Conditions: Alzheimer's Disease
Keywords: Aducanumab BIIB037
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1643
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Monthly intravenous (IV) infusions arm 2: Monthly intravenous (IV) infusions

Interventions: intervention 1: Aducanumab (BIIB037) intervention 2: Aducanumab (BIIB037) intervention 3: Placebo
Intervention descriptions: intervention 1: Low dose intervention 2: High dose intervention 3: Placebo

Protocol document:
Prot_000.pdf: 
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n 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.
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Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A 0 2 1 4 2
U nite d States
P R O T O C O L N U M B E R:
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Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
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P R O T O C O L TI T L E: A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, 
Place b o -C o ntr olle d, 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
E U D R A C T N O:
2 0 1 5 -0 0 0 9 6 7 -1 5
D A T E:
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FI N A L
S u perse des pre vi o us Versi o n 5. 0 date d 1 8 Se pte m ber 2 0 1 7.
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Bi o ge n M A  I nc.
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T A B L E O F C O N T E N T S
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 2 ................................................................................................................... 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 p erie 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


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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


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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 ma 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 -De si 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


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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


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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


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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 of I nterest .................................................................................................... 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


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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 S c 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 -T er 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 bl e 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 2
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 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 2
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 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 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 2
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 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 


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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) 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 S tate E xa mi nati o n 
( M M S E) s u g gesti ve of a re d ucti o n i n t he pr o gressi o n of cli nical 
i m pair me nt f or a d uca n u ma b-treate d s u bjects.  T hese res ults,
al o n g wit h t he o bser ve d safet y a n d t olera bilit y pr ofile , warra nt 
f urt her P hase 3 i n vesti gati o n of a d uca n u ma b i n a patie nt 
p o p ulati o n s pa n ni n g t he earl y sta ges of t he A D c o nti n u u m.  
P hase of De vel o p me nt:
3
St u d y O bjecti ves a n d E n d p oi nts 
( place b o-c o ntr olle d peri o d of t he 
st u d y):
T he pri mar y o bjecti ve of t he st u d y is t o e val uate t he efficac y of 
m o nt hl y d oses of a d uca n u ma b i n sl o wi n g c o g niti ve a n d 
f u ncti o nal i m pair me nt as meas ure d b y c ha n ges i n t he C D R-S B
sc ore as c o m pare d wit h place b o i n s u bjects wit h earl y A D.  
T he pri mar y e n d p oi nt t hat relates t o t his o bjecti ve is t he c ha n ge 
fr o m baseli ne i n C D R-S B sc ore at Wee k 7 8.
Sec o n dar y o bjecti ves a n d e n d p oi nts are as f oll o ws:
T o assess t he effect of m o nt hl y d oses of a d uca n u ma b as 


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 5
Pr ot oc ol N u m ber:
2 2 1 A D 3 0 2
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 2
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 2
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 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 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 2
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 2
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 2
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 2
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 2
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 2
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 1
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
M M S E
X
X
X
A D C S -A D L -M CI
X 1 7
X
X
A D A S -C o g 1 3
X 1 7
X
X
N PI -1 0
X 1 8
X
E Q -5 D ( S R) 
X 1 9
X
E Q -5 D (I R- S)
X 1 9
X
m P D Q -2 0
X 1 9
X
C- S S R S
X
X
A E Re p or ti 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); 
A p o E = a p oli p o pr otei n E; A RI A = a m yl oi d -relate d i ma gi n g a b n or malities; 
; C D R = Cli nical De me ntia Rati n g scale; 
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 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 bject; E Q-5 D ( S R) = E Q -5 D, s u bject self -re p orte d; H b A 1c = gl yc os ylate d he m o gl o bi n; HI V = h u ma n i m m u n o deficie nc y vir us; 
L T E = l o n g-ter m e xte nsi o n; M M S E = Mi ni Me ntal State E xa mi nati o n; m P D Q -2 0 = m o difie d Percei 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 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; R B A N S = Re peata ble 




Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 2
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 5
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
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
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); A RI A = a m yl oi d -relate d 
i ma gi n g a b n or malities; 
; C D R = Cli nical De me ntia Rati n g scale; 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 C T = disc o nti n ue treat me nt; 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 Q -5 D ( S R) = E Q -5 D, s u bject self -re p orte d; 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 M S E = Mi ni Me ntal State E xa mi nati o n; m P D Q -2 0 = m o difie d Percei ve d Defic its Q uesti o n naire-2 0; 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; R N A = ri b o n ucleic aci d; S A E = seri o us 
a d verse e ve nt; U V = u nsc he d ule d visit ; w ks = wee k s.
1 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.
2 S u bj ects 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 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.  (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 a ssess me nts re q uire d f or b ot h visits perf or me d at t his si n gle visit.  N ote: S u bjects w h o 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 ar e n ot re q uire d if t he s u bject 


Pr ot oc ol 2 2 1 A D 3 0 2
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 nteri 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 be meas ure d w it h 
t he s u bject s u pi ne a n d after t he s u bject has bee n resti n g f or at least 1 0 mi n utes.
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.
1 0 A m yl oi d P E T at Wee k 7 8 w ill onl 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 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 2
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; 
R N A = ri b o n ucleic aci d; 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 2
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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 2
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 ollecti 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 2
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 3
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
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 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 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; 
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 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 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; R N A = ri b o n ucleic aci d; 
S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit.
1 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y ( Secti o n 1 5. 5 ).
  
 
4 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 2
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 2
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; R N A = ri b o n ucleic aci d .
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 2
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 2
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 Rat i 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 A ssess 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; R N A = ri b o n ucleic aci d; 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 p le 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 p les o n a s pecifie d case 
re p ort f or m.


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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
E Q -5 D -(I R-I)
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
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; R N A = ri b o n ucleic aci d; 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 2
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 b le 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 2
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 2
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 2
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
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); 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 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 C T = disc o nti n ue treat me nt ; E C G = electr ocar di o gra m; E O T = e n d of treat me nt; 
 
; 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; 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; 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;
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; P K = p har mac o ki netic ; R N A = ri b o n uclei c aci d; S A E = seri o us a d verse e ve nt; U V = 
u nsc he d ule d visit; w ks = wee ks.
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 Visit at Wee k 3 5 4.  S u bjects w h o disc o nti n ue t reat 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 Visit at 1 8 wee ks after t heir 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, atte n d a F U Visit 1 8 w ee 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 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 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 wi t 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 ngle visit.  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 u bjects w h o disc o nti n ue treat me nt earl y, 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 ni fica nt c ha n ges i n c o g niti ve stat us are 
sus 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 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
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 ).




Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 5
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
N PI -1 0
X
X
X
E Q -5 D ( S R) 
X
X
X
E Q -5 D (I R -S)
X
X
X
m P D Q -2 0
X
X
X
M O C A
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 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 morr ha ge or s u perficial 
si der osis; 
; C D R = Cli nical De me ntia Rati n g scale; 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; E C G = electr ocar di o gra m; E O T = e n d of treat me nt; 
 
; 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 Q -5 D ( S R) = E Q -5 D, s u bject self -re p orte d; 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; m P D Q -2 0 = m o difie d Percei ve d Deficits Q uesti o n naire -2 0; 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; 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 mo gra p h y ; P K = p har mac o ki netic; R N A = ri b o n ucleic aci d; S A E = seri o us a d verse e ve nt; S o E = sc he d ule of e ve nts; U V = u nsc he d ule d visit.
1 S u bjects w h o disc o nti n ue st u d y treat me nt pre mat urel y d uri n g t he place b o -c o ntr olle d peri o d are t o re mai n i n t he st u d y, atte n d a F U Visit 1 8 w ee ks after t heir 
fi nal d ose as liste d i n Ta ble 2 a n d Ta ble 3 , 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.  (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 o r b ot h visits perf or me d at t his 
si n gle visit.  If t he s u bject w h o disc o nti n ue d treat me nt b ut re mai ne d i n t he st u d y c h o oses t o e nr oll i n t he L T E peri o d, he or s he will f oll o w t he S o E i n Ta ble 1 1 .


Pr ot oc ol 2 2 1 A D 3 0 2
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 In 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 
ma 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 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.
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 2
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 2
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 8
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
E Q -5 D -(I R-S)
X
X
X
X
X
X
X
M O C A
X
C- S S R S
X
X
X
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 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 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; E C G = electr ocar di o gra m; E O T = e n d of treat me nt; 
 
; 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 ; 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; 
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; 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; P K = p har mac o ki netic; R N A = ri b o n ucleic aci d; 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 disc o nti n ue st u d y treat me nt d uri n g t he L T E peri o d are t o re mai n i n t he st u d y, atte n d a F U Visit as liste d i n Ta ble 9 , a n d t he n will 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.
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 ments 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 a ssess 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 
ma na ge me nt of rec urre nt A RI A, see Secti o n 7. 2. 1. 7 .
4 T his assess me nt is o nl y t o be perf or me d if t he E O T Visit is at or bef ore Wee k 1 8 2.
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 2
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 2
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 2
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 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 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 we re p u blis he d by 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 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 ], 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 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 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 V ersi 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 2
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 7

1 F U safet y 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 dra w 
fr o m st u d y.
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  u p t o 7 6 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:

6 5 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.

7 visits f or cli nical assess me nts.


4 visits f or a m y l oi d P E T sca n (i n a s u bset of s u bjects).


1 0 visits f or brai n M RI .

1 F U 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 n t) 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 ntrolle d or L T E peri o d s h o ul d ha ve 
u nsc he d ule d visits 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 ( o pti o nal) 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, t he Re peata ble Ba tter y f or Assess me nt of 
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) a n d 
A p o E ge n ot y pi n g m ust be perf or me d at Scree ni n g Visit 1.  A p o E ge n ot y pi n g ma y  be perf or me d 
at 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 ny 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 as well as C S F c ollecti o n ma y  be perf or me d at a n y 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.  C S F c ollecti o n at Scree ni n g 
usi n g st u d y -s pecific pr oce d ures is preferre d; h o we ver, if a C S F sa m ple has bee n o btai ne d wit hi n 


Pr ot oc ol 2 2 1 A D 3 0 2
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
3 m o nt hs pri or t o S cree ni n g, t his sa m ple ma y be use d i n lie u of re q uiri n g a n L P at S cree ni n g.  
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 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 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 S cree 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 ng 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 ntil 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 ments.
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 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 L T 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 2
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 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 stu 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 2
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 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 nt al 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 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 mitt e 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 2
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 uate l y ma na ge d.  


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 pr ess 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 pr i 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 n i 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 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 patitis C vir us a nti b o d y or he patitis B 
vi r 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 2
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 py 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 bili t 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 2
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 or s u bjec ts 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 5
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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 6
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 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 ud 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 oced 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 xclusi 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 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 ve rifie 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 ul e 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 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 ratio.  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.


Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 6. 0
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C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
8 7
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 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 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 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 p t 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) w it 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 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 ordi 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 gn me nt.

T he s u bject e x perie nces a n A E t hat d oes n ot res ol ve or re q uires c o nti n ue d treat me nt 
t hat meets e xcl usi o nar y criteria (see Secti o n 1 1. 5. 1. 2 ).  

T he s u bject e x perie nces a se vere i nf usi o n reacti o n.

At t he discreti o n of t he I n 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 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 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.  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 uired 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.  


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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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C O N FI D E N TI A L
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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 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) 


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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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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 


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C O N FI D E N TI A L
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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.


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Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
9 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 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 2
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 ght.

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 v erit 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 2
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 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).  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 2
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 0 2
1 5.
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G, A N D 
R E S P O N SI BI LI TI E S
T hr o u g h o ut t he c o urse of t he st u d y , e ver y eff ort m ust be ma de t o re mai n alert t o p ossi ble A Es.  
If a n A E occ urs, t he first c o ncer n s h o ul d be f or t he safety of t he s u bject.  If necessar y, 
a p pr o priate me dical i nter ve nti o n s h o ul d be pr o vi de d.
At t he si g ni n g of t he I C F, eac h s u bject or his/ her le gall y  a ut h orize d 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 di sease te m p orally 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 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 2
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 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 quire 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 an 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 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 treatme 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 pitalizatio 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 .






Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 0 6

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt
T o re p ort i nitial or F U i nf or mati o n o n a n S A E, fa x or e 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 re p ort e 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 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 oca l 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 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 2
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 2
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 ghl 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 2
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 2
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 1 0
1 6.
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F
S A M P L E SI Z E
T he o bjecti ves of t he st u d y  a n d t he e n d p oi nts t o be a nalyz e d are liste d i n Secti o n 6 .
1 6. 1.
De m o gr a p h y a n d B aseli ne Dise ase C h ar acteristics
De m o gra p hics a n d baseli ne data will be s u m marize d b y  treat me nt gr o u p wit h s u m mar y  statistics 
( mea n, sta n dar d de viati o n [ S D], me dia n, a n d ra n ge) or wit h fre q ue nc y distri b uti o ns.
1 6. 2.
Effic ac y a n d P h ar m ac o d y n a mics
1 6. 2. 1.
A n al ysis P o p ul ati o n
T he i nte nt -t o-treat (I T T) p o p ulati o n, defi ne d as all s u bjects w h o were ra n d o mize d a nd 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 versi o n s pri or t o Versi o n 4 w h o d o n ot ha ve t he o p p ort u ni t 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 ].


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 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 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 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 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 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.  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 2
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 ysis of t he S ec 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, time, 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 nalys 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 2
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 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 nt eri 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 2
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 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 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, an 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 1 ) was reassesse d i n a blin 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 2
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 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 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 2
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 2
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 2
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 2
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 2
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 2
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 2
Versi o n 6. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 2 4
2 1.
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L
I ha ve rea d t he f ore g oi n g pr ot oc ol, “ A P hase 3 M ultice nter, Ra n d o mize d, D o u ble-Bli n d, 
Place b o -C o ntr olle d, Parallel -Gr o u p St u d y  t o E val uate t he Efficac y a n d Safet y of A d uca n u ma b 
( BIIB 0 3 7) i n S u bjects wit h Earl y  Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)


C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A 0 2 1 4 2
U nite d States
P R O T O C O L N U M B E R:
2 2 1 A D 3 0 2
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
3
P R O T O C O L TI T L E: A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, 
Place b o -C o ntr olle d, 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
E U D R A C T N O:
2 0 1 5- 0 0 0 9 6 7- 1 5
D A T E:
1 8 Se pte m ber 2 0 1 7
Versi o n 5. 0
FI N A L
S u perse des pre vi o us Versi o n 4. 0 date d 2 4 Marc h 2 0 1 7.




P r ot oc ol 2 2 1 A D 3 0 2
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
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 2 ................................................................................................................... 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 diti 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


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


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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
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 2
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 Primar 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 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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 ma 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 v e 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 2
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 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 2
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 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 2
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 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 
S A E
seri o us a d verse e ve nt


Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
S A P
statistical a nal ysis pla n
S B
s u m of b o xes
S B P
s yst olic bl o o d press ure
S D
sta n dar d de viati o n
S R
s u bject rate d
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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) 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 
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 2
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 2

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 oca ti 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 utes 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 2
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 2
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 ontr 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 mat el 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).


P r ot oc ol 2 2 1 A D 3 0 2
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 2
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).


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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 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
C D R 
X
X
X
M M S E
X
X
X
A D C S -A D L -M CI
X 1 6
X
X
A D A S -C o g 1 3
X 1 6
X
X
N PI -1 0
X 1 7
X
E Q -5 D ( S R) 
X 1 8
X
E Q -5 D (I R -S)
X 1 8
X
m P D Q -2 0
X 1 8
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); 
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 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 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 bject; 
E Q -5 D ( S R) = E Q-5 D, s u bject self-re p orte d; 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 Percei 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 hiatric I n ve nt or y -1 0;  P B M C 




P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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 4
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 - MCI = 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 scale; 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 Rat i 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 bject; E Q-5 D ( S R) = E Q -5 D, s u bject self -re p orte d; E O T = E n d of Treat me nt; FU = 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; m P D Q -2 0 = m o difie d Percei ve d Deficits Q uesti o n naire -2 0; 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; R N A = ri b o n ucleic aci d; 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 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.  
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 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 as sess 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 nteri 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 be meas ure d w it h 
t he s u bject s u pi ne a n d after t he s u bject has bee n resti n g f or at least 1 0 mi n utes.  
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 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 treat me nt i nf usi o n.
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.  N ote:  F or s u bjects w h o per ma ne ntl y disc o nti n ue treat me nt a n d c o nti n ue i n 
t he st u d y, t he fi nal a d uca n u ma b c o nce ntrati o n sa m ple will be c ollecte d at t he s u bject’s ne xt visit.
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 p leti 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 p erf or me d.  
  
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 dy a n d ma y be sc he d ule d wit hi n 
a wi n d o w of ± 7 da ys .
 
 


P r ot oc ol 2 2 1 A D 3 0 2
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; R N A = ri b o n ucleic aci d; 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.


P r ot oc ol 2 2 1 A D 3 0 2
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.  


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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 9
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 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; 
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 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; R N A = ri b o n ucleic aci d; 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 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 .  
 


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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


P r ot oc ol 2 2 1 A D 3 0 2
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 2
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 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 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; 
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 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 - 10; 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; R N A = ri b o n ucleic aci d; 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 Visit 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 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 wee ks a fter 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 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 t he L T E peri od pre mat urel y are t o ret ur n t o t he site f or t he 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 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 .  


P r ot oc ol 2 2 1 A D 3 0 2
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
 


P r ot oc ol 2 2 1 A D 3 0 2
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; R N A = ri b o n ucleic aci d .
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 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 2
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 :  
Dosi 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 2
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 2
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 2
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 2 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 2
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 2
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 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 Scree ni n g , treatme 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 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 y s).  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 




Pr ot oc ol 2 2 1 A D 3 0 2
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 3
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) a n d 
A p o E ge n ot y pi n g m ust be perf or me d at Scree ni n g Visit 1.  A p o E ge n ot y pi n g ma y  be perf or me d 
at 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 ny 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 as well as C S F c ollecti o n ma y  be perf or me d at a n y 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.  C S F c ollecti o n at Scree ni n g 
usi n g st u d y -s pecific pr oce d ures is preferre d; h o we ver, if a C S F sa m ple has bee n o btai ne d wit hi n 
3 m o nt hs pri or t o S cree ni n g, t his sa m ple ma y be use d i n lie u of re q uiri n g a n LP at S cree ni n g.  
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 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 discre ti 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 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 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 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 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 2
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 2
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 2
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 2
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 
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, 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 2
Versi o n 5. 0
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer’s Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 0
be a vaila ble b y p h o ne t o pr o vi de i nf or mati o n t o t he I n 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 o f t he st u dy 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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Versi o n 5. 0
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C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d 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 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 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 to 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 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 doc 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 we e 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.  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 


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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 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 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 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, 
exce 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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C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 2
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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.
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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 s t 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 pecifi e 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 uch 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 2
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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 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
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 m it 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 2
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C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
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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 a ll 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 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 us e 
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 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 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 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.  


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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.
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 2
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 2
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 2
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 P I- 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 a c 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 2
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 dic ati 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 gravit y, p H, pr otei n, gl uc ose, bl o o d , ket o nes, a n d 
micr osc o pic e xa mi nati o n (if a b n or 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 2
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 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).  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 2
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 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 
m a 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 l a 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 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 2
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 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 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 u iri 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.

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 .






Pr ot oc ol 2 2 1 A D 3 0 2
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 1

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 us t 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 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 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 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 steri lizati 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 2
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 3

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 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 g ati 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 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 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 4

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 2
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 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 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 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 orica l 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 nd 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 2
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 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 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 2
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 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 ser u m c o nce ntrati o ns a n d P K para meters of a d uca n u ma b will be s u m marize d descri pti vel y.   




Pr ot oc ol 2 2 1 A D 3 0 2
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 ud 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 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 i s esti mate d t o be 2.


Pr ot oc ol 2 2 1 A D 3 0 2
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 oint fr o m eac h st u d y.  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 reasse ss 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 2
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 ns tr 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 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 the 
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 
an 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 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 2
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 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 us t be gi ve n t o t he s u bject, care gi ver a n d/ or le gally 
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) an 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 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 n l 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 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 2
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 s t 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 ulator 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 b y 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 ua lit 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 2
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 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 xe c 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 natio 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 ocol 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 di ficati 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 2
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 written 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 le a 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 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 2
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, D e 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 os s 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 
ne t 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 de r 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 he i 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 2
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 orr is 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 tr eate 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 loi d -relate d i ma gi n g a b n or malities i n a m yl oi d-
m o dif y i n g t hera pe utic trials: Rec o m me n dati o ns fr o m t he Alz hei mer’s Ass ociati o n Researc h 
R o u n dta ble W or k gr o u p. Alz hei mers De me nt. 2 0 1 1; 7( 4): 3 6 7- 3 8 5.
S pires -J o nes T L, Miel ke M L, R oz kal ne A, et al. Passi ve i m m u n ot hera p y ra pi dl y i ncreases 
str uct ural plasticit y i n a m o use m o del of Alz hei mer disease. Ne ur o bi ol Dis. 2 0 0 9; 3 3( 2): 2 1 3- 2 0.
Wa hl u n d L O, Bar k h of F, Faze kas F, 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; 32( 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 2
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 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)


C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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
P R O T O C O L N U M B E R:
2 2 1 A D 3 0 2
Bi o ge n I dec Researc h L i mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
3
P R O T O C O L TI T L E: A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, 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
E U D R A C T N O:
2 0 1 5 -0 0 0 9 6 7 -1 5
D A T E:
2 4 Marc h 2 0 1 7
Versi o n 4 . 0
Fi n al
S u perse des pre vi o us Versi o n 3. 0 date d 2 1 J ul y 2 0 1 6 .




Pr ot oc ol 2 2 1 A D 3 0 2
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 2 ................................................................................................................... 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 p erie 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.
Place 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 2
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 2
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
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 2
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 veri t 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.
Safet 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 2
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 2
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.
St 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 F i 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 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


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 2
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 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 2
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 2
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 2
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 pl e 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 2
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 2

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 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 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 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 2
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 2
     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 we e 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 2
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 2
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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
A D C S -A D L -M CI
X 1 6
X
X
A D A S - C o g 1 3
X 1 6
X
X
N PI -1 0
X 1 7
X
E Q -5 D ( S R) 
X 1 8
X
E Q -5 D (I R -S)
X 1 8
X
m P D Q -2 0
X 1 8
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 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 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 b scale ( 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 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 veri t 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 bject; 
E Q -5 D ( S R) = E Q-5 D, s u bject self-re p orte d; 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 Percei 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 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; R B A N S = Re peata ble Batter y f or t he 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 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 Visi t 1, Scree ni n g Visit 2, a n d Scree ni n g Visit 
3; W k = Wee k.




Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 
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
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 m ita 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 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 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 scale; 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; 
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 Q-5 D ( S R) = E Q -5 D, s u bjec t self-re p orte d; 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 M S E
= Mi ni -Me ntal State E xa mi nati o n; m P D Q -2 0 = m o difie d Percei ve d Deficits Q uesti o n naire -2 0; 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 c ells; P E T = p ositr o n e missi o n t o m o gra p h y; R N A = ri b o n ucleic aci d; S A E = seri o us 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 2
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 -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 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 re s 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; R N A = ri b o n ucleic aci d; 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 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 as sess 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 the 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 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 2
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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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 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 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; 
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 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; R N A = ri b o n ucleic aci d ; 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 dose ( 1: 1 rati o).


Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 p artici 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 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; 


Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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 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 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; R N A = ri b o n ucleic aci d ; 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 a re 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 p r e 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 st u d y per 
t he sc hed 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 2
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; R N A = ri b o n ucleic aci d .
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 nd 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 u e 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 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 2
Versi o n 4 . 0
P hase 3 St u d y o f A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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.
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 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.
7 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 ode


Pr ot oc ol 2 2 1 A D 3 0 2
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 n ical 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 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 b ject’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 o f 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 2
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 h a 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) wi ll 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 2
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 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 ( Aβ) 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 m yl 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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.  An 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 2
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 2 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 us i 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).  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 on 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 on 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 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 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 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 .  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 2
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-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 o ll 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 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 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 2
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 2
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 bje ct 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 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 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 onti 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 m iti 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 n istrati 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 ol le 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 2
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 as well as C S F c ollecti o n ma y be perf or m e d at a n y 
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 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 o r’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 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 weeks 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 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 2
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 oca l 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 
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 urati o n of t he st u d y, 
a n d t he use of t he sa me i nf or mant/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 2
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 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 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 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 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 me ter).

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.
P rese nce of dia betes mellit us that , 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 2
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 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 of t he 
s ki n.  

S u bje cts 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 
Scr ee 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 y ste mic c ortic oster oi ds or ot her 
i m m u n os u p pressa nts.
1 4. Rece nt hist or y  ( wit hi n 1 year of Scree ni n g) of alc o h ol or s u bsta nce a b use as deter mi ne d 
b y  t he I n vesti gat or, a p ositi ve uri ne dr u g (d ue t o n o n -prescri pti o n dr u g) or alc o h ol test at
Scree ni n g , or use of ca n na bi n oi ds ( prescri pti o n or recreati o nal).
1 5. Cli nicall y  si g nifica nt s yste mic ill ness or seri o us i nfecti o n (e. g., p ne u m o nia, se ptice mia) 
wit hi n 3 0 da y s pri or t o or d uri n g Scree ni n g.
1 6. 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 o f 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.
Me dic ati o ns


Pr ot oc ol 2 2 1 A D 3 0 2
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 the 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 n e 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 
receive 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.  
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


Pr ot oc ol 2 2 1 A D 3 0 2
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 nsive 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 , 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 nfide 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 2
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 2
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 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) 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 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 .  No 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 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 2
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 ntat i 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, o r a ny 
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 2
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 s i 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 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 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 2
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 n e 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 ar e 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 2
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 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 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 2
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 st a 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 n e, 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 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.  Me dicati o ns
use d t o tre at 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 dicati o n .
1 1. 5. 2.
C o nc o mit a nt Pr oce d ures
A c o nc o mita nt pr oce d ure is a n y  t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera py) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, r o uti ne c ol o n osc o p y, bacterial c ult ures) 
perf or me d bet wee n t he ti me t he s u bject is e nr olle d i n t he st u d y a n d u ntil t he s u bject’s fi nal cli nic 
visit (i ncl u di n g 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 2
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 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 2
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 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 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 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 nci es.
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 2
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 - MCI

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 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 2
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 ur e 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 wo 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 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 2
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 2
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 oncer n s h o ul d be f or t he safet y 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 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 de rati 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 2
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 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 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 2
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 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 
In 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 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 
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 2
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- ho 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.

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 2
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 u e 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 ves ti 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 2
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 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 2
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 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 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 h e 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 ntirel 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 2
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 yp 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 r e 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 or der t o 
c o ntr ol f or a T ype I err or f o r 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 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 statistic all 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 2
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 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.
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 2
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 det er 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 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 xim 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. 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 2
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 ment 
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 m a 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 ma 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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)


C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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
P R O T O C O L N U M B E R:
2 2 1 A D 3 0 2
Bi o ge n I dec Researc h L i mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
3
P R O T O C O L TI T L E: A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, 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
E U D R A C T N O:
2 0 1 5 -0 0 0 9 6 7 -1 5
D A T E:
2 1 J ul y 2 0 1 6
Versi o n 3. 0
Fi n al
S u perse des pre vi o us (Ori gi nal ) Versi o n 1 . 0 date d 0 9 A pril 2 0 1 5 a n d Versi o n 2. 0 date d 
2 6 Ma y
2 0 1 6.
/ N C T 0 2 4 8 4 5 4 7




Pr ot oc ol 2 2 1 A D 3 0 2
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 2 ................................................................................................................... 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 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 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 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 2
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 2
- C ha n ge fr o m ba seli 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 2
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 2
     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 2
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 2
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 2
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 2
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 2
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 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
C D R 
X
X
X
M M S E
X
X
X
A D C S -A D L -M CI
X 1 6
X
X
A D A S -C o g 1 3
X 1 6
X
X
N PI -1 0
X 1 7
X
E Q -5 D ( S R) 
X 1 8
X
E Q -5 D (I R -S)
X 1 8
X
m P D Q -2 0
X 1 8
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 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 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 b scale ( 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 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 N A = d e o x y ri 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 bject; 




Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 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 
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
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 m ita 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 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 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 scale; 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; 
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 Q-5 D ( S R) = E Q -5 D, s u bject self -re p orte d; 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 M S E
= Mi ni -Me ntal State E xa mi nati o n; m P D Q -2 0 = m o difie d Percei ve d Deficits Q uesti o n naire -2 0; 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; R N A = ri b o n ucleic aci d; S A E = seri o us 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 2
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; R N A = ri b o n ucleic aci d; 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 2
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 c a 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 2
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 2
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 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 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; 


Pr ot oc ol 2 2 1 A D 3 0 2
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 missi o n t o m o gra p h y; R N A = ri b o n ucleic aci d ; 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 uir e d f or wo 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 yloi d P E T c o h ort.
 


Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 2
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 2
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
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 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; 
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 E T = p ositr o n e missi o n t o m o gra p h y; R N A = ri b o n ucleic aci d ; 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 o r 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 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.
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 c o h ort.
 


Pr ot oc ol 2 2 1 A D 3 0 2
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: 
B r 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 2
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 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 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 2
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 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 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 ma i 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 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 2
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 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 2
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 lated ta u pr otei n s.  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 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 ut e 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 oth 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 co 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 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 
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 ng [ 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 ved 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 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, P erls’ 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 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 uc a 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 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 2
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 der ate 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 no ge nicit y 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 b ser 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 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 6 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 .  
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 nse t 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 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 (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 ( 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 (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 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 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 2
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
wit h statistical si g 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 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 u ri 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 usi o n


Pr ot oc ol 2 2 1 A D 3 0 2
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 h e 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 pla ce 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 2
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 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 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 n t 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 
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 2
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 2 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 eval 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 o f 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 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 r ecei ve d 


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 ubjects 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 2
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 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
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.  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 wil l be all o we d t o res u me 
treat me nt.  


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 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 ntrally 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 ment.    

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 uld 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 2
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 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 a nd 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 2
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 2
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 co 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 2
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 med 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 MO 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 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 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 to 
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 
clinic 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 2
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 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 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.
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 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 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 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 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 2
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 2
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 bjec t 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. 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 
inf 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 ontr 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 y s).  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 2
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 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 as well as C S F c ollecti o n 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 co 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 m a 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 AD 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 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  
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 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 
treatme 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 minate 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 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 2
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 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 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 nsi e 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:  

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 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 u tin 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 2
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 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, but 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 mu n os u p pressa nts.
1 4. Rece nt hist or y  ( wit hi n 1 year of Scree ni n g) of alc o h ol or s u bsta nce a b use as deter mi ne d 
b y  t he I n vesti gat or, a p ositi ve uri ne dr u g (d ue t o n o n -prescri pti o n dr u g) or alc o h ol test at
Scree ni n g , or use of ca n na bi n oi ds (prescri pti o n or recreati o nal).
1 5. Cli nicall y  si g nifica nt s yste mic ill ness or seri o us i nfecti o n (e. g., p ne u m o nia, se ptice mia) 
wit hi n 3 0 da y s pri or t o or d uri n g Scree ni n g.
1 6. 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 tes t 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  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 hyl actic 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 2
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 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 ad 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 2
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 nt l 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 u t 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.
Ha s 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 2
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 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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 nistrati o n of all Scree ni n g assess me nts.  W he n a s u bject si g ns t he
f ull i nf or me d c o nse nt f or m (IC F) , t hat s u bject is c o nsi dere d t o be e nr olle d i n t he st u d y .  
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 m e 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 ven 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 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 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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 with 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 Sectio 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 2
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 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 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 2
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 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 .
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 2
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 trea t 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 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 2
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 we e 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 s yste 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, pla s 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 
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 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 2
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 2
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 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 ne e), 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 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 pplie 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 2
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 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 u re me nt of am 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 ap 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 ocols 
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 2
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 2
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 2
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 .
Pre -treat me nt, no 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 2
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 on 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 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 pres c 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 2
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 u lat 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 v e 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 2
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 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 Of ficial 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 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 bl is 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 2
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 om 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 g ar 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 n c 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 2
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 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 r es 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 with 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 req 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 2
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 2
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 ntif ic 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 2
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 peat e 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 naly sis 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 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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)


C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis 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
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
P R O T O C O L N U M B E R:
2 2 1 A D 3 0 2
Bi o ge n I dec Researc h L i mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
3
P R O T O C O L TI T L E: A P hase 3 M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d, 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
E U D R A C T N O:
2 0 1 5 -0 0 0 9 6 7 -1 5
D A T E:
2 6 Ma y 2 0 1 6
Versi o n 2 . 0
Fi n al
S u perse des pre vi o us (Ori gi nal ) Versi o n 1 . 0 date d 0 9 A pril 2 0 1 5.




Pr ot oc ol 2 2 1 A D 3 0 2
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 2 ................................................................................................................... 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 2
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 ............................................................................................................... 6 0
8.
S E L E C TI O N O F S U BJ E C T S.................................................................................... 6 1
8. 1.
I ncl usi o n Criteria........................................................................................................ 6 1
8. 2.
E xcl usi o n Criteria ....................................................................................................... 6 2
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 5
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 6
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 7
9. 1.
Scree ni n g a n d E nr oll me nt ...........................................................................................6 7
9. 2.
Ra n d o mizati o n a n d Re gistrati o n of S u bjects ..............................................................6 7
9. 3.
Bli n di n g Pr oce d ures .................................................................................................... 6 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 ........................................... 6 9
1 0. 1.
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 6 9
1 0. 2.
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 7 0
1 1.
S T U D Y T R E A T M E N T U S E ..................................................................................... 7 1
1 1. 1.
Re gi me n ...................................................................................................................... 7 1


Pr ot oc ol 2 2 1 A D 3 0 2
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 1
1 1. 1. 2.
Place b o ........................................................................................................................ 7 1
1 1. 2.
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 7 1
1 1. 3.
Preca uti o ns .................................................................................................................. 7 1
1 1. 4.
C o m plia nce ................................................................................................................. 7 1
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 1
1 1. 5. 1.
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 7 1
1 1. 5. 1. 1.
All o we d C o nc o mita nt T hera p y................................ ................................................... 7 2
1 1. 5. 1. 2.
Disall o we d C o nc o mita nt T hera p y .............................................................................. 7 2
1 1. 5. 2.
C o nc o mita nt Pr oce d ures ............................................................................................. 7 2
1 1. 6.
C o nti n uati o n of Treat me nt .......................................................................................... 7 3
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 4
1 2. 1.
A d uca n u ma b ............................................................................................................... 7 4
1 2. 1. 1.
A d uca n u ma b Pre parati o n............................................................................................ 7 4
1 2. 1. 2.
A d uca n u ma b St ora ge .................................................................................................. 7 5
1 2. 1. 3.
A d uca n u ma b Ha n dli n g a n d Dis p osal ......................................................................... 7 5
1 2. 1. 4.
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 7 5
1 2. 2.
Place b o ........................................................................................................................ 7 5
1 2. 3.
A d diti o nal Pr ot oc ol -Desi g nate d Pr o d ucts .................................................................. 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 ......................................................................................................... 7 6
1 3. 1.
Cli nical Efficac y  Assess me nts.................................................................................... 7 6
1 3. 2.
P har mac o ki netic Assess me nts .................................................................................... 7 6
1 3. 3.
P har mac o d y na mic Assess m e nts ................................................................................. 7 6
1 3. 4.
A d diti o nal Assess me nts.............................................................................................. 7 7
7 7
1 3. 4. 2.
A p o E Ge n ot y pi n g .......................................................................................................7 7
7 8
1 3. 4. 4.
Healt h O utc o mes Assess me nts ................................................................................... 7 8
1 4.
S A F E T Y A S S E S S M E N T S ................................ ........................................................7 9
1 4. 1.
Cli nical Safet y  Assess me nts....................................................................................... 7 9
1 4. 2.
La b orat or y  Safety Assess me nts ..................................................................................7 9


Pr ot oc ol 2 2 1 A D 3 0 2
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 .................................................................................... 8 0
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 1
1 5. 1.
Defi ni ti o ns .................................................................................................................. 8 1
1 5. 1. 1.
A d verse E ve nt ............................................................................................................. 8 1
1 5. 1. 2.
Seri o us A d verse E ve nt ................................................................................................ 8 1
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 2
1 5. 2.
Safet y  Classificati o ns.................................................................................................. 8 2
1 5. 2. 1.
I n vesti gat or Assess me nt of E ve nts ............................................................................. 8 2
1 5. 2. 2.
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................ 8 3
1 5. 2. 3.
Se verit y  of E ve nts....................................................................................................... 8 3
1 5. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................8 3
1 5. 3.
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 8 3
1 5. 3. 1.
A d verse E ve nts ........................................................................................................... 8 3
1 5. 3. 2.
A d verse E ve nts of S pecial I nterest ............................................................................. 8 4
1 5. 3. 3.
Seri o us A d verse E ve nts ..............................................................................................8 4
1 5. 3. 4.
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 8 4
1 5. 3. 4. 1.
Deat hs ......................................................................................................................... 8 5
1 5. 3. 5.
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 8 5
1 5. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................8 5
1 5. 4. 1.
Pre g na nc y ...................................................................................................................8 5
1 5. 4. 2.
O ver d ose ..................................................................................................................... 8 5
1 5. 4. 3.
Me dical E mer ge nc y .................................................................................................... 8 6
1 5. 4. 3. 1.
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 8 6
1 5. 5.
C o ntrace pti o n Re q uire me nts ...................................................................................... 8 6
1 5. 6.
Safet y  Res p o nsi bilities................................................................................................ 8 7
1 5. 6. 1.
T he I n vesti gat or .......................................................................................................... 8 7
1 5. 6. 2.
Bi o ge n ......................................................................................................................... 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 ...........8 9
1 6. 1.
De m o gra p h y a n d Baseli ne Disease C haracteristics .................................................... 8 9
1 6. 2.
Efficac y  a n d P har mac o d yna mics ................................................................................ 8 9
1 6. 2. 1.
A nal y sis P o p ulati o n .................................................................................................... 8 9


Pr ot oc ol 2 2 1 A D 3 0 2
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 9
1 6. 2. 2. 1.
Ge neral C o nsi derati o ns ...............................................................................................8 9
1 6. 2. 2. 2.
D ose Re gi me ns t o be E val uate d ................................................................................. 8 9
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 0
1 6. 2. 2. 4.
A nal y sis of t he Pri mar y E n d p oi nt............................................................................... 9 1
1 6. 2. 2. 5.
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 9 1
1 6. 2. 2. 6.
Tertiar y  E n d p oi nts A nalysis ....................................................................................... 9 1
1 6. 3.
P har mac o ki netics ........................................................................................................ 9 2
1 6. 3. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 2
1 6. 3. 2.
Met h o d of A nal ys is..................................................................................................... 9 2
1 6. 4.
Safet y .......................................................................................................................... 9 2
1 6. 4. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 2
1 6. 4. 2.
Met h o ds of A nal ys is................................................................................................... 9 2
1 6. 4. 2. 1.
A d verse E ve nts ........................................................................................................... 9 2
1 6. 4. 2. 2.
Cli nical L a b orat or y Res ults........................................................................................ 9 3
1 6. 4. 2. 3.
Vital Si g ns .................................................................................................................. 9 3
1 6. 4. 2. 4.
E C G ............................................................................................................................ 9 3
1 6. 4. 2. 5.
C ol u m bia S uici de Se verit y  Rati n g Scale .................................................................... 9 3
1 6. 5.
I m m u n o ge nicity Data ................................................................................................. 9 3
1 6. 5. 1.
A nal y sis P o p ulati o n .................................................................................................... 9 3
1 6. 5. 2.
Met h o ds of A nal ys is................................................................................................... 9 3
1 6. 6.
I nteri m A nalys es ......................................................................................................... 9 3
1 6. 6. 1.
I nteri m F utilit y A nal ysis ............................................................................................. 9 3
1 6. 6. 2.
I nteri m S u peri orit y A nal ysis.......................................................................................9 4
1 6. 7. 
Sa m ple Size C o nsi derati o ns ................................ .......................................................9 4
1 7.
E T HI C A L  R E Q UI R E M E N T S ...................................................................................9 5
1 7. 1.
Declarati o n of Helsi n ki ...............................................................................................9 5
1 7. 2.
Et hics C o m mittee/I nstit uti o nal Re vie w B oar d ........................................................... 9 5
1 7. 3.
S u bject I nf or mati o n a n d C o nse nt ...............................................................................9 5
1 7. 4.
S u bject Data Pr otecti o n ..............................................................................................9 6
1 7. 5.
C o m pe nsati o n f or I nj ur y .............................................................................................9 6


Pr ot oc ol 2 2 1 A D 3 0 2
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 6
1 7. 7.
Re gistrati o n of St u d y a n d Di scl os ure of St u d y Res ults.............................................. 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 ....................................................................... 9 7
1 8. 1.
St u d y  Site I nitiati o n.................................................................................................... 9 7
1 8. 2.
Q ualit y  Ass ura nce....................................................................................................... 9 7
1 8. 3.
M o nit ori n g of t he St u d y ..............................................................................................9 7
1 8. 4.
St u d y  F u n di n g............................................................................................................. 9 7
1 8. 5.
P u blicati o ns ................................................................................................................. 9 7
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 8
1 9. 1.
E xter nal C o ntract Or ga nizati o ns ................................................................................. 9 8
1 9. 1. 1.
C o ntract Researc h Or ga nizati o n ................................................................................. 9 8
1 9. 1. 2.
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 9 8
1 9. 1. 3.
Electr o nic Data Ca pt ure ..............................................................................................9 8
1 9. 1. 4.
Ce ntral La b orat ories f or La b orat or y  Assess me nts ..................................................... 9 8
1 9. 1. 5.
Ce ntral Facilit y  f or Ot her Assess me nts...................................................................... 9 8
1 9. 1. 6.
Ne ur o c o g niti ve Assess me nts ...................................................................................... 9 9
1 9. 2.
St u d y  C o m mittees....................................................................................................... 9 9
1 9. 2. 1.
A d vis or y  C o m mittee................................................................................................... 9 9
1 9. 2. 2.
I n de pe n de nt Data M o nit ori n g C o m mittee .................................................................. 9 9
1 9. 3.
C ha n ges t o Fi nal St u d y  Pr ot oc ol ................................................................................ 9 9
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 0
1 9. 5.
Rete nti o n of St u d y  Data............................................................................................ 1 0 0
1 9. 6.
St u d y  Re p ort Si g nat or y.............................................................................................1 0 0
2 0.
R E F E R E N C E S ......................................................................................................... 1 0 1
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 4
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 2
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 
D uri n g Titrati o n .......................................................................................................... 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........... 9 0
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 2
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 2
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 2
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 2
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 2
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 o se 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 pro 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 uu 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 2
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 2

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 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 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 2
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 2
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 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 2
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 2
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 2
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 2
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 2
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 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
C D R 
X
X
X
M M S E
X
X
X
A D C S -A D L -M CI
X 1 6
X
X
A D A S -C o g 1 3
X 1 6
X
X
N PI -1 0
X 1 7
X
E Q -5 D ( S R) 
X 1 8
X
E Q -5 D (I R -S)
X 1 8
X
m P D Q -2 0
X 1 8
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 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 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 b scale ( 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 ot ei n E; 
C D R = Cli nical De me ntia Rati n g scale; 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 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 bject; E Q -5 D ( S R) = E Q -5 D, s u bject self -re p orte d; H b A1c = gl yc os ylate d he m o gl o bi n; HI V = h u ma n 




Pr ot oc ol 2 2 1 A D 3 0 2
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 2
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 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 
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
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 m ita 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 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 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 scale; 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; E C G = electr oc ar 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 Q -5 D ( S R) = E Q -5 D, s u bject self -
re p orte d; 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 M S E = Mi ni-Me ntal State E xa mi nati o n; m P D Q -2 0 = m o difie d Percei ve d 
Deficits Q uesti o n naire -2 0; 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; R N A = ri b o n ucleic aci d; S A E = seri o us 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 2
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; R N A = ri b o n ucleic aci d; 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 2
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 2
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 2
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
A m yl oi d P E T 5
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2 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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 2
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 me nt after A RI A, a n M RI a n d M O C A 
will be p erf 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 2
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 d isc 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 2
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 as well as C S F c ollecti o n 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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
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 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 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 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 onse 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 MC, 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.  


