der ati o ns f or M ulti ple C o m p aris o n A dj ust me nts
A se q ue ntial (cl ose d) testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y p e I  err or rate d ue t o 
m ulti ple c o m paris o ns f or t he pri mar y  e n d p oi nt.  T he or der of treat me nt c o m paris o ns is as 
f oll o ws: a d uca n u ma b hi g h -d ose vers us place b o a n d a d uc a n u ma b l o w -d ose vers us place b o.  All 
c o m paris o ns after t he i nitial c o m paris o n wit h p > 0. 0 5 will n ot be c o nsi dere d statisticall y  
si g nifica nt.
Sec o n dar y  e n d p oi nts ha ve bee n ra n k pri oritize d, i n t he or der s h o w n i n Secti o n 6 .  In or der t o 
c o ntr ol f or a T ype I err or f or t he sec o n dar y e n d p oi nts, a se q ue ntial cl ose d testi n g pr oce d ure will 
be use d a n d will i ncl u de b ot h t he or der of t he sec o n dar y  e n d p oi nts a n d treat me nt c o m paris o ns.  
S pecificall y, f or eac h of t he sec o n dar y e n d p oi nts, a se q ue ntial (cl ose d) testi n g pr oce d ure, as f or 
t he pri mar y e n d p oi nt, will be use d t o c o ntr ol t he o verall T ype I err or rate d ue t o m ulti ple 
treat me nt c o m paris o ns.  If statistical si g nifica nce is n ot ac hie ve d f or 1 or 2 c o m paris o ns, all 
e n d p oi nt(s) of a l o wer ra n k will n ot be c o nsi dere d s tatisticall y si g nifica nt f or 1 or 2, res pecti vely.  
1 6. 2. 2. 4.
A n al ysis of t he Pri m ar y E n d p oi nt
T he p o p ulati o n f or t he pri mar y  e n d p oi nt a nalys is will be s u bjects i n t he I T T p o p ulati o n.  A 
mi xe d m o del re peate d meas ures ( M M R M) m o del will be use d as t he pri mar y a nal ys is t o a nalyz e 
c ha n ge fr o m baseli ne C D R- S B usi n g fi xe d effects of treat me nt, ti me, treat me nt- b y -ti me 
i nteracti o n, baseli ne C D R-S B, baseli ne C D R -S B b y  ti me, baseli ne M M S E, A D s y m pt o matic 
me dicati o n use at baseli ne, re gi o n, a n d la b orat or y A p o E ε 4 stat us.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 2
1 6. 2. 2. 5.
A n al y sis of t he Sec o n d ar y E n d p oi nts
1 6. 2. 2. 5. 1. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n M M S E 
T he p o p ulati o n f or t he a nal ysis will be s u bjects i n t he I T T p o p ulati o n.  A M M R M m o del will be 
use d as t he pri mar y  a nalysis t o a nal y ze c ha n ge fr o m baseli ne M M S E usi n g fi xe d effects of 
treat me nt, ti me, treat me nt-b y -ti me i nteracti o n, baseli ne M M S E val ue, baseli ne M M S E b y ti me 
i nteracti o n, A D s y m pt o matic me d icati o n use at baseli ne, re gi o n, a n d la b orat or y A p o E ε 4 stat us 
1 6. 2. 2. 5. 2. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n A D A S -C o g 1 3
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n.  A n M M R M m o del will be use d as t he 
pri mar y  a nalys is t o a nalyze c ha n ge fr o m baseli ne A D A S -C o g 1 3 usi n g fi xe d effects of treat me nt, 
ti me, treat me nt-b y -ti me i nteracti o n, baseli ne A D A S- C o g 1 3, baseli ne A D A S-C o g 1 3 b y ti me 
i nteracti o n, baseli ne M M S E , A D s y m pt o matic me d icati o n use at baseli ne, re gi o n, a n d la b orat or y 
A p o E ε 4 stat us.
1 6. 2. 2. 5. 3. C h a n ge Fr o m B aseli ne t o Wee k 7 8 i n A D C S -A D L -M CI
T he p o p ulati o n will be s u bjects i n t he I T T p o p ulati o n.  A n M M R M m o del will be use d as t he 
pri mar y  a nal ys is t o a nalyze c ha n ge fr o m baseli ne A D C S -A D L -M CI usi n g fi xe d effects of 
treat me nt, ti me, treat me nt-b y -ti me i nteracti o n, baseli ne A D C S-A D L -M CI, baseli ne A D C S -
A D L -M CI b y  ti me i nteracti o n, baseli ne M M S E , A D s y m pt o matic me d icati o n use at baseli ne, 
re gi o n, a n d la b orat or y A p o E ε 4 stat us.
1 6. 2. 2. 6.
Terti ar y E n d p oi nts A n al ysis
1 6. 2. 2. 6. 1. Pl ace b o -C o ntr olle d Peri o d
W here a p pr o priate, a n M M R M m o del will be use d as t he pri mar y  a nalys is t o a nal yze c ha n ge 
fr o m baseli ne usi n g fi xe d effects of treat me nt, ti me, treat me nt by ti me i nteracti o n, baseli ne 
val ue, baseli ne val ue b y t i me i nteracti o n, baseli ne M M S E, A D s y m pt o matic me d icati o n use at 
base li ne, re gi o n, a n d la b orat or y A p o E ε 4 stat us.
Ot her wise, a n a nal ys is of c o varia nce ma y be use d t o a nal yze t hese e x pl orat or y e n d p oi nts or 
descri pti ve s u m mar y  statistics ma y be prese nte d.




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 4
1 6. 5. 2. 2.
Cli nic al L a b or at or y Res ults
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 nalys is 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 
cate g 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.  
1 6. 5. 2. 3.
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n cli nicall y rele va nt a b n or malities.
1 6. 5. 2. 4.
E C G
T he n u m ber a n d perce nta ge of s u bjects wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or 
a b n or mal A E) will be s u m marize d b y  treat me nt gr o u p.  
1 6. 5. 2. 5.
C ol u m bi a S uici de Se verit y R ati n g Sc ale
T he C- S S R S data will be s u m marize d b y  treat me nt gr o u p.
1 6. 6.
I m m u n o ge nicit y D at a
1 6. 6. 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 ulati 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 nicity.  
1 6. 6. 2.
Met h o ds of A n al ysis
A nti -a d uca n u ma b ser u m a nti b o dies will be s u m marize d usi n g s hift ta bles.
1 6. 7.
I nteri m A n al yses
1 6. 7. 1.
I nteri m F utilit y A n al ysis
A n i nteri m a nal ys is f or f utilit y of t he pri mar y e n d p oi nt will occ ur after a p pr o xi matel y  5 0 % of t he 
s u bjects ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  I n or der t o mai ntai n t he treat me nt 
bli n d, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di ng will perf or m t he i nteri m f utilit y  a nalys is.  T his i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he I D M C ma y rec o m me n d ter mi nati n g 
t he st u d y f or f utilit y if it is e vi de nt t hat t he efficac y of a d uca n u ma b is u nli kel y t o be ac hie ve d.  
T he f utilit y  criteria will be disc usse d i n detail i n t he S A P.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 5
1 6. 7. 2. 
I nteri m S u peri orit y A n al ysis
A n i nteri m a nal ys is f or s u peri orit y m a y be perf or me d after a p pr o xi matel y 5 0 % of t he s u bjects 
ha ve c o m plete d t he Wee k 7 8 Visit ( or disc o nti n ue d).  T he O’ Brie n- Fle mi n g b o u n dar y  a p pr oac h 
will be use d f or t he a nal ysis.  I n or der t o mai ntai n t he treat me nt bli n d i n t he e ve nt of t his i nteri m 
a nal ys is, a n i n de pe n de nt gr o u p e xter nal t o Bi o ge n t hat will n ot be i n v ol ve d i n t he c o n d uct of t he 
st u d y after u n bli n di n g will perf or m t he i nteri m s u peri orit y  a nalys is.  T he i n de pe n de nt gr o u p will 
prese nt t he u n bli n de d i nteri m a nal ys is t o t he I D M C.  T he ai m of t his i nteri m a nal ysis is t o all o w 
t he p ossi bilit y t o de m o nstrate treat me nt effect earl y.  T he a nal ys is will be disc usse d in detail i n 
t he S A P.
1 6. 8.
S a m ple Size C o nsi der ati o ns
T he st u d y ’s sa m ple size is base d, i n part, o n res ults fr o m a pr ot oc ol-s pecifie d i nteri m a nalys is 
fr o m St u d y 2 2 1 A D 1 0 3, w hic h i ncl u de d 1 -ye ar data fr o m 1, 3 , a n d 1 0 m g/ k g treat me nt gr o u ps.
A sa m ple size of 4 5 0 s u bjects per treat me nt gr o u p ( 1 3 5 0 i n t otal) was pla n ne d t o ha ve
a p pr o xi matel y 9 0 % p o wer t o detect a tr ue mea n differe nce of 0. 5 i n c ha n ge fr o m baseli ne 
C D R -S B at Wee k 7 8 bet wee n t he 2 treat me nt gr o u ps.  T his p o wer calc ulati o n wa s base d o n a 
2- si de d t-test ass u mi n g e q ual varia nce wit h a fi nal si g nifica nce le vel of 0. 0 5, a n S D of 1. 9 2, a n d 
a dr o p-o ut rate of 3 0 %.  T he S D esti mate of 1. 9 2 f or Wee k 7 8 reflect e d a 3 9 % i ncrease o ver t he 
S D fr o m t he pr ot oc ol -s pecifie d i nteri m a nalys is of 1-ye ar data.
T he ass u me d tr ue mea n differe nce of 0. 5 bet wee n t he 2 treat me nt gr o u ps re prese nts a n 
a p pr o xi matel y 2 5 % re d ucti o n i n t he place b o mea n c ha n ge fr o m baseli ne at Wee k 7 8 if t he 
place b o mea n c ha n ge is esti mate d t o be 2.
As defi ne d i n t he pri or versi o ns of t he pr ot oc ol, t he sa m ple size f or t his st u d y (a n d f or t he 
i de nticall y desi g ne d St u d y 2 2 1 A D 3 0 2) was reassesse d i n a bli n de d ma n ner a p pr o xi matel y 
3 m o nt hs bef ore e nr oll me nt c o m plet i o n. At t he ti me of t his reassess me nt ( N o ve m ber 2 0 1 7),
a b o ut 1 0. 6 % of t he data was a vaila ble o n t he pri mar y e n d p oi nt fr o m St u d y  2 2 1 A D 3 0 1 a n d St u d y  
2 2 1 A D 3 0 2 c o m bi ne d; base d o n t he p o ole d bli n de d data (i.e., treat me nt gr o u ps c o m bi ne d) fr o m 
t he 2 st u dies, t he S D f or t he pri mar y e n d p oi nt was esti mate d.  As a res ult of t his a nal y sis, t he 
sa m ple size has bee n a dj uste d fr o m 1 3 5 0 t o 1 6 0 5 ( 4 5 0 t o 5 3 5 per treat me nt) t o ass ure a de q uate 
p o wer t o detect a mea n treat me nt effect of 0. 5 .


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 6
1 7.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n, 
, a n d t he I n vesti gat or m ust c o m ply 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 ulati o 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 to 
i n di vi d uals s ufficie ntl y q ualifie d b y e d ucati o n, trai ni n g, a n d e x perie nce, i n acc or da nce wit h 
a p plica ble I C H a n d G C P g ui deli nes.  T he I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y- relate d d uties ha ve bee n dele gate d.
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/I nstit uti o n al Re vie w B o ar d
T he I n vesti gat or m ust o btai n E C/I R B a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y  
d oc u me nts pri or t o starti n g t he st u d y.  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 E C.  A c o p y  of t he a p pr o ve d IC 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 gree me nt of t he rele va nt E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) 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 C/I R B a p pr o val, w hic h s pecificall y  i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y .  Pr ot oc ol a me n d me nts 
will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he E C/I R B at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he E C/IR B a n d Bi o ge n.
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 nclu 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 prese ntati ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns.  S u bjects ca n c o m plete t he ne ur oc o g niti ve scales 
( C D R, M M S E, a n d R B A N S) as well as A p o E ge n ot ypi n g as a n i nitial o pti o nal scree 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 3 scales, t he f ull 
c o nse nt p r 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.  


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 7
S u bjects ma y  als o pr ocee d directl y 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 , the 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/ or et h nicit y will be c ollecte d a n d will be use d 
d uri n g a nal ys is of st u d y res ults ( o nl y i n c o u ntries w here per mitte d b y l ocal la w/re g ulati o n).
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, care gi ver a n d/ or le gall y 
a ut h orize d re prese ntati ve.  T he si g ne d a n d date d I C F will be retai ne d wit h t he st u d y  rec or ds.  
L ocal re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal ( wet 
si g nat ure) a n d c o pies of t he si g ne d a n d date d I CFs.
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 us t 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).
T he s u bject will n ot be i de ntifie d b y  na me i n t he C R F or i n a n y st u d y re p orts a n d t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n, its part ner(s) a n d desi g nee(s), E C/I R Bs, 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.
D uri n g t he st u d y , s u bjects’ race a n d/or et h nicit y  will be c ollecte d ( o nly i n c o u ntries w here 
per mitte d b y  l ocal la w/re g ulati o n).  T hese data ma y be use d i n t he a nalys is of t he safety, 
efficac y, a n d/ or p har mac o ki netic pr ofile of t he st u d y treat me nt.  It is u n k n o w n if t he p ote nc y or 
effects of t he st u d y treat me nt are i nfl ue nce d by race or et h nicit y.  
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 vesti gat ors s h o ul d a d dres s a ny 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 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 8
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 bjects 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 Ass ur a nce
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.  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 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.
T he Cli nical M o nit or(s) will visit t he I n vesti gat or(s) 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.
D uri n g t he se visits, C R Fs a n d s u p p orti n g 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.  
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 pr ot oc ol a d here nce, q ualit y  of data, 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.
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 ntract(s) bet wee n t he i nstit uti o n, I n 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 .




Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 0
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 raters 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.
1 9. 2.
St u d y C o m mittees
1 9. 2. 1.
A d vis or y C o m mittee
A n a d vis or y  c o m mittee will be f or me d t o pr ovi de scie ntific a n d me dical directi o n f or t he st u d y 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y c o m mittee will meet 
peri o dicall y t o m o nit or s u bject accr ual a n d o versee st u d y c o n d uct, i ncl u di n g a d visi n g o n st u d y 
desi g n a n d e xec uti o n.  T he a d vis or y  c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts 
d uri n g t he st u d y.  
Me m bers of t he a d vis or y c o m mittee will i ncl u de e xter nal e x perts i n Alz hei mer’s disease.  
Bi o ge n will desi g nate o ne of t he partici pati n g e xter nal e x perts t o be t he c hair pers o n of t he 
a d vis or y c o m mittee.
1 9. 2. 2.
I n de pe n de nt D at a M o nit ori n g C o m mittee 
T he I D M C will be f or me d t o re vie w o n g oi n g safet y a n d t olera bilit y data.  Me m bers of t he I D M C 
will n ot be all o we d t o partici pate as In vesti gat ors i n t his st u d y .  T he I D 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.  T he I D M C, base d o n 
t he nat ure, fre q ue nc y, a n d/ or se verity of a n A E(s) 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. A n I D 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 I D M C.  
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 E C/I R B a n d re g ulat or y  a ut h orities if re q uire d 
b y  l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he i n vesti gati o n, or 
t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he E C/I R B 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 dy.  If re q uire d b y l ocal la w, s uc h m o dific ati 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 IC F ma y  re q uire si milar m o dificati o ns (see 
Secti o ns 1 7. 2 a n d 1 7. 3 ).


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 1
1 9. 4.
Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d N otific ati o n of St u d y 
C o m pleti o n or Ter mi n ati o n
W h ere re q uire d, t he re g ulat or y a ut h orities a n d E C/IR Bs 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  recor 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 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 o n 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 In vesti gat or lea v es 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 St u d y  In vesti gat ors as a si g nat or y  f or t he 
st u d y re p ort.  T his deter mi nati o n will be ma de b y se veral fact ors i ncl u di n g b ut n ot li mite d t o t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n, t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or 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 ge n.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 2
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 mer'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.
C h o w S, C ha n g M. A da pti ve Desi g n Met h o ds i n Cli nical Trials, Sec o n d E diti o n. Sec o n d E diti o n 
e d. B oca Rat o n, F L: C ha p ma n a n d Hall/ C R C; 2 0 1 1.
D u b ois B, Fel d ma n H H, Jac o va C, et al. Re visi n g t he defi niti o n of Alz hei mer's disease: a ne w 
le xic o n. La ncet Ne ur ol. 2 0 1 0; 9( 1 1): 1 1 1 8- 2 7.
D u b ois B, Fel d ma n H H, Jac o va C, et al. A d va nci n g researc h dia g n ostic criteria f or Alz hei mer's 
disease: t he I W G -2 criteria. La ncet Ne ur ol. 2 0 1 4; 1 3( 6): 6 1 4 - 2 9.
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 yp 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.
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.
Le n der ki n g W R, Stee nr o d A, R ü dell K, et al. O pti o ns f or E val uati n g Treat me nt Be nefit i n M CI  
a n d Pr o dr o mal Alz hei mer’s Disease: C o nte nt Vali dit y  of t he Percei ve d Deficits Q uesti o n naire 
( P D Q) i n Patie nts wit h Earl y Sy m pt o ms of C o g niti ve Decli ne. A d va nces i n Alz hei mer’s Disease. 
2 0 1 4; 3: 1 - 1 0. E p u b Marc h 2 0 1 4.
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 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 mer's a n d De me ntia. 
2 0 1 1; 7( 3): 2 6 3 - 2 6 9.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 3
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.
M orris J C, Ble n n o w
K, Fr oelic h L, et al. Har m o nize d dia g n ostic criteria f or Alz hei mer's disease: 
rec o m me n dati o ns. J Inter n Me d. 2 0 1 4; 2 7 5( 3): 2 0 4 - 1 3.
Ostr o witz ki S, De pt ula D, T h urfjell L, et al. Mec ha nis m of a m y l oi d re m o val i n patie nts wit h 
Alz hei mer disease treate d wit h ga n te ner u ma b. Arc h Ne ur ol. 2 0 1 2; 6 9( 2): 1 9 8-2 0 7. E p u b 2 0 1 1 Oct 
1 0.
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 osite d f or ms of a m yl 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 o z 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.
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 dly 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, et 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.
Weller R O, S u bas h M, Prest o n S D, et al. Peri vasc ular drai na ge of a m yl oi d -beta pe pti des fr o m 
t he brai n a n d its fail ure i n cere bral a myl oi d a n gi o pat h y  a n d Alz hei mer's disease. Brai n Pat h ol. 
2 0 0 8; 1 8( 2): 2 5 3 - 6 6.
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/ 0 2/ 2 7.


Pr ot oc ol 2 2 1 A D 3 0 1
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
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 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
I ha ve rea d t he f ore g oi n g pr ot oc ol, “ A P hase 3 M ultice nter, Ra n d o mize d, D o u ble-Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b 
( BIIB 0 3 7) i n S u bjects wit h Earl y  Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)

SAP_001.pdf: 
Statistical Analysis Plan 
Placebo-Controlled Period
Final V1.0 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
1
        ENGAGE 
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Statistical Analysis Plan 
Placebo-Controlled Period 




Statistical Analysis Plan 
Placebo-Controlled Period 
Final V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
3 
 
Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 5 
1 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS ........................................................................ 7 
1.1 
PRIMARY OBJECTIVE AND ENDPOINT ........................................................................................................ 7 
1.2 
SECONDARY OBJECTIVES AND ENDPOINTS ............................................................................................... 7 
1.3 
TERTIARY OBJECTIVES AND ENDPOINTS ................................................................................................... 7 
1.3.1 
Tertiary Objectives ......................................................................................................................... 7 
1.3.2 
Tertiary Endpoints .......................................................................................................................... 8 
1.4 
ADDITIONAL EXPLORATORY OBJECTIVES AND ENDPOINTS ...................................................................... 9 
1.4.1 
Additional Exploratory Objectives ................................................................................................. 9 
1.4.2 
Additional Exploratory Endpoints .................................................................................................. 9 
2 
STUDY DESIGN ....................................................................................................................................... 10 
2.1 
STUDY OVERVIEW .................................................................................................................................. 10 
2.2 
STUDY SCHEMATIC ................................................................................................................................. 12 
2.3 
SCHEDULE OF EVENTS ............................................................................................................................ 13 
3 
SAMPLE SIZE JUSTIFICATION .......................................................................................................... 13 
4 
STATISTICAL ANALYSIS METHODS ............................................................................................... 13 
4.1 
GENERAL CONSIDERATIONS ................................................................................................................... 13 
4.1.1 
Analysis Population ...................................................................................................................... 14 
4.2 
BACKGROUND CHARACTERISTICS .......................................................................................................... 15 
4.2.1 
Accounting of Subject ................................................................................................................... 16 
4.2.2 
Demographics and Baseline Characteristics ................................................................................ 16 
4.2.3 
Concomitant Medications and Non-Drug Therapies .................................................................... 17 
4.2.4 
Protocol Deviations ...................................................................................................................... 18 
4.2.5 
Study Drug Exposure and Study Drug Compliance ...................................................................... 18 
4.3 
EFFICACY ANALYSIS ............................................................................................................................... 19 
4.3.1 
General Considerations ................................................................................................................ 19 
4.3.2 
Primary Efficacy Endpoint ........................................................................................................... 21 
 
Primary analysis ....................................................................................................................................... 21 
 
Sensitivity analysis ................................................................................................................................... 22 
4.3.2.2.1 
Pattern mixture model .................................................................................................................... 22 
4.3.2.2.2 
Copy increment from reference method ........................................................................................ 23 
4.3.2.2.3 
Imputation by natural disease progression ..................................................................................... 23 
4.3.2.2.4 
Tipping point analysis.................................................................................................................... 23 
 
Supplementary analysis ............................................................................................................................ 24 
4.3.2.3.1 
Censoring after intercurrent events ................................................................................................ 24 
4.3.2.3.2 
Per-protocol analysis ..................................................................................................................... 24 
4.3.2.3.3 
Responder analysis ........................................................................................................................ 24 
4.3.2.3.4 
Slope analysis ................................................................................................................................ 25 
4.3.2.3.5 
Divergence effect analysis ............................................................................................................. 25 
 
CDR subscores and CDR global score ..................................................................................................... 25 
4.3.3 
Secondary Efficacy Endpoints ...................................................................................................... 26 
 
Primary analysis of MMSE ...................................................................................................................... 26 
 
Primary analysis of ADAS-Cog 13 .......................................................................................................... 26 
 
Primary analysis of ADCS-ADL-MCI ..................................................................................................... 26 
 
Sensitivity/Supplementary analysis .......................................................................................................... 27 
4.3.4 
Tertiary Endpoints for Efficacy and Quality of Life ..................................................................... 27 
4.3.5 
Subgroup Analysis ........................................................................................................................ 27 
4.4 
AMYLOID PET ANALYSIS ....................................................................................................................... 28 
4.4.1 
Amyloid PET substudy .................................................................................................................. 28 
4.4.2 
Amyloid PET SUVR regions-of-interest and reference regions .................................................... 28 
4.4.3 
Amyloid PET analysis population ................................................................................................. 29 
4.4.4 
By visit summary and MMRM model ............................................................................................ 29 
4.4.5 
Correlation between amyloid PET and CDR sum of boxes .......................................................... 30 
4.5 
SAFETY ANALYSIS .................................................................................................................................. 30 


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4.5.1 
General Considerations ................................................................................................................ 30 
4.5.2 
Clinical Adverse Events ................................................................................................................ 32 
Summary and incidence analysis ............................................................................................................. 33
Incidence rate analysis ............................................................................................................................. 34
Subgroup analysis for protocol version 4 ................................................................................................. 35
4.5.3 
ARIA – AE of special interest........................................................................................................ 35 
Background .............................................................................................................................................. 35
Incidence and summary of ARIA ............................................................................................................. 37
Summary of recurrent ARIA-E ................................................................................................................ 38
Exposure adjusted analysis ....................................................................................................................... 39
Time to event analysis .............................................................................................................................. 39
Subgroup analysis for protocol version 4 ................................................................................................. 39
4.5.4 
Clinical Laboratory Data ............................................................................................................. 39 
Quantitative analyses ............................................................................................................................... 40
Qualitative analyses ................................................................................................................................. 41
4.5.5 
C-SSRS Data ................................................................................................................................. 43 
4.5.6 
ECG Data ..................................................................................................................................... 43 
4.5.7 
Vital Sign Data ............................................................................................................................. 43 
4.6 
PHARMACOKINETICS ANALYSIS .............................................................................................................. 44 
4.6.1 
Serum Concentration Profile ........................................................................................................ 45 
4.6.2 
Serum PK Parameters .................................................................................................................. 45 
4.6.3 
Subgroup analysis for protocol version 4 ..................................................................................... 45 
4.7 
IMMUNOGENICITY ANALYSIS .................................................................................................................. 46 
4.7.1 
Background ................................................................................................................................... 46 
4.7.2 
Immunogenicity analysis ............................................................................................................... 46 
4.8 
ADDITIONAL EXPLORATORY ENDPOINTS ................................................................................................ 47 
 
 47 
 
 47 
5 
INTERIM ANALYSIS.............................................................................................................................. 47 
6 
APPENDIX ................................................................................................................................................ 49 
6.1 
ANALYSIS DISPLAY ................................................................................................................................. 49 
6.2 
PROTOCOL DEVIATION CLASSIFICATION ................................................................................................. 49 
6.3 
IMPLEMENTATION OF THE COPY INCREMENT FROM REFERENCE AND PATTERN MIXTURE MODEL ......... 53 
6.3.1 
Copy Increment from Reference ................................................................................................... 53 
6.3.2 
Pattern Mixture Model .................................................................................................................. 53 
7 
REFERENCES .......................................................................................................................................... 55 


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List of Abbreviations 
Aβ 
β-amyloid 
AD 
Alzheimer’s disease 
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(13 items) 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living Inventory (Mild Cognitive Impairment version) 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ApoE 
apolipoprotein E 
ApoE ε4  
apolipoprotein E4 
ApoE ε4+ 
apolipoprotein E4 carrier 
ApoE ε4- 
apolipoprotein E4 non-carrier 
ARIA 
amyloid related imaging abnormalities 
ARIA-E 
amyloid related imaging abnormality-edema  
ARIA-H 
amyloid related imaging abnormality-hemorrhage or superficial 
siderosis 
 
 
AST 
aspartate aminotransferase 
BL 
baseline 
BLQ 
below the limit of quantification 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
 
 
CDR 
Clinical Dementia Rating  
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CIR 
copy increment from reference 
Cmax 
observed maximum serum aducanumab concentration 
Cmin 
observed minimum serum aducanumab concentration 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CTCAT 
Common Toxicity Criteria for Adverse Events 
CV 
coefficient of variation 
EAIR 
exposure-adjusted incidence rate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D 
EuroQol health status measure 
 
EQ-5D (IR-S) 
EuroQol health status measure, informant reported on subject 


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EQ-5D (SR) 
EuroQol health status measure, subject self-reported 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl-transferase 
HCP 
health care professional 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDH 
lactate dehydrogenase 
LMCI 
late mild cognitive impairment 
LTE 
long-term extension 
LOCF 
last observation carried forward 
MCI 
mild cognitive impairment 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures 
MMSE 
Mini-Mental State Examination 
MOCA 
Montreal Cognitive Assessment 
mPDQ-20 
Perceived Deficits Questionnaire-20 modified version 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI-10 
Neuropsychiatric Inventory-10 
PCS 
potentially clinically significant 
PET 
positron emission tomography 
pH 
potential of hydrogen 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model 
PP 
per-protocol 
RBANS 
Repeatable Battery for Assessment of Neuropsychological 
Status 
ROI 
region of interest 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
SUVR 
standard uptake value ratio 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 


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1 DESCRIPTION OF OBJECTIVES AND ENDPOINTS 
1.1 Primary Objective and Endpoint 
The primary objective of this study is to evaluate the efficacy of monthly doses of 
aducanumab in slowing cognitive and functional impairment as measured by changes in the 
Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in 
subjects with early Alzheimer’s Disease (AD). 
The primary endpoint that relates to this objective is change from baseline in CDR-SB score 
at Week 78. 
 
