Donanemab Follow-On Study: Safety, Tolerability, And Efficacy in Symptomatic Alzheimer's Disease With Validation of Remote Neuropsychological Assessments
Phase: PHASE2
Conditions: Alzheimer Disease, Dementia, Brain Diseases, Central Nervous System Diseases, Cognitive Impairment
Sponsor: Eli Lilly and Company

Pr ot oc ol I 5 T- M C- A A C H ( b) 
D o na ne ma b F oll o w- O n St u d y: Safet y, T olera bilit y, A n d Efficac y i n S y m pt o matic Alz hei mer's Disease 
Wit h Vali dati o n of Re m ote Ne ur o ps yc h ol o gical Assess me nts
N C T 0 4 6 4 0 0 7 7
A p pr o val Date: 1 1- O C T- 2 0 2 1

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s . It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of d o n a n e m a b ( L Y 3 0 0 2 8 1 3) , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s : T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e . Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r e l e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title: D o na ne ma b F o ll ow- O n St u d y : Safet y, T olera bilit y, A n d Ef ficac y i n 
S y m pt o m atic Alz hei mer’s Disease w ith Vali dat i on o f Re m ot e 
Ne ur o ps yc h ol o gical Assess me nts
Pr ot oc ol N u m ber : I 5 T-M C -A A C H
A me n d me nt N u m ber: b
C o m p o u n d : D o na ne ma b ( L Y 3 0 0 2 8 1 3)
St u d y P h ase : P hase 2
S h ort Title: D o na ne ma b F o ll ow- O n St u d y , w ith Vali dat i on o f Re m ot e S c al e Assess me nt
Acr o n y m : T R AI L B L A Z E R -E X T
S p o ns or N a me : El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress : I n dia na p olis, I n dia na, U S A 4 6 2 8 5
Re g ul at or y A ge nc y I de ntifier N u m ber
I N D: 1 0 9 1 5 7
A p pr o v al D ate: Pr ot oc ol A me n d me nt ( b) El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date 
pr o vi de d bel o w.
A p pr o v al D at e: 1 1- O ct- 2 0 2 1 G M T

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A m e n d m e nt a
2 7 -J a n -2 0 2 1
Ori gi n al Pr ot o c ol
0 1 -S e p -2 0 2 0
A me n d me nt b
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt all o w s f or better c haracterizati o n of t he i nci de nce a n d se verity of  A RI A at a n 
earlier ti me p oi nt.
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1. 3. Sc he d ule of 
Act i vities
A d de d M RI at V 2 . A d de d te xt t o 
C o m me nt fiel d a b o ut M RI at V 2 , 
i ncl u di n g te xt a b o ut M RI ti mi n gs 
r elat i ve t o t he first a n d f o urt h 
i nf usi ons .
T o all o w f or better c haracterizat i on of t he 
i nci de nce a n d se verity of  ARI A at a n earlier 
ti me p oi nt.
C ha n ge d V 2 i nter val t olera nce
fr om “± 7” da ys t o “ 7 t o + 1 0” 
da ys.
T o pr o vi de a d di tio nal ti m e t o perf or m a n d 
re vie w M RI pri or t o i nf usi on.
6. 5. 1. Sta n dar d of 
Care f or 
Alz hei mer’s Disease
A d de d “ W he n me dicall y 
i n dicate d, i nitiati on, i ncrease , or 
di sc o nti n uati on of s y m pt o mat ic 
treat me nts f or A D is per mitte d.”
Cl arificat i on.
7. 1. Disc o nt i n uati on 
of  St u d y 
I nter ve nti o n
A d de d cr oss -r efere nce t o t he 
Ma n ual o f O perati o ns re gar di n g 
i nf or mat i on a b o ut per ma ne nt 
di sc o nti n uati on g ui da nce.
T o pr o vi d e f urt her g ui da nce.
7. 1. 1. 1. D ue t o 
A RI A
A d de d cr oss -r efere nces t o t he 
Ma n ual o f O perati o ns re gar di n g 
i nf or mat i on a b o ut te m p orar y a n d 
p er m a ne nt disc o nt i n uati on 
g ui da nce.
T o pr o vi d e f urt her g ui da nce.
M o difie d te xt re gar di n g 
c o nsi deri n g rei nit iati n g I P.
Rec o m me n dat i on of D M C .
8. 2. 5. Ma g net ic 
Res o na nce I m a gi n g
A d de d te xt , “U nsc he d ule d M RIs 
ma y be perf or me d at t he 
di scretio n of  in vest i gat or.”
Cl arificat i on.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
8. 3. 6. 2. D osi n g 
Rec halle n ge a n d 
Pr e m e dicat i on f or 
I nf usi ons
A d de d d osi n g rec halle n ge details. 
Cl arificat i on/ pr o vi di n g i nf or mati o n.
8. 3. 7. A m yl o i d-
Relate d I m a gi n g 
A b n or m alities 
( A RI A-E a n d 
A RI A- H)
A d de d te xt “W hile m ost cases of 
A RI A- E are as y m pt o m at ic, 
serio us cases ha ve bee n re p orte d. 
A vaila ble data s u g gest seri o us 
cases are m ost li kel y t o occ ur 
earl y in d osi n g, after t he first, 
sec o n d, or t hir d i nf usi o n. ”
Pr o vi de d a d di tio nal  inf or m atio n.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5
T a ble of C o nte nts
1.
Pr ot oc ol S u m m ar y ......................................................................................................8
1. 1.
S y n o psis .......................................................................................................................8
1. 2.
Sc he ma .......................................................................................................................1 2
1. 3.
Sc he d ule of Act i vities ( S o A) ......................................................................................1 3
2.
I ntr o d ucti o n ..............................................................................................................2 5
2. 1.
St u d y  Ratio nale ..........................................................................................................2 5
2. 2.
Bac k gr o u n d ................................................................................................................2 5
2. 2. 1.
Di sease State ..............................................................................................................2 5
2. 2. 2.
Vi de o Assess me nt ......................................................................................................2 6
2. 2. 3.
D o na ne ma b ................................................................................................................2 7
2. 3.
Be nefit/ Ris k Assess me nt ............................................................................................2 8
3.
O bjecti ves a n d E n d p oi nts .........................................................................................2 9
4.
St u d y Desi g n .............................................................................................................3 2
4. 1.
O verall Desi g n ............................................................................................................3 2
4. 1. 1.
Scree ni n g ....................................................................................................................3 3
4. 1. 2.
Part A: Vi de o Assess me nt ...........................................................................................3 3
4. 1. 3.
Part B: O pe n -La bel D o na ne ma b .................................................................................3 3
4. 1. 4.
Part C: I ma gi n g a n d C o g nit i ve/ F u ncti o nal Meas ures...................................................3 4
4. 2.
S ci e nt ific Rati o nale f or St u d y Desi g n.........................................................................3 4
4. 3.
J ustificati o n f or D ose..................................................................................................3 5
4. 4.
E n d of St u d y  Defi niti on ..............................................................................................3 5
5.
St u d y P o p ul ati o n ......................................................................................................3 6
5. 1.
I ncl usi on Cri t eria ........................................................................................................3 6
5. 2.
E xcl usi o n Cri t eria .......................................................................................................3 8
5. 3.
Lifest yle C o nsi derat i ons .............................................................................................3 9
5. 4.
Scree n Fail ures ...........................................................................................................4 0
6.
St u d y I nter ve nti o n ....................................................................................................4 1
6. 1.
St u d y  I nter ve nti on(s) A d m i nistere d ............................................................................4 1
6. 2.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y .............................................................4 2
6. 3.
Meas ures t o Mi ni mize Bias: Ra n d o mizat i on a n d Bli n di n g ..........................................4 2
6. 4.
St u d y  I nter ve nti on C o m plia nce ...................................................................................4 2
6. 5.
C o nc o mita nt T hera p y ................................................................................................. 4 3
6. 5. 1.
Sta n dar d of Care f or Alz hei mer’s Disease ...................................................................4 3
6. 5. 2.
Me dicat i ons f or I nf usi on React i ons .............................................................................4 3
6. 5. 3.
E xcl u de d Me dicat i ons ................................................................................................. 4 3
6. 6.
D ose M o dificat i on ......................................................................................................4 4
6. 7.
I nterve nti o n after t he E n d of t he St u d y ........................................................................4 4
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ....................................................................................4 5
7. 1.
Di sc o nti n uatio n of  St u d y I nter ve nti on ........................................................................4 5
7. 1. 1.
T e m p orar y  Disc o nti n uati on ........................................................................................4 7
7. 2.
P arti cipa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y .............................................4 7