Pr ot oc ol 2 2 1 A D 3 0 2
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
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 2
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.
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  to 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 2
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. 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 2
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
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 2
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
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 2
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
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 2
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 6
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.


Pr ot oc ol 2 2 1 A D 3 0 2
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 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 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 


Pr ot oc ol 2 2 1 A D 3 0 2
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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.
6 8
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 .  


Pr ot oc ol 2 2 1 A D 3 0 2
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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.
6 9
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 


Pr ot oc ol 2 2 1 A D 3 0 2
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 0
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.  


Pr ot oc ol 2 2 1 A D 3 0 2
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
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.


Pr ot oc ol 2 2 1 A D 3 0 2
Versi o n 2. 0
P hase 3 St u d y of  A d uca n u ma b i n Earl y Alz hei mer's Disease  
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 2
1 1. 5. 1. 1.
All o we d C o nc o mit a nt T her a p y

Me dicati o ns f or c hr o nic c o n diti o ns are all o we d at a sta ble d ose d uri n g t he st u d y  as 
l o n g as t he s u bject has bee n sta ble o n t he me dicati o n(s) f or at least 4 wee ks pri or t o 
Scree ni n g Visit 1 .  

S y m pt o matic t hera pies f or A D, i ncl u di n g b ut n ot li mite d t o d o ne pezil, ri vasti g mi ne, 
gala nta mi ne, tacri ne, a n d me ma nti ne, are all o we d pr o vi de d t hat s u bjects are recei vi n g 
a sta ble d ose f or at least 8 wee ks pri or t o Scree ni n g Visit 1 a n d t hat t he y sta y on a 
sta ble d ose w hile i n t he st u d y.

Vacci nati o ns wit h li ve or atte n uate d vacci nes are all o we d d uri n g t he st u d y.  
A d mi nistrati o n of a n y  vacci nati o n/ b o oster s h o ul d n ot be gi ve n < 1 0 da y s pri or t o a n y 
d osi n g visit a n d f or 1 0 da y s after a d osi n g visit .
1 1. 5. 1. 2.
Dis all o we d C o nc o mit a nt T her a p y

Me dicati o ns wit h platelet a nti -a g gre ga nt or a nti-c oa g ula nt pr o perties, e xce pt t he use 
of as piri n at a d ose of ≤3 2 5 m g per da y .

N o n -prescri pti o n narc otic me dicati o n .

I m m u n os u p pressi ve dr u gs (i ncl u di n g sys te mic c ortic oster oi ds).  L o cal c ortic oster oi ds 
(i ncl u di n g i n hale d a n d t o pical c ortic oster oi ds) are all o we d; certai n s yste mic 
c ortic oster oi ds m a y  be per mitte d at t he S p o ns or ’s dis creti o n.

Pare nteral i m m u n o gl o b uli n, bl o o d pr o d ucts, plas ma deri vati ves, plas ma e xc ha n ge, 
a n d plas ma p heresis.

A n y  i n vesti gati o nal dr u g.
S u bjects s h o ul d be i nstr ucte d t o c o nti n ue t he me dicati o ns t hat t he y  were recei vi n g at e nr oll me nt 
(see all o we d c o nc o mita nt t hera py a b o ve ) a n d a v oi d starti n g a ny ne w me dicati o ns or her bal 
pre parati o ns d uri n g t he st u d y peri o d, as it ma y  c o nf o u n d t he res ults of t he st u d y.  H o we ver, 
me dicall y  i n dicate d me dicati o n or treat me nt s h o ul d n ot be wit h hel d.  S u bjects s h o ul d i nf or m t he 
I n vesti gat or of a ny c ha n ges i n me dicati o n .  T he c ha n ge s h o ul d be re vie we d b y  t he I n vesti gat or 
an d t he st u d y  me dical m o nit or t o deter mi ne w het her t he s u bject’s st u d y treat me nt s h o ul d be 
s us pe n de d, wit h t he e xce pti o n of me dicati o ns use d t o treat A Es, w hic h w o ul d n ot res ult i n 
a ut o matic wit h dra wal .  T he S p o ns or ma y  be c o ns ulte d if re q uire d.  
S u bjects s h o ul d ha ve a n u nsc he d ule d v isit f or a c ha n ge i n A D me dicati o n, a n d all cli nical 
assess me nts f or t he pri mar y  a n d sec o n dar y o bjecti ves s h o ul d be perf or me d pri or t o t he c ha n ge i n 
me dicati o n .
1 1. 5. 2.
C o nc o mit a nt Pr oce d ures
A c o nc o mita nt pr oce d ure is a n y  t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera py) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, r o uti ne c ol o n osc o p y, bacterial c ult ures) 
perf or me d bet wee n t he ti me t he s u bject is e nr olle d i n t he st u d y a n d t he F U or E O T V isit, u nless 
t he s u bjects is bei n g f oll o we d f or st u dy -relate d t o xicit y.  


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


Pr ot oc ol 2 2 1 A D 3 0 2
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. 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 2
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. 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 2
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 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 2
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
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 2
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
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 2
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 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 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 2
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. 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 2
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
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 2
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
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 2
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
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 2
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
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 2
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 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
(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)


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 
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  
P R O T O C O L N U M B E R:  
2 2 1 A D 3 0 2  
Bi o ge n  I dec Researc h L i mited  
I n n o vati o n H o use 
7 0 N or de n R oa d  
Mai de n hea d Ber ks hire  
S L 6  4 A Y  
U nite d Ki n g d o m  
P H A S E O F D E V E L O P M E N T:  
3  
P R O T O C O L TI T L E:   A P hase 3 M ultice nter, 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 v al 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   
E U D R A C T N O:  
2 0 1 5 ‐0 0 0 9 6 7 ‐1 5
D A T E:  
0 9  A pril  2 0 1 5  
Versi o n 1. 0  
Fi n al   
/ N C T 0 2 4 8 4 5 4 7




Pr ot oc ol 2 2 1 A D 3 0 2 
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 2 ................................................................................................................... 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.
I N 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 2 
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.
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 ........................................... 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 2 
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 2 
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 2 
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 HI 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 2 
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.
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L ......................................... 9 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 2 
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 2 
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 2 
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 2 
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 2 
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 2  
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 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 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; R N A = ri b o n ucleic aci d; 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 2 
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 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 2 
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 2 
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 2 
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 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; 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. 
6 T o be perf or me d 1 4 ± 7 da ys after t he i n dicate d d osi n g visit (i.e., W ee ks 1 0 6, 1 3 4 a n d 1 6 2) a n d at W ee k 1 8 2. 


Pr ot oc ol 2 2 1 A D 3 0 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 bje ctive 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 2 
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 2 
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 2 
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 ulti 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 2 
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 2 
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 2 
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 2 
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 .   
 T o e val uate 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 gic al, 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 m a nt/care 
pa rt ner. 


Pr ot oc ol 2 2 1 A D 3 0 2 
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 2 
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 2 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 ng 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 olle d pe ri 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 2 
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 assi g n me nt i n the 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 of A R I 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 2 
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 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 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 2 
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 2 
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 2 
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 
After  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 2 
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 safety 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 2 
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 as well as C S F 
collecti o n ma y 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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 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 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 2 
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 2 
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 2 
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 
P lace b o ( 0. 9 % s o di u m c hl ori de) will be s u p plie d b y t he st u d y site. 
1 1. 2.  
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule 
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 2 
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 d y. 
 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 matic wit h drawal.  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 2 
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 2 
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 2 
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 k e d stora 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 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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 r e 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 2 
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 2 
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 2 
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 2 
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 e n 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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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 2 
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, C S F sa m ples, a n d D N A f or s pecialize d A p o E ε 4 ge n ot y pi n g, P K, 
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 ti meframe 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 pre vail 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 2 
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 sites .  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 2 
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 stu 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 2 
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 Alzhei 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 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 2 
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 mar- 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 hei 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, Pr a 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 cere 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 m er’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 2 
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 2 
Versi o n 1 
P hase 3 St u d y of A d uca n u ma b i n Earl y Alz hei mer's Diseas e   
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d her ei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc. 
9 0  
 
2 1.  
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L 
I h a ve rea d t he f ore g oi n g pr ot oc ol, “ A P hase 3 M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
P lace b o- C o ntr olle d, Parallel- Gr o u p St u d y t o E val uate t he Effi cac y a n d Safet y of A d uca n u ma b 
( BII B 0 3 7) i n S u bjects wit h Earl y Alz hei mer's Disease”, a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica bl e I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y of t h eir res p o nsi bilities a n d o bli gati o ns. 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or’s Si g n at ure  
  
  
  
Date 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I n v esti gat or’s N a me ( Pri nt) 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
St u d y Site ( Pri nt) 
 
 
 

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St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d
Fi n al  V 1. 0  
C O N FI D E N TI A L  
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         E N G A G E 
2 2 1 A D 3 0 2 / N C T 0 2 4 8 4 5 4 7
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  




 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 
 
T a ble of C o nte nts  
LI S T O F A B B R E VI A TI O N S  .............................................................................................................................. 5  
1  
D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S  ........................................................................ 7  
1. 1  
P RI M A R Y O BJ E C TI V E A N D E N D P OI N T  ........................................................................................................ 7  
1. 2  
S E C O N D A R Y O BJ E C TI V E S A N D E N D P OI N T S  ............................................................................................... 7  
1. 3  
T E R TI A R Y O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................................... 7  
1. 3. 1  
Terti ary O bjectives  ......................................................................................................................... 7  
1. 3. 2  
Terti ary E n d p oi nts  .......................................................................................................................... 8  
1. 4  
A D DI TI O N A L E X P L O R A T O R Y O BJ E C TI V E S A N D E N D P OI N T S  ...................................................................... 9  
1. 4. 1  
A d diti o n al Ex pl or at ory O bjectives  ................................................................................................. 9  
1. 4. 2  
A d diti o n al Ex pl or at ory E n d p oi nts  .................................................................................................. 9  
2  
S T U D Y D E SI G N  ....................................................................................................................................... 1 0  
2. 1  
S T U D Y O V E R VI E W  .................................................................................................................................. 1 0  
2. 2  
S T U D Y S C H E M A TI C  ................................................................................................................................. 1 2  
2. 3  
S C H E D U L E O F E V E N T S  ............................................................................................................................ 1 3  
3  
S A M P L E SI Z E J U S TI FI C A TI O N  .......................................................................................................... 1 3  
4  
S T A TI S TI C A L A N A L Y SI S  M E T H O D S  ............................................................................................... 1 3  
4. 1  
G E N E R A L C O N SI D E R A TI O N S  ................................................................................................................... 1 3  
4. 1. 1  
A n alysis P o p ul ati o n  ...................................................................................................................... 1 4  
4. 2  
B A C K G R O U N D C H A R A C T E RI S TI C S  .......................................................................................................... 1 5  
4. 2. 1  
Acc o u nti n g of S u bject  ................................................................................................................... 1 6  
4. 2. 2  
De m o gr a p hics a n d B aseli ne C h ar acteristics  ................................................................................ 1 6  
4. 2. 3  
C o nc o mit a nt Me dic ati o ns a n d N o n -Dr u g T her a pies  .................................................................... 1 7  
4. 2. 4  
Pr ot oc ol Devi ati o ns  ...................................................................................................................... 1 8  
4. 2. 5  
St u dy Dr u g Ex p os ure a n d St u dy Dr u g C o m pli a nce  ...................................................................... 1 8  
4. 3  
E F FI C A C Y A N A L Y SI S  ............................................................................................................................... 1 9  
4. 3. 1  
Ge ner al C o nsi der ati o ns  ................................................................................................................ 1 9  
4. 3. 2  
Pri m ary Effic acy E n d p oi nt  ........................................................................................................... 2 1  
 
Pri mar y a nal ysis  ....................................................................................................................................... 2 1  
 
Se nsiti vit y a nal ysis  ................................................................................................................................... 2 2  
4. 3. 2. 2. 1  
Patter n mi xt ure m o del  .................................................................................................................... 2 2  
4. 3. 2. 2. 2  
C o p y i ncre me nt fr o m refere nce met h o d  ........................................................................................ 2 3  
4. 3. 2. 2. 3  
I m p utati o n b y nat ural disease pr o gressi o n ..................................................................................... 2 3  
4. 3. 2. 2. 4  
Ti p pi n g p oi nt a nal ysis .................................................................................................................... 2 3  
 
S u p ple me ntar y a nal ysis  ............................................................................................................................ 2 4  
4. 3. 2. 3. 1  
Ce ns ori n g after i nterc urre nt e ve nts  ................................................................................................ 2 4  
4. 3. 2. 3. 2  
Per -pr ot oc ol a nal ysis  ..................................................................................................................... 2 4  
4. 3. 2. 3. 3  
Res p o n der a nal ysis  ........................................................................................................................ 2 4  
4. 3. 2. 3. 4  
Sl o pe a nal ysis  ................................................................................................................................ 2 5  
4. 3. 2. 3. 5  
Di ver ge nce effect a nal ysis  ............................................................................................................. 2 5  
 
C D R s u bsc ores a n d C D R gl o bal sc ore  ..................................................................................................... 2 5  
4. 3. 3  
Sec o n d ary Effic acy E n d p oi nts  ...................................................................................................... 2 6  
 
Pri mar y a nal ysis of M M S E  ...................................................................................................................... 2 6  
 
Pri mar y a nal ysis of A D A S -C o g 1 3  .......................................................................................................... 2 6  
 
Pri mar y a nal ysis of A D C S -A D L -M CI  ..................................................................................................... 2 6  
 
Se nsiti vit y/ S u p ple me ntar y a nal ysis  .......................................................................................................... 2 7  
4. 3. 4  
Terti ary E n d p oi nts f or Effic acy a n d Q u ality of Life  ..................................................................... 2 7  
4. 3. 5  
S u b gr o u p A n alysis  ........................................................................................................................ 2 7  
4. 4  
A M Y L OI D P E T  A N A L Y SI S  ....................................................................................................................... 2 8  
4. 4. 1  
A myl oi d P E T s u bst u dy  .................................................................................................................. 2 8  
4. 4. 2  
A myl oi d P E T S U V R re gi o ns -of -i nterest a n d refere nce re gi o ns .................................................... 2 8  
4. 4. 3  
A myl oi d P E T a n alysis p o p ul ati o n  ................................................................................................. 2 9  
4. 4. 4  
By visit s u m m a ry a n d M M R M m o del ............................................................................................ 2 9  
4. 4. 5  
C orrel ati o n bet wee n a myl oi d P E T a n d C D R s u m of b oxes  .......................................................... 3 0  
4. 5  
S A F E T Y A N A L Y SI S  .................................................................................................................................. 3 0  


 
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4. 5. 1  
Ge ner al C o nsi der ati o ns  ................................................................................................................ 3 0  
4. 5. 2  
Cli nic al A dverse Eve nts  ................................................................................................................ 3 2  
 
S u m mar y a n d i nci de nce a nal ysis  ............................................................................................................. 3 3  
 
I nci de nce rate a nal ysis  ............................................................................................................................. 3 4  
 
S u b gr o u p a nal ysis f or pr ot oc ol versi o n 4  ................................................................................................. 3 5  
4. 5. 3  
A RI A –  A E of s peci al i nterest ........................................................................................................ 3 5  
 
Bac k gr o u n d  .............................................................................................................................................. 3 5  
 
I nci de nce a n d s u m mar y of A RI A  ............................................................................................................. 3 7  
 
S u m mar y of rec urre nt A RI A -E  ................................................................................................................ 3 8  
 
E x p os ure a dj uste d a nal ysis  ....................................................................................................................... 3 9  
 
Ti me t o e ve nt a nal ysis  .............................................................................................................................. 3 9  
 
S u b gr o u p a nal ysis f or pr ot oc ol versi o n 4  ................................................................................................. 3 9  
4. 5. 4  
Cli nic al L a b or at ory D at a  ............................................................................................................. 3 9  
 
Q ua ntitati ve a nal yses  ............................................................................................................................... 4 0  
 
Q ualitati ve a nal yses  ................................................................................................................................. 4 1  
4. 5. 5  
C -S S R S D at a  ................................................................................................................................. 4 3  
4. 5. 6  
E C G D at a  ..................................................................................................................................... 4 3  
4. 5. 7  
Vit al Si g n D at a  ............................................................................................................................. 4 3  
4. 6  
P H A R M A C O KI N E TI C S A N A L Y SI S  .............................................................................................................. 4 4  
4. 6. 1  
Ser u m C o nce ntr ati o n Pr ofile  ........................................................................................................ 4 5  
4. 6. 2  
Ser u m P K P ar a meters  .................................................................................................................. 4 5  
4. 6. 3  
S u b gr o u p a n alysis f or pr ot oc ol versi o n 4  ..................................................................................... 4 5  
4. 7  
IM M U N O G E NI CI T Y A N A L Y SI S  .................................................................................................................. 4 6  
4. 7. 1  
B ack gr o u n d  ................................................................................................................................... 4 6  
4. 7. 2  
I m m u n oge nicity a n alysis  ............................................................................................................... 4 6  
4. 8  
A D DI TI O N A L E X P L O R A T O R Y E N D P OI N T S  ................................................................................................ 4 7  
 
 4 7  
 
 4 7  
5  
I N T E RI M A N A L Y SI S.............................................................................................................................. 4 7  
6  
A P P E N DI X  ................................................................................................................................................ 4 9  
6. 1  
A N A L Y SI S D I S P L A Y ................................................................................................................................. 4 9  
6. 2  
P R O T O C O L D E VI A TI O N C L A S SI FI C A TI O N  ................................................................................................. 4 9  
6. 3  
IM P L E M E N T A TI O N O F T H E  C O P Y IN C R E M E N T F R O M R E F E R E N C E A N D P A T T E R N M I X T U R E M O D E L  ......... 5 3  
6. 3. 1  
C o py I ncre me nt fr o m Refere nce  ................................................................................................... 5 3  
6. 3. 2  
P atter n Mixt ure M o del  .................................................................................................................. 5 3  
7  
R E F E R E N C E S  .......................................................................................................................................... 5 5  
 


 
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List of A b bre vi ati o ns  
A β  
β -a m yl oi d 
A D  
Alz hei mer’s disease  
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 D NI  
Alz hei mer’s Disease Ne ur oi ma gi n g I nitiati ve  
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A N C O V A  
a nal ysis of c o varia nce  
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 p o E ε 4 +  
a p oli p o pr otei n E 4 carrier  
A p o E ε 4 - 
a p oli p o pr otei n E 4 n o n -carrier 
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  
B L  
baseli ne  
B L Q  
bel o w t he li mit of q ua ntificati o n  
B MI  
b o d y mass i n de x  
b p m  
beats per mi n ute  
B U N  
bl o o d urea nitr o ge n  
 
 
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  
CI R  
c o p y i ncre me nt fr o m refere nce  
C ma x  
o bser ve d ma xi m u m ser u m a d uca n u ma b c o nce ntrati o n  
C mi n  
o bser ve d mi ni m u m ser u m a d uca n u ma b c o nce ntrati o n  
C S F  
cere br os pi nal fl ui d  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C T C A T  
C o m m o n T o xicit y Criteria f or A d verse E ve nts  
C V  
c oefficie nt of variati o n  
E AI R  
e x p os ure -a dj uste d i nci de nce rate  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E Q -5 D  
E ur o Q ol healt h stat us meas ure  
 
 
 
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  


 
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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 Practic e 
G G T  
ga m ma -gl uta m yl -tra nsferase 
H C P  
healt h care pr ofessi o nal  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o 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 R B 
i nstit uti o nal re vie w b oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I T T 
i nte nt-t o-treat 
I X R S 
I nteracti ve V oice/ We b Res p o nse S yste m 
L D H  
lactate de h y dr o ge nase 
L M CI  
late mil d c o g niti ve i m pair me nt 
L T E  
l o n g-ter m e xte nsi o n 
L O C F  
last o bser vati o n carrie d f or war d 
M CI  
mil d c o g niti ve i m pair me nt  
M C M C  
Mar k o v c hai n M o nte Carl o  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
mi 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 -A A  
Nati o nal I nstit ute o n A gi n g -Alz hei mer’s Ass ociati o n  
N PI -1 0  
Ne ur o ps yc hiatric I n ve nt or y -1 0  
P C S  
p ote ntiall y cli nicall y si g nifica nt  
P E T  
p ositr o n e missi o n t o m o gra p h y  
p H  
p ote ntial of h y dr o ge n  
PI  
Pri nci pal I n vesti gat or 
P K  
p har mac o ki netic(s)  
P M M  
patter n mi xt ure m o del  
P P  
per -pr ot oc ol  
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 OI  
re gi o n of i nterest 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
S U V R  
sta n dar d u pta ke val ue rati o 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
 
 
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
W H O  
W orl d Healt h Or ga nizati o n  


 
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1  D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S  
1. 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 h is 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 
Cli nical De me ntia R ati n g-S u m of B o xes  (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 Alz hei mer’s D isease (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.  
 
1. 2  Sec o n d ar y  O bjecti ves a n d E n d p oi nts  
T he s ec o n dar y o bjecti ves of t his st u d y are : 
o  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 Mi ni -Me ntal State E xa mi nati o n 
(M M S E ). 
o  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 Alz hei mer’s Disease Assess me nt Scale -
C o g niti ve S u bscales ( 1 3 ite ms) [ A D A S -C o g 1 3 ]. 
o  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 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 ]. 
T he se c o n dar y e n d p oi nts are : 
o  C ha n ge  fr o m baseli ne i n M M S E sc ore at Wee k 7 8 . 
o  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 . 
o  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 . 
 
1. 3  Terti ar y O bjecti ves a n d E n d p oi nts  
1. 3. 1  Terti 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 uca n u ma b.   
Bi o mar ker/ Efficac y/ Q ualit y of Life  


 
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•  T o ass ess 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 nte nt 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  (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 hiatri c 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]). 
•  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) . 
•  T o assess t he c orre lati 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 har mac o ki ne tic ( P K) para meters of a d uca n u ma b 
i n ser u m  
1. 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 d verse e ve nts ( A Es ) a n d seri o us a d verse e ve nts (S A Es ). 
•  Brai n ma g netic res o na nce i ma gi n g  (M RI ) fi n di n gs i ncl u di n g i nci de nce of a m yl oi d 
relate d i ma gi n g a b n or malit y-e de ma ( A RI A -E ) a n d 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 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/ Q ualit y of Life 
•  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 a t 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 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  o ver ti me . 
P har mac o ki netics : 


 
St atistic al A n al ysis Pl a n  
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•  Ser u m c o nce ntrati o ns a n d P K para meters of a d uca n u ma b.  
1. 4  A d diti o n al E x p l or at or y O bjecti ves a n d E n d p oi nts 
1. 4. 1  A d diti o n al E x pl or at or y O bjecti ves  
 
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1. 4. 2  A d diti o n al E x pl or at or y E n d p oi nt s 
 
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St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
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2  S T U D Y D E SI G N  
2. 1  St u d y O ver vie w  
St u d y 2 2 1 A D 3 0 2  (E M E R G E ) 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 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, f oll o we d b y a n o pti o nal d ose -bli n d e d l o n g-ter m 
e xte nsi o n ( L T E ) per i o d of u p t o 5 years. A p pr o xi matel y 1 6 0 5  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 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.  
 
T a ble 1 : 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 : Pl ace b o-C o ntr olle d Peri o d  
D ose (e ver y 4 wee ks ) 
1  
2  
3  
4  
5  
6  
7 t o 2 0  
Tre at me nt 
G r o u p 
Tre at me nt Gr o u p Str atifie d b y 
A p o E St at us 2  
D ose ( m g/ k g)  
Hi g h D ose  
Hi g h D ose  - A p o E ε 4 ( +)  
1  
1  
3  
3  
6  
6  
1 0 1 
Hi g h D ose  - A p o E ε 4 ( -) 
1  
1  
3  
3  
6  
6  
1 0  
L o w D ose  
L o w D ose  - A p o E ε 4 ( +)  
1  
1  
3  
3  
3  
3  
3  
L o w D ose  - A p o E ε 4 ( -) 
1  
1  
3  
3  
3  
3  
6  
Pl ace b o  
Pl ace b o  - A p o E ε 4 ( +)  
sali ne 
Pl ace b o  - A p o E ε 4 ( -) 
sali ne 
1 1 0 m g/ k g is t he tar get d ose f or all A p o E ε4 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 1 -3 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 a t 6 m g/ k g.   
2 A p o E ε 4 stat us rec or de d i n t he I nteracti ve V oice/ W e b Res p o nse S yste m (I X R S).   
 
S u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 1 of t he 3  treat me nt gr o u ps: a d uca n u ma b hi g h 
d ose, a d uca n u ma b l o w d ose a n d place b o, wit h stratificati o n base d u p o n t heir  a p oli p o pr otei n 
E 4  (A p o E  ε 4) carrier stat us  (carrier/ n o n-carrier) a n d site. D uri n g t he place b o -c o ntr olle d 
peri o d, su 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).  D ose le vels ma y be differe nt i n t he 
sa me treat me nt gr o u p base d u p o n s u bjects’ A p o E ε 4 carrier stat us, a n d s pecificall y, A p o E ε 4 


 
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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 plac e 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  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 mize 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 oc ol 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.  
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 
years ). T he treat me nt gr o u p f or t he L T E peri o d w ill be assi g ne d at t he sa me ti me as t he 
ra n d o mizati o n f or t he place b o-c o ntr olle d peri o d, re gar dless of w het her a s u bject e nteri n g t he 
L T E peri o d or n ot. S u bjects w h o are assi g ne d t o 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 assi g ne d t o  1 of 2 acti ve treat me nt gr o u ps 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 n d ra n d o mizati o n will be stratifie d b y t heir 
A p o E ε 4 carrier stat us ; f or t h ose w h o e nter t he L T E peri o 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 . S u bjects w h o are assi g ne d t o eit her a d uca n u ma b l o w d ose or 
a d uca n u ma b hi g h d ose gr o u p i n t he place b o-c o ntr olle d peri o d will c o nti n ue i n t he sa me 
treat me nt gr o u p for t he L T E peri o d ; t h ose 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 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 nt ati 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 ). 
I n di vi d ual d ose a dj ust me nts ma y be i m ple me nte d i n s u bjects w h o de vel o p a m yl oi d relate d 
i ma gi n g a b n or malities (A RI A ). See  Pr ot oc ol Secti o n  7. 2. 1 . 
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 oll e 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 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 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 .  
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 pe ri 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.  
 


 
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1 2  
 
2. 2  St u d y Sc he m atic  
Fi g ure 1 : St u d y Des i 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.  
* 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 ( stratifie d b y 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 . 


 
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Pl ace b o -C o ntr olle d Peri o d  
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1 3  
 
2. 3  Sc he d ule of E ve n ts 
See Pr ot oc ol Secti o n 4. 2.  
 
3  S A M P L E SI Z E J U S TI FI C A TI O N  
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 ysis 
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  ( 1 3 5 0 i n t otal) was p la 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 was  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 sta n dar d 
de viati o 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 
reflecte 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 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 esti mate d t o be 2.  
As defi ne d i n 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 1 ) was  reassesse d i n a bli n de d ma n ner i n N o ve m ber 2 0 1 7 (a p pr o xi matel y 3 
m o nt hs bef ore e nr oll me nt c o m pleti o n a n d wit h a b o ut 1 0. 6 % of t he data a vaila ble o n t he 
pri mar y e n d p oi nt 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 c o m bi ne d ). At t his ti me p oi nt, t he 
S D of t he pri mar y e n d p oi nt was esti mate d base d o n t he p o ole d bli n de d data fr o m t w o st u dies 
usi n g a m o difie d versi o n of G o ul d -S hi h si m ple -a dj ust me nt o ne sa m ple varia nce  ( Z uc ker et al. 
1 9 9 9) : 
𝑠𝑎𝑑𝑗
2
= 𝑠𝑜𝑠
2 −
2 𝑁
9 (𝑁−1 ) 𝛿2 , 
w here 𝑁 de n otes t he n u m ber of s u bjects i ncl u de d i n t he a nal ysis f or bli n de d sa m ple size re -
esti mati o n  (s u bjects wit h b ot h baseli ne a n d Wee k 7 8 C D R-S B a vaila ble at t he ti me of sa m ple 
size re-esti mati o n) , δ is t he ass u me d tr ue treat me nt effect (sa me treat me nt effect ass u me d f or 
b ot h t he hi g h d ose gr o u p a n d l o w d ose gr o u p  i n t his a nal ysis), a n d 𝑠𝑜𝑠
2  is t he u na dj uste d o ne 
sa m ple varia nce of t he pri mar y e n d p oi nt esti mate fr o m t he p o ole d bli n de d data.  
As a res ult of t his a nal ysis, t he sa m ple size has bee n i ncrease 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 gr o u p) t o ass ure a de q uate p o wer f or detecti n g a me a n treat me nt effect of 0. 5 . 
 
4  S T A TI S TI C A L A N A L Y SI S M E T H O D S  
4. 1  Ge ner al C o nsi der ati o ns  
T his statistical a nal ysis pla n (S A P ) o nl y c o vers t he a nal yse s f or t he pri mar y, sec o n dar y a n d 
tertiar y o bjecti ves f or t he place b o-c o ntr olle d p orti o n of t he st u d y. Hereafter, t h e place b o -
c o ntr olle d p orti o n of t he st u d y will be referre d t o as “t he st u d y” i n t he rest of t his S A P (e. g., 


 
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c o m pleti o n of t he st u d y mea ns c o m pleti o n of t he place b o -c o ntr olle d p orti o n). A se parate 
S A P will be pre pare d f or t he a nal yses of t he L T E peri o d  a n d i nte grate d a nal yses acr oss b ot h 
p orti o ns of t he st u d y.  T he a nal yses of a d diti o nal e x pl orat or y e n d p oi nts will be d oc u me nte d 
se paratel y.  
S u m mar y ta bles will be prese nte d  usi n g descri pti ve s u m mar y statistics . F or c o nti n u o us 
varia bles , s u m mar y statistics will ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, 
sta n dar d de viati o n, me dia n, 2 5 % perce ntile, 7 5 % perce ntile,  mi ni m u m a n d ma xi m u m . F or 
cate g orical varia bles , 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.  
T here are t w o t y pes of a nal ysis dis pla ys f or ta bles: b y treat me nt gr o u p (a nal ysis dis pla y A i n 
A p pe n di x 6. 1 ) a n d b y treat me nt gr o u p stratifie d b y A p o E stat us ( a nal ysis dis pla y B i n 
A p pe n di x 6. 1 ; here A p o E stat us refers t o t he stat us rec or de d i n I X R S [see Ta ble 1  f or 
c orres p o n de nce bet wee n treat me nt gr o u ps a n d treat me nt gr o u ps stratifie d b y A p o E stat us ]). 
T he a nal ysis dis pla y f or eac h a nal ysis will be defi ne d i n eac h secti o n. All t he listi n gs will be 
prese nte d b y treat me nt gr o u p stratifie d b y A p o E stat us, u nless ot her wise s pecifie d.  
U nless ot her wise s pecifie d, b aseli ne val ue is defi ne d as t he m ost rece nt n o n -missi n g 
meas ure me nt c ollecte d pri or t o t he first d ose. C ha n ge fr o m baseli ne will be defi ne d as p ost -
baseli ne val ue mi n us baseli ne val ue.  
U nless state d ot her wise, all statistical tests will be 2 -si de d wit h statistical si g nifica nce le vel of 
0. 0 5 .  
T he statistical s oft ware, S A S ®  will be use d f or all s u m maries  a n d a nal yses .  
4. 1. 1  A n al ysis P o p ul ati o n  
•  I nte nt-t o-treat (I T T) p o p ulati o n :  
T he I nte nt-t o-treat p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt ( a d uca n u ma b  or place b o) .  
 
•  Per -pr ot oc ol ( P P) p o p ulati o n :  
T he per -pr ot oc ol p o p ulati o n is defi ne d as al l s u bjects i n t he I T T p o p ulati o n a n d als o 
o  ha d n o  vi olati o ns of t he f oll o wi n g i ncl usi o n criteria: 
▪ 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 xcl u de 
me ntal deficits ot her t ha n M CI or mil d A D;  
▪ M ust ha ve a p ositi ve a m yl oi d P E T sca n;  
▪ M ust ha ve:  
•  A C D R -Gl o bal Sc ore of 0. 5;  
•  A 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 ) 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 ye d Me m or y I n 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).  
o  ha d at least 1 4 i nf usi o ns . 
o  di d n ot ma ke a n y c ha n ge t o c o nc o mita nt  A D  s y m pt o matic me dicati o ns d uri n g 
t he st u d y. 
 


 
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1 5  
 
•  
1 8F -fl or beta pir am yl oi d P E T a nal ysis p o p ulati o n : 
T he 1 8F -fl or beta pir a m yl oi d P E T a nal ysis p o p ulati o n  is defi ne d as all ra n d o mize d s u bjects 
w h o recei ve d at least o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) , used  1 8F -
fl or beta pir li ga n d f or a m yl oi d P E T sca n, a n d ha d a n e val ua ble  baseli ne a m yl oi d P E T 
S U V R val ue  f or t he c o m p osite re gi o n-of -i nterest usi n g cere bell u m as the refere nce 
re gi o n. 
 
•  
1 8F -fl ute meta m ol a m yl oi d P E T a nal ysis p o p ulati o n  (a p plica ble o nl y t o Ja pa n): 
T he 1 8F -fl ute meta m ol a m yl oi d P E T a nal ysis p o p ulati o n is defi ne d as all ra n d o mize d 
s u bjects w h o recei ve d at least o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o), used  
1 8F -fl ute meta m ol li ga n d f or a m yl oi d P E T sca n, a n d ha d a n e val ua ble  baseli ne a m yl oi d 
P E T S U V R val ue  f or t he c o m p osite re gi o n-of -i nterest usi n g cere bell u m as t he refere nce 
re gi o n. 
 
•  Safet y p o p ulati o n :  
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least o ne d ose 
of st u d y treat me nt (a d uca n u ma b or place b o).  It is t he sa me p o p ulati o n  as t he I T T 
p o p ulati o n.  
 
•  Safet y  M RI  p o p ulati o n :  
T he safet y M RI p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) a n d ha d at least o ne p ost -baseli ne 
M RI  assess me nt . 
 
•  P K  a nal ysis p o p ulati o n :  
T he P K a nal ysis p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) a n d ha d at least o ne meas ura ble 
a d uca n u ma b c o nce ntrati o n i n ser u m.  
 
•  I m m u n o ge nicit y p o p ulati 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 ra n d o mize d s u bjects w h o 
recei ve d at least o ne d ose of st u d y treat me nt (a duca n u ma b or place b o) a n d had  at least 
o ne p ost -d ose sa m ple e val ua ble f or i m m u n o ge nicit y. 
 
4. 2  B ac k gr o u n d C h ar acteristics  
T he s u m maries i n t his secti o n will be base d o n t he I T T p o p ulati o n.  U nless ot her wise 
s pecifie d, s u m mar y ta bles will be prese nte d b y treat me nt gr o u p (a nal ysis dis pla y A i n 
A p pe n di x 6. 1 ) a n d b y treat me nt gr o u p stratifie d b y A p o E stat us ( a nal ysis dis pla y B i n 
A p pe n di x 6. 1 ; here A p o E stat us refers t o t he stat us rec or de d i n I X R S [see Ta ble 1  f or 
c orres p o n de nce bet wee n treat me nt gr o u ps a n d treat me nt gr o u ps stratifie d b y A p o E stat us ]). 
All t he listi n gs will be prese nte d b y treat me nt gr o u p stratifie d b y A p o E stat us, u nless 
ot her wise s pecifie d.  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
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C O N FI D E N TI A L  
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1 6  
 
4. 2. 1  Acc o u nti n g of S u bject  
Dis p osit i o n of s u bjects will be s u m marize d a n d the s u m mar y data will i ncl u de  n u m ber ( %) of 
s u bjects ra n d o mize d a n d d ose d, n u m ber ( %) of s u bjects w h o c o m plete d t he treat me nt/st u d y, 
a n d n u m ber ( %) of s u bjects w h o disc o nti n ue d treat me nt a n d/ or wit h dre w fr o m st u d y. F or 
s u bjects w h o disc o nti n ued  treat me nt a n d/ or wit h dre w fr o m st u d y, the reas o ns f or 
disc o nti n uati o n a n d / or wit h dra wal , a n d da ys o n treat me nt a n d da ys o n st u d y  will be 
s u m marize d a n d liste d. T he n u m ber of s u bjects disc o nti n ui n g treat me nt pri or t o eac h 
sc he d ule d cli nical efficac y assess me nt will be s u m marize d ( prese nte d b y treat me nt gr o u p), 
i.e., t he n u m ber of s u bjects disc o nti n ui n g treat me nt bet wee n Da y 1 a n d Wee k 2 6, t he n u m ber 
of  s u bjects disc o nti n ui n g treat me nt bet wee n  Wee k 2 6 a n d Wee k 5 0 visit, etc. A si milar 
s u m mar y will be d o ne f or s u bjects w h o wit h dre w fr o m st u d y ( prese nte d b y treat me nt gr o u p). 
T i me t o treat me nt disc o nti n uati o n a n d ti me t o st u d y wit h dra wal will be dis pla ye d by Ka pla n -
Meier pl ot  ( prese nte d b y treat me nt gr o u p). 
N u m ber of s u bjects i n eac h a nal ysis p o p ulati o n will be s u m marize d. N u m ber of s u bjects 
d ose d will be s u m marize d b y re gi o n, c o u ntr y a n d site. I n a d diti o n, n u m ber of s u bjects w h o 
c o m plete d t he treat me nt/st u d y will be s u m marize d b y  re gi o n a n d c o u ntr y (prese nte d b y 
treat me nt gr o u p). 
T he cate g orizati o n of re gi o n is base d n ot o nl y o n c o nsi derati o n of ge o gra p h y b ut als o o n t y pe 
of healt h care s yste m a n d access t o healt h care i n eac h c o u ntr y. T his re gi o n cate g or y will be 
use d i n all a nal ysis, i ncl u di n g t he de m o gra p hics, t he c o variate i n statistical m o dels a n d 
s u b gr o u p a nal ysis. T he cate g ories f or re gi o ns will be: 
o  Re gi o n 1: U nite d States ( U S);  
o  Re gi o n 2: E ur o pea n c o u ntries (i ncl u di n g Bel gi u m, Fi nla n d , Fra nce, Ger ma n y, 
Ital y, Net herla n ds, P ola n d , S pai n, S we de n a n d S witzerla n d ), pl us Ca na da; 
o  Re gi o n 3: Asia c o u ntries (i ncl u di n g Ja pa n).  
 
4. 2. 2  De m o gr a p hics a n d  B aseli ne C h ar acteristics  
T he de m o gra p hic data i ncl u di n g a ge, ge n der, et h nicit y, race, hei g ht, wei g ht, a n d b o d y mass 
i n de x ( B MI) will be s u m marize d. A ge will als o be cate g orize d a n d prese nte d usi n g t he 
f oll o wi n g t w o gr o u pi n gs: < 5 0, 5 0 -6 0 , 61 -7 0 , 7 1 -8 0 , 8 1 -8 5 , > 8 5 years , a n d ≤ 6 4, 6 5 -7 4, ≥ 7 5 .  
S u m mar y of t he baseli ne c haracteristics of A D i ncl u de s la b orat or y A p o E ε 4 stat us (carrier or 
n o n -carrier), b aseli ne cli nical sta ge ( M CI d ue t o A D  or mil d A D) , baseli ne cli nical 
assess me nt i ncl u di n g R B A N S dela ye d me m or y i n de x, C D R gl o bal sc ore, C D R -S B , C D R 
c o g niti ve s u bsc ore, C D R f u ncti o nal s u bsc ore, M M S E, A D A S -C o g 1 3 , A D C S-A D L -M C I, 
n u m ber of years of f or mal e d ucati o n, n u m ber of years si nce first A D s y m pt o m , n u m b er of 
years si nce dia g n osis of A D , A D treat me nt use t hat was st o p pe d pri or t o e nteri n g t he st u d y 
( yes or n o) a n d A D s y m pt o matic me dicati o n use at baseli ne ( yes or n o ; see Secti o n 4. 2. 3  f or 
defi niti o n of A D s y m pt o matic me dicati o n use at baseli ne ). A p o E ε 4 carrier will be f urt her 
classifie d as h o m oz y g ote a n d h eter oz y g ote . M M S E  will als o be cate g orize d b y t he f oll o wi n g 
s u b gr o u ps: < 2 4, 2 4 -2 6, 2 7 -3 0 . S u bject listi n gs will  be ge nerate d f or de m o gra p hics a n d 
baseli ne c haracteristics.  


 
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C O N FI D E N TI A L  
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Me dical hist or y  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). T he n u m ber ( %) of s u bjects wit h hist or y  (i ncl u di n g b ot h o n g oi n g a n d n ot 
o n g oi n g me dical c o n diti o ns) will be s u m marize d  b y s yste m or ga n class a n d preferre d ter m . A 
listi n g of me dical hist or y will be ge nerate d.  
Pre vi o us t hera pies f or t he treat me nt of A D st o p pe d pri or t o e nteri n g t he st u d y , t otal durati o n 
of pre vi o us t hera pies a n d reas o n f or st o p pi n g treat me nt  will be s u m marize d  ( prese nte d b y 
treat me nt gr o u p). A listi n g of pre vi o us t hera pies will als o be ge nerate d.  
 