1.2 Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
o To assess the effect of monthly doses of aducanumab as compared with placebo 
on clinical progression as measured by the Mini-Mental State Examination 
(MMSE). 
o To assess the effect of monthly doses of aducanumab as compared with placebo 
on clinical progression as measured by Alzheimer’s Disease Assessment Scale-
Cognitive Subscales (13 items) [ADAS-Cog 13]. 
o To assess the effect of monthly doses of aducanumab as compared with placebo 
on clinical progression as measured by Alzheimer’s Disease Cooperative Study-
Activities of Daily Living Inventory (Mild Cognitive Impairment version) 
[ADCS-ADL-MCI]. 
The secondary endpoints are: 
o Change from baseline in MMSE score at Week 78. 
o Change from baseline in ADAS-Cog 13 score at Week 78. 
o Change from baseline in ADCS-ADL-MCI score at Week 78. 
 
1.3 Tertiary Objectives and Endpoints 
1.3.1 Tertiary Objectives 
Safety and Tolerability 
• To assess the safety and tolerability of monthly doses of aducanumab.   
• To assess the immunogenicity of aducanumab.   
Biomarker/Efficacy/Quality of Life 


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• To assess the effect of aducanumab on cerebral amyloid plaque content as 
measured by amyloid positron emission tomography (PET) imaging (in a subset 
of approximately 400 subjects). 
• To assess the effect of aducanumab on behavior as measured by the 
Neuropsychiatric Inventory-10 (NPI-10). 
• To assess the effect of aducanumab on subject health status, measured by EuroQol 
health status measures (EQ-5D [informant-rated and subject self-reported]). 
• To assess the effect of aducanumab on subject self-reported cognitive function, 
measured by the modified Perceived Deficits Questionnaire-20 (mPDQ-20). 
• To assess the correlation between primary endpoint and cerebral amyloid plaque 
content as measured by PET imaging.   
Pharmacokinetics 
• To collect and characterize the pharmacokinetic (PK) parameters of aducanumab 
in serum  
1.3.2 Tertiary Endpoints 
Safety and Tolerability 
• Incidence of all adverse events (AEs) and serious adverse events (SAEs). 
• Brain magnetic resonance imaging (MRI) findings including incidence of amyloid 
related imaging abnormality-edema (ARIA-E) and amyloid related imaging 
abnormality-hemorrhage or superficial siderosis (ARIA-H). 
• Clinical laboratory shifts in reported values. 
• Clinically significant changes in vital sign measurements and electrocardiograms 
(ECGs). 
• Incidence of anti-aducanumab antibodies in serum.   
Biomarkers/Efficacy/Quality of Life 
• Change from baseline in amyloid PET signal at Week 26 (in a subset of sites and 
subjects). 
• Change from baseline in amyloid PET signal at Week 78 (in a subset of sites and 
subjects). 
• Change from baseline in NPI-10 score at Week 78. 
• Change from baseline in subject-self-reported EQ-5D index score at Week 78. 
• Change from baseline in informant-rated subject EQ-5D index score at Week 78. 
• Change from baseline in mPDQ-20 at Week 78. 
• Correlation between the primary endpoint and cerebral amyloid plaque content as 
measured by PET imaging over time. 
Pharmacokinetics: 


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• Serum concentrations and PK parameters of aducanumab. 
1.4 Additional Exploratory Objectives and Endpoints 
1.4.1 Additional Exploratory Objectives 
 
• 
 
 
• 
 
 
• 
 
  
• 
 
 
 
• 
 
 
• 
 
   
 
• 
 
 
• 
 
 
1.4.2 Additional Exploratory Endpoints 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 


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• 
 
 
• 
 
 
2 STUDY DESIGN 
2.1 Study Overview 
Study 221AD301 (ENGAGE) is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in subjects with early AD, including mild cognitive impairment (MCI) 
due to AD and a subset of mild AD, followed by an optional dose-blinded long-term 
extension (LTE) period of up to 5 years. Approximately 1605 subjects will be enrolled across 
approximately 150 centers globally.  The primary study objective is to evaluate the efficacy 
of monthly doses of aducanumab on the CDR-SB relative to placebo.  Secondary objectives 
include assessment of the effect of monthly doses of aducanumab on clinical progression as 
compared to placebo. The safety of monthly doses of aducanumab will also be evaluated. 
 
Table 1: Dosing Scheme for Aducanumab by Treatment Group and ApoE ε4 Carrier 
Status: Placebo-Controlled Period 
Dose (every 4 weeks) 
1 
2 
3 
4 
5 
6 
7 to 20 
Treatment 
Group 
Treatment Group Stratified by 
ApoE Status2  
Dose (mg/kg) 
High Dose 
High Dose - ApoE ε4 (+) 
1 
1 
3 
3 
6 
6 
101 
High Dose - ApoE ε4 (-) 
1 
1 
3 
3 
6 
6 
10 
Low Dose 
Low Dose - ApoE ε4 (+) 
1 
1 
3 
3 
3 
3 
3 
Low Dose - ApoE ε4 (-) 
1 
1 
3 
3 
3 
3 
6 
Placebo 
Placebo - ApoE ε4 (+) 
saline 
Placebo - ApoE ε4 (-) 
saline 
1 10 mg/kg is the target dose for all ApoE ε4 carriers assigned to the aducanumab high-dose group.  Subjects 
enrolled under protocol versions 1-3 and assigned to the previous high-dose of 6 mg/kg will be titrated to 10 
mg/kg upon receipt of at least 2 doses at 6 mg/kg.   
2 ApoE ε4 status recorded in the Interactive Voice/Web Response System (IXRS).   
 
Subjects will be randomized in a 1:1:1 ratio to 1 of the 3 treatment groups: aducanumab high 
dose, aducanumab low dose and placebo, with stratification based upon their apolipoprotein 
E4 (ApoE ε4) carrier status (carrier/non-carrier) and site. During the placebo-controlled 
period, subjects will receive infusions of aducanumab or placebo approximately every 4 
weeks for approximately 18 months (a total of 20 doses). Dose levels may be different in the 
same treatment group based upon subjects’ ApoE ε4 carrier status, and specifically, ApoE ε4 


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carriers will receive placebo, aducanumab 3 mg/kg, or aducanumab 10 mg/kg whereas ApoE 
ε4 non-carriers will receive placebo, aducanumab 6 mg/kg, or aducanumab 10 mg/kg.  
Aducanumab will be titrated for up to 6 doses prior to reaching the target dose as shown in 
Table 1 and Figure 1. Note: As of Protocol Version 4, 10 mg/kg is the target dose for all 
ApoE ε4 carriers in the high-dose group. ApoE ε4 carriers who were randomized to the high 
dose group when the target dose was 6 mg/kg (under protocol versions prior to Version 4) 
must have received 2 or more doses at 6 mg/kg prior to being titrated up to 10 mg/kg.  
At the end of the double-blind, placebo-controlled treatment period, subjects who meet the 
extension entry criteria may enter a long-term safety and efficacy extension period, with all 
subjects receiving aducanumab approximately every 4 weeks (up to a total of 65 doses over 5 
years). The treatment group for the LTE period will be assigned at the same time as the 
randomization for the placebo-controlled period, regardless of whether a subject entering the 
LTE period or not. Subjects who are assigned to the placebo group during the 
placebo-controlled period will be assigned to 1 of 2 active treatment groups in a 1:1 ratio 
(aducanumab low dose: aducanumab high dose) and randomization will be stratified by their 
ApoE ε4 carrier status; for those who enter the LTE period, aducanumab will be titrated for 
up to 6 doses prior to reaching the target dose following the same schedule described for the 
placebo-controlled period. Subjects who are assigned to either aducanumab low dose or 
aducanumab high dose group in the placebo-controlled period will continue in the same 
treatment group for the LTE period; those who enter the LTE period will maintain the dosing 
scheme outlined in the protocol at the time of transition from the placebo-controlled period to 
the LTE period (e.g. subjects who are on stable dosing in the placebo-controlled period will 
continue on the same dose, subjects who are on a titration regimen during the transition will 
continue to titrate into the LTE period, and ApoE ε4 carrier subjects who are enrolled in the 
LTE and randomized to the high-dose group prior to implementation of version 4 of the 
protocol will be allowed to titrate to 10 mg/kg). 
Individual dose adjustments may be implemented in subjects who develop amyloid related 
imaging abnormalities (ARIA). See Protocol Section 7.2.1. 
The total duration of study participation for each subject only participating in the placebo-
controlled period of the study will be up to approximately 102 weeks, including a series of 
Screening visits within 8 weeks before administration of the first dose, a 76-week 
placebo-controlled treatment period, and a safety follow-up (FU) period of approximately 
18 weeks after the final dose. The total duration of study participation for each subject 
participating in the placebo-controlled period and the LTE period will vary and be up to 
approximately 362 weeks, including a series of Screening visits within 8 weeks before 
administration of the first dose, a 76-week placebo-controlled treatment period, a 4-week FU 
period, a 256-week aducanumab dose-blind treatment period, and a safety FU period of 
approximately 18 weeks after the final dose.  
Investigators, study site staff (except for the designated unblinded pharmacist/technician), 
and study subjects will be blinded to the subjects’ randomized treatment assignment for the 
placebo-controlled period.  During the LTE period, investigators and subjects will remain 
blinded to the treatment assignment in the placebo-controlled period and the aducanumab 
dose for the LTE period. 
 


 
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2.2 Study Schematic 
Figure 1: Study Design 
 
ApoE ε4 +/- = apolipoprotein E4 positive/negative; FU = follow-up; P = placebo; R = randomization date. 
*Subjects who are assigned to placebo during the placebo-controlled period are randomized in a 1:1 ratio to high and low dose aducanumab treatment (stratified by their 
ApoE ε4 carrier status) for the long-term extension period on Study Day 1. 


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2.3 Schedule of Events 
See Protocol Section 4.2. 
 
3 SAMPLE SIZE JUSTIFICATION 
The study’s sample size is based, in part, on results from a protocol-specified interim analysis 
from Study 221AD103 which included 1 year data from 1, 3 and 10 mg/kg treatment groups. 
A sample size of 450 subjects per treatment group (1350 in total) was planned to have 
approximately 90% power to detect a true mean difference of 0.5 in change from baseline 
CDR-SB at Week 78 between the 2 treatment groups.  This power calculation was based on a 
2-sided t-test assuming equal variance with a final significance level of 0.05, a standard 
deviation (SD) of 1.92 and a drop-out rate of 30%.  The SD estimate of 1.92 for Week 78 
reflected a 39% increase over the SD from the protocol-specified interim analysis of 1-year 
data. 
The assumed true mean difference of 0.5 between the 2 treatment groups represents an 
approximately 25% reduction in the placebo mean change from baseline at Week 78 if the 
placebo mean change is estimated to be 2. 
As defined in the protocol, the sample size for this study (and for the identically designed 
Study 221AD302) was reassessed in a blinded manner in November 2017 (approximately 3 
months before enrollment completion and with about 10.6% of the data available on the 
primary endpoint from Studies 221AD301 and 221AD302 combined). At this timepoint, the 
SD of the primary endpoint was estimated based on the pooled blinded data from two studies 
using a modified version of Gould-Shih simple-adjustment one sample variance (Zucker et al. 
1999): 
𝑠𝑎𝑑𝑗
2
= 𝑠𝑜𝑠
2 −
2𝑁
9(𝑁−1) 𝛿2, 
where 𝑁 denotes the number of subjects included in the analysis for blinded sample size re-
estimation (subjects with both baseline and Week 78 CDR-SB available at the time of sample 
size re-estimation), δ is the assumed true treatment effect (same treatment effect assumed for 
both the high dose group and low dose group in this analysis), and 𝑠𝑜𝑠
2  is the unadjusted one 
sample variance of the primary endpoint estimate from the pooled blinded data.  
As a result of this analysis, the sample size has been increased from 1350 to 1605 (450 to 535 
per treatment group) to assure adequate power for detecting a mean treatment effect of 0.5. 
 
4 STATISTICAL ANALYSIS METHODS 
4.1 General Considerations 
This statistical analysis plan (SAP) only covers the analyses for the primary, secondary and 
tertiary objectives for the placebo-controlled portion of the study. Hereafter, the placebo-
controlled portion of the study will be referred to as “the study” in the rest of this SAP (e.g., 


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completion of the study means completion of the placebo-controlled portion). A separate 
SAP will be prepared for the analyses of the LTE period and integrated analyses across both 
portions of the study. The analyses of additional exploratory endpoints will be documented 
separately.  
Summary tables will be presented using descriptive summary statistics. For continuous 
variables, summary statistics will generally include: number of subjects with data, mean, 
standard deviation, median, 25% percentile, 75% percentile, minimum and maximum. For 
categorical variables, this will generally include: number of subjects randomized or dosed, 
number with data, and the percent of those with data in each category.  
There are two types of analysis displays for tables: by treatment group (analysis display A in 
Appendix 6.1) and by treatment group stratified by ApoE status (analysis display B in 
Appendix 6.1; here ApoE status refers to the status recorded in IXRS [see Table 1 for 
correspondence between treatment groups and treatment groups stratified by ApoE status]). 
The analysis display for each analysis will be defined in each section. All the listings will be 
presented by treatment group stratified by ApoE status, unless otherwise specified. 
Unless otherwise specified, baseline value is defined as the most recent non-missing 
measurement collected prior to the first dose. Change from baseline will be defined as post-
baseline value minus baseline value.  
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.05.  
The statistical software, SAS® will be used for all summaries and analyses.  
4.1.1 Analysis Population 
• Intent-to-treat (ITT) population:  
The Intent-to-treat population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo).  
 
• Per-protocol (PP) population:  
The per-protocol population is defined as all subjects in the ITT population and also 
o had no violations of the following inclusion criteria: 
▪ Must have at least 6 years of education or work experience to exclude 
mental deficits other than MCI or mild AD; 
▪ Must have a positive amyloid PET scan; 
▪ Must have: 
• A CDR-Global Score of 0.5; 
• A Repeatable Battery for Assessment of Neuropsychological 
Status (RBANS) score of 85 or lower indicative of objective 
cognitive impairment (based upon the Delayed Memory Index 
score); 
• An MMSE score between 24 and 30 (inclusive). 
o had at least 14 infusions. 
o did not make any change to concomitant AD symptomatic medications during 
the study. 
 


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• 
18F-florbetapir amyloid PET analysis population: 
The 18F-florbetapir amyloid PET analysis population is defined as all randomized subjects 
who received at least one dose of study treatment (aducanumab or placebo), used 18F-
florbetapir ligand for amyloid PET scan, and had an evaluable baseline amyloid PET 
SUVR value for the composite region-of-interest using cerebellum as the reference 
region. 
 
• 
18F-flutemetamol amyloid PET analysis population (applicable only to Japan): 
The 18F-flutemetamol amyloid PET analysis population is defined as all randomized 
subjects who received at least one dose of study treatment (aducanumab or placebo), used 
18F-flutemetamol ligand for amyloid PET scan, and had an evaluable baseline amyloid 
PET SUVR value for the composite region-of-interest using cerebellum as the reference 
region. 
 
• Safety population:  
The safety population is defined as all randomized subjects who received at least one dose 
of study treatment (aducanumab or placebo). It is the same population as the ITT 
population. 
 
• Safety MRI population:  
The safety MRI population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo) and had at least one post-baseline 
MRI assessment. 
 
• PK analysis population:  
The PK analysis population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo) and had at least one measurable 
aducanumab concentration in serum. 
 
• Immunogenicity population:  
The analysis population for immunogenicity is defined as all randomized subjects who 
received at least one dose of study treatment (aducanumab or placebo) and had at least 
one post-dose sample evaluable for immunogenicity. 
 
4.2 Background Characteristics 
The summaries in this section will be based on the ITT population. Unless otherwise 
specified, summary tables will be presented by treatment group (analysis display A in 
Appendix 6.1) and by treatment group stratified by ApoE status (analysis display B in 
Appendix 6.1; here ApoE status refers to the status recorded in IXRS [see Table 1 for 
correspondence between treatment groups and treatment groups stratified by ApoE status]). 
All the listings will be presented by treatment group stratified by ApoE status, unless 
otherwise specified. 


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4.2.1 Accounting of Subject 
Disposition of subjects will be summarized and the summary data will include number (%) of 
subjects randomized and dosed, number (%) of subjects who completed the treatment/study, 
and number (%) of subjects who discontinued treatment and/or withdrew from study. For 
subjects who discontinued treatment and/or withdrew from study, the reasons for 
discontinuation and/or withdrawal, and days on treatment and days on study will be 
summarized and listed. The number of subjects discontinuing treatment prior to each 
scheduled clinical efficacy assessment will be summarized (presented by treatment group), 
i.e., the number of subjects discontinuing treatment between Day 1 and Week 26, the number 
of subjects discontinuing treatment between Week 26 and Week 50 visit, etc. A similar 
summary will be done for subjects who withdrew from study (presented by treatment group). 
Time to treatment discontinuation and time to study withdrawal will be displayed by Kaplan-
Meier plot (presented by treatment group). 
Number of subjects in each analysis population will be summarized. Number of subjects 
dosed will be summarized by region, country and site. In addition, number of subjects who 
completed the treatment/study will be summarized by region and country (presented by 
treatment group). 
The categorization of region is based not only on consideration of geography but also on type 
of health care system and access to health care in each country. This region category will be 
used in all analysis, including the demographics, the covariate in statistical models and 
subgroup analysis. The categories for regions will be: 
o Region 1: United States (US); 
o Region 2: European countries (including Austria, Denmark, France, Germany, 
Italy, Portugal, Spain and United Kingdom), plus Australia and Canada; 
o Region 3: Asia countries (including Japan, South Korea and Taiwan). 
 
4.2.2 Demographics and Baseline Characteristics 
The demographic data including age, gender, ethnicity, race, height, weight, and body mass 
index (BMI) will be summarized. Age will also be categorized and presented using the 
following two groupings: <50, 50-60, 61-70, 71-80, 81-85, >85 years, and ≤ 64, 65-74, ≥ 75.  
Summary of the baseline characteristics of AD includes laboratory ApoE ε4 status (carrier or 
non-carrier), baseline clinical stage (MCI due to AD or mild AD), baseline clinical 
assessment including RBANS delayed memory index, CDR global score, CDR-SB, CDR 
cognitive subscore, CDR functional subscore, MMSE, ADAS-Cog 13, ADCS-ADL-MCI, 
number of years of formal education, number of years since first AD symptom, number of 
years since diagnosis of AD, AD treatment use that was stopped prior to entering the study 
(yes or no) and AD symptomatic medication use at baseline (yes or no; see Section 4.2.3 for 
definition of AD symptomatic medication use at baseline). ApoE ε4 carrier will be further 
classified as homozygote and heterozygote. MMSE will also be categorized by the following 
subgroups: <24, 24-26, 27-30. Subject listings will be generated for demographics and 
baseline characteristics. 


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Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number (%) of subjects with history (including both ongoing and not 
ongoing medical conditions) will be summarized by system organ class and preferred term. A 
listing of medical history will be generated. 
Previous therapies for the treatment of AD stopped prior to entering the study, total duration 
of previous therapies and reason for stopping treatment will be summarized (presented by 
treatment group). A listing of previous therapies will also be generated. 
 
4.2.3 Concomitant Medications and Non-Drug Therapies 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary. All concomitant non-drug therapies will be coded using the MedDRA 
dictionary.  A concomitant medication/therapy will be defined as any therapy that was taken 
on or after the day of the first dose of study drug. This includes therapies that start prior to the 
initiation of the first dose if their use continues on or after the date of first dose. To define 
concomitant use for therapies with missing start or stop dates, the following additional 
criteria will be used: 
• if both the start and stop dates of a therapy are missing, that therapy will be 
considered concomitant. 
• if the start date of a therapy is missing and the stop date of that therapy fall on or after 
the date of the first dose, that therapy will be considered concomitant.  
• if the start date of a therapy is prior to the date of the first dose and the stop date of 
that therapy is missing and the therapy is listed as continuing, that therapy will be 
considered concomitant, or 
• if the start date of a therapy is prior to the date of the first dose and the stop date of 
that therapy is missing and the therapy is not listed as continuing, that therapy will be 
considered non-concomitant. 
For a therapy with a partial start date, the year/month of the therapy date will be compared to 
that of the first dosing date to determine whether the therapy is concomitant. 
The number (%) of subjects taking concomitant medication and non-drug therapies will be 
summarized. Non-drug therapies will be presented by treatment group. Concomitant 
medications and non-drug therapies will be listed.  
AD symptomatic medications taken concomitantly at baseline are defined as AD 
symptomatic medications that were being taken at the time of the first dose, i.e., started prior 
to the first dose and continued until after the first dose. The number (%) of subjects taking 
AD symptomatic medications concomitantly at baseline will be summarized. In addition, 
number of subjects using Cholinesterase inhibitors only, Memantine only, or both at baseline 
will be summarized. Subjects who have any change in AD symptomatic medications after the 
initiation of study treatment will be summarized by the timing of change, i.e., the number of 
subjects changing between Day 1 and Week 26, the number of subjects changing between 
Week 26 and Week 50, etc. The summary for AD symptomatic medication use during study 


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will be presented by treatment group. The start and stop date of AD symptomatic medication 
will be listed for these subjects. 
 
4.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations based on Protocol Deviation Classification 
(see Appendix 6.2). The major protocol deviations will be summarized (presented by 
treatment group). Listings will be generated for the major and minor protocol deviations, 
respectively. A listing will be generated for subjects with incorrect stratification ApoE status, 
i.e., treatment stratification ApoE ε4 status in IXRS different from the laboratory ApoE ε4 
status.  
 
4.2.5 Study Drug Exposure and Study Drug Compliance 
A summary table of study drug exposure and compliance will be provided. Number of 
infusions (aducanumab or placebo) received will be summarized as a categorical variable 
(categories as integers from 1 to 20, and 1-5, 6-10, 11-15, and 15-20) as well as a continuous 
variable. Number of weeks on study treatment (aducanumab or placebo), calculated as (date 
of last dose – date of first dose + 29)/7, will be summarized as a categorical variable (every 8 
weeks from 0 to >= 72 weeks) as well as a continuous variable. Percentage of study treatment 
taken up to the last dose, calculated as (the actual number of infusions / by the number of 
infusions a subject is expected to take until the date of last infusion)*100, will be summarized 
as a continuous variable. This table will be presented by treatment group.  
Due to the use of titration regimen in the study and possible dose reduction due to ARIA, 
another summary table will be provided including the following information: number of total 
infusions (categories of 1-5, 6-10, 11-15, and 15-20) as well as a continuous variable, number 
of infusions at each dose level (1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg, respectively) 
summarized as a categorical variable as well as a continuous variable, number of subjects 
with dose increase (placebo to 1 mg/kg, 1 to 3 mg/kg, 3 to 6 mg/kg and 6 to 10 mg/kg, 
respectively), number of subjects with dose reduction (1 mg/kg to placebo, 3 to 1 mg/kg, 6 to 
3 mg/kg and 10 to 6 mg/kg, respectively), maximum dose level received, and cumulative 
dose (as a continuous variable). This table will be presented by treatment group stratified by 
ApoE status.  
A listing of study drug administration records, including dose level at each infusion, 
cumulative number of infusions and cumulative dose will be provided. A listing of 
aducanumab lot numbers will be provided. 
A listing of study drug administration records for placebo subjects who received any doses of 
active treatment will be provided.  
 