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6
7. 2. 1.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Partici pa nts ...............................................4 8
7. 3.
L ost t o F oll o w -U p ......................................................................................................4 8
8.
St u d y Assess me nts a n d Pr oce d ures .........................................................................5 0
8. 1.
Efficac y Assess me nts ................................................................................................. 5 0
8. 1. 1.
C o g ni tive a n d F u nct i onal Meas ures ............................................................................5 0
8. 1. 2.
Or der of Assess me nts a n d Rater R oles ........................................................................5 1
8. 1. 3.
Bi o m ar ker Efficac y Meas ures.....................................................................................5 3
8. 2.
S af et y Assess me nts ....................................................................................................5 3
8. 2. 1.
P h ysical a n d Ne ur ol o gical E xa mi nat i ons ....................................................................5 3
8. 2. 2.
Vi t al Sig ns.................................................................................................................. 5 4
8. 2. 3.
Electr ocar di o gra ms .....................................................................................................5 4
8. 2. 4.
Cli nical Safet y  La b orat or y Assess me nts .....................................................................5 5
8. 2. 5.
Ma g net ic Res o na nce I ma gi n g.....................................................................................5 6
8. 2. 6.
He pati c Safet y M o ni t ori n g..........................................................................................5 6
8. 2. 7.
S ui ci dal I deati on a n d Be ha vi or Ris k M o nit ori n g .........................................................5 7
8. 3.
A d verse E ve nts a n d Seri o us A d verse E ve nts ..............................................................5 8
8. 3. 1.
Ti me Peri o d a n d Fre q ue nc y  for C ollect i n g A E a n d S A E 
I nf or mat i on .................................................................................................................5 8
8. 3. 2.  
Met h o d of Detecti n g A Es a n d S A Es ...........................................................................5 9
8. 3. 3.
F o ll ow- U p of A Es a n d S A Es ......................................................................................5 9
8. 3. 4.
Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es............................................................5 9
8. 3. 5.
Pre g na nc y ...................................................................................................................5 9
8. 3. 6.
H y perse nsi tivi t y, I ncl u di n g I nf usi on- Relate d Reacti o ns ..............................................6 0
8. 3. 7.
A m yl o i d-Relate d I m a gi n g A b n or malities ( A RI A-E a n d A RI A -H) ..............................6 0
8. 3. 8.
A d verse E ve nts of S pecial I nterest ..............................................................................6 1
8. 3. 9.
Pr o d uct C o m plai nt s ....................................................................................................6 2
8. 4.
Treat me nt of O ver d ose ...............................................................................................6 2
8. 5.
P har mac o ki net ics........................................................................................................6 3
8. 6.
P har mac o d y na mics .....................................................................................................6 3
8. 6. 1.
Cl eara nce of A m yl o i d De p osits ..................................................................................6 3
8. 7.
Ge net ics .....................................................................................................................6 3
8. 8.
Bi o m ar kers .................................................................................................................6 3
8. 9.
I mm u n o ge nicit y Assess me nts .....................................................................................6 4
8. 1 0.
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics ..................................................6 4
9.
St atistic al C o nsi der ati o ns .........................................................................................6 5
9. 1.
Stati stical H y p ot heses................................................................................................. 6 5
9. 2.
S a m ple Si ze Deter mi nat i on .........................................................................................6 5
9. 3.
P o p ul at i ons f or A nal yses ............................................................................................6 6
9. 4.
Stati stical A nal yses .....................................................................................................6 6
9. 4. 1.
Ge neral C o nsi derati o ns ...............................................................................................6 6
9. 4. 2.
Pri mar y E n d p o i nt(s) ...................................................................................................6 7
9. 4. 3.
Sec o n dar y  E n d p oi nt(s)................................................................................................6 8
9. 4. 4.
Terti ar y/ E x pl orat or y E n d p oi nt(s) ................................................................................6 8
9. 4. 5.
Ot her Safet y A nal yse(s) ..............................................................................................6 9
9. 4. 6.
Ot her A nal yse(s) .........................................................................................................6 9
9. 5.
I nteri m A nal yses.........................................................................................................6 9

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7
9. 6.
Data M o nit ori n g C o m mittee ( D M C) ...........................................................................7 0
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns ................................7 1
1 0. 1.
A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns ............................................................................................................7 1
1 0. 1. 1.
Re g ulat or y  a n d Et hical C o nsi derati ons ........................................................................7 1
1 0. 1. 2.
Fi na ncial Discl o s ure ...................................................................................................7 1
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess ..........................................................................................7 1
1 0. 1. 4.
Data Pr otecti o n ...........................................................................................................7 2
1 0. 1. 5.
Di sse mi nati on of Cli nical St u d y  Data .........................................................................7 2
1 0. 1. 6.
Data Q ualit y Ass ura nce ..............................................................................................7 3
1 0. 1. 7.
S o urce D oc u me nts ......................................................................................................7 4
1 0. 1. 8.
St u d y  a n d Site Start a n d Clos ure .................................................................................7 4
1 0. 1. 9.
P u blicat i on P olic y .......................................................................................................7 5
1 0. 1. 1 0. I n vesti gat or I nf or mati on .............................................................................................7 5
1 0. 2.
A p pe n di x 2: Cli nical La b orat or y  Tests........................................................................7 6
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or 
Rec or di n g, E val uat i n g, F oll o w-U p, a n d Re p orti n g ......................................................7 9
1 0. 3. 1.
Defi nit i on o f A E .........................................................................................................7 9
1 0. 3. 2.
Defi nit i on o f S A E .......................................................................................................8 0
1 0. 3. 3.
Rec or di n g a n d F o ll ow- U p of A E a n d/ or S A E .............................................................8 1
1 0. 3. 4.
Re p orti n g of  S A Es......................................................................................................8 3
1 0. 4.
A p pe n di x 4: Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w-U p 
Assess me nts ...............................................................................................................8 4
1 0. 5.
A p pe n di x 5: Fl or beta pir F 1 8 A m yl o i d P E T I ma gi n g ..................................................8 6
1 0. 6.
A p pe n di x 6: Fl orta uci pir F 1 8 Ta u P E T I ma gi n g ........................................................8 9
1 0. 7.
A p pe n di x 7: A b bre viat i ons .........................................................................................9 0
1 0. 8.
A p pe n di x 8: Pr o visi o ns f or C ha n ges i n St u d y  C o n d uct D uri n g 
E xce pt i onal Ci rc u msta nces.........................................................................................9 4
1 0. 9.
A p pe n di x 9: Pr ot oc ol A me n d me nt Hist or y ................................................................. 9 8
1 1.
Refere nces .................................................................................................................9 9

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8
1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title: D o na ne ma b F o ll ow- O n St u d y : Safet y, T olera bilit y, A n d Efficac y  i n 
S y m pt o m atic Alz hei mer’s Disease w ith Vali dat i on o f Re m ot e 
Ne ur o ps yc h ol o gical Assess me nts
S h ort Title: D o na ne ma b F o ll ow- O n St u d y , wit h Vali dati on of Re m ote Scale Assess me nt
R ati o n ale :
P art A
Re m ote assess me nts of i n di vi d uals wit h A D via tele m e dici ne ha ve t he p ote ntial t o re d uce 
b ur de ns ass ociate d wit h cli nical care a n d researc h partici pat i on. Researc h c o m pari n g cli nical 
i nter vie wi n g c o n d ucte d t hr o u g h vi de o c o nfere nci n g a n d tra dit i onal o n -sit e c o n ditio n s has 
s u g geste d ge nerall y g o o d a gree me nt i n a variet y of c o n di tio ns, i ncl u di n g de m e nt ia a n d c o g niti ve 
i m pair me nt of vari o us ca uses. H o we ver, li mite d data is a vaila ble o n t he vali dit y of re m ote 
we b -base d assess me nt of c o g nit i ve a n d f u ncti onal meas u res t ypicall y i m ple me nte d i n A D 
researc h st u dies. T heref ore, t he aim of  St u d y I 5 T-M C -A A C H ( A A C H ) Part A i s t o e valuate t he 
vali dit y of  r e mote (at -h o me) vi de o assess me nts of c o g nit i ve a n d f u ncti onal meas ures.
St u d y  A A C H Part A is a mul tice nter, ra n d o mize d, m ult i ple cr oss o ver st u d y t o vali date re m ote 
assess me nt of c o g nit i ve a n d f u ncti onal scales. Partici pa nts will be assesse d re m otel y (t hr o u g h 
vi de oc o nfere nci n g) as well as o n- sit e.
P art B
Part B i s a mul tice nter, o pe n -label st u d y of d o na ne ma b treat me nt f or partici pa nts wit h 
s y m pt o mat ic A D a n d naï ve t o d o na ne ma b.
St u d y  A A C H Part B will pr o vi de a d dit i onal safet y a n d cli nical inf or m atio n as a n o pe n -la bel 
st u d y. P arti ci pa nts fr o m a s p o ns or -a p pr o ve d ori gi nati n g d o na ne ma b st u d y w h o were assi g ne d 
pl ace b o will recei ve d o na ne ma b i n t he si n gle o pe n -label ar m . 
P art C
T h ose w h o recei ve d d o na ne ma b i n a n ori gi nati n g st u d y  ma y part ici pate i n a si n gle i ma gi n g a n d 
c o g nitive/f u nct i onal assess me nt visit . 
St u d y  A A C H Part C will assess t he l o n g -t er m effect of d o na ne ma b o n P E T i ma gi n g bio m ar kers, 
c o g nitio n , a n d f u nct i oni n g i n partici pa nts w h o ha ve n ot recei ve d I P f or at least 5 2 wee ks.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9
O bjecti ves a n d E n d p oi nt s
O bject i ves
E n d p oi nts
Pri mar y
P art A
T o e val uate t he relia bilit y of  V T C c o mpare d 
wi t h o n-site a d mi nistere d c o g niti ve a n d 
f u ncti onal meas ures
T he i ntraclass c orrelat i on bet wee n V T C a n d 
o n -site assess me nt f or P AI R 1 f or 

A D A S -C o g 1 3

A D C S -A D L

M M S E

C D R -S B
P art B
T o e val uate safet y  a n d t olera bility of  
d o na ne ma b
Sta n dar d safet y assess me nts i n Part B : 

S p o nta ne o usl y re p orte d A Es

Cli nical la b orat or y  t ests

Vi t al si g n a n d b o d y wei g ht 
meas ure me nts

1 2- lea d E C Gs

P h ysical a n d ne ur ol o gical 
e xa mi nat i ons
M RI ( A RI A a n d e mer ge nt ra di o l ogi cal 
fi n di n gs)
I nf usi on -r elate d reactio ns
C- S S R S
Sec o n dar y
T o assess t he effect of d o na ne ma b o n cli nical 
pr o gressi o n i n part ici pa nts wit h s y m pt o matic 
A D 
C ha n ge fr o m baseli ne u p t o Wee k 7 2 as 
meas ure d i n Part B b y : 

M M S E sc ore

A D A S -C o g 1 3 sc ore

i A D R S sc ore

A D C S -i A D L sc ore

C D R -S B
T o assess t he effect of d o na ne ma b o n brai n 
a m yl o i d de p ositio n 
C ha n ge i n brai n a m yl o i d pla q ue de p ositio n 
fr om baseli ne at Wee k 3 6 of Part B as 
meas ure d b y fl or beta pir F 1 8 P E T sca n