4. 2. 3  C o nc o mit a nt Me dic ati o ns  a n d N o n -D r u g T her a pies  
All c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) 
me dicati o n dicti o nar y. All c o nc o mita nt n o n -dr u g t hera pies will be c o de d usi n g t he Me d D R A 
dicti o nar y.  A c o nc o mita nt me dicati o n/ t hera p y will be defi ne d as a n y t hera p y t hat was ta ke n 
o n or after t he da y of t he first d ose of st u d y dr u g . T his i ncl u des t hera pies t hat start pri or t o t he 
i nitiati o n of t he first d ose if t heir use c o nti n ues o n or after t he date of first d ose. T o  defi ne 
c o nc o mita nt use f or t hera pies wit h missi n g start or st o p dates, t he f oll o wi n g a dditi o nal 
criteria will be use d:  
•  if b ot h t he start a n d st o p dates of a t hera p y are missi n g, t hat t hera p y will be 
c o nsi dere d c o nc o mita nt.  
•  if t he start date of a t hera p y is missi n g a n d t he st o p date of t hat t hera p y fall o n or after 
t he date of t he first d ose, t hat t hera p y will be c o nsi dere d c o nc o mita nt.  
•  if t he start date of a t hera p y is pri or t o t he date of t he first d ose a n d t he st o p date of 
t hat t hera p y is missi n g a n d t he t hera p y is liste d as c o nti n ui n g, t hat t hera p y will be 
c o nsi dere d c o nc o mita nt, or  
•  if t he start date of a t hera p y is pri or t o t he date of t he first d ose a n d t he st o p date of 
t hat t hera p y is missi n g a n d t he t hera p y is n ot liste d as c o nti n ui n g, t hat t hera p y will be 
c o nsi dere d n o n -c o nc o mita nt.  
F or a t hera p y wit h a partial start date, t he year/ m o nt h of t he t hera p y date will be c o m pare d t o 
t hat of t he first d osi n g date t o deter mi ne w hether t he t hera p y is c o nc o mita nt.  
T he n u m ber ( % ) of s u bjects ta ki n g c o nc o mita nt me dicati o n a n d n o n -dr u g t hera pies will be 
s u m marize d. N o n -dr u g t hera pies will be prese nte d b y treat me nt gr o u p.  C o nc o mita nt 
me dicati o ns a n d n o n -dr u g t hera pies will be liste d.  
A D s y m pt o matic me dicati o ns ta ke n c o nc o mita ntl y a t baseli ne are defi ne d as A D 
s y m pt o matic me dicati o ns t hat were  bei n g ta ke n at t he ti me of t he first d o se, i.e., starte d pri or 
t o t he first d ose a n d c o nti n ue d u ntil after t he first d ose. T he n u m ber ( %) of s u bjects ta ki n g 
A D s y m pt o matic  me dicati o n s c o nc o mitantl y at baseli ne  will be s u m mari ze d . I n a d diti o n, 
n u m ber of s u bjects usi n g C h oli nesterase i n hi bit ors  o nl y , Me ma nti ne o nl y , or b ot h at baseli ne 
will be s u m marize d . S u bjects w h o ha ve a n y  c ha n ge i n A D s y m pt o matic me dicati o ns after t he 
i nitiati o n of st u d y treat me nt will be s u m marize d b y t he  ti mi n g of c ha n ge, i.e., t he n u m ber of 
s u bjects c ha n gi n g bet wee n Da y 1 a n d Wee k 2 6, t he n u m ber of s u bjects c ha n gi n g bet wee n 
Wee k 2 6 a n d  Wee k 5 0, etc . T he  s u m mar y f or A D s y m pt o matic me dicati o n use d uri n g st u d y 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
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C O N FI D E N TI A L  
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1 8  
 
will be prese nte d b y treat me nt gr o u p. T he start a n d st o p date  of A D s y m pt o matic me dicati o n 
will be liste d f or t hese s u bjects.  
 
4. 2. 4  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns i de ntifie d d uri n g site m o nit ori n g  will be ca pt ure d i n a Pr ot oc ol De viati o n 
l o g a n d cate g orize d as maj or or mi n or de viati o ns base d o n Pr ot oc ol De viati o n Classificati o n 
(see A p pe n di x 6. 2 ). T he maj or  pr ot oc ol de viati o ns will be s u m marize d ( prese nte d b y 
treat me nt gr o u p). Listi n gs will be ge nerate d f or t he maj or a n d mi n or pr ot oc ol de viati o n s, 
res pecti vel y. A listi n g will be ge nerate d f or s u bjects wit h i nc orrect stratificati o n A p o E  stat us, 
i.e., treat me nt stratificati o n A p o E ε 4 stat us i n I X R S differe nt fr o m  t he la b orat or y A p o E ε 4 
stat us.  
 
4. 2. 5  St u d y Dr u g E x p os ure a n d St u d y Dr u g C o m pli a nce  
A s u m mar y ta ble of st u d y dr u g e x p os ure a n d c o m plia nce will be pr o vi de d. N u m ber of 
i nf usi o ns (a d uca n u ma b or place b o ) recei ve d will be s u m mari ze d as a cate g orical varia ble 
(cate g ories as i nte gers fr o m 1 t o 2 0, a n d 1-5, 6 -1 0, 1 1 -1 5, a n d 1 5 -2 0) as well as a c o nti n u o us 
varia ble. N u m ber of wee ks o n st u d y treat me nt (a d uca n u ma b or place b o ), calc ulate d as ( date 
of last d ose –  date of first d ose +  2 9 )/ 7, will be s u m marize d as a cate g orical varia ble (e ver y 8 
wee ks fr o m 0 t o > = 7 2 wee ks) as well as a c o nti n u o us varia ble. Perce nta ge of st u d y treat me nt 
ta ke n u p t o t he last d ose, calc ulate d as (t he act ual n u m ber of i nf usi o ns  / b y t he n u m ber of 
i nf usi o ns a s u bject is e x pecte d t o ta ke u ntil t he date of last i nf usi o n) * 1 0 0, will be s u m marize d 
as a c o nti n u o us varia ble.  T his ta ble  will be prese nte d b y treat me nt gr o u p.  
D ue t o t he use of titrati o n re gi me n i n t he st u d y a n d p ossi ble d ose re d ucti o n d ue t o A RI A, 
a n ot her s u m mar y ta ble will be pr o vi de d i ncl u di n g t he f oll o wi n g i nf or mati o n: n u m ber of t otal 
i nf usi o ns (cate g ories of 1-5, 6 -1 0, 1 1 -1 5, a n d 1 5 -2 0)  as well as a c o nti n u o us varia ble , n u m ber 
of i nf u si o ns at eac h d ose le vel ( 1 m g/ k g, 3 m g/ k g, 6 m g/ k g a n d 1 0 m g/ k g, res pecti vel y) 
s u m marize d as a cate g orical varia ble as well as a c o nti n u o us varia ble , n u m ber of s u bjects 
wit h d ose i ncrease ( place b o t o 1 m g/ k g, 1 t o 3 m g/ k g, 3 t o 6 m g/ k g a n d 6 t o 1 0 m g/ k g , 
res pecti vel y), n u m ber of s u bjects wit h d ose re d ucti o n ( 1 m g/ k g  t o place b o, 3 t o 1  m g/ k g, 6 t o 
3 m g/ k g a n d 1 0 t o 6 m g/ k g, res pecti vel y) , ma xi m u m d ose le vel recei ve d, a n d c u m ulati ve 
d ose (as a c o nti n u o us varia ble ). T his ta ble will be prese nte d  b y treat me nt g r o u p stratifie d b y 
A p o E stat us .  
A listi n g of st u d y dr u g a d mi nistrati o n rec or ds , i ncl u di n g d ose le vel  at eac h i nf usi o n, 
c u m ulati ve n u m ber of i nf usi o ns a n d c u m ulati ve d ose will be pr o vi de d.  A listi n g of 
a d uca n u ma b l ot n u m bers will be pr o vi de d.  
A listi n g of st u d y dr u g a d mi nistrati o n rec or ds f or place b o s u bjects w h o recei ve d a n y d oses of 
acti ve treat me nt  will be pr o vi de d.   
 


 
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Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
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4. 3  Effic ac y  A n al ysis  
4. 3. 1  Ge ner al C o nsi der ati o ns  
F or  efficac y e n d p oi nts, the f oll o wi n g treat me nt gr o u ps  of a d uca n u ma b (per  ra n d o mizati o n) 
will be e val uate d a n d c o m pare d wit h place b o : 
•  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  carriers  [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 ns 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).   
All efficac y a nal yses will be perf or me d  o n t he I T T p o p ulati o n . I n a d diti o n, t he pri mar y a n d 
sec o n dar y e n d p oi nts will als o be perf or me d o n t he per -pr ot oc ol p o p ulati o n. T he efficac y 
a nal ysis will be prese nte d b y treatme nt  gr o u p  ( per ra n d o mizati o n), i.e., a d uca n u ma b hi g h-
d ose, a d uca n u ma b l o w -d ose a n d place b o  (a nal ysis dis pla y A i n A p pe n di x 6. 1 ).  
T he pri mar y,  se nsiti vit y a n d s u p ple me ntar y  a nal yses f or t he pri mar y a n d sec o n dar y  e n d p oi nts 
are liste d i n Ta ble 2 . 
 
T a ble 2 . A n al ysis f or Pri m ar y a n d Sec o n d ar y E n d p oi nts  
E n d p oi nt  
A n al ysis  
A n al ysis 
P o p ul ati o n  
S A P 
Secti o n  
C D R -S B  
Pri mar y: A nal ysis of c ha n ge fr o m baseli ne at Wee k 
7 8 ( M M R M)  
I T T 
4. 3. 2. 1  
Se nsiti vit y: Patter n mi xt ure m o del ( A N C O V A)  
I T T 
4. 3. 2. 2. 1  
Se nsiti vit y: C o p y i ncre me nt fr o m refere nce met h o d  
( A N C O V A) 
I T T 
4. 3. 2. 2. 2  
Se nsiti vit y: I m p utati o n b y nat ural  disease pr o gressi o n 
( A N C O V A) 
I T T 
4. 3. 2. 2. 3  
Se nsiti vit y: Ti p pi n g p oi nt a nal ysis ( A N C O V A)  
I T T 
4. 3. 2. 2. 4  
S u p ple me ntar y: Ce ns ori n g after i nterc urre nt e ve nts 
( M M R M) * 
I T T 
4. 3. 2. 3. 1  
S u p ple me ntar y: Per -pr ot oc ol a nal ysis ( M M R M)  
Per -pr ot oc ol  
4. 3 . 2. 3. 2 
S u p ple me ntar y: Res p o n der a nal ysis ( L o gistic 
re gressi o n) 
I T T 
4. 3. 2. 3. 3  
S u p ple me ntar y: Sl o pe a nal ysis ( M M R M)  
I T T 
4. 3. 2. 3. 4  
S u p ple me ntar y: Di ver ge nce effect a nal ysis ( M M R M)  
I T T 
4. 3. 2. 3. 5  
M M S E,  
Pri mar y: A nal ysis of c ha n ge fr o m baseli ne at Wee k 
7 8 ( M M R M)  
I T T 
4. 3. 3. 1 , 
4. 3. 3. 2 , 
4. 3. 3. 3  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
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A D A S -C o g 1 3, 
A D C S -A D L -
M CI  
Se nsiti vit y: Patter n mi xt ure m o del ( A N C O V A)  
I T T 
4. 3. 3. 4  
S u p ple me ntar y: Ce ns ori n g after i nterc urre nt e ve nts 
( M M R M) * 
I T T 
4. 3. 3. 4  
S u p ple me ntar y: Per -pr ot oc ol a nal ysis ( M M R M)  
Per -pr ot oc ol  
4. 3. 3. 4  
S u p ple me ntar y: Sl o pe a nal ysis ( M M R M)  
I T T 
4. 3. 3. 4  
S u p ple me ntar y: Di ver ge nce effect a nal ysis ( M M R M)  
I T T 
4. 3. 3. 4  
* A nal ysis e xcl u des data c ollecte d after t he f oll o wi n g i nterc urre nt e ve nts: ( 1) pre mat ure disc o nti n uati o n of t he 
st u d y treat me nt a n d ( 2) a n y c ha n ge t o c o nc o mita nt A D s y m pt o matic me dicati o ns d uri n g t he st u d y . All ot her 
a nal yses will i ncl u de data c ollecte d after i nterc urre n t e ve nts [I C H E 9 ( R 1) A d de n d u m 2 0 1 7]. 
  
 
Visit wi n d o ws f or m a p pi n g effic acy e n d p oi nt  
F or efficac y data t hat are s u m marize d or a nal yze d b y visit, data c ollecte d o n all sc he d ule d 
visits a n d all u nsc he d ule d visits will be ma p pe d t o a n a p pr o priate a nal ysis visit usi n g t he 
wi n d o wi n g sc he me s h o w n i n  Ta ble 3 . If t here are 2 or m ore assess me nts a vaila ble i n t he 
sa me a nal ysis wi n d o w f or a s u bject, t he assess me nt t hat is cl osest t o t he tar get visit da y will 
be use d f or a nal ysis. If t here are 2 or m ore assess me nts i n t he sa me a nal ysis wi n d o w wit h t he 
sa me dista nce fr o m t he tar get visit da y, t he later assess me nt will be use d.  
 
T a ble 3 . Visit Wi n d o ws f or Effic ac y E n d p oi nts 
A n al ysis visit  
T ar get visit d a y  
A n al ysis visit wi n d o w  
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 6  
1 8 3  
[9 2 , 2 6 6 ] 
Wee k 5 0  
3 5 1  
[2 6 7 , 4 4 8 ] 
Wee k 7 8  
5 4 7  
[4 4 9 , t he e n d da y of t he place b o -c o ntr olle d peri o d  * ] 
* T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E. 
 
H a n dli n g of missi n g i te ms f or sc ales 
If a n y of t he i n di vi d ual ite ms f or t he pri mar y a n d sec o n dar y e n d p oi nts is missi n g, t he t otal 
sc ore of t he c orres p o n di n g e n d p oi nt will be i m p ute d b y  pr orati n g t he o bser ve d sc ores [ va n 
Gi n kel  2 0 1 0 ]. 
F or A D A S -C o g 1 3 , if 3 or fe wer of 1 3 ite ms  ( < 2 5 %) are missi n g, t he t otal sc ore will be 
i m p ute d b y t he f oll o wi n g al g orit h m: T otal sc ore = t otal sc ore fr o m t he c o m plete d ite ms * 
[ ma xi m u m t otal sc ore ( = 8 5) / ma xi m u m t otal sc ore f or t he c o m plete d ite ms]. T he i m p ute d 
n u m ber will be  r o u n de d u p t o t he nearest i nte ger. If m ore t ha n 3 ite ms are missi n g, t he t otal 
sc ore of A D A S-C o g 1 3 at t hat visit will be c o nsi dere d missi n g.  
F or A D C S -A D L -M CI , if 4  or fe wer of 1 8 ite ms  ( < 2 5 %) are missi n g, t he t otal sc ore will be 
i m p ute d b y a si milar al g orit h m as t hat f or A D A S -C o g 1 3 . T he i m p ute d n u m ber will be 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 1  
 
r o u n de d u p t o t he nearest i nte ger. If m ore t ha n 4  ite ms are missi n g, t he t otal sc ore f or A D C S-
A D L -M CI  at t hat visit will be c o nsi dere d missi n g.  
T he sa me i m p utati o n al g orit h m will be a p plie d t o C D R -S B  a n d M M S E,  if o nl y 1 b o x ( of 6) 
of C D R  is missi n g or if o nl y 2 or fe wer  ite ms ( o ut of 1 1 ) are missi n g f or M M S E.  If t he sc ore 
fr o m m ore t ha n 1 b o x of C D R or m ore t ha n 2  ite ms of M M S E is n ot a vaila ble, t he C D R-S B  
or M M S E  at t hat visit will be c o nsi dere d  missi n g.   
T he t otal sc ore of t he tertiar y e n d p oi nt N PI -1 0 will be i m p ute d usi n g t he sa me pr orati n g 
pri nci ple if o nl y 1 ite m ( o ut of 1 0) is  missi n g. F or E Q -5 D a n d m P D Q -2 0 , if a n y ite m is 
missi n g, a n y t otal or s u m i n v ol vi n g t hat ite m will be  c o nsi dere d missi n g.   
 
C o ns i der ati o ns f or m ulti ple  co 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 pe 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 -d ose vers us place b o.  
A ll 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  1. 2 . I n or der t o 
c o ntr ol f or a T y pe 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 1 or 2  
treat me nt 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 t hat 1 or  2 treat me nt c o m paris o ns, res pecti vel y.   
T here will be n o m ulti ple c o m paris o n a dj ust me nts f or t he se nsiti vit y  a n d s u p ple me ntar y  
a nal yses f or t he pri mar y a n d sec o n dar y efficac y e n d p oi nts,  t he tertiar y efficac y e n d p oi nts, t he 
s u b gr o u p a nal yses or t he a d diti o nal a nal yses. 
 
4. 3. 2  Pri m ar y Effic ac y E n d p oi nt  
 Pri m ar y a n al ysis  
T he esti ma n d of t he pri mar y a nal ysis is t he mea n differe nce of t he c ha n ge fr o m baseli ne 
C D R -S B sc ores at Wee k 7 8 bet wee n treat me nt gr o u ps i n t he I T T p o p ulati o n  [I C H E 9 ( R 1) 
A d de n d u m  2 0 1 4, 2 0 1 7 ]. All o bser ve d data will be i ncl u de d i n t he pri mar y a nal ysis, i ncl u di n g 
da ta c ollecte d after i nterc urre nt e ve nts [I C H E 9 ( R 1) A d de n d u m  2 0 1 7 ], i.e., treat me nt 
disc o nti n uati o n or a c ha n ge i n c o nc o mita nt use of A D s y m pt o matic me dicati o n. 
T he c ha n ge fr o m baseli ne C D R -S B sc ores will be s u m marize d b y treat me nt gr o u p at eac h 
p ost -baseli ne visit . 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 ysis t o a nal yze 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  
gr o u p , ti me (cate g orical), treat me nt gr o u p -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  i nteracti o n, baseli ne M M S E, A D s y m pt o matic me dicati o n use at baseli ne  
( yes/ n o; see Secti o n 4. 2. 3  f or defi niti o n of A D s y m pt o matic me dicati o n use at baseli ne ), 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 2  
 
re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . A n u nstr uct ure d c o varia nce 
matri x will be use d t o m o del t he wit hi n -patie nt varia nce -c o varia nce err ors.  If t he 
u nstr uct ure d c o varia nce str uct ure matri x res ults i n a lac k of c o n ver ge nce, t he heter o ge ne o us 
T oe plitz c o varia nce str uct ure f oll o we d b y t he heter o ge ne o us first -or der a ut ore gressi ve 
c o varia nce str uct ure will be use d.  T he Ke n war d -R o ger a p pr o xi mati o n will be use d t o 
esti mate t he de n o mi nat or de grees of free d o m.  I n t he pri mar y a nal ysis, missi n g data are 
ass u me d t o be missi n g at ra n d o m  [ R u bi n 1 9 7 6].  
 
 Se nsiti vit y a n al ysis  
T he f oll o wi n g  se nsiti vit y a nal yses will be perf or me d t o assess t he r o b ust ness of t he pri mar y 
a nal ysis  t o de viati o n fr o m t he missi n g -at-ra n d o m ass u m pti o n . All t he se nsiti vit y a nal yses will 
be c o n d ucte d f or t he I T T p o p ulati o n.  
4. 3. 2. 2. 1  P atter n mi xt ure m o del  
T he patter n mi xt ure m o del ( P M M) re prese nts a ge neral a n d fle xi ble fra me w or k t o m o del t he 
pre dicti ve distri b uti o n of missi n g data c o n diti o nal o n t he o bser ve d data  [ Little 1 9 9 3, 1 9 9 4]. It 
all o ws f or m ulati n g ass u m pti o ns re gar di n g missi n g data i n a tra ns pare nt a n d cli nicall y 
i nter preta ble ma n ner.  
I n t he P M M fra me w or k, s u bjects are gr o u pe d i nt o missi n g patter ns s o t hat s u bjects i n t he 
sa me patter n s hare si milar missi n g ness c haracteristics. I n t his a nal ysis, missi n g patter ns will 
be defi ne d acc or di n g t o t he reas o ns f or earl y wit h dra w al fr o m st u d y  as re p orte d o n t he 
electr o nic case re p ort f or m (e C R F) . T he f oll o wi n g t w o patter ns will be c o nsi dere d: 
•  S u bjects w h o wit h dra w d ue t o reas o ns t hat ma y be relate d t o efficac y, i ncl u di n g 
c o nse nt wit h dra w n, wit h dra wal b y pare nt/ g uar dia n, i n vesti gat or decisi o n, l oss of 
ca pacit y, c ha n ge of treat me nt, a n d disease pr o gressi o n;  
•  S u bjects w h o wit h dra w d ue t o reas o ns t h at are u nli kel y relate d t o efficac y, i ncl u di n g 
a d verse e ve nt, l ost t o f oll o w -u p, deat h, pre g na nc y, rel ocati o n, pr ot oc ol a me n d me nt, 
site ter mi nate d b y s p o ns or/i n vesti gat or, st u d y visit b ur de n, a n d ot her. 
S u bjects w h o wit h dra w d ue t o reas o ns t hat ma y be rela te d t o efficac y will be pe nalize d a n d 
t heir missi n g data will be i m p ute d usi n g t he c o p y i ncre me nt  fr o m refere nce (CI R ) met h o d 
[ Car pe nter et al. 2 0 1 3] (see Secti o n 4. 3. 2. 2. 2  f or descri pti o n of t he CI R met h o d). S u bjects 
w h o wit h dra w d ue t o reas o ns t hat are u nli kel y relate d t o efficac y will be ha n dle d usi n g t he 
missi n g -at-ra n d o m ass u m pti o n a n d t heir missi n g data will be i m p ute d usi n g t he sta n dar d 
m ulti ple i m p utati o n met h o d  [R u bi n  1 9 8 7 ]. S u bjects wit h missi n g data d ue t o reas o ns ot her 
t ha n earl y wit h dra wal (s uc h as ite m missi n g, o ut of wi n d o w, etc.) will be ha n dle d usi n g t he 
missi n g -at-ra n d o m ass u m pti o n. F or  b ot h i m p utati o n met h o ds , t he f oll o wi n g c o variates will 
be i ncl u de d i n t he i m p utati o n m o del : treat me nt gr o u p, baseli ne C D R-S B, baseli ne M M S E, 
A D s y m pt o matic me dicati o n use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  
(carrier/ n o n-carrier) . I m ple me ntati o n details ca n be f o u n d i n A p pe n di x  6. 3. 2 . 
T he i m p ute d datasets will be a nal yze d b y a n a nal ysis of c o varia nce ( A N C O V A ) m o del 
a dj usti n g treat me nt gr o u p, baseli ne  C D R -S B,  baseli ne M M S E, A D s y m pt o matic me dicati o n 
use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . T he 
a nal yze d res ults fr o m t he i m p ute d datasets will be c o m bi ne d base d o n R u bi n’s r ules  [R u bi n 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 3  
 
1 9 8 7 ] ass u mi n g t hat t he statistics esti mate d fr o m eac h i m p ute d dataset are n or mall y 
distri b ute d . 
If i nter me diate missi n g  val ues are  e nc o u ntere d (s uc h as data missi n g at Wee k 2 6 b ut are 
a vaila ble at s u bse q ue nt visits ), a Mar k o v c hai n M o nte Carl o ( M C M C) met h o d t hat ass u mes 
m ulti variate n or malit y will be use d t o i m p ute t he i nter me diate missi n g val ues  a n d pr o d uce a 
m o n ot o ne missi n g patter n ( data wit h o nl y ter mi nal missi n g a n d n o i nter me diate missi n g) [ Li 
1 9 8 8; Sc hafer 1 9 9 7].  
4. 3. 2. 2. 2  C o p y i ncre me nt fr o m refere nce met h o d  
T he c o p y i ncre me nt fr o m refere nce ( CI R) met h o d will be a p plie d t o  i m p ute t he p ost-
wit h dra wal data f or a n y a d u can u ma b -treate d s u bject w h o wit h dra ws fr o m st u d y earl y base d 
o n data fr o m t he place b o gr o u p  rat her t ha n t he s u bject’s o w n ra n d o mize d treat me nt gr o u p  
[Car pe nter et al. 2 0 1 3 ]. S pecificall y, f or a s u bject  o n a d uca n u ma b hi g h d ose ( or a d uca n u ma b 
l o w d ose) w h o wit h dra ws earl y, his or her  mea n traject or y after earl y wit h dra wal is ass u me d 
t o be parallel t o t he mea n traject or y of t he place b o  gr o u p , a n d t he differe nce bet wee n t he t w o 
mea ns  is t he sa me as t he differe nce at the ti me of wit h dra wal. T his  met h o d ass u mes t hat a n y 
be nefit gai ne d fr o m pre vi o us treat me nt will be retai ne d, b ut s u bjects pr o gress as if t he y were 
o n place b o after wit h dra wal fr o m st u d y . F or a n y s u bject o n place b o w h o wit h dra ws earl y, his 
or her p ost -wit h dra wal pr ofile will be i m p ute d f oll o wi n g t he missi n g -at-ra n d o m pri nci ple.  
I m ple me ntati o n details ca n be f o u n d i n A p pe n di x  6. 3. 1 .  
After all missi n g data ha ve bee n i m p ute d, a n A N C O V A m o del a dj usti n g treat me nt gr o u p, 
baseli ne  C D R -S B,  baseli ne M M S E, A D s y m pt o matic me dicati o n use at baseli ne  ( yes/ n o), 
re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier)  will be a p plie d t o a nal yze t he 
c ha n ge fr o m baseli ne C D R -S B.  
4. 3. 2. 2. 3  I m p ut ati o n b y n at ur al dise ase pr o gressi o n  
S u bjects are ass u me d t o e x hi bit a n e v ol uti o n of t he disease si milar as t he nat ural disease 
pr o gressi o n after earl y wit h dra wal fr o m st u d y  (f or all treat me nt gr o u ps). T he nat ural disease 
pr o gressi o n is deter mi ne d base d o n a s na ps h ot of t he Alz hei mer’s Disease Ne ur oi ma gi n g 
I nitiati ve ( A D NI) data base [M ueller et al. 2 0 0 5 ] o btai ne d  i n Ma y 2 0 1 7.  A s u b p o p ulati o n was 
defi ne d  t hat satisfies t he maj or i nclusi o n criteria of St u d y 2 2 1 A D 3 0 2  (a n d t he i de nticall y 
desi g ne d St u d y 2 2 1 A D 3 0 1 ). I n t his s u b p o p ulati o n, t he mea n c ha n ge fr o m baseli ne C D R -S B 
at Wee k 7 8 is esti mate d t o be a b o ut 1. 5 2 f or s u bjects wit h late mil d c o g niti ve i m pair me nt 
( L M CI) a n d a b o ut 2. 0 6 f or s u bjects wit h mil d A D. T he missi n g data at Wee k 7 8 f or t his 
st u d y will be i m p ute d usi n g t he li near e xtrap olati o n a p pr oac h base d o n s u bjects’ baseli ne 
cli nical sta ge ( M CI d ue t o A D or mil d A D). F or e xa m ple , ass u mi n g a  mil d  A D patie nt w h ose  
last n o n-missi n g c ha n ge fr o m baseli ne C D R -S B meas ure me nt is 0. 5  at Wee k 2 6, the c ha n ge 
fr o m baseli ne C D R-S B at Wee k 7 8 f or t his patie nt will be i m p ute d as 0. 5 + 2. 0 6 *( 7 8 -2 6)/ 7 8, 
w hic h is 1. 8 7 . A s i milar al g orit h m will be a p plie d t o t he M CI patie nts. After i m p utati o n, t he 
c ha n ge fr o m baseli ne C D R -S B  at Wee k 7 8 will be a nal yze d b y a n A N C O V A m o del 
a dj usti n g treat me nt gr o u p, baseli ne  C D R -S B,  baseli ne M M S E, A D s y m pt o matic me dicati o n 
use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . 
4. 3. 2. 2. 4  Ti p pi n g p oi nt a n al ysis  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 4  
 
T he ti p pi n g -p oi nt a nal ysis is a pr o gressi ve stress -testi n g t o assess h o w se vere de part ures fr o m 
missi n g -at-ra n d o m m ust be i n or der t o o vert ur n t he c o ncl usi o n of t he pri mar y a nal ysis [ Ya n 
et al. 2 0 0 9]. F or o ur st u d y, s u bjects are ass u me d t o ha ve w orse sc ores after earl y wit h dra wal  
fr o m st u d y c o m pare d t o s u bjects w h o re mai n o n st u d y.  
T he missi n g data are first i m p ute d b y t he sta n dar d m ulti ple i m p utati o n (ass u mi n g missi n g at 
ra n d o m). T o reflect t he w orse perf or ma nce after earl y wit h dra wal, pre-s pecifie d s hift 
para meters 𝑠𝑎 a n d 𝑑𝑗 are a d de d t o t he i m p ute d val ues f or s u bjects o n place b o a n d 
a d uca n u ma b (i ncl u de b ot h l o w d ose a n d hi g h d ose), res pecti vel y. T he a dj uste d m ulti ple 
i m p ute d datasets will t he n be a nal yze d b y a n A N C O V A m o del a n d t he res ults will be 
c o m bi ne d usi n g t he R u bi n’s r ule f or i nfere nce. 
A ra n ge of  s hift para meters 𝑠𝑜 a n d 𝑠𝑁 will be a p plie d a n d p-val ue will be calc ulate d f or eac h 
c o m bi nati o n of 𝑁𝛿 a n d 𝑁𝑠. T he ti p pi n g re gi o n is defi ne d as t he c o m bi nati o ns of 𝑜𝑠 a n d 𝛿𝑡 s uc h 
t hat t he treat me nt effect is n o l o n ger si g nifica nt ( p-val ue greater t ha n t he si g nifica nce le vel).  
T he scie ntific pla usi bilit y of t he ti p pi n g re gi o n will be e val uate d. If i m pla usi ble de part ures 
fr o m t he missi n g-at-ra n d o m ass u m pti o n (lar ge δ ) are nee de d i n or der t o c ha n ge t he res ults 
fr o m statisticall y si g nifica nt t o i nsi g nifica nt, t he res ults of t he pri mar y a nal ysis are c o nsi dere d 
t o be r o b ust t o de part ure fr o m t he missi n g -at-ra n d o m ass u m pti o n.  
 
 S u p ple me nt ar y a n al ysis  
4. 3. 2. 3. 1  Ce ns ori n g after i nterc urre nt e ve nts   
T he pri mar y a nal ysis ( Secti o n 4. 3. 2. 1 ) will be re peate d wit h t he data ce ns ore d after a n y of t he 
f oll o wi n g i nterc urre nt e ve nts (if m ulti ple e ve nts occ ur t o t he sa me s u bject, data after t he 
earliest e ve nt will be ce ns ore d):  
o  pre mat u re disc o nti n uati o n of t he st u d y treat me nt; 
o  a n y c ha n ge t o c o nc o mita nt A D s y m pt o matic me dicati o ns d uri n g t he st u d y . 
T h e esti mate of t his  a nal ysis reflects t he treat me nt effect of a d uca n u ma b if t he dr u g is ta ke n 
as directe d.  
4. 3. 2. 3. 2  Per -pr ot oc ol a n al ysis  
T he per -pr ot oc ol a nal ysis will be d o ne usi n g t he sa me m o del as t he pri mar y a nal ysis ( Secti o n  
4. 3. 2. 1 ) a n d a p pl yi n g i n t he per-pr ot oc ol p o p ulati o n ( Secti o n  4. 1. 1 ).  
4. 3. 2. 3. 3  Res p o n der a n al ysis  
T o f urt her assess w het her s u bjects o n a d uca n u ma b pr o gress  differe ntl y fr o m t h ose o n 
place b o, res p o n der a nal ysis will be c o n d ucte d. T he res p o n ders wil l be deter mi ne d b y a 
t hres h ol d of t he pri mar y e n d p oi nt, i.e., s u bjects w h ose c ha n ge fr o m baseli ne C D R-S B at 
Wee k 7 8 is s maller t ha n  or e q ual t o  t he t hres h ol d will be classifie d as res p o n ders a n d 
ot her wise will be classifie d as n o n -res p o n ders. All s u bjects wit h missi n g data at Wee k 7 8  will 
be classifie d as n o n -res p o n ders. 
T he res p o n der a nal ysis will be c o n d ucte d f or  t w o t hres h ol d val ues: 0 . 5 or 1. 5, i.e., s u bjects 
w h ose c ha n ge fr o m baseli ne C D R -S B at Wee k 7 8 ≤ 0 . 5 or ≤ 1. 5. T he  n u m ber of res p o n ders 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
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C O N FI D E N TI A L  
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a n d the res p o nse rate  will be s u m marize d b y treat me nt gr o u p . T he dic h ot o mize d res p o nse, 
res p o n der vs. n o n-res p o n der, will be m o dele d usi n g a l o gistic re gressi o n wit h t he f oll o wi n g 
c o variates: treat me nt gr o u p , baseli ne CD R -S B, baseli ne M M S E,  A D s y m pt o matic me dicati o n 
use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat o y A p o E ε 4 stat us  (carrier/ n o n-carrier) . I n 
a d diti o n t o t he t w o selecte d t hres h ol d val ues, t he c o nti n u o us res p o n der c ur ve t hat dis pla ys t he 
perce nta ge of res p o n ders u n der a wi de r a n ge of t hres h ol d val ues will be prese nte d b y 
treat me nt gr o u p.   
Si nce all missi n g data will be c o nsi dere d as n o n -res p o nse, w hic h is a s pecial f or m of missi n g-
n ot -at-ra n d o m, t his a nal ysis ca n pr o vi de a d diti o nal i nsi g hts f or t he r o b ust ness of t he pri mar y 
a nal ysis res ults.  
4. 3. 2. 3. 4  Sl o pe a n al ysis  
Sl o pe a nal ysis will be c o n d ucte d t o assess t he differe nce bet wee n eac h a d uca n u ma b treat me nt 
gr o u p  a n d place b o i n t he sl o pe of c ha n ge fr o m baseli ne i n C D R -S B  u p t o Wee k 7 8. A 
re d ucti o n i n t he sl o pe of  t he a d uca n u ma b treat me nt gr o u p c o m pare d wit h place b o w o ul d 
i n dicate a sl o wer rate of disease pr o gressi o n, t h us reflecti n g a disease m o dif yi n g effect of 
a d uca n u ma b. A n M M R M m o del will be use d, wit h de pe n de nt varia ble as t he c ha n ge fr o m 
baseli ne C D R -S B sc or e at eac h visit a n d wit h fi xe d effects of treat me nt gr o u p , ti me (as a 
c o nti n u o us varia ble), treat me nt  gr o u p -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  ( yes/ n o), re gi o n, 
a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . T he c o nti n u o us ti me varia ble is 
calc ulate d as n u m ber of years si nce t he 1 st i nf usi o n, s o t he sl o pe esti mate reflects t he a n n ual 
rate of c ha n ge. T he sa me met h o ds as i n t he pri mar y a nal ysis will be c o nsi dere d f or t h e 
c o varia nce str uct ure a n d t he de grees of free d o m . 
4. 3. 2. 3. 5  Di ver ge nce effect a n al ysis  
A di ver ge nce effect a nal ysis will be perf or me d t o assess w het her t he treat me nt differe nce 
bet wee n t he a d uca n u ma b treate d patie nts a n d t he place b o patie nts i ncreases o ver ti me [ Li  
2 0 1 7]. A li near tre n d test will be c o n d ucte d o n treat me nt differe nce at Wee k 2 6, 5 0 a n d 7 8 
esti mate d fr o m t he M M R M m o del of Secti o n 4. 3. 2. 1 , t o assess if t he sl o pe of t he treat me nt 
differe nce is p ositi ve or n ot. Let t he esti mate of treat me nt differe nce be 𝑠𝑎 at ti me p oi nt 𝑑𝑗, 
w here 𝑠𝑜=  2 6, 5 0 a n d 7 8 ( wee k). T he least -s q uare esti mate of t he sl o pe is 
𝑠𝑁𝑁𝛿= ∑(𝑁𝑠−𝑜̅)𝑠𝛿
∑(𝑡𝑖−𝑡̅) 2 , 
w here  𝑡̅ is t he mea n of 𝑡𝑖’s. T he h y p ot hesis t o be teste d is 
𝐻0 : 𝛽𝐷𝐼𝐹≤0  vers us  𝐻𝑎: 𝛽𝐷𝐼𝐹> 0 . 
Gi ve n 𝛽𝐷𝐼𝐹 is a li near c o m bi nati o n of t he treat me nt differe nce 𝛿𝑖, t his a nal ysis ca n be 
i m ple me nte d b y t he “esti mate” state me nt i n t he S A S pr oc mi xe d pr oce d ure.  
 
 C D R s u bsc ores a n d C D R gl o b al sc ore  
T he C D R is c o m prise d of 6 d o mai ns: Me m or y, Orie ntati o n, J u d g me nt a n d Pr o ble m S ol vi n g, 
C o m m u nit y Affairs, H o me a n d H o b bies, a n d Pers o nal Care. C D R -S B is t he s u m of t he sc ores 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
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C O N FI D E N TI A L  
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f or t hese 6 d o mai ns. I n a d diti o n, t w o C D R s u bsc ores ha ve bee n pr o p ose d [Tracte n ber g 
2 0 0 5 ]: a “c o g niti ve” s u b sc ore e q uali n g t he s u m of t he Me m or y, Orie ntati o n, a n d J u d g me nt 
a n d Pr o ble m S ol vi n g b o x  sc ores, an d a “f u ncti o nal” s u b sc ore e q uali n g t he s u m of 
C o m m u nit y Affair s, H o me a n d H o b bies a n d P ers o nal C are b o x sc ores . F or eac h of t he 6 b o x 
sc ores, a n d t he C D R c o g niti ve s u bsc ore a n d C D R f u ncti o nal s u bsc ore, t he baseli ne val ue a n d 
t he c ha n ge fr o m baseli ne at eac h p ost -baseli ne visit will be s u m marize d b y treat me nt gr o u p. 
T he sa me M M R M m o del as t he pri mar y a nal ysis will als o be a p plie d t o t he C D R c o g niti ve 
s u bsc ore a n d C D R f u ncti o nal s u bsc ore. 
T he C D R gl o bal sc ore is a c o m p osite sc ore o btai ne d b y c o m bi ni n g t he 6 b o x sc ores usi n g a 
sc ori n g al g orit h m t hat wei g hts me m or y as t he pri mar y d o mai n a n d all ot her d o mai ns as 
sec o n dar y [ M orris 1 9 9 3]. T he distri b uti o n of C D R gl o bal sc ore will be s u m marize d (as a 
cate g orical varia ble) b y treat me nt gr o u p at eac h p ost -baseli ne vi sit.  
 
4. 3. 3  Sec o n d ar y  Effic ac y  E n d p oi nts  
 Pri m ar y a n al ysis of M M S E  
T he c ha n ge fr o m baseli ne M M S E sc ores will be s u m marize d b y treat me nt gr o u p at eac h p ost -
baseli ne visit. 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 M M S E usi n g fi xe d effects of treat me nt  gr o u p , ti me (cate g orical), treat me nt gr o u p -
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 medicati o n use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4  stat us 
(carrier/ n o n-carrier) . T he s a me met h o ds as i n t he pri mar y a nal ysis will be c o nsi dere d f or t he 
c o varia nce str uct ure  a n d t he de grees of free d o m .  
 Pri m ar y a n al ysis of A D A S -C o g 1 3  
T he c ha n ge fr o m baseli ne A D A S -C o g 1 3 sc ores will be s u m marize d b y treat me nt gr o u p at 
eac h p ost-baseli ne visit. 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 A S -C o g 1 3 usi n g fi xe d effects of treat me nt  gr o u p , ti me 
(categ orical) , treat me nt gr o u p -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 dicati o n use at baseli ne  
( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . T he s a me met h o ds as i n 
t he pri mar y a nal ysis will be c o nsi dere d f or t he c o varia nce str uct ure a n d t he de grees of 
free d o m.  
 Pri m ar y a n al ysis of A D C S -A D L -M CI  
T he c ha n ge fr o m baseli ne A D C S -A D L -M CI  sc ores will be s u m marize d b y treat me nt gr o u p at 
eac h p ost-baseli ne visit. 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  gr o u p , ti me 
(cate g orical), treat me nt gr o u p -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 dicati o n use at 
baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . T he s a me 
met h o ds as i n t he pri mar y a nal ysis will be c o nsi dere d f or t he c o varia nce str uct ure a n d t he 
de grees of free d o m .  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
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T he pri mar y a nal ysis of A D C S -A D L -M CI will use t he p o ole d data fr o m b ot h St u dies 
2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2  (a nal ysis f or eac h i n di vi d ual st u d y will als o be perf or me d ). 
P o ole d data  will be use d  f or t he pri mar y a nal ysis beca use  f u ncti o nal o utc o mes are e x pecte d 
to be less se nsiti ve t o c ha n ge wit hi n t he st u d y d urati o n t ha n c o g niti o n meas ures d ue t o ceili n g 
effects [ R oc k w o o d 2 0 0 7], as s u bjects e nteri n g t he st u d y will ha ve n o or little meas ura ble 
i m pair me nt at baseli ne. It has als o bee n o bser ve d i n pre vi o us st u dies of m ore i m paire d 
patie nts ( mil d t o m o derate/se vere) t hat  f u ncti o nal o utc o me treat me nt effect sizes are s mall 
[ Ha nse n 2 0 0 7].  
 Se nsiti vit y / Su p ple me nt ar y  a n al ysis  
T he f oll o wi n g se nsiti vit y  a n d s u p ple me ntar y  a nal yses t hat are pla n ne d f or t he pri mar y 
efficac y e n d p oi nt will als o be c o n d ucte d f or t he sec o n dar y efficac y e n d p oi nts:  
•  Patter n mi xt ure m o del  
•  Ce ns ori n g after i nterc urre nt e ve nts  
•  Per -pr ot oc ol a nal ysis  
•  Sl o pe a nal ysis  
•  Di ver ge nce effect a nal ysis  
 
4. 3. 4  T erti ar y E n d p oi nts  f or Effic ac y a n d Q u alit y of Life 
T he baseli ne val ue a n d t he c ha n ge fr o m baseli ne at eac h p ost -baseli ne visit f or N PI-1 0 will 
be s u m mari ze d b y treat me nt gr o u p . A n  M M R M m o del will be use d t o a nal yze t he c ha n ge 
fr o m baseli ne i n N PI-1 0 usi n g fi xe d effects of treat me nt  gr o u p , ti me (cate g orical), treat me nt 
gr o u p -b y -ti me i nteracti o n, baseli ne N PI -1 0 , baseli ne N PI -1 0 b y ti me  i nteracti o n, baseli ne 
M M S E, A D s y m pt o matic me dicati o n use at baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E 
ε 4 stat us (carrier/ n o n-carrier) . Sa me met h o ds as i n t he pri mar y a nal ysis will be c o nsi dere d f or 
t he c o varia nce str uct ure a n d t he de grees of free d o m. 
F or t he f oll o wi n g tertiar y e n d p oi nts f or patie nt -re p orte d o utc o mes a n d q ualit y of life , s u bject 
self-re p orte d E Q-5 D i n de x sc ore  ( S R), i nf or ma nt-rate d s u bject E Q-5 D i n de x sc ore  (I R-S) , 
a n d m P D Q -2 0 , t he baseli ne val ue a n d t he c ha n ge fr o m baseli ne at eac h p ost-baseli ne visit 
will be s u m marize d b y treat me nt gr o u p . A d diti o nal a nal yses f or t hese e n d p oi nts will be 
pr o vi de d i n a se parate d oc u me nt .  
 
4. 3. 5  S u b gr o u p A n al ysis  
S u b gr o u p a nal yses  will be perf or me d f or  t he pri mar y e n d p oi nt (C D R -S B ) a n d sec o n dar y 
e n d p oi nts  (M M S E , A D A S-C o g 1 3 , A D A S-A D L -M CI ). T he f oll o wi n g pre-defi ne d s u b gr o u ps  
will be c o nsi dere d : 
•  La b orat or y A p o E ε 4  stat us (carrier or n o n-carrier)  
•  Baseli ne cli nical sta ge ( M CI d ue t o A D or mil d A D)  per t he I n vesti gat or’s assess me nt 
base d o n t he Nati o nal I nstit ute o n A gi n g -Alz hei mer’s Ass ociati o n ( NI A -A A ) criteria 
•  U se of A D s y m pt omatic me dicati o n at baseli ne  ( yes or n o)  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
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•  Baseli ne M M S E ( M M S E ≤ 2 6 or M M S E ≥ 2 7)  
•  R e gi o n ( U S , E ur o pe/ Ca na da/ A ustralia, Asia; see Secti o n 4. 2. 1  f or defi niti o n of 
re gi o n) 
•  A ge cate g or y  (≤ 6 4 , 6 5 -7 4 , ≥ 7 5 ) 
•  Ge n der  (fe male or male) 
A selecti ve set of s u b gr o u p a nal yses will be perf or me d f or A m yl oi d P E T data. Details will be 
defi ne d i n Secti o ns 4. 4 . 
 