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4.3 Efficacy Analysis 
4.3.1 General Considerations 
For efficacy endpoints, the following treatment groups of aducanumab (per randomization) 
will be evaluated and compared with placebo: 
• Aducanumab high-dose (10 mg/kg in ApoE ε4 carriers [including 6 mg/kg for 
subjects enrolled under protocol versions 1-3 who do not have the opportunity to 
uptitrate to 10 mg/kg prior to completing Week 78 of the study] and 10 mg/kg in 
ApoE ε4 non-carriers). 
• Aducanumab low-dose (3 mg/kg in ApoE ε4 carriers and 6 mg/kg in 
ApoE ε4 non-carriers).   
All efficacy analyses will be performed on the ITT population. In addition, the primary and 
secondary endpoints will also be performed on the per-protocol population. The efficacy 
analysis will be presented by treatment group (per randomization), i.e., aducanumab high-
dose, aducanumab low-dose and placebo (analysis display A in Appendix 6.1).  
The primary, sensitivity and supplementary analyses for the primary and secondary endpoints 
are listed in Table 2. 
 
Table 2. Analysis for Primary and Secondary Endpoints 
Endpoint 
Analysis 
Analysis 
Population 
SAP 
Section 
CDR-SB 
Primary: Analysis of change from baseline at Week 
78 (MMRM) 
ITT 
4.3.2.1 
Sensitivity: Pattern mixture model (ANCOVA) 
ITT 
4.3.2.2.1 
Sensitivity: Copy increment from reference method 
(ANCOVA) 
ITT 
4.3.2.2.2 
Sensitivity: Imputation by natural disease progression 
(ANCOVA) 
ITT 
4.3.2.2.3 
Sensitivity: Tipping point analysis (ANCOVA) 
ITT 
4.3.2.2.4 
Supplementary: Censoring after intercurrent events 
(MMRM)* 
ITT 
4.3.2.3.1 
Supplementary: Per-protocol analysis (MMRM) 
Per-protocol 
4.3.2.3.2 
Supplementary: Responder analysis (Logistic 
regression) 
ITT 
4.3.2.3.3 
Supplementary: Slope analysis (MMRM) 
ITT 
4.3.2.3.4 
Supplementary: Divergence effect analysis (MMRM) 
ITT 
4.3.2.3.5 
MMSE,  
Primary: Analysis of change from baseline at Week 
78 (MMRM) 
ITT 
4.3.3.1, 
4.3.3.2, 
4.3.3.3 


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ADAS-Cog 13, 
ADCS-ADL-
MCI 
Sensitivity: Pattern mixture model (ANCOVA) 
ITT 
4.3.3.4 
Supplementary: Censoring after intercurrent events 
(MMRM)* 
ITT 
4.3.3.4 
Supplementary: Per-protocol analysis (MMRM) 
Per-protocol 
4.3.3.4 
Supplementary: Slope analysis (MMRM) 
ITT 
4.3.3.4 
Supplementary: Divergence effect analysis (MMRM) 
ITT 
4.3.3.4 
* Analysis excludes data collected after the following intercurrent events: (1) premature discontinuation of the 
study treatment and (2) any change to concomitant AD symptomatic medications during the study. All other 
analyses will include data collected after intercurrent events [ICH E9 (R1) Addendum 2017]. 
  
 
Visit windows for mapping efficacy endpoint 
For efficacy data that are summarized or analyzed by visit, data collected on all scheduled 
visits and all unscheduled visits will be mapped to an appropriate analysis visit using the 
windowing scheme shown in Table 3. If there are 2 or more assessments available in the 
same analysis window for a subject, the assessment that is closest to the target visit day will 
be used for analysis. If there are 2 or more assessments in the same analysis window with the 
same distance from the target visit day, the later assessment will be used.  
 
Table 3. Visit Windows for Efficacy Endpoints 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 26 
183 
[92, 266] 
Week 50 
351 
[267, 448] 
Week 78 
547 
[449, the end day of the placebo-controlled period *] 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, and is the last day in study for subjects who do not enter LTE. 
 
Handling of missing items for scales 
If any of the individual items for the primary and secondary endpoints is missing, the total 
score of the corresponding endpoint will be imputed by prorating the observed scores [van 
Ginkel 2010]. 
For ADAS-Cog13, if 3 or fewer of 13 items (<25%) are missing, the total score will be 
imputed by the following algorithm: Total score = total score from the completed items * 
[maximum total score (=85) / maximum total score for the completed items]. The imputed 
number will be rounded up to the nearest integer. If more than 3 items are missing, the total 
score of ADAS-Cog 13 at that visit will be considered missing. 
For ADCS-ADL-MCI, if 4 or fewer of 18 items (<25%) are missing, the total score will be 
imputed by a similar algorithm as that for ADAS-Cog 13. The imputed number will be 


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rounded up to the nearest integer. If more than 4 items are missing, the total score for ADCS-
ADL-MCI at that visit will be considered missing. 
The same imputation algorithm will be applied to CDR-SB and MMSE, if only 1 box (of 6) 
of CDR is missing or if only 2 or fewer items (out of 11) are missing for MMSE. If the score 
from more than 1 box of CDR or more than 2 items of MMSE is not available, the CDR-SB 
or MMSE at that visit will be considered missing.  
The total score of the tertiary endpoint NPI-10 will be imputed using the same prorating 
principle if only 1 item (out of 10) is missing. For EQ-5D and mPDQ-20, if any item is 
missing, any total or sum involving that item will be considered missing.  
 
Considerations for multiple comparison adjustments 
A sequential (closed) testing procedure will be used to control the overall Type I error rate 
due to multiple comparisons for the primary endpoint.  The order of treatment comparisons is 
as follows:  aducanumab high-dose versus placebo and aducanumab low-dose versus placebo.  
All comparisons after the initial comparison with p > 0.05 will not be considered statistically 
significant. 
Secondary endpoints have been rank prioritized, in the order shown in Section 1.2. In order to 
control for a Type I error for the secondary endpoints, a sequential closed testing procedure 
will be used and will include both the order of the secondary endpoints and treatment 
comparisons.  Specifically, for each of the secondary endpoints, a sequential (closed) testing 
procedure, as for the primary endpoint, will be used to control the overall Type I error rate 
due to multiple treatment comparisons.  If statistical significance is not achieved for 1 or 2 
treatment comparisons, all endpoint(s) of a lower rank will not be considered statistically 
significant for that 1or 2 treatment comparisons, respectively.   
There will be no multiple comparison adjustments for the sensitivity and supplementary 
analyses for the primary and secondary efficacy endpoints, the tertiary efficacy endpoints, the 
subgroup analyses or the additional analyses. 
 
4.3.2 Primary Efficacy Endpoint 
 Primary analysis 
The estimand of the primary analysis is the mean difference of the change from baseline 
CDR-SB scores at Week 78 between treatment groups in the ITT population [ICH E9 (R1) 
Addendum 2014, 2017]. All observed data will be included in the primary analysis, including 
data collected after intercurrent events [ICH E9 (R1) Addendum 2017], i.e., treatment 
discontinuation or a change in concomitant use of AD symptomatic medication. 
The change from baseline CDR-SB scores will be summarized by treatment group at each 
post-baseline visit. A mixed model repeated measures (MMRM) model will be used as the 
primary analysis to analyze change from baseline CDR-SB using fixed effects of treatment 
group, time (categorical), treatment group-by-time interaction, baseline CDR-SB, baseline 
CDR-SB by time interaction, baseline MMSE, AD symptomatic medication use at baseline 
(yes/no; see Section 4.2.3 for definition of AD symptomatic medication use at baseline), 


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region, and laboratory ApoE ε4 status (carrier/non-carrier). An unstructured covariance 
matrix will be used to model the within-patient variance-covariance errors.  If the 
unstructured covariance structure matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order autoregressive 
covariance structure will be used.  The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. In the primary analysis, missing data are 
assumed to be missing at random [Rubin 1976].  
 
 Sensitivity analysis 
The following sensitivity analyses will be performed to assess the robustness of the primary 
analysis to deviation from the missing-at-random assumption. All the sensitivity analyses will 
be conducted for the ITT population. 
4.3.2.2.1 Pattern mixture model 
The pattern mixture model (PMM) represents a general and flexible framework to model the 
predictive distribution of missing data conditional on the observed data [Little 1993, 1994]. It 
allows formulating assumptions regarding missing data in a transparent and clinically 
interpretable manner.  
In the PMM framework, subjects are grouped into missing patterns so that subjects in the 
same pattern share similar missingness characteristics. In this analysis, missing patterns will 
be defined according to the reasons for early withdrawal from study as reported on the 
electronic case report form (eCRF). The following two patterns will be considered: 
• Subjects who withdraw due to reasons that may be related to efficacy, including 
consent withdrawn, withdrawal by parent/guardian, investigator decision, loss of 
capacity, change of treatment, and disease progression; 
• Subjects who withdraw due to reasons that are unlikely related to efficacy, including 
adverse event, lost to follow-up, death, pregnancy, relocation, protocol amendment, 
site terminated by sponsor/investigator, study visit burden, and other. 
Subjects who withdraw due to reasons that may be related to efficacy will be penalized and 
their missing data will be imputed using the copy increment from reference (CIR) method 
[Carpenter et al. 2013] (see Section 4.3.2.2.2 for description of the CIR method). Subjects 
who withdraw due to reasons that are unlikely related to efficacy will be handled using the 
missing-at-random assumption and their missing data will be imputed using the standard 
multiple imputation method [Rubin 1987]. Subjects with missing data due to reasons other 
than early withdrawal (such as item missing, out of window, etc.) will be handled using the 
missing-at-random assumption. For both imputation methods, the following covariates will 
be included in the imputation model: treatment group, baseline CDR-SB, baseline MMSE, 
AD symptomatic medication use at baseline (yes/no), region, and laboratory ApoE ε4 status 
(carrier/non-carrier). Implementation details can be found in Appendix 6.3.2. 
The imputed datasets will be analyzed by an analysis of covariance (ANCOVA) model 
adjusting treatment group, baseline CDR-SB, baseline MMSE, AD symptomatic medication 
use at baseline (yes/no), region, and laboratory ApoE ε4 status (carrier/non-carrier). The 
analyzed results from the imputed datasets will be combined based on Rubin’s rules [Rubin 


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1987] assuming that the statistics estimated from each imputed dataset are normally 
distributed. 
If intermediate missing values are encountered (such as data missing at Week 26 but are 
available at subsequent visits), a Markov chain Monte Carlo (MCMC) method that assumes 
multivariate normality will be used to impute the intermediate missing values and produce a 
monotone missing pattern (data with only terminal missing and no intermediate missing) [Li 
1988; Schafer 1997]. 
4.3.2.2.2 Copy increment from reference method 
The copy increment from reference (CIR) method will be applied to impute the post-
withdrawal data for any aducanumab-treated subject who withdraws from study early based 
on data from the placebo group rather than the subject’s own randomized treatment group 
[Carpenter et al. 2013]. Specifically, for a subject on aducanumab high dose (or aducanumab 
low dose) who withdraws early, his or her mean trajectory after early withdrawal is assumed 
to be parallel to the mean trajectory of the placebo group, and the difference between the two 
means is the same as the difference at the time of withdrawal. This method assumes that any 
benefit gained from previous treatment will be retained, but subjects progress as if they were 
on placebo after withdrawal from study. For any subject on placebo who withdraws early, his 
or her post-withdrawal profile will be imputed following the missing-at-random principle. 
Implementation details can be found in Appendix 6.3.1.  
After all missing data have been imputed, an ANCOVA model adjusting treatment group, 
baseline CDR-SB, baseline MMSE, AD symptomatic medication use at baseline (yes/no), 
region, and laboratory ApoE ε4 status (carrier/non-carrier) will be applied to analyze the 
change from baseline CDR-SB. 
4.3.2.2.3 Imputation by natural disease progression 
Subjects are assumed to exhibit an evolution of the disease similar as the natural disease 
progression after early withdrawal from study (for all treatment groups). The natural disease 
progression is determined based on a snapshot of the Alzheimer’s Disease Neuroimaging 
Initiative (ADNI) database [Mueller et al. 2005] obtained in May 2017. A subpopulation was 
defined that satisfies the major inclusion criteria of Study 221AD301 (and the identically 
designed Study 221AD302). In this subpopulation, the mean change from baseline CDR-SB 
at Week 78 is estimated to be about 1.52 for subjects with late mild cognitive impairment 
(LMCI) and about 2.06 for subjects with mild AD. The missing data at Week 78 for this 
study will be imputed using the linear extrapolation approach based on subjects’ baseline 
clinical stage (MCI due to AD or mild AD). For example, assuming a mild AD patient whose 
last non-missing change from baseline CDR-SB measurement is 0.5 at Week 26, the change 
from baseline CDR-SB at Week 78 for this patient will be imputed as 0.5+2.06*(78-26)/78, 
which is 1.87. A similar algorithm will be applied to the MCI patients. After imputation, the 
change from baseline CDR-SB at Week 78 will be analyzed by an ANCOVA model 
adjusting treatment group, baseline CDR-SB, baseline MMSE, AD symptomatic medication 
use at baseline (yes/no), region, and laboratory ApoE ε4 status (carrier/non-carrier). 
4.3.2.2.4 Tipping point analysis 


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The tipping-point analysis is a progressive stress-testing to assess how severe departures from 
missing-at-random must be in order to overturn the conclusion of the primary analysis [Yan 
et al. 2009]. For our study, subjects are assumed to have worse scores after early withdrawal 
from study compared to subjects who remain on study.  
The missing data are first imputed by the standard multiple imputation (assuming missing at 
random). To reflect the worse performance after early withdrawal, pre-specified shift 
parameters 𝛿𝑐 and 𝛿𝑡 are added to the imputed values for subjects on placebo and 
aducanumab (include both low dose and high dose), respectively. The adjusted multiple 
imputed datasets will then be analyzed by an ANCOVA model and the results will be 
combined using the Rubin’s rule for inference. 
A range of shift parameters 𝛿𝑐 and 𝛿𝑡 will be applied and p-value will be calculated for each 
combination of 𝛿𝑐 and 𝛿𝑡. The tipping region is defined as the combinations of 𝛿𝑐 and 𝛿𝑡 such 
that the treatment effect is no longer significant (p-value greater than the significance level). 
The scientific plausibility of the tipping region will be evaluated. If implausible departures 
from the missing-at-random assumption (large δ) are needed in order to change the results 
from statistically significant to insignificant, the results of the primary analysis are considered 
to be robust to departure from the missing-at-random assumption. 
 
 Supplementary analysis 
4.3.2.3.1 Censoring after intercurrent events  
The primary analysis (Section 4.3.2.1) will be repeated with the data censored after any of the 
following intercurrent events (if multiple events occur to the same subject, data after the 
earliest event will be censored): 
o premature discontinuation of the study treatment; 
o any change to concomitant AD symptomatic medications during the study. 
The estimate of this analysis reflects the treatment effect of aducanumab if the drug is taken 
as directed. 
4.3.2.3.2 Per-protocol analysis 
The per-protocol analysis will be done using the same model as the primary analysis (Section 
4.3.2.1) and applying in the per-protocol population (Section 4.1.1).  
4.3.2.3.3 Responder analysis 
To further assess whether subjects on aducanumab progress differently from those on 
placebo, responder analysis will be conducted. The responders will be determined by a 
threshold of the primary endpoint, i.e., subjects whose change from baseline CDR-SB at 
Week 78 is smaller than or equal to the threshold will be classified as responders and 
otherwise will be classified as non-responders. All subjects with missing data at Week 78 will 
be classified as non-responders. 
The responder analysis will be conducted for two threshold values: 0.5 or 1.5, i.e., subjects 
whose change from baseline CDR-SB at Week 78 ≤ 0.5 or ≤ 1.5. The number of responders 


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and the response rate will be summarized by treatment group. The dichotomized response, 
responder vs. non-responder, will be modeled using a logistic regression with the following 
covariates: treatment group, baseline CDR-SB, baseline MMSE, AD symptomatic medication 
use at baseline (yes/no), region, and laboratoy ApoE ε4 status (carrier/non-carrier). In 
addition to the two selected threshold values, the continuous responder curve that displays the 
percentage of responders under a wide range of threshold values will be presented by 
treatment group.   
Since all missing data will be considered as non-response, which is a special form of missing-
not-at-random, this analysis can provide additional insights for the robustness of the primary 
analysis results. 
4.3.2.3.4 Slope analysis 
Slope analysis will be conducted to assess the difference between each aducanumab treatment 
group and placebo in the slope of change from baseline in CDR-SB up to Week 78. A 
reduction in the slope of the aducanumab treatment group compared with placebo would 
indicate a slower rate of disease progression, thus reflecting a disease modifying effect of 
aducanumab. An MMRM model will be used, with dependent variable as the change from 
baseline CDR-SB score at each visit and with fixed effects of treatment group, time (as a 
continuous variable), treatment group-by-time interaction, baseline CDR-SB, baseline CDR-
SB by time, baseline MMSE, AD symptomatic medication use at baseline (yes/no), region, 
and laboratory ApoE ε4 status (carrier/non-carrier). The continuous time variable is 
calculated as number of years since the 1st infusion, so the slope estimate reflects the annual 
rate of change. The same methods as in the primary analysis will be considered for the 
covariance structure and the degrees of freedom. 
4.3.2.3.5 Divergence effect analysis 
A divergence effect analysis will be performed to assess whether the treatment difference 
between the aducanumab treated patients and the placebo patients increases over time [Li 
2017]. A linear trend test will be conducted on treatment difference at Week 26, 50 and 78 
estimated from the MMRM model of Section 4.3.2.1, to assess if the slope of the treatment 
difference is positive or not. Let the estimate of treatment difference be 𝛿𝑖 at time point 𝑡𝑖, 
where 𝑡𝑖= 26, 50 and 78 (week). The least-square estimate of the slope is 
𝛽𝐷𝐼𝐹= ∑(𝑡𝑖−𝑡̅)𝛿𝑖
∑(𝑡𝑖−𝑡̅)2 , 
where  𝑡̅ is the mean of 𝑡𝑖’s. The hypothesis to be tested is 
𝐻0: 𝛽𝐷𝐼𝐹≤0 versus 𝐻𝑎: 𝛽𝐷𝐼𝐹> 0. 
Given 𝛽𝐷𝐼𝐹 is a linear combination of the treatment difference 𝛿𝑖, this analysis can be 
implemented by the “estimate” statement in the SAS proc mixed procedure.  
 
 CDR subscores and CDR global score 
The CDR is comprised of 6 domains: Memory, Orientation, Judgment and Problem Solving, 
Community Affairs, Home and Hobbies, and Personal Care. CDR-SB is the sum of the scores 


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for these 6 domains. In addition, two CDR subscores have been proposed [Tractenberg 
2005]: a “cognitive” subscore equaling the sum of the Memory, Orientation, and Judgment 
and Problem Solving box scores, and a “functional” subscore equaling the sum of 
Community Affairs, Home and Hobbies and Personal Care box scores. For each of the 6 box 
scores, and the CDR cognitive subscore and CDR functional subscore, the baseline value and 
the change from baseline at each post-baseline visit will be summarized by treatment group. 
The same MMRM model as the primary analysis will also be applied to the CDR cognitive 
subscore and CDR functional subscore. 
The CDR global score is a composite score obtained by combining the 6 box scores using a 
scoring algorithm that weights memory as the primary domain and all other domains as 
secondary [Morris 1993]. The distribution of CDR global score will be summarized (as a 
categorical variable) by treatment group at each post-baseline visit.  
 
4.3.3 Secondary Efficacy Endpoints 
 Primary analysis of MMSE 
The change from baseline MMSE scores will be summarized by treatment group at each post-
baseline visit. An MMRM model will be used as the primary analysis to analyze change from 
baseline MMSE using fixed effects of treatment group, time (categorical), treatment group-
by-time interaction, baseline MMSE value, baseline MMSE by time interaction, AD 
symptomatic medication use at baseline (yes/no), region, and laboratory ApoE ε4 status 
(carrier/non-carrier). The same methods as in the primary analysis will be considered for the 
covariance structure and the degrees of freedom.  
 Primary analysis of ADAS-Cog 13 
The change from baseline ADAS-Cog 13 scores will be summarized by treatment group at 
each post-baseline visit. An MMRM model will be used as the primary analysis to analyze 
change from baseline ADAS-Cog 13 using fixed effects of treatment group, time 
(categorical), treatment group-by-time interaction, baseline ADAS-Cog 13, baseline ADAS-
Cog 13 by time interaction, baseline MMSE, AD symptomatic medication use at baseline 
(yes/no), region, and laboratory ApoE ε4 status (carrier/non-carrier). The same methods as in 
the primary analysis will be considered for the covariance structure and the degrees of 
freedom.  
 Primary analysis of ADCS-ADL-MCI 
The change from baseline ADCS-ADL-MCI scores will be summarized by treatment group at 
each post-baseline visit. An MMRM model will be used as the primary analysis to analyze 
change from baseline ADCS-ADL-MCI using fixed effects of treatment group, time 
(categorical), treatment group-by-time interaction, baseline ADCS-ADL-MCI, baseline 
ADCS-ADL-MCI by time interaction, baseline MMSE, AD symptomatic medication use at 
baseline (yes/no), region, and laboratory ApoE ε4 status (carrier/non-carrier). The same 
methods as in the primary analysis will be considered for the covariance structure and the 
degrees of freedom.  


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The primary analysis of ADCS-ADL-MCI will use the pooled data from both Studies 
221AD301 and 221AD302 (analysis for each individual study will also be performed). 
Pooled data will be used for the primary analysis because functional outcomes are expected 
to be less sensitive to change within the study duration than cognition measures due to ceiling 
effects [Rockwood 2007], as subjects entering the study will have no or little measurable 
impairment at baseline. It has also been observed in previous studies of more impaired 
patients (mild to moderate/severe) that functional outcome treatment effect sizes are small 
[Hansen 2007].  
 Sensitivity/Supplementary analysis 
The following sensitivity and supplementary analyses that are planned for the primary 
efficacy endpoint will also be conducted for the secondary efficacy endpoints: 
• Pattern mixture model  
• Censoring after intercurrent events 
• Per-protocol analysis 
• Slope analysis 
• Divergence effect analysis 
 
4.3.4 Tertiary Endpoints for Efficacy and Quality of Life 
The baseline value and the change from baseline at each post-baseline visit for NPI-10 will 
be summarized by treatment group. An MMRM model will be used to analyze the change 
from baseline in NPI-10 using fixed effects of treatment group, time (categorical), treatment 
group-by-time interaction, baseline NPI-10, baseline NPI-10 by time interaction, baseline 
MMSE, AD symptomatic medication use at baseline (yes/no), region, and laboratory ApoE 
ε4 status (carrier/non-carrier). Same methods as in the primary analysis will be considered for 
the covariance structure and the degrees of freedom. 
For the following tertiary endpoints for patient-reported outcomes and quality of life, subject 
self-reported EQ-5D index score (SR), informant-rated subject EQ-5D index score (IR-S), 
and mPDQ-20, the baseline value and the change from baseline at each post-baseline visit 
will be summarized by treatment group. Additional analyses for these endpoints will be 
provided in a separate document.  
 
4.3.5 Subgroup Analysis 
Subgroup analyses will be performed for the primary endpoint (CDR-SB) and secondary 
endpoints (MMSE, ADAS-Cog13, ADAS-ADL-MCI). The following pre-defined subgroups 
will be considered: 
• Laboratory ApoE ε4 status (carrier or non-carrier) 
• Baseline clinical stage (MCI due to AD or mild AD) per the Investigator’s assessment 
based on the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria 
• Use of AD symptomatic medication at baseline (yes or no) 


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• Baseline MMSE (MMSE ≤ 26 or MMSE ≥ 27) 
• Region (US, Europe/Canada/Australia, Asia; see Section 4.2.1 for definition of 
region) 
• Age category (≤ 64, 65-74, ≥ 75) 
• Gender (female or male) 
A selective set of subgroup analyses will be performed for Amyloid PET data. Details will be 
defined in Sections 4.4. 
 
4.4 Amyloid PET Analysis 
4.4.1 Amyloid PET substudy  
Every subject enrolled into the study must have a positive amyloid PET scan by visual read 
either at screening or obtained within 12 months of screening. Subjects enrolled into the 
amyloid PET substudy will have the quantitative standard uptake value ratio (SUVR) scores 
at screening and at each planned post-baseline visit. The amyloid PET substudy will include a 
subset of approximately 400 subjects in countries other than Japan where PET scans will be 
performed using 18F-florbetapir ligand, and a small subset of subjects in Japan where either 
18F-florbetapir ligand or 18F-flutemetamol ligand will be used. In the placebo-controlled 
period, amyloid PET assessments are scheduled at screening, Week 26, and Week 78.   
 