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 0
T o assess t he effect of d o na ne ma b o n brai n 
r e gio n v o l umes 
C ha n ge i n v ol u metric M RI meas ures fr o m 
baseli ne t o Wee k 7 2 i n Part B
T o assess peri p heral P K a n d prese nce of 
a nt i-d o na ne ma b a nt i b o dies
P K of  d o na ne ma b i n Part B.
A D As a gai nst d o na ne ma b i n Part B i ncl u di n g 

treat me nt -e mer ge nt A D As 

ne utralizi n g a nt i b o dies
A b bre viati o ns: A D = Alz hei mer’s disease; A D A = a n ti 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 ; A D C S -A D L = 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; A D C S -i A D L = Alz hei mer’s Disease C o o perati ve St u d y – i nstr u me ntal Acti vities of
Dail y  Li vi n g; A E = a d verse e ve nt; A RI A = a m y l oi d-relate d i ma gi n g a b n or mality ; C D R-S B = Cli nical De me ntia 
Rati n g Scale – S u m of B o xes; 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;
i A D R S = i nte grate d Alz hei mer’s Disease Rati n g Scale; M M S E = Mi ni Me ntal State E xa mi nati o n; 
M RI
= ma g netic res o na nce i ma gi n g; P E T = p ositr o n e missi o n t o m o gra p h y; P K = p har mac o ki netics;
V T C = vi de o telec o nfere nce.
O ver all Desi g n
P art A:
T he vi de o vali dat i on peri o d is a m ul tiple cr oss o ver desi g n wi t h partici pa nts alter nati n g bet wee n 
i n-cli nic assess me nt s a n d at -h o me assess me nt s of  c o g nitive a n d f u nct i onal scales o ver a 
mi ni m u m o f 1 a n d a ma xi m u m o f 3 cr oss o vers . T otal ti me i n Part A ca n var y fr o m a mi ni m u m o f 
4 wee ks ( 1 cr oss o ver [ 1 P AI R]) t o a ma xi m u m o f 2 4 wee ks ( 3 cr oss o vers [ 3 P AI R S]). 
P arti cipa nts d o n ot recei ve st u d y  I P d urin g t he vi de o vali dat i on peri o d . Partici pa nts are 
ra n d omize d 1: 1 i n re gar ds t o or der of i n -cli nic or at -h o me f or t he first assess me nt, eit her:

Gr o u p 1: C o g nit i ve/f u ncti o nal scale assess me nt at t he st u d y sit e (o n -sit e), foll o we d b y  a n 
at -h o me assess me nt ( V T C) , or

Gr o u p 2: C o g nit i ve/f u ncti o nal scale assess me nt at h ome ( V T C), f oll o we d b y assess me nt 
o n -sit e. 
P art B:
Part B i s a mul tice nter, o pe n-label, f o ll ow- o n st u d y  of d o na ne ma b i n partici pa nts wit h 
s y m pt o mat ic A D . Partici pa nts w h o recei ve d place b o i n t he ori gi nat i n g trial recei ve d o na ne ma b 
7 0 0 m g I V Q 4 W f or 3 d oses, t he n 1 4 0 0 m g i nt ra ve n o usl y e ver y 4 wee ks f or u p to 3 6 wee ks, (u p 
t o 4 8 wee ks t otal d uratio n i n Part B).
P arti cipa nts ma y  recei ve d o na ne ma b t hr o u g h Wee k 3 6 or Wee k 4 8. Criteria f or sc he d ule d d ose 
di sc o nti n uati on at 3 6 wee ks are defi ne d b y t he s p o ns or a n d ma y be base d o n res ults of t he 
parti ci pa nt’s fl or be t a pir F 1 8 P E T sca n at Wee k 3 6 or res ults fr om e xter nal st u dies s uc h as St u d y  
A A C G .
P art C:
P arti cipa nts w h o recei ve d d o na ne ma b i n t he ori gi nati n g trial ma y  p artici pate i n a n i ma gi n g a n d 
c o g nitive/f u nct i onal assess me nt visit ( V isit 2 0 1). V isit 2 0 1 occ urs a n yt i me at least 5 2 wee ks 
fr om t he partici pa nt’s last d o u ble -bli n d visit i n t he ori gi nati n g st u d y . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 1
Discl os ure St ate me nt : 
T his is a si n gle-ar m tr e at me nt st u d y wit h 1 ar m t hat is n ot bli n de d.
N u m ber of P artici p a nt s:
A p pr o xi matel y  2 0 0 partici pa nts will be e nr o lle d s uc h t hat a p pr o xi matel y 1 5 0 partici pa nts 
c o mplete t he st u d y .
I nter ve nti o n Gr o u ps a n d D ur ati o n :
Part A: T he vi de o vali dat i on peri o d i s a mul tiple cr oss o ver desi g n wit h partici pa nts alter nat i n g 
bet wee n i n- cli nic assess me nt a n d at -h o me assess me nt of c o g nitive a n d f u nct i onal scales o ver a 
mi ni m u m o f 1 a n d a ma xi m u m o f 3 cr oss o vers . T otal ti me i n Part A ca n var y fr o m a mi ni m u m o f 
4 wee ks ( 1 cr oss o ver [1 P AI R ]) t o a ma xi m u m of 2 4 wee ks ( 3 cr oss o vers [3 P AI R S ]). 
P arti cipa nts d o n ot recei ve st u d y  I P d urin g t he vide o vali dat i on peri o d . Partici pa nts are 
ra n d omize d 1: 1 i n re gar ds t o or der of i n -cli nic or at -h o me f or t he first assess me nt, eit her:

Gr o u p 1: C o g nit i ve/f u ncti o nal scale assess me nt at t he st u d y sit e ( o n-sit e), foll o we d b y  a n 
at -h o me assess me nt ( V T C; vi de o telec o nfere nce) or

Gr o u p 2: C o g nit i ve/f u ncti o nal scale assess me nt at h ome ( V T C), f oll o we d b y assess me nt 
o n -sit e. 
Part B : Partici pa nts w h o recei ve d place b o i n t he ori gi nat i n g trial recei ve d o na ne ma b 7 0 0 m g I V 
Q 4 W f or 3 d oses, t he n 1 4 0 0 m g I V e ver y 4 wee ks f or u p t o 3 6 wee ks (u p t o 4 8 wee ks t otal 
d urati o n i n Part B). 
Part C: Partici pa nts w h o recei ve d d o na ne ma b i n t he ori gi nat i n g trial ma y p artici pat e i n a n 
i ma gi n g a n d c o g nitive/f u nct i onal assess me nt visit ( Visit 2 0 1). V isit 2 0 1 occ urs a n y time at l east 
5 2 wee ks fr o m t he partici pa nt’s last d o u ble -bli n d visit i n t he ori gi nat i n g st u d y.
T he m a xi m u m t ot al d uratio n of  st u d y partici pati on f or eac h partici pa nt, i ncl u di n g scree ni n g a n d 
t he p osttreat me nt f o ll ow- u p peri o ds, i s u p t o 1 2 4 wee ks:

Scree ni n g : u p t o 3 0 da ys pri or t o V isit 6 0 2

Part A, Vi de o assess me nt: u p t o 2 4 wee ks

Part B, O pe n -lab el d o na ne ma b : u p t o 7 2 wee ks (treat me nt recei ve d f or 3 6 or 4 8 wee ks)

Part B, F oll o w - u p: u p t o 2 4 wee ks
N ote: Part C is n ot a d de d t o t he ma xi m u m t ot al d uratio n of  st u d y partici pat i on beca use Part C is 
a si n gle visit , a n d Part B partici pa nts d o n ot partici pate i n Part C.
D at a M o nit ori n g C o m mittee: N o

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 2
1. 2.
Sc he m a
A b bre viati o ns: I P = i n vesti gati o nal pr o d uct; I V = i ntra ve n o us; L Y = d o na ne ma b; P B O = place b o; Q 4 W = e ver y 
4 wee ks; S o A = Sc he d ule of Acti vities; V = visit .
* Partici pa nt s h o ul d partici pate i n P AI R 1 t o pr ocee d t o Part B or Part C. V 6 0 1 occ urs u p t o 3 0 da ys pri or t o V 6 0 2. 
Visits i n Part A are eac h se parate d b y 4 wee ks. T he ti me bet w ee n t he fi nal visit of Part A a n d t he first visit of 
Part B or Part C is ≥4 wee ks.
♦
I P is a d mi nistere d u p t o V 1 3 b ut ma y be disc o nti n ue d as earl y as V 1 0. Visits c o nti n ue u ntil e n d of st u d y as 
i n dicate d i n t he S o A. 
●I ma gi n g a n d c o g niti ve & f u ncti o nal mea s ures visit occ urs a n y ti me ≥5 2 wee ks after t he partici pa nt’s last d o u ble -
bli n d visit i n t he ori gi nati n g st u d y. See V 2 0 1 i n t he S o A f or pr oce d ures.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 3
1. 3.
Sc he d ule of Acti vities ( S o A)
Scree ni n g a n d Part A
Scree ni n g
Part A: Vi de o Vali dati o n
C o m me nts
Visit N u m ber
6 0 1
6 0 2- 6 0 7
Wee ks R elati ve t o B aseli ne ( V 1)
See f o ot n ote a.
Visit Int e r val T olera nce ( da ys)
–
± 4
± 4
E ntr y a n d A d mi nistr ati ve
F ull inf or me d c o nse nt (p artici pa nt a n d st u d y 
p art ner)
X
I ncl usi o n a n d e xcl usi o n criteria, re vie w a n d 
c o nfir m
X
I nter val me dical hist or y, i ncl u di n g rele va nt 
c ha n ges si nce last visit of ori gi nati n g st u d y
X
S u bsta nce use (alc o h ol, caffei ne, t o bacc o 
use) 
X
C o nc o mita nt me dicati o ns
X
X
X
A Es
X
X
X
Cli nic al Assess me nts
P h y sical/ ne ur ol o gical e xa mi nati o n
X
C o m plete p h ysical a n d ne ur ol o gical 
e xa m, as descri be d i n Secti o n 8. 2. 1 .
A n y  cli nicall y si g nifica nt c ha n ges 
fr o m baseli ne o n 
p h y sical/ ne ur ol o gical e xa mi nati o ns 
s h o ul d be n ote d o n t he A E C R F.  