4. 4  A m yl oi d P E T A n al ysis  
4. 4. 1  A m yl oi d P E T s u bst u d y  
E ver y s u bject e nr olle d i nt o t he st u d y m ust ha ve a p ositi ve a m yl oi d P E T sca n b y vis ual rea d 
eit her at scree ni n g or o btai ne d wit hi n 1 2 m o nt hs of scr ee ni n g. S u bjects e nr olle d i nt o t he 
a m yl oi d P E T s u bst u d y will ha ve t he q ua ntitati ve sta n dar d u pta ke val ue rati o ( S U V R) sc ores 
at scree ni n g a n d at eac h pla n ne d p ost -baseli ne visit. T he a m yl oi d P E T s u bst u d y will i ncl u de a 
s u bset of a p pr o xi matel y 4 0 0  s u bjects i n c o u ntries ot her t ha n Ja pa n w here P E T sca ns will be 
perf or me d usi n g 1 8F -fl or beta pir li ga n d, a n d a s mall s u bset of s u bjects i n Ja pa n w here eit her 
1 8F -fl or beta pir li ga n d or 1 8F -fl ute meta m ol li ga n d will be use d. I n t he place b o-c o ntr olle d 
peri o d, a m yl oi d P E T  assess me nts are sc he d ule d at scree ni n g, Wee k 2 6, a n d Wee k  7 8.   
 
4. 4. 2  A m yl oi d P E T S U V R r e gi o ns -of -i nterest a n d refere nce re gi o ns  
A m yl oi d P E T sta n dar dize d u pta ke val ue rati o ( S U V R) is a q ua ntitati ve meas ure of cere bral 
a m yl oi d pla q ue b ur de n . T he S U V R will be calc ulate d f or t he f oll o wi n g tar get brai n re gi o ns-
of -i nterest ( R OIs): c o m p osite R OI, fr o ntal c orte x, parietal c orte x, lateral te m p oral c orte x, 
se ns ori m ot or c orte x, a nteri or ci n g ulate c orte x, p osteri or ci n g ulate c orte x, me dial te m p oral 
c orte x, occi pital c orte x, striat u m, a n d statistical R OI  n or malize d t o refere nce re gi o n acti vit y . 
A d diti o nall y, S U V R R OIs  i ncl u di n g p o ns a n d dee p s u bc ortical w hite matter w hic h are 
belie ve d t o be least affecte d b y a m yl oi d pat h ol o g y will als o be e val uate d.  T he  co m p osite R OI  
will c o m prise of maj or c ortical re gi o ns part of t he fr o ntal, parietal, lateral te m p oral, 
se ns ori m ot or, a nteri or, p osteri or ci n g ulate a n d occi pital c ortices  t o ser ve as a s u m mar y 
meas ure of gl o bal cere bral a m yl oi d b ur de n . T he s tatistical R OI is a re gi o n of i nterest 
c o nsisti n g of  t he p osteri or ci n g ulate c orte x, prec u ne us a n d me dial fr o ntal c orte x t hat  has bee n 
de m o nstrate d t o  yiel d o pti mal gr o u p se parati o n bet wee n s u bjects wit h l o w a n d hi g h a m yl oi d 
b ur de n acr oss differe nt refere nce re gi o ns.  A ne g ati ve c ha n ge fr o m baseli ne i n c o m p osite R OI 
S U V R  i n dicates a re d ucti o n i n a m yl oi d b ur de n a n d a ne gati ve  treat me nt differe nce 
(a d uca n u ma b  mi n us place b o) fa v ors a d uca n u ma b . T he c o m p osite R OI will ser ve as t he R OI 
of pri mar y f oc us.  
T he f oll o wi n g  refere nce re gi o ns will be e m pl o ye d : cere bell u m, cere bell u m cr o p pe d, 
cere bellar w hite matter, cere bellar gre y matter, dee p s u bc ortical w hite matter, p o ns, 
cere bell u m + p o ns, cere bellar w hite matter + p o ns, dee p s u bc ortical w hite matter + 
cere bell u m, dee p s u bc ortical w hite matter + p o ns a n d dee p s u bc ortical w hite matter + 
cere bell u m + p o ns. Cere bell u m will ser ve as t he refere nce re gi o n of pri mar y f oc us. 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
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T he c o m p osite R OI S U V R usi n g cere bell u m as t he refere nce re gi o n will be use d as t he 
pri mar y e n d p oi nt f or a m yl oi d P E T a nal ysis.  
4. 4. 3  A m yl oi d P E T a n al ysis p o p ul ati o n  
T here are t w o a m yl oi d P E T a nal ysis p o p ulati o n: 1 8F -fl or beta pir am yl oi d P E T a nal ysis 
p o p ulati o n  a n d 1 8F -fl ute meta m ol am yl oi d P E T a nal ysis p o p ulati o n . 
T he f oll o wi n g bac k gr o u n d c haracteristics ta bles will be ge nerate d f or  t he 1 8F -fl or beta pir 
a m yl oi d P E T a nal ysis p o p ulati o n  a n d will be prese nte d b y treat me nt gr o u p: n u m ber of 
s u bjects e nr olle d b y re gi o n a n d c o u ntr y, de m o gra p h y, baseli ne disease c haracteristics, 
me dical hist or y. T he c o nte nt of t hese ta bles will be t he sa me as t h ose descri be d i n secti o n 4. 2  
f or t he I T T p o p ulati o n, wit h t he a d diti o n of baseli ne a m yl oi d P E T S U V R val ues s u m marize d 
f or t he baseli ne c haracteristics of A D. 
4. 4. 4  B y visit s u m m ar y a n d M M R M m o del  
T he baseli ne a n d c ha n ge fr o m baseli ne a m yl oi d P E T  S U V R val ues will be s u m marize d b y 
treat me nt gr o u ps ( place b o, l o w d ose a n d hi g h d ose) a n d b y visit f or eac h of t he tar get R OIs 
usi n g cere bell u m as t he  refere nce re gi o n f or eac h of t he a m yl oi d P E T a nal ysis p o p ulati o ns. I n 
a d diti o n, t he baseli ne a n d c ha n ge fr o m baseli ne a m yl oi d c o m p osite R OI val ues will be 
s u m marize d b y treat me nt gr o u ps b y visit f or eac h of t he refere nce re gi o ns f or eac h of t he 
a m yl oi d P E T a nal ysis p o p ulati o ns .  
F or t he 1 8F -fl or beta pir a m yl oi d P E T a nal y sis p o p ulati o n, a n M M R M m o del will be use d t o 
a nal yze c ha n ge fr o m baseli ne S U V R  f or eac h tar get R OI wit h cere bell u m as t he refere nce 
re gi o n. Fi xe d effects of t he m o del will i ncl u de treat me nt gr o u ps ( place b o, l o w d ose a n d hi g h 
d ose), visit ( Wee k 2 6 a n d Wee k  7 8), treat me nt gr o u p -b y -visit i nteracti o n, baseli ne S U V R 
(c o nti n u o us), baseli ne S U V R b y visit i nteracti o n, baseli ne M M S E (c o nti n u o us), la b orat or y 
A p o E ε 4 stat us (carrier a n d n o n -carrier), a n d baseli ne a ge (c o nti n u o us). Visit a n d treat me nt 
gr o u p will be tr eate d as cate g orical varia bles i n t he m o del al o n g wit h t heir i nteracti o ns.  A n 
u nstr uct ure d c o varia nce matri x will be use d t o m o del t he wit hi n -patie nt varia nce -c o varia nce 
err ors.  If t he u nstr uct ure d c o varia nce str uct ure matri x res ults i n a lac k of c o n ver ge nce  i n a n y 
of t he para meters , t he heter o ge ne o us T oe plitz c o varia nce str uct ure f oll o we d b y t he 
heter o ge ne o us first -or der a ut ore gressi ve c o varia nce str uct ure will be use d  f or all t he 
para meters .  T he Ke n war d-R o ger a p pr o xi mati o n will be use d t o esti mate t he d e n o mi nat or 
de grees of free d o m. A dj uste d mea ns f or eac h treat me nt gr o u p , pair wise a dj uste d differe nces 
wit h place b o, 9 5 % c o nfi de nce i nter vals f or t he differe nces a n d ass ociate d p -val ues will be 
prese nte d at wee k 2 6 a n d wee k 7 8. T he sa me M M R M m o del will als o  be use d t o a nal yze t he 
c ha n ge fr o m baseli ne S U V R  f or t he c o m p osite R OI wit h eac h of t he refere nce re gi o ns. N o 
m ulti ple c o m paris o n a dj ust me nt will be use d f or a m yl oi d P E T a nal ysis.  
S u b gr o u p a nal ysis will be c o n d ucte d o n t he 1 8F -fl or beta pir a m yl oi d P E T a nal ysis p o p ulati o n 
usi n g t he sa me M M R M m o del f or c o m p osite R OI usi n g cere bell u m as refere nce re gi o n f or 
t he f oll o wi n g stratificati o n fact ors: la b orat or y A p o E stat us (carrier or n o n -carrier, a n d t his 
m o del will n ot use A p o E stat us as a c o variat e), baseli ne cli nical sta ge ( M CI d ue t o A D or 
mil d  A D ) a n d baseli ne c o m p osite R OI S U V R val ue i n q uartiles. 
Visit wi n d o ws f or by visit a n alysis  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 0  
 
F or a m yl oi d P E T  b y visit s u m maries  a n d M M R M m o dels , t he a nal ysis visit s h o ul d be 
defi ne d usi n g visit wi n d o ws (see  Ta ble 4  bel o w). T he rati o nale is t o use t he sa me a nal ysis 
visit wi n d o ws as f or t he efficac y e n d p oi nts f or Wee k 2 6 a n d Wee k 7 8. If t here is m ore t ha n 1 
val ue i n t he s a me a nal ysis visit wi n d o w ( > 1 val ue f or t he sa me a nal ysis visit) f or a certai n 
para meter f or a s u bject, t he n t he cl osest rec or d t o t he tar get visit da y  will be use d  f or t he b y 
visit a nal ysis.  If t h e y are wit h t he sa me dista nce fr o m t he tar get visit da y, t he n the rec or d 
wit h t he later ti me will be use d f or t he b y visit a nal ysis.   
T a ble 4 : Visit Wi n d o ws f or a m yl oi d P E T d at a 
A n al ysis v isit  
T ar get v isit d a y  A n al ysis v isit w i n d o w 
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 6  
1 8 3  
[ 9 2, 2 6 6 ] 
Wee k 7 8  
5 4 7  
[ 4 4 9, t he e n d da y of t he place b o-c o ntr olle d peri o d * *]  
* T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter i n L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E. 
 
4. 4. 5  C orrel ati o n bet wee n  a m yl oi d P E T a n d C D R s u m of b o xes  
Pe ars o n a n d S pe ar m a n c orrel ati o n  
Pears o n a n d S pear ma n c orrelati o n s bet wee n c ha n ge fr o m baseli ne a m yl oi d P E T c o m p osite 
R OI usi n g cere bell u m as refere nce re gi o n at Wee k 7 8 a n d c ha n ge fr o m baseli ne C D R -S B at 
Wee k 7 8  will be c o n d ucte d b y treat me nt gr o u ps ( place b o, l o w d ose a n d hi g h d ose, a n d acti ve 
t otal) i n t he 1 8F -fl or betapir  a m yl oi d P E T a nal ysis p o p ulati o n . Pears o n a n d S pear ma n partial 
c orrelati o n s a dj usti n g f or baseli ne a m yl oi d P E T c o m p osite R OI a n d baseli ne C D R -S B will 
als o be c o n d ucte d b y treat me nt gr o u ps  at Wee k 7 8 . T he esti mate d c orrelati o n c oefficie nts, p -
val ues a n d t he 9 5 % c o nfi de nce i nter vals will be pr o vi de d. Gi ve n t hat re d ucti o ns i n cere bral 
β -a m yl oi d (A β ) c o nte nt ma y prece de cli nical effects (e. g., sl o wi n g of cli nical decli ne), 
Pears o n a n d S pear ma n c orrelati o ns a n d partial c orrelati o ns bet wee n c ha n ge fr o m baseli n e 
a m yl oi d P E T c o m p osite R OI at Wee k 2 6 a n d c ha n ge fr o m baseli ne C D R -S B at Wee k 7 8  will 
als o be c o n d ucte d.  
C orrelati o n a nal ysis will be d o ne o n eac h i n di vi d ual st u d y as well as i n t he p o ole d data of t he 
2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2 st u dies. T he c orrelati o n a nal ys is base d o n t he p o ole d data will be 
c o nsi dere d as t he pri mar y a nal ysis.  
 
4. 5  S afet y A n al ysis   
4. 5. 1  Ge ner al C o nsi der ati o ns  
A n alysis p o p ul ati o n  
Safet y p o p ulati o n  will be use d f or safet y a nal yses o f A Es , cli nical la b orat or y data, 
C ol u m bia S uici de Se verit y Rati n g Scale  ( C-S S R S)  data, E C G  data a n d vital si g n data (all 
t he safet y data e xce pt f or A RI A data ). Safet y  M RI  p o p ulati o n  will be use d f or a nal yses of 
A RI A data .  
 


 
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Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 1  
 
S afety t re at me nt gr o u ps  
Differe nt fr o m t he ra n d o mizati o n treat me nt gr o u ps, if a s u bject w h o was ra n d o mize d t o 
place b o gr o u p acci de ntall y recei ve d o ne or m ore d oses of t he acti ve treat me nt d uri n g t he 
st u d y, he/s he will be classifie d as eit her l o w or hi g h d ose gr o u p f or all t he safet y a nal yses, 
de pe n di n g o n t he A p o E stat us a n d t h e ma xi mal d ose le vel of t he acti ve treat me nt recei ve d 
(Ta ble 5 ). A listi n g of s uc h s u bjects will be pr o vi de d, as descri be d i n secti o n 4. 2. 5 .  Safet y 
treat me nt gr o u ps will be  t he sa me as t he ra n d o mizati o n treat me nt gr o u ps f or ot her s u bjects 
(s u bjects ra n d o mize d t o acti ve treat me nt gr o u ps, a n d s u bjects ra n d o mize d t o place b o wit h out 
a n y acci de ntal acti ve d ose) . Safet y treat me nt gr o u ps will be use d f or all t he safet y a nal yses 
u nless ot her wise s pecifie d.  
 
T a ble 5 : S afet y tre at me nt gr o u ps f or pl ace b o s u bjects wit h acci de nt al acti ve tre at me nt 
Ra n d o mizati o n 
treat me nt 
gr o u p  
Ra n d o mizati o n 
A p o E stat us  
Safet y treat me nt gr o u p classificati o n 
base d o n t he ma xi m u m d ose le vel of 
t he acci de ntal acti ve treat me nt  
> 0 t o 3 
m g/ k g  
> 3 t o 6 
m g/ k g  
> 6 m g/ k g  
Place b o  
A p o E ε 4 ( +) 
L o w d ose  Hi g h d ose  
Hi g h d ose  
A p o E ε 4 (-) 
L o w d ose  
L o w d ose  
Hi g h d ose  
 
S afety a n alysis dis pl ay s 
A Es , cli nical la b orat or y data, C -S S R S data, E C G data a n d vital si g n data (all t he safet y data 
e xce pt f or A RI A data) will be s u m marize d b y treat me nt gr o u p  ( place b o, l o w d ose, hi g h d ose 
a n d BII B 0 3 7 t otal; a nal ysis dis pla y  A  i n A p pe n di x 6. 1 ), u nless ot her wise s pecifie d . All t he 
A RI A relate d ta bles will be prese nte d b y treat me nt gr o u p stratifie d b y A p o E stat us  ( 3 
c ol u m ns u n der eac h treat me nt gr o u p: A p o E ε4 +, A p o E ε4 - a n d t otal; a nal ysis dis pla y  B  i n 
A p pe n di x 6. 1 ), u nless ot her wise s pecifie d . A  s u bset of A E ta bles will als o be prese nte d b y 
treat me nt gr o u p stratifie d b y A p o E st at us i n a d diti o n t o b y treat me nt gr o u p. All t he listi n gs 
will be prese nte d  b y treat me nt gr o u p stratifie d b y A p o E stat us . 
 
I nci de nce, i nci de nce pr o p orti o n a n d i nci de nce r ate  
•  I nci de nce a n d i nci de nce pr o p orti o n will be pr o vi de d i n i nci de nce ta bles. I nci de nce is 
defi ne d as t he n u m ber of s u bjects w h o e x perie nce d a n e ve nt. I nci de nce pr o p orti o n is 
defi ne d as t he n u m ber of s u bjects w h o e x perie nce d  a n e ve nt di vi de d b y t otal n u m ber of 
s u bjects i n t he a nal ysis p o p ulati o n, i.e., perce nta ge. Eac h s u bject will be c o u nte d o nl y 
o nce wit hi n eac h cate g or y.  
  


 
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Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 2  
 
•  I nci de nce a n d i nci de nce rate will be pr o vi de d i n i nci de nce rate ta bles. T w o differe nt ki n ds 
of i nci de nce rate ta bles will be pr o vi de d as a p pr o priate f or differe nt a nal yses. Defi niti o ns 
are pr o vi de d bel o w.  
 
( 1) F oll o w -u p a dj uste d i nci de nce rate  –  defi ne d as  t he n u m ber of s u bjects w h o 
e x perie nce d  a n e ve nt di vi de d b y t he t otal of e ntire f oll o w-u p  ti me a m o n g t he s u bjects 
i n t he a nal ysis p o p ulati o n. T he e ntire f oll o w-u p ti me f or a s u bject is defi ne d as t he 
ti me fr o m t he first d ose u ntil t he last da y o n st u d y. Eac h s u bject will be c o u nte d o nl y 
o nce wit hi n eac h cate g or y.   
( 2) E x p os ure -a dj uste d i nci de nce rate ( E AI R) –  defi ne d as t he n u m ber of s u bjects w h o 
e x perie nce  a n e ve nt di vi de d b y t he  t otal e x p os ure a dj uste d f oll o w -u p  ti me a m o n g t he 
s u bjects i n t he a nal ysis p o p ulati o n. T he e x p os ure a dj uste d f oll o w-u p ti me is defi ne d 
as t he ti me fr o m t he first d ose  u ntil t he i nitial occ urre nce of t he e ve nt f or t h ose w h o 
e x perie nce d a n e ve nt, or  fr o m t he first d ose u ntil t he e n d of f oll o w-u p (t he last da y o n 
st u d y) f or t h ose w h o di d n ot. Eac h s u bject will be c o u nte d o nl y o nce wit hi n eac h 
cate g or y. 
 
4. 5. 2  Cli nic al A d verse E ve nts  
Tre at me nt -e mer ge nt A E s ( T E A Es) 
All A E s will be a nal yze d base d o n t he pri nci ple of treat me nt e mer ge nce.  A treat me nt -
emer ge nt A E was defi ne d as a n A E t hat starte d or w orse ne d after t he start of first i nf usi o n of 
st u d y treat me nt.  
T o defi ne treat me nt e mer ge nce f or A E s wit h missi n g start or st o p  date  or ti me  t he f oll o wi n g 
a dditi o nal criteria will be use d:  
•  if b ot h t he start a n d st o p dates f or a partic ular A E  are missi n g, t he n t hat A E  is c o nsi dere d 
treat me nt e mer ge nt; 
•  if t he start date f or a partic ular A E  is missi n g a n d t he st o p date/ti me falls after t he first 
d ose date/ti me, t he n t hat A E  is c o nsi dere d treat me nt e mer ge nt; 
•  if t he start date f or a partic ular A E was t he sa me as t he first d ose date, a n d t he start ti me 
was missi n g, t he n t hat e ve nt is c o nsi dere d treat me nt e mer ge nt.  
F or A E s wit h a part ial start date, t he year/ m o nt h of t he e ve nt date will be c o m pare d t o t hat of 
t he first d osi n g date t o deter mi ne w het her the e ve nt is treat me nt e mer ge nt.  
I n a d diti o n, S A Es t hat occ urre d si nce a s u bject was scree ne d i n t he st u d y a n d pri or t o t he first 
i nf usio n of st u d y treat me nt, w hic h b y defi niti o n are n ot treat me nt -e mer ge nt, will be a nal yze d 
se paratel y. 
O nl y T E A Es will be i ncl u de d i n t he A E ta bles, u nless  ot her wise s pecifie d. L isti n gs of A Es 
will i ncl u de all e ve nts, w het her treat me nt -e mer ge nt or n ot . 
As s pe cifie d i n t he pr ot oc ol, s u bjects were e x pecte d t o ret ur n t o t he st u d y site f or a n E n d of 
St u d y visit 1 8 wee ks after t he last a d mi nistrati o n of st u d y treat me nt.  H o we ver, s o me s u bjects 
ma y elect t o c o nti n ue st u d y partici pati o n o n a m o difie d sc he d ule after di sc o nti n ui n g 
treat me nt, p ossi bl y i n s u bsta ntial e xcess of 1 8 wee ks.  F or m ost ge neral A E s u m maries, A Es 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 3  
 
wit h a n o nset m ore t ha n 1 8 wee ks after t he last d ose will be e xcl u de d ( will s pecif y i n t he 
f o ot n ote of t he s pecific ta ble). F or i nci de nce rate a nal yses excl u di n g A Es m ore t ha n 1 8 wee ks 
after t he last d ose, t he “last da y o n st u d y” i n f oll o w -u p ti me calc ulati o n will be re place d wit h 
“ 1 8 wee ks after last d ose or last da y o n st u d y, w hic he ver earlier”.  S u m maries  of deat hs a n d 
A Es lea di n g t o st u d y wit h dra wal, a n d ot her s electe d a nal yses will i ncl u de all A Es re gar dless 
of t he ti me si nce t he last d ose.  Listi n gs will i ncl u de all A Es, u nless ot her wise s pecifie d.   
 S u m m ar y a n d i nci de nce a n al ysis  
O verall s u m mar y of A E ta ble will s u m marize t he n u m ber of s u bjects wit h a n y A E, wit h a n y 
A E  b y ma xi m u m se verit y, t he n u m ber of s u bjects wit h a n y relate d A E (relate d t o st u d y dr u g 
as assesse d b y i n vesti gat or), t he n u m ber of s u bjects wit h S A E, t he n u m ber of s u bjects wit h 
relate d S A E, t he n u m ber of s u bjects wit h A E lea di n g t o st u d y dr u g disc o nti n uati o n, t he 
n u m ber of s u bjects wit h A E lea di n g t o st u d y wit h dra wal, a n d t he n u m ber of deat hs . T his 
ta ble will be d o ne b y treat me nt gr o u p as well as b y treat me nt gr o u p stratifie d b y A p o E stat us . 
T he s orti n g or der  f or A E i nci de nce ta bles, u nless  ot her wise s pecifie d, will be b y decreasi n g 
fre q ue nc y or der of “BII B 0 3 7 t otal” c ol u m n  wit hi n eac h cate g or y  i n t he ta bles prese nte d b y 
treat me nt gr o u p, a n d b y decreasi n g fre q ue nc y or der of “ BII B 0 3 7 hi g h d ose total” c ol u m n 
wit hi n eac h cate g or y i n t he ta bles prese nte d b y treat me nt gr o u p stratifie d b y A p o E stat us . A 
s u bject is c o u nte d o nl y o nce wit hi n eac h cate g or y i n eac h ta ble. F or e xa m ple, f or t he ta ble of 
A Es b y s yste m or ga n class a n d preferre d ter ms s orte d b y decreasi n g fre q ue nc y  prese nte d b y 
treat me nt gr o u p, s yste m or ga n class will be prese nte d i n decreasi n g fre q ue nc y or der of 
BII B 0 3 7 t otal c ol u m n, a n d wit hi n eac h s yste m or ga n class, preferre d ter ms will be prese nte d 
i n decreasi n g fre q ue nc y or der of BII B 0 3 7 t otal c ol u m n. A s u bject is c o u nte d o nl y o nce 
wit hi n  eac h s yste m or ga n class a n d preferre d ter m.   
T he f oll o wi n g A E i nci de nce ta bles will be pr o vi de d  (prese nte d b ot h b y  treat me nt gr o u p a n d 
b y treat me nt gr o u p stratifie d b y A p o E stat us, u nless ot her wise s pecifie d): 
1.  A Es b y s yste m or ga n class a n d preferre d ter m s orte d b y decreasi n g fre q ue nc y  
2.  A Es b y s yste m or ga n class a n d preferre d ter m s orte d b y al p ha betical or der  (b y 
treat me nt gr o u p)  
3.  A Es b y s yste m or g a n class, hi g h le vel gr o u p ter m a n d preferre d ter m  (b y treat me nt 
gr o u p o nl y ) 
4.  A Es b y s yste m or ga n class  (b y trea t me nt gr o u p) 
5.  A Es wit h at least 2 % hi g her i n i nci de nce f or eit her l o w or hi g h d ose c o m pare d t o 
place b o  b y s yste m or ga n class a n d preferre d ter m  
6.  A Es b y preferre d ter m   
7.  A Es wit h a n i nci de nce of 5 % or m ore  i n a n y treat me nt gr o u p b y preferre d ter m  
8.  Se vere A Es b y s yste m or ga n class a n d preferre d ter m  ( b y treat me nt gr o u p) 
9.  Se vere A Es b y preferre d ter m   
1 0.  A Es b y ma xi m u m se verit y b y s yste m or ga n class a n d preferre d ter m  (b y treat me nt 
gr o u p ) ( S yste m or ga n class will be prese nte d al p ha beticall y. Preferre d ter ms will be 
prese nte d i n decreasi n g fre q ue nc y or der. Ma xi m u m se verit y will be prese nte d wit hi n 
eac h preferre d ter m i n t he or der of mil d, m o derate, se vere, u n k n o w n a n d t otal. A 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 4  
 
s u bject will be c o u nte d o nl y o nce at t he ma xi m u m se verit y wit hi n eac h s yste m or ga n 
class a n d preferre d ter m.)   
1 1.  A Es b y ma xi m u m se verit y b y preferre d ter m (b y treat me nt gr o u p ) ( Preferre d ter ms 
will be prese nte d i n decreasi n g fre q ue nc y or der. Ma xi m u m se verit y will be prese nte d 
wit hi n eac h preferre d ter m i n t he or der of mil d, m o derate, se vere, u n k n o w n a n d t otal. 
A s u bject will be c o u nte d o nl y o nce at t he ma xi m u m se verit y wit hi n eac h preferre d 
ter m.) 
1 2.  Relate d A Es b y s yste m or ga n class a n d preferre d ter m   
1 3.  S A Es b y s yste m or ga n class a n d preferre d ter m   
1 4.  S A Es b y preferre d ter m   
1 5.  Relate d S A Es b y s yste m or ga n class a n d preferre d ter m   
1 6.  A Es t hat le d t o disc o nti n uati o n of st u d y treat me nt b y s yste m or ga n class a n d preferre d 
ter m 
1 7.  A Es t hat le d t o wit h dra wal fr o m st u d y  b y s yste m or ga n class a n d preferre d ter m   
1 8.  S A Es wit h fat al o utc o me b y s yste m or ga n class a n d preferre d ter m  
1 9.  A Es t hat occ urre d wit hi n 2 h o urs fr o m i nf usi o n start b y s yste m or ga n class a n d 
preferre d ter m  (b y treat me nt gr o u p )  
2 0.  A Es b y 1 2 wee ks  i nter vals fr o m first i nf usi o n t o t he e n d of st u d y b y s yste m or ga n 
class a n d preferre d ter m (b y treat me nt gr o u p ) 
2 1.  Pre -treat me nt S A Es t hat occ urre d si nce scree ni n g a n d pri or t o first i nf usi o n b y s yste m 
or ga n class a n d preferre d ter m  
 
T he f oll o wi n g listi n gs will be pr o vi de d.  
1.  Listi n g of A Es  
2.  Listi n g of S A Es   
3.  Listi n g of A Es t hat le d t o disc o nti n uati o n of st u d y treat me nt 
4.  Listi n g of A Es t hat le d t o wit h dra wal fr o m st u d y  
5.  Listi n g of A Es t hat occ urre d wit hi n 2 h o urs fr o m i nf usi o n start  
6.  Listi n g of A Es relate d t o P E T li ga n ds   
7.  Listi n g of S A Es wit h fatal o utc o me  
8.  Listi n g of A Es f or s u bjects  wit h treat me nt-e mer ge nt p ositi ve a nti -BII B 0 3 7 a nti b o d y  
 I nci de nce r ate a n al ysis  
F oll o w -u p a dj uste d i nci de nce rate  f or t he place b o-c o ntr olle d peri o d will be s u m mari ze d b y 
s yste m or ga n class a n d preferre d ter ms b ot h b y treat me nt gr o u p a n d b y treat me nt gr o u p 
stratifie d b y A p o E stat us.  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 5  
 
 S u b gr o u p a n al ysis f or pr ot oc ol versi o n 4  
D ue t o t he c ha n ge i n ma xi mal d ose fr o m 6 m g/ k g t o 1 0 m g/ k g f or A p o E ε 4 carrier hi g h d ose 
gr o u p i n pr ot oc ol versi o n 4, n ot all s u bjects ha ve ha d o p p ort u nit y t o recei ve t he pr ot oc ol 
s pecifie d hi g h d ose ( 6 d oses i n titrati o n bef ore recei ve 1 0 m g/ k g) i n t he place b o-c o ntr olle d 
peri o d . I nci de nce ta bles of A Es a n d S A Es will be pr o vi de d f or A p o E ε 4 carriers w h o were 
ra n d o mize d t o t he hi g h d ose gr o u p, stratifie d b y t he e x pecte d n u m ber of d oses at 1 0 m g/ k g 
(cate g ories of 0, 1-6, 7 -1 3, 1 4, a n d a t otal c ol u m n of ha vi n g at least o ne d ose) a s u bject w o ul d 
ha ve recei ve d base d o n t he first i nf usi o n date a n d t he date c o nse nti n g t o pr ot oc ol versi o n 4. 
Ra n d o mizati o n treat me nt gr o u ps will be use d f or t his a nal ysis.  
 
4. 5. 3  A RI A –  A E of s peci al i nterest  
 B ac k gr o u n d  
A RI A is  a n A E of s pecial i nterest i n t his st u d y. Please see pr ot oc ol secti o n 7. 2. 1 f or A RI A 
ma na ge me nt a n d d ose dis p ositi o n g ui deli nes. Si nce A RI A is a brai n M RI fi n di n g, A RI A data 
are c ollecte d u n der t w o data s o urces: ( 1) safet y M RI data  as rec or de d o n  brai n M RI 
w or ks heet  b y ce ntral M RI rea der ; ( 2) A E e C R F. F or eac h A RI A e ve nt, t he i nf or mati o n of 
start/e n d date, se verit y, l ocati o ns i n brai n re gi o ns a n d stat us o n M RI sca n is c ollecte d o n t he 
brai n M RI w or ks heet  b y ce ntral M RI rea der. A RI A se verit y is deter mi ne d b y ce ntral M RI 
rea der base d o n n u m ber a n d size of t he A RI A re gi o ns o n i ma gi n g. A n A E rec or d is t he n 
e ntere d i nt o  t he e C R F b y t he i n vesti gat or wit h t he start/e n d date a n d se verit y i nf or mati o n 
fr o m brai n M RI w or ks heet, a n d wit h i nf or mati o n o n t he s y m pt o matic stat us a n d acti o n ta ke n  
t o war ds st u d y dr u g. If A RI A is s y m pt o matic, t he s y m pt o ms will be e ntere d i nt o A E e C R F 
a n d t he se verit y of t he s y m pt o ms will be deter mi ne d b y t he i n vesti gat or. A E e C R F data will 
be use d as t he pri mar y s o u rce f or A RI A a nal ysis as it c o ntai ns t he c o m plete i nf or mati o n of 
A RI A as well as ass ociate d s y m pt o ms . Safet y M RI data will als o be use d t o s h o w t he 
c o nsiste nc y bet wee n t w o data s o urces , pr o vi de details o n M RI assess me nts , a n d f or a n y 
s pecific a nal ysis t hat re q uires i nf or mati o n fr o m M RI. 
A RI A i ncl u des A RI A -E  (vas o ge nic e de ma)  a n d A RI A-H  ( he m orr ha ge). A RI A-H i ncl u des 
A RI A -H micr o he m orr ha ge, A RI A -H macr o he m orr ha ge a n d A RI A -H s u perficial si der osis.  
Ta ble 6  s h o ws t he re p orte d ter m o n M RI w or ks heet, t he c orres p o n di n g re p orte d ter m o n A E 
e C R F, a n d t he Me d D R A preferre d ter m  a n d l o wer le vel ter m  f or eac h t y pe of A RI A. 
 
T a ble 6 : Re p orte d a n d Me d D R A ter ms f or A RI A 
Re p orte d ter m o n 
M RI w or ks heet  
Re p orte d ter m o n A E 
e C R F  
Me d D R A versi o n 2 1. 0 
preferre d ter m  
Me d D R A 
versi o n 2 1. 0 
l o wer le vel ter m 
A RI A -E  
As y m pt o matic A RI A -E  
S y m pt o matic A RI A -E  
A m yl oi d relate d 
i ma gi n g a b n or malit y-
oe de ma/eff usi o n  
A RI A -E  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 6  
 
A RI A -H 
micr o he m orr ha ge  
As y m pt o matic A RI A -H 
( Micr o he m orr ha ge)  
S y m pt o matic A RI A -H 
( Micr o he m orr ha ge) 
A m yl oi d relate d 
i ma gi n g a b n or malit y-
micr o hae m orr ha ges 
a n d hae m osi deri n 
de p osits  
A RI A -H  
A RI A -H 
macr o he m orr ha ge  
As y m pt o matic A RI A -H 
( Macr o he m orr ha ge) 
S y m pt o ma tic A RI A-H 
( Macr o he m orr ha ge) 
A m yl oi d relate d 
i ma gi n g a b n or malit y-
micr o hae m orr ha ges 
a n d hae m osi deri n 
de p osits  
A RI A -H  
A RI A -H 
s u perficial 
si der osis 
As y m pt o matic A RI A -H 
( S u perficial Si der osis) 
S y m pt o matic A RI A -H 
( S u perficial Si der osis) 
s u perficial si der osis of 
t he ce ntral ner v o us 
s yste m 
s u perficial 
si der osis of t he 
ce ntral ner v o us 
s yste m 
 
F or a n y s pecific A RI A e ve nt, t he start date of t he d urati o n  base d o n M RI  is t he date of t he 
M RI assess me nt t hat i nitiall y i de ntifies t he A RI A e ve nt, a n d t he e n d date of t he d urati o n  
base d o n M RI  is t he date of t he M RI assess me nt t hat s h o ws t he c o m plete res ol uti o n of t his 
A RI A e ve nt (i n t he case of A RI A -E), or t he date of t he M RI assess me nt t hat s h o ws A RI A 
bei n g sta ble (i n t he case of A RI A -H). S ta ble wa s defi ne d as ‘ N o c ha n ge’ or ‘ decrease’ i n 
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 f oll o w-u p M RI s.  
F or  s y m pt o matic A RI A e ve nts, if t here is a n y relate d s y m pt o m t hat pr ocee ds t he first M RI 
i de ntificati o n, t he n t he s y m pt o m o nset date will be use d as t he start date of t he s y m pt o matic 
A RI A d urati o n. T he e n d date of t he s y m pt o matic A RI A d urati o n will be t he dat e of t he 
res ol uti o n or sta ble M RI as defi ne d a b o ve f or t he d urati o n  base d o n M RI .  
If t he se verit y i ncreases, or t he e ve nt c ha n ges fr o m as y m pt o matic t o s y m pt o matic, or fr o m 
n o n -seri o us t o seri o us, m ore t ha n o ne A E rec or ds will be a d de d t o e C R F t o ca pt ure t he 
c ha n ge wit h ne w start/e n d A E dates (t he e n d date of t he pre vi o us rec or d will be t he start date 
of t he ne xt rec or d). F or a nal ysis, rec or ds wit h c ha n ges i n se verit y or s y m pt o matic stat us  or 
seri o us ness are c o nsi dere d as a si n gle A RI A e ve nt. T he se verit y/s y m pt o matic 
stat us/seri o us ness f or t hat e ve nt is defi ne d as t he w orst le vel a m o n g all t he A E rec or ds t hat 
bel o n g t o t hat e ve nt.  
 
If t he sa me t y pe of A RI A e ve nt ha p pe ns a gai n after t he pre vi o us e ve nt has e n de d, t he n it is 
c o nsi dere d a rec urre nt e ve nt of A RI A  of t hat t y pe . Rec urre nt e ve nts will be referre d as t he 
sec o n d e ve nt , t he t hir d e ve nt , a n d etc.  
If t he d urati o n base d o n M RI  of a n A RI A -E e ve nt o verla ps wit h t he d urati o n base d o n M RI 
of a n A RI A -H e ve nt, t he n t hese 2 A RI A e ve nts are c o nsi dere d  as c o nc urre nt  e ve nts . 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 7  
 
 Inci de nce a n d s u m m ar y of  A RI A  
I nci de nce of A RI A -E, A RI A -H, A RI A -E a n d A RI A -H  ( n ot necessaril y c o nc urre nt), 
c o nc urre nt A RI A -E a n d A RI A -H, A RI A -E or A RI A -H, is olate d A RI A -H ( o nl y A RI A -H, n o 
A RI A -E), A RI A -H micr o he m orr ha ge, A RI A -H macr o he m orr ha ge a n d A RI A -H s u perficial 
si der osis will be s u m marize d base d o n b ot h A E e C R F a n d M RI data . If t here is a n y 
discre pa nc y i n i nci de nce bet wee n t he t w o data  s o urces, a listi n g of t he s u bjects a n d A RI A 
e ve nts wit h discre pa nc y will be pr o vi de d.  I n a d diti o n, t he i nci de nce ta ble base d o n A E e C R F 
s o urce will als o be d o ne b y treat me nt gr o u p ( place b o, l o w d ose, hi g h d ose a n d BII B 0 3 7 t otal; 
a nal ysis dis pla y  A  i n A p pen di x 6. 1 ).    
N u m ber of s u bjects wit h eac h t y pe of A RI A, m a xi m u m se verit y a n d w orst s y m pt o matic 
stat us of t he t y pe of A RI A bei n g a nal yze d will be s u m marize d base d o n A E e C R F. F or 
s u bjects wit h s y m pt o matic A RI A, t he ma xi m u m  se verit y of s y m pt o ms will als o be 
s u m marize d.   
N u m ber of s u bjects wit h A RI A -H micr o he m orr ha ge  e ve nt s p ost-baseli ne ( br o ke n d o w n b y 
cate g ories of 1 -4, 5 -9 a n d > = 1 0) stratifie d b y w het her t he y ha ve ha d micr o he m orr ha ge at 
baseli ne will be s u m mari ze d base d o n safet y M RI data.  T he s u m mar y will be c o n d ucte d 
base d o n t he M RI t hat s h o ws t he ma xi m u m n u m ber of micr o he m orr ha ges as well as t he last 
M RI i n t he st u d y peri o d.  
S u m mar y of c o nc urre nt A RI A -E a n d A RI A -H  will be pr o vi de d  i ncl u di n g t he f oll o wi n g 
i nf or mati o n: n u m ber of s u bjects wit h c o nc urre nt A RI A -E  a n d A RI A -H (a n d f urt her br o ke n 
d o w n  t o eac h t y pe of A RI A-H), t he se verit y of A RI A -E base d o n M RI, t he s y m pt o matic 
stat us of A RI A-E, t he se verit y of s y m pt o ms base d o n A E e C R F. F or s u bjects wit h rec urre nt 
A RI A -E e ve nts , if t here is a n e ve nt c o nc urre nt wit h A RI A -H, it will be use d f or t he 
s u m mar y, a n d t he first c o nc urre nt e ve nt will be use d if t here are m ore t ha n o ne e ve nt 
c o nc urre nt wit h  A RI A -H.  
A n i nci de nce ta ble of A Es c o nsi dere d b y t he i n vesti gat or t o be relate d t o A RI A b y s yste m 
or ga n class a n d preferre d ter m f or s u bjects wit h s y m pt o matic A RI A will be pr o vi de d, as well 
as a listi n g of t hese A Es.  Si milarl y, a n i nci de nce ta ble of A Es r elate d t o A RI A f or s u bjects 
wit h s y m pt o matic A RI A  a n d se vere s y m pt o ms will be pr o vi de d, as well as a listi n g of t hese 
A Es.  
Listi n gs  of A E rec or ds f or eac h t y pe of A RI A e ve nts a n d  listi n gs of M RI assess me nts f or 
s u bjects wit h eac h t y pe of A RI A e ve nts will be pr o vi de d.  
M o ntreal C o g niti ve Assess me nt  (M O C A ) is perf or me d at baseli ne a n d at eac h u nsc he d ule d 
A RI A m o nit ori n g visit  f or A RI A s u bjects (a p pr o xi matel y e ver y 4 wee ks) e xce pt f or mil d 
asy m pt o matic micr o he m orr ha ge s u bjects . A n i nci de nce ta ble of s u bjects wit h A RI A e ve nts 
w h ose M O C A t otal sc ores decrease  2 p oi nts or m ore fr o m baseli ne will be pr o vi de d. A listi n g 
of M RI assess me nts a n d M O C A t otal sc ore s f or s u bjects wit h A RI A e ve nts will be pr o vi de d.   
Li ne pl ots of M M S E mea n c ha n ge fr o m baseli ne val ues a n d sta n dar d err ors at eac h pla n ne d 
visit  ( baseli ne, Wee k 2 6, Wee k 5 0 a n d Wee k 7 8) will be pr o vi de d b y treat me nt gr o u p 
stratifie d b y A p o E stat us a n d wit h s tratificati o n o n t he f oll o wi n g fact ors:  
( 1) A RI A -E  se verit y base d o n M RI . T he gr o u ps are: s u bjects wit h o ut A RI A-E, s u bjects 
wit h mil d A RI A -E, s u bjects wit h m o derate A RI A -E a n d s u bjects wit h se vere A RI A -
E.  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 8  
 
( 2) Wit hi n A RI A -E s u bjects, stratif y b y t he se verit y of t he c o nc urre nt s y m pt o ms base d o n 
A E e C R F. T he gr o u ps are: s u bjects wit h o ut s y m pt o ms, s u bjects wit h mil d s y m pt o ms, 
s u bjects wit h m o derate s y m pt o ms, a n d s u bjects wit h se vere s y m pt o ms.  
F or s u bjects wit h rec urre nt A RI A -E e ve nts, t he first A RI A -E e ve nt will be use d f or t he 
classificati o n f or eac h of t he fact ors.   
 S u m m ar y  of  rec urre nt A RI A -E  
F oll o w -u p a dj uste d i nci de nce rate of s u bjects wit h A RI A -E, wit h 2 or m ore e ve nts  of A RI A -
E, wit h 3 o r m ore e ve nts of A RI A -E a n d wit h m ore t ha n 3 e ve nt s of A RI A -E base d o n  t heir 
e ntire f oll o w -u p ti me will be s u m marize d base d o n A E e C R F. T he e ntire f oll o w -u p ti me is 
fr o m t he first d ose u ntil t he last da y i n t he place b o-c o ntr olle d peri o d.  
N u m ber of t otal A R I A-E e ve nts  a n d t he M RI se verit y of eac h e ve nt  will be  s u m mari ze d 
base d o n A E e C R F. N u m ber of t otal s y m pt o matic A RI A-E e ve nts, t he M RI se verit y of eac h 
s y m pt o matic e ve nt a n d t he se verit y of t he s y m pt o ms of eac h s y m pt o matic e ve nt will be 
s u m marize d base d o n A E e C R F. 
S u m mar y of first A RI A -E e ve nt s ta ble base d o n A E e C R F will s u m marize t he n u m ber of 
s u bjects wit h a first e ve nt of A RI A -E, t he M RI se verit y of t he e ve nts, t he s ym pt o matic stat us 
of t he e ve nt s, t he se verit y of t he s y m pt o ms f or s y m pt o matic e ve nts, w het her S A E or n ot, 
n u m ber of res ol ve d a n d u nres ol ve d e ve nts, d urati o n of t he res ol ve d e ve nts, ti me fr o m first 
i nf usi o n i n st u d y (acti ve or place b o) t o o nset, n u m ber of d oses recei ve d si nce t he start of t he 
st u d y t o o nset, d ose le vel of t he last i nf usi o n recei ve d pri or t o o nset, d osi n g stat us (c o nti n ue 
as pla n ne d, d ose i nterr u pte d, d ose re d uce d, or d ose disc o nti n ue d) after t he e ve n ts, a n d t he 
n u m ber of s u bjects wit h rec urre nt A RI A -E e ve nts.  T he sa me s u m mar y of first A RI A -E 
e ve nt s ta ble will als o be d o ne  o n s u bjects w h o ha d rec urre nt A RI A -E e ve nts . 
S u m mar y of rec urre nt A RI A -E e ve nts ta ble base d o n A E e C R F will s u m marize t he f oll o wi n g 
i nf or mati o n f or b ot h t he sec o n d a n d t hir d e ve nt of A RI A -E e ve nt s: t he n u m ber of s u bjects 
wit h t he pre vi o us e ve nt of  A RI A -E, t he n u m ber of s u bjects wit h at least o ne d ose a n d o ne 
M RI after t he pre vi o us A RI A -E res ol uti o n, t he n u m ber of s u bjects wit h t his e ve nt of  A RI A -
E, t he M RI se verit y of t he e ve nts, t he s y m pt o matic stat us of t he e ve nts, t he se verit y of t he 
s y m pt o ms f or s y m pt o matic e ve nts, w het her S A E or n ot, n u m ber of res ol ve d a n d u nres ol ve d 
e ve nts, d urati o n of t he  res ol ve d e ve nts, ti me fr o m first i nf usi o n i n st u d y (acti ve or place b o) t o 
o nset, ti me fr o m pre vi o us  res ol uti o n t o o nset, n u m ber of d oses recei ve d si nce t he start of t he 
st u d y t o o nset, d ose le vel of t he last i nf usi o n recei ve d pri or t o o nset, d osi n g stat us (c o nti n ue 
as pla n ne d, d ose i nte rr u pte d, d ose re d uce d, or d ose disc o nti n ue d) after t he e ve nt s. T he 
n u m ber of s u bjects wit h m ore t ha n 3 e ve nts of A RI A -E, a n d t he n u m ber of s u bjects w h o 
disc o nti n ue d st u d y treat me nt after rec urre nt A RI A -E o nset will als o be s u m marize d.  
A listi n g of s u bjects w h o wit h dre w fr o m t he st u d y wit h u nres ol ve d A RI A-E or s u bjects wit h 
o n g oi n g A RI A -E at t he ti me of data c ut off (als o c o nsi dere d as u nres ol ve d) will be pr o vi de d  
wit h  t he details of t he e ve nt i ncl u di n g t he d urati o n fr o m o nset t o last f oll o w-u p.   
F or s u bjects wit h rec urre nt A RI A -E , a listi n g of st u d y dr u g a d mi nistrati o n , M RI assess me nts , 
se verit y a n d s y m pt o matic stat us of eac h e ve nt , a n d e n d-of -treat me nt reas o n (if prese nt) will 
be pr o vi de d.   