4.4.2 Amyloid PET SUVR regions-of-interest and reference regions  
Amyloid PET standardized uptake value ratio (SUVR) is a quantitative measure of cerebral 
amyloid plaque burden. The SUVR will be calculated for the following target brain regions-
of-interest (ROIs): composite ROI, frontal cortex, parietal cortex, lateral temporal cortex, 
sensorimotor cortex, anterior cingulate cortex, posterior cingulate cortex, medial temporal 
cortex, occipital cortex, striatum, and statistical ROI normalized to reference region activity. 
Additionally, SUVR ROIs including pons and deep subcortical white matter which are 
believed to be least affected by amyloid pathology will also be evaluated. The composite ROI 
will comprise of major cortical regions part of the frontal, parietal, lateral temporal, 
sensorimotor, anterior, posterior cingulate and occipital cortices to serve as a summary 
measure of global cerebral amyloid burden. The statistical ROI is a region of interest 
consisting of the posterior cingulate cortex, precuneus and medial frontal cortex that has been 
demonstrated to yield optimal group separation between subjects with low and high amyloid 
burden across different reference regions. A negative change from baseline in composite ROI 
SUVR indicates a reduction in amyloid burden and a negative treatment difference 
(aducanumab minus placebo) favors aducanumab. The composite ROI will serve as the ROI 
of primary focus. 
The following reference regions will be employed: cerebellum, cerebellum cropped, 
cerebellar white matter, cerebellar grey matter, deep subcortical white matter, pons, 
cerebellum + pons, cerebellar white matter + pons, deep subcortical white matter + 
cerebellum, deep subcortical white matter + pons and deep subcortical white matter + 
cerebellum + pons. Cerebellum will serve as the reference region of primary focus. 


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The composite ROI SUVR using cerebellum as the reference region will be used as the 
primary endpoint for amyloid PET analysis. 
4.4.3 Amyloid PET analysis population 
There are two amyloid PET analysis population: 18F-florbetapir amyloid PET analysis 
population and 18F-flutemetamol amyloid PET analysis population. 
The following background characteristics tables will be generated for the 18F-florbetapir 
amyloid PET analysis population and will be presented by treatment group: number of 
subjects enrolled by region and country, demography, baseline disease characteristics, 
medical history. The content of these tables will be the same as those described in section 4.2 
for the ITT population, with the addition of baseline amyloid PET SUVR values summarized 
for the baseline characteristics of AD. 
4.4.4 By visit summary and MMRM model  
The baseline and change from baseline amyloid PET SUVR values will be summarized by 
treatment groups (placebo, low dose and high dose) and by visit for each of the target ROIs 
using cerebellum as the reference region for each of the amyloid PET analysis populations. In 
addition, the baseline and change from baseline amyloid composite ROI values will be 
summarized by treatment groups by visit for each of the reference regions for each of the 
amyloid PET analysis populations.  
For the 18F-florbetapir amyloid PET analysis population, an MMRM model will be used to 
analyze change from baseline SUVR for each target ROI with cerebellum as the reference 
region. Fixed effects of the model will include treatment groups (placebo, low dose and high 
dose), visit (Week 26 and Week 78), treatment group-by-visit interaction, baseline SUVR 
(continuous), baseline SUVR by visit interaction, baseline MMSE (continuous), laboratory 
ApoE ε4 status (carrier and non-carrier), and baseline age (continuous). Visit and treatment 
group will be treated as categorical variables in the model along with their interactions. An 
unstructured covariance matrix will be used to model the within-patient variance-covariance 
errors.  If the unstructured covariance structure matrix results in a lack of convergence in any 
of the parameters, the heterogeneous Toeplitz covariance structure followed by the 
heterogeneous first-order autoregressive covariance structure will be used for all the 
parameters.  The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom. Adjusted means for each treatment group, pairwise adjusted differences 
with placebo, 95% confidence intervals for the differences and associated p-values will be 
presented at week 26 and week 78. The same MMRM model will also be used to analyze the 
change from baseline SUVR for the composite ROI with each of the reference regions. No 
multiple comparison adjustment will be used for amyloid PET analysis. 
Subgroup analysis will be conducted on the 18F-florbetapir amyloid PET analysis population 
using the same MMRM model for composite ROI using cerebellum as reference region for 
the following stratification factors: laboratory ApoE status (carrier or non-carrier, and this 
model will not use ApoE status as a covariate), baseline clinical stage (MCI due to AD or 
mild AD) and baseline composite ROI SUVR value in quartiles. 
Visit windows for by visit analysis 


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For amyloid PET by visit summaries and MMRM models, the analysis visit should be 
defined using visit windows (see Table 4 below). The rationale is to use the same analysis 
visit windows as for the efficacy endpoints for Week 26 and Week 78. If there is more than 1 
value in the same analysis visit window (>1 value for the same analysis visit) for a certain 
parameter for a subject, then the closest record to the target visit day will be used for the by 
visit analysis.  If they are with the same distance from the target visit day, then the record 
with the later time will be used for the by visit analysis.   
Table 4: Visit Windows for amyloid PET data 
Analysis visit  
Target visit day  Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 26 
183 
[92, 266] 
Week 78 
547 
[449, the end day of the placebo-controlled period**] 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter in LTE, and is the last day in study for subjects who do not enter LTE. 
 
4.4.5 Correlation between amyloid PET and CDR sum of boxes  
Pearson and Spearman correlation 
Pearson and Spearman correlations between change from baseline amyloid PET composite 
ROI using cerebellum as reference region at Week 78 and change from baseline CDR-SB at 
Week 78 will be conducted by treatment groups (placebo, low dose and high dose, and active 
total) in the 18F-florbetapir amyloid PET analysis population. Pearson and Spearman partial 
correlations adjusting for baseline amyloid PET composite ROI and baseline CDR-SB will 
also be conducted by treatment groups at Week 78. The estimated correlation coefficients, p-
values and the 95% confidence intervals will be provided. Given that reductions in cerebral 
β-amyloid (Aβ) content may precede clinical effects (e.g., slowing of clinical decline), 
Pearson and Spearman correlations and partial correlations between change from baseline 
amyloid PET composite ROI at Week 26 and change from baseline CDR-SB at Week 78 will 
also be conducted.  
Correlation analysis will be done on each individual study as well as in the pooled data of the 
221AD301 and 221AD302 studies. The correlation analysis based on the pooled data will be 
considered as the primary analysis. 
 
4.5 Safety Analysis  
4.5.1 General Considerations 
Analysis population 
Safety population will be used for safety analyses of AEs, clinical laboratory data, 
Columbia Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital sign data (all 
the safety data except for ARIA data). Safety MRI population will be used for analyses of 
ARIA data.  
 


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Safety treatment groups  
Different from the randomization treatment groups, if a subject who was randomized to 
placebo group accidentally received one or more doses of the active treatment during the 
study, he/she will be classified as either low or high dose group for all the safety analyses, 
depending on the ApoE status and the maximal dose level of the active treatment received 
(Table 5). A listing of such subjects will be provided, as described in section 4.2.5.  Safety 
treatment groups will be the same as the randomization treatment groups for other subjects 
(subjects randomized to active treatment groups, and subjects randomized to placebo without 
any accidental active dose). Safety treatment groups will be used for all the safety analyses 
unless otherwise specified.  
 
Table 5: Safety treatment groups for placebo subjects with accidental active treatment 
Randomization 
treatment 
group 
Randomization 
ApoE status 
Safety treatment group classification 
based on the maximum dose level of 
the accidental active treatment  
>0 to 3 
mg/kg 
>3 to 6 
mg/kg 
>6 mg/kg 
Placebo 
ApoE ε4 (+) 
Low dose 
High dose 
High dose 
ApoE ε4 (-) 
Low dose 
Low dose 
High dose 
 
Safety analysis displays 
AEs, clinical laboratory data, C-SSRS data, ECG data and vital sign data (all the safety data 
except for ARIA data) will be summarized by treatment group (placebo, low dose, high dose 
and BIIB037 total; analysis display A in Appendix 6.1), unless otherwise specified. All the 
ARIA related tables will be presented by treatment group stratified by ApoE status (3 
columns under each treatment group: ApoE ε4+, ApoE ε4- and total; analysis display B in 
Appendix 6.1), unless otherwise specified. A subset of AE tables will also be presented by 
treatment group stratified by ApoE status in addition to by treatment group. All the listings 
will be presented by treatment group stratified by ApoE status. 
 
Incidence, incidence proportion and incidence rate 
• Incidence and incidence proportion will be provided in incidence tables. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion is 
defined as the number of subjects who experienced an event divided by total number of 
subjects in the analysis population, i.e., percentage. Each subject will be counted only 
once within each category. 
  


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• Incidence and incidence rate will be provided in incidence rate tables. Two different kinds 
of incidence rate tables will be provided as appropriate for different analyses. Definitions 
are provided below. 
 
(1) Follow-up adjusted incidence rate – defined as the number of subjects who 
experienced an event divided by the total of entire follow-up time among the subjects 
in the analysis population. The entire follow-up time for a subject is defined as the 
time from the first dose until the last day on study. Each subject will be counted only 
once within each category.  
(2) Exposure-adjusted incidence rate (EAIR) – defined as the number of subjects who 
experience an event divided by the total exposure adjusted follow-up time among the 
subjects in the analysis population. The exposure adjusted follow-up time is defined 
as the time from the first dose until the initial occurrence of the event for those who 
experienced an event, or from the first dose until the end of follow-up (the last day on 
study) for those who did not. Each subject will be counted only once within each 
category. 
 
4.5.2 Clinical Adverse Events 
Treatment-emergent AEs (TEAEs) 
All AEs will be analyzed based on the principle of treatment emergence.  A treatment-
emergent AE was defined as an AE that started or worsened after the start of first infusion of 
study treatment.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
• if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent; 
• if the start date for a particular AE is missing and the stop date/time falls after the first 
dose date/time, then that AE is considered treatment emergent; 
• if the start date for a particular AE was the same as the first dose date, and the start time 
was missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of 
the first dosing date to determine whether the event is treatment emergent. 
In addition, SAEs that occurred since a subject was screened in the study and prior to the first 
infusion of study treatment, which by definition are not treatment-emergent, will be analyzed 
separately. 
Only TEAEs will be included in the AE tables, unless otherwise specified. Listings of AEs 
will include all events, whether treatment-emergent or not. 
As specified in the protocol, subjects were expected to return to the study site for an End of 
Study visit 18 weeks after the last administration of study treatment. However, some subjects 
may elect to continue study participation on a modified schedule after discontinuing 
treatment, possibly in substantial excess of 18 weeks.  For most general AE summaries, AEs 


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with an onset more than 18 weeks after the last dose will be excluded (will specify in the 
footnote of the specific table). For incidence rate analyses excluding AEs more than 18 weeks 
after the last dose, the “last day on study” in follow-up time calculation will be replaced with 
“18 weeks after last dose or last day on study, whichever earlier”.  Summaries of deaths and 
AEs leading to study withdrawal, and other selected analyses will include all AEs regardless 
of the time since the last dose.  Listings will include all AEs, unless otherwise specified.   
 Summary and incidence analysis 
Overall summary of AE table will summarize the number of subjects with any AE, with any 
AE by maximum severity, the number of subjects with any related AE (related to study drug 
as assessed by investigator), the number of subjects with SAE, the number of subjects with 
related SAE, the number of subjects with AE leading to study drug discontinuation, the 
number of subjects with AE leading to study withdrawal, and the number of deaths. This 
table will be done by treatment group as well as by treatment group stratified by ApoE status. 
The sorting order for AE incidence tables, unless otherwise specified, will be by decreasing 
frequency order of “BIIB037 total” column within each category in the tables presented by 
treatment group, and by decreasing frequency order of “BIIB037 high dose total” column 
within each category in the tables presented by treatment group stratified by ApoE status. A 
subject is counted only once within each category in each table. For example, for the table of 
AEs by system organ class and preferred terms sorted by decreasing frequency presented by 
treatment group, system organ class will be presented in decreasing frequency order of 
BIIB037 total column, and within each system organ class, preferred terms will be presented 
in decreasing frequency order of BIIB037 total column. A subject is counted only once 
within each system organ class and preferred term.  
The following AE incidence tables will be provided (presented both by treatment group and 
by treatment group stratified by ApoE status, unless otherwise specified): 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class and preferred term sorted by alphabetical order (by 
treatment group)  
3. AEs by system organ class, high level group term and preferred term (by treatment 
group only) 
4. AEs by system organ class (by treatment group) 
5. AEs with at least 2% higher in incidence for either low or high dose compared to 
placebo by system organ class and preferred term  
6. AEs by preferred term  
7. AEs with an incidence of 5% or more in any treatment group by preferred term  
8. Severe AEs by system organ class and preferred term (by treatment group) 
9. Severe AEs by preferred term  
10. AEs by maximum severity by system organ class and preferred term (by treatment 
group) (System organ class will be presented alphabetically. Preferred terms will be 
presented in decreasing frequency order. Maximum severity will be presented within 
each preferred term in the order of mild, moderate, severe, unknown and total. A 


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subject will be counted only once at the maximum severity within each system organ 
class and preferred term.)  
11. AEs by maximum severity by preferred term (by treatment group) (Preferred terms 
will be presented in decreasing frequency order. Maximum severity will be presented 
within each preferred term in the order of mild, moderate, severe, unknown and total. 
A subject will be counted only once at the maximum severity within each preferred 
term.) 
12. Related AEs by system organ class and preferred term  
13. SAEs by system organ class and preferred term  
14. SAEs by preferred term  
15. Related SAEs by system organ class and preferred term  
16. AEs that led to discontinuation of study treatment by system organ class and preferred 
term 
17. AEs that led to withdrawal from study by system organ class and preferred term  
18. SAEs with fatal outcome by system organ class and preferred term 
19. AEs that occurred within 2 hours from infusion start by system organ class and 
preferred term (by treatment group)  
20. AEs by12 weeks intervals from first infusion to the end of study by system organ 
class and preferred term (by treatment group) 
21. Pre-treatment SAEs that occurred since screening and prior to first infusion by system 
organ class and preferred term  
 
The following listings will be provided.  
1. Listing of AEs 
2. Listing of SAEs  
3. Listing of AEs that led to discontinuation of study treatment 
4. Listing of AEs that led to withdrawal from study 
5. Listing of AEs that occurred within 2 hours from infusion start 
6. Listing of AEs related to PET ligands  
7. Listing of SAEs with fatal outcome 
8. Listing of AEs for subjects with treatment-emergent positive anti-BIIB037 antibody  
 Incidence rate analysis 
Follow-up adjusted incidence rate for the placebo-controlled period will be summarized by 
system organ class and preferred terms both by treatment group and by treatment group 
stratified by ApoE status.  


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 Subgroup analysis for protocol version 4 
Due to the change in maximal dose from 6 mg/kg to 10 mg/kg for ApoE ε4 carrier high dose 
group in protocol version 4, not all subjects have had opportunity to receive the protocol 
specified high dose (6 doses in titration before receive 10mg/kg) in the placebo-controlled 
period. Incidence tables of AEs and SAEs will be provided for ApoE ε4 carriers who were 
randomized to the high dose group, stratified by the expected number of doses at 10 mg/kg 
(categories of 0, 1-6, 7-13, 14, and a total column of having at least one dose) a subject would 
have received based on the first infusion date and the date consenting to protocol version 4. 
Randomization treatment groups will be used for this analysis. 
 
4.5.3 ARIA – AE of special interest 
 Background 
ARIA is an AE of special interest in this study. Please see protocol section 7.2.1 for ARIA 
management and dose disposition guidelines. Since ARIA is a brain MRI finding, ARIA data 
are collected under two data sources: (1) safety MRI data as recorded on brain MRI 
worksheet by central MRI reader; (2) AE eCRF. For each ARIA event, the information of 
start/end date, severity, locations in brain regions and status on MRI scan is collected on the 
brain MRI worksheet by central MRI reader. ARIA severity is determined by central MRI 
reader based on number and size of the ARIA regions on imaging. An AE record is then 
entered into the eCRF by the investigator with the start/end date and severity information 
from brain MRI worksheet, and with information on the symptomatic status and action taken 
towards study drug. If ARIA is symptomatic, the symptoms will be entered into AE eCRF 
and the severity of the symptoms will be determined by the investigator. AE eCRF data will 
be used as the primary source for ARIA analysis as it contains the complete information of 
ARIA as well as associated symptoms. Safety MRI data will also be used to show the 
consistency between two data sources, provide details on MRI assessments, and for any 
specific analysis that requires information from MRI. 
ARIA includes ARIA-E (vasogenic edema) and ARIA-H (hemorrhage). ARIA-H includes 
ARIA-H microhemorrhage, ARIA-H macrohemorrhage and ARIA-H superficial siderosis. 
Table 6 shows the reported term on MRI worksheet, the corresponding reported term on AE 
eCRF, and the MedDRA preferred term and lower level term for each type of ARIA. 
 
Table 6: Reported and MedDRA terms for ARIA 
Reported term on 
MRI worksheet 
Reported term on AE 
eCRF 
MedDRA version 21.0 
preferred term 
MedDRA 
version 21.0 
lower level term 
ARIA-E 
Asymptomatic ARIA-E 
Symptomatic ARIA-E 
Amyloid related 
imaging abnormality-
oedema/effusion 
ARIA-E 


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ARIA-H 
microhemorrhage 
Asymptomatic ARIA-H 
(Microhemorrhage)  
Symptomatic ARIA-H 
(Microhemorrhage) 
Amyloid related 
imaging abnormality-
microhaemorrhages 
and haemosiderin 
deposits 
ARIA-H 
ARIA-H 
macrohemorrhage 
Asymptomatic ARIA-H 
(Macrohemorrhage) 
Symptomatic ARIA-H 
(Macrohemorrhage) 
Amyloid related 
imaging abnormality-
microhaemorrhages 
and haemosiderin 
deposits 
ARIA-H 
ARIA-H 
superficial 
siderosis 
Asymptomatic ARIA-H 
(Superficial Siderosis) 
Symptomatic ARIA-H 
(Superficial Siderosis) 
superficial siderosis of 
the central nervous 
system 
superficial 
siderosis of the 
central nervous 
system 
 
For any specific ARIA event, the start date of the duration based on MRI is the date of the 
MRI assessment that initially identifies the ARIA event, and the end date of the duration 
based on MRI is the date of the MRI assessment that shows the complete resolution of this 
ARIA event (in the case of ARIA-E), or the date of the MRI assessment that shows ARIA 
being stable (in the case of ARIA-H). Stable was defined as ‘No change’ or ‘decrease’ in 
number, size, severity or number of locations between 2 consecutive MRIs including the 
initial detection MRI and the follow-up MRIs.  
For symptomatic ARIA events, if there is any related symptom that proceeds the first MRI 
identification, then the symptom onset date will be used as the start date of the symptomatic 
ARIA duration. The end date of the symptomatic ARIA duration will be the date of the 
resolution or stable MRI as defined above for the duration based on MRI.  
If the severity increases, or the event changes from asymptomatic to symptomatic, or from 
non-serious to serious, more than one AE records will be added to eCRF to capture the 
change with new start/end AE dates (the end date of the previous record will be the start date 
of the next record). For analysis, records with changes in severity or symptomatic status or 
seriousness are considered as a single ARIA event. The severity/symptomatic 
status/seriousness for that event is defined as the worst level among all the AE records that 
belong to that event. 
 
If the same type of ARIA event happens again after the previous event has ended, then it is 
considered a recurrent event of ARIA of that type. Recurrent events will be referred as the 
second event, the third event, and etc.  
If the duration based on MRI of an ARIA-E event overlaps with the duration based on MRI 
of an ARIA-H event, then these 2 ARIA events are considered as concurrent events. 


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 Incidence and summary of ARIA 
Incidence of ARIA-E, ARIA-H, ARIA-E and ARIA-H (not necessarily concurrent), 
concurrent ARIA-E and ARIA-H, ARIA-E or ARIA-H, isolated ARIA-H (only ARIA-H, no 
ARIA-E), ARIA-H microhemorrhage, ARIA-H macrohemorrhage and ARIA-H superficial 
siderosis will be summarized based on both AE eCRF and MRI data. If there is any 
discrepancy in incidence between the two data sources, a listing of the subjects and ARIA 
events with discrepancy will be provided. In addition, the incidence table based on AE eCRF 
source will also be done by treatment group (placebo, low dose, high dose and BIIB037 total; 
analysis display A in Appendix 6.1).   
Number of subjects with each type of ARIA, maximum severity and worst symptomatic 
status of the type of ARIA being analyzed will be summarized based on AE eCRF. For 
subjects with symptomatic ARIA, the maximum severity of symptoms will also be 
summarized.   
Number of subjects with ARIA-H microhemorrhage events post-baseline (broken down by 
categories of 1-4, 5-9 and >=10) stratified by whether they have had microhemorrhage at 
baseline will be summarized based on safety MRI data. The summary will be conducted 
based on the MRI that shows the maximum number of microhemorrhages as well as the last 
MRI in the study period. 
Summary of concurrent ARIA-E and ARIA-H will be provided including the following 
information: number of subjects with concurrent ARIA-E and ARIA-H (and further broken 
down to each type of ARIA-H), the severity of ARIA-E based on MRI, the symptomatic 
status of ARIA-E, the severity of symptoms based on AE eCRF. For subjects with recurrent 
ARIA-E events, if there is an event concurrent with ARIA-H, it will be used for the 
summary, and the first concurrent event will be used if there are more than one event 
concurrent with ARIA-H.  
An incidence table of AEs considered by the investigator to be related to ARIA by system 
organ class and preferred term for subjects with symptomatic ARIA will be provided, as well 
as a listing of these AEs. Similarly, an incidence table of AEs related to ARIA for subjects 
with symptomatic ARIA and severe symptoms will be provided, as well as a listing of these 
AEs. 
Listings of AE records for each type of ARIA events and listings of MRI assessments for 
subjects with each type of ARIA events will be provided.  
Montreal Cognitive Assessment (MOCA) is performed at baseline and at each unscheduled 
ARIA monitoring visit for ARIA subjects (approximately every 4 weeks) except for mild 
asymptomatic microhemorrhage subjects. An incidence table of subjects with ARIA events 
whose MOCA total scores decrease 2 points or more from baseline will be provided. A listing 
of MRI assessments and MOCA total scores for subjects with ARIA events will be provided.  
Line plots of MMSE mean change from baseline values and standard errors at each planned 
visit (baseline, Week 26, Week 50 and Week 78) will be provided by treatment group 
stratified by ApoE status and with stratification on the following factors:  
(1) ARIA-E severity based on MRI. The groups are: subjects without ARIA-E, subjects 
with mild ARIA-E, subjects with moderate ARIA-E and subjects with severe ARIA-
E. 


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(2) Within ARIA-E subjects, stratify by the severity of the concurrent symptoms based on 
AE eCRF. The groups are: subjects without symptoms, subjects with mild symptoms, 
subjects with moderate symptoms, and subjects with severe symptoms.  
For subjects with recurrent ARIA-E events, the first ARIA-E event will be used for the 
classification for each of the factors.  
 Summary of recurrent ARIA-E 
Follow-up adjusted incidence rate of subjects with ARIA-E, with 2 or more events of ARIA-
E, with 3 or more events of ARIA-E and with more than 3 events of ARIA-E based on their 
entire follow-up time will be summarized based on AE eCRF. The entire follow-up time is 
from the first dose until the last day in the placebo-controlled period. 
Number of total ARIA-E events and the MRI severity of each event will be summarized 
based on AE eCRF. Number of total symptomatic ARIA-E events, the MRI severity of each 
symptomatic event and the severity of the symptoms of each symptomatic event will be 
summarized based on AE eCRF. 
Summary of first ARIA-E events table based on AE eCRF will summarize the number of 
subjects with a first event of ARIA-E, the MRI severity of the events, the symptomatic status 
of the events, the severity of the symptoms for symptomatic events, whether SAE or not, 
number of resolved and unresolved events, duration of the resolved events, time from first 
infusion in study (active or placebo) to onset, number of doses received since the start of the 
study to onset, dose level of the last infusion received prior to onset, dosing status (continue 
as planned, dose interrupted, dose reduced, or dose discontinued) after the events, and the 
number of subjects with recurrent ARIA-E events. The same summary of first ARIA-E 
events table will also be done on subjects who had recurrent ARIA-E events. 
Summary of recurrent ARIA-E events table based on AE eCRF will summarize the following 
information for both the second and third event of ARIA-E events: the number of subjects 
with the previous event of ARIA-E, the number of subjects with at least one dose and one 
MRI after the previous ARIA-E resolution, the number of subjects with this event of ARIA-
E, the MRI severity of the events, the symptomatic status of the events, the severity of the 
symptoms for symptomatic events, whether SAE or not, number of resolved and unresolved 
events, duration of the resolved events, time from first infusion in study (active or placebo) to 
onset, time from previous resolution to onset, number of doses received since the start of the 
study to onset, dose level of the last infusion received prior to onset, dosing status (continue 
as planned, dose interrupted, dose reduced, or dose discontinued) after the events. The 
number of subjects with more than 3 events of ARIA-E, and the number of subjects who 
discontinued study treatment after recurrent ARIA-E onset will also be summarized.  
A listing of subjects who withdrew from the study with unresolved ARIA-E or subjects with 
ongoing ARIA-E at the time of data cutoff (also considered as unresolved) will be provided 
with the details of the event including the duration from onset to last follow-up.  
For subjects with recurrent ARIA-E, a listing of study drug administration, MRI assessments, 
severity and symptomatic status of each event, and end-of-treatment reason (if present) will 
be provided.  