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 4
Scree ni n g
Part A: Vi de o Vali dati o n
C o m me nts
Visit N u m ber
6 0 1
6 0 2- 6 0 7
Wee ks R elati ve t o B aseli ne ( V 1)
See f o ot n ote a.
Visit Int e r val T olera nce ( da ys)
–
± 4
± 4
Cli nici a n- A d mi nistere d Assess me nts ( Electr o nic)
A D A S -C o g 1 3
X
X
A d mi nister t he A D A S -C o g 1 3, 
A D C S -A D L, C D R -S B, a n d M M S E 
pri or t o me dical pr oce d ures t hat 
c o ul d be stressf ul t o t he partici pa nt 
( bl o o d dra ws, etc.; Secti o n 8. 1. 2 ). 
T hese tests i ncl u de t he a u di o v oice 
rec or di n g of t he rater’s q uesti o ns a n d 
t he partici pa nt a n d st u d y part ner 
res p o nses t o assess me nt q uesti o ns.
A D C S -A D L
X
X
C D R -S B
X
X
M M S E
X
X
R a n d o miz ati o n 
Ra n d o mizati o n
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 5
Part B
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
E ntr y a n d A d mi nistr ati ve
Re vie w M RI, 
cli nical la bs, a n d 
cli nical stat us
X
C o nfir m partici pa nt d oes 
n ot meet disc o nti n uati o n 
criteria ( Secti o n 7. 2 ).
C o nc o mita nt 
me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A Es
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Cli nic al Assess me nts
Hei g ht
X
Wei g ht
X
X
X
X
X  
X
X  
X  
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 6
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Vital si g ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Sitti n g B P, p ulse, a n d 
te m perat ure ( wit h sitti n g 
vitals) will be meas ure d at 
all visits. 
Sitti n g B P a n d p ulse will 
be meas ure d after 
a p pr o xi matel y 5 mi n utes i n 
t he sitti n g p ositi o n o nl y. 
I n a d diti o n, ort h ostatic B P 
a n d p ulse will be meas ure d 
at V1, V 4, V 7 , V 10 , V 1 3 , 
V 1 4 , E D, a n d U Vs . 
P h y sical/ ne ur ol o gi
cal e xa mi nati o n
X
X
X
X
X  
X
X  
X  
X
I ncl u des n e ur ol o gical 
e xa mi nati o n
V 6 0 1 is a brief p h ysical 
a n d ne ur ol o gical e xa m, as 
descri be d i n Secti o n 8. 2. 1 .
A n y  cli nicall y si g nifica nt 
c ha n ges fr o m baseli ne o n 
p h y sical/ ne ur ol o gical 
e xa mi nati o ns s h o ul d be 
n ote d o n t he A E C R F .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 7
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
1 2 -lea d E C G 
(ce ntral or l ocal)
X
X
X
X
X  
X
X
Perf or m pri or t o 
a d mi nistrati o n of I P, w he n 
a p pr o priate.
E C G at V 14 n ot re q uire d 
f or partici pa nts w h o 
c o m plete d d osi n g at V 1 0. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 8
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
P E T Sc a ns a n d M RI
M RI
X  
X  
X
X
X
X
Perf or m pri or t o V 1 at U P
if last rec or de d M RI fr o m 
or i gi nati n g st u d y occ urre d 
> 1 2 m o nt hs bef ore V 1.
M RI at V 2 is t o be 
perf or me d a n d re vie we d 
pri or t o V 2 i nf usi o n a n d 
m a y  occ ur n o s o o ner t ha n 
2 1 da ys after t he first 
i nf usi o n. If i nf usi o ns are 
s us pe n de d after t he first, 
sec o n d, or t hir d d ose, a n 
M RI is t o be perf or me d 
a n d re vie we d pri or t o t he 
f o urt h i nf usi o n.
M RI
at V 4 is t o be 
perf or me d a n d re vie we d 
pri or t o V 4 i nf usi o n.
M RI at V 4 m a y  occ ur 
1 4 da ys bef ore t he 
sc he d ule d visit date 
wit h o ut pr ot oc ol de viati o n.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 9
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
Fl or beta pir F 1 8
P E T sca n
X
X e
Fl or beta pir F 1 8 P E T sca n 
m a y  occ ur ± 1 4 da ys fr o m 
sc he d ule d visit date 
wit h o ut pr ot oc ol de viati o n.
Cli nici a n- A d mi nistere d Assess me nts ( Electr o nic)
A D A S -C o g 1 3
X
X
X
X
X  
X  
X  
X  
X  
X
A d mi nister t he A D A S -
C o g 1 3, A D C S-A D L, C D R -
S B, a n d M M S E pri or t o 
me dical pr oce d ures t hat 
c o ul d be stressf ul t o t he 
partici pa nt ( bl o o d dra ws, 
etc. ; Secti o n 8. 1. 2 ). T hese 
tests i ncl u de t he a u di o 
v oice rec or di n g of t he 
rater’s q uesti o ns a n d t he 
partici pa nt a n d st u d y 
part ner res p o nses t o 
assess me nt questi o ns.
A D C S -A D L
X
X
X
X
X  
X  
X  
X  
X  
X
C D R -S B ( Gl o bal 
S u m of B o xes -
C D R)
X
X
X
X
X  
X  
X  
X  
X  
X
M M S E
X
X
X
X
X  
X  
X  
X  
X  
X
Cli nici a n- A d mi nistere d Assess me nts ( P a per)
C- S S R S 
Scree ni n g/ Baseli ne
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 0
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
C- S S R S Si nce Last 
Visit
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Self - Har m 
S u p ple me nt F or m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Self -Har m 
F oll o w -U p F or m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re q uire d if tri g gere d b y 
t he Self-Har m S u p ple me nt 
F or m per i nstr ucti o ns.
L a b or at or y Tests a n d S a m ple C ollecti o ns f
He mat ol o g y
X  
X  
X  
X  
X
X
X
X  
X
X
La bs at V 1 4 n ot re q uire d 
f or partici pa nts w h o 
c o m plete d d osi n g at V 1 0.
Perf or m pri or t o V 1 at U P
if last rec or de d la bs fr o m 
t he ori gi nati n g st u d y were 
c ollecte d > 6 m o nt hs bef ore 
V 1.
Cli nical C he mistr y 
X  
X  
X  
X  
X
X
X
X  
X
X
P- t a u
X
X
X
X
X  
X  
X  
X  
X  
X
Nf L
X
X
X
X
X  
X  
X  
X  
X  
X
A 
X
X
X
X
X  
X  
X  
X  
X  
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 1
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
P K sa m ple 
( pr ed ose)
X
X  
X  
X
X
X
D o n ot c ollect if t he last I P 
i nf usi o n was > 6 m o nt hs 
pri or t o t he sc he d ule d visit.
Pre d ose c ollecti o ns ma y be 
c ollecte d fr o m t he I V site 
pri or t o t he i nf usi o n.
Ra n d o m P K sa m ple 
c ollecte d f or partici pa nts 
w h o d o n ot recei ve d ose at 
V 1 3.
P K sa m ple 
( post d ose)
X
X
X
D o n ot c ollect if t he last I P 
i nf usi o n was > 6 m o nt hs 
pri or t o t he sc he d ule d visit.
C ollect wit hi n 3 0 mi n utes 
of I P a d mi nistrati o n. 
C ollect fr o m t he ar m t hat 
I P was n ot a d mi nistere d 
t hr o u g h.
P K sa m ple 
(ra n d o m)
X  
X  
X  
X  
X
D o n ot c ollect if t he last I P 
i nf usi o n was > 6 m o nt hs 
pri or t o t he sc he d ule d visit.
I m m u n o ge nicit y 
( A D A) sa m ples
X  
X  
X  
X  
X
X
X  
X  
X  
X  
X  
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 2
Part B: O pe n -La bel
Part B: F oll o w - Up, U V , 
E D
C o m me nts
Visit N u m ber
U P b
1
2
3
4
5
6
7
8
9
1 0
1 1 c
1 2 c
1 3 c
1 4 c
1 5
8 0 1 d
8 0 2 d
U V
E D
E D o nl y if partici pa nt has 
c o m plete d V 1 a n d recei ve d I P 
i n Part B.
Wee ks R elati ve t o 
B aseli ne ( V 1)
0
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
6 0
7 2
8 4
9 6
9 9 7
Pr oce d ures f or s o me visits 
m a y  ta ke m ore t ha n 1 da y.
Visit Int e r val 
T olera nce ( da ys)
–
-7 t o 
+ 1 0
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
St ore d S a m ples
E x pl o rat or y 
bi o mar ker sa m ples 
X
X
X
X
X
X  
X
C ollect u nless n ot all o we d 
or  u nfeasi ble d ue t o l ocal 
re g ulati o ns.
R a n d o miz ati o n a n d D osi n g
C o ntact I W R S -
dis pe nsati o n of I P
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
O nl y c o ntact I W R S at 
V 1 1, V 1 2, a n d V 1 3 f or 
partici pa nts recei vi n g I P 
f or 4 8 wee ks.
A d mi nister I P
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A d mi nistere d b y I V at 
st u d y site. 
T he partici pa nt s h o ul d be 
o bser ve d f or a mi ni m u m of 
6 0 mi n utes f oll o wi n g t he 
e n d of eac h i nf usi o n.
O nl y a d mi nister I P at V 1 1, 
V 1 2, a n d V 1 3 f or 
partici pa nts recei vi n g I P 
f or 4 8 wee ks.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 3
Part C
Part C
C o m me nts
Visit N u m ber
2 0 1
Ti mi n g
A n y  ti me ≥5 2 wee ks after 
partici pa nt’s last d o u ble -bli n d 
visit i n t he or i gi nati n g st u d y.
Pr oce d ures ma y ta ke m ore t ha n 
1 da y .
P E T Sc a ns
Fl orta uci pir F 1 8 P E T sca n
X g
Fl or beta pir F 1 8 P E T sca n
X g
Cli nici a n A d mi nistere d Assess me nts ( Electr o nic)
A D A S -C o g 1 3
X
If a P E T sca n is d o ne o n t he sa me 
da y , ad mi nister t he A D A S -C o g 1 3, 
A D C S -A D L, C D R -S B, a n d 
M M S E pri or t o P E T sca n . T hese 
tests i ncl u de t he a u di o v oice 
rec or di n g of t he rater’s q uesti o ns 
a n d t he partici pa nt a n d st u d y 
part ner res p o nses t o assess me nt 
q uesti o ns.
A D C S -A D L
X
C D R -S B ( Gl o bal S u m of 
B o xes - C D R)
X
M M S E
X
P- t a u
X
Nf L
X
A 
X
E x pl o rat or y bi o mar ker sa m ples
X
C ollect u nless n ot all o we d or 
u nfeasi ble d ue t o l ocal re g ulati o ns.
A E s
X
C o nc o mita nt me dicati o ns
X