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 9  
 
 E x p os ure a dj uste d a n al ysis  
E x p os ure a dj uste d i nci de nce rate of A RI A -E e ve nts will  be s u m marize d base d o n safet y M RI 
data . T he e x p os ure a dj uste d f oll o w -u p ti me is fr o m t he first d ose u ntil t he i nitial occ urre nce 
of A RI A -E f or t h ose w h o e x perie nce d A RI A -E, a n d u ntil t he e n d of f oll o w -u p f or t h ose w h o 
di d n ot. Si nce A RI A is a n M RI fi n di n g, t he da y of t he last M RI assess me nt i n t he place b o-
c o ntr olle d peri o d will be use d as t he e n d of f oll o w -u p f or t h ose w h o di d n’t e x perie nce t he 
e ve nt.  
St u d y dr u g a d mi nistrati o n  i nf or mati o n pri or t o first A RI A -E o nset  will be  s u m marize d f or 
A RI A -E s u bjects, i ncl u di n g n u m ber of t otal i nf usi o ns, n u m ber of i nf usi o ns at eac h d ose le vel 
( place b o, 1 m g/ k g, 3 m g/ k g, 6 m g/ k g a n d 1 0 m g/ k g), d ose le vel of t he last i nf usi o n, 
ma xi m u m d ose le vel recei ve d, a n d c u m ulati ve d ose  as a c o nti n u o us varia ble.   
 Ti me t o e ve nt a n al ysis  
Ka pla n -Meier pl ot of ti me t o first A RI A -E e ve nt will be pr o d uce d base d o n safet y M RI data. 
Ti me t o e ve nt is calc ulate d as date of t he M RI assess me nt  t hat i nitiall y detects A RI A-E e ve nt 
- date of first i nf usi o n (a d uca n u ma b or place b o) + 1. Ce ns or ti me f or s u bjects wit h o ut A RI A-
E  is calc ulate d as date of last M RI assess me nt i n t he place b o -c o ntr olle d peri o d - date of first 
i nf usi o n (a d uca n u ma b or place b o) + 1. Esti mate d pr o p orti o n wit h A RI A -E a n d n u m ber of 
su bjects at ris k at selecte d ti me p oi nts will als o be prese nte d.  T he pl ot will be prese nte d b y 
treat me nt gr o u p stratifie d b y A p o E stat us. 
 S u b gr o u p a n al ysis f or pr ot oc ol versi o n 4  
D ue t o t he c ha n ge i n ma xi mal d ose fr o m 6 m g/ k g t o 1 0 m g/ k g f or A p o E ε4 carrier hi g h d ose 
gr o u p i n pr ot oc ol versi o n 4, n ot all s u bjects ha ve ha d o p p ort u nit y t o recei ve t he pr ot oc ol 
s pecifie d hi g h d ose ( 6 d oses i n titrati o n bef ore recei ve 1 0 m g/ k g) i n t he place b o -c o ntr olle d 
peri o d. I nci de nce of A RI A e ve nts a n d s u m mar y of first A RI A -E e v e nts ta bles will be 
pr o vi de d  f or A p o E ε4 carriers w h o were ra n d o mize d t o t he hi g h d ose gr o u p , stratifie d b y t he 
e x pecte d n u m ber of d oses at 1 0 m g/ k g ( cate g ories of 0, 1 -6, 7 -1 3, 1 4 , a n d a t otal c ol u m n of 
ha vi n g at least o ne d ose ) a s u bject w o ul d ha ve receive d base d o n t he first i nf usi o n date a n d 
t he date c o nse nti n g t o pr ot oc ol versi o n 4. Ra n d o mizati o n treat me nt gr o u ps will be use d f or 
t his a nal ysis. 
 
4. 5. 4  Cli nic al L a b or at or y D at a  
T he f oll o wi n g cli nical la b orat or y para meters are assesse d i n t he pr ot oc ol  a n d will be 
a nal yze d: 
o  He mat ol o g y:   
•  W hi te bl o o d cells  (le u k oc ytes ), l y m p h oc ytes, ne utr o p hils, m o n oc ytes, 
e osi n o p hils, bas o p hils  
•  Re d bl o o d cells  (er yt hr oc ytes ), er yt hr oc ytes distri b uti o n wi dt h, 
er yt hr oc ytes mea n c or p usc ular v ol u me, er yt hr oc ytes mea n c or p usc ular 
he m o gl o bi n, er yt hr oc ytes mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 0  
 
•  He m o gl o bi n  
•  He mat ocrit  
•  Platelet c o u nt  
o  Bl o o d c he mistr y:  
•  Li ver: a la ni ne ami n otra nsferase  (A L T ), as partate ami n otra nsferase  (A S T ), 
al kali ne p h os p hatase  ( A L P), t otal bilir u bi n, direct bilir u bi n , 
ga m ma -gl uta m yl -tra nsferase ( G G T) 
•  Re nal: b l o o d urea nitr o ge n ( B U N), creati ni ne  
•  Electr ol ytes: s o di u m, p otassi u m, c hl ori de, bicar b o nate  
•  Ot her: gl uc ose, calci u m, p h os p h or us, al b u mi n,  uric aci d,  lactate 
de h y dr o ge nase ( L D H), t otal pr otei n  
o  Uri nal ysis: s pecific gra vit y, p ote ntial of h y dr o ge n ( p H ), c ol or, bl o o d,  gl uc ose, 
ket o nes , pr otei n , w hite bl o o d cells, re d bl o o d cells 
 Q u a ntit ati ve a n al ys es  
F or n u meric la b orat or y para meters, act ual val ues, c ha n ge fr o m baseli ne a n d perce nt c ha n ge 
fr o m baseli ne will be s u m marize d b y visit. N u m ber of e val ua ble s u bjects, mea n, sta n dar d 
de viati o n, me dia n, 2 5 % a n d 7 5 % q uartiles, mi n i m u m a n d ma x i m um  val ues will be prese nte d 
at eac h visit.  
P l ots of mea n val ues  ( wit h sta n dar d err or) f or n u meric  la b orat or y para meters at eac h visit will 
be pr o vi de d.  
Listi n gs of i n di vi d ual la b orat or y meas ure me nts b y patie nts f or all t he para meters will be 
pr o vi de d.  
 
Visit wi n d o ws f or by visit s u m m aries  
F or la b orat or y b y vis it s u m maries, t he a nal ysis visit s h o ul d be defi ne d usi n g visit wi n d o ws 
(see Ta ble 7  bel o w).  If t here is m ore t ha n 1 val ue i n t he sa me anal ysis v isit w i n d o w f or a 
certai n para meter f or a s u bject , t he n t he cl osest rec or d t o t he tar get v isit d a y will be use d  f or 
t he b y visit a nal ysis.  If t here are 2 val ue s i n t he sa me a nal ysis v isit w i n d o w wit h t he sa me 
dista nce fr o m t he tar get v isit d a y f or a certai n para meter f or a s u bject , t he n t he rec or d wit h 
t he later date will be use d f or t he b y visit a nal ysis.  If t here are 2 val ues  o n t he sa me da y f or a 
certai n para meter f or a s u bject, t he n t he rec or d wit h t he later ti me will be use d f or t he b y visit 
a nal ysis . 
 
T a ble 7 : Visit Wi n d o ws f or L a b or at or y b y Visit S u m m aries 
A n al ysis v isit  
T ar get v isit d a y  A n al ysis v isit w i n d o w 
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 4  
1 6 9  
[ 2, 2 5 2 ] 
Wee k 4 8  
3 3 7  
[2 5 3 , 4 2 0 ] 
Wee k 7 2  
5 0 5  
[4 2 1 , 5 2 5 ] 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 1  
 
A n al ysis v isit  
T ar get v isit d a y  A n al ysis v isit w i n d o w 
Wee k 7 8  
5 4 7  
[5 2 6 , t he e n d da y of t he place b o-c o ntr olle d peri o d * ] 
* T he e n d da y of t he place b o-c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E.  
 
 Q u alit ati ve a n al yses  
F or all q ualitati ve a nal yses, all val ues will be i ncl u de d ( n ot j ust t he “a nal yze d rec or d” wit hi n 
eac h visit wi n d o w i n t he q ua ntitati ve a nal yses).  
 
S hift a n alyses  
La b orat or y data will be s u m marize d usi n g s hift ta bles w here a p pr o priate.  Eac h s u bject’s 
he mat ol o g y , bl o o d c he mistr y  a n d uri nal ysis n u meric val ues will be fla g ge d as “l o w”, 
“ n or mal”, or “ hi g h” relati ve t o t he n or mal ra n ges of t he ce ntral la b orat or y or as “ u n k n o w n” if 
n o res ult is a vaila ble.  Eac h s u bject’s uri nal ysis cate g orical val ues will  be fla g ge d as 
“ p ositi ve”  or  “ ne gati ve”, or “ u n k n o w n” if n o val ue is a vaila ble.   
S hifts fr o m baseli ne t o hi g h/l o w stat us will be prese nte d f or he mat ol o g y, bl o o d c he mistr y  a n d 
uri nal ysis  n u meric para meters, a n d s hifts fr o m baseli ne t o a b n or mal  ( p ositi ve) will be 
prese nte d  f or uri nal ysis cate g orical para meters .  S hift t o l o w i ncl u des n or mal t o l o w, hi g h t o 
l o w, a n d u n k n o w n t o l o w; S hift t o hi g h i ncl u des n or ma l t o hi g h, l o w t o hi g h, a n d u n k n o w n t o 
hi g h. S u bjects nee d t o ha ve at least o ne p ost -baseli ne  e val uati o n a n d a baseli ne val ue n ot l o w 
or hi g h  or p ositi ve  (i ncl u di n g missi n g) i n or der t o be i nclu de d i n t he a nal ysis.  A listi n g of 
la b orat or y n or mal ra n ges will be pr o vi de d. 
 
Gr a de a n alyses  
W orst p ost -baseli ne gra de will be s u m marize d f or eac h la b orat or y para meter  i n b ot h 
e xcl usi ve wa y a n d c u m ulati ve wa y . S u bjects nee d t o ha ve at least o ne p ost -baseli ne  
e val uati o n i n or der t o be i ncl u de d i n t he a nal ysis. C o m m o n T o xicit y Criteria f or A d verse 
E ve nts v 4 . 0. 3 ( C T C A E) p u blis he d o n 2 0 1 0 -0 6 -1 4 will be use d f or gra de deter mi nati o n . 
Gra de deter mi nati o n is base d s olel y o n la b orat or y val ues n ot ta ki n g A Es i nt o acc o u nt.  
 
P ote nti ally C li nic ally S i g nific a nt l ab or at ory a b n or m alities  a n alyses  
F or he mat ol o g y , bl o o d c he mistr y  a n d uri nal ysis , t he n u m ber of s u bjects wit h p ote ntiall y 
cli nicall y si g nifica nt la b orat or y a b n or malities p ost -baseli ne will be s u m marize d f or t he 
para meters pr o vi de d i n  Ta ble 8 . S u bjects nee d t o ha ve at least o ne p ost -baseli ne  e val uati o n 
a n d a baseli ne val ue n ot p ote ntiall y cli nicall y si g nifica nt (i ncl u di n g missi n g) i n or der t o be 
i nclu de d i n t he a nal ysis.   
T a ble 8 : Criteri a t o Deter mi ne P ote nti all y Cli nic all y Si g nific a nt ( P C S) L a b or at or y 
A b n or m alities  
Cli nic al L a b or at or y O utlier Criteri a  
P ar a meter n a me  
P C S L o w  
P C S Hi g h  
H E M A T O L O G Y  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 2  
 
Cli nic al L a b or at or y O utlier Criteri a  
P ar a meter n a me  
P C S L o w  
P C S Hi g h  
W hite bl o o d cells  
< 3. 0 x 1 0 9/ L  
> 1 6 x 1 0 9/ L  
L y m p h oc ytes  
< 0. 8 x 1 0 9/ L  
> 1 2 x 1 0 9/ L  
Ne utr o p hils  
< 1. 5 x 1 0 9/ L  
> 1 3. 5 x 1 0 9/ L  
M o n oc ytes  
N/ A  
> 2. 5 x 1 0 9/ L  
E osi n o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
Bas o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
Re d bl o o d cells  
≤3. 5 x 1 0 1 2/ L 
≥6. 4 x 1 0 1 2/ L 
He m o gl o bi n - Fe males  
≤9 5 g/ L  
≥1 7 5 g/ L  
He m o gl o bi n - Males  
≤1 1 5 g/ L  
≥1 9 0 g/ L  
He mat ocrit - Fe males  
≤3 2 %  
≥5 4 %  
He mat ocrit - Males  
≤3 7 %  
≥6 0 %  
Platelet c o u nt  
≤7 5 x 1 0 9/ L 
≥7 0 0 x 1 0 9/ L 
B L O O D C H E MI S T R Y  
Ala ni ne a mi n otra nsferase ( A L T)  
N/ A  
> 3 x U L N  
As partate a mi n otra nsferase ( A S T)  
N/ A  
> 3 x U L N  
Al kali ne p h os p hatase ( A L P) 
N/ A  
> 3 x U L N  
T otal bilir u bi n  
N/ A  
> 1. 5 x U L N   
Bl o o d urea nitr o ge n ( B U N)  
N/ A  
≥1 0 .7 m m ol/ L  
Creati ni ne  
N/ A  
≥1 7 6. 8 u m ol / L  
S o di u m  
≤1 2 6 m m ol/ L  
≥1 5 6 m m ol/ L  
P otassi u m  
≤3 m m ol/ L  
≥6 m m ol/ L  
C hl ori de  
≤9 0 m m ol/ L  
≥1 1 8 m m ol/ L  
Bicar b o nate  
≤1 6 m m ol/ L  
≥3 5 m m ol/ L  
Gl uc ose  
≤2. 2 m m ol/ L  
≥9. 7 m m ol/ L  
Calci u m  
≤2 m m ol/ L  
≥3 m m ol/ L  
P h os p h or us  
≤0. 6 m m ol/ L  
≥1. 7 m m ol/ L  
Al b u mi n  
≤2 5 g/ L  
≥6 2 5 g/ L  
T otal pr otei n  
≤4 5 g/ L  
≥1 0 0 g/ L  
U RI N A L Y SI S  
Gl uc ose  
N/ A  
≥ + + + +  
Ket o nes  
N/ A  
≥ + + + +  
Pr otei n  
N/ A  
≥ + +  
U L N = u p per li mit of n or mal  
 
P ote nti al seri o us he p at ot oxicity  
 
P ote ntial seri o us he pat ot o xicit y is defi ne d as A L T or A S T > 3 x U L N a n d t otal bilir u bi n > 2 x 
U L N at a n y ti me p ost -baseli ne, n ot necessaril y c o nc urre nt. A scatter pl ot of t he ma xi m u m 
p ost -baseli ne A L T or A S T val ue relati ve t o U L N a n d ma xi m u m p ost -baseli ne t ot al bilir u bi n 
val ue relati ve t o U L N ( n ot necessaril y c o nc urre nt) f or eac h s u bject will be pr o vi de d.  A li ne 
pl ot of A L T, A S T, A L K a n d t otal bilir u bi n val ues o ver ti me f or s u bjects wit h p ote ntial 
seri o us he pat ot o xicit y will be pr o vi de d. I n a d diti o n, s u bjects wit h  A L T > 1 x U L N, > 3 x U L N, 
> 5 x U L N , > 1 0 x U L N or > 2 0 x U L N , s u bjects wit h A S T > 1 x U L N, > 3 x U L N, > 5 x U L N , 
> 1 0 x U L N  or > 2 0 x U L N, s u bjects wit h t otal bilir u bi n > 1 x U L N or > 2 x U L N, s u bjects wit h 
A L P > 1 x U L N or > 1. 5 x U L N, a n d  s u bjects wit h A S T or A L T > 3 x U L N p ost -baseli ne 
acc o m pa nie d b y c o nc urre ntl y ele vate d t otal bilir u bi n  > 1. 5 x U L N or  > 2 x U L N  will be 
prese nte d . C o nc urre nt is defi ne d as o n t he sa me da y. A listi n g of s u bjects wit h p ote ntial 
seri o us he pat ot o xicit y will be pr o vi de d.  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 3  
 
 
4. 5. 5  C -S S R S  D at a  
T he C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) is a n assess me nt t hat e val uates 
s uici dal i deati o n a n d be ha vi or.  T here are 5 “ Yes/ N o” q uesti o ns o n suici d al i deati o n  
f oll o wi n g t he i ncreasi n g se verit y or der: ( 1) Wis h t o be dea d , ( 2) N o n -s pecific acti ve s uici dal 
t h o u g hts, ( 3) Acti ve s uici dal i deati o n wit h a n y met h o ds ( n o t pla n) wit h o ut i nte nt t o act , ( 4) 
Acti ve s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n , ( 5) Acti ve s uici dal 
i deati o n wit h s pecific pla n a n d i nte nt, a n d 6 “ Yes/ N o” q uesti o ns o n  suici dal be ha vi or 
f oll o wi n g t he i ncreasi n g se verit y or der: ( 6) Pre parat or y acts or be ha vi or, ( 7) A b orte d atte m pt, 
( 8) I nterr u pte d atte m pt, ( 9) Act ual atte m pt, ( 1 0) S uici dal be ha vi or,  ( 1 1) S uici de ( o nl y at p ost-
baseli ne visits) .  A n ot her “ Yes/ N o” q uesti o n of w het her t he s u bject has e n ga ge d i n n o n -
s uici dal self-i nj uri o us be ha vi or is als o c ollecte d.  
 
I n t he s u m mar y ta ble f or C-S S R S, n u m ber of s u bjects w h o a ns were d “ Yes” t o eac h of t he 1 1 
q uesti o ns p ost -baseli ne , s u bjects w h o a ns wer e d “ Yes” t o at least o ne q uesti o n f or s uici dal 
i deati o n, s u bjects w h o a ns were d “ Yes” t o at least o ne q uesti o n f or s uici dal be ha vi or, a n d 
s u bjects w h o ha ve e n ga ge d i n n o n-s uici dal self-i nj uri o us be ha vi or will be prese nte d. A listi n g 
of s u bjects wit h a n y s ui ci dal i deati o n or be ha vi or at baseli ne or p ost -baseli ne will be 
pr o vi de d.   
 
4. 5. 6  E C G D at a  
S hift fr o m n or mal or u n k n o w n E C G at baseli ne t o a b n or mal , n ot a d verse e ve nt or a b n or mal, 
a d verse e ve nt  p ost -baseli ne E C G will be s u m marize d  f or t he place b o-c o ntr olle d peri o d .  
S u bjects wit h a b n or mal p ost -baseli ne E C G stat us will be liste d.  
 
4. 5. 7  Vit al Si g n D at a  
V ital si g n para meters i ncl u de b o d y te m perat ure, s yst olic bl o o d press ure, diast olic bl o o d 
press ur e, heart rate, res pirati o n rate  a n d wei g ht . Vital si g ns will be meas ure d wit h t he s u bject 
s u pi ne a n d after t he s u bject has bee n resti n g f or at least 1 0 mi n utes. T he descri pti ve statistics 
f or act ual val ues a n d c ha n ge fr o m baseli ne will be s u m marize d at eac h visit . P l ot of mea n 
vital si g n val ues at eac h visit will be pr o vi de d . 
T he a nal ysis of vital si g ns will als o f oc us o n t he i nci de nce of cli nicall y rele va nt o utliers 
base d o n t he f oll o wi n g  criteria. T he i nci de nce a n d perce nta ge  of cli nicall y rele va nt o utliers 
deter mi ne d b y eac h criteri o n  will be s u m marize d . A listi n g of s u bjects wit h cli nicall y rele va nt 
vital si g ns will be pr o vi de d . 
 
T a ble 9 : Criteri a Use d t o Assess P ote nti al Cli nic all y Rele v a nt O utliers i n Vit al Si g ns 
V ari a ble  
L o w  
Hi g h  
S yst olic Bl o o d Press ure  
< 9 0 m m H g or > 2 0 m m H g 
decrease fr o m Baseli ne ( B L)  
> 1 8 0 m m H g or > 2 0 m m H g 
i ncrease fr o m B L 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 4  
 
Diast olic Bl o o d Press ure  
< 5 0 m m H g or > 1 5 m m H g 
decrease fr o m B L  
> 1 0 5 m g H g or > 1 5 m m H g 
i ncrease fr o m B L 
Heart Rate  
< 5 0 b p m or >  1 5 b p m decrease fr o m 
B L  
> 1 2 0 b p m or >  1 5 b p m i ncrease 
fr o m B L 
Te m perat ure  
> 2 de gree C decrease fr o m B L  
> 3 8. 5 C or > 2 de grees C  i ncrease 
fr o m B L 
Res pirati o n Rate  
< 1 0 breat hs per mi n ute or >  5 0 % 
decrease fr o m B L  
> 2 5 breat hs per mi n ute or > 5 0 % 
i ncrease fro m B L  
Wei g ht  
> 7 % decrease fr o m B L  
> 7 % i ncrease fr o m B L  
B L = baseli ne;  b p m = bea ts per mi n ute 
 
Visit wi n d o ws f or by visit s u m m aries  
F or vital si g n b y visit s u m maries, t he a nal ysis visit s h o ul d be defi ne d usi n g  wi n d o w s (see 
Ta ble 1 0  bel o w) . If t here is m ore t ha n 1 val ue i n t he sa me a nal ysis visit w i n d o w f or a certai n 
para meter f or a s u bject , t he n t he cl osest rec or d t o t he tar get visit da y will be use d f or t he b y 
visit a nal ysis.  If t here are 2 val ue s i n t he sa me a nal ysis visit w i n d o w wit h t he sa me dista nce 
fr o m t he tar get visit d a y f or a certai n para meter f or a s u bject, t he n t he rec or d wit h t he later 
date will be use d f or t he b y visit a na l ysis.   
 
T a ble 1 0 : Visit Wi n d o ws f or Vit al Si g n b y Visit S u m m aries 
A n al ysis v isit 
T ar get v isit d a y  A n al ysis v isit w i n d o w 
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 4  
2 9            
[ 2, 4 2 ] 
Wee k 8  
5 7  
[ 4 3, 7 0 ] 
Wee k 1 2  
8 5  
[ 7 1, 9 8 ] 
Wee k 1 6  
1 1 3  
[ 9 9, 1 2 6] 
Wee k 2 0  
1 4 1  
[ 1 2 7, 1 5 4] 
Wee k 2 4  
1 6 9  
[ 1 5 5, 1 8 2] 
Wee k 2 8  
1 9 7  
[ 1 8 3, 2 1 0] 
Wee k 3 2  
2 2 5  
[ 2 1 1, 2 3 8] 
Wee k 3 6  
2 5 3  
[ 2 3 9, 2 6 6] 
Wee k 4 0  
2 8 1  
[ 2 6 7, 2 9 4] 
Wee k 4 4  
3 0 9  
[ 2 9 5, 3 2 2] 
Wee k 4 8  
3 3 7  
[ 3 2 3, 3 5 0] 
Wee k 5 2  
3 6 5  
[ 3 5 1, 3 7 8]  
Wee k 5 6  
3 9 3  
[ 3 7 9, 4 0 6] 
Wee k 6 0  
4 2 1  
[ 4 0 7, 4 3 4] 
Wee k 6 4  
4 4 9  
[ 4 3 5, 4 6 2] 
Wee k 6 8  
4 7 7  
[ 4 6 3, 4 9 0] 
Wee k 7 2  
5 0 5  
[ 4 9 1, 5 1 8] 
Wee k 7 6  
5 3 3  
[ 5 1 9, t he e n d da y of t he place b o-c o ntr olle d peri o d * ] 
* T he e n d da y of  t he place b o-c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E.  
 
 
4. 6  P h ar m ac o ki netics A n al ysis  
T he P K a nal ysis p o p ulati o n will be use d f or t he descri pti o n of t he c o nce ntrati o n -ti me pr ofiles 
a n d f or t he esti mati o n of P K para met ers. Ra n d o mizati o n treat me nt gr o u ps will be use d f or 




 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 6  
 
 
4. 7  I m m u n o ge nicit y A n al ysis  
4. 7. 1  B ac k gr o u n d  
Defi niti o n of b aseli ne v al ue  
 
B aseli ne val ue is defi ne d as t he lat est i m m u n o ge nicit y data c ollecte d pri or t o t he first d ose . If 
n o i m m u n o ge nicit y data are c ollecte d pri or t o t he first d ose, baseli ne val ue is missi n g a n d will 
be i m p ute d as a nti -dr u g a nti b o d y ne gati ve f or i m m u n o ge nicit y a nal yses.  
 
T re at me nt-e mer ge nt a nti-a d uc a n u m a b a nti b o dy  p ositive  res p o nses 
 
P ost -baseli ne p ositi ve a nti -a d uca n u ma b a nti b o d y res p o nses are defi ne d as treat me nt-e mer ge nt 
if a s u bject is eit her  ( 1) a nti b o d y ne gati ve at baseli ne; or  ( 2) a nti b o d y p ositi ve at baseli ne b ut 
t he p ost-ba seli ne a nti b o d y res p o nse is m ore t ha n 2-f ol d i ncrease i n titer c o m pare d t o t he 
baseli ne res p o nse.  
 
P ersiste nt a n d tr a nsie nt p ositive res p o nses f or t he pl ace b o-c o ntr olle d peri o d  
 
S u bjects wit h t reat me nt-e mer ge nt p ositi ve a nti -a d uca n u ma b a nti b o d y res p o nses in t he 
place b o -c o ntr olle d peri o d will be f urt her classifie d  as tra nsie nt p ositi ve, if o nl y a si n gle 
p ositi ve e val uati o n occ urs or m ore t ha n 1 p ositi ve e val uati o n b ut occ ur wit h < 1 1 2 da ys ( 1 6 
wee ks) a part, or as persiste nt  p ositi ve , if m ore t ha n o ne c o nsec uti ve p ositi ve e val uati o n 
occ urs ≥ 1 1 2 da ys ( 1 6 wee ks) a part or  a p ositi ve e val uati o n occ urs at t he last  a vaila ble ti me 
p oi nt  wit h n o f urt her ne gati ve res ults a vaila ble  (i ncl u di n g l o n g-ter m e xte nsi o n). 
 
4. 7. 2  Im m u n o ge nicit y a n al ysis  
I m m u n o ge nicit y p o p ulati o n will be use d t o a nal yze i m m u n o ge nicit y data. Safet y treat me nt 
gr o u ps will be use d f or i m m u n o ge nicit y a nal ysis. Ta bles will be prese nte d b y treat me nt gr o u p 
( place b o, l o w d ose, hi g h d ose a n d BII B 0 3 7 t otal; a nal ysis dis pla y  A  i n A p pe n di x 6. 1 ). 
L isti n gs will be prese nte d  b y treat me nt gr o u p stratifie d b y A p o E stat us . 
A s u m mar y ta ble of s u bjects wit h treat me nt-e mer ge nt p ositi ve anti -a d uca n u ma b a nti b o d y 
res p o nses res ults will be pr o vi de d . T he n u m ber a n d perce nta ge of a nti-a d uca n u ma b  p ositi ve 
res p o nses will be s u m marize d at eac h visit  a n d at a n y ti me p ost -baseli ne . S u bjects wit h  
persiste nt  res p o nse a n d s u bjects wit h tra nsie nt res p o nse will be prese nte d. A listi n g of 
s u bjects wit h a nti-a d uca n u ma b a nti b o d y p ositi ve res ults will als o be pr o vi de d.  
 
Visit wi n d o ws f or by visit s u m m aries  
F or i m m u n o ge nicit y b y visit s u m maries, t he a nal ysis visit s h o ul d be defi ne d usi n g visit 
wi n d o ws (see Ta ble 1 1 Ta ble 7  bel o w). If t here is m ore t ha n 1 val ue i n t he sa me a nal ysis v isit 
w i n d o w f or a s u bject, t he n t he cl osest recor d t o t he tar get visit da y will be use d f or t he b y 
visit a nal ysis.  If t here are 2 val ue s i n t he sa me a nal ysis visit w i n d o w wit h t he sa me dista nce 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 7  
 
fr o m t he tar get visit d a y f or a certai n para meter f or a s u bject, t he n t he rec or d wit h t he later 
date will be use d f or t he b y visit a nal ysis .  If t here are 2 val ues o n t he sa me da y f or a certai n 
para meter f or a s u bject, t he n t he rec or d wit h t he later ti me will be use d f or t he b y visit 
a nal ysis . 
T a ble 1 1 : Visit Wi n d o ws f or I m m u n o ge nicit y b y Visit S u m m aries 
A n al ysis v isit  
T ar get v isit d a y  A n al ysis v isit w i n d o w 
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 4  
1 6 9  
[ 2, 1 9 6 ] 
Wee k 3 2  
2 2 5  
[1 9 7 , 3 0 8 ] 
Wee k 5 6  
3 9 3  
[3 9 3 , 4 7 0 ] 
Wee k 7 8  
5 4 7  
[4 7 0 , t he e n d da y of t he place b o -c o ntr olle d peri o d *] 
* T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E. 
 
 
4. 8  A d diti o n al E x pl or at or y E n d p oi nt s 
 
 
 
 
 
 
 
 
 
5  I N T E RI M A N A L Y SI S  
A n i nteri m a nal ysis will occ ur after a p pr o xi matel y 5 0 % of t he s u bjects ha ve ha d t he 
o p p ort u nit y t o c o m plete t he Wee k 7 8 visit  f or b ot h 2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2. T o mai ntai n 
t he i nte grit y of t he st u d y i n t he e ve nt of t he i nteri m a nal ysis,  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 a nal ysis. T he ID M C will re vie w t he u n bli n de d res ults of  t he i nteri m a nal ysis pr o vi de d 
b y t he i n de pe n de nt gr o u p  a n d will ma ke a rec o m me n dati o n t o Bi o ge n base d o n pre -s pecifie d 
criteria. 
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 be perf or me d  t o allo w earl y 
ter mi nati o n of t he st u dies 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 base d o n c o n diti o nal p o wer , w hic h is t he c ha nce t hat t he 
pri mar y efficac y e n d p oi nt a nal ysis will be statisticall y  si g nifica nt i n fa v or of a d uca n u ma b at 
t he pla n ne d fi nal a nal ysis, gi ve n t he data at t he i nteri m a nal ysis. T he c o n diti o nal p o wer is 
calc ulate d ass u mi n g t hat t he f ut ure u n o bser ve d effect is e q ual t o t he ma xi m u m li keli h o o d 
esti mate of w hat is o bser ve d i n t he  i nteri m data: 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
4 8  
 
𝑠𝑎(𝑑(1 ) ≥𝑗𝑠|𝑜(𝑠)) = 1 −𝑁 ( 𝑁𝛿 √𝑁2 −𝑠(𝑜)√𝑠1
√𝛿2 −𝑡1
−𝑖(𝑡)√𝑡2 −𝑡1
√𝑖1
)  
w here 𝐻 is t he fracti o n of i nf or mati o n a n d 𝛽(𝐷) is t he o bser ve d Z-statistic at t he i nteri m 
a nal ysis , 𝐼(1 ) is t he Z-statistic a n d α is t he t y pe I err or at t he fi nal a nal ysis,  𝐹1  a n d 𝐻2  are t he 
n u m ber of s u bjects at t he i nteri m a n d at t he fi nal a nal ysis, res pecti vel y.  
T he f utilit y decisi o n will pri maril y be base d o n t he c o n diti o nal p o wer f or t he pri mar y efficac y 
e n d p oi nt. T he st u d y will n ot be c o nsi dere d as f utile u nless b ot h st u dies 2 2 1 A D 3 0 1 a n d 
2 2 1 A D 3 0 2 ha ve c o n diti o nal p o wer f or t he pri mar y efficac y e n d p oi nt less t ha n 2 0 % i n b ot h 
t he hi g h-d ose a n d l o w -d ose treat me nt gr o u ps. Gi ve n t he i ns ufficie nt k n o wle d ge of 
a d uca n u ma b’s p ote ntial effects o n vari o us f u ncti o nal/c o g niti o n e n d p oi nts or i n certai n 
s u b gr o u ps at t he prese nt ti me, ot her data i n a d diti o n t o t he pre-s pecifie d f utilit y criteria will 
be c o nsi dere d as well, a n d t he I D M C ma y rec o m me n d t he st u dies t o be c o nti n ue d as pla n ne d 
base d o n t he wei g ht of t he e vi de nce.  
A n i nteri m a nal ysis f or s u peri orit y ma y be perf or me d , t o all o w t he p ossi bilit y t o de m o nstrate 
t he treat me nt effect earl y. If a n i nteri m a nal ysis f or s u peri orit y is perf or me d, t he O’ Brie n-
Fle mi n g st o p pi n g b o u n dar y will be use d. If a n i nteri m a nal ysis f or s u peri orit y is n ot 
perf or me d, t he n n o al p ha a dj ust me nt will be use d f or t he fi nal a nal ysis after all s u bjects ha ve 
ha d t he c ha nce t o c o m plete t he Wee k 7 8 visit.  
 