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39 
 
 Exposure adjusted analysis 
Exposure adjusted incidence rate of ARIA-E events will be summarized based on safety MRI 
data. The exposure adjusted follow-up time is from the first dose until the initial occurrence 
of ARIA-E for those who experienced ARIA-E, and until the end of follow-up for those who 
did not. Since ARIA is an MRI finding, the day of the last MRI assessment in the placebo-
controlled period will be used as the end of follow-up for those who didn’t experience the 
event.  
Study drug administration information prior to first ARIA-E onset will be summarized for 
ARIA-E subjects, including number of total infusions, number of infusions at each dose level 
(placebo, 1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg), dose level of the last infusion, 
maximum dose level received, and cumulative dose as a continuous variable.   
 Time to event analysis 
Kaplan-Meier plot of time to first ARIA-E event will be produced based on safety MRI data. 
Time to event is calculated as date of the MRI assessment that initially detects ARIA-E event 
- date of first infusion (aducanumab or placebo) +1. Censor time for subjects without ARIA-
E is calculated as date of last MRI assessment in the placebo-controlled period - date of first 
infusion (aducanumab or placebo) +1. Estimated proportion with ARIA-E and number of 
subjects at risk at selected timepoints will also be presented. The plot will be presented by 
treatment group stratified by ApoE status. 
 Subgroup analysis for protocol version 4 
Due to the change in maximal dose from 6 mg/kg to 10 mg/kg for ApoE ε4 carrier high dose 
group in protocol version 4, not all subjects have had opportunity to receive the protocol 
specified high dose (6 doses in titration before receive 10mg/kg) in the placebo-controlled 
period. Incidence of ARIA events and summary of first ARIA-E events tables will be 
provided for ApoE ε4 carriers who were randomized to the high dose group, stratified by the 
expected number of doses at 10 mg/kg (categories of 0, 1-6, 7-13, 14, and a total column of 
having at least one dose) a subject would have received based on the first infusion date and 
the date consenting to protocol version 4. Randomization treatment groups will be used for 
this analysis. 
 
4.5.4 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol and will be 
analyzed: 
o Hematology:   
• White blood cells (leukocytes), lymphocytes, neutrophils, monocytes, 
eosinophils, basophils 
• Red blood cells (erythrocytes), erythrocytes distribution width, 
erythrocytes mean corpuscular volume, erythrocytes mean corpuscular 
hemoglobin, erythrocytes mean corpuscular hemoglobin concentration 


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Final V1.0 
 
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40 
 
• Hemoglobin 
• Hematocrit 
• Platelet count 
o Blood chemistry:  
• Liver: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, direct bilirubin, 
gamma-glutamyl-transferase (GGT) 
• Renal: blood urea nitrogen (BUN), creatinine 
• Electrolytes: sodium, potassium, chloride, bicarbonate  
• Other: glucose, calcium, phosphorus, albumin, uric acid, lactate 
dehydrogenase (LDH), total protein  
o Urinalysis: specific gravity, potential of hydrogen (pH), color, blood, glucose, 
ketones, protein, white blood cells, red blood cells 
 Quantitative analyses  
For numeric laboratory parameters, actual values, change from baseline and percent change 
from baseline will be summarized by visit. Number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum and maximum values will be presented 
at each visit.  
Plots of mean values (with standard error) for numeric laboratory parameters at each visit will 
be provided.  
Listings of individual laboratory measurements by patients for all the parameters will be 
provided.  
 
Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows 
(see Table 7 below).  If there is more than 1 value in the same analysis visit window for a 
certain parameter for a subject, then the closest record to the target visit day will be used for 
the by visit analysis.  If there are 2 values in the same analysis visit window with the same 
distance from the target visit day for a certain parameter for a subject, then the record with 
the later date will be used for the by visit analysis.  If there are 2 values on the same day for a 
certain parameter for a subject, then the record with the later time will be used for the by visit 
analysis. 
 
Table 7: Visit Windows for Laboratory by Visit Summaries 
Analysis visit  
Target visit day  Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 24 
169 
[2, 252] 
Week 48 
337 
[253, 420] 
Week 72 
505 
[421, 525] 


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41 
 
Analysis visit  
Target visit day  Analysis visit window 
Week 78 
547 
[526, the end day of the placebo-controlled period*] 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, and is the last day in study for subjects who do not enter LTE. 
 
 Qualitative analyses 
For all qualitative analyses, all values will be included (not just the “analyzed record” within 
each visit window in the quantitative analyses). 
 
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate.  Each subject’s 
hematology, blood chemistry and urinalysis numeric values will be flagged as “low”, 
“normal”, or “high” relative to the normal ranges of the central laboratory or as “unknown” if 
no result is available.  Each subject’s urinalysis categorical values will be flagged as 
“positive” or “negative”, or “unknown” if no value is available.   
Shifts from baseline to high/low status will be presented for hematology, blood chemistry and 
urinalysis numeric parameters, and shifts from baseline to abnormal (positive) will be 
presented for urinalysis categorical parameters.  Shift to low includes normal to low, high to 
low, and unknown to low; Shift to high includes normal to high, low to high, and unknown to 
high. Subjects need to have at least one post-baseline evaluation and a baseline value not low 
or high or positive (including missing) in order to be included in the analysis. A listing of 
laboratory normal ranges will be provided. 
 
Grade analyses 
Worst post-baseline grade will be summarized for each laboratory parameter in both 
exclusive way and cumulative way. Subjects need to have at least one post-baseline 
evaluation in order to be included in the analysis. Common Toxicity Criteria for Adverse 
Events v4.0.3 (CTCAE) published on 2010-06-14 will be used for grade determination. 
Grade determination is based solely on laboratory values not taking AEs into account.  
 
Potentially Clinically Significant laboratory abnormalities analyses 
For hematology, blood chemistry and urinalysis, the number of subjects with potentially 
clinically significant laboratory abnormalities post-baseline will be summarized for the 
parameters provided in Table 8. Subjects need to have at least one post-baseline evaluation 
and a baseline value not potentially clinically significant (including missing) in order to be 
included in the analysis.  
Table 8: Criteria to Determine Potentially Clinically Significant (PCS) Laboratory 
Abnormalities 
Clinical Laboratory Outlier Criteria 
Parameter name  
PCS Low 
PCS High 
HEMATOLOGY  


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42 
 
Clinical Laboratory Outlier Criteria 
Parameter name  
PCS Low 
PCS High 
White blood cells  
<3.0 x 109/L  
>16 x 109/L  
Lymphocytes  
<0.8 x 109/L  
>12 x 109/L  
Neutrophils  
<1.5 x 109/L  
>13.5 x 109/L  
Monocytes  
N/A  
>2.5 x 109/L  
Eosinophils  
N/A  
>1.6 x 109/L  
Basophils  
N/A  
>1.6 x 109/L  
Red blood cells  
≤3.5 x 1012/L 
≥6.4 x 1012/L 
Hemoglobin - Females  
≤95 g/L  
≥175 g/L  
Hemoglobin - Males  
≤115 g/L  
≥190 g/L  
Hematocrit - Females  
≤32%  
≥54%  
Hematocrit - Males  
≤37%  
≥60%  
Platelet count  
≤75 x 109/L 
≥700 x 109/L 
BLOOD CHEMISTRY  
Alanine aminotransferase (ALT)  
N/A  
>3 x ULN  
Aspartate aminotransferase (AST)  
N/A  
>3 x ULN  
Alkaline phosphatase (ALP) 
N/A  
>3 x ULN  
Total bilirubin  
N/A  
>1.5 x ULN  
Blood urea nitrogen (BUN)  
N/A  
≥10.7 mmol/L  
Creatinine  
N/A  
≥176.8 umol/L  
Sodium  
≤126 mmol/L  
≥156 mmol/L  
Potassium  
≤3 mmol/L  
≥6 mmol/L  
Chloride  
≤90 mmol/L  
≥118 mmol/L  
Bicarbonate  
≤16 mmol/L  
≥35 mmol/L  
Glucose  
≤2.2 mmol/L  
≥9.7 mmol/L  
Calcium  
≤2 mmol/L  
≥3 mmol/L  
Phosphorus  
≤0.6 mmol/L  
≥1.7 mmol/L  
Albumin  
≤25 g/L  
≥625 g/L 
Total protein  
≤45 g/L  
≥100 g/L  
URINALYSIS  
Glucose  
N/A  
≥ ++++  
Ketones  
N/A  
≥ ++++  
Protein  
N/A  
≥ ++ 
ULN = upper limit of normal  
 
Potential serious hepatotoxicity 
 
Potential serious hepatotoxicity is defined as ALT or AST > 3x ULN and total bilirubin > 2x 
ULN at any time post-baseline, not necessarily concurrent. A scatterplot of the maximum 
post-baseline ALT or AST value relative to ULN and maximum post-baseline total bilirubin 
value relative to ULN (not necessarily concurrent) for each subject will be provided. A line 
plot of ALT, AST, ALK and total bilirubin values over time for subjects with potential 
serious hepatotoxicity will be provided. In addition, subjects with ALT > 1x ULN, >3x ULN, 
>5x ULN, >10x ULN or >20x ULN, subjects with AST > 1x ULN, >3x ULN, >5x ULN, 
>10x ULN or >20x ULN, subjects with total bilirubin >1x ULN or >2x ULN, subjects with 
ALP >1x ULN or >1.5x ULN, and subjects with AST or ALT > 3x ULN post-baseline 
accompanied by concurrently elevated total bilirubin >1.5x ULN or > 2x ULN will be 
presented. Concurrent is defined as on the same day. A listing of subjects with potential 
serious hepatotoxicity will be provided.  


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Placebo-Controlled Period 
Final V1.0 
 
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43 
 
 
4.5.5 C-SSRS Data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates 
suicidal ideation and behavior.  There are 5 “Yes/No” questions on suicidal ideation 
following the increasing severity order: (1) Wish to be dead, (2) Non-specific active suicidal 
thoughts, (3) Active suicidal ideation with any methods (not plan) without intent to act, (4) 
Active suicidal ideation with some intent to act, without specific plan, (5) Active suicidal 
ideation with specific plan and intent, and 6 “Yes/No” questions on suicidal behavior 
following the increasing severity order: (6) Preparatory acts or behavior, (7) Aborted attempt, 
(8) Interrupted attempt, (9) Actual attempt, (10) Suicidal behavior, (11) Suicide (only at post-
baseline visits).  Another “Yes/No” question of whether the subject has engaged in non-
suicidal self-injurious behavior is also collected.  
 
In the summary table for C-SSRS, number of subjects who answered “Yes” to each of the 11 
questions post-baseline, subjects who answered “Yes” to at least one question for suicidal 
ideation, subjects who answered “Yes” to at least one question for suicidal behavior, and 
subjects who have engaged in non-suicidal self-injurious behavior will be presented. A listing 
of subjects with any suicidal ideation or behavior at baseline or post-baseline will be 
provided.  
 
4.5.6 ECG Data 
Shift from normal or unknown ECG at baseline to abnormal, not adverse event or abnormal, 
adverse event post-baseline ECG will be summarized for the placebo-controlled period.  
Subjects with abnormal post-baseline ECG status will be listed. 
 
4.5.7 Vital Sign Data 
Vital sign parameters include body temperature, systolic blood pressure, diastolic blood 
pressure, heart rate, respiration rate and weight. Vital signs will be measured with the subject 
supine and after the subject has been resting for at least 10 minutes. The descriptive statistics 
for actual values and change from baseline will be summarized at each visit. Plot of mean 
vital sign values at each visit will be provided. 
The analysis of vital signs will also focus on the incidence of clinically relevant outliers 
based on the following criteria. The incidence and percentage of clinically relevant outliers 
determined by each criterion will be summarized. A listing of subjects with clinically relevant 
vital signs will be provided. 
 
Table 9: Criteria Used to Assess Potential Clinically Relevant Outliers in Vital Signs 
Variable 
Low 
High 
Systolic Blood Pressure 
<90 mm Hg or >20 mm Hg 
decrease from Baseline (BL) 
>180 mm Hg or >20 mm Hg 
increase from BL 


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44 
 
Diastolic Blood Pressure 
< 50 mm Hg or >15 mm Hg 
decrease from BL 
>105 mg Hg or >15 mm Hg 
increase from BL 
Heart Rate 
<50 bpm or > 15 bpm decrease from 
BL 
>120 bpm or > 15 bpm increase 
from BL 
Temperature 
>2 degree C decrease from BL 
>38.5 C or >2 degrees C increase 
from BL 
Respiration Rate 
< 10 breaths per minute or > 50% 
decrease from BL 
>25 breaths per minute or >50% 
increase from BL 
Weight 
>7% decrease from BL 
>7 % increase from BL 
BL= baseline; bpm = beats per minute 
 
Visit windows for by visit summaries 
For vital sign by visit summaries, the analysis visit should be defined using windows (see 
Table 10 below). If there is more than 1 value in the same analysis visit window for a certain 
parameter for a subject, then the closest record to the target visit day will be used for the by 
visit analysis.  If there are 2 values in the same analysis visit window with the same distance 
from the target visit day for a certain parameter for a subject, then the record with the later 
date will be used for the by visit analysis.   
 
Table 10: Visit Windows for Vital Sign by Visit Summaries 
Analysis visit 
Target visit day  Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 4 
29            
[2, 42] 
Week 8 
57 
[43, 70] 
Week 12 
85 
[71, 98] 
Week 16 
113 
[99, 126] 
Week 20 
141 
[127, 154] 
Week 24 
169 
[155, 182] 
Week 28 
197 
[183, 210] 
Week 32 
225 
[211, 238] 
Week 36 
253 
[239, 266] 
Week 40 
281 
[267, 294] 
Week 44 
309 
[295, 322] 
Week 48 
337 
[323, 350] 
Week 52 
365 
[351, 378] 
Week 56 
393 
[379, 406] 
Week 60 
421 
[407, 434] 
Week 64 
449 
[435, 462] 
Week 68 
477 
[463, 490] 
Week 72 
505 
[491, 518] 
Week 76 
533 
[519, the end day of the placebo-controlled period*] 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, and is the last day in study for subjects who do not enter LTE. 
 
 
4.6 Pharmacokinetics Analysis 
The PK analysis population will be used for the description of the concentration-time profiles 
and for the estimation of PK parameters. Randomization treatment groups will be used for 




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46 
 
 
4.7 Immunogenicity Analysis 
4.7.1 Background 
Definition of baseline value 
 
Baseline value is defined as the latest immunogenicity data collected prior to the first dose. If 
no immunogenicity data are collected prior to the first dose, baseline value is missing and will 
be imputed as anti-drug antibody negative for immunogenicity analyses. 
 
Treatment-emergent anti-aducanumab antibody positive responses 
 
Post-baseline positive anti-aducanumab antibody responses are defined as treatment-emergent 
if a subject is either (1) antibody negative at baseline; or (2) antibody positive at baseline but 
the post-baseline antibody response is more than 2-fold increase in titer compared to the 
baseline response. 
 
Persistent and transient positive responses for the placebo-controlled period 
 
Subjects with treatment-emergent positive anti-aducanumab antibody responses in the 
placebo-controlled period will be further classified as transient positive, if only a single 
positive evaluation occurs or more than 1 positive evaluation but occur with < 112 days (16 
weeks) apart, or as persistent positive, if more than one consecutive positive evaluation 
occurs ≥ 112 days (16 weeks) apart or a positive evaluation occurs at the last available time 
point with no further negative results available (including long-term extension). 
 
4.7.2 Immunogenicity analysis 
Immunogenicity population will be used to analyze immunogenicity data. Safety treatment 
groups will be used for immunogenicity analysis. Tables will be presented by treatment group 
(placebo, low dose, high dose and BIIB037 total; analysis display A in Appendix 6.1). 
Listings will be presented by treatment group stratified by ApoE status. 
A summary table of subjects with treatment-emergent positive anti-aducanumab antibody 
responses results will be provided. The number and percentage of anti-aducanumab positive 
responses will be summarized at each visit and at any time post-baseline. Subjects with 
persistent response and subjects with transient response will be presented. A listing of 
subjects with anti-aducanumab antibody positive results will also be provided.  
 
Visit windows for by visit summaries 
For immunogenicity by visit summaries, the analysis visit should be defined using visit 
windows (see Table 11Table 7 below). If there is more than 1 value in the same analysis visit 
window for a subject, then the closest record to the target visit day will be used for the by 
visit analysis.  If there are 2 values in the same analysis visit window with the same distance 


Statistical Analysis Plan 
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47 
 
from the target visit day for a certain parameter for a subject, then the record with the later 
date will be used for the by visit analysis.  If there are 2 values on the same day for a certain 
parameter for a subject, then the record with the later time will be used for the by visit 
analysis. 
Table 11: Visit Windows for Immunogenicity by Visit Summaries 
Analysis visit  
Target visit day  Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 24 
169 
[2, 196] 
Week 32 
225 
[197, 308] 
Week 56 
393 
[393, 470] 
Week 78 
547 
[470, the end day of the placebo-controlled period*] 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, and is the last day in study for subjects who do not enter LTE. 
 
 
4.8 Additional Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
5 INTERIM ANALYSIS 
An interim analysis will occur after approximately 50% of the subjects have had the 
opportunity to complete the Week 78 visit for both 221AD301 and 221AD302. To maintain 
the integrity of the study in the event of the interim analysis, an independent group external to 
Biogen that will not be involved in the conduct of the study after unblinding will perform the 
interim analysis. The IDMC will review the unblinded results of the interim analysis provided 
by the independent group and will make a recommendation to Biogen based on pre-specified 
criteria. 
An interim analysis for futility of the primary endpoint will be performed to allow early 
termination of the studies if it is evident that the efficacy of aducanumab is unlikely to be 
achieved. The futility criteria will be based on conditional power, which is the chance that the 
primary efficacy endpoint analysis will be statistically significant in favor of aducanumab at 
the planned final analysis, given the data at the interim analysis. The conditional power is 
calculated assuming that the future unobserved effect is equal to the maximum likelihood 
estimate of what is observed in the interim data: 


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𝐶𝑃(𝑍(1) ≥𝑍𝛼|𝑍(𝑡)) = 1 −𝜙 (𝑍𝛼 √𝑛2 −𝑍(𝑡)√𝑛1
√𝑛2 −𝑛1
−𝑍(𝑡)√𝑛2 −𝑛1
√𝑛1
) 
where 𝑡 is the fraction of information and 𝑍(𝑡) is the observed Z-statistic at the interim 
analysis, 𝑍(1) is the Z-statistic and α is the type I error at the final analysis, 𝑛1 and 𝑛2 are the 
number of subjects at the interim and at the final analysis, respectively. 
The futility decision will primarily be based on the conditional power for the primary efficacy 
endpoint. The study will not be considered as futile unless both studies 221AD301 and 
221AD302 have conditional power for the primary efficacy endpoint less than 20% in both 
the high-dose and low-dose treatment groups. Given the insufficient knowledge of 
aducanumab’s potential effects on various functional/cognition endpoints or in certain 
subgroups at the present time, other data in addition to the pre-specified futility criteria will 
be considered as well, and the IDMC may recommend the studies to be continued as planned 
based on the weight of the evidence. 
An interim analysis for superiority may be performed, to allow the possibility to demonstrate 
the treatment effect early. If an interim analysis for superiority is performed, the O’Brien-
Fleming stopping boundary will be used. If an interim analysis for superiority is not 
performed, then no alpha adjustment will be used for the final analysis after all subjects have 
had the chance to complete the Week 78 visit. 
 
 
 
 
 




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Informed Consent 
Subject/informant/legally authorized representative did not sign Main ICF, PET 
ICF, and/or Substudy ICFs (and substudy procedures were conducted). Not clear 
on the ICF who has been signing the document (patient or legal representative).   
Major 
Informed Consent 
Principal Investigator / individual obtaining consent did not sign Main ICF, PET ICF, 
and/or Substudy ICFs (and substudy procedures were conducted).  
Major 
Informed Consent 
Not clear on the the ICF who has been signing the document (patient or legally 
authorized representative).   
Major 
Informed Consent 
ICF signed by either only patient or only care giver/legally authorized 
representative, when ICF should have been signed by both. 
Major 
Informed Consent 
Incorrect or outdated version of Main ICF, PET ICF, and/or Substudy ICFs signed by 
subject/informant/legally authorized representative. 
Major 
Informed Consent 
IEC/IRB contact details or site's contact details not included on ICF. 
Minor 
Informed Consent 
Incorrect completion of ICF (i.e., subject/study partner/LAR/person obtaining 
consent did not provide date of signature; subject/study partner/LAR/person 
obtaining consent noted incorrect date of signature; subject/study 
partner/LAR/person obtaining consent printed name when should have signed, 
subject/study partner/LAR/person obtaining consent signed on line for printed 
name, printed name on line for signature, etc.) 
Minor 
Informed Consent 
Site personnel who signed ICF is not on Site Personnel Signature Delegation Log 
and/or not authorized by PI to sign ICF 
Major 
Informed Consent 
No evidence (source documentation) that Informed Consent was obtained from 
the study subject / study partner. 
Major 
Informed Consent 
ICF obtained by subject is not in subject's native language. 
Major 
Informed Consent 
Protocol specific procedures such as physical exam, medical history, neurological 
history, ECGs, rater scales, lab tests, blood draws, including first study drug dose 
performed prior to the date of the consent. 
Major 
Informed Consent 
Subject and/or Study Partner/Caregiver not signing ICFs at time of reconsent. 
Major 
Informed Consent 
Untimely reconsenting of subject/caregiver on newly approved ICFs. 
Major 
Investigational Product 
Compliance 
IP storage temperature out of range and site used IP without confirmation from 
Biogen regarding usability  
Case by case 
basis 
Investigational Product 
Compliance 
Incorrect cohort IP dispensed to subject   
Major 
Investigational Product 
Compliance 
IP is not stored in blinded manner. 
Major 
Investigational Product 
Compliance 
Unblinded pharmacist discarded/destroyed used IP vial prior to IP accountability 
being conducted by unblinded CRA and without previous approval. 
case by case 
basis 
Investigational Product 
Compliance 
IP temperature log is not being maintained nor checked by the unblinded 
pharmacist.  
Major 
Investigational Product 
Compliance 
Non-compliant with IP usage according to DHA (note: this does not include 
deviation regarding removing overfill on saline bag) 
Major 
Investigational Product 
Compliance 
Dosing based on weight calculation is inaccurate (i.e., discrepancies between 
Weight Communication Form and IXRS entry, ratio not respected when preparing 
dose, etc.)  
Major 
Investigational Product 
Compliance 
Overdose of IP occurs. 
Major 
Investigational Product 
Compliance 
Overdose Form not faxed to Quintiles Lifecycle Safety within 24 hours of site being 
made aware of an overdose. 
Major 
Investigational Product 
Compliance 
Titration schedule not respected when dosing subject. 
Major 
Investigational Product 
Compliance 
Down-dosing / discontinuation of dosing not respected by the unblinded 
pharmacist following ARIA-H and ARIA-E cases, as prescribed by the protocol, 
investigator, Medical Monitor, and/or sponsor. 
Major 


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Investigational Product 
Compliance 
Missed infusion visit (not due to temporary discontinuation of dosing as 
prescribed by the protocol, investigator, Medical Monitor, and/or sponsor due to 
ARIA-H or ARIA-E case). 
case by casis 
Investigational Product 
Compliance 
IP storage temperature out of range (2-8 oC). 
Minor 
Investigational Product 
Compliance 
Administration of expired IP. 
Major 
Investigational Product 
Compliance 
IP rounding discrepancies not in accordance with the Directions for Handling & 
Administration document (DHA). 
Minor 
Investigational Product 
Compliance 
Administration of IP that was rejected after a temperature excursion. 
Major 
Investigational Product 
Compliance 
IP administered in less than 21 days. 
Minor 
Laboratory assessments 
criteria 
Ambient samples received at central laboratory that should have been shipped 
frozen. 
Minor 
Laboratory assessments 
criteria 
Frozen samples received at central laboratory that should have been shipped 
ambient. 
Minor 
Laboratory assessments 
criteria 
Lab samples not drawn, or results unavailable. 
Minor 
Laboratory assessments 
criteria 
Laboratory results not acknowledged by PI, or medically qualified and delegated 
study personnel. 
case by case 
Laboratory assessments 
criteria 
Pre-dose and/or post-dose PK samples not collected, or not collected within 
protocol specified time. 
Minor 
Laboratory assessments 
criteria 
 
 
Minor 
Laboratory assessments 
criteria 
Lab specimens temperature log is not being maintained nor checked by applicable 
study personnel. 
Major 
Laboratory assessments 
criteria 
Use of incorrect lab kit. 
Minor 
Laboratory assessments 
criteria 
 PBMC not collected, or not collected within protocol specified time. 
Minor 
Other 
Site repeatedly commits same minor deviations. 
Major 
Randomization criteria 
Subject recorded as randomized in IXRS by mistake but not dosed. 
Major 
Randomization criteria 
Subject randomized to wrong arm due to mis-entry of ApoE ε4 carrier status. 
Major 
Regulatory or Ethics Approval 
Criteria 
No evidence that IRB / CEC / LEC approved the final protocol. 
Major 
Regulatory or Ethics Approval 
Criteria 
No evidence that IRB / CEC / LEC was notified of protocol amendments in a timely 
manner. 
Minor 
Regulatory or Ethics Approval 
Criteria 
Failure to notify or obtain approval from the IRB / CEC / LEC of a change of 
investigator. 
Minor 
Regulatory or Ethics Approval 
Criteria 
Failure to obtain or keep updated regulatory authorization to conduct a study. 
Major 
Regulatory or Ethics Approval 
Criteria 
Failure to obtain IRB / CEC / LEC approval of a subject directed document (e.g., 
subject questionnaires, advertisements, etc.) 
Major 
Regulatory or Ethics Approval 
Criteria 
Failure in Safety Reporting as per local requirements (SUSARS, line listings, 
progress reports, etc.) 
Minor 
Serious Adverse Event Criteria  
SAEs not appropriately reported (i.e., reported as an AE when SAE criteria have 
been met, or SAE not reported within 24 hours). 
Major 
Serious Adverse Event Criteria  
Pregnancies not appropriately reported within 24 hours of study site staff 
becoming aware of the pregnancy. 
Major 
Serious Adverse Event Criteria  
Adverse Events of Special Interest not reported within 72 hours following the 
receipt of abnormal MRI findings from the central MRI reader. 
Major 
Serious Adverse Event Criteria  
SAEs not appropriately reported to the IRB/EC. 
Minor 
Study Procedures criteria 
Inconsistent rater used for primary, secondary endpoints 
Major 