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 4
A b bre viati o ns : A β = a m y l oi d beta; 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 ; A D C S -
A D L = 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; A E = a d verse e ve nt; B P = bl o o d press ure; C D R -S B = Cli nical 
De me ntia Rati n g Scale – S u m of B o xes; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; C R F = case re p ort f or m; E C G = electr ocar di o gra m; E D = earl y 
disc o nti n uat i o n; I P = i n vesti gati o nal pr o d uct; I V = i ntra ve n o us; I W R S = i nteracti ve we b-res p o nse s yste m; M M S E = Mi ni Me ntal State E xa mi nati o n; 
M RI
= ma g netic res o na nce i ma gi n g; Nf L = ne ur ofila me nt li g ht c hai n ; 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 netics; P- ta u = p h os p h or ylate d 
ta u; U P = u nsc he d ule d pr oce d ure; U V = u nsc he d ule d visit; V = visit .
a
V 6 0 1 occ urs u p t o 3 0 da ys pri or t o V 6 0 2 . V 6 0 2 ca n n ot occ ur < 3 0 da ys fr o m t he partici pa nt’s last d o u ble -bli n d visit of t he ori gi nati n g st u d y. V 6 0 2 t hr o u g h 
V 6 0 7 ea c h  occ ur 4 wee ks a part. Part A visits ma y occ ur u p t o 2 4 wee ks pri or t o Part B ( V 1 ), f or eli gi ble partici pa nts. T he e xact wee k relati ve t o V 1 de pe n ds 
o n t he n u m ber of P AI Rs i n whi c h t he partici pa nt elects t o partici pate. T he ti me bet wee n t he fi nal visit of Part A a n d t he first visit of Part B or Part C is 
≥4 wee ks.
b
U P ta kes place at t he start of Part B ( pri or t o V 1), a n d is o nl y c o n d ucte d if : partici pa nt’s last M RI fr o m t he ori gi nati n g st u d y is > 1 2 m o nt hs fr o m V 1, or last 
la bs fr o m t he ori gi nati n g st u d y were c ollecte d > 6 m o nt hs fr o m V 1. T he i n vesti gat or c o nfir ms c o nti n ue d eli gi bilit y as descri be d i n Secti o n 7. 2 .
c
V 1 1 a n d V 1 2 d o n ot occ ur f or partici pa nts wit h a fi nal d ose at or bef ore V 1 0. Partici pa nts res u me t he visit sc he d ule wit h V 1 3 ( Wee k 4 8) . V 1 4 ma y be 
o pti o nal f or s o me partici pa nts, as deter mi ne d b y t he s p o ns or. 
d
F oll o w -u p visits are n ot re q uire d if t he partici pa nt meets release re q uire me nts deter mi ne d b y t he s p o ns or.
e
F or Part B E D visit, c ollect fl or beta pir F 1 8 P E T sca n o nl y if a fl or beta pir F 1 8 P E T sca n has n ot y et bee n perf or me d a n d partici pa nt has recei ve d at least 
3 d oses of d o na ne ma b . 
f
U n sc he d ule d la b tests ma y be perf or me d at t he discreti o n of t he i n vesti gat or . C ollect la bs pri or t o a d mi nistrati o n of I P, u nless ot her wise n ote d. 
g
Perf or m t he fl orta uci pir F 1 8 a n d fl or beta pir F 1 8 P E T sca ns ≥1 6 h o urs a part fr o m eac h ot her . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 5
2.
I ntr o d ucti o n
2. 1.
St u d y R ati o n ale
P art A
Re m ote assess me nts of i n di vi d uals wit h A D via tele m e dici ne ha ve t he p ote ntial t o re d uce 
b ur de ns ass ociate d wit h cli nical care a n d researc h partici pat i on. Researc h c o m pari n g cli nical 
i nter vie wi n g c o n d ucte d t hr o u g h vi de o c o nf ere nci n g a n d tra ditio nal  o n-site c o n ditio n s has 
s u g geste d ge nerall y g o o d a gree me nt i n a variet y of c o n di tio ns, i ncl u di n g de m e nt ia a n d c o g niti ve 
i m pair me nt of vari o us ca uses. H o we ver, li mite d dat a is a vaila ble o n t he vali dity of r e mot e 
we b -base d assess me nt  of c o g niti ve a n d f u ncti onal meas ures t ypicall y i m ple me nte d i n A D 
researc h st u dies. T heref ore, t he aim of  St u d y I 5 T-M C -A A C H ( A A C H ) Part A i s t o e valuate t he 
vali dit y of  r e mot e ( at -h o me ) vi de o assess me nts of c o g nit i ve a n d f u ncti onal meas ures .
St u d y  A A C H P art A is a m ult ice nter, ra n d o mize d, m ulti ple cr oss o ver st u d y t o vali date re m ote 
assess me nt of c o g nit i ve a n d f u ncti onal scales. Partici pa nts will be assesse d r e mot e l y (t hr o u g h 
vi de oc o nfere nci n g) as well as o n -sit e.
P art B
Part B is a m ult ice nter, o pe n -label , st u d y of d o na ne ma b tr e at me nt f or partici pa nts wit h 
s y m pt o mat ic A D a n d naï ve t o d o na ne ma b.
St u d y  A A C H Part B will pr o vi de a d dit i onal safet y a n d cli nical i nf or mati o n as a n o pe n-la bel 
st u d y. P arti ci pa nts fr o m a s p o ns or-a p pr o ve d ori gi nati n g d o na ne m a b st u d y w h o were assi g ne d 
pl ace b o will recei v e d o na ne ma b i n t he si n gle o pe n -label ar m . 
P art C
T h ose w h o recei ve d d o na ne ma b i n a n ori gi nati n g st u d y ma y part ici pate i n a si n gle i ma gi n g a n d 
c o g nitive/f u nct i onal assess me nt visit . 
St u d y  A A C H Part C will assess t he lo n g- t er m effect of d o na ne ma b o n P E T i m a gi n g bio m ar kers, 
c o g nitio n , a n d f u nct i oni n g i n partici pa nts w h o ha ve n ot recei ve d I P f or at least 5 2 wee ks.
2. 2.
B ac k gr o u n d
2. 2. 1.
Dise ase St ate
A D is a n a ge-r elate d ne ur o de ge nerat i ve dis or der c haracterize d b y pr o gressi ve decli ne i n 
c o g nitive f unct i on a n d t he a bilit y t o perf or m acti vities o f dail y li vi n g . T he a m yl o i d h y p ot hesis of 
A D p ost ulates t hat t he acc u m ulati o n of  A β is a n earl y a n d necessar y e ve nt i n t he pat h o ge nesis o f 
A D . T his h y p ot hesis s u g gests t hat i nter ve nt i ons t hat slo w t he acc u m ulati o n of A β pla q ue i n t he 
brai n or i ncrease cleara nce of A β ma y be a ble t o sl o w t he pr o gressi o n o f t he A D cli nical 
s y n dr ome . A n ot her hall mar k ne ur o pat h ol o gical lesio n  of AD is c o m prise d of i ntra ne ur o nal, 
ne ur ofi brillar y  ta n gles c o nsisti n g of ta u pr otei ns, w hic h s prea d t hr o u g h t he brai n a n d mar k 
di sease pr o gressio n ( Braa k a n d Braa k 1 9 9 6) . T he relat i ons hi p bet wee n t hese 2 pat h ol o gies is st ill 
u nclear, alt h o u g h t he prese nce of b ot h is necessar y f or t he dia g n osis of defi nite A D.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 6
C o n ver gi n g e vi de nce fr o m b ot h ge net ic at-ris k a n d a ge at-ris k c o h orts s u g gests t hat t he 
pat h o p h ysi o l ogi c al pr ocess of A D be gi ns well m ore t ha n a deca de bef ore t he cli nical sta ge n o w 
rec o g nize d as A D de me nt ia, a n d t hat ne ur o de ge nerati o n is alrea d y a p pare nt o n M RI b y t he sta ge 
of  M CI. Li ke ma n y  dis or ders, A D occ urs o n a c o nti n u u m fr o m as y m pt o matic ( precli nical) t o 
M CI, a n d t he n t o de me nt ia i n mil d, m o derate, a n d se vere sta ges . Rece nt cli nical tri al r es ults i n 
mil d -t o-m o derate A D de me nt ia, as well as e vi de nce fr om tra ns ge nic a ni mal e x peri me nts, s u g gest 
t hat treati n g A D d uri n g t he earlier sta ges c o ul d ha ve t he greatest p ote ntial be nefit o n t he disease 
a n d i n hi bit i n g pr o gressi o n, partic ularl y w he n c onsi deri n g t hera pies tar gete d at A β re d ucti o n 
( D o o d y et al. 2 0 1 4; Fleis her et al. 2 0 1 5; Sie mers et al. 2 0 1 6).
2. 2. 2.
Vi de o Assess me nt
V T C i n healt hcare setti n gs is c o m m o n a n d is use d t o carr y  o ut c o g nitive assess me nts, t o c o n d uct 
ps yc hiatric i nter vie ws a n d c o ns ult at i ons, a n d t o hel p wit h t he ma na ge me nt of c hr o nic c o n ditio n s
(C ull u m et al. 2 0 1 4 ; I g nat o wicz et al. 2 0 1 9). Researc h c o m pari n g cli nical i nter vie wi n g 
c o n d ucte d t hr o u g h vi de o c o nfere nci n g a n d tra dit i onal o n -site c o n ditio ns i n dicates ge nerall y g o o d 
a gree me nt i n a variety of  c o n ditio ns, i ncl u di n g de me nt ia a n d c o g niti ve i m pair me nt of vari o us 
ca uses (Casta n h o et al . 2 0 1 7). 
A rece nt s y st e mat ic re vie w a n d meta-a nal ysis assesse d t he effect of V T C a d mi nistrati o n o n a d ult 
c o g nitive tests a n d i n vesti gate d w het her t he sc ores ac q uire d d uri n g a V T C a d mi nistrati o n were 
differe nt fr o m t hose ac q ui re d d uri n g o n-site a d mi nistratio n ( Brearl y  2 0 1 7). T he re vie w 