 
 
 
 




 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 0  
 
I nf or m e d C o ns e nt 
S u bj ect/i nf or m a nt/l e g ally a ut h oriz e d r e pr es e nt ativ e di d n ot si g n M ai n I C F, P E T 
I C F, a n d/ or S u bst u d y I C Fs ( a n d s u bst u d y pr oc e d ur es w er e c o n d uct e d). N ot cl e ar 
o n t h e I C F w h o h as b e e n si g ni n g t h e d oc u m e nt ( p ati e nt or l e g al r e pr es e nt ativ e).   
M aj or  
I nf or m e d C o ns e nt 
Pri nci p al I n v esti g at or / i n di vi d u al o bt ai ni n g c o ns e nt di d n ot si g n M ai n I C F, P E T I C F, 
a n d/ or S u bst u d y I C Fs ( a n d  s u bst u d y pr oc e d ur es w er e c o n d uct e d).  
M aj or  
I nf or m e d C o ns e nt 
N ot cl e ar o n t h e t h e  I C F w h o h as b e e n si g ni n g t h e d oc u m e nt ( p ati e nt or l e g ally 
a ut h oriz e d r e pr es e nt ativ e).   
M aj or  
I nf or m e d C o ns e nt 
I C F si g n e d b y eit h er o nly p ati e nt or o nl y c ar e giv er/l e g ally a ut h oriz e d 
r e pr es e nt ativ e, w h e n I C F s h o ul d h a v e b e e n si g n e d b y b ot h. 
M aj or  
I nf or me d C o ns e nt  
I nc orr ect or o ut d at e d v ersi o n of M ai n I C F, P E T I C F, a n d/ or S u bst u d y I C Fs si g n e d b y 
s u bj ect/i nf or m a nt/l e g ally a ut h oriz e d r e pr es e nt ativ e. 
M aj or  
I nf or m e d C o ns e nt 
I E C/I R B c o nt act d et ails or sit e's c o nt act d et ails n ot i ncl u d e d o n I C F. 
Mi n or  
I nf or m e d C o ns e nt 
I nc orr ect c o m pl eti o n of I C F (i. e., s u bj ect/st u d y p art n er/L A R/ p ers o n o bt ai ni n g 
c o ns e nt di d n ot pr o vi d e d at e of si g n at ur e; s u bj ect/st u d y p art n er/L A R/ p ers o n 
o bt ai ni n g c o ns e nt n ot e d i nc orr ect d at e of si g n at ur e; s u bj ect/st u d y 
p art n er/L A R/ p ers o n  o bt ai ni n g c o ns e nt pri nt e d n a m e w h e n s h o ul d h a v e si g n e d, 
s u bj ect/st u d y p art n er/L A R/ p ers o n o bt ai ni n g c o ns e nt si g n e d o n li n e f or pri nt e d 
n a m e, pri nt e d n a m e o n li n e f or si g n at ur e, etc.)  
Mi n or  
I nf or m e d C o ns e nt 
Sit e p ers o n n el w h o si g n e d I C F is n ot o n Sit e P ers o n n el Si g n at ur e D el e g ati o n L o g 
a n d/ or n ot a ut h oriz e d b y PI t o si g n I C F  
M aj or  
I nf or m e d C o ns e nt 
N o e vi d e nc e (s o urc e d oc u m e nt ati o n) t h at I nf or m e d C o ns e nt w as o bt ai n e d fr o m 
t h e st u d y s u bj ect / st u d y p art n er.  
M aj or  
I nf or m e d C o ns e nt 
I C F o bt ai n e d b y s u bj ect is n ot i n s u bj ect's n ativ e l a n g u a g e. 
M aj or  
I nf or m e d C o ns e nt 
Pr ot oc ol s p ecific pr oc e d ur es s uc h as p h ysic al ex a m, m e dic al hist or y, n e ur ol o gic al 
hist ory, E C Gs, r at er sc al es, l a b t ests, bl o o d dr a ws, i ncl u di n g first st u d y dr u g d os e 
p erf or m e d pri or t o t h e d at e of t h e c o ns e nt.  
M aj or  
I nf or m e d C o ns e nt 
S u bj ect a n d/ or St u d y P art n er/ C ar e gi v er n ot si g ni n g I C Fs at ti m e of r ec o ns e nt.  
M aj or  
I nf or m e d C o ns e nt 
U nti m el y r ec o ns e nti n g of s u bj ect/c ar e giv er o n n e wly a p pr o v e d I C Fs. 
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P st or a g e t e m p er at ur e o ut of r a n g e a n d  sit e us e d I P wit h o ut c o nfir m ati o n fr o m 
Bi o g e n r e g ar di n g us a bilit y  
C as e b y c as e 
b asis  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I nc orr ect c o h ort I P dis p e ns e d t o s u bj ect   
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P is n ot st or e d i n bli n d e d m a n n er. 
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
U n bli n d e d p h ar m acist disc ar d e d/ d estr o y e d us e d I P vi al pri or t o I P acc o u nt a bilit y 
b ei n g c o n d uct e d b y u n bli n d e d C R A a n d wit h o ut pr e vi o us a p pr o v al.  
c as e b y c as e 
b asis  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P t e m p er at ur e l o g is n ot b ei n g m ai nt ai n e d n or c h ec k e d b y t h e u n bli n d e d 
p h ar m acist.  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
N o n -c o m pli a nt wit h I P us a g e acc or di n g t o D H A ( n ot e: t his d o es n ot i ncl u d e 
d e vi ati o n r e g ar di n g r e m o vi n g o v erfill o n s ali n e b a g)  
M a j or 
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
D osi n g b as e d o n w ei g ht c alc ul ati o n is i n acc ur at e (i. e., discr e p a nci es b et w e e n 
W ei g ht C o m m u nic ati o n F or m a n d I X R S e ntr y, r ati o n ot r es p ect e d w h e n pr e p ari n g 
d os e, etc.)  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
O v er d os e of I P occ urs.  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
O v er d os e F or m n ot f ax e d t o Q ui ntil es Lif ec ycl e S af et y wit hi n 2 4 h o urs of sit e b ei n g 
m a d e a w ar e of a n o v er d os e.  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
Titr ati o n sc h e d ul e n ot r es p ect e d w h e n d osi n g s u bj ect. 
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
D o w n -d osi n g / disc o nti n u ati o n of d osi n g n ot r es p ect e d b y t h e u n bli n d e d 
p h ar m acist f oll o wi n g A RI A -H a n d A RI A -E c as es, as pr escri b e d b y t h e pr ot oc ol, 
i n v esti g at or, M e dic al M o nit or, a n d/ or s p o ns or.  
M aj or  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 1  
 
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
Miss e d i nf usi o n visit ( n ot d u e t o t e m p or ary disc o nti n u ati o n of d osi n g as 
pr escri b e d b y t h e pr ot oc ol, i n v esti g at or, M e dic al M o nit or, a n d/ or s p o ns or d u e t o 
A RI A -H or A RI A -E c as e).  
c as e b y c asis 
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P st or a g e t e m p er at ur e o ut of r a n g e ( 2-8 o C).  
Mi n or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
A d mi nistr ati o n of ex pir e d I P.  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P r o u n di n g discr e p a nci es n ot i n acc or d a nc e wit h t h e Dir ecti o ns f or H a n dli n g & 
A d mi nistr ati o n d oc u m e nt ( D H A).  
Mi n or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
A d mi nistr ati o n of I P t h at w as r ej ect e d aft er a t e m p er at ur e exc ursi o n.  
M aj or  
I n v esti g ati o n al Pr o d uct 
C o m pli a nc e  
I P a d mi nist er e d i n l ess t h a n 2 1 d a ys.  
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
A m bi e nt s a m pl es r ec ei v e d at c e ntr al l a b or at or y t h at s h o ul d h a v e b e e n s hi p p e d 
fr oz e n. 
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
Fr oz e n s a m pl es r ec ei v e d at c e ntr al l a b or at or y t h at s h o ul d h a v e b e e n s hi p p e d 
a m bi e nt.  
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
L a b s a m pl es n ot dr a w n, or r es ults u n a v ail a bl e.  
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
L a b or at ory r es ults n ot ac k n o wl e d g e d by PI, or m e dic ally q u alifi e d a n d d el e g at e d 
st u d y p ers o n n el.  
c as e b y c as e 
L a b or at ory ass ess m e nts 
crit eri a 
Pr e -d os e a n d/ or p ost -d os e P K s a m pl es n ot c oll ect e d, or n ot c oll ect e d wit hi n 
pr ot oc ol s p ecifi e d ti m e.  
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
C S F c ell c o u nts a n d diff er e nti als n ot s e nt t o l oc al l a b or at ory f or a n al ysis (f or 
s u bj ects p artici p ati n g wit hi n C S F s u bst u d y). 
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
L a b s p eci m e ns t e m p er at ur e l o g is n ot b ei n g m ai nt ai n e d n or c h ec k e d b y a p plic a bl e 
st u d y p ers on n el.  
M aj or  
L a b or at ory ass ess m e nts 
crit eri a 
Us e of i nc orr ect l a b kit.  
Mi n or  
L a b or at ory ass ess m e nts 
crit eri a 
 P B M C n ot c oll ect e d, or n ot c oll ect e d wit hi n pr ot oc ol s p ecifi e d ti m e.  
Mi n or  
Ot h er  
Sit e r e p e at e dl y c o m mits s a m e mi n or d e vi ati o ns.  
M aj or  
R a n d o miz ati o n crit eri a  
S u bj ect r ec or d e d as r a n d o miz e d i n I X R S b y mist a k e b ut n ot d os e d.  
M aj or  
R a n d o miz ati o n crit eri a  
S u bj ect r a n d o miz e d t o wr o n g ar m d u e t o mis -e ntry of A p o E ε 4 c arri er st at us.  
M aj or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
N o e vi d e nc e t h at I R B / C E C / L E C a p pr o v e d t h e fi n al pr ot oc ol.  
M aj or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
N o e vi d e nc e t h at I R B / C E C / L E C w as n otifi e d of pr ot oc ol a m e n d m e nts i n a ti m el y 
m a n n er.  
Mi n or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
F ail ur e t o n otif y or o bt ai n a p pr o v al fr o m t h e I R B / C E C / L E C of a c h a n g e of 
i n v esti g at or. 
Mi n or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
F ail ur e t o o bt ai n or k e e p u p d at e d r e g ul at ory a ut h oriz ati o n t o c o n d uct a st u d y.  
M aj or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
F ail ur e t o o bt ai n I R B / C E C / L E C a p pr o v al of a s u bj ect dir ect e d d oc u m e nt ( e. g., 
s u bj ect q u esti o n n air es, a d v ertis e m e nts, etc.) 
M aj or  
R e g ul at ory or Et hics A p pr o v al 
Crit eri a  
F ail ur e i n S af et y R e p orti n g as p er l oc al r e q uir e m e nts ( S U S A R S, li n e listi n gs, 
pr o gr ess r e p orts, etc.)  
Mi n or  
S eri o us A d v ers e E v e nt Crit eri a  
S A Es n ot a p pr o pri at el y r e p ort e d (i. e., r e p ort e d as a n A E w h e n S A E crit eri a h a v e 
b e e n m et, or S A E n ot r e p ort e d wit hi n 2 4 h o urs).  
M aj or  
S eri o us A d v ers e E v e nt Crit eri a  
Pr e g n a nci es n ot a p pr o pri at el y r e p ort e d wit hi n 2 4 h o urs of st u d y sit e st aff 
b ec o mi n g a w ar e of t h e pr e g n a ncy.  
M aj or  
S eri o us A d v ers e E v e nt Crit eri a  
A d v ers e Ev e nts of S p eci al I nt er est n ot r e p ort e d wit hi n 7 2 h o urs f oll o wi n g t h e 
r ec ei pt of a b n or m al M RI fi n di n gs fr o m t h e c e ntr al M RI r e a d er. 
M aj or  
S eri o us A d v ers e E v e nt Crit eri a  
S A Es n ot a p pr o pri at el y r e p ort e d t o t h e I R B/ E C.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
I nc o nsist e nt r at er us e d f or pri m ar y, s ec o n d ar y e n d p oi nts 
M aj or  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 2  
 
St u d y Pr oc e d ur es crit eri a  
C D R r at ers w er e p erf or mi n g ot h er ass ess m e nts o n s u bj ects t h ey p erf or m e d C D Rs 
f or.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
S ec o n d ar y e n d p oi nt ass ess m e nts r at ers w er e p erf or mi n g ot h er ass ess m e nts o n 
s u bj ects t h e y p erf or m e d t h es e ass ess m e nts f or. 
M aj or  
St u d y Pr oc e d ur es crit eri a  
M O C A w as a d mi nist er e d b y a r at er r at h er t h a n t h e tr e ati n g H C P.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
Ass ess m e nt p erf or m e d b y n o n -q u alifi e d r at er  
M aj or  
St u d y Pr oc e d ur es crit eri a  
A n y eli gi bilit y crit eri a n ot c o nfir m e d pri or t o d osi n g, b ut d e e m e d eli gi bl e p ost -
r a n d o miz ati o n (i ncl u di n g v erific ati o n of eli gi bility b as e d o n c a nc er crit eri a wit h 
M e dic al M o nit or [i ncl usi o n crit eri o n # 1 0]).  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
M RI a n d/ or P E T sc a n b ei n g c o n d uct e d as p art of Scr e e ni n g Visit 2 or Scr e e ni n g 
Visit 3 pr oc e d ur es wit h o ut PI v erific ati o n of eli gi bilit y at Scr e e ni n g Visit 1 
(i ncl u di n g l a b or at or y a n d c o g niti v e ass ess m e nt eli gi bilit y) wit h o ut p er missi o n of 
t h e s p o ns or/ M e dical M o nit or. Pl e as e n ot e t h at A p o E ε 4 r es ults ar e n ot n ec ess ar y 
t o m o v e o nt o Scr e e ni n g Visits 2 or 3. 
Mi n or  
St u d y Pr oc e d ur es crit eri a  
P E T sc a n b ei n g c o n d uct e d as p art of Scr e e ni n g Visit 3 pri or t o M RI c e ntr al r e a d 
c o nfir mi n g eli gi bilit y at Scr e e ni n g Visit 2, wit h o ut p er missi o n of t h e 
s p o ns or/ M e dic al M o nit or. 
Mi n or  
St u d y Pr oc e d ur es crit eri a  
D os e r e d ucti o n a d mi nist er e d b y PI/s u b -I w h e n pr ot oc ol r e q uir es r et ur n t o l ast 
d os e f oll o wi n g t e m p or ary disc o nti n u ati o n of I P f oll o wi n g A RI A e v e nt u n d er 
Pr ot oc ol v. 3.  
c as e b y c as e 
St u d y Pr oc e d ur es crit eri a  
 w as n ot a d mi nist er e d. 
Mi n or  
St u d y Pr oc e d ur es crit eri a  
Pri m ar y e n d p oi nt ass ess m e nt n ot c o n d uct e d or a d mi nist er e d at a st u d y visit, as 
p er pr ot oc ol. Pl e as e n ot e t h at d evi ati o n will n ot a p ply f or a n y c o g nitiv e 
ass ess m e nts t h at w er e n ot a d mi nist er e d or c o m pl et e d, d u e t o s u bj ect's d ecli n e i n 
c o g niti o n. 
M aj or  
St u d y Pr oc e d ur es crit eri a  
S ec o n d ar y e n d p oi nt ass ess m e nts n ot c o n d uct e d or a d mi nist er e d at a st u d y visit, 
as p er pr ot oc ol. Pl e as e n ot e t h at d e vi ati o n will n ot a p pl y f or a n y c o g nitiv e 
ass ess m e nts t h at w er e n ot a d mi nist er e d or c o m pl et e d, d u e t o s u bj ect's d ecli n e i n 
c o g niti o n. 
M aj or  
St u d y Pr oc e d ur es crit eri a  
T erti ar y e n d p oi nt effic ac y ass ess m e nts ( wit h t h e exc e pti o n of  t h e 
 a n d 
) n ot c o n d uct e d or a d mi nist er e d at a st u dy visit, as p er pr ot oc ol. Pl e as e n ot e 
t h at d e vi ati o n will n ot a p pl y f or a n y c o g nitiv e ass ess m e nts t h at w er e n ot 
a d mi nist er e d or c o m pl et e d, d u e t o s u bj ect's d ecli n e i n c o g niti o n.  
Mi n or  
St u d y  Pr oc e d ur es crit eri a  
C -S S R S n ot c o n d uct e d or a d mi nist er e d at a st u d y visit, as p er pr ot oc ol.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
S yst olic bl o o d pr ess ur e, di ast olic bl o o d pr ess ur e, h e art r at e, b o d y t e m p er at ur e, 
a n d/ or r es pir at ory r at e n ot ass ess e d as p art of vit al si g ns, or vit al si g ns n ot 
m e as ur e d wit h t h e s u bj ect s u pi n e a n d/ or aft er t h e s u bj ect h as b e e n r esti n g f or at 
l e ast 1 0 mi n ut es. 
Mi n or  
St u d y Pr oc e d ur es crit eri a  
S er u m pr e g n a nc y t est n ot c o n d uct e d at Scr e e ni n g Visit 1, or uri n e pr e g n a nc y t est 
n ot c o n d uct e d at a p plic a bl e st u d y visits f or s u bj ects of c hil d -b e ari n g p ot e nti al.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
M RI a n d/ or P E T sc a n b ei n g c o n d uct e d o n s u bs e q u e nt s u bj ects s h o ul d sit e n ot 
r ec ei v e p assi n g Q C r e p ort o n first i n-vi v o sc a n.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
A RI A m a n a g e m e nt n ot b ei n g f oll o w e d as p er pr ot oc ol s p ecific ati o ns.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
N o n -I E C/I R B a p pr o v e d d oc u m e nt(s) dis p e ns e d t o s u bj ect 
M aj or  
St u d y Pr oc e d ur es crit eri a  
U nsc h e d ul e d visit n ot c o n d uct e d d u e t o A D m e dic ati o n c h a n g e, or c o n d uct e d 
aft er A D m e dic ati o n c h a n g e occ urr e d.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
St u d y M RIs n ot c o n d uct e d wit hi n st u d y visit sc h e d ul e.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
St u d y M RIs miss e d  
M aj or  
St u d y Pr oc e d ur es crit eri a  
A d mi nistr ati o n of r ati n g sc al es o v er t h e t el e p h o n e.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
Miss e d M O C A at a n U nsc h e d ul e d M RI visit.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
Miss e d M O C A at D a y 1 Visit.  
Mi n or  
St u d y Pr oc e d ur es crit eri a  
Miss e d p h ysic al ex a m, n e ur ol o gic al ex a m, or E C G at st u d y visit.  
Mi n or  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 3  
 
St u d y Pr oc e d ur es crit eri a  
Miss e d P E T sc a n at ti m e p oi nts f or P E T s u bst u d y s u bj ects.  
M aj or  
St u d y Pr oc e d ur es crit eri a  
Li g a n d d os e a d mi nistr ati o n err or 
M aj or  
St u d y Pr oc e d ur es crit eri a  
I nf usi o n c o n d uct e d pri or t o r ec ei pt a n d r e vi e w of M RI c e ntr al r e a d r es ults  
C as e b y c as e  
Visit Sc h e d ul e Crit eri a  
St u d y visit or pr oc e d ur es c o n d uct e d o ut of wi n d o w. Pl e as e n ot e s p eci al att e nti o n 
t o t h e A D C S-A DL -M CI, A D A S -C o g, a n d N PI at Scr e e ni n g Visit 2 b ei n g c o n d uct e d 
wit hi n 1 4 d a ys of Scr e e ni n g Visit 1.  
Mi n or  
Visit Sc h e d ul e Crit eri a  
Occ urr e nc e of r a n d o miz ati o n o utsi d e of 6 0 -d a y  scr e e ni n g wi n d o w wit h o ut 
s p o ns or a p pr o v al. 
Mi n or  
Visit Sc h e d ul e Crit eri a  
Occ urr e nc e of r a n d o miz ati o n o utsi d e of 9 0 d a ys.  
M aj or  
 
 
6. 3  I m ple me nt ati o n of t he C o p y I ncre me nt fr o m Refere nce a n d P atter n 
Mi xt ure M o del  
6. 3. 1  C o p y I ncre me nt fr o m Refere nce 
T he dataset will first be i m p ute d t o m o n ot o ne missi n g usi n g P R O C MI wit h t he M C M C a n d 
i m p ute = m o n ot o ne o pti o n. I m p utati o n will be carrie d o ut 1 0 0 0 ti mes a n d a n y i nter nal missi n g 
o bser vati o ns, i ncl u di n g missi n g baseli ne c o variates a n d i nter me diate missi n g i n  t he res p o nse 
varia ble will be re place d wit h t he a vera ge acr oss all i m p utati o ns.  
F or t he res ulte d data wit h m o n ot o ne missi n g, t he f oll o wi n g ste ps will be use d t o create 
i m p ute d datasets: 
( 1) Data fr o m all patie nts will be use d t o fit a m ulti variate n or mal dist ri b uti o n wit h 
u nstr uct ure d mea n a n d u nstr uct ure d varia nce us i n g a Ba yesia n a p pr oac h wit h a 
n o ni nf or mati ve pri or f or t he mea n a n d a c o nj u gate  pri or f or t he varia nce c o varia nce 
matri x.  
( 2) Dra w a pse u d o -i n de pe n de nt sa m ple f or t he li near pre dict or para meters a n d t he 
c o varia nce para meters fr o m t he j oi nt p osteri or distri b uti o n  o btai ne d i n ste p ( 1). B ot h 
ste ps ( 1) a n d ( 2) will be d o ne usi n g P R O C M C M C i n S A S. 
( 3) Use t he li near pre dict or para meters a n d t he c o varia nce  para meters o btai ne d i n ste p ( 2) 
t o c o nstr uct ne w mea n vect ors se paratel y f or eac h treat me nt gr o u p ( place b 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 pecificall y, t he ne wl y c o nstr ucte d 
mea n vect or f or s o me o ne o n treat me nt gr o u p 𝑠 w h ose last o bser ve d visit was vis it 𝑎 
is calc ulate d as 
𝑑𝑗
(𝑠) = {
𝑜𝑠,𝑁,
𝑁𝛿 𝑁≤𝑠
𝑜𝑠,𝛿−𝑡𝑖,𝑡+ 𝑡𝑡,𝑖,𝐻𝛽 𝐷> 𝐼 
Here 𝐹 re prese nts t he place b o gr o u p. F or patie nts wit h n o p ost -baseli ne rec or ds, or 
patie nts o n t he place b o gr o u p,  t he ne wl y c o nstr ucte d mea n vect or is t he sa me as t he 
place b o mea n.  
( 4) Usi n g 𝐻𝑎
(𝛽) fr o m ste p ( 3) a n d c o varia nce para meters fr o m ste p ( 2) , fi n d t he c o n diti o nal 
n or mal distri b uti o n of t he visit wit h missi n g data, a n d use t his c o n diti o nal distri b uti o n 
t o i m p ute t he missi n g data.  
6. 3. 2  P atter n Mi xt ure M o del  
S u bjects will be assi g ne d o ne of t he f oll o wi n g t hree patter ns:  


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 4  
 
1.  C o m pleter: s u bjects wit h n o missi n g data at Wee k 2 6, 5 0 a n d 7 8  
2.  S u bjects w h o wit h dre w d ue t o reas o ns t hat ma y be relate d t o efficac y, i ncl u di n g 
c o nse n t wit h dra w n, wit h dra wal b y pare nt/ g uar dia n, i n vesti gat or decisi o n, l oss of 
ca pacit y, c ha n ge of treat me nt, a n d disease pr o gressi o n;  
3.  All t he ot her s u bjects wit h missi n g data.  
T he dataset will first be i m p ute d t o m o n ot o ne missi n g usi n g P R O C MI wit h t he M C M C a n d 
i m p ute = m o n ot o ne o pti o n. I m p utati o n will be carrie d o ut 1 0 0 0 ti mes a n d a n y i nter nal missi n g 
o bser vati o ns, i ncl u di n g missi n g baseli ne c o variates a n d i nter me diate missi n g i n t he res p o nse 
varia ble will be re place d wit h t he a vera ge acr oss all i m p utati o ns.  
F o r t he res ulte d data wit h m o n ot o ne missi n g, t he f oll o wi n g ste ps will be use d t o create 
i m p ute d datasets: 
( 1) S u bset s u bjects i n patter n 1 a n d patter n 2, a n d i m p ute t he missi n g data usi n g t he c o p y 
i ncre me nt fr o m refere nce met h o d descri be d i n Secti o n 6. 3. 1 . 
( 2) S u bset s u bjects i n patter n 1 a n d patter n 3, a n d i m p ute t he missi n g data usi n g P R O C 
MI wit h t he M O N O T O N E R E G o pti o n . 
( 3) C o m bi ne d datasets o btai ne d i n ste ps ( 1) a n d ( 2).  
 
 
 
 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 5  
 
7  R E F E R E N C E S  
Car pe nter J R, R o ger J H, Ke n war d M G. A nal ysis of l o n git u di nal trials wit h pr ot oc ol 
de viati o n: a fra me w or k f or rele va nt, accessi ble ass u m pti o ns, a n d i nfere nce via m ulti ple 
i m p utati o n. J Bi o p har m Stat. 2 0 1 3; 2 3( 6): 1 3 5 2-7 1.  
 
Ha nse n R A, Gartle h ner G, L o hr K N, et al. F u ncti o nal o utc o mes of dr u g treat me nt i n 
Alz hei mer's disease: A s yste matic re vie w a n d meta -a nal ysis. Dr u gs & a gi n g. 2 0 0 7; 2 4( 2): 1 5 5 -
6 7.  
 
I C H E 9 ( R 1): A d de n d u m t o statistical pri nci ples f or cli nical trials o n c h o osi n g a p pr o priat e 
esti ma n ds a n d defi ni n g se nsiti vit y a nal yses i n cli nical trials . E n d orse d b y t he I C H Steeri n g 
C o m mittee. 2 0 1 4.  
 
I C H E 9 ( R 1): A d de n d u m o n Esti ma n ds a n d Se nsiti vit y A nal ysis i n Cli nical Trials t o t he 
G ui deli ne o n Statistical Pri nci ples f or Cli nical Trials. E ur o pea n Me dici nes A ge nc y. 2 0 1 7.  
 
Li, J. a n d Barlas, S. Di ver ge nce effect a nal ysis i n disease -m o dif yi n g trials. Statistics i n 
Bi o p har mace utical Researc h . 2 0 1 7 ; 9: 3 9 0-3 9 8.  
 
Li, K. H. ( 1 9 8 8), "I m p utati o n Usi n g Mar k o v C hai ns,"  J o ur n al of St atistic al C o m p ut at i o n a n d 
Si m ul ati o n , 3 0, 5 7– 7 9.  
 
Little, R.J. A. ( 1 9 9 3). Patter n ‑ mi xt ure m o dels f or m ulti variate i nc o m plete data. J o ur n al of t he 
A meric a n St atistic al Ass oci ati o n, 8 8 , 1 2 5-1 3 4.  
 
Little, R.J. A. ( 1 9 9 4). A class of patter n ‑ mi xt ure m o dels f or n or mal missi n g data. Bi o metrik a,  
8 1 , 4 7 1-4 8 3 . 
 
M orris J C. T he Cli nical De me ntia Rati n g ( C D R): c urre nt versi o n a n d sc ori n g 
r ules. Ne ur ol o g y.  1 9 9 3; 4 3 ( 1 1): 2 4 1 2– 2 4 1 4.  
 
M ueller S G, Wei ner M W, T hal LJ, et al. T he Alz hei mer's Disease Ne ur oi ma gi n g I nitiati ve. 
I n: Pettrella J R, D orais wa m y P M, e ds. Ne ur oi ma gi n g Cli nics of N ort h A merica: Alz hei mer's 
Disease: 1 0 0 Years of Pr o gress. P hila del p hia: Else vier Sa u n ders; 2 0 0 5: 8 6 9 – 8 7 7.  
 
R oc k w o o d K. T he meas uri n g, mea ni n g a n d i m p orta nce of acti vities of dail y  li vi n g ( A D Ls) as 
a n o utc o me. I nt Ps yc h o geriatr. 2 0 0 7; 1 9( 3): 4 6 7 -8 2. E p u b 2 0 0 7/ 0 3/ 1 5.  
 
R u bi n, D. B. ( 1 9 7 6) “I nfere nce a n d missi n g data.” Bi o metri ka, 6 3( 3), 5 8 1 -5 9 2.  
 
R u bi n D. B. M ulti ple I m p utati o n f or N o nres p o nse i n S ur ve ys. J o h n Wile y & S o ns. 1 9 8 7.  
 
Sc hafer J. L. A nal ysis of I nc o m plete M ulti variate Data. C ha p ma n a n d Hall, Ne w Y or k. 1 9 9 7.  
 
Tracte n ber g R E, Wei ner M F, C u m mi n gs J L, Patters o n M B, T hal LJ. I n de pe n de nce of 
c ha n ges i n be ha vi or fr o m c o g niti o n a n d f u ncti o n i n c o m m u nit y -d welli n g pers o ns wit h 


 
St atistic al A n al ysis Pl a n  
Pl ace b o -C o ntr olle d Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
5 6  
 
Alz h ei mer’s disease: a fact or a nal ytic a p pr oac h.  J Ne ur o ps yc hiatr y Cli n 
Ne ur osci.  2 0 0 5; 1 7 ( 1): 5 1– 6 0.  
 
va n Gi n kel, J. R., Sijts ma, K., va n der Ar k, L. A., & Ver m u nt, J. K. ( 2 0 1 0). I nci de nce of 
missi n g ite m sc ores i n pers o nalit y meas ure me nt, a n d si m ple ite m -sc ore 
im p utati o n.  Met h o d ol o gy: E ur o pe a n J o ur n al of Rese arc h Met h o ds f or t he Be h avi or al a n d 
S oci al Scie nces, 6 ( 1), 1 7-3 0.  
 
Ya n, X., Lee, S., a n d Li, N. ( 2 0 0 9), “ Missi n g data ha n dli n g met h o ds i n me dical de vice 
cli nical trials,” J o ur nal of Bi o p har mace utical Statis tics, 1 9( 6), 1 0 8 5-1 0 9 8.  
 
Z uc ker, D. M., Wittes, J. T., Sc ha be n ber ger, O. a n d Brittai n, E. I nter nal pil ot st u dies II: 
c o m paris o n of vari o us pr oce d ures. Statistics i n Me dici ne. 1 9 9 9; 1 8: 3 4 9 3 – 3 5 0 9.  






 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3  
 
T a ble of C o nte nts  
LI S T O F A B B R E VI A TI O N S  .............................................................................................................................. 5  
1  
D E S C RI P TI O N O F L O N G -T E R M E X T E N SI O N ( L T E)  O B J E C TI V E S A N D E N D P OI N T S  ........... 7  
1. 1  
T E R TI A R Y L T E  O BJ E C TI V E S  ..................................................................................................................... 7  
1. 2  
T E R TI A R Y L T E  E N D P OI N T S ....................................................................................................................... 7  
1. 3  
A D DI TI O N A L E X P L O R A T O R Y L T E  O BJ E C TI V E  .......................................................................................... 7  
1. 4  
A D DI TI O N A L E X P L O R A T O R Y L T E  E N D P OI N T S  .......................................................................................... 8  
2  
S T U D Y D E SI G N  ......................................................................................................................................... 8  
2. 1  
S T U D Y O V E R VI E W  .................................................................................................................................... 8  
2. 2  
S T U D Y S C H E M A TI C  ................................................................................................................................. 1 1  
2. 3  
S C H E D U L E O F E V E N T S F O R L T E  P E RI O D  ................................................................................................. 1 2  
3  
S T A TI S TI C A L A N A L Y SI S M E T H O D S  ............................................................................................... 1 2  
3. 1  
G E N E R A L C O N SI D E R A TI O N S  ................................................................................................................... 1 2  
3. 1. 1  
A n alysis P o p ul ati o n  ...................................................................................................................... 1 2  
3. 1. 2  
A n alyses peri o d  ............................................................................................................................. 1 3  
3. 2  
B A C K G R O U N D C H A R A C T E RI S TI C S  .......................................................................................................... 1 4  
3. 2. 1  
Acc o u nti n g of S u bject  ................................................................................................................... 1 4  
3. 2. 2  
De m o gr a p hics a n d B aseli ne C h ar acteristics  ................................................................................ 1 4  
3. 2. 3  
C o nc o mit a nt Me dic ati o ns a n d N o n -Dr u g T her a pies  .................................................................... 1 4  
3. 2. 4  
Pr ot oc ol Devi ati o ns  ...................................................................................................................... 1 5  
3. 2. 5  
St u dy Dr u g Ex p os ure a n d St u dy Dr u g C o m pli a nce  ...................................................................... 1 5  
3. 3  
E F FI C A C Y A N A L Y SI S  ............................................................................................................................... 1 6  
3. 3. 1  
Ge ner al C o nsi der ati o ns  ................................................................................................................ 1 6  
3. 3. 2  
By Visit S u m m ary a n d M M R M M o del  .......................................................................................... 1 7  
3. 4  
A M Y L OI D P E T  A N A L Y SI S  ........................................................................................................................ 1 7  
3. 4. 1  
A myl oi d P E T s u bst u dy  .................................................................................................................. 1 7  
3. 4. 2  
A myl oi d P E T re gi o ns -of -i nterest a n d refere nce re gi o ns .............................................................. 1 8  
3. 4. 3  
A myl oi d P E T A n alysis P o p ul ati o n  ................................................................................................ 1 8  
3. 4. 4  
By Visit S u m m ary a n d M M R M M o del  .......................................................................................... 1 8  
3. 5  
S A F E T Y A N A L Y S E S  ................................................................................................................................. 1 9  
3. 5. 1  
Ge ner al C o nsi der ati o ns  ................................................................................................................ 1 9  
3. 5. 2  
Cli nic al A dverse Eve nts  ................................................................................................................ 2 1  
 
S u m mar y a n d i nci de nce a nal ysis  ............................................................................................................. 2 2  
 
I nci de nce a n d i nci de nce rate a nal ysis f or place b o-c o ntr olle d a n d L T E acti ve treat me nt peri o d  .............. 2 3  
3. 5. 3  
A RI A - A E of S peci al I nterest ........................................................................................................ 2 4  
 
Bac k gr o u n d  .............................................................................................................................................. 2 4  
 
I nci de nce a n d s u m mar y of ARI A  ............................................................................................................. 2 4  
 
S u m mar y of rec urre nt A RI A -E  ................................................................................................................ 2 5  
 
E x p os ure a dj uste d a nal ysis  ....................................................................................................................... 2 6  
 
Ti me t o e ve nt a nal ysis  .............................................................................................................................. 2 6  
3. 5. 4  
Cli nic al L a b or at ory D at a  ............................................................................................................. 2 7  
 
Q ua ntitati ve a nal yses  ............................................................................................................................... 2 7  
 
Q ualitati ve a nal yses  ................................................................................................................................. 2 8  
3. 5. 5  
C -S S R S D at a  ................................................................................................................................. 3 0  
3. 5. 6  
E C G D at a  ..................................................................................................................................... 3 0  
3. 5. 7  
Vit al Si g n D at a  ............................................................................................................................. 3 0  
3. 6  
P H A R M A C O KI N E TI C S A N A L Y SI S  .............................................................................................................. 3 2  
3. 6. 1  
Ser u m C o nce ntr ati o n Pr ofile  ........................................................................................................ 3 2  
3. 6. 2  
Ser u m P K P ar a meters  .................................................................................................................. 3 2  
3. 7  
IM M U N O G E NI CI T Y A N A L Y SI S  .................................................................................................................. 3 3  
3. 7. 1  
B ack gr o u n d  ................................................................................................................................... 3 3  
3. 7. 2  
I m m u n o ge nicity a n alysis ............................................................................................................... 3 3  
4  
A P P E N DI X  ................................................................................................................................................ 3 5  


 
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L o n g -Ter m E xte nsi o n  Peri o d  
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4. 1  
A N A L Y SI S D I S P L A Y ................................................................................................................................. 3 5  
 
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
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5  
 
List of A b bre vi ati o ns  
A β  
β -a m yl oi d 
A D  
Alz hei mer’s disease  
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 D NI  
Alz hei mer’s Disease Ne ur oi ma gi n g I nitiati ve  
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A N C O V A  
a nal ysis of c o varia nce  
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 p o E ε 4 +  
a p oli p o pr otei n E 4 carrier  
A p o E ε 4 - 
a p oli p o pr otei n E 4 n o n -carrier 
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  
B L  
baseli ne  
B L Q  
bel o w t he li mit of q ua ntificati o n  
B MI  
b o d y mass i n de x  
b p m  
beats per mi n ute  
B U N  
bl o o d urea nitr o ge n  
 
 
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  
CI R  
c o p y i ncre me nt fr o m refere nce  
C ma x  
o bser ve d ma xi m u m ser u m a d uca n u ma b c o nce ntrati o n  
C mi n  
o bser ve d mi ni m u m ser u m a d uca n u ma b c o nce ntrati o n  
C S F  
cere br os pi nal fl ui d  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C T C A T  
C o m m o n T o xicit y Criteria f or A d verse E ve nts  
C V  
c oefficie nt of variati o n  
E AI R  
e x p os ure -a dj uste d i nci de nce rate  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E Q -5 D  
E ur o Q ol healt h stat us mea s ure 
 
 
 
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 


 
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L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
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F U  
F oll o w -u p  
G C P  
G o o d Cli nical Practice  
G G T  
ga m ma -gl uta m yl -tra nsferase 
H C P  
healt h care pr ofessi o nal  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o 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 R B 
i nstit uti o nal re vie w b oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I T T 
i nte nt-t o-treat 
I X R S 
I nteracti ve V oice/ We b Res p o nse S yste m 
L D H  
lactate de h y dr o ge nase 
L M CI  
late mil d c o g niti ve i m pair me nt 
L T E  
l o n g-ter m e xte nsi o n 
L O C F  
last o bser vati o n carrie d f or war d 
M CI  
mil d c o g niti ve i m pair me nt  
M C M C  
Mar k o v c hai n M o nte Carl o  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
mi 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 -A A  
Nati o nal I nstit ute o n A gi n g -Alz hei mer’s Ass ociati o n  
N PI -1 0  
Ne ur o ps yc hiatric I n ve nt or y -1 0  
P C S  
p ote ntiall y cli nicall y si g nifica nt  
P E T  
p ositr o n e missi o n t o m o gra p h y  
p H  
p ote ntial of h y dr o ge n  
PI  
Pri nci pal I n vesti gat or  
P K  
p har mac o ki netic(s)  
P M M  
patter n mi xt ure m o del  
P P  
per -pr ot oc ol  
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 OI  
re gi o n of i nterest 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S U S A R  
s us pecte d u ne x pected seri o us a d verse reacti o n  
S U V R  
sta n dar d u pta ke val ue rati o 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
 
 
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
W H O  
W orl d Healt h Or ga nizati o n  


 
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1  D E S C RI P TI O N O F L O N G -T E R M  E X T E N SI O N  ( L T E) 
O B J E C TI V E S  A N D E N D P OI N T S   
1. 1  
Terti ar y L T E O bjecti 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 uca n u ma b i n s u bjects 
wit h earl y Alz hei mer’s Disease  (A 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 diol o gical, a n d healt h o utc o mes assess me nts.  
 
1. 2  
 Terti ar y L T E E n d p oi nts  
•  T he i nci de nce of a d verse e ve nts ( A Es ) a n d seri o us a d verse e ve nts (S A Es ); brai n 
ma g netic res o na nce i ma gi n g ( M RI ) fi n di n gs (i ncl u di n g t he i nci de nce of a m yl oi d 
relate d i ma gi n g a b n or malit y-e de ma [A RI A -E ] a n d 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 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 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. 
•  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 peri o ds of t he 
st u d y: 
− Cli nical De me ntia Rati n g s u m of b o xes ( C D R -S B ) sc ore. 
− Mi ni -Me ntal State E xa mi nati o n ( M M S E ) sc ore. 
− 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 sc ore ]. 
− 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 sc ore ]. 
− A m yl oi d p ositr o n e missi o n t o m o gra p h y ( P E T ) si g nal (i n a s u bset of sites a n d 
s u bjects). 
− Ne ur o ps yc hiatric I n ve nt or y -1 0 ( N PI -1 0 ) t otal sc ores. 
− Inf or ma nt -rate d E ur o Q ol healt h stat us meas ures  (E Q -5 D ) i n de x sc ore.  
 
1. 3  
A d diti o n al E x pl or at or y L T E O bjecti ve  
•  
 
  
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
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1. 4  
A d diti o n al E x pl or at or y L T E E n d p oi nts  
•  
 
 
− 
 
 
− 
 
 
− 
 
 
− 
 
 
− 
 
  
− 
 
− 
 
− 
 
 
2  S T U D Y D E SI G N  
2. 1  
St u d y O ver vie w  
St u d y 2 2 1 A D 3 0 2  (E M E R G E ) 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 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, f oll o we d b y a n o pti o nal d ose -bli n d e d l o n g-ter m 
e xte nsi o n ( L T E ) peri o d of u p t o 5 years . A p pr o xi matel y 1 6 0 5  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 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 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. T he 
o bjecti ves of L T E  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.   
S u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 1 of t he 3  treat me nt gr o u ps: a d uca n u ma b hi g h 
d ose, a d uca n u ma b l o w d ose a n d place b o , wit h stratificati o n base d u p o n t heir a p oli p o pr otei n 
E 4  (A p o E  ε 4) carrier stat us  (carrier/ n o n-carrier) a n d site . D uri n g t he place b o -c o ntr olle d 
peri o d, su 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).  D ose le vels ma y be differe nt i n t he 
sa me treat me nt gr o u p base d u p o n s u bjects’ A p o E ε 4 carrier stat us, a n d s pecificall y, 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 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
9  
 
Ta ble 1  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 ε4 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 mize 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 oc ol 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.  
 
T a ble 1 : 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: Pl ace b o -c o ntr olle d Peri o d  
D ose (e ver y 4 wee ks) 
1  
2  
3  
4  
5  
6  
7 t o 2 0  
Tre at me nt 
Gr o u p  
Tre at me nt Gr o u p Str atifie d b y 
A p o E St at us 2  
D ose ( m g/ k g)  
H i g h D ose 
Hi g h D ose  - A p o E ε 4 ( +)  
1  
1  
3  
3  
6  
6  
1 0 1 
Hi g h D ose  - A p o E ε 4 ( -) 
1  
1  
3  
3  
6  
6  
1 0  
L o w D ose  
L o w D ose  - A p o E ε 4 ( +)  
1  
1  
3  
3  
3  
3  
3  
L o w D ose  - A p o E ε 4 ( -) 
1  
1  
3  
3  
3  
3  
6  
Pl ace b o  
Pl ace b o  - A p o E ε 4 ( +)  
saline  
Pl ace b o  - A p o E ε 4 ( -) 
sali ne 
1 1 0 m g/ k g is t he tar get d ose f or all A p o E ε4 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 1 -3 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.   
2 A p o E ε 4 stat us rec or de d i n t he I nteracti ve V oice/ W e b Res p o nse S yste m (I X R S).   
 
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 nt er 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 
years ). T he treat me nt gr o u p f or t he L T E peri o d will be assi g ne d at t he sa me ti me as t he 
ra n d o mizati o n f or t he place b o-c o ntr olle d peri o d, re gar dless of w het her a s u bject e nteri n g t he 
L T E peri o d or n ot. S u bjects w h o are assi g ne d t o 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 assi g ne d t o 1 of 2 acti ve treat me nt gr o u ps i n a 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)  a n d ra n d o mizati o n will be stratifie d b y t heir 
A p o E ε 4 carrier stat us; f or t h ose w h o e nter t he L T E peri o 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 descr i be d f or t he 
place b o -c o ntr olle d peri o d . S u bjects w h o are assi g ne d t o eit her a d uca n u ma b l o w d ose or 
a d uca n u ma b hi g h d ose gr o u p i n t he place b o-c o ntr olle d peri o d will c o nti n ue i n t he sa me 
treat me nt gr o u p f or t he L T E peri o d; t h ose 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 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 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 or t he late start s u bjects as s h o w n i n  Ta ble 2   a n d Fi g ure 1 . 
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 0  
 
T a ble 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: L o n g -Ter m E xte nsi o n Peri o d  
D ose s (e ver y 4 wee ks ) 
1  
2  
3  
4  
5  
6  
7 -
E O S  
L T E Tre at me nt 
Gr o u p  
L T E Tre at me nt Gr o u p 
Str atifie d b y A p o E St at us 1 
D ose ( m g/ k g)  
E arl y St art Hi g h 
D ose  
E arl y St art Hi g h D ose –  
A p o E ε 4 ( +) 
1 0  
E arl y St art Hi g h  D ose –  
A p o E ε 4 (-) 
1 0  
E arl y St art L o w 
D ose  
E arl y St art L o w D ose –  
A p o E ε 4 ( +) 
3  
E arl y St art L o w D ose –  
A p o E ε 4 (-) 
6  
L ate  St art Hi g h 
D ose  
L ate St art Hi g h D ose –  
A p o E ε 4 ( +) 
1  
1  
3  
3  
6  
6  
1 0  
L at e St art Hi g h D ose –  
A p o E ε 4 (-) 
1  
1  
3  
3  
6  
6  
1 0  
L ate  St art L o w 
D ose  
L ate St art L o w D ose –  
A p o E ε 4 ( +) 
1  
1  
3  
L ate St art L o w D ose –  
A p o E ε 4 (-) 
1  
1  
3  
3  
3  
3  
6  
1 A p o E ε 4 stat us rec or de d i n t he I nteracti ve V oice/ W e b Res p o nse S yste m (I X R S).   
 
I n di vi d ual d ose a dj ust me nts ma y be i m ple me nte d i n s u bjects w h o de vel o p a m yl oi d relate d 
i ma gi n g a b n or malities (A RI A ). See  Pr ot oc ol Secti o n  7. 2. 1 . 
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 wi ll 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 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 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 o f 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 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 .  
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.  


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 1  
 
2. 2  
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. 
* 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 ( stratifie d b y 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 . 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 2  
 
2. 3  
Sc he d ule of E ve nts f or L T E peri o d  
See pr ot oc ol s ecti o n 4. 2. 
 
3  S T A TI S TI C A L A N A L Y SI S M E T H O D S  
3. 1  
Ge ner al C o nsi der ati o ns  
T his statistical a nal ysis pla n (S A P ) c o vers t he a nal ys es of t he L T E peri o d a n d t he a nal yses 
acr oss b ot h t he place b o -c o ntr olle d peri o d a n d t he L T E peri o d .  
S u m mar y ta bles will be prese nte d  usi n g descri pti ve s u m mar y statistics . F or c o nti n u o us 
varia bles , s u m mar y statistics will ge nerall y i ncl u de: n u m ber of s u bjects wit h data, mea n, 
sta n dar d de viati o n, me dia n, 2 5 % perce ntile, 7 5 % perce ntile,  mi ni m u m a n d ma xi m u m.  F or 
cate g orical varia bles , 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.  
T here are t w o t y pes of a nal ysis dis pla ys f or t he a nal yses of t he L T E peri o d: b y L T E treat me nt 
gr o u p (a nal ysis dis pla y A i n A p pe n di x 4. 1 ) a n d b y L T E treat me nt gr o u p stratifie d b y A p o E 
stat us (a nal ysis dis pla y B i n A p pe n di x 4. 1 ; here A p o E stat us refers t o t he stat us rec or de d i n 
I X R S [see Ta ble 2  f or c orres p o n de nce bet wee n L T E treat me nt gr o u ps a n d L T E treat me nt 
gr o u ps stratifie d b y A p o E stat us ]). T he a nal ysis dis pl a y f or eac h a nal ysis will be defi ne d i n 
eac h secti o n. All t he listi n gs will be prese nte d b y L T E treat me nt gr o u p stratifie d b y A p o E 
stat us, u nless ot her wise s pecifie d. 
U nless ot her wise s pecifie d, baseli ne refers t o t he b aseli ne val ue f or t he place b o -c o ntr olle d 
peri o d a n d is defi ne d as t he m ost rece nt n o n-missi n g meas ure me nt c ollecte d pri or t o t he first 
d ose. C ha n ge fr o m baseli ne will be defi ne d as p ost -baseli ne val ue mi n us baseli ne val ue.  
U nless state d ot her wise, all statistical tests will be 2 -si de d wit h statistical si g nifica nce le vel of 
0. 0 5.  
T he statistical s oft ware, S A S ®  will be use d f or all s u m maries  a n d a nal yses .  
 
3. 1. 1  A n al ysis P o p ul ati o n  
•  I nte nt-t o-treat (I T T) p o p ulati o n:  
T he I nte nt-t o-treat p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o).  
 
•  
1 8F -fl or beta pir am yl oi d P E T a nal ysis p o p ulati o n : 
T he 1 8F -fl or beta pir a m yl oi d P E T a nal ysis p o p ulati o n is defi ne d as all ra n d o mize d s u bjects 
w h o recei ve d at least o ne d ose of st u d y treat me nt (a d u ca n u ma b or place b o), use d 1 8F -
fl or beta pir li ga n d f or a m yl oi d P E T sca n, a n d ha d a n e val ua ble  baseli ne a m yl oi d P E T 
S U V R val ue f or t he c o m p osite re gi o n -of -i nterest usi n g cere bell u m as t he refere nce 
re gi o n. 
 