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Study Procedures criteria 
CDR raters were performing other assessments on subjects they performed CDRs 
for.  
Major 
Study Procedures criteria 
Secondary endpoint assessments raters were performing other assessments on 
subjects they performed these assessments for. 
Major 
Study Procedures criteria 
MOCA was administered by a rater rather than the treating HCP. 
Major 
Study Procedures criteria 
Assessment performed by non-qualified rater 
Major 
Study Procedures criteria 
Any eligibility criteria not confirmed prior to dosing, but deemed eligible post-
randomization (including verification of eligibility based on cancer criteria with 
Medical Monitor [inclusion criterion #10]). 
Minor 
Study Procedures criteria 
MRI and/or PET scan being conducted as part of Screening Visit 2 or Screening 
Visit 3 procedures without PI verification of eligibility at Screening Visit 1 
(including laboratory and cognitive assessment eligibility) without permission of 
the sponsor/Medical Monitor. Please note that ApoE ε4 results are not necessary 
to move onto Screening Visits 2 or 3. 
Minor 
Study Procedures criteria 
PET scan being conducted as part of Screening Visit 3 prior to MRI central read 
confirming eligibility at Screening Visit 2, without permission of the 
sponsor/Medical Monitor. 
Minor 
Study Procedures criteria 
Dose reduction administered by PI/sub-I when protocol requires return to last 
dose following temporary discontinuation of IP following ARIA event under 
Protocol v. 3. 
case by case 
Study Procedures criteria 
 
Minor  
Study Procedures criteria 
Primary endpoint assessment not conducted or administered at a study visit, as 
per protocol. Please note that deviation will not apply for any cognitive 
assessments that were not administered or completed, due to subject's decline in 
cognition. 
Major 
Study Procedures criteria 
Secondary endpoint assessments not conducted or administered at a study visit, 
as per protocol. Please note that deviation will not apply for any cognitive 
assessments that were not administered or completed, due to subject's decline in 
cognition. 
Major 
Study Procedures criteria 
Tertiary endpoint efficacy assessments 
 
not conducted or administered at a study visit, as per protocol. Please note 
that deviation will not apply for any cognitive assessments that were not 
administered or completed, due to subject's decline in cognition. 
Minor 
Study Procedures criteria 
C-SSRS not conducted or administered at a study visit, as per protocol. 
Minor 
Study Procedures criteria 
Systolic blood pressure, diastolic blood pressure, heart rate, body temperature, 
and/or respiratory rate not assessed as part of vital signs, or vital signs not 
measured with the subject supine and/or after the subject has been resting for at 
least 10 minutes. 
Minor 
Study Procedures criteria 
Serum pregnancy test not conducted at Screening Visit 1, or urine pregnancy test 
not conducted at applicable study visits for subjects of child-bearing potential. 
Major 
Study Procedures criteria 
MRI and/or PET scan being conducted on subsequent subjects should site not 
receive passing QC report on first in-vivo scan. 
Minor 
Study Procedures criteria 
ARIA management not being followed as per protocol specifications. 
Major 
Study Procedures criteria 
Non-IEC/IRB approved document(s) dispensed to subject 
Major 
Study Procedures criteria 
Unscheduled visit not conducted due to AD medication change, or conducted 
after AD medication change occurred. 
Major 
Study Procedures criteria 
Study MRIs not conducted within study visit schedule. 
Minor 
Study Procedures criteria 
Study MRIs missed 
Major 
Study Procedures criteria 
Administration of rating scales over the telephone. 
Minor 
Study Procedures criteria 
Missed MOCA at an Unscheduled MRI visit. 
Major 
Study Procedures criteria 
Missed MOCA at Day 1 Visit. 
Minor 
Study Procedures criteria 
Missed physical exam, neurological exam, or ECG at study visit. 
Minor 


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Study Procedures criteria 
Missed PET scan at timepoints for PET substudy subjects. 
Major 
Study Procedures criteria 
Ligand dose administration error 
Major 
Study Procedures criteria 
Infusion conducted prior to receipt and review of MRI central read results  
Case by case 
Visit Schedule Criteria 
Study visit or procedures conducted out of window. Please note special attention 
to the ADCS-ADL-MCI, ADAS-Cog, and NPI at Screening Visit 2 being conducted 
within 14 days of Screening Visit 1. 
Minor 
Visit Schedule Criteria 
Occurrence of randomization outside of 60-day screening window without 
sponsor approval. 
Minor 
Visit Schedule Criteria 
Occurrence of randomization outside of 90 days. 
Major 
 
 
6.3 Implementation of the Copy Increment from Reference and Pattern 
Mixture Model 
6.3.1 Copy Increment from Reference 
The dataset will first be imputed to monotone missing using PROC MI with the MCMC and 
impute=monotone option. Imputation will be carried out 1000 times and any internal missing 
observations, including missing baseline covariates and intermediate missing in the response 
variable will be replaced with the average across all imputations. 
For the resulted data with monotone missing, the following steps will be used to create 
imputed datasets: 
(1) Data from all patients will be used to fit a multivariate normal distribution with 
unstructured mean and unstructured variance using a Bayesian approach with a 
noninformative prior for the mean and a conjugate prior for the variance covariance 
matrix. 
(2) Draw a pseudo-independent sample for the linear predictor parameters and the 
covariance parameters from the joint posterior distribution obtained in step (1). Both 
steps (1) and (2) will be done using PROC MCMC in SAS. 
(3) Use the linear predictor parameters and the covariance parameters obtained in step (2) 
to construct new mean vectors separately for each treatment group (placebo, 
aducanumab low dose, aducanumab high dose). Specifically, the newly constructed 
mean vector for someone on treatment group 𝑇 whose last observed visit was visit 𝑘 
is calculated as 
𝜇𝑇
(𝑘) = {
𝜇𝑖,𝑇,
𝑖𝑓 𝑖≤𝑘
𝜇𝑘,𝑇−𝜇𝑘,𝑃+ 𝜇𝑖,𝑃, 𝑖𝑓 𝑖> 𝑘 
Here 𝑃 represents the placebo group. For patients with no post-baseline records, or 
patients on the placebo group, the newly constructed mean vector is the same as the 
placebo mean. 
(4) Using 𝜇𝑇
(𝑘) from step (3) and covariance parameters from step (2), find the conditional 
normal distribution of the visit with missing data, and use this conditional distribution 
to impute the missing data.  
6.3.2 Pattern Mixture Model 
Subjects will be assigned one of the following three patterns: 


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1. Completer: subjects with no missing data at Week 26, 50 and 78 
2. Subjects who withdrew due to reasons that may be related to efficacy, including 
consent withdrawn, withdrawal by parent/guardian, investigator decision, loss of 
capacity, change of treatment, and disease progression; 
3. All the other subjects with missing data. 
The dataset will first be imputed to monotone missing using PROC MI with the MCMC and 
impute=monotone option. Imputation will be carried out 1000 times and any internal missing 
observations, including missing baseline covariates and intermediate missing in the response 
variable will be replaced with the average across all imputations. 
For the resulted data with monotone missing, the following steps will be used to create 
imputed datasets: 
(1) Subset subjects in pattern 1 and pattern 2, and impute the missing data using the copy 
increment from reference method described in Section 6.3.1. 
(2) Subset subjects in pattern 1 and pattern 3, and impute the missing data using PROC 
MI with the MONOTONE REG option. 
(3) Combined datasets obtained in steps (1) and (2). 
 
 
 
 


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7 REFERENCES 
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat. 2013;23(6):1352-71. 
 
Hansen RA, Gartlehner G, Lohr KN, et al. Functional outcomes of drug treatment in 
Alzheimer's disease: A systematic review and meta-analysis. Drugs & aging. 2007;24(2):155-
67. 
 
ICH E9 (R1): Addendum to statistical principles for clinical trials on choosing appropriate 
estimands and defining sensitivity analyses in clinical trials. Endorsed by the ICH Steering 
Committee. 2014. 
 
ICH E9 (R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the 
Guideline on Statistical Principles for Clinical Trials. European Medicines Agency. 2017. 
 
Li, J. and Barlas, S. Divergence effect analysis in disease-modifying trials. Statistics in 
Biopharmaceutical Research. 2017; 9: 390-398. 
 
Li, K. H. (1988), "Imputation Using Markov Chains," Journal of Statistical Computation and 
Simulation, 30, 57–79. 
 
Little, R.J.A. (1993). Pattern‑mixture models for multivariate incomplete data. Journal of the 
American Statistical Association, 88 , 125-134. 
 
Little, R.J.A. (1994). A class of pattern‑mixture models for normal missing data. Biometrika, 
81, 471-483. 
 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring 
rules. Neurology. 1993;43(11):2412–2414. 
 
Mueller SG, Weiner MW, Thal LJ, et al. The Alzheimer's Disease Neuroimaging Initiative. 
In: Pettrella JR, Doraiswamy PM, eds. Neuroimaging Clinics of North America: Alzheimer's 
Disease: 100 Years of Progress. Philadelphia: Elsevier Saunders; 2005:869–877. 
 
Rockwood K. The measuring, meaning and importance of activities of daily living (ADLs) as 
an outcome. Int Psychogeriatr. 2007;19(3):467-82. Epub 2007/03/15. 
 
Rubin, D. B. (1976) “Inference and missing data.” Biometrika, 63(3), 581-592. 
 
Rubin D.B. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons. 1987. 
 
Schafer J.L. Analysis of Incomplete Multivariate Data. Chapman and Hall, New York. 1997. 
 
Tractenberg RE, Weiner MF, Cummings JL, Patterson MB, Thal LJ. Independence of 
changes in behavior from cognition and function in community-dwelling persons with 


Statistical Analysis Plan 
Placebo-Controlled Period 
Final V1.0 
 
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The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
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Alzheimer’s disease: a factor analytic approach. J Neuropsychiatry Clin 
Neurosci. 2005;17(1):51–60. 
 
van Ginkel, J. R., Sijtsma, K., van der Ark, L. A., & Vermunt, J. K. (2010). Incidence of 
missing item scores in personality measurement, and simple item-score 
imputation. Methodology: European Journal of Research Methods for the Behavioral and 
Social Sciences, 6(1), 17-30. 
 
Yan, X., Lee, S., and Li, N. (2009), “Missing data handling methods in medical device 
clinical trials,” Journal of Biopharmaceutical Statistics, 19(6), 1085-1098. 
 
Zucker, D. M., Wittes, J. T., Schabenberger, O. and Brittain, E. Internal pilot studies II: 
comparison of various procedures. Statistics in Medicine. 1999;18: 3493–3509. 


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ENGAGE 
221AD301 
 
 
 
 
 
 
 
Statistical Analysis Plan 
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Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 5 
1 
DESCRIPTION OF LONG-TERM EXTENSION (LTE) OBJECTIVES AND ENDPOINTS ........... 7 
1.1 
TERTIARY LTE OBJECTIVES ..................................................................................................................... 7 
1.2 
TERTIARY LTE ENDPOINTS....................................................................................................................... 7 
1.3 
ADDITIONAL EXPLORATORY LTE OBJECTIVE .......................................................................................... 7 
1.4 
ADDITIONAL EXPLORATORY LTE ENDPOINTS .......................................................................................... 8 
2 
STUDY DESIGN ......................................................................................................................................... 8 
2.1 
STUDY OVERVIEW .................................................................................................................................... 8 
2.2 
STUDY SCHEMATIC ................................................................................................................................. 11 
2.3 
SCHEDULE OF EVENTS FOR LTE PERIOD ................................................................................................. 12 
3 
STATISTICAL ANALYSIS METHODS ............................................................................................... 12 
3.1 
GENERAL CONSIDERATIONS ................................................................................................................... 12 
3.1.1 
Analysis Population ...................................................................................................................... 12 
3.1.2 
Analyses period ............................................................................................................................. 13 
3.2 
BACKGROUND CHARACTERISTICS .......................................................................................................... 14 
3.2.1 
Accounting of Subject ................................................................................................................... 14 
3.2.2 
Demographics and Baseline Characteristics ................................................................................ 14 
3.2.3 
Concomitant Medications and Non-Drug Therapies .................................................................... 14 
3.2.4 
Protocol Deviations ...................................................................................................................... 15 
3.2.5 
Study Drug Exposure and Study Drug Compliance ...................................................................... 15 
3.3 
EFFICACY ANALYSIS ............................................................................................................................... 16 
3.3.1 
General Considerations ................................................................................................................ 16 
3.3.2 
By Visit Summary and MMRM Model .......................................................................................... 17 
3.4 
AMYLOID PET ANALYSIS ........................................................................................................................ 17 
3.4.1 
Amyloid PET substudy .................................................................................................................. 17 
3.4.2 
Amyloid PET regions-of-interest and reference regions .............................................................. 18 
3.4.3 
Amyloid PET Analysis Population ................................................................................................ 18 
3.4.4 
By Visit Summary and MMRM Model .......................................................................................... 18 
3.5 
SAFETY ANALYSES ................................................................................................................................. 19 
3.5.1 
General Considerations ................................................................................................................ 19 
3.5.2 
Clinical Adverse Events ................................................................................................................ 21 
 
Summary and incidence analysis ............................................................................................................. 22 
 
Incidence and incidence rate analysis for placebo-controlled and LTE active treatment period .............. 23 
3.5.3 
ARIA - AE of Special Interest........................................................................................................ 24 
 
Background .............................................................................................................................................. 24 
 
Incidence and summary of ARIA ............................................................................................................. 24 
 
Summary of recurrent ARIA-E ................................................................................................................ 25 
 
Exposure adjusted analysis ....................................................................................................................... 26 
 
Time to event analysis .............................................................................................................................. 26 
3.5.4 
Clinical Laboratory Data ............................................................................................................. 27 
 
Quantitative analyses ............................................................................................................................... 27 
 
Qualitative analyses ................................................................................................................................. 28 
3.5.5 
C-SSRS Data ................................................................................................................................. 30 
3.5.6 
ECG Data ..................................................................................................................................... 30 
3.5.7 
Vital Sign Data ............................................................................................................................. 30 
3.6 
PHARMACOKINETICS ANALYSIS .............................................................................................................. 32 
3.6.1 
Serum Concentration Profile ........................................................................................................ 32 
3.6.2 
Serum PK Parameters .................................................................................................................. 32 
3.7 
IMMUNOGENICITY ANALYSIS .................................................................................................................. 33 
3.7.1 
Background ................................................................................................................................... 33 
3.7.2 
Immunogenicity analysis ............................................................................................................... 33 
4 
APPENDIX ................................................................................................................................................ 35 


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4.1 
ANALYSIS DISPLAY ................................................................................................................................. 35 
 
 


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List of Abbreviations 
Aβ 
β-amyloid 
AD 
Alzheimer’s disease 
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(13 items) 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living Inventory (Mild Cognitive Impairment version) 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ApoE 
apolipoprotein E 
ApoE ε4  
apolipoprotein E4 
ApoE ε4+ 
apolipoprotein E4 carrier 
ApoE ε4- 
apolipoprotein E4 non-carrier 
ARIA 
amyloid related imaging abnormalities 
ARIA-E 
amyloid related imaging abnormality-edema  
ARIA-H 
amyloid related imaging abnormality-hemorrhage or superficial 
siderosis 
 
 
AST 
aspartate aminotransferase 
BL 
baseline 
BLQ 
below the limit of quantification 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
 
 
CDR 
Clinical Dementia Rating  
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CIR 
copy increment from reference 
Cmax 
observed maximum serum aducanumab concentration 
Cmin 
observed minimum serum aducanumab concentration 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CTCAT 
Common Toxicity Criteria for Adverse Events 
CV 
coefficient of variation 
EAIR 
exposure-adjusted incidence rate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D 
EuroQol health status measure 
 
 
 
EQ-5D (IR-S) 
EuroQol health status measure, informant reported on subject 
EQ-5D (SR) 
EuroQol health status measure, subject self-reported 


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FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl-transferase 
HCP 
health care professional 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDH 
lactate dehydrogenase 
LMCI 
late mild cognitive impairment 
LTE 
long-term extension 
LOCF 
last observation carried forward 
MCI 
mild cognitive impairment 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures 
MMSE 
Mini-Mental State Examination 
MOCA 
Montreal Cognitive Assessment 
mPDQ-20 
Perceived Deficits Questionnaire-20 modified version 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI-10 
Neuropsychiatric Inventory-10 
PCS 
potentially clinically significant 
PET 
positron emission tomography 
pH 
potential of hydrogen 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model 
PP 
per-protocol 
RBANS 
Repeatable Battery for Assessment of Neuropsychological 
Status 
ROI 
region of interest 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
SUVR 
standard uptake value ratio 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 


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1 DESCRIPTION OF LONG-TERM EXTENSION (LTE) 
OBJECTIVES AND ENDPOINTS  
1.1 
Tertiary LTE Objectives 
• To evaluate the long-term safety and tolerability profile of aducanumab in subjects 
with early Alzheimer’s Disease (AD). 
• To evaluate the long-term efficacy of aducanumab treatment as measured by clinical, 
radiological, and health outcomes assessments.  
 
1.2 
 Tertiary LTE Endpoints 
• The incidence of adverse events (AEs) and serious adverse events (SAEs); brain 
magnetic resonance imaging (MRI) findings (including the incidence of amyloid 
related imaging abnormality-edema [ARIA-E] and amyloid related imaging 
abnormality-hemorrhage or superficial siderosis [ARIA-H]); and the incidence of 
anti-aducanumab antibodies in serum over the placebo-controlled and LTE periods of 
the study. 
• Change in the following measures over the placebo-controlled and LTE periods of the 
study: 
− Clinical Dementia Rating sum of boxes (CDR-SB) score. 
− Mini-Mental State Examination (MMSE) score. 
− Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13 items) 
[ADAS-Cog 13 score]. 
− Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory 
(Mild Cognitive Impairment version) [ADCS-ADL-MCI score]. 
− Amyloid positron emission tomography (PET) signal (in a subset of sites and 
subjects). 
− Neuropsychiatric Inventory-10 (NPI-10) total scores. 
− Informant-rated EuroQol health status measures (EQ-5D) index score.  
 
1.3 
Additional Exploratory LTE Objective 
• 
 
  
 


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1.4 
Additional Exploratory LTE Endpoints 
• 
 
 
− 
 
 
− 
 
 
− 
 
 
− 
 
 
− 
 
  
− 
. 
− 
 
− 
 
 
2 STUDY DESIGN 
2.1 
Study Overview 
Study 221AD301 (ENGAGE) is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in subjects with early AD, including mild cognitive impairment (MCI) 
due to AD and a subset of mild AD, followed by an optional dose-blinded long-term 
extension (LTE) period of up to 5 years. Approximately 1605 subjects will be enrolled across 
approximately 150 centers globally.  The primary study objective is to evaluate the efficacy 
of monthly doses of aducanumab on the CDR-SB relative to placebo. Secondary objectives 
include assessment of the effect of monthly doses of aducanumab on clinical progression as 
compared to placebo. The safety of monthly doses of aducanumab will also be evaluated. The 
objectives of LTE are to evaluate the long-term safety and tolerability profile of aducanumab 
in subjects with early AD, and to evaluate the long-term efficacy of aducanumab treatment as 
measured by clinical, radiological, and health-outcomes assessments.  
Subjects will be randomized in a 1:1:1 ratio to 1 of the 3 treatment groups: aducanumab high 
dose, aducanumab low dose and placebo, with stratification based upon their apolipoprotein 
E4 (ApoE ε4) carrier status (carrier/non-carrier) and site. During the placebo-controlled 
period, subjects will receive infusions of aducanumab or placebo approximately every 4 
weeks for approximately 18 months (a total of 20 doses). Dose levels may be different in the 
same treatment group based upon subjects’ ApoE ε4 carrier status, and specifically, ApoE ε4 
carriers will receive placebo, aducanumab 3 mg/kg, or aducanumab 10 mg/kg whereas ApoE 
ε4 non-carriers will receive placebo, aducanumab 6 mg/kg, or aducanumab 10 mg/kg.  
Aducanumab will be titrated for up to 6 doses prior to reaching the target dose as shown in 


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Table 1 and Figure 1. Note: As of Protocol Version 4, 10 mg/kg is the target dose for all 
ApoE ε4 carriers in the high-dose group. ApoE ε4 carriers who were randomized to the high 
dose group when the target dose was 6 mg/kg (under protocol versions prior to Version 4) 
must have received 2 or more doses at 6 mg/kg prior to being titrated up to 10 mg/kg. 
 
Table 1: Dosing Scheme for Aducanumab by Treatment Group and ApoE ε4 Carrier 
Status: Placebo-controlled Period 
Dose (every 4 weeks) 
1 
2 
3 
4 
5 
6 
7 to 20 
Treatment 
Group 
Treatment Group Stratified by 
ApoE Status2  
Dose (mg/kg) 
High Dose 
High Dose - ApoE ε4 (+) 
1 
1 
3 
3 
6 
6 
101 
High Dose - ApoE ε4 (-) 
1 
1 
3 
3 
6 
6 
10 
Low Dose 
Low Dose - ApoE ε4 (+) 
1 
1 
3 
3 
3 
3 
3 
Low Dose - ApoE ε4 (-) 
1 
1 
3 
3 
3 
3 
6 
Placebo 
Placebo - ApoE ε4 (+) 
saline 
Placebo - ApoE ε4 (-) 
saline 
1 10 mg/kg is the target dose for all ApoE ε4 carriers assigned to the aducanumab high-dose group.  Subjects 
enrolled under protocol versions 1-3 and assigned to the previous high-dose of 6 mg/kg will be titrated to 10 
mg/kg upon receipt of at least 2 doses at 6 mg/kg.   
2 ApoE ε4 status recorded in the Interactive Voice/Web Response System (IXRS).   
 
At the end of the double-blind, placebo-controlled treatment period, subjects who meet the 
extension entry criteria may enter a long-term safety and efficacy extension period, with all 
subjects receiving aducanumab approximately every 4 weeks (up to a total of 65 doses over 5 
years). The treatment group for the LTE period will be assigned at the same time as the 
randomization for the placebo-controlled period, regardless of whether a subject entering the 
LTE period or not. Subjects who are assigned to the placebo group during the 
placebo-controlled period will be assigned to 1 of 2 active treatment groups in a 1:1 ratio 
(aducanumab low dose: aducanumab high dose) and randomization will be stratified by their 
ApoE ε4 carrier status; for those who enter the LTE period, aducanumab will be titrated for 
up to 6 doses prior to reaching the target dose following the same schedule described for the 
placebo-controlled period. Subjects who are assigned to either aducanumab low dose or 
aducanumab high dose group in the placebo-controlled period will continue in the same 
treatment group for the LTE period; those who enter the LTE period will maintain the dosing 
scheme outlined in the protocol at the time of transition from the placebo-controlled period to 
the LTE period (e.g. subjects who are on stable dosing in the placebo-controlled period will 
continue on the same dose, subjects who are on a titration regimen during the transition will 
continue to titrate into the LTE period, and ApoE ε4 carrier subjects who are enrolled in the 
LTE and randomized to the high-dose group prior to implementation of version 4 of the 
protocol will be allowed to titrate to 10 mg/kg). Aducanumab will be titrated for up to 6 doses 
prior to reaching the target dose for the late start subjects as shown in Table 2  and Figure 1. 
 


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Table 2: Dosing Scheme for Aducanumab by Treatment Group and ApoE ε4 Carrier 
Status: Long-Term Extension Period 
Doses (every 4 weeks) 
1 
2 
3 
4 
5 
6 
7-
EOS 
LTE Treatment 
Group 
LTE Treatment Group 
Stratified by ApoE Status1 
Dose (mg/kg) 
Early Start High 
Dose 
Early Start High Dose – 
ApoE ε4 (+) 
10 
Early Start High Dose – 
ApoE ε4 (-) 
10 
Early Start Low 
Dose 
Early Start Low Dose – 
ApoE ε4 (+) 
3 
Early Start Low Dose – 
ApoE ε4 (-) 
6 
Late Start High 
Dose 
Late Start High Dose – 
ApoE ε4 (+) 
1 
1 
3 
3 
6 
6 
10 
Late Start High Dose – 
ApoE ε4 (-) 
1 
1 
3 
3 
6 
6 
10 
Late Start Low 
Dose 
Late Start Low Dose – 
ApoE ε4 (+) 
1 
1 
3 
Late Start Low Dose – 
ApoE ε4 (-) 
1 
1 
3 
3 
3 
3 
6 
1 ApoE ε4 status recorded in the Interactive Voice/Web Response System (IXRS).   
 
Individual dose adjustments may be implemented in subjects who develop amyloid related 
imaging abnormalities (ARIA). See Protocol Section 7.2.1. 
The total duration of study participation for each subject only participating in the placebo-
controlled period of the study will be up to approximately 102 weeks, including a series of 
screening visits within 8 weeks before administration of the first dose, a 76-week 
placebo-controlled treatment period, and a safety follow-up (FU) period of approximately 
18 weeks after the final dose. The total duration of study participation for each subject 
participating in the placebo-controlled period and the LTE period will vary and be up to 
approximately 362 weeks, including a series of Screening visits within 8 weeks before 
administration of the first dose, a 76-week placebo-controlled treatment period, a 4-week FU 
period, a 256-week aducanumab dose-blind treatment period, and a safety FU period of 
approximately 18 weeks after the final dose.  
Investigators, study site staff (except for the designated unblinded pharmacist/technician), 
and study subjects will be blinded to the subjects’ randomized treatment assignment for the 
placebo-controlled period.  During the LTE period, investigators and subjects will remain 
blinded to the treatment assignment in the placebo-controlled period and the aducanumab 
dose for the LTE period. 


 
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2.2 
Study Schematic 
Figure 1: Study Design 
 
ApoE ε4 +/- = apolipoprotein E4 positive/negative; FU = follow-up; P = placebo; R = randomization date. 
*Subjects who are assigned to placebo during the placebo-controlled period are randomized in a 1:1 ratio to high and low dose aducanumab treatment (stratified by their 
ApoE ε4 carrier status) for the long-term extension period on Study Day 1. 


