A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease
Phase: PHASE3
Conditions: Alzheimer's Disease
Sponsor: Biogen



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 
 
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 
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. 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 
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 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 
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 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   
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 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   
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 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 
Bi o ge n M A I nc. 
9 
 
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. 
 
 
 
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I n v esti gat or’s Si g n at ure  
  
  
  
Date 
 
 
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I n v esti gat or’s N a me ( Pri nt) 
 
 
 
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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 , 

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 5
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 
Bi o ge n M A
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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Bi o ge n M A
I nc.
6 7
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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C O N FI D E N TI A L
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Bi o ge n M A
I nc.
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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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Bi o ge n M A
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.  

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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 
Bi o ge n M A
I nc.
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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 
Bi o ge n M A
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
I nc.
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.
9 0
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)

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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
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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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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o 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
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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
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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.
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
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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.
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
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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 
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 

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 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 

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 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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P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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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
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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
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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
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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
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C O N FI D E N TI A L
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Bi o ge n M A  I nc.
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
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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
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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
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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.
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I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
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St u d y  Site ( Pri nt)