•  
1 8F -fl ute meta m ol a m yl oi d P E T a nal ysis p o p ulati o n : 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 3  
 
T h e 1 8F -fl ute meta m ol a m yl oi d P E T a nal ysis p o p ulati o n is defi ne d as all ra n d o mize d 
s u bjects w h o recei ve d at least o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o), use d 
1 8F -fl ute meta m ol li ga n d f or a m yl oi d P E T sca n, a n d ha d a n e val ua ble  baseli ne a m yl oi d 
P E T  S U V R val ue f or t he c o m p osite re gi o n -of -i nterest usi n g cere bell u m as t he refere nce 
re gi o n. 
 
•  Safet y p o p ulati o n :  
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least o ne d ose 
of st u d y treat me nt (a d uca n u ma b or place b o). It is t he  sa me p o p ulati o n as t he I T T 
p o p ulati o n.  
 
•  Safet y  M RI  p o p ulati o n :  
T he safet y M RI p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) a n d ha d at least o ne p ost -baseli ne 
M RI assess me nt.  
 
•  P K a nal ysis p o p ulati o n:   
T he P K  a nal ysis  p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) a n d ha d at least o ne meas ura ble 
a d uca n u ma b c o nce ntrati o n i n ser u m.  
 
•  I m m u n o ge nicit y p o p ulati 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 ra n d o mize d s u bjects w h o 
recei ve d at least o ne d ose of st u d y treat me nt (a d uca n u ma b or place b o) a n d ha d at least 
o ne p ost -d ose sa m ple e val uate d f or i m m u n o ge nicit y.  
 
 
3. 1. 2  A n al yses peri o d  
De pe n di n g o n  t he p ur p ose, differe nt a nal yses will be c o n d ucte d o n t he f oll o wi n g st u d y 
peri o ds:  
1.  L T E peri o d. O nl y data i n t he L T E peri o d will be i ncl u de d i n t hese a nal yses. F or 
e xa m ple, i nci de nce ta ble of a d verse e ve nts i n t he L T E peri o d.  
2.  Place b o -c o ntr olle d a n d L T E per i o d. All t he data i n t he place b o -c o ntr olle d a n d L T E 
peri o d s will be i ncl u de d i n t hese a nal yses. F or e xa m ple, mea n pl ot of act ual 
la b orat or y val ues i n t he place b o -c o ntr olle d a n d L T E peri o d.  
3.  Place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d. Acti ve treat me n t peri o d is 
defi ne d as t he st u d y peri o d(s) t hat a s u bject is assi g ne d t o a d uca n u ma b. F or earl y start 
s u bjects –  s u bjects w h o are assi g ne d t o a d uca n u ma b i n b ot h place b o -c o ntr olle d a n d 
L T E peri o d, all t he data ( place b o -c o ntr olle d a n d L T E peri o ds) will be i nc l u de d i n t he 
a nal yses. F or late start s u bjects  –  s u bjects w h o are assi g ne d t o  a d uca n u ma b i n t he 
L T E peri o d, o nl y data i n t he L T E peri o d will be i ncl u de d. F or e xa m ple, i nci de nce 
ta ble of a d verse e ve nts i n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d.     


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 4  
 
S u bjects  t o be i ncl u de d i n a certai n o ut p ut  is deter mi ne d b y b ot h t he a nal ysis p o p ulati o n a n d 
t he a nal ysis  peri o d. F or e xa m ple, t he i nci de nce ta ble of a d verse e ve nts i n t he L T E peri o d  will 
i ncl u de s u bjects i n t he safet y p o p ulati o n f or t he L T E peri od, i.e., all ra n d o mize d s u bjects w h o 
recei ve d at least o ne d ose of st u d y treat me nt i n t he L T E peri o d. T he i nci de nce ta ble of 
a d verse e ve nts i n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d will i ncl u de 
s u bjects i n t he safet y p o p ulati o n f or t he acti ve treat me nt peri o d, i.e., all ra n d o mize d s u bjects 
w h o recei ve d at least o ne d ose of st u d y treat me nt i n t he acti ve treat me nt peri o d. I n t his S A P 
we d o n ot se paratel y defi ne t he a nal ysis p o p ulati o n i n eac h a nal ysis  peri o d.  
 
3. 2  
B ac k gr o u n d C h ar acteristics  
T he s u m maries i n t his secti o n will be base d o n t he I T T p o p ulati o n. A nal ysis  peri o d will be 
s pecifie d f or eac h ta ble or fi g ure. U nless ot her wise s pecifie d, s u m mar y ta bles will be 
prese nte d b y L T E treat me nt gr o u p a n d b y L T E treat me nt gr o u p stratifie d b y A p o E status  (see 
Ta ble 2  f or c orres p o n de nce bet wee n L T E treat me nt gr o u ps a n d L T E treat me nt gr o u ps 
stratifie d b y A p o E stat us). L isti n gs will i ncl u de all data i n t he place b o -c o ntr olle d a n d L T E 
peri o d s (all data i n t he st u d y), wit h a n i n dicator of t he st u d y peri o d ( pre-d osi n g, place b o -
c o ntr olle d, or L T E) f or eac h rec or d t o i n dicate w he n t he e ve nt occ urre d. Listi n gs will be 
prese nte d b y  L T E  treat me nt gr o u p stratifie d b y A p o E stat us. 
3. 2. 1  Acc o u nti n g of S u bject  
Dis p ositi o n i n t he L T E peri o d will be s u m marize d f or  s u bjects e nr olle d i n L T E. T he 
s u m mar y data will i ncl u de n u m ber ( %) of s u bjects d ose d  i n t he L T E peri o d, n u m ber ( %) of 
s u bjects w h o c o m plete d t he treat me nt/st u d y i n L T E, a n d n u m ber ( %) of s u bjects w h o 
disc o nti n ue d treat me nt a n d/ or wit h dre w fr o m  st u d y i n L T E. F or s u bjects w h o disc o nti n ue d  
treat me nt a n d/ or wit h dre w fr o m st u d y, the reas o ns f or  disc o nti n uati o n a n d/ or wit h dra wal, 
da ys o n treat me nt a n d da ys o n st u d y will be  s u m marize d a n d liste d. Ti me t o treat me nt 
disc o nti n uati o n a n d ti me t o st u d y with dra wal i n t he L T E peri o d will be dis pla ye d b y Ka pla n -
Meier pl ot  ( prese nte d b y L T E treat me nt gr o u p). 
3. 2. 2  De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hics, baseli ne c haracteristics , me dical hist or y a n d A D treat me nt hist or y will be 
s u m marize d f or s u bjects e nr olle d i n t he L T E peri o d  a n d s u bjects n ot e nr olle d i n t he L T E 
peri o d, res pecti vel y . De m o gra p hics a n d baseli ne c haracteristics will als o be s u m mari ze d  f or 
all I T T s u bjects  ( prese nte d b y L T E treat me nt gr o u p). Please refer t o t he S A P f or t he place b o -
c o ntr ol le d peri o d f or m ore details.  
3. 2. 3  C o nc o mit a nt Me dic ati o ns a n d N o n -Dr u g  T her a pies  
T he n u m ber ( %) of s u bjects ta ki n g c o nc o mita nt me dicati o n a n d n o n -dr u g t hera pies i n t he 
L T E peri o d will be s u m marize d. N o n -dr u g t hera pies will be prese nte d b y L T E treat me nt 
gr o u p. I n a d diti o n, n u m ber of s u bjects i n t he I T T p o p ulati o n t hat ha ve ta ke n a n y c o nc o mita nt 
me dicati o ns i n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d  will be s u m marize d . 
C o nc o mita nt me dicati o ns a n d n o n -dr u g t hera pies will be liste d.   


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 5  
 
F or s u bjects e nr olle d i n t he L T E peri o d, t he n u m ber ( %) of s u bjects ta ki n g c o nc o mita nt A D 
s y m pt o matic me dicati o ns, n u m ber of s u bjects usi n g C h oli nesterase i n hi bit ors o nl y , 
Me ma nti ne  o nl y , or b ot h at t he baseli ne of t he place b o -c o ntr olle d peri o d will be s u m marize d.  
A si mil ar s u m mar y will be pr o vi de d f or s u bjects ta ki n g A D s y m pt o matic me dicati o n 
c o nc o mita ntl y at t he baseli ne of t he L T E peri o d.  S u bjects w h o ha ve a n y c ha n ge i n A D 
s y m pt o matic me dicati o ns d uri n g t he L T E peri o d  will be s u m marize d b y t he ti mi n g of c ha n ge, 
i.e., t he n u m ber of  s u bjects c ha n gi n g bet wee n Wee k 8 0  a n d Wee k 1 0 6 , t he n u m ber of 
s u bjects c ha n gi n g bet wee n Wee k 1 0 6 a n d Wee k 1 3 4 , etc. T he s u m mar y f or A D s y m pt o matic 
me dicati o n use d uri n g t he L T E peri o d will be prese nte d b y L T E treat me nt gr o u p.  T he start 
a n d st o p  date  of A D s y m pt o matic me dicati o n  will be liste d f or s u bjects  w h o ha ve a n y c ha n ge 
t o A D s y m pt o matic me dicati o ns d uri n g t he c o m bi ne d place b o-c o ntr olle d a n d L T E peri o ds . 
Please refer t o t he place b o -c o ntr olle d S A P f or d efi niti o ns of c o nc o mita nt t hera pies a n d  A D 
s y m pt o matic me dicati o n use at baseli ne. 
3. 2. 4  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns i de ntifie d d uri n g site m o nit ori n g will be ca pt ure d i n a Pr ot oc ol De viati o n 
l o g a n d cate g orize d as maj or or mi n or de viati o ns base d o n Pr ot oc ol De viati o n Classificati o n 
(see A p pe n di x  of t he place b o -c o ntr olle d S A P ). T he maj or pr ot oc ol de viati o ns occ urre d i n t he 
L T E peri o d will be s u m marize d f or s u bjects e nr olle d i n L T E. T he maj or pr ot oc ol de viati o ns 
f or all I T T s u bjects i n t he c o m bi ne d place b o-c o ntr olle d a n d L T E peri o ds  will al s o be 
s u m marize d.  M aj or a n d mi n or pr ot oc ol de viati o ns  f or all I T T s u bjects will be liste d, 
res pecti vel y, acr oss t he place b o -c o ntr olle d peri o d a n d t he L T E peri o d. All s u m maries f or 
pr ot oc ol de viati o ns will be prese nte d b y L T E treat me nt gr o u p.  
3. 2. 5  St u d y Dr u g E x p os ure a n d St u d y Dr u g C o m pli a nce  
A s u m mar y ta ble of st u d y dr u g e x p os ure a n d c o m plia nce i n t he L T E peri o d will be pr o vi de d. 
N u m ber of i nf usi o ns (a d uca n u ma b or place b o) recei ve d will be s u m mari ze d as a cate g orical 
varia ble  (cate g ories of  1 -5, 6 -1 0, 1 1 -1 5, 1 6 -2 0 , 2 1 -2 6 , 2 7-3 9, 4 0 -5 2  a n d 5 3 -6 5 ) as well as a 
c o nti n u o us varia ble. N u m ber of wee ks o n st u d y treat me nt (a d uca n u ma b or place b o), 
calc ulate d as ( date of last d ose –  date of first d ose + 2 9 )/ 7, will be s u m mari ze d as a cate g orical 
varia ble  (e ver y 6 m o nt hs f or  t he first 2 years of L T E, a n d t he n e ver y year ) as well as a 
c o nti n u o us varia ble. Perce nta ge of st u d y treat me nt ta ke n u p t o t he last d ose, calc ulate d as (t he 
act ual n u m ber of i nf usi o ns / b y t he n u m ber of i nf usi o ns a s u bject is e x pecte d t o ta ke u ntil t he 
da te of last i nf usi o n) *1 0 0, will be s u m marize d as a c o nti n u o us varia ble. T his ta ble will be 
prese nte d b y L T E treat me nt gr o u p. A si milar ta ble will als o be pr o vi de d o n t he place b o -
c o ntr olle d a n d L T E acti ve treat me nt peri o d i n or der t o s u m marize t he e x p os ure d ata w hile 
s u bjects are o n a d uca n u ma b.  
D ue t o t he use of titrati o n re gi me n i n t he st u d y a n d p ossi ble d ose re d ucti o n d ue t o A RI A, 
a n ot her s u m mar y ta ble will be pr o vi de d i ncl u di n g t he f oll o wi n g i nf or mati o n  i n t he L T E 
peri o d : n u m ber of t otal i nf usi o ns (cate g ories of 1-5, 6 -1 0, 1 1 -1 5, 1 6 -2 0 , 2 1 -2 6 , 2 7-3 9, 4 0 -5 2 
a n d 5 3 -6 5 ) as well as a c o nti n u o us varia ble , n u m ber of i nf usi o ns at eac h d ose le vel ( 1 m g/ k g, 
3 m g/ k g, 6 m g/ k g a n d 1 0 m g/ k g, res pecti vel y) s u m marize d as a cate g orical varia ble as well 
as a c o nti n u o us var ia ble, n u m ber of s u bjects wit h d ose i ncrease ( place b o t o 1 m g/ k g, 1 t o 3 
m g/ k g, 3 t o 6 m g/ k g a n d 6 t o 1 0 m g/ k g, res pecti vel y), n u m ber of s u bjects wit h d ose re d ucti o n 
( 1 m g/ k g t o place b o, 3 t o 1 m g/ k g, 6 t o 3 m g/ k g a n d 1 0 t o 6 m g/ k g, res pecti vel y), ma xi m u m 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 6  
 
d ose le vel recei ve d, a n d c u m ulati ve d ose (as a c o nti n u o us varia ble). T his ta ble will be 
s u m marize d b y L T E  treat me nt gr o u p stratifie d b y A p o E stat us. A si milar ta ble will als o be 
pr o vi de d o n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d i n or der t o  s u m marize 
t he titrati o n a n d d ose re d ucti o n data w hile s u bjects are o n a d uca n u ma b.  
A listi n g of st u d y dr u g a d mi nistrati o n rec or ds, i ncl u di n g d ose le vel at eac h i nf usi o n, 
c u m ulati ve n u m ber of i nf usi o ns a n d c u m ulati ve d ose will be pr o vi de d f or t he place b o -
co ntr olle d a n d L T E peri o d.  A listi n g of a d uca n u ma b l ot n u m bers will be pr o vi de d f or t he 
place b o -c o ntr olle d a n d L T E peri o d . 
 
3. 3  
Effic ac y  A n al ysis  
3. 3. 1  Ge ner al C o nsi der ati o ns  
T he a nal ysis p o p ulati o n  f or efficac y a nal ysis is t he sa me as t he I T T p o p ulati o n a n d data fr o m 
b ot h t he place b o -c o ntr olle d a n d L T E peri o ds will be i ncl u de d . All efficac y a nal yses will be 
prese nte d b y L T E treat me nt gr o u p, i.e, late start l o w d ose, late start hi g h d ose, earl y start l o w 
d ose, earl y start hi g h d ose (a nal ysis dis pla y A i n A p pe n di x 4. 1 ). 
T he f oll o wi n g t w o c o m paris o ns will be e val uate d f or t he l o n g-ter m efficac y of a d uca n u ma b: 
•  T he earl y start l o w d ose c o m pare d wit h t he late start l o w d ose;  
•  T he earl y start hi g h d ose c o m pare d wit h t he late start hi g h d ose.  
T here  will be n o m ulti ple c o m paris o n a dj ust me nts.  
 
Visit wi n d o ws f or m a p pi n g effic acy e n d p oi nt  
F or efficac y data t hat are s u m marize d or a nal yze d b y visit, data c ollecte d o n all sc he d ule d 
visits a n d all u nsc he d ule d visits will be ma p pe d t o a n a p pr o priate a nal ys is visit usi n g t he 
wi n d o wi n g sc he me s h o w n i n  Ta ble 3 . If t here are 2 or m ore assess me nts a vaila ble i n t he 
sa me a nal ysis wi n d o w f or a s u bject, t he assess me nt t hat is cl osest t o t he tar get visit da y will 
be use d f or a nal ysis. If t he re are 2 or m ore assess me nts i n t he sa me a nal ysis wi n d o w wit h t he 
sa me dista nce fr o m t he tar get visit da y, t he later assess me nt will be use d.  
 
T a ble 3 : Visit Wi n d o ws f or Effic ac y E n d p oi nts 
A n al ysis visit  
T ar get visit d a y  
A n al ysis visit wi n d o w  
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 6  
1 8 3  
[ 92 , 2 66 ] 
Wee k 5 0  
3 5 1  
[ 2 67 , 4 48 ] 
Wee k 7 8  
5 4 7  
[ 44 9 , t he e n d da y of t he place b o-c o ntr olle d peri o d * ] 
Wee k 1 0 6  
7 4 3  
[6 4 5 , 8 40 ] 
Wee k 1 3 4  
9 3 9  
[ 8 41 , 1 0 36 ] 
Wee k 1 6 2  
1 1 3 5  
[ 1 0 37 , 1 2 04 ] 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 7  
 
A n al ysis visit  
T ar get visit d a y  
A n al ysis visit wi n d o w  
Wee k 1 8 2  
1 2 7 5  
[1 2 0 5 , 1 3 6 5]  
Wee k 2 3 2  
1 6 2 5  
[1 5 3 5, 1 7 1 5]  
Wee k 2 8 4  
1 9 8 9  
[1 8 9 9, 2 0 7 9 ] 
Wee k 3 3 8  
2 3 6 7  
≥ 2 2 7 7  
* T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, a n d is t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E. 
 
H a n dli n g of missi n g ite ms f or sc ales  
Please refer t o t he p lace b o-c o ntr olle d S A P f or t he i m p utati o n met h o d. Sa me met h o d will be 
a p plie d t o efficac y e n d p oi nts c ollecte d i n t he L T E peri o d.  
 
3. 3. 2  B y Visit S u m m ar y  a n d M M R M M o del  
T he baseli ne a n d c ha n ge fr o m baseli ne C D R -S B sc ores at eac h p ost -baseli ne visit will be 
s u m marize d b y L T E treat me nt gr o u p. A mi xe d m o del re peate d meas ures ( M M R M) m o del 
will be use d t o a nal yze c ha n ge fr o m baseli ne C D R -S B usi n g fi xe d effects of L T E treat me nt 
gr o u p , ti me (cate g orical), L T E treat me nt gr o u p -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  i nteracti o n, baseli ne M M S E, A D s y m pt o matic me dicati o n use at 
baseli ne  ( yes/ n o), re gi o n, a n d la b orat or y A p o E ε 4 stat us  (carrier/ n o n-carrier) . A n 
u nstr uct ure d c o varia nce matri x will be use d t o m o del t he wit hi n -patie nt varia nce -c o varia nce 
err ors.  If t he u nstr uct ure d c o varia nce str uct ure matri x res ults i n a lac k of c o n ver ge nce, t he 
heter o ge ne o us T oe plitz c o varia nce str uct ure f oll o we d b y t he heter o ge ne o us first -or der 
a ut ore gressi ve c o varia nce str uct ure will be use d.  T he Ke n war d -R o ger a p pr o xi mati o n will be 
use d t o esti mate t he de n o mi nat or de grees of free d o m.  Visits wit h t o o fe w data ma y be 
e xcl u de d fr o m t he M M R M a nal ysis a n d be a nal yze d b y A N C O V A i nstea d.  
T he b y visit s u m mar y a n d M M R M a nal ysis will be si milarl y perf or me d f or C D R c o g niti ve 
s u bsc ore, C D R f u ncti o nal s u bsc ore, M M S E, 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 . 
O nl y t he b y visit s u m mar y will be perf or me d f or C D R b o x sc ores  a n d i nf or ma nt-rate d E Q-
5 D.  T he distri b uti o n of  C D R gl o bal sc ore will be s u m marize d as a cate g orical varia ble at 
eac h p ost-baseli ne visit.  
 
 
3. 4  
A m yl oi d P E T a n al ysis  
3. 4. 1  A m yl oi d P E T s u bst u d y  
Please refer t o t he place b o -c o ntr olle d S A P.  
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 8  
 
3. 4. 2  A m yl oi d P E T r e gi o ns -of -i nterest a n d refere nce re gi o ns  
Please refer t o t he place b o -c o ntr olle d S A P.  
 
3. 4. 3  A m yl oi d P E T A n al ysis P o p ul ati o n  
Please refer t o t he place b o -c o ntr olle d S A P.  
 
3. 4. 4  B y Visit S u m m ar y a n d M M R M M o del  
All t he a nal yses will be prese nte d b y L T E treat me nt gr o u p  (earl y start l o w d ose, earl y start 
hi g h d ose, late start l o w d ose, late start hi g h d ose ). T he f oll o wi n g t w o c o m paris o ns will be 
e val uate d f o r a m yl oi d P E T S U V R i n t he L T E peri o d: 
•  T he earl y start l o w d ose c o m pare d wit h t he late start l o w d ose;  
•  T he earl y start hi g h d ose c o m pare d wit h t he late start hi g h d ose.  
 
T he baseli ne a n d c ha n ge fr o m baseli ne a m yl oi d P E T S U V R val ues  will be s u m marize d b y 
L T E  treat me nt gr o u ps b y visit f or all t he visits i n t he place b o-c o ntr olle d a n d L T E peri o d f or 
eac h of t he tar get  R OI s usi n g cere bell u m as t he  refere nce re gi o n f or eac h of t he a m yl oi d P E T 
a nal ysis p o p ulati o ns . I n a d diti o n, the baseli ne a n d c ha n ge fr o m baseli ne  a m yl oi d c o m p osite 
R OI val ue s will be s u m marize d b y L T E treat me nt gr o u ps b y visit f or eac h refere nce re gi o ns 
f or eac h of t he a m yl oi d P E T a nal ysis p o p ulati o ns.  
F or t he 1 8F -fl or beta pir a m yl oi d P E T a nal ysis p o p ulati o n , a n M M R M m o del will be use d t o 
a nal yze c ha n ge fr o m baseli ne S U V R f or eac h  tar get R OI wit h cere bell u m as t he refere nce 
re gi o n f or all t he visits i n t he place b o-c o ntr olle d a n d L T E peri o d. Fi xe d effects of t he m o del 
will i ncl u de L T E treat me nt gr o u ps, visit, treat me nt gr o u p -b y -visit i nteracti o n, bas eli ne S U V R 
(c o nti n u o us), baseli ne S U V R b y visit i nteracti o n, baseli ne M M S E (c o nti n u o us), la b orat or y 
A p o E ε 4 stat us (carrier a n d n o n -carrier), a n d baseli ne a ge (c o nti n u o us). Visit a n d treat me nt 
gr o u p will be treate d as cate g orical varia bles i n t he m o del al o n g wit h t heir i nteracti o ns. A n 
u nstr uct ure d c o varia nce matri x will be use d t o m o del t he wit hi n -patie nt varia nce -c o varia nce 
err ors.  If t he u nstr uct ure d c o varia nce str uct ure matri x res ults i n a lac k of c o n ver ge nce i n a n y 
of t he para meters, t he heter o ge ne o us T oe plitz c o varia nce str uct u re f oll o we d b y t he 
heter o ge ne o us first -or der a ut ore gressi ve c o varia nce str uct ure will be use d f or all t he 
para meters.  T he Ke n war d -R o ger a p pr o xi mati o n will be use d t o esti mate t he de n o mi nat or 
de grees of free d o m. A dj uste d mea ns f or eac h treat me nt gr o u p, pai r wise a dj uste d differe nces 
f or t he c o m paris o ns, 9 5 % c o nfi de nce i nter vals f or t he differe nces a n d ass ociate d p-val ues 
will be prese nte d at eac h visit. Visits wit h t o o fe w data ma y be e xcl u de d fr o m t he M M R M 
a nal ysis a n d be a nal yze d b y A N C O V A i nstea d. T he sa m e M M R M m o del will als o be use d t o 
a nal yze t he c ha n ge fr o m baseli ne S U V R f or t he c o m p osite R OI wit h eac h of t he refere nce 
re gi o ns. N o m ulti ple c o m paris o n a dj ust me nt will be use d f or a m yl oi d P E T a nal ysis. 
 
Visit Wi n d o ws f or by visit a n alyses  
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
1 9  
 
F or a m yl oi d P E T  b y visit s u m maries a n d M M R M m o dels, t he a nal ysis visit s h o ul d be 
defi ne d usi n g visit wi n d o ws (see Ta ble 4  bel o w).  T he rati o nale is t o use t he sa me a nal ysis 
visit wi n d o ws as f or t he efficac y e n d p oi nts f or t he visits t hat t he efficac y e n d p oi nts are als o 
c ollecte d . Si nce t he visit f or t he efficac y meas ure me nts is o n Wee k 1 3 4, w hile t he visit f or 
a m yl oi d P E T meas ure me nts is o n Wee k 1 3 2, t he start of t he a nal ysis visit wi n d o w f or Wee k 
1 3 2 a m yl oi d P E T is 2 wee ks earlier t ha n t hat f or e fficac y, w hile t he sa me e n d of t he a nal ysis 
visit wi n d o w as Wee k 1 3 4 is use d t o be c o nser vati ve. If t here is m ore t ha n 1  val ue i n t he 
sa me a nal ysis visit wi n d o w ( > 1 val ue f or t he sa me a nal ysis visit) f or a certai n para meter f or a 
s u bject, t he n t he cl osest rec or d t o t he tar get visit da y will be use d f or t he b y visit a nal ysis.  If 
t he y are wit h t he sa me dista nce fr o m t he tar get visit da y, t hen t he  rec or d wit h t he later ti me  
will be use d  f or t he b y visit a nal ysis.   
 
T a ble 4 . Visit Wi n do ws f or a m yl oi d P E T d at a  
A n al ysis visit *  
T ar get visit d a y  
A n al ysis visit wi n d o w  
Baseli ne  
1  
M ost rece nt n o n -missi n g pre -d ose val ue  
Wee k 2 6  
1 8 3  
[ 9 2, 2 6 6] 
Wee k 7 8  
5 4 7  
[ 4 4 9, t he e n d da y of t he place b o-c o ntr olle d peri o d 1] 
Wee k 1 3 2  
9 2 5  
[ 8 2 7, 1 0 3 6] 
Wee k 1 8 2  
1 2 7 5  
[1 2 0 5 , 1 3 6 5] 
Wee k 2 6 0  
1 8 2 1  
[ 1 7 3 1, 1 9 1 1] 
Wee k 3 3 8  
2 3 6 7  
≥ 2 2 7 7  
*   A nal ysis visit is t he visit at w hic h t he s pecific wee k starte d.  
1. T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E, a n d is 
t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E.  
2. T he start da y of t he L T E peri o d is t he da y of first i nf usi o n i n L T E peri o d.  
 
 
3. 5  
S afet y A n al yses  
3. 5. 1  Ge ner al C o nsi der ati o ns  
A n alysis p o p ul ati o n  
Safet y p o p ulati o n  will be use d f or safet y a nal yses o f A Es , cli nical la b orat or y data, C ol u m bia 
S uici de Se verit y Rati n g Scale ( C-S S R S)  data, E C G  data a n d vital si g n data (all t he safet y 
data e xce pt f or A RI A data ). Safet y  M RI  p o p ulati o n  will be use d f or a nal yses of A RI A data.  
 
L T E s afety tre at me nt gr o u ps  
Si nce all t he s u bjects are  s u p p ose d t o recei ve acti ve treat me nt i n L T E, t he L T E safet y 
treat me nt gr o u ps w hic h are e xactl y t he sa me as t he L T E ra n d o mizati o n treat me nt gr o u ps will 
be use d  f or all t he safet y a nal yses. S u bjects w h o were ra n d o mize d t o place b o gr o u p b ut 
acci de ntall y recei ve d o ne or m ore d oses of t he acti ve treat me nt d uri n g t he  place b o -c o ntr olle d 
peri o d will still be classifie d as late start f or all t he safet y a nal yses t hat i n v ol ves L T E, b ut 
t heir a p plica ble safet y data i n t he place b o-c o ntr olle d peri o d will be i ncl u de d i n t he a nal ysis 
f or place b o-c o ntr olle d a n d L T E acti ve treat m e nt peri o d. 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 0  
 
 
S afety a n alysis peri o d  
A nal ysis peri o d will be s pecifie d f or eac h o ut p ut.  Safet y data i n t he s pecifie d a nal ysis peri o d 
will be i ncl u de d i n t he a nal ysis. Listi n gs will i ncl u de all data i n t he place b o -c o ntr olle d a n d 
L T E peri o d , u nless ot her wise  s pecifie d. 
 
S afety a n alysis dis pl ays  
F or eit her a nal ysis peri o d i n t his S A P ( L T E peri o d, place b o -c o ntr olle d a n d L T E peri o d, or 
place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d), A E s, cli nical la b orat or y data, C -S S R S 
data, E C G data a n d vital si g n data (a ll t he safet y data e xce pt f or A RI A data) will be 
s u m marize d b y L T E treat me nt gr o u p (late start l o w d ose, late start hi g h d ose, earl y start l o w 
d ose, earl y start hi g h d ose, a n d i n a d diti o n late start t otal, earl y start t otal a n d BII B 0 3 7 t otal; 
a nal ysis dis p la y A i n A p pe n di x 4. 1 ), u nless ot her wise s pecifie d . A RI A ta bles will be 
prese nte d b y L T E treat me nt gr o u p stratifie d b y A p o E stat us ( 3 c ol u m ns u n der eac h of t he 4 
L T E treat me nt gr o u ps: A p o E ε4 +, A p o E ε4 - a n d t otal, a n d i n a d diti o n late start t otal a n d 
earl y start t otal; a nal ysis dis pla y B i n A p pe n di x 4. 1 ), u nless ot her wise s pecifie d . A s u bset of 
A E ta bles  will als o be prese nte d b y L T E treat me nt gr o u p stratifie d b y A p o E stat us  i n a d diti o n 
t o b y L T E treat me nt gr o u p. Listi n gs will be prese nte d b y L T E treat me nt gr o u p stratifie d b y 
A p o E stat us , wit h a n i n dicat or of t he st u d y peri o d ( pre -d osi n g, place b o -c o ntr olle d, or L T E) 
f or eac h rec or d w he n t he e ve nt/assess me nt occ urr e d. 
 
L T E b aseli ne f or l ate st art s u bjects  
Place b o -c o ntr olle d baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt c ollecte d pri or t o 
t he first d ose (t he baseli ne use d f or place b o-c o ntr olle d peri o d a nal yses). L T E baseli ne is 
defi ne d as t he last n o n -missi n g meas ure me nt c ollecte d pri or t o t he first d ose of t he L T E 
peri o d. F or a nal yses o n t he L T E peri o d or o n t he place b o -c o ntr olle d a n d L T E acti ve 
treat me nt peri o d, L T E baseli ne will be use d f or late start s u bjects w h o are assi g ne d t o 
recei vi n g a d uca n u ma b i n the L T E peri o d. St u d y da y a n d a nal ysis visit wi n d o w f or a nal yses 
usi n g L T E baseli ne will be deri ve d base d o n t he first da y of st u d y dr u g i n L T E.  
 
I nci de nce, i nci de nce pr o p orti o n a n d i nci de nce r ate 
•  I nci de nce a n d i nci de nce pr o p orti o n will be pr o vi de d i n i ncide nce ta bles. I nci de nce is 
defi ne d as t he n u m ber of s u bjects w h o e x perie nce d a n e ve nt. I nci de nce pr o p orti o n is 
defi ne d as t he n u m ber of s u bjects w h o e x perie nce d a n e ve nt di vi de d b y t he t otal n u m ber 
of s u bjects i n t he a nal ysis p o p ulati o n, i.e., perce nta ge. Eac h s u bject will be c o u nte d o nl y 
o nce wit hi n eac h cate g or y.  
  
•  I nci de nce a n d i nci de nce rate will be pr o vi de d i n i nci de nce rate ta bles. T w o differe nt ki n ds 
of i nci de nce rate ta bles will be pr o vi de d as a p pr o priate f or differe nt a nal yses. Defi niti o ns 
are pr o vi de d bel o w. 
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 1  
 
( 1) F oll o w -u p a dj uste d  i nci de nce rate –  defi ne d as t he n u m ber of s u bjects w h o 
e x perie nce d a n e ve nt di vi de d b y t he t otal of e ntire f oll o w -u p ti me a m o n g t he s u bjects 
i n t he a nal ysis p o p ulati o n. T he e ntire f oll o w-u p ti me f or a s u bject is defi ne d as t he 
ti me fr o m t he first d ose u ntil t he last da y o n st u d y. Eac h s u bject will be c o u nte d o nl y 
o nce wit hi n eac h cate g or y.  
( 2) E x p os ure -a dj uste d i nci de nce rate ( E AI R) –  defi ne d as t he n u m ber of s u bjects w h o 
e x perie nce a n e ve nt di vi de d b y t he t otal e x p os ure a dj uste d f oll o w -u p ti me a m o n g t he 
s u bjects i n t he a nal ysis p o p ulati o n. T he e x p os ure a dj uste d f oll o w-u p ti me is defi ne d 
as t he ti me fr o m t he first d ose u ntil t he i nitial occ urre nce of t he e ve nt f or t h ose w h o 
e x perie nce d a n e ve nt, or fr o m t he first d ose u ntil t he e n d of f oll o w -u p (t he last da y o n 
st u d y) f or t h ose w h o di d n ot. Eac h s u bject will be c o u nte d o nl y o nce wit hi n eac h 
cate g or y. 
 
3. 5. 2  Cli nic al A d verse E ve nts   
Tre at me nt -e mer ge nt A Es  ( T E A Es) 
All A Es will be a nal yze d base d o n t he pri nci ple of treat me nt e mer ge nce.  A treat me nt-
e mer ge nt A E was defi ne d as a n A E t hat starte d or w orse ne d after t he start of first i nf usi o n of 
st u d y treat me nt.  
T o defi ne treat me nt e mer ge nce f or A E s wit h missi n g start or st o p date or ti me  t he f oll o wi n g 
a dditi o nal criteria will be use d:  
•  if b ot h t he start a n d st o p dates f or a partic ular A E  are missi n g, t he n t hat A E  is c o nsi dere d 
treat me nt e mer ge nt; 
•  if t he start date f or a partic ular A E  is missi n g a n d t he st o p date/ti me falls after t he first 
d ose date/ti me, t he n t hat A E  is c o nsi dere d treat me nt e mer ge nt; 
•  if t he start date f or a partic ular A E was t he sa me as t he first d ose date, a n d t he start ti me 
was missi n g, t he n t hat e ve nt is c o nsi dere d treat me nt e mer ge nt.  
F or A E s wit h a partial start date, t he year/ m o nt h of t he e ve nt date will be c o m pare d t o t hat  of 
t he first d osi n g date t o deter mi ne w het her the e ve nt is treat me nt e mer ge nt.  
I n a d diti o n, S A Es t hat occ urre d si nce a s u bject was scree ne d i n t he st u d y a n d pri or t o t he first 
i nf usi o n of st u d y treat me nt, w hic h b y defi niti o n are n ot treat me nt-e mer ge nt, wi ll be a nal yze d 
se paratel y. 
O nl y T E A Es will be i ncl u de d i n t he A E ta bles, u nless ot her wise s pecifie d. Listi n gs of A Es 
will i ncl u de all e ve nts, w het her treat me nt -e mer ge nt or n ot.  
 
As s pecifie d i n t he pr ot oc ol, s u bjects were e x pecte d t o ret ur n t o t he st u d y s ite f or a n E n d of 
St u d y visit 1 8 wee ks after t he last a d mi nistrati o n of st u d y treat me nt. H o we ver, s o me s u bjects 
ma y elect t o c o nti n ue st u d y partici pati o n o n a m o difie d sc he d ule after disc o nti n ui n g 
treat me nt, p ossi bl y i n s u bsta ntial e xcess of 1 8 wee ks.  F or m ost ge neral A E s u m maries, A Es 
wit h a n o nset m ore t ha n 1 8 wee ks after t he last d ose will be e xcl u de d ( will s pecif y i n t he 
f o ot n ote of t he s pecific ta ble). F or i nci de nce rate a nal yses e xcl u di n g A Es m ore t ha n 1 8 wee ks 
after t he last d ose, t he “last da y o n s t u d y” i n f oll o w-u p ti me calc ulati o n will be re place d wit h 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 2  
 
“ 1 8 wee ks after last d ose or last da y o n st u d y, w hic he ver earlier”.  S u m maries  of deat hs a n d 
A Es lea di n g t o st u d y wit h dra wal, a n d ot her s electe d a nal yses will i ncl u de all A Es re gar dless 
of t he ti me si nce t he last d ose.  Listi n gs will i ncl u de all A Es, u nless ot her wise s pecifie d. 
 
 
 S u m m ar y a n d i nci de nce a n al ysis  
O verall s u m mar y of A E ta ble will  be d o ne f or t he L T E peri o d, as well as f or t he place b o -
c o ntr olle d a n d L T E acti ve treat me nt peri o d prese nte d b y L T E treat me nt gr o u p as well as L T E 
treat me nt gr o u p stratifie d b y A p o E stat us. T he f oll o wi n g i nf or mati o n will be s u m mari ze d : t he 
n u m ber of s u bjects wit h a n y A E, wit h a n y A E b y ma xi m u m se verit y, t he n u m ber of s u bjects 
wit h a n y relate d A E (relate d t o st u d y dr u g as assesse d b y i n vesti gat or), t he n u m ber of 
s u bjects wit h S A E, t he n u m ber of s u bjects wit h relate d S A E, t he n u m ber of s u bjects wit h A E 
lea di n g t o st u d y dr u g disc o nti n uati o n, t he n u m ber of s u bjects wit h A E lea di n g t o st u d y 
wit h dra wal, a n d t he n u m ber of  deat hs .  
T he s orti n g or der  of A E i nci de nce ta bles , u nless  ot her wise s pecifie d, will be b y decreasi n g 
fre q ue nc y or der of “ BII B 0 3 7 t otal” c ol u m n wit hi n eac h cate g or y i n t he ta bles prese nte d b y 
L T E treat me nt gr o u p , a n d b y decreasi n g fre q ue nc y or der of “ BII B 03 7 earl y start t otal” 
c ol u m n wit hi n eac h cate g or y i n t he ta bles prese nte d b y L T E treat me nt gr o u p stratifie d b y 
A p o E stat us . A s u bject is c o u nte d o nl y o nce wit hi n eac h cate g or y i n eac h ta ble. F or e xa m ple, 
f or t he ta ble of A Es b y s yste m or ga n class a n d preferre d ter ms s orte d b y decreasi n g 
fre q ue nc y prese nte d b y L T E treat me nt gr o u p , s yste m or ga n class will be prese nte d i n 
decreasi n g fre q ue nc y or der of BII B 0 3 7 t otal c ol u m n, a n d wit hi n eac h s yste m or ga n class, 
preferre d ter ms will be prese nte d i n decreasi n g fre q ue nc y or der of BII B 0 3 7 t otal c ol u m n. A 
s u bject is c o u nte d o nl y o nce wit hi n eac h s yste m or ga n class a n d preferre d ter m.   
T he f oll o wi n g A E i nci de nce ta bles will be pr o vi de d f or t he L T E peri o d  ( prese nte d b ot h b y 
L T E treat me nt gr o u p a n d b y L T E treat me nt gr o u p stratifie d b y A p o E stat us, u nless ot her wise 
s pecifie d): 
1.  A Es b y s yste m or ga n class a n d preferre d ter m s orte d b y decreasi n g fre q ue nc y  
2.  A Es b y s yste m or ga n class a n d preferre d ter m s orte d b y al p ha betical or der a nal ysis  
( b y L T E treat me nt gr o u p)  
3.  A Es b y s yste m or ga n class, hi g h le vel gr o u p ter m a n d preferre d ter m ( b y L T E 
treat me nt gr o u p) 
4.  A Es b y s yste m or ga n class ( b y L T E treat me nt gr o u p) 
5.  A Es b y preferre d ter m  
6.  A Es wit h a n i nci de nce of 5 % or m ore  i n a n y treat me nt gr o u p b y preferre d ter m  
7.  Se vere A Es b y s yste m or ga n class a n d preferre d ter m  
8.  Se vere A Es b y preferre d ter m ( b y L T E treat me nt gr o u p) 
9.  A Es b y ma xi m u m se verit y b y s yste m or ga n class a n d preferre d ter m ( b y L T E 
treat me nt gr o u p) ( S yste m or ga n class will be prese nte d al p ha beticall y. Preferre d ter ms 
will be prese n te d i n decreasi n g fre q ue nc y or der. Ma xi m u m se verit y will be prese nte d 
wit hi n eac h preferre d ter m i n t he or der of mil d, m o derate, se vere, u n k n o w n a n d t otal. 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 3  
 
A s u bject will be c o u nte d o nl y o nce at t he ma xi m u m se verit y wit hi n eac h s yste m 
or ga n class a n d prefe rre d ter m.)  
1 0.  A Es b y ma xi m u m se verit y b y preferre d ter m ( b y L T E treat me nt gr o u p) ( Preferre d 
ter ms will be prese nte d i n decreasi n g fre q ue nc y or der. Ma xi m u m se verit y will be 
prese nte d wit hi n eac h preferre d ter m i n t he or der of mil d, m o derate, se vere, u n k n o w n 
a n d t otal. A s u bject will be c o u nte d o nl y o nce at t he ma xi m u m se verit y wit hi n eac h 
preferre d ter m.)  
1 1.  Relate d A Es b y s yste m or ga n class a n d preferre d ter m  
1 2.  S A Es b y s yste m or ga n class a n d preferre d ter m  
1 3.  S A Es b y preferre d ter m  
1 4.  Relate d S A Es b y s yste m or ga n cl ass a n d preferre d ter m  
1 5.  A Es t hat le d t o disc o nti n uati o n of st u d y treat me nt b y s yste m or ga n class a n d preferre d 
ter m  
1 6.  A Es t hat le d t o wit h dra wal fr o m st u d y  b y s yste m or ga n class a n d preferre d ter m  
1 7.  S A Es wit h fatal o utc o me  b y s yste m or ga n class a n d preferre d  ter m  
1 8.  A Es t hat occ urre d wit hi n 2 h o urs fr o m i nf usi o n start b y s yste m or ga n class a n d 
preferre d ter m ( b y L T E treat me nt gr o u p) 
 
T he f oll o wi n g listi n gs will be pr o vi de d  f or t he place b o -c o ntr olle d a n d L T E peri o d : 
1.  Listi n g of A Es  
2.  Listi n g of S A Es   
3.  Listi n g of A Es  t hat le d t o disc o nti n uati o n of st u d y treat me nt 
4.  Listi n g of A Es t hat le d t o wit h dra wal fr o m st u d y  
5.  Listi n g of A Es t hat occ urre d wit hi n 2 h o urs fr o m i nf usi o n start  
6.  Listi n g of A Es relate d t o P E T li ga n ds   
7.  Listi n g of S A Es wit h fatal o utc o me  
8.  Listi n g of A Es f or s u bjects wit h treat me nt-e mer ge nt p ositi ve a nti -BII B 0 3 7 a nti b o d y  
 
 I nci de nce a n d i nci de nce  r ate a n al ysis  f or pl ace b o-c o ntr olle d a n d L T E acti ve 
tre at me nt peri o d 
D ue t o t he differe nt le n gt h of place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d i n earl y 
start vers us late start s u bjects, b ot h i nci de nce ta bles a n d f oll o w-u p a dj uste d i nci de nce rate  
ta bles will be use d f or A E a nal yses i n t his peri o d. T he e ntire f oll o w -u p ti me  is fr o m t he first 
d ose i n acti ve treat me nt peri o d ( first d ose i n place b o -c o ntr olle d peri o d f or earl y start s u bjects 
a n d first d ose i n L T E peri o d f or late start s u bjects) u ntil t he last da y i n t he st u d y.   