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2.3 
Schedule of Events for LTE period  
See protocol section 4.2. 
 
3 STATISTICAL ANALYSIS METHODS 
3.1 
General Considerations 
This statistical analysis plan (SAP) covers the analyses of the LTE period and the analyses 
across both the placebo-controlled period and the LTE period.  
Summary tables will be presented using descriptive summary statistics. For continuous 
variables, summary statistics will generally include: number of subjects with data, mean, 
standard deviation, median, 25% percentile, 75% percentile, minimum and maximum. For 
categorical variables, this will generally include: number of subjects randomized or dosed, 
number with data, and the percent of those with data in each category. 
There are two types of analysis displays for the analyses of the LTE period: by LTE treatment 
group (analysis display A in Appendix 4.1) and by LTE treatment group stratified by ApoE 
status (analysis display B in Appendix 4.1; here ApoE status refers to the status recorded in 
IXRS [see Table 2 for correspondence between LTE treatment groups and LTE treatment 
groups stratified by ApoE status]). The analysis display for each analysis will be defined in 
each section. All the listings will be presented by LTE treatment group stratified by ApoE 
status, unless otherwise specified. 
Unless otherwise specified, baseline refers to the baseline value for the placebo-controlled 
period and is defined as the most recent non-missing measurement collected prior to the first 
dose. Change from baseline will be defined as post-baseline value minus baseline value.  
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.05.  
The statistical software, SAS® will be used for all summaries and analyses.  
 
3.1.1 Analysis Population 
• Intent-to-treat (ITT) population:  
The Intent-to-treat population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo).  
 
• 
18F-florbetapir amyloid PET analysis population: 
The 18F-florbetapir amyloid PET analysis population is defined as all randomized subjects 
who received at least one dose of study treatment (aducanumab or placebo), used 18F-
florbetapir ligand for amyloid PET scan, and had an evaluable baseline amyloid PET 
SUVR value for the composite region-of-interest using cerebellum as the reference 
region. 
 
• 
18F-flutemetamol amyloid PET analysis population: 


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The 18F-flutemetamol amyloid PET analysis population is defined as all randomized 
subjects who received at least one dose of study treatment (aducanumab or placebo), used 
18F-flutemetamol ligand for amyloid PET scan, and had an evaluable baseline amyloid 
PET SUVR value for the composite region-of-interest using cerebellum as the reference 
region. 
 
• Safety population:  
The safety population is defined as all randomized subjects who received at least one dose 
of study treatment (aducanumab or placebo). It is the same population as the ITT 
population. 
 
• Safety MRI population:  
The safety MRI population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo) and had at least one post-baseline 
MRI assessment. 
 
• PK analysis population:  
The PK analysis population is defined as all randomized subjects who received at least 
one dose of study treatment (aducanumab or placebo) and had at least one measurable 
aducanumab concentration in serum. 
 
• Immunogenicity population:  
The analysis population for immunogenicity is defined as all randomized subjects who 
received at least one dose of study treatment (aducanumab or placebo) and had at least 
one post-dose sample evaluated for immunogenicity. 
 
 
3.1.2 Analyses period 
Depending on the purpose, different analyses will be conducted on the following study 
periods: 
1. LTE period. Only data in the LTE period will be included in these analyses. For 
example, incidence table of adverse events in the LTE period.  
2. Placebo-controlled and LTE period. All the data in the placebo-controlled and LTE 
periods will be included in these analyses. For example, mean plot of actual 
laboratory values in the placebo-controlled and LTE period. 
3. Placebo-controlled and LTE active treatment period. Active treatment period is 
defined as the study period(s) that a subject is assigned to aducanumab. For early start 
subjects – subjects who are assigned to aducanumab in both placebo-controlled and 
LTE period, all the data (placebo-controlled and LTE periods) will be included in the 
analyses. For late start subjects – subjects who are assigned to aducanumab in the 
LTE period, only data in the LTE period will be included. For example, incidence 
table of adverse events in the placebo-controlled and LTE active treatment period.     


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Subjects to be included in a certain output is determined by both the analysis population and 
the analysis period. For example, the incidence table of adverse events in the LTE period will 
include subjects in the safety population for the LTE period, i.e., all randomized subjects who 
received at least one dose of study treatment in the LTE period. The incidence table of 
adverse events in the placebo-controlled and LTE active treatment period will include 
subjects in the safety population for the active treatment period, i.e., all randomized subjects 
who received at least one dose of study treatment in the active treatment period. In this SAP 
we do not separately define the analysis population in each analysis period. 
 
3.2 
Background Characteristics 
The summaries in this section will be based on the ITT population. Analysis period will be 
specified for each table or figure. Unless otherwise specified, summary tables will be 
presented by LTE treatment group and by LTE treatment group stratified by ApoE status (see 
Table 2 for correspondence between LTE treatment groups and LTE treatment groups 
stratified by ApoE status). Listings will include all data in the placebo-controlled and LTE 
periods (all data in the study), with an indicator of the study period (pre-dosing, placebo-
controlled, or LTE) for each record to indicate when the event occurred. Listings will be 
presented by LTE treatment group stratified by ApoE status. 
3.2.1 Accounting of Subject 
Disposition in the LTE period will be summarized for subjects enrolled in LTE. The 
summary data will include number (%) of subjects dosed in the LTE period, number (%) of 
subjects who completed the treatment/study in LTE, and number (%) of subjects who 
discontinued treatment and/or withdrew from study in LTE. For subjects who discontinued 
treatment and/or withdrew from study, the reasons for discontinuation and/or withdrawal, 
days on treatment and days on study will be summarized and listed. Time to treatment 
discontinuation and time to study withdrawal in the LTE period will be displayed by Kaplan-
Meier plot (presented by LTE treatment group). 
3.2.2 Demographics and Baseline Characteristics 
Demographics, baseline characteristics, medical history and AD treatment history will be 
summarized for subjects enrolled in the LTE period and subjects not enrolled in the LTE 
period, respectively. Demographics and baseline characteristics will also be summarized for 
all ITT subjects (presented by LTE treatment group). Please refer to the SAP for the placebo-
controlled period for more details.  
3.2.3 Concomitant Medications and Non-Drug Therapies 
The number (%) of subjects taking concomitant medication and non-drug therapies in the 
LTE period will be summarized. Non-drug therapies will be presented by LTE treatment 
group. In addition, number of subjects in the ITT population that have taken any concomitant 
medications in the placebo-controlled and LTE active treatment period will be summarized. 
Concomitant medications and non-drug therapies will be listed.  


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For subjects enrolled in the LTE period, the number (%) of subjects taking concomitant AD 
symptomatic medications, number of subjects using Cholinesterase inhibitors only, 
Memantine only, or both at the baseline of the placebo-controlled period will be summarized. 
A similar summary will be provided for subjects taking AD symptomatic medication 
concomitantly at the baseline of the LTE period. Subjects who have any change in AD 
symptomatic medications during the LTE period will be summarized by the timing of change, 
i.e., the number of subjects changing between Week 80 and Week 106, the number of 
subjects changing between Week 106 and Week 134, etc. The summary for AD symptomatic 
medication use during the LTE period will be presented by LTE treatment group. The start 
and stop date of AD symptomatic medication will be listed for subjects who have any change 
to AD symptomatic medications during the combined placebo-controlled and LTE periods. 
Please refer to the placebo-controlled SAP for definitions of concomitant therapies and AD 
symptomatic medication use at baseline. 
3.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations based on Protocol Deviation Classification 
(see Appendix of the placebo-controlled SAP). The major protocol deviations occurred in the 
LTE period will be summarized for subjects enrolled in LTE. The major protocol deviations 
for all ITT subjects in the combined placebo-controlled and LTE periods will also be 
summarized.  Major and minor protocol deviations for all ITT subjects will be listed, 
respectively, across the placebo-controlled period and the LTE period. All summaries for 
protocol deviations will be presented by LTE treatment group. 
3.2.5 Study Drug Exposure and Study Drug Compliance 
A summary table of study drug exposure and compliance in the LTE period will be provided. 
Number of infusions (aducanumab or placebo) received will be summarized as a categorical 
variable (categories of 1-5, 6-10, 11-15, 16-20, 21-26, 27-39, 40-52 and 53-65) as well as a 
continuous variable. Number of weeks on study treatment (aducanumab or placebo), 
calculated as (date of last dose – date of first dose +29)/7, will be summarized as a categorical 
variable (every 6 months for the first 2 years of LTE, and then every year) as well as a 
continuous variable. Percentage of study treatment taken up to the last dose, calculated as (the 
actual number of infusions / by the number of infusions a subject is expected to take until the 
date of last infusion)*100, will be summarized as a continuous variable. This table will be 
presented by LTE treatment group. A similar table will also be provided on the placebo-
controlled and LTE active treatment period in order to summarize the exposure data while 
subjects are on aducanumab.  
Due to the use of titration regimen in the study and possible dose reduction due to ARIA, 
another summary table will be provided including the following information in the LTE 
period: number of total infusions (categories of 1-5, 6-10, 11-15, 16-20, 21-26, 27-39, 40-52 
and 53-65) as well as a continuous variable, number of infusions at each dose level (1 mg/kg, 
3 mg/kg, 6 mg/kg and 10 mg/kg, respectively) summarized as a categorical variable as well 
as a continuous variable, number of subjects with dose increase (placebo to 1 mg/kg, 1 to 3 
mg/kg, 3 to 6 mg/kg and 6 to 10 mg/kg, respectively), number of subjects with dose reduction 
(1 mg/kg to placebo, 3 to 1 mg/kg, 6 to 3 mg/kg and 10 to 6 mg/kg, respectively), maximum 


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dose level received, and cumulative dose (as a continuous variable). This table will be 
summarized by LTE treatment group stratified by ApoE status. A similar table will also be 
provided on the placebo-controlled and LTE active treatment period in order to summarize 
the titration and dose reduction data while subjects are on aducanumab.  
A listing of study drug administration records, including dose level at each infusion, 
cumulative number of infusions and cumulative dose will be provided for the placebo-
controlled and LTE period. A listing of aducanumab lot numbers will be provided for the 
placebo-controlled and LTE period. 
 
3.3 
Efficacy Analysis 
3.3.1 General Considerations 
The analysis population for efficacy analysis is the same as the ITT population and data from 
both the placebo-controlled and LTE periods will be included. All efficacy analyses will be 
presented by LTE treatment group, i.e, late start low dose, late start high dose, early start low 
dose, early start high dose (analysis display A in Appendix 4.1). 
The following two comparisons will be evaluated for the long-term efficacy of aducanumab: 
• The early start low dose compared with the late start low dose; 
• The early start high dose compared with the late start high dose. 
There will be no multiple comparison adjustments.  
 
Visit windows for mapping efficacy endpoint 
For efficacy data that are summarized or analyzed by visit, data collected on all scheduled 
visits and all unscheduled visits will be mapped to an appropriate analysis visit using the 
windowing scheme shown in Table 3. If there are 2 or more assessments available in the 
same analysis window for a subject, the assessment that is closest to the target visit day will 
be used for analysis. If there are 2 or more assessments in the same analysis window with the 
same distance from the target visit day, the later assessment will be used.  
 
Table 3: Visit Windows for Efficacy Endpoints 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 26 
183 
[92, 266] 
Week 50 
351 
[267, 448] 
Week 78 
547 
[449, the end day of the placebo-controlled period*] 
Week 106 
743 
[645, 840] 
Week 134 
939 
[841, 1036] 
Week 162 
1135 
[1037, 1204] 


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Analysis visit 
Target visit day  
Analysis visit window 
Week 182 
1275 
[1205, 1365] 
Week 232 
1625 
[1535, 1715] 
Week 284 
1989 
[1899, 2079] 
Week 338 
2367 
≥ 2277 
* The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, and is the last day in study for subjects who do not enter LTE. 
 
Handling of missing items for scales 
Please refer to the placebo-controlled SAP for the imputation method. Same method will be 
applied to efficacy endpoints collected in the LTE period. 
 
3.3.2 By Visit Summary and MMRM Model 
The baseline and change from baseline CDR-SB scores at each post-baseline visit will be 
summarized by LTE treatment group. A mixed model repeated measures (MMRM) model 
will be used to analyze change from baseline CDR-SB using fixed effects of LTE treatment 
group, time (categorical), LTE treatment group-by-time interaction, baseline CDR-SB, 
baseline CDR-SB by time interaction, baseline MMSE, AD symptomatic medication use at 
baseline (yes/no), region, and laboratory ApoE ε4 status (carrier/non-carrier). An 
unstructured covariance matrix will be used to model the within-patient variance-covariance 
errors.  If the unstructured covariance structure matrix results in a lack of convergence, the 
heterogeneous Toeplitz covariance structure followed by the heterogeneous first-order 
autoregressive covariance structure will be used.  The Kenward-Roger approximation will be 
used to estimate the denominator degrees of freedom. Visits with too few data may be 
excluded from the MMRM analysis and be analyzed by ANCOVA instead. 
The by visit summary and MMRM analysis will be similarly performed for CDR cognitive 
subscore, CDR functional subscore, MMSE, ADAS-Cog 13, ADCS-ADL-MCI and NPI-10. 
Only the by visit summary will be performed for CDR box scores and informant-rated EQ-
5D. The distribution of CDR global score will be summarized as a categorical variable at 
each post-baseline visit. 
 
 
3.4 
Amyloid PET analysis 
3.4.1 Amyloid PET substudy 
Please refer to the placebo-controlled SAP. 
 


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3.4.2 Amyloid PET regions-of-interest and reference regions 
Please refer to the placebo-controlled SAP. 
 
3.4.3 Amyloid PET Analysis Population 
Please refer to the placebo-controlled SAP. 
 
3.4.4 By Visit Summary and MMRM Model  
All the analyses will be presented by LTE treatment group (early start low dose, early start 
high dose, late start low dose, late start high dose). The following two comparisons will be 
evaluated for amyloid PET SUVR in the LTE period: 
• The early start low dose compared with the late start low dose; 
• The early start high dose compared with the late start high dose. 
 
The baseline and change from baseline amyloid PET SUVR values will be summarized by 
LTE treatment groups by visit for all the visits in the placebo-controlled and LTE period for 
each of the target ROIs using cerebellum as the reference region for each of the amyloid PET 
analysis populations. In addition, the baseline and change from baseline amyloid composite 
ROI values will be summarized by LTE treatment groups by visit for each reference regions 
for each of the amyloid PET analysis populations.  
For the 18F-florbetapir amyloid PET analysis population, an MMRM model will be used to 
analyze change from baseline SUVR for each target ROI with cerebellum as the reference 
region for all the visits in the placebo-controlled and LTE period. Fixed effects of the model 
will include LTE treatment groups, visit, treatment group-by-visit interaction, baseline SUVR 
(continuous), baseline SUVR by visit interaction, baseline MMSE (continuous), laboratory 
ApoE ε4 status (carrier and non-carrier), and baseline age (continuous). Visit and treatment 
group will be treated as categorical variables in the model along with their interactions. An 
unstructured covariance matrix will be used to model the within-patient variance-covariance 
errors.  If the unstructured covariance structure matrix results in a lack of convergence in any 
of the parameters, the heterogeneous Toeplitz covariance structure followed by the 
heterogeneous first-order autoregressive covariance structure will be used for all the 
parameters.  The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom. Adjusted means for each treatment group, pairwise adjusted differences 
for the comparisons, 95% confidence intervals for the differences and associated p-values 
will be presented at each visit. Visits with too few data may be excluded from the MMRM 
analysis and be analyzed by ANCOVA instead. The same MMRM model will also be used to 
analyze the change from baseline SUVR for the composite ROI with each of the reference 
regions. No multiple comparison adjustment will be used for amyloid PET analysis. 
 
Visit Windows for by visit analyses 
 


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For amyloid PET by visit summaries and MMRM models, the analysis visit should be 
defined using visit windows (see Table 4 below).  The rationale is to use the same analysis 
visit windows as for the efficacy endpoints for the visits that the efficacy endpoints are also 
collected. Since the visit for the efficacy measurements is on Week 134, while the visit for 
amyloid PET measurements is on Week 132, the start of the analysis visit window for Week 
132 amyloid PET is 2 weeks earlier than that for efficacy, while the same end of the analysis 
visit window as Week 134 is used to be conservative. If there is more than 1 value in the 
same analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
 
Table 4. Visit Windows for amyloid PET data 
Analysis visit * 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 26 
183 
[92, 266] 
Week 78 
547 
[449, the end day of the placebo-controlled period1] 
Week 132 
925 
[827, 1036] 
Week 182 
1275 
[1205, 1365] 
Week 260 
1821 
[1731, 1911] 
Week 338 
2367 
≥ 2277 
*   Analysis visit is the visit at which the specific week started. 
1. The end day of the placebo-controlled period is the last day before the first infusion in LTE, and is 
the last day in study for subjects who do not enter LTE.  
2. The start day of the LTE period is the day of first infusion in LTE period. 
 
 
3.5 
Safety Analyses 
3.5.1 General Considerations 
Analysis population 
Safety population will be used for safety analyses of AEs, clinical laboratory data, Columbia 
Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital sign data (all the safety 
data except for ARIA data). Safety MRI population will be used for analyses of ARIA data.  
 
LTE safety treatment groups  
Since all the subjects are supposed to receive active treatment in LTE, the LTE safety 
treatment groups which are exactly the same as the LTE randomization treatment groups will 
be used for all the safety analyses. Subjects who were randomized to placebo group but 
accidentally received one or more doses of the active treatment during the placebo-controlled 
period will still be classified as late start for all the safety analyses that involves LTE, but 
their applicable safety data in the placebo-controlled period will be included in the analysis 
for placebo-controlled and LTE active treatment period. 


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Safety analysis period  
Analysis period will be specified for each output. Safety data in the specified analysis period 
will be included in the analysis. Listings will include all data in the placebo-controlled and 
LTE period, unless otherwise specified. 
 
Safety analysis displays 
For either analysis period in this SAP (LTE period, placebo-controlled and LTE period, or 
placebo-controlled and LTE active treatment period), AEs, clinical laboratory data, C-SSRS 
data, ECG data and vital sign data (all the safety data except for ARIA data) will be 
summarized by LTE treatment group (late start low dose, late start high dose, early start low 
dose, early start high dose, and in addition late start total, early start total and BIIB037 total; 
analysis display A in Appendix 4.1), unless otherwise specified. ARIA tables will be 
presented by LTE treatment group stratified by ApoE status (3 columns under each of the 4 
LTE treatment groups: ApoE ε4+, ApoE ε4- and total, and in addition late start total and 
early start total; analysis display B in Appendix 4.1), unless otherwise specified. A subset of 
AE tables will also be presented by LTE treatment group stratified by ApoE status in addition 
to by LTE treatment group. Listings will be presented by LTE treatment group stratified by 
ApoE status, with an indicator of the study period (pre-dosing, placebo-controlled, or LTE) 
for each record when the event/assessment occurred. 
 
LTE baseline for late start subjects 
Placebo-controlled baseline is defined as the last non-missing measurement collected prior to 
the first dose (the baseline used for placebo-controlled period analyses). LTE baseline is 
defined as the last non-missing measurement collected prior to the first dose of the LTE 
period. For analyses on the LTE period or on the placebo-controlled and LTE active 
treatment period, LTE baseline will be used for late start subjects who are assigned to 
receiving aducanumab in the LTE period. Study day and analysis visit window for analyses 
using LTE baseline will be derived based on the first day of study drug in LTE.  
 
Incidence, incidence proportion and incidence rate 
• Incidence and incidence proportion will be provided in incidence tables. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion is 
defined as the number of subjects who experienced an event divided by the total number 
of subjects in the analysis population, i.e., percentage. Each subject will be counted only 
once within each category. 
  
• Incidence and incidence rate will be provided in incidence rate tables. Two different kinds 
of incidence rate tables will be provided as appropriate for different analyses. Definitions 
are provided below. 
 


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(1) Follow-up adjusted incidence rate – defined as the number of subjects who 
experienced an event divided by the total of entire follow-up time among the subjects 
in the analysis population. The entire follow-up time for a subject is defined as the 
time from the first dose until the last day on study. Each subject will be counted only 
once within each category.  
(2) Exposure-adjusted incidence rate (EAIR) – defined as the number of subjects who 
experience an event divided by the total exposure adjusted follow-up time among the 
subjects in the analysis population. The exposure adjusted follow-up time is defined 
as the time from the first dose until the initial occurrence of the event for those who 
experienced an event, or from the first dose until the end of follow-up (the last day on 
study) for those who did not. Each subject will be counted only once within each 
category. 
 
3.5.2 Clinical Adverse Events  
Treatment-emergent AEs (TEAEs) 
All AEs will be analyzed based on the principle of treatment emergence.  A treatment-
emergent AE was defined as an AE that started or worsened after the start of first infusion of 
study treatment.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
• if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent; 
• if the start date for a particular AE is missing and the stop date/time falls after the first 
dose date/time, then that AE is considered treatment emergent; 
• if the start date for a particular AE was the same as the first dose date, and the start time 
was missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of 
the first dosing date to determine whether the event is treatment emergent. 
In addition, SAEs that occurred since a subject was screened in the study and prior to the first 
infusion of study treatment, which by definition are not treatment-emergent, will be analyzed 
separately. 
Only TEAEs will be included in the AE tables, unless otherwise specified. Listings of AEs 
will include all events, whether treatment-emergent or not.  
 
As specified in the protocol, subjects were expected to return to the study site for an End of 
Study visit 18 weeks after the last administration of study treatment. However, some subjects 
may elect to continue study participation on a modified schedule after discontinuing 
treatment, possibly in substantial excess of 18 weeks.  For most general AE summaries, AEs 
with an onset more than 18 weeks after the last dose will be excluded (will specify in the 
footnote of the specific table). For incidence rate analyses excluding AEs more than 18 weeks 
after the last dose, the “last day on study” in follow-up time calculation will be replaced with 


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“18 weeks after last dose or last day on study, whichever earlier”.  Summaries of deaths and 
AEs leading to study withdrawal, and other selected analyses will include all AEs regardless 
of the time since the last dose.  Listings will include all AEs, unless otherwise specified. 
 
 
 Summary and incidence analysis 
Overall summary of AE table will be done for the LTE period, as well as for the placebo-
controlled and LTE active treatment period presented by LTE treatment group as well as LTE 
treatment group stratified by ApoE status. The following information will be summarized: the 
number of subjects with any AE, with any AE by maximum severity, the number of subjects 
with any related AE (related to study drug as assessed by investigator), the number of 
subjects with SAE, the number of subjects with related SAE, the number of subjects with AE 
leading to study drug discontinuation, the number of subjects with AE leading to study 
withdrawal, and the number of deaths.  
The sorting order of AE incidence tables, unless otherwise specified, will be by decreasing 
frequency order of “BIIB037 total” column within each category in the tables presented by 
LTE treatment group, and by decreasing frequency order of “BIIB037 early start total” 
column within each category in the tables presented by LTE treatment group stratified by 
ApoE status. A subject is counted only once within each category in each table. For example, 
for the table of AEs by system organ class and preferred terms sorted by decreasing 
frequency presented by LTE treatment group, system organ class will be presented in 
decreasing frequency order of BIIB037 total column, and within each system organ class, 
preferred terms will be presented in decreasing frequency order of BIIB037 total column. A 
subject is counted only once within each system organ class and preferred term.  
The following AE incidence tables will be provided for the LTE period (presented both by 
LTE treatment group and by LTE treatment group stratified by ApoE status, unless otherwise 
specified): 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class and preferred term sorted by alphabetical order analysis 
(by LTE treatment group)  
3. AEs by system organ class, high level group term and preferred term (by LTE 
treatment group) 
4. AEs by system organ class (by LTE treatment group) 
5. AEs by preferred term  
6. AEs with an incidence of 5% or more in any treatment group by preferred term  
7. Severe AEs by system organ class and preferred term  
8. Severe AEs by preferred term (by LTE treatment group) 
9. AEs by maximum severity by system organ class and preferred term (by LTE 
treatment group) (System organ class will be presented alphabetically. Preferred terms 
will be presented in decreasing frequency order. Maximum severity will be presented 
within each preferred term in the order of mild, moderate, severe, unknown and total. 


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A subject will be counted only once at the maximum severity within each system 
organ class and preferred term.)  
10. AEs by maximum severity by preferred term (by LTE treatment group) (Preferred 
terms will be presented in decreasing frequency order. Maximum severity will be 
presented within each preferred term in the order of mild, moderate, severe, unknown 
and total. A subject will be counted only once at the maximum severity within each 
preferred term.) 
11. Related AEs by system organ class and preferred term  
12. SAEs by system organ class and preferred term  
13. SAEs by preferred term  
14. Related SAEs by system organ class and preferred term  
15. AEs that led to discontinuation of study treatment by system organ class and preferred 
term  
16. AEs that led to withdrawal from study by system organ class and preferred term  
17. SAEs with fatal outcome by system organ class and preferred term  
18. AEs that occurred within 2 hours from infusion start by system organ class and 
preferred term (by LTE treatment group) 
 
The following listings will be provided for the placebo-controlled and LTE period: 
1. Listing of AEs 
2. Listing of SAEs  
3. Listing of AEs that led to discontinuation of study treatment 
4. Listing of AEs that led to withdrawal from study 
5. Listing of AEs that occurred within 2 hours from infusion start 
6. Listing of AEs related to PET ligands  
7. Listing of SAEs with fatal outcome  
8. Listing of AEs for subjects with treatment-emergent positive anti-BIIB037 antibody  
 
 Incidence and incidence rate analysis for placebo-controlled and LTE active 
treatment period 
Due to the different length of placebo-controlled and LTE active treatment period in early 
start versus late start subjects, both incidence tables and follow-up adjusted incidence rate 
tables will be used for AE analyses in this period. The entire follow-up time is from the first 
dose in active treatment period (first dose in placebo-controlled period for early start subjects 
and first dose in LTE period for late start subjects) until the last day in the study.  