c o nclu de d t hat st u dies i ncl u di n g partici pa nts wit h a mea n a ge of 6 5 t o 7 5, as well as st u dies t hat 
utilize d a hi g h -s pee d net w or k c o n nect i on, i n dicate d c o nsiste nt perf or ma nce acr oss V T C a n d 
o n -site c o n ditio ns (st u di es wit h slo wer c o n nect i ons were m ore varia ble). F urt her m or e, s u b gr o u p 
a nal yses i n dicate d t hat V T C sc ores f or u nti me d tas ks a n d t h ose all o wi n g f or re petiti o n fell 1/ 1 0t h 
of  a sta n dar d de viati on bel o w o n -site sc ores. Test-s pecific a nal yses i n dicate d t hat ver ball y 
me diate d tas ks were n ot affecte d b y  V T C a d mi nist r atio n b ut t as ks wit h a m ot or c o m p o ne nt 
yiel de d m ore varia ble data.
Wit h s pecific re gar d t o i nstr u me nts t hat are of te n use d i n A D cli nical trials, the feasi bility of t he 
M M S E b y  V T C i n a n ol der p o p ul at i on wi t h de me ntia has bee n i n vest i gate d b y se veral a ut h ors 
(Ci e mi ns et al. 2 0 0 9; C ull u m et al. 2 0 1 4; Casta n h o et al 2 0 1 7 ) a n d n o differe nces were re p orte d 
bet wee n vi de o a n d o n -site a d mi nistratio ns. 
V T C of  t he A D A S-C o g 1 3 has n ot bee n i n vest i gate d as ofte n as t he M M S E. Res ults fr o m 
2 st u dies s h o w n o differe nce i n baseli ne a n d f o ll ow- u p sc ores of t he A D A S -C o g 1 3 bet wee n 
o n -sit e a n d V T C testi n g (Car ote n ut o et al. 2 0 1 8; Y os hi da et al . 2 0 2 0). O ne of t hese st u dies 
re p orte d t hat i n patient s wit h more pr o n o u nce d c o g nit i ve deficits ( M M S E < 1 7), t he assess me nt 
via V T C o veresti mate d t he c o g niti ve i m pair me nt (Car ote n ut o et al. 2 0 1 8 ).
T here are a c o u ple n ota ble li mitati ons of t hese st u dies: t he re mote assess me nt di d n ot ta ke place 
at t he partici pa nt ’s h o me or ot her desi g nate d e xter nal e n vir o n me nt, b ut rat her, o n -sit e, wit h t he 
parti ci pa nt bei n g l ocate d i n a differe nt r o o m fr o m t he test a d mi nistrat or. Als o , in m o st st u dies
descri be d a b o ve, a tec h nicia n was a vaila b le t o set u p t he a u dio vis ual  a n d V T C har d ware . As 
s uc h, re m ote a d mi nistrati o n i n a real-w orl d ( at -h o me ) setti n g nee ds t o be f urt her i n vest i gate d. 
F urt her, t est sc ores are relia ble if t he scale is a d mi nistere d i n acc or da nce wit h h o w t hat scale has 
bee n vali date d. A n y m o dificat i on t o a n assess me nt -vali date d versi o n ca n i n vali date test sc ores. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 7
T o all o w f or re mote a d mi nistrati o n, certai n scale ele me nts nee d t o be m o difie d as t he y re q uire 
p h ysical i nteract i on bet wee n st u d y  part ner a n d rater f or its a d mi nistrati o n. H o w t hese 
m o dificati o ns ha ve bee n o perati o nalize d (a n d t h us, t o w hat e xte nt vali dity has bee n esta blis he d) 
is n ot clear.
T heref ore, t his st u d y ai ms t o e val uate t he relia bilit y of  r e mot e a d mi nistrati o n, c o mpare d t o
o n -sit e a d mi nistrati o n, of  t he s pecific c o g nitive a n d f u nct i onal meas ures descri be d .
2. 2. 3.
D o n a ne m a b
D o na ne ma b is a n a nt i b o d y directe d at t he p yr o glut a m at e mo dificati o n of  t he t hir d a mi n o aci d of 
A β ( N 3 p G A β) e pit o pe t hat is prese nt o nl y in brai n a m y l oi d pla q ues. It is bei n g st u die d f or t he 
treat me nt of A D . T he m ec ha nis m of actio n of  d o na ne ma b a nti b o d y is t o tar get a n d re m o ve 
de p osi te d a m yl oi d pla q ue, a ke y pat h olo gi cal hall mar k of A D, via micr o glial-me diate d 
cleara nce. 
2. 2. 3. 1.
D o n a ne m a b Cli nic al St u dies
T he first h u ma n d ose st u d y  of d o na ne ma b was St u d y I 5 T-M C -A A C C ( A A C C) . St u d y A A C C 
was a P hase 1, d o u bl e- bli n d, ra n d o mize d wit hi n c o h ort, place b o -c o ntr olle d, parallel-gr o u p, 
si n gle-d os e f ol l owe d b y m ult i ple-d ose, d ose -escalati o n st u d y in patie nts wit h M CI d u e t o A D or 
mil d -t o-m o derate A D t o assess t he safet y,  t olera bilit y, P D, a n d P K of si n gle a n d m ulti ple I V 
d oses of d o na ne ma b . After si n gle -d ose a d mi nistrati o n fr om 0. 1 m g/ k g t o 3. 0 m g/ k g, t he m ea n 
ter mi nal eli mi nati on half -life was a p pr o xi matel y 4 da ys, i ncreasi n g t o a p pr o xi matel y 1 0 da ys 
( 2 4 3 h o urs) at t he 1 0-m g/ k g d ose le vel . T he P K of a si n gle d ose of 1. 0 m g/ k g I V of d o na ne ma b
i n y o u n g, heal t hy s u bjects was i n disti n g uis ha ble fr o m t he P K i n A D patie nts at t he sa me d ose 
le vel.
I n St u d y  A A C C, fl or beta pir F 1 8 sca ns were perf or me d at baseli ne a n d after t he last m ult i ple-
asce n di n g d ose, se parate d b y a p pr o xi matel y 7 mo nt hs, t o assess t he P D effects of d o na ne ma b . 
T he c ha n ge fr o m baseli ne i n gre y  matter Sta n dar dize d U pta ke Val ue rati o wi t h cere bell u m as a 
refere nce r e gio n was c o m pare d acr oss d ose c o h orts . T here was a hi g hl y si g nifica nt re d ucti o n 
fr om baseli ne i n cere bral a m yl o i d b y P E T at t he hi g hest d ose, 1 0 m g/ k g ( p <. 0 0 0 2). T he a nal ysis 
s h o we d c o nsiste nt re d ucti o n i n c ortical a m yl o i d a m on g t he patie nts w h o recei ve d 3 t o 5 d oses of 
1 0 m g/ k g of d o na ne ma b . T he mea n o bser ve d re d ucti o n i n fl or beta pir F 1 8 P E T si g nal  
c orres p o n ds t o a mea n 5 0 % re d ucti o n i n t otal brai n fi brillar a m yl o i d. Mea ni n gf ul tar get 
e n ga ge me nt (a m yl o i d re d ucti o n) was li kel y n ot ac hie ve d at d oses s maller t ha n or e q ual t o 
3 m g/ k g I V Q 4 W beca use of t he ra pi d eli mi nat i on of  d o na ne ma b a n d t he lac k of s ustai ne d 
e x p os ure.
St u d y  I 5 T-M C -A A C D ( A A C D) is a P hase 1 b si n gle - a n d m ult i ple-d ose st u d y  t o assess t he 
safety,  t olera bilit y, P K, a n d P D of I V d o na ne ma b i n patie nts wit h M CI d ue t o A D or 
mil d -t o-m o derate A D . St u d y A A C D has c o m p lete d cli nical acti vity a n d patie nts are n o l o n ger 
bei n g d ose d , b ut t he st u d y has n ot c o m plete d data base l oc k . It is e val uati n g 6 1 patie nts i n 
7 treat me nt gr o u ps recei vi n g si n gle- d ose, Q 2 W or Q 4 W d osi n g of eit her 1 0 m g/ k g, 2 0 m g/ k g, or 
4 0 m g/ k g of d o na ne ma b . Treat m e nt d uratio ns bei n g assesse d i ncl u de si n gle -d ose, 6 -m o nt h 
d osi n g Q 2 W, or u p t o 7 2 wee ks of Q 4 W d osi n g . S afet y,  P K, a n d P D data fr o m t his o n g oi n g 
st u d y are use d t o i nf or m furt her de vel o p me nt of d o na ne ma b . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 8
St u d y  I 5 T-M C -A A C G ( A A C G) is a n o n g oi n g P hase 2, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o 
e val uate t he safet y a n d efficac y of d o na ne ma b i n patie nts wit h earl y s y m pt o mat ic A D . 
St u d y A A C G is e val uati n g a p pr o xi matel y  27 2 pat ie nts ra n d omize d t o d o na ne ma b ( 7 0 0 m g Q 4 W 
f or 3 d oses, t he n 1 4 0 0 m g Q 4 W) or place b o . 
St u d y  I 5 T-M C -A A CI ( A A CI) is a n o n g o i n g P hase 2, d o u ble-bli n d, pl ace b o -c o ntr olle d st u d y t o 
e val uate t he safety a n d efficac y of d o na ne ma b i n patie nts wit h earl y s y m pt o mat ic A D . 
St u d y A A CI i s e val uati n g a p pr o xi matel y 5 0 0 patie nts ra n d omize d t o d o na ne ma b ( 7 0 0 m g I V 
Q 4 W f or 3 d oses, t he n 1 4 0 0 m g I V Q 4 W) or pl ace b o.
See t he I B f or detaile d n o ncli nical, safety, a n d P K i nf or mat i on re gar di n g d o na ne ma b .
2. 3.
Be nefit/ Ris k Assess me nt
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of  d o na ne ma b ma y b e f o u n d i n t he I B.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
2 9
3.
O bjecti ves a n d E n d p oi nts
O bject i ves
E n d p oi nts
Pri mar y
P art A
T o e val uate t he relia bilit y of  V T C c o mpare d 
wi t h o n -sit e a d mi nistere d c o g niti ve a n d 
f u ncti onal meas ures
T he i ntraclass c orrelat i on bet wee n V T C a n d 
o n -sit e assess me nt f or P AI R 1 f or 