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 4  
 
T he f oll o wi n g i nci de nce a n d f oll o w-u p a dj uste d i nci de nce rate ta bles will be pr o vi de d f or t he 
place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d  ( prese nte d b ot h b y L T E treat me nt gr o u p 
a n d b y L T E treat me nt gr o u p stratifie d b y A p o E stat us, u nless ot her wise s pecifie d) : 
1.  A Es b y s yste m or ga n class a n d preferre d ter m s orte d b y decreasi n g fre q ue nc y  
2.  A Es b y s yste m or ga n class, hi g h le vel gr o u p ter m a n d pr eferre d ter m ( b y L T E 
treat me nt gr o u p) 
3.  A Es b y preferre d ter m  
4.  Se vere A Es b y s yste m or ga n class a n d preferre d ter m (b y L T E treat me nt gr o u p ) 
5.  Se vere A Es b y preferre d ter m  
6.  Relate d A Es b y s yste m or ga n class a n d preferre d ter m  
7.  S A Es b y s yste m or ga n class a n d pre ferre d ter m  
8.  S A Es b y preferre d ter m  
9.  Relate d S A Es b y s yste m or ga n class a n d preferre d ter m  
 
 
3. 5. 3  A RI A - A E of S peci al Interest  
 B ac k gr o u n d  
Please refer t o t he place b o -c o ntr olle d S A P f or details.  
 
 
 I nci de nce a n d s u m m ar y of A RI A 
I nci de nce of A RI A-E, A RI A -H, A RI A -E a n d A RI A -H  ( n ot necessaril y c o nc urre nt), 
c o nc urre nt A RI A -E a n d A RI A -H, A RI A -E or A RI A -H, is olate d A RI A -H ( o nl y A RI A -H, n o 
A RI A -E), A RI A -H micr o he m orr ha ge, A RI A -H macr o he m orr ha ge a n d A RI A -H s u perficial 
si der osis i n t he L T E peri o d a n d i n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d 
will be s u m marize d base d o n b ot h A E e C R F a n d M RI data.  If t here is a n y discre pa nc y i n 
i nci de nce bet wee n t he t w o data s o urces, a listi n g of t he s u bjects a n d A RI A e ve nts wit h 
discre pa nc y will be pr o vi de d. I n a d diti o n, t he i nci de nce ta ble base d o n A E e C R F s o urce will 
als o be d o ne b y L T E treat me nt gr o u p (a nal ysis dis pla y A i n A p pe n di x 4. 1 ).  
N u m ber of s u bjects wit h eac h t y pe of A RI A, ma xi m u m se verit y a n d w orst s y m pt o matic 
stat us of t he t y pe of ARI A bei n g a nal yze d i n t he L T E peri o d a n d i n t he place b o -c o ntr olle d 
a n d L T E acti ve treat me nt peri o d will be s u m mari ze d base d o n A E e C R F.  F or s u bjects wit h 
s y m pt o matic A RI A, t he ma xi m u m se verit y of s y m pt o ms will als o be s u m marize d.  
S u m mar y of c o nc urre nt A RI A -E a n d A RI A -H will be pr o vi de d i ncl u di n g t he f oll o wi n g 
i nf or mati o n f or t he L T E peri o d a n d f or t he place b o-c o ntr olle d a n d L T E acti ve treat me nt 
peri o d : n u m ber of s u bjects wit h c o nc urre nt A RI A-E a n d A RI A -H (a n d f urt her br o ke n d o w n 
t o eac h t y pe of A RI A-H), t h e se verit y of A RI A -E base d o n M RI, t he s y m pt o matic stat us of 
A RI A -E, t he se verit y of s y m pt o ms base d o n A E e C R F. F or s u bjects wit h rec urre nt A RI A -E 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 5  
 
e ve nts, if t here is a n e ve nt c o nc urre nt wit h A RI A -H, it will be use d f or t he s u m mar y, a n d t he 
first c o nc urre nt e ve nt will be use d if t here are m ore t ha n o ne e ve nt  c o nc urre nt wit h A RI A -H.  
A n i nci de nce ta ble of A Es c o nsi dere d b y t he i n vesti gat or t o be relate d t o A RI A b y s yste m 
or ga n class a n d preferre d ter m f or s u bjects wit h s y m pt o matic A RI A i n t he place b o-c o ntr oll e d 
a n d L T E acti ve treat me nt peri o d  will be pr o vi de d, as well as a listi n g of t hese A Es. Si milarl y, 
a n i nci de nce ta ble of A Es relate d t o A RI A f or s u bjects wit h s y m pt o matic A RI A a n d se vere 
s y m pt o ms will be pr o vi de d, as well as a listi n g of t hese A Es. 
Listi n g s of A E rec or ds f or eac h t y pe of A RI A e ve nts a n d listi n gs of M RI assess me nts f or 
s u bjects wit h eac h t y pe of A RI A e ve nts will be pr o vi de d.  
M o ntreal C o g niti ve Assess me nt  ( M O C A) is perf or me d at baseli ne, Wee k 8 0 (t he first visit i n 
L T E)  a n d eac h u nsc he d ule d A RI A m o nit ori n g visit f or A RI A s u bjects (a p pr o xi matel y e ver y 
4 wee ks) e xce pt f or mil d as y m pt o matic micr o he m orr ha ge s u bjects . A n i nci de nce ta ble of late 
start s u bjects wit h A RI A e ve nts o nl y i n t he L T E peri o d ( n o A RI A i n t he place b o-c o ntr olle d 
peri o d) w h ose M O C A t otal sc ores decrease 2 p oi nts or m ore  fr o m Wee k 8 0  will be pr o vi de d. 
Si nce Wee k 8 0 M O C A was n ot a pla n ne d st u d y e ve nt u ntil pr ot oc ol versi o n 4, s o me s u bjects 
ma y n ot ha ve a Wee k 8 0 M O C A  sc ore. F or t hese s u bjects, t heir Wee k 8 0 M O C A will be 
i m p ute d as t heir baseli ne M O C A pl us t he mea n c ha n ge fr o m baseli ne at Wee k 8 0 fr o m 
s u bjects w h o ha ve a Wee k 8 0 M O C A a n d di d n ot e x perie nce a n y A RI A i n t he place b o -
c o ntr olle d peri o d  wit hi n eac h treat me nt gr o u p a n d A p o E stat us . A listi n g of M RI assess me nts 
a n d M O C A t ot al sc ore f or s u bjects wit h A RI A e ve nts i n eit her place b o-c o ntr olle d or L T E 
peri o d will be pr o vi de d.  
 
 S u m m ar y of rec urre nt A RI A -E  
F oll o w -u p a dj uste d i nci de nce rate of s u bjects wit h A RI A -E, wit h 2 or m ore e ve nts  of A RI A -
E, wit h 3 or m ore e ve nts  of A RI A -E a n d wit h m ore t ha n 3 e ve nt s of A RI A -E o ver t heir e ntire 
f oll o w-u p ti me f or t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d will be 
s u m marize d base d o n A E e C R F.  
N u m ber of t otal A RI A -E e ve nts i n t he place b o -c o ntr olle d a n d L T E acti ve peri o d a n d t he M RI 
se verit y of eac h e ve nt will be s u m marize d base d o n A E e C R F. N u m ber of s y m pt o matic 
A RI A -E e ve nts  i n t he place b o-c o ntr olle d a n d L T E acti ve peri o d , a n d t he se verit y of t he 
s y m pt o ms of eac h s y m pt o matic e ve nt will be s u m marize d base d o n A E e C R F.  
S u m mar y of firs t A RI A-E e ve nts ta ble base d o n A E e C R F will s u m marize t he n u m ber of 
s u bjects wit h a first e ve nt of A RI A -E, t he M RI se verit y of t he e ve nts, t he s y m pt o matic stat us 
of t he e ve nts, t he se verit y of t he s y m pt o ms f or s y m pt o matic e ve nts, w het her S A E or n ot, 
n u m ber  of res ol ve d a n d u nres ol ve d e ve nts, d urati o n of t he res ol ve d e ve nts, ti me fr o m first 
acti ve i nf usi o n i n st u d y t o o nset, n u m ber of d oses recei ve d si nce t he start of t he peri o d t o 
o nset, d ose le vel of t he last i nf usi o n recei ve d pri or t o o nset, d osi n g stat us (c o nti n ue as 
pla n ne d, d ose i nterr u pte d, d ose re d uce d, or d ose disc o nti n ue d) after t he e ve nts, a n d t he 
n u m ber of s u bjects wit h rec urre nt A RI A -E e ve nts. T his ta ble will be d o ne o n t he place b o -
c o ntr olle d a n d L T E acti ve treat me nt peri o d. T he sa me s u m mar y of fi rst A RI A-E e ve nts ta ble 
will als o be d o ne o n  t he s u bset of s u bjects w h o ha d rec urre nt A RI A-E e ve nts.  
S u m mar y of rec urre nt A RI A -E e ve nts ta ble base d o n A E e C R F will s u m marize t he f oll o wi n g 
i nf or mati o n f or b ot h t he sec o n d a n d t hir d e ve nt of A RI A -E e ve nts: t he n u m ber of s u bjects 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 6  
 
wit h t he pre vi o us e ve nt of A RI A -E, t he n u m ber of s u bjects wit h at least o ne d ose a n d o ne 
M RI after t he pre vi o us A RI A -E res ol uti o n, t he n u m ber of s u bjects wit h t his e ve nt  of A RI A -
E, t he M RI se verit y of t he e ve nts, t he s y m pt o matic stat us of t he e ve nts, t he se verit y of t he 
s y m pt o ms f or s y m pt o matic e ve nts, w het her S A E or n ot, n u m ber of res ol ve d a n d u nres ol ve d 
e ve nts, d urati o n of t he res ol ve d e ve nts, ti me fr o m first i nf usi o n i n st u d y (acti ve or place b o) t o 
o nset, ti me fr o m pre vi o us res ol uti o n t o o nset, n u m ber of d oses recei ve d si nce t he start of t he 
peri o d  t o o nset, d ose le vel of t he last i nf usi o n recei ve d pri or t o o nset, d osi n g stat us (c o nti n ue 
as pla n ne d, d ose i nterr u pte d, d ose re d uce d, or d ose disc o nti n ue d) after t he e ve nts. T he 
n u m ber of  s u bjects wit h m ore t ha n 3 e ve nt s of A RI A -E, a n d t he n u m ber of s u bjects w h o 
disc o nti n ue d st u d y treat me nt after rec urre nt A RI A -E o nset will als o be s u m marize d. T his 
ta ble will be d o ne o n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d.  
A listi n g of s u bjects w h o wit h dre w fr o m t he st u d y wit h u nres ol ve d A RI A -E or s u bjects wit h 
o n g oi n g A RI A -E at t he ti me of data c ut off (als o c o nsi dere d as u nres ol ve d) will be pr o vi de d 
wit h t he details of t he e ve nt i ncl u di n g t he d urati o n fr o m o nset t o last f oll o w -u p.  
F or s u bjects wit h rec urre nt A RI A -E , a listi n g of st u d y dr u g a d mi nistrati o n, M RI assess me nts , 
se verit y a n d s y m pt o matic stat us of eac h e ve nt , a n d e n d-of -treat me nt reas o n (if prese nt) will 
be pr o vi de d.  
    
 E x p os ure a dj uste d a n al ysis  
E x p os ure a dj uste d i nci de nce r ate of A RI A -E e ve nts will be s u m marize d base d o n safet y M RI 
data  f or t he place b o-c o ntr olle d a n d L T E acti ve treat me nt peri o d. T he e x p os ure a dj uste d 
f oll o w-u p ti me is fr o m t he first acti ve d ose u ntil t he i nitial occ urre nce of A RI A -E f or t h ose 
w h o e x perie nce d  A RI A -E, a n d u ntil t he e n d of f oll o w -u p f or t h ose w h o di d n ot. Si nce A RI A 
is a n M RI fi n di n g, t he da y of t he last M RI assess me nt i n t he place b o-c o ntr olle d a n d L T E 
acti ve treat me nt peri o d will be use d as t he e n d of f oll o w -u p f or t h ose w h o di d n’t e x perie nce 
the e ve nt.  
St u d y dr u g a d mi nistrati o n i nf or mati o n pri or t o first A RI A -E o nset  will be s u m marize d f or 
A RI A -E s u bjects f or t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d, i ncl u di n g 
n u m ber of t otal i nf usi o ns, n u m ber of i nf usi o ns at eac h d ose le vel ( plac e b o, 1 m g/ k g, 3 m g/ k g, 
6 m g/ k g a n d 1 0 m g/ k g), d ose le vel of t he last i nf usi o n, ma xi m u m d ose le vel recei ve d, a n d 
c u m ulati ve d ose as a c o nti n u o us varia ble.   
 
 Ti me t o e ve nt a n al ysis  
Ka pla n -Meier pl ot of ti me t o first A RI A -E e ve nt will be pr o d uce d base d o n sa fet y M RI data 
f or t he place b o-c o ntr olle d a n d L T E acti ve treat me nt peri o d. O nl y A RI A -E e ve nts t hat 
occ urre d d uri n g t his peri o d will be i ncl u de d. Ti me t o e ve nt is calc ulate d as date of t he M RI 
assess me nt t hat i nitiall y detects  t he A RI A -E e ve nt - date of t he first acti ve i nf usi o n + 1. 
Ce ns or ti me f or s u bjects wit h o ut A RI A -E is calc ulate d as date of t he last M RI assess me nt i n 
t he st u d y - date of t he first acti ve i nf usi o n + 1. Esti mate d pr o p orti o n wit h A RI A-E a n d 
n u m ber of s u bjects at ris k at selecte d ti me p oi nts w ill als o be prese nte d. T he pl ot will be 
prese nte d b y L T E treat me nt gr o u p stratifie d b y A p o E stat us.  


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 7  
 
3. 5. 4  Cli nic al L a b or at or y D at a  
T he f oll o wi n g cli nical la b orat or y para meters are assesse d i n t he pr ot oc ol  a n d will be 
a nal yze d: 
o  He mat ol o g y:   
•  W hite bl o o d cells (l e u k oc ytes ), l y m p h oc ytes, ne utr o p hils, m o n oc ytes, 
e osi n o p hils, bas o p hils  
•  Re d bl o o d cells  (er yt hr oc ytes ), er yt hr oc ytes distri b uti o n wi dt h, 
er yt hr oc ytes mea n c or p usc ular v ol u me, er yt hr oc ytes mea n c or p usc ular 
he m o gl o bi n, er yt hr oc ytes mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
•  He m o gl o bi n  
•  He mat ocrit  
•  Platelet c o u nt  
o  Bl o o d c he mistr y:  
•  Li ver: a la ni ne ami n otra nsferase  (A L T ), as partate ami n otra nsferase  (A S T ), 
al kali ne p h os p hatase  ( A L P), t otal bilir u bi n, direct bilir u bi n, 
ga m ma -gl uta m yl -tra nsferase ( G G T) 
•  Re nal: b l o o d urea nitr o ge n  ( B U N), creati ni ne  
•  Electr ol ytes: s o di u m, p otassi u m, c hl ori de, bicar b o nate  
•  Ot her: gl uc ose, calci u m, p h os p h or us, al b u mi n,  uric aci d,  lactate 
de h y dr o ge nase ( L D H), t otal pr otei n  
o  Uri nal ysis: s pecific gra vit y, p ote ntial of h y dr o ge n ( p H) , c ol or, bl o o d, gl uc ose, 
ket o nes, pr otei n , w hite bl o o d cells, re d bl o o d cells 
 
 Q u a ntit ati ve a n al yses  
F or n u meric la b orat or y para meters, act ual val ues  will be s u m marize d b y visit  f or all t he visits 
i n t he place b o -c o ntr olle d a n d L T E peri o d . N u m ber of e val ua ble s u bjects, mea n, sta n dar d 
de viati o n, me dia n, 2 5 % a n d 7 5 % q uartiles, mi n i m u m a n d ma x i m u m val ues will be prese nte d 
at eac h visit.  
Pl ots of mea n act ual val ues ( wit h sta n dar d err or) f or n u meric la b orat or y para meters at eac h 
visit f or all t he visits i n t he place b o -c o ntr olle d a n d L T E peri o d will be pr o vi de d.  
S u m mar y of c ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne f or n u meric la b orat or y 
para meters will be d o ne o n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d . Place b o -
c o ntr olle d baseli ne  will be use d f or e arl y start s u bjects a n d L T E baseli ne will be use d f or late 
start s u bjects. C ha n ge a n d perce nt c ha n ge fr o m baseli ne will be calc ulate d base d o n t he L T E  
baseli ne  f or late start s u bjects. N u m ber of e val ua ble s u bjects, mea n, sta n dar d de viati o n, 
me dia n, 2 5 % a n d  7 5 % q uartiles, mi n i m u m a n d ma xi m u m val ues will be prese nte d at eac h 
visit.  


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 8  
 
Listi n gs of i n di vi d ual la b orat or y meas ure me nts b y patie nts f or all t he para meters will be 
pr o vi de d.  
 
Visit wi n d o ws f or by visit s u m m aries  
F or la b orat or y b y visit s u m maries, t he a nal ysis visit s h o ul d be defi ne d usi n g visit wi n d o ws 
(see Ta ble 5  bel o w).  If t here is m ore t ha n 1 val ue i n t he sa me a nal ysis visit wi n d o w f or a 
certai n para meter f or a s u bject, t he n t he cl osest rec or d t o t he tar get visit da y  will be use d  f or 
t he b y visit a nal ysis.  If t here are 2 val ues i n t he sa me a nal ysis visit wi n d o w wit h t he sa me 
dista nce fr o m t he tar get visit da y f or a certai n para meter f or a s u bject, t he n t he rec or d wit h 
t he later date will be use d f or t he b y visit a nal ysis.  If t here are 2 val ues o n t he sa me da y f or a 
certai n para meter f or a s u bject, t he n t he rec or d wit h t he later ti me will be use d f or t he b y visit 
a nal ysis. 
 
T a ble 5 : Visit Wi n d o ws f or L a b or at or y b y Visit S u m m aries  
 
A n al ysis visit  
A n al ysis visit wi n d o w 1 
F or s u bjects w h o recei ve d 
t he first d ose of 
a d uc a n u m a b i n t he pl ace b o -
c o ntr olle d peri o d  
F or s u bjects w h o recei ve d t he 
first d ose of a d uc a n u m a b i n 
t he L T E peri o d 
Baseli ne  
Last  val ue  pri or t o t he first d ose of 
a d uca n u ma b  
Last  val ue  pr i or t o t he first d ose of 
a d uca n u ma b  
Wee k 2 4  
[ 2, 2 5 2] 
[ 2, 2 5 2] 
Wee k 4 8  
[ 2 5 3, 4 2 0] 
[ 2 5 3, 4 2 0] 
Wee k 7 2  
[ 4 2 1, 5 2 5] 
[ 4 2 1, 5 8 8] 
Wee k 7 8  
[ 5 2 6, e n d da y of t he place b o -
c o ntr olle d peri o d 2] 
N A  
Wee k 1 0 4  
[start da y of t he L T E peri o d 3, 8 1 2] 
[ 5 8 9, 8 6 8 ] 
Wee k 1 2 8  
[ 8 13, 9 8 0]  
N A  
Wee k 1 5 2  
[ 9 8 1, 1 1 4 8] 
[8 6 9 , 12 4 6 ] 
Wee k 1 7 6  
[1 1 4 9 , 1 4 2 8] 
N A  
Wee k 2 3 2  
[ 1 4 2 9, 1 8 0 6] 
[ 1 2 4 7, 1 7 0 8] 
Wee k 2 8 4  
[ 1 8 0 7, 2 1 7 0] 
≥ 1 7 0 9  
Wee k 3 3 6  
≥2 1 7 1  
N A  
1.  Visit wi n d o w s are defi ne d base d o n da ys relati ve t o t he first d ose of a d uca n u ma b.  
2.  T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E, or  t he 
last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E.  
3.  T he start da y of t he L T E peri o d is t he da y of first i nf usi o n i n L T E peri o d.  
 
 
 Q u alit ati ve a n al yses  
F or q ualitati ve a nal yses, all val ues will be i ncl u de d ( n ot j ust t he “a nal yze d rec or d” wit hi n 
eac h visit wi n d o w i n t he q ua ntitati ve a nal yses).  
 
S hif t a n alyses 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
2 9  
 
La b orat or y data will be s u m marize d usi n g  s hift ta bles w here a p pr o priate f or t he place b o -
c o ntr olle d a n d L T E acti ve treat me nt peri o d. Eac h s u bject’s he mat ol o g y, bl o o d c he mistr y a n d 
uri nal ysis n u meric val ues will be fla g ge d as “l o w”, “ n or mal”, or “ hi g h” relati ve t o t he n or mal 
ra n ges of t he ce ntral la b orat or y or as “ u n k n o w n” if n o res ult is a vaila ble.  Eac h s u bject’s 
uri nal ysis cate g orical val ues will be fla g ge d as “ p ositi ve” or “ ne gati ve”, or “ u n k n o w n” if n o 
val ue is a vaila ble.   
S hifts fr o m baseli n e t o hi g h/l o w stat us will be prese nte d f or he mat ol o g y, bl o o d c he mistr y a n d 
uri nal ysis n u meric para meters, a n d s hifts fr o m baseli ne t o a b n or mal ( p ositi ve) will be 
prese nte d f or uri nal ysis cate g orical para meters .  S hift t o l o w i ncl u des n or mal t o l o w, hi g h t o 
l o w, a n d u n k n o w n t o l o w; S hift t o hi g h i ncl u des n or mal t o hi g h, l o w t o hi g h, a n d u n k n o w n t o 
hi g h. S u bjects nee d t o ha ve at least o ne p ost -baseli ne e val uati o n a n d a baseli ne val ue n ot l o w 
or hi g h or p ositi ve (i ncl u di n g missi n g) i n or der t o be i ncl u de d i n t he a nal ysis.  
F or earl y start s u bjects, t he place b o -c o ntr olle d baseli ne  will be use d a n d s hifts t hat occ urre d 
i n eit her place b o-c o ntr olle d or L T E peri o d will be i ncl u de d. F or late start s u bjects, t he L T E 
baseli ne will be use d a n d s hifts t hat occ urre d i n t he  L T E peri o d base d o n L T E baseli ne will 
be i ncl u de d.  
 
Gr a de a n alyses  
W orst p ost -baseli ne gra de will be s u m marize d f or eac h la b orat or y para meter i n b ot h 
e xcl usi ve wa y a n d c u m ulati ve wa y  f or t he place b o -c o ntr olle d a n d L T E acti ve treat me nt 
peri o d.  S u bjects ne e d t o ha ve at least o ne p ost -baseli ne e val uati o n i n t he acti ve treat me nt 
peri o d i n or der t o be i nclu de d i n t he a nal ysis. C o m m o n T o xicit y Criteria f or A d verse E ve nts 
v 4. 0. 3 ( C T C A E) p u blis he d o n 2 0 1 0 -0 6 -1 4 will be use d f or gra de deter mi nati o n. Gra de 
deter mi n ati o n is base d s olel y o n la b orat or y val ues n ot ta ki n g A Es i nt o acc o u nt.  
 
P ote nti ally Cli nic ally Si g nific a nt l a b or at ory a b n or m alities a n alyses  
Please refer t o t he place b o -c o ntr olle d S A P f or t he para meters a n d criteria f or p ote ntiall y 
cli nicall y si g nifica nt  la b orat or y a b n or malities a nal yses.  
T he n u m ber of s u bjects wit h p ote ntiall y cli nicall y si g nifica nt la b orat or y a b n or malities p ost -
baseli ne will be s u m mari ze d f or t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d .  
S u bjects nee d t o ha ve at least o ne p o st-baseli ne e val uati o n i n t he acti ve treat me nt peri o d a n d 
a baseli ne val ue n ot p ote ntiall y cli nicall y si g nifica nt (i ncl u di n g missi n g) i n or der t o be 
i nclu de d i n t he a nal ysis.  
Sa me as t he s hift a nal ysis, f or earl y start s u bjects, t he place b o -c o ntr olle d bas eli ne will be 
use d a n d a b n or malities t hat occ urre d i n eit her place b o -c o ntr olle d or L T E peri o d will be 
i ncl u de d. F or late start s u bjects, t he L T E baseli ne will be use d a n d P C S a b n or malities t hat 
occ urre d i n t he L T E peri o d base d o n L T E baseli ne will be i ncl u de d.  
 
P ote nti al seri o us he p at ot oxicity  
 
I n t his S A P, we defi ne pote ntial seri o us he pat ot o xicit y as A L T or A S T > 3 x U L N a n d t otal 
bilir u bi n > 2 x U L N at a n y ti me p ost -baseli ne  i n t he place b o -c o ntr olle d a n d L T E acti ve 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 0  
 
treat me nt peri o d (n ot necessaril y c o nc urr e nt). A scatter pl ot of t he ma xi m u m p ost-baseli ne 
A L T or A S T val ue relati ve t o U L N a n d ma xi m u m p ost -baseli ne t otal bilir u bi n val ue relati ve 
t o U L N ( n ot necessaril y c o nc urre nt) f or eac h s u bject will be pr o vi de d. A li ne pl ot of A L T, 
A S T, A L K a n d t otal bilir u b i n val ues o ver ti me i n t he acti ve treat me nt peri o d f or s u bjects wit h 
p ote ntial seri o us he pat ot o xicit y will be pr o vi de d. I n a d diti o n, s u bjects wit h A L T > 1 x U L N, 
> 3 x U L N, > 5 x U L N , > 1 0 x U L N or > 2 0 x U L N, s u bjects wit h A S T > 1 x U L N, > 3 x U L N, > 5 x 
U L N , > 1 0 x U L N or > 2 0 x U L N, s u bjects wit h t otal bilir u bi n > 1 x U L N or > 2 x U L N, s u bjects 
wit h A L P > 1 x U L N or > 1. 5 x U L N, a n d s u bjects wit h A S T or A L T > 3 x U L N p ost -baseli ne 
acc o m pa nie d b y c o nc urre ntl y ele vate d t otal bilir u bi n  > 1. 5 x U L N or  > 2 x U L N i n t he acti ve 
treat me nt peri o d will be prese nte d. C o nc urre nt is defi ne d as o n t he sa me da y. A listi n g of 
s u bjects wit h p ote ntial seri o us he pat ot o xicit y will be pr o vi de d.  
 
3. 5. 5  C -S S R S D at a  
T he C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) is a n assess me nt t hat e val uates 
s uici dal i deati o n a n d be ha vi or.  T here are 5 “ Yes/ N o” q uesti o ns o n s uici dal i deati o n 
f oll o wi n g t he i ncreasi n g se verit y or der: ( 1) Wis h t o be dea d , ( 2) N o n -s pecific acti ve s uici dal 
t h o u g hts, ( 3) Acti ve s uici dal i deati o n wit h a n y met h o ds ( n o t pla n) wit h o ut i nte nt t o act , ( 4) 
Acti ve s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n , ( 5) Acti ve s uici dal 
i deati o n wit h s pecific pla n a n d i nte nt, a n d 6 “ Yes/ N o” q uesti o ns o n s uici dal be ha vi or 
f oll o wi n g t he i ncreasi n g se verit y or der: ( 6) Pre parat or y acts or be ha vi or, ( 7) A b orte d atte m pt, 
( 8) I nterr u pte d atte m pt, ( 9) Act ual atte m pt, ( 1 0) S uici dal be ha vi or, ( 1 1) S uici de ( o nl y at p ost -
baseli ne visits).  A n ot her “ Yes/ N o” q uesti o n of w het her t he s u bject has e n ga ge d i n n o n -
s uici dal self-i nj uri o us be ha vi or is als o c ollecte d.  
T he s u m mar y ta ble f or C -S S R S will be c o n d ucte d f or t he place b o -c o ntr olle d a n d L T E  acti ve 
treat me nt peri o d. N u m ber of s u bjects w h o a ns were d “ Yes” t o eac h of t he 1 1 q uesti o ns p ost-
baseli ne, s u bjects w h o a ns were d “ Yes” t o at least o ne q uesti o n f or s uici dal  i deati o n, s u bjects 
w h o a ns were d “ Yes” t o at least o ne q uesti o n f or s uici dal be ha vi or, a n d s u bjects w h o ha ve 
e n ga ge d i n n o n -s uici dal self-i nj uri o us be ha vi or will be prese nte d. A listi n g of s u bjects wit h 
a n y s uici dal i deati o n or be ha vi or at baseli ne or p ost -baseli ne will be pr o vi de d  f or place b o -
c o ntr olle d a n d L T E peri o d . 
 
3. 5. 6  E C G D at a  
S hift fr o m n or mal or u n k n o w n E C G at baseli ne t o a b n or mal , n ot a d verse e ve nt or a b n or mal, 
a d verse e ve nt  p ost -baseli ne E C G will be s u m marize d f or t he place b o -c o ntr olle d a n d L T E 
acti ve treat me nt gr o u p.  F or earl y start s u bjects, t he place b o -c o ntr olle d baseli ne will be use d. 
F or late start s u bjects, t he L T E baseli ne will be use d. S u bjects wit h a b n or mal E C G stat us will 
be liste d.  
 
3. 5. 7  Vit al Si g n D at a  
V ital si g n para meters i ncl u de b o d y te m perat ure, s yst olic bl o o d press ure, diast olic bl o o d 
press ur e, heart rate, res pirati o n rate  a n d wei g ht . Vital si g ns will be meas ure d wit h t he s u bject 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 1  
 
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. T he descri pti ve statistics 
f or act ual val ues will be s u m marize d at eac h visit i n t he place b o-c o ntr olle d a n d L T E peri o d.  
Pl ot of mea n vital si g n val ues  i n t he place b o-c o ntr olle d a n d L T E peri o d  will be pr o vi de d .  
S u m mar y of c ha n ge fr o m baseli ne i ncl u di n g n u m ber of e val ua ble  s u bjects, mea n, sta n dar d 
de viati o n, me dia n, 2 5 % a n d 7 5 % q uartiles,  mi ni m u m, a n d ma xi m u m val ues will be 
s u m marize d at eac h visit i n t he place b o-c o ntr olle d a n d L T E acti ve treat me nt peri o d. Place b o -
c o ntr olle d baseli ne will be use d f or earl y start s u bjects a n d L T E baseli ne will be use d f or late 
start a nal ysis.  
T he a nal ysis of vital si g ns will als o f oc us o n t he i nci de nce of cli nicall y rele va nt o utliers. 
Please refer t o t he place b o -c o ntr olle d S A P f or t he criteria t o assess p ote ntial cli nicall y 
rele va nt o utliers i n vital si g n. T he i nci de nce a n d perce nta ge of cli nicall y rele va nt o utliers 
deter mi ne d b y eac h criteri o n  will be s u m marize d i n t he place b o-c o ntr olle d a n d L T E acti ve 
treat me nt peri o d. A listi n g of s u bjects wit h cli nicall y rele va nt vital si g ns i n t he place b o -
c o ntr olle d a n d L T E ac ti ve treat me nt peri o d will als o be pr o vi de d . 
 
Visit wi n d o ws f or by visit s u m m aries  
F or vital si g n b y visit s u m maries, t he a nal ysis visit s h o ul d be defi ne d usi n g  wi n d o w s (see 
Ta ble 6  bel o w ). F or t he sa me para meter f or a s u bject,  if t here is m ore t ha n 1 rec or d i n t he 
sa me a nal ysis v isit w i n d o w, t he n select t he rec or d cl osest t o t he tar get visit da y.  If t here are 2 
rec or ds i n t he sa me a nal ysis visit wi n d o w wit h t he sa me dista nce fr o m t he tar get visit d a y, 
t he n select t he rec or d wit h t he later date.   
 
T a ble 6 : Visit Wi n d o ws f or Vit al Si g n b y Visit S u m m aries 
 
A n al ysis visit wi n d o w 1 
A n al ysis visit  
F or s u bjects w h o recei ve d t he 
first d ose of a d uc a n u m a b i n 
t he pl ace b o-c o ntr olle d peri o d  
F or s u bjects w h o recei ve d t he 
first d ose of a d uc a n u m a b i n 
t he L T E peri o d 
Baseli ne  
Last  val ue  pri or t o t he first d ose of 
a d uca n u ma b  
Last  val ue  pri or t o t he first d ose of 
a d uca n u ma b  
Wee k 4  
[ 2, 4 2] 
[ 2, 4 2] 
Wee k 8  
[ 4 3, 7 0] 
[ 4 3, 7 0] 
Wee k x  
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤7 2 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2  
…  
…  
…  
Wee k 7 6  
[ 5 1 9, t he e n d da y of t he place b o-
c o ntr olle d peri o d 1] 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
Wee k 8 0  
[t he start da y of t he L T E peri o d2, 5 7 4] 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
Wee k x   
[ 7x  -1 3 , 7x + 1 4 ] f or 84  ≤ x  ≤1 7 6  
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
…  
…  
…  
Wee k 1 8 0  
[ 1 2 4 7, 1 2 6 7] 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
Wee k 1 8 2  
[ 1 2 6 8, 1 2 8 1] 
N A  
Wee k 1 8 4  
[ 1 2 8 2, 1 3 0 2] 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
Wee k 1 8 8  
[ 1 3 0 3, 1 3 3 0] 
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
Wee k x   
[ 7x  -1 3 , 7 x + 1 4 ] f or 1 8 8 ≤ x  ≤3 3 2  
[ 7 x -1 3 , 7 x + 14 ] f or 8 ≤ x ≤2 5 2 
…  
…  
…  
Wee k 2 5 6  
[ 7x  -1 3 , 7x + 1 4 ] f or 1 8 8 ≤ x ≤3 3 2 
[ 1 7 7 9, 1 7 9 9] 
Wee k 2 6 0  
[ 7x  -1 3 , 7x + 1 4 ] f or 1 8 8 ≤ x ≤3 3 2 
≥ 1 8 0 0  
…  
…  
…  
Wee k 3 3 6  
[ 2 3 3 9, 2 3 5 9] 
N A  




 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 3  
 
3. 7  
I m m u n o ge nicit y A n al ysis  
3. 7. 1  B ac k gr o u n d  
Defi niti o n of L T E b aseli ne v al ue  
 
Place b o -c o ntr olle d b aseli ne val ue is defi ne d as t he latest  i m m u n o ge nicit y data c ollecte d pri or 
t o t he first d ose. If n o i m m u n o ge nicit y data are c ollecte d pri or t o t he first d ose, baseli ne val ue 
is missi n g a n d will be i m p ute d as a nti-dr u g a nti b o d y ne gati ve f or i m m u n o ge nicit y a nal yses.  
L T E baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt c ollecte d pri or t o t he first d ose 
of t he L T E peri o d. F or a nal yses o n t he place b o -c o ntr olle d a n d L T E acti ve treat me nt peri o d, 
L T E baseli ne will be use d f or late start s u bjects w h o are assi g ne d t o recei vi n g a d uca n u ma b i n 
t he L T E peri o d. St u d y da y a n d a nal ysis visit wi n d o w f or a nal yses usi n g L T E baseli ne will be 
deri ve d base d o n t he first da y of st u d y dr u g i n L T E.  
 
Tre at me nt -e mer ge nt a nti-a d uc a n u m a b a nti b o dy p ositive res p o nses f or t he pl ace b o -c o ntr olle d 
a n d L T E  active tre at me nt peri o d  
 
P ost -bas eli ne p ositi ve a nti -a d uca n u ma b a nti b o d y res p o nses f or t he acti ve treat me nt peri o d are 
defi ne d as treat me nt -e mer ge nt if a s u bject is eit her ( 1) a nti b o d y ne gati ve at baseli ne; or ( 2) 
a nti b o d y p ositi ve at baseli ne b ut t he p ost -baseli ne a nti b o d y res p o nse is m o re t ha n 2-f ol d 
i ncrease i n titer c o m pare d t o t he baseli ne res p o nse. Place b o -c o ntr olle d baseli ne will be use d 
f or earl y start s u bjects a n d L T E baseli ne will be use d f or late start s u bjects. 
 
Persiste nt a n d tr a nsie nt p ositive res p o nses f or t he pl ace b o -c o ntr o lle d a n d L T E active 
tre at me nt peri o d 
 
S u bjects wit h treat me nt -e mer ge nt p ost -baseli ne p ositi ve a nti -a d uca n u ma b a nti b o d y res p o nses 
i n t he place b o-c o ntr olle d a n d L T E acti ve treat me nt  peri o d will be f urt her classifie d  as 
tra nsie nt p ositi ve, if o nl y a si n gle p ositi ve e val uati o n occ urs or m ore t ha n 1 p ositi ve 
e val uati o n b ut occ ur wit h < 1 1 2 da ys ( 1 6 wee ks) a part, or as persiste nt  p ositi ve , if m ore t ha n 
o ne c o nsec uti ve p ositi ve e val uati o n occ urs ≥1 1 2 da ys ( 1 6 wee ks) a part  i n t he acti ve treat me nt 
peri o d  or a p ositi ve e val uati o n occ urs at t he last  a vaila ble  ti me p oi nt wit h n o f urt her ne gati ve 
res ults a vaila ble.  
 
3. 7. 2  Im m u n o ge nicit y a n al ysis  
I m m u n o ge nicit y p o p ulati o n will be use d t o a nal yze i m m u n o ge nicit y data. L T E safet y 
treat me nt gr o u ps will be use d f or i m m u n o ge nicit y anal ysis. Ta bles will be prese nte d b y L T E 
treat me nt gr o u p (late start l o w d ose, late start hi g h d ose, earl y start l o w d ose, earl y start hi g h 
d ose, a n d i n a d diti o n late start t otal, earl y start t otal a n d BII B 0 3 7 t otal ; a nal ysis dis pla y  A  i n 
A p pe n di x 4. 1 ). L isti n gs will be prese nte d  b y treat me nt gr o u p stratifie d b y A p o E stat us . 
 
A s u m mar y ta ble of s u bjects wit h treat me nt -e mer ge nt p ositi ve a nti-a d uca n u ma b a nti b o d y 
res p o nses i n t he place b o-c o ntr olle d a n d L T E acti ve treat me nt peri o d w ill be pr o vi de d. T he 
n u m ber a n d perce nta ge of a nti -a d uca n u ma b  p ositi ve res ults  will be s u m marize d at eac h visit 
as well as at a n y ti me p ost -baseli ne i n t his peri o d. S u bjects wit h  persiste nt  res p o nse a n d 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 4  
 
s u bjects wit h tra nsie nt res p o nse i n t his peri o d will be prese nte d. A listi n g of i m m u n o ge nicit y 
data i n place b o -c o ntr olle d a n d L T E peri o d f or s u bjects wit h a nti -a d uca n u ma b a nti b o d y 
p ositi ve res ults will als o be pr o vi de d. 
 
Visit wi n d o ws f or by visit s u m m aries  
F or i m m u n o ge nicit y b y visit s u m maries, t he a nal ysis  visit s h o ul d be defi ne d usi n g visit 
wi n d o ws (see Ta ble 7  bel o w). If t here is m ore t ha n 1 val ue i n t he sa me a nal ysis visit w i n d o w 
f or a s u bject, t he n t he cl osest rec or d t o t he tar get visit da y will be use d f or t he b y visit 
a nal ysis.  If t here are 2 val ue s i n t he sa me a nal ysis v isit w i n d o w wit h t he sa me dista nce fr o m 
t he tar get visit d a y f or a certai n para meter f or a s u bject, t he n t he rec or d wit h t he later date 
will be use d f or t he b y visit a nal ysis.  If t here are 2 val ues o n t he sa me da y f or a certai n 
para meter f or a s u bject, t he n t he rec or d wit h t he later ti me will be use d f or t he b y visit 
a nal ysis . 
 
T a ble 7 : Visit Wi n d o ws f or I m m u n o ge nicit y b y Visit S u m m aries  
 
A n al ysis visit  
A n al ysis visit wi n d o w 1 
F or s u bjects w h o recei ve d t he 
first d ose of a d uc a n u m a b i n 
t he pl ace b o-c o ntr olle d peri o d  
F or s u bjects w h o recei ve d t he 
first d ose of a d uc a n u m a b i n 
t he L T E peri o d 
Baseli ne  
Last  val ue  pri or t o t he first d o se of 
a d uca n u ma b  
Last  val ue  pri or t o t he first d ose of 
a d uca n u ma b  
Wee k 2 4  
[ 2, 1 9 6] 
[ 2, 2 5 2] 
Wee k 3 2  
[ 1 9 7, 3 0 8] 
N A  
Wee k 5 6  
[ 3 0 9, 4 7 0] 
[ 2 5 3, 4 2 0] 
Wee k 7 8  
[ 4 7 1, e n d da y of t he place b o-
c o ntr olle d peri o d 2] 
[4 2 1 , 6 0 9 ] 
Wee k 8 0  
[start da y of t he L T E peri o d3, 6 4 4 ] 
N A  
Wee k 1 0 4  
[ 6 4 5, 8 1 2] 
[ 6 1 0, 1 2 6 0] 
Wee k 1 2 8  
[ 8 1 3, 9 8 0] 
N A  
Wee k 1 5 2  
[ 9 8 1, 1 1 6 9] 
N A  
Wee k 1 8 2  
[ 1 1 7 0, 1 8 2 0] 
≥ 1 2 6 1  
Wee k 3 3 8  
≥ 1 8 2 1  
N A  
1.  Visit wi n d o w s are deri ve d base d o n t he first d ose of a d uca n u ma b.  
2.  T he e n d da y of t he place b o -c o ntr olle d peri o d is t he last da y bef ore t he first i nf usi o n i n L T E f or 
s u bjects w h o e nter L T E, or t he last da y i n st u d y f or s u bjects w h o d o n ot e nter L T E. 
3.  T he start da y of t he L T E peri o d is t he da y of first d ose i n t he L T E peri o d.  
 
 
 
 
 
 
 
 
 
 
 
 


 
St atistic al A n al ysis Pl a n  
L o n g -Ter m E xte nsi o n  Peri o d  
Fi n al  V 1. 0  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.  
3 5  
 
4  A p pe n di x  
4. 1  
A n al ysis Dis pl a y  
A nal ysi s dis pla y A 
BII B 0 3 7 late start 
 
BII B 0 3 7 earl y start 
 
BII B 0 3 7  
t otal 
L o w d ose  
Hi g h d ose  
T otal  
 
L o w d ose  
Hi g h d ose  
T otal  
 
 
A nal ysis dis pla y B  
Pa ge 1 of 2  
BII B 0 3 7 late start l o w d ose  
 
BII B 0 3 7 late start hi g h  d ose  
 
 
BII B 0 3 7 late 
start t otal 
A p o E e 4 +  
3 m g/ k g  
A p o E e 4 - 
6 m g/ k g  
 
T otal  
 A p o E e 4 +  
1 0 m g/ k g  
A p o E e 4 - 
1 0 m g/ k g  
 
T otal  
 
 
Pa ge 2 of 2  
BII B 0 3 7 earl y start l o w d ose  
 
BII B 0 3 7 earl y start hi g h  d ose  
 
 
BII B 0 3 7 earl y 
start t otal 
A p o E e 4 +  
3 m g/ k g  
A p o E e 4 - 
6 m g/ k g  
 
T otal  
 A p o E e 4 +  
1 0 m g/ k g  
A p o E e 4 - 
1 0 m g/ k g  
 
T otal