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The following incidence and follow-up adjusted incidence rate tables will be provided for the 
placebo-controlled and LTE active treatment period (presented both by LTE treatment group 
and by LTE treatment group stratified by ApoE status, unless otherwise specified): 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class, high level group term and preferred term (by LTE 
treatment group) 
3. AEs by preferred term  
4. Severe AEs by system organ class and preferred term (by LTE treatment group) 
5. Severe AEs by preferred term  
6. Related AEs by system organ class and preferred term  
7. SAEs by system organ class and preferred term  
8. SAEs by preferred term  
9. Related SAEs by system organ class and preferred term  
 
 
3.5.3 ARIA - AE of Special Interest 
 Background 
Please refer to the placebo-controlled SAP for details. 
 
 
 Incidence and summary of ARIA 
Incidence of ARIA-E, ARIA-H, ARIA-E and ARIA-H (not necessarily concurrent), 
concurrent ARIA-E and ARIA-H, ARIA-E or ARIA-H, isolated ARIA-H (only ARIA-H, no 
ARIA-E), ARIA-H microhemorrhage, ARIA-H macrohemorrhage and ARIA-H superficial 
siderosis in the LTE period and in the placebo-controlled and LTE active treatment period 
will be summarized based on both AE eCRF and MRI data. If there is any discrepancy in 
incidence between the two data sources, a listing of the subjects and ARIA events with 
discrepancy will be provided. In addition, the incidence table based on AE eCRF source will 
also be done by LTE treatment group (analysis display A in Appendix 4.1). 
Number of subjects with each type of ARIA, maximum severity and worst symptomatic 
status of the type of ARIA being analyzed in the LTE period and in the placebo-controlled 
and LTE active treatment period will be summarized based on AE eCRF. For subjects with 
symptomatic ARIA, the maximum severity of symptoms will also be summarized.  
Summary of concurrent ARIA-E and ARIA-H will be provided including the following 
information for the LTE period and for the placebo-controlled and LTE active treatment 
period: number of subjects with concurrent ARIA-E and ARIA-H (and further broken down 
to each type of ARIA-H), the severity of ARIA-E based on MRI, the symptomatic status of 
ARIA-E, the severity of symptoms based on AE eCRF. For subjects with recurrent ARIA-E 


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events, if there is an event concurrent with ARIA-H, it will be used for the summary, and the 
first concurrent event will be used if there are more than one event concurrent with ARIA-H. 
An incidence table of AEs considered by the investigator to be related to ARIA by system 
organ class and preferred term for subjects with symptomatic ARIA in the placebo-controlled 
and LTE active treatment period will be provided, as well as a listing of these AEs. Similarly, 
an incidence table of AEs related to ARIA for subjects with symptomatic ARIA and severe 
symptoms will be provided, as well as a listing of these AEs. 
Listings of AE records for each type of ARIA events and listings of MRI assessments for 
subjects with each type of ARIA events will be provided.  
Montreal Cognitive Assessment (MOCA) is performed at baseline, Week 80 (the first visit in 
LTE) and each unscheduled ARIA monitoring visit for ARIA subjects (approximately every 
4 weeks) except for mild asymptomatic microhemorrhage subjects. An incidence table of late 
start subjects with ARIA events only in the LTE period (no ARIA in the placebo-controlled 
period) whose MOCA total scores decrease 2 points or more from Week 80 will be provided. 
Since Week 80 MOCA was not a planned study event until protocol version 4, some subjects 
may not have a Week 80 MOCA score. For these subjects, their Week 80 MOCA will be 
imputed as their baseline MOCA plus the mean change from baseline at Week 80 from 
subjects who have a Week 80 MOCA and did not experience any ARIA in the placebo-
controlled period within each treatment group and ApoE status. A listing of MRI assessments 
and MOCA total score for subjects with ARIA events in either placebo-controlled or LTE 
period will be provided.  
 
 Summary of recurrent ARIA-E 
Follow-up adjusted incidence rate of subjects with ARIA-E, with 2 or more events of ARIA-
E, with 3 or more events of ARIA-E and with more than 3 events of ARIA-E over their entire 
follow-up time for the placebo-controlled and LTE active treatment period will be 
summarized based on AE eCRF.  
Number of total ARIA-E events in the placebo-controlled and LTE active period and the MRI 
severity of each event will be summarized based on AE eCRF. Number of symptomatic 
ARIA-E events in the placebo-controlled and LTE active period, and the severity of the 
symptoms of each symptomatic event will be summarized based on AE eCRF. 
Summary of first ARIA-E events table based on AE eCRF will summarize the number of 
subjects with a first event of ARIA-E, the MRI severity of the events, the symptomatic status 
of the events, the severity of the symptoms for symptomatic events, whether SAE or not, 
number of resolved and unresolved events, duration of the resolved events, time from first 
active infusion in study to onset, number of doses received since the start of the period to 
onset, dose level of the last infusion received prior to onset, dosing status (continue as 
planned, dose interrupted, dose reduced, or dose discontinued) after the events, and the 
number of subjects with recurrent ARIA-E events. This table will be done on the placebo-
controlled and LTE active treatment period. The same summary of first ARIA-E events table 
will also be done on the subset of subjects who had recurrent ARIA-E events.  
Summary of recurrent ARIA-E events table based on AE eCRF will summarize the following 
information for both the second and third event of ARIA-E events: the number of subjects 


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with the previous event of ARIA-E, the number of subjects with at least one dose and one 
MRI after the previous ARIA-E resolution, the number of subjects with this event of ARIA-
E, the MRI severity of the events, the symptomatic status of the events, the severity of the 
symptoms for symptomatic events, whether SAE or not, number of resolved and unresolved 
events, duration of the resolved events, time from first infusion in study (active or placebo) to 
onset, time from previous resolution to onset, number of doses received since the start of the 
period to onset, dose level of the last infusion received prior to onset, dosing status (continue 
as planned, dose interrupted, dose reduced, or dose discontinued) after the events. The 
number of subjects with more than 3 events of ARIA-E, and the number of subjects who 
discontinued study treatment after recurrent ARIA-E onset will also be summarized. This 
table will be done on the placebo-controlled and LTE active treatment period. 
A listing of subjects who withdrew from the study with unresolved ARIA-E or subjects with 
ongoing ARIA-E at the time of data cutoff (also considered as unresolved) will be provided 
with the details of the event including the duration from onset to last follow-up.  
For subjects with recurrent ARIA-E, a listing of study drug administration, MRI assessments, 
severity and symptomatic status of each event, and end-of-treatment reason (if present) will 
be provided.  
    
 Exposure adjusted analysis  
Exposure adjusted incidence rate of ARIA-E events will be summarized based on safety MRI 
data for the placebo-controlled and LTE active treatment period. The exposure adjusted 
follow-up time is from the first active dose until the initial occurrence of ARIA-E for those 
who experienced ARIA-E, and until the end of follow-up for those who did not. Since ARIA 
is an MRI finding, the day of the last MRI assessment in the placebo-controlled and LTE 
active treatment period will be used as the end of follow-up for those who didn’t experience 
the event. 
Study drug administration information prior to first ARIA-E onset will be summarized for 
ARIA-E subjects for the placebo-controlled and LTE active treatment period, including 
number of total infusions, number of infusions at each dose level (placebo, 1 mg/kg, 3 mg/kg, 
6 mg/kg and 10 mg/kg), dose level of the last infusion, maximum dose level received, and 
cumulative dose as a continuous variable.   
 
 Time to event analysis 
Kaplan-Meier plot of time to first ARIA-E event will be produced based on safety MRI data 
for the placebo-controlled and LTE active treatment period. Only ARIA-E events that 
occurred during this period will be included. Time to event is calculated as date of the MRI 
assessment that initially detects the ARIA-E event - date of the first active infusion +1. 
Censor time for subjects without ARIA-E is calculated as date of the last MRI assessment in 
the study - date of the first active infusion +1. Estimated proportion with ARIA-E and 
number of subjects at risk at selected timepoints will also be presented. The plot will be 
presented by LTE treatment group stratified by ApoE status.  


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3.5.4 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol and will be 
analyzed: 
o Hematology:   
• White blood cells (leukocytes), lymphocytes, neutrophils, monocytes, 
eosinophils, basophils 
• Red blood cells (erythrocytes), erythrocytes distribution width, 
erythrocytes mean corpuscular volume, erythrocytes mean corpuscular 
hemoglobin, erythrocytes mean corpuscular hemoglobin concentration 
• Hemoglobin 
• Hematocrit 
• Platelet count 
o Blood chemistry:  
• Liver: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, direct bilirubin, 
gamma-glutamyl-transferase (GGT) 
• Renal: blood urea nitrogen (BUN), creatinine 
• Electrolytes: sodium, potassium, chloride, bicarbonate  
• Other: glucose, calcium, phosphorus, albumin, uric acid, lactate 
dehydrogenase (LDH), total protein  
o Urinalysis: specific gravity, potential of hydrogen (pH), color, blood, glucose, 
ketones, protein, white blood cells, red blood cells 
 
 Quantitative analyses  
For numeric laboratory parameters, actual values will be summarized by visit for all the visits 
in the placebo-controlled and LTE period. Number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum and maximum values will be presented 
at each visit.  
Plots of mean actual values (with standard error) for numeric laboratory parameters at each 
visit for all the visits in the placebo-controlled and LTE period will be provided.  
Summary of change from baseline and percent change from baseline for numeric laboratory 
parameters will be done on the placebo-controlled and LTE active treatment period. Placebo-
controlled baseline will be used for early start subjects and LTE baseline will be used for late 
start subjects. Change and percent change from baseline will be calculated based on the LTE 
baseline for late start subjects. Number of evaluable subjects, mean, standard deviation, 
median, 25% and 75% quartiles, minimum and maximum values will be presented at each 
visit.  


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Listings of individual laboratory measurements by patients for all the parameters will be 
provided.  
 
Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows 
(see Table 5 below).  If there is more than 1 value in the same analysis visit window for a 
certain parameter for a subject, then the closest record to the target visit day will be used for 
the by visit analysis.  If there are 2 values in the same analysis visit window with the same 
distance from the target visit day for a certain parameter for a subject, then the record with 
the later date will be used for the by visit analysis.  If there are 2 values on the same day for a 
certain parameter for a subject, then the record with the later time will be used for the by visit 
analysis. 
 
Table 5: Visit Windows for Laboratory by Visit Summaries  
 
Analysis visit  
Analysis visit window1 
For subjects who received 
the first dose of 
aducanumab in the placebo-
controlled period 
For subjects who received the 
first dose of aducanumab in 
the LTE period 
Baseline 
Last value prior to the first dose of 
aducanumab 
Last value prior to the first dose of 
aducanumab 
Week 24 
[2, 252] 
[2, 252] 
Week 48 
[253, 420] 
[253, 420] 
Week 72 
[421, 525] 
[421, 588] 
Week 78 
[526, end day of the placebo-
controlled period2] 
NA 
Week 104 
[start day of the LTE period3, 812] 
[589, 868] 
Week 128 
[813, 980] 
NA 
Week 152 
[981, 1148] 
[869, 1246] 
Week 176 
[1149, 1428] 
NA 
Week 232 
[1429, 1806] 
[1247, 1708] 
Week 284 
[1807, 2170] 
≥ 1709 
Week 336 
≥2171 
NA 
1. Visit windows are defined based on days relative to the first dose of aducanumab. 
2. The end day of the placebo-controlled period is the last day before the first infusion in LTE, or the 
last day in study for subjects who do not enter LTE.  
3. The start day of the LTE period is the day of first infusion in LTE period. 
 
 
 Qualitative analyses 
For qualitative analyses, all values will be included (not just the “analyzed record” within 
each visit window in the quantitative analyses). 
 
Shift analyses 


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Laboratory data will be summarized using shift tables where appropriate for the placebo-
controlled and LTE active treatment period. Each subject’s hematology, blood chemistry and 
urinalysis numeric values will be flagged as “low”, “normal”, or “high” relative to the normal 
ranges of the central laboratory or as “unknown” if no result is available.  Each subject’s 
urinalysis categorical values will be flagged as “positive” or “negative”, or “unknown” if no 
value is available.   
Shifts from baseline to high/low status will be presented for hematology, blood chemistry and 
urinalysis numeric parameters, and shifts from baseline to abnormal (positive) will be 
presented for urinalysis categorical parameters.  Shift to low includes normal to low, high to 
low, and unknown to low; Shift to high includes normal to high, low to high, and unknown to 
high. Subjects need to have at least one post-baseline evaluation and a baseline value not low 
or high or positive (including missing) in order to be included in the analysis. 
For early start subjects, the placebo-controlled baseline will be used and shifts that occurred 
in either placebo-controlled or LTE period will be included. For late start subjects, the LTE 
baseline will be used and shifts that occurred in the LTE period based on LTE baseline will 
be included.  
 
Grade analyses 
Worst post-baseline grade will be summarized for each laboratory parameter in both 
exclusive way and cumulative way for the placebo-controlled and LTE active treatment 
period. Subjects need to have at least one post-baseline evaluation in the active treatment 
period in order to be included in the analysis. Common Toxicity Criteria for Adverse Events 
v4.0.3 (CTCAE) published on 2010-06-14 will be used for grade determination. Grade 
determination is based solely on laboratory values not taking AEs into account.  
 
Potentially Clinically Significant laboratory abnormalities analyses 
Please refer to the placebo-controlled SAP for the parameters and criteria for potentially 
clinically significant laboratory abnormalities analyses.  
The number of subjects with potentially clinically significant laboratory abnormalities post-
baseline will be summarized for the placebo-controlled and LTE active treatment period.  
Subjects need to have at least one post-baseline evaluation in the active treatment period and 
a baseline value not potentially clinically significant (including missing) in order to be 
included in the analysis.  
Same as the shift analysis, for early start subjects, the placebo-controlled baseline will be 
used and abnormalities that occurred in either placebo-controlled or LTE period will be 
included. For late start subjects, the LTE baseline will be used and PCS abnormalities that 
occurred in the LTE period based on LTE baseline will be included. 
 
Potential serious hepatotoxicity 
 
In this SAP, we define potential serious hepatotoxicity as ALT or AST > 3x ULN and total 
bilirubin > 2x ULN at any time post-baseline in the placebo-controlled and LTE active 


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treatment period (not necessarily concurrent). A scatterplot of the maximum post-baseline 
ALT or AST value relative to ULN and maximum post-baseline total bilirubin value relative 
to ULN (not necessarily concurrent) for each subject will be provided. A line plot of ALT, 
AST, ALK and total bilirubin values over time in the active treatment period for subjects with 
potential serious hepatotoxicity will be provided. In addition, subjects with ALT > 1x ULN, 
>3x ULN, >5x ULN, >10x ULN or >20x ULN, subjects with AST > 1x ULN, >3x ULN, >5x 
ULN, >10x ULN or >20x ULN, subjects with total bilirubin >1x ULN or >2x ULN, subjects 
with ALP >1x ULN or >1.5x ULN, and subjects with AST or ALT > 3x ULN post-baseline 
accompanied by concurrently elevated total bilirubin >1.5x ULN or > 2x ULN in the active 
treatment period will be presented. Concurrent is defined as on the same day. A listing of 
subjects with potential serious hepatotoxicity will be provided.  
 
3.5.5 C-SSRS Data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates 
suicidal ideation and behavior.  There are 5 “Yes/No” questions on suicidal ideation 
following the increasing severity order: (1) Wish to be dead, (2) Non-specific active suicidal 
thoughts, (3) Active suicidal ideation with any methods (not plan) without intent to act, (4) 
Active suicidal ideation with some intent to act, without specific plan, (5) Active suicidal 
ideation with specific plan and intent, and 6 “Yes/No” questions on suicidal behavior 
following the increasing severity order: (6) Preparatory acts or behavior, (7) Aborted attempt, 
(8) Interrupted attempt, (9) Actual attempt, (10) Suicidal behavior, (11) Suicide (only at post-
baseline visits).  Another “Yes/No” question of whether the subject has engaged in non-
suicidal self-injurious behavior is also collected.  
The summary table for C-SSRS will be conducted for the placebo-controlled and LTE active 
treatment period. Number of subjects who answered “Yes” to each of the 11 questions post-
baseline, subjects who answered “Yes” to at least one question for suicidal ideation, subjects 
who answered “Yes” to at least one question for suicidal behavior, and subjects who have 
engaged in non-suicidal self-injurious behavior will be presented. A listing of subjects with 
any suicidal ideation or behavior at baseline or post-baseline will be provided for placebo-
controlled and LTE period. 
 
3.5.6 ECG Data 
Shift from normal or unknown ECG at baseline to abnormal, not adverse event or abnormal, 
adverse event post-baseline ECG will be summarized for the placebo-controlled and LTE 
active treatment group.  For early start subjects, the placebo-controlled baseline will be used. 
For late start subjects, the LTE baseline will be used. Subjects with abnormal ECG status will 
be listed. 
 
3.5.7 Vital Sign Data 
Vital sign parameters include body temperature, systolic blood pressure, diastolic blood 
pressure, heart rate, respiration rate and weight. Vital signs will be measured with the subject 


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supine and after the subject has been resting for at least 10 minutes. The descriptive statistics 
for actual values will be summarized at each visit in the placebo-controlled and LTE period.  
Plot of mean vital sign values in the placebo-controlled and LTE period will be provided.  
Summary of change from baseline including number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum, and maximum values will be 
summarized at each visit in the placebo-controlled and LTE active treatment period. Placebo-
controlled baseline will be used for early start subjects and LTE baseline will be used for late 
start analysis.  
The analysis of vital signs will also focus on the incidence of clinically relevant outliers. 
Please refer to the placebo-controlled SAP for the criteria to assess potential clinically 
relevant outliers in vital sign. The incidence and percentage of clinically relevant outliers 
determined by each criterion will be summarized in the placebo-controlled and LTE active 
treatment period. A listing of subjects with clinically relevant vital signs in the placebo-
controlled and LTE active treatment period will also be provided. 
 
Visit windows for by visit summaries 
For vital sign by visit summaries, the analysis visit should be defined using windows (see 
Table 6 below). For the same parameter for a subject, if there is more than 1 record in the 
same analysis visit window, then select the record closest to the target visit day.  If there are 2 
records in the same analysis visit window with the same distance from the target visit day, 
then select the record with the later date.   
 
Table 6: Visit Windows for Vital Sign by Visit Summaries 
Analysis visit window1 
Analysis visit 
For subjects who received the 
first dose of aducanumab in 
the placebo-controlled period 
For subjects who received the 
first dose of aducanumab in 
the LTE period 
Baseline 
Last value prior to the first dose of 
aducanumab 
Last value prior to the first dose of 
aducanumab 
Week 4 
[2, 42] 
[2, 42] 
Week 8 
[43, 70] 
[43, 70] 
Week x  
[7x -13, 7x+14] for 8 ≤ x ≤72 
[7x -13, 7x+14] for 8 ≤ x ≤252 
… 
… 
… 
Week 76 
[519, the end day of the placebo-
controlled period1] 
[7x -13, 7x+14] for 8 ≤ x ≤252 
Week 80 
[the start day of the LTE period2, 574] 
[7x -13, 7x+14] for 8 ≤ x ≤252 
Week x  
[7x -13, 7x+14] for 84 ≤ x ≤176 
[7x -13, 7x+14] for 8 ≤ x ≤252 
… 
… 
… 
Week 180 
[1247, 1267] 
[7x -13, 7x+14] for 8 ≤ x ≤252 
Week 182  
[1268, 1281] 
NA 
Week 184 
[1282, 1302] 
[7x -13, 7x+14] for 8 ≤ x ≤252 
Week 188 
[1303, 1330] 
[7x -13, 7x+14] for 8 ≤ x ≤252 
Week x  
[7x -13, 7x+14] for 188 ≤ x ≤332 
[7x -13, 7x+14] for 8 ≤ x ≤252 
… 
… 
… 
Week 256 
[7x -13, 7x+14] for 188 ≤ x ≤332 
[1779, 1799] 
Week 260 
[7x -13, 7x+14] for 188 ≤ x ≤332 
≥ 1800 
… 
… 
… 
Week 336 
[2339, 2359] 
NA 




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3.7 
Immunogenicity Analysis 
3.7.1 Background 
Definition of LTE baseline value 
 
Placebo-controlled baseline value is defined as the latest immunogenicity data collected prior 
to the first dose. If no immunogenicity data are collected prior to the first dose, baseline value 
is missing and will be imputed as anti-drug antibody negative for immunogenicity analyses. 
LTE baseline is defined as the last non-missing measurement collected prior to the first dose 
of the LTE period. For analyses on the placebo-controlled and LTE active treatment period, 
LTE baseline will be used for late start subjects who are assigned to receiving aducanumab in 
the LTE period. Study day and analysis visit window for analyses using LTE baseline will be 
derived based on the first day of study drug in LTE.  
 
Treatment-emergent anti-aducanumab antibody positive responses for the placebo-controlled 
and LTE active treatment period 
 
Post-baseline positive anti-aducanumab antibody responses for the active treatment period are 
defined as treatment-emergent if a subject is either (1) antibody negative at baseline; or (2) 
antibody positive at baseline but the post-baseline antibody response is more than 2-fold 
increase in titer compared to the baseline response. Placebo-controlled baseline will be used 
for early start subjects and LTE baseline will be used for late start subjects. 
 
Persistent and transient positive responses for the placebo-controlled and LTE active 
treatment period 
 
Subjects with treatment-emergent post-baseline positive anti-aducanumab antibody responses 
in the placebo-controlled and LTE active treatment period will be further classified as 
transient positive, if only a single positive evaluation occurs or more than 1 positive 
evaluation but occur with < 112 days (16 weeks) apart, or as persistent positive, if more than 
one consecutive positive evaluation occurs ≥112 days (16 weeks) apart in the active treatment 
period or a positive evaluation occurs at the last available time point with no further negative 
results available.  
 
3.7.2 Immunogenicity analysis 
Immunogenicity population will be used to analyze immunogenicity data. LTE safety 
treatment groups will be used for immunogenicity analysis. Tables will be presented by LTE 
treatment group (late start low dose, late start high dose, early start low dose, early start high 
dose, and in addition late start total, early start total and BIIB037 total; analysis display A in 
Appendix 4.1). Listings will be presented by treatment group stratified by ApoE status. 
 
A summary table of subjects with treatment-emergent positive anti-aducanumab antibody 
responses in the placebo-controlled and LTE active treatment period will be provided. The 
number and percentage of anti-aducanumab positive results will be summarized at each visit 
as well as at any time post-baseline in this period. Subjects with persistent response and 


Statistical Analysis Plan 
Long-Term Extension Period 
Final V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
34 
 
subjects with transient response in this period will be presented. A listing of immunogenicity 
data in placebo-controlled and LTE period for subjects with anti-aducanumab antibody 
positive results will also be provided. 
 
Visit windows for by visit summaries 
For immunogenicity by visit summaries, the analysis visit should be defined using visit 
windows (see Table 7 below). If there is more than 1 value in the same analysis visit window 
for a subject, then the closest record to the target visit day will be used for the by visit 
analysis.  If there are 2 values in the same analysis visit window with the same distance from 
the target visit day for a certain parameter for a subject, then the record with the later date 
will be used for the by visit analysis.  If there are 2 values on the same day for a certain 
parameter for a subject, then the record with the later time will be used for the by visit 
analysis. 
 
Table 7: Visit Windows for Immunogenicity by Visit Summaries  
 
Analysis visit  
Analysis visit window1 
For subjects who received the 
first dose of aducanumab in 
the placebo-controlled period 
For subjects who received the 
first dose of aducanumab in 
the LTE period 
Baseline 
Last value prior to the first dose of 
aducanumab 
Last value prior to the first dose of 
aducanumab 
Week 24 
[2, 196] 
[2, 252] 
Week 32 
[197, 308] 
NA 
Week 56 
[309, 470] 
[253, 420] 
Week 78 
[471, end day of the placebo-
controlled period2] 
[421, 609] 
Week 80 
[start day of the LTE period3, 644] 
NA 
Week 104 
[645, 812] 
[610, 1260] 
Week 128 
[813, 980] 
NA 
Week 152 
[981, 1169] 
NA 
Week 182 
[1170, 1820] 
≥ 1261 
Week 338 
≥ 1821 
NA 
1. Visit windows are derived based on the first dose of aducanumab.  
2. The end day of the placebo-controlled period is the last day before the first infusion in LTE for 
subjects who enter LTE, or the last day in study for subjects who do not enter LTE. 
3. The start day of the LTE period is the day of first dose in the LTE period.  
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Long-Term Extension Period 
Final V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
35 
 
4 Appendix 
4.1 
Analysis Display 
Analysis display A 
BIIB037 late start 
 
BIIB037 early start 
 
BIIB037 
total 
Low dose 
High dose 
Total 
 
Low dose 
High dose 
Total 
 
 
Analysis display B 
Page 1 of 2 
BIIB037 late start low dose  
 
BIIB037 late start high dose  
 
 
BIIB037 late 
start total 
ApoE e4+ 
3 mg/kg 
ApoE e4- 
6 mg/kg 
 
Total 
 
ApoE e4+ 
10 mg/kg 
ApoE e4- 
10 mg/kg 
 
Total 
 
 
Page 2 of 2 
BIIB037 early start low dose  
 
BIIB037 early start high dose  
 
 
BIIB037 early 
start total 
ApoE e4+ 
3 mg/kg 
ApoE e4- 
6 mg/kg 
 
Total 
 
ApoE e4+ 
10 mg/kg 
ApoE e4- 
10 mg/kg 
 
Total