A D A S -C o g 1 3

A D C S -A D L

M M S E

C D R -S B
P art B
T o e val uate safet y a n d t olera bility of  
d o na ne ma b
Sta n dar d safet y assess me nts i n Part B : 

S p o nta ne o usl y re p orte d A Es

Cli nical la b orat or y  t ests

Vi t al si g n a n d b o d y wei g ht 
meas ure me nts

1 2- lea d E C Gs

P h ysical a n d ne ur ol o gical 
e xa mi nat i ons
M RI ( A RI A a n d e mer ge nt ra di o l ogi cal 
fi n di n gs)
I nf usi on -r elate d reactio ns
C- S S R S
Sec o n dar y
T o assess t he effect of d o na ne ma b o n cli nical 
pr o gressi o n i n part ici pa nts wit h s y m pt o matic 
A D
C ha n ge fr o m baseli ne u p t o Wee k 7 2 as 
meas ure d i n Part B b y : 

M M S E sc ore

A D A S -C o g 1 3 sc ore

i A D R S sc ore

A D C S -i A D L sc ore

C D R -S B

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 0
T o assess t he effect of d o na ne ma b o n brai n 
a m yl o i d de p ositio n
C ha n ge i n brai n a m yl o i d pla q ue de p ositio n 
fr om baseli ne at Wee k 3 6
of  Part B as 
meas ure d b y fl or beta pir F 1 8 P E T sca n
T o assess t he effect of d o na ne ma b o n brai n 
r e gio n v o l umes 
C ha n ge i n v ol u metric M RI meas ures fr o m 
baseli ne t o Wee k 7 2 i n Part B
T o assess peri p heral P K a n d prese nce of 
a nt i-d o na ne ma b a nt i b o dies
P K of  d o na ne ma b i n Part B .
A D As a gai nst d o na ne ma b i n Part B i ncl u di n g 

treat me nt -e mer ge nt A D As 

ne utralizi n g a nt i b o dies
Terti ar y/ E x pl orat or y
T o assess l o n g -t er m effect of d o na ne ma b o n 
brai n a m yl o i d de p ositio n, brai n ta u 
de p osi tio n, bl o o d -base d bi o mar kers, a n d 
cli nical pr o gressi o n of A D i n partici pa nts w h o 
recei ve d d o na ne ma b i n t he ori gi nat i n g st u d y
C ha n ge i n t he f o ll owi n g e n d p o i nts fr o m 
baseli ne i n t he ori gi n at i n g st u d y t hr o u g h 
≥5 2 wee ks after t he partici pa nt’s last 
d o u bl e- bli n d visit i n t he ori gi nat i n g stu d y, 
usi n g Part C assess me nts: 

A m yl o i d pla q ue de p ositio n as 
meas ure d b y fl or beta pir F 1 8 P E T 
sca n

Ta u de p osi tio n as m eas ure d b y 
florta uci pir F 1 8 P E T sca n

Nf L

P- t a u

A 

M M S E sc ore

A D A S -C o g 1 3 sc ore

i A D R S sc ore

A D C S -i A D L sc ore

C D R -S B
T o assess t he effect of d o na ne ma b o n 
bl o o d -base d bi o mar kers
C ha n ge fr o m baseli ne t o Wee k 7 2 i n t he 
f oll owi n g bl o o d -base d bi o mar kers i n Part B:

Nf L

P- t a u

A 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 1
T o e val uate t he relia bilit y of  V T C c o mpare d 
wi t h o n -sit e a d mi nistere d c o g niti ve a n d 
f u ncti onal meas ures
T he i ntraclass c orrelat i on bet wee n V T C a n d 
o n -sit e assess me nt f or P AI R 2 a n d P AI R 3 
c o mpare d wi t h int raclass c orrelat i on of 
P AI R 1 f or 

A D A S -C o g 1 3

A D C S -A D L

M M S E

C D R -S B
T o assess cli nical pr o gressi o n as me as ure d b y 
V T C vers us F 2 F -a d mi nistere d c o g nitive a n d 
f u ncti onal meas ures
C ha n ge fr o m V 6 0 2 t o V 6 0 8 as meas ure d b y  

A D A S -C o g 1 3

A D C S -A D L

M M S E

C D R -S B
A b bre viati o ns: A β = a m y l oi d beta; A D = Alz hei mer’s disease; A D A = a nti dr u g a nti b o d y; 
A 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 ; A D C S -A D L = 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; A D C S -i A D L = Alz hei mer’s Disease 
C o o perati ve St u d y – i nstr u me ntal Acti vities of Dail y Li vi n g; A E = a d verse e ve nt; A RI A = a m y l oi d-relate d 
i ma gi n g a b n or malit y; C D R-S B = Cli nical De me ntia Rati n g Scale – S u m of B o xes; 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; F 2 F = face t o face; i A D R S = i nte grate d Alz hei mer’s Disease 
Rati n g Scale; M M S E
= Mi n i Me ntal State E xa mi nati o n; M RI = ma g netic res o na nce i ma gi n g; Nf L = 
ne ur ofila me nt li g ht c hai n; 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 netics; P -ta u = p h os p h or ylate d 
ta u; V = visit; V T C = vi de o telec o nfere nce.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 2
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
P art A:
T he vi de o vali dat i on peri o d is a m ul tiple cr oss o ver desi g n wi t h p artici pa nts alter nati n g bet wee n 
i n-cli nic assess me nt s a n d at -h o me assess me nt s of  c o g nitive a n d f u nct i onal scales o ver a 
mi ni m u m o f 1 a n d a ma xi m u m o f 3 cr oss o vers. T otal ti me i n Part A ca n va r y fr o m a mi ni m u m of 
4 wee ks ( 1 cr oss o ver [ 1 P AI R]) t o a ma xi m u m of 2 4 wee ks ( 3 cr oss o vers [ 3 P AI R S]).
P arti cipa nts d o n ot recei ve st u d y  I P d uri n g t he vi de o vali dat i on peri o d . Partici pa nts are 
ra n d omize d 1: 1 i n re gar ds t o or d e r of i n-cli nic or at -h o me f or t he first assess me nt , eit her :

Gr o u p 1: C o g nit i ve/f u ncti o nal scale assess me nt at t he st u d y sit e (o n -sit e), foll o we d b y  a n 
at -h o me assess me nt ( V T C; vi de o telec o nfere nce), or

Gr o u p 2: C o g nit i ve/f u ncti o nal scale assess me nt at h ome ( V T C ), foll o we d b y assess me nt
o n -sit e. 
P art B:
Part B is a m ult ice nter, o pe n-label, f oll ow- o n st u d y of d o na ne ma b i n part ici pa nts wit h 
s y m pt o mat ic A D . Partici pa nts w h o recei ve d place b o i n t he ori gi nat i n g trial recei ve:

d o na ne ma b 7 0 0 m g I V Q 4 W f or 3 d oses, t he n

d o na ne ma b 1 4 0 0 m g I V Q 4 W f or u p t o 3 6 wee ks i n Part B.
P arti cipa nts ma y  recei ve d o na ne ma b t hr o u g h Wee k 3 6 or Wee k 4 8. Criteria f or sc he d ule d d ose 
di sc o nti n uati on at 3 6 wee ks are defi ne d b y t he s p o ns or a n d ma y be base d o n res ults of t he 
parti ci pa nt’s fl or beta pir F 1 8 P E T sca n at Wee k 3 6 or res ults fr o m e xter nal st u dies s uc h as St u d y  
A A C G .
P art C:
P arti cipa nts w h o recei ve d d o na ne ma b i n t he ori gi nati n g trial ma y p artici pate i n a n i ma gi n g a n d 
c o g nitive/f u nct i onal assess me nt visit ( Visit 2 0 1). V isit 2 0 1 occ urs a n y time at l east 5 2 wee k s 
fr om t he partici pa nt’s last d o u ble -bli n d visit i n t he ori gi nati n g st u d y. 
O ver all St u d y:
T he m a xi m u m t ot al d uratio n of  st u d y partici pati on f or eac h partici pa nt, i ncl u di n g scree ni n g a n d 
t he p osttreat me nt f o ll ow- u p peri o ds, i s u p t o 1 2 4 wee ks:

Scree ni n g : u p t o 3 0 da y s prior t o V isit 6 0 2

Part A, Vi de o assess me nt: u p t o 2 4 wee ks

Part B, O pe n -lab el  d o na ne ma b : u p t o 7 2 wee ks (treat me nt recei ve d f or 3 6 or 4 8 wee ks)

Part B, F oll o w - u p: u p t o 2 4 wee ks
N ote: Part C is n ot a d de d t o t he ma xi m u m t ot al d uratio n of  st u d y partici pat i on beca use Part C i s 
a si n gle visit , a n d Part B partici pa nts d o n ot partici pate i n Part C .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 3
4. 1. 1.
Scree ni n g
At  or bef ore Visit 6 0 1 (ra n d o mizati o n f or Part A), t he st u d y  will be e x plai ne d t o t he partici pa nt 
(a n d his or her le gal re prese ntative, if a p plica ble) a n d st u d y  part ner. I nf or me d c o nse nt m ust be 
o btai ne d bef ore a n y st u d y  pr oce d ures are c o n d ucte d. T he scree ni n g peri o d c o nsists of t he visit 
wi n d o w of V isit 6 0 1. Visit 6 0 1 occ urs u p t o 3 0 da ys pri or t o Visit 6 0 2.
If t he treat ment  recei ve d i n t he ori gi nati n g st u d y is u n k n o w n at t he ti me of scree ni n g, 
parti ci pa nts must meet scree ni n g eli gi bilit y crit eri a of Parts A, B, a n d C t o be ra n d o mize d i nt o 
t he st u d y.
If t he treat me nt recei ve d i n t he ori gi nati n g st u d y is k n o w n at t he ti me of scree ni n g, partici pa nts 
m ust m eet scree ni n g eli gi bilit y crit eria of 

Part A 
a n d eit her 

Part B (if partici pa nt recei ve d place b o i n t he ori gi nati n g st u d y ) or 

Part C (if partici pa nt recei ve d d o na ne ma b i n t he ori gi nati n g st u d y a n d c o nse nts t o 
parti ci pate i n t his visit). 
C urre nt or pla n ne d use of c o nc o mit a nt me dicat i ons, t he effects of vacat i ons or a bse nces o n 
pr ot oc ol  c o mplia nce, a n d ge neral c o m plia nce wit h t he pr ot oc ol will be disc u sse d at Visit 6 0 1. 
St u d y  assess me nts are s h o w n i n t he So A ( Secti o n 1. 3 ). 
4. 1. 2.
P art A: V i de o Assess me nt
P art A is a m ult ice nter, ra n d omize d, m ulti p le cr oss o ver st u d y t o vali date re m ote assess me nt of 
c o g nitive a n d f u nct i onal scales. Part A be gi n s at Visit 6 0 1 (ra n d o mizat i on), after scree ni n g is 
c o mplete . Parti ci pa nts are ra n d o mize d t o o ne of 2 gr o u ps, as descri be d i n t he Sc he ma a n d 
O verall Desi g n ( Secti o ns 1. 2 a n d 4. 1 , res pecti vel y) t o be assesse d b ot h r e motel y  (t hr o u g h V T C) 
as well as o n -sit e. 
Part A c o nsists of  6 assess me nts or 3 pairs: 

P ai r 1 c o mprises V isits 6 0 2 a n d 6 0 3

P ai r 2 c o mprises V isits 6 0 4 a n d 6 0 5

P ai r 3 c o mprises V isits 6 0 6 a n d 6 0 7
I n eac h pair, eac h partici pa nt is assesse d o nce re m otel y t hr o u g h V T C a n d o nce i n pers o n o n-sit e. 
T he parti ci pa nt ma y elect t o pr ocee d t o Part B ( Visit 1) at a n y ti me after parti ci pat i n g i n Part A 
P ai r 1. 
4. 1. 3.
P art B: O pe n -L a bel D o n a ne m a b
Part B i s a n o pe n-labe l d o na ne ma b p hase be gi n ni n g at V isit 1 . Partici pa nts s h o ul d parti ci pate i n,
at a mi ni m u m, P ai r 1 of Part A bef ore starti n g Part B. 
At  Visit 1, a p p oi nt me nt s s h o ul d be ma de f or all re mai ni n g visits a n d s h o ul d be sc he d ule d as 
close as p ossi ble t o t he tar get date, relat i ve t o Visit 1. 
Assess me nts a n d pr oce d ures will be perf or me d as i n dicate d i n t he S o A ( Secti o n 1. 3 ). Pr oce d ures 
f or s o me visits m a y t a k e m o re t ha n 1 da y.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 4
T he st u d y  in vesti gat or a n d site cli nical st u d y  t e a m will not ha ve access t o fl or beta pir F 1 8 P E T 
res ults d uri n g t he st u d y t o i ncrease o bjecti vity of  c o g nitive assess me nts . 
P arti cipa nt s w h o meet e ntr y criteria f or Part B will be e nr o lle d t o recei ve u p t o 4 8 wee ks of 
treat me nt wit h d o na ne ma b I V Q 4 W. 
4. 1. 4.
P art C: I m a gi n g a n d C o g niti ve /F u ncti o n al Me as ures
P arti cipa nts w h o pre vi o usl y recei ve d d o na ne ma b i n a n ori gi nat i n g st u d y will be gi ve n t he o ptio n 
of  p artici pat i n g i n Visi t 2 0 1 i n Part C . T his visit ta kes place at least 5 2 wee ks after t he 
parti ci pa nt’s last d o u ble- bli n d visit i n t he ori gi nat i n g st u d y.
T he st u d y  in vesti gat or a n d site cli nical st u d y  t e a m will not ha ve access t o fl or beta pir F 1 8 P E T 
or fl orta uci pir F 1 8 P E T res ul ts d uri n g t he st u d y t o i ncrease o bjecti vity of  c o g nitive assess me nts . 
P arti cipa nts i n Part C d o n ot partici pate i n Part B, a n d d o n ot recei ve I P.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
O verall, S t u d y A A C H is c o m prise d of 3 parts: A, B , a n d C (as i n dicate d i n Sect i on 4. 1 ).
T he o bj ect i ve of P art A is t o a d dress t he scie ntific nee d f or vali dati n g re m ote cli nical o utc o me 
assess me nts, as a met h o dol o g y  t hat re d uces site b ur de n. T he st u d y d esig n al ter nates bet wee n i n 
pers o n, o n -site cli nic assess me nts wit h h o me V T C assess me nts. 
P art B i n v ol ves treat me nt wit h d o na ne ma b a n d is desi g ne d t o c ollect data o n t he safety,  
t olera bilit y, a n d ot her cli nical o utc o m e effects of d o na ne ma b f or u p t o 4 8 wee ks of treat me nt i n 
parti ci pa nts wit h s y m pt o mat ic A D . T he pri mar y  o bjecti ve of Part B is t o f urt her acc u m ulate a n d 
descri be data o n t he safet y a n d t olera bilit y of d o na ne ma b. T his st u d y o bjecti ve is e na ble d 
t hr o u g h usi n g a c o h ort of parti ci pa nt s w h o were ra n d omize d t o recei ve d place b o i n a n 
ori gi nati n g st u d y  (rat her t ha n d o na ne ma b), a n d n o w ha ve o p p ort u nity f or access t o d o na ne ma b 
treat me nt. As a n o pe n -lab el  st u d y, t here will be n o place b o gr o u p. T he p ote ntia l d urat i on of dr u g 
e x p os ure of 3 6 or 4 8 wee ks was c h ose n as a d urati o n s ufficie nt t o ha ve a si g nifica nt P D effect o n 
flor beta pi r a m yl o i d lo weri n g base d o n P hase 1 data . Safet y me as ures will i ncl u de t he c ollect i on 
of A E re p orti n g (incl u di n g i nf usi o n- r elate d reactio ns) , la b orat or y assess me nts, M RI assess me nts, 
vit al si g ns a n d weig h t, E C G, p h ysical e xa mi nati ons, ne ur ol o gical e xa mi nat i ons, a n d assess me nts 
of  s uici dal i deati on a n d be ha vi or t o facilitate a c o m pre he nsi ve safet y e val uat i on.
I mm u n o ge nicit y testi n g will be perf or m e d. I n a d diti o n t o cli nical o utc o mes, i ma gi n g bi omar kers 
(fl or beta pir a n d v o l umetric M RI ) will als o be meas ure d . Fl or beta pi r F 1 8 P E T sca ns will be use d 
t o assess t he direct effect of d o na ne ma b o n a m yl oi d pla q ue re m o val, w hic h is a k n o w n hallmar k 
pat h ol o g y  of AD a n d h y p ot hesize d t o c o ntri b ute t o t he c o g nit i ve a n d f u ncti onal decli ne i n pe o ple 
wi t h A D. A m yl oi d pat h ol og y  is t he orize d t o be a me diat or f or cli nical decli ne , a n d t heref ore , it is 
h y p ot hesize d t hat t he re m o val of a m yl o i d ma y slo w  cli nical decli ne. V o l umetric M RI will assess 
t he effect of d o na ne ma b o n brai n re gi o nal v o l umes.
P art C has a n e x pl orat i on scie nt ific rati onal e, e xa mi ni n g partici pa nts w h o pre vi o usl y recei ve d 
d o na ne ma b, b ut are n o l o n ger recei vi n g d o na ne ma b f o ll owi n g t he c o m ple tio n of  t he ori gi nati n g 
cli nical trial. T his e x pl orat or y o bjecti ve is directe d t o war d assessi n g l o n g-t er m effect of 
d o na ne ma b o n brai n a m yl o i d de p ositi on, brai n ta u de p ositi o n, a n d cli nical pr o gressi o n of A D i n 
parti ci pa nts o ver t he int er val peri o d w he n t he y no l o n ger recei ve d o na ne ma b.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 5
4. 3.
J u stific ati o n f or D ose
T he d o na ne ma b tar get d ose of  1 4 0 0 mg a d mi nistere d I V o nce Q 4 W was selecte d base d o n 
c urre nt precli nical p har mac ol o g y a n d t o xic olo g y  data a n d cli nical P K, P D, a n d safety data . Pri or 
a n d o n g o i n g e x p os ures i ncl u de 0. 1 m g/ k g, 0. 3 m g/ k g, 1 m g/ k g, 3 m g/ k g, 1 0 m g/ k g, 2 0 m g/ k g, 
a n d 4 0 m g/ k g i n si n gle - a n d/ or mul ti- d ose d osi n g sc he d ules. Data fr o m St u d ies A A C C a n d 
A A C D s u g geste d t hat P K of d o na ne ma b was li near w he n t he d ose was ≥1 0 m g/ k g . Mea n half -
life was a b o ut 8 t o 1 0 da ys w he n t he d ose was ≥1 0 m g/ k g, s o mi ni mal acc u m ulat i on i n plas ma 
P K was pre dicte d f or 1 4 0 0 m g Q 4 W I V d osi n g . Hi g h le vels of fl or beta pir F 1 8 P E T si g nal  
re d uctio ns were see n wit h a si n gle d ose of 2 0 m g/ k g, a n d were c o m para ble t o fl or bet a pir F 1 8
P E T re d ucti o ns see n wit h a 1 0 m g/ k g Q 2 wee k d osi n g sc he d ule at 3 m o nt hs (see Sect i on 2 a n d 
t he I B f or details). 
Base d o n t his as well as decrease d patie nt b ur de n wit h a Q 4 W d osi n g sc he d ule c o m pare d wit h a 
Q 2 W d osi n g sc he d ule a n d c o m para ble safet y (see Secti o n 2 ), 1 4 0 0 mg Q 4 W
d osi n g was selecte d 
as t he hi g hest d ose re gi me n f or r o b ust a m yl o i d pla q ue lo weri n g . Preli mi nar y  s afet y data fr o m 
A A C D s h o we d t hat t he 1 4 0 0 m g d ose of d o na ne ma b ha d a n acce pta ble safet y pr ofile base d o n 
t he a bilit y t o m o ni t or a n d ma na ge A Es a nd A Es of s peci al i nterest i ncl u di n g A RI A- E; A RI A- H 
a n d h y perse nsit i vity react i ons ; a n d t he o verall fre q ue nc y, se verit y,  a n d serio us ness of A Es at t hi s 
d ose l e vel. 
Pr ot oc ol  a me n d me nt (a) inc or p orates a titrati o n sc he d ule of 7 0 0 m g I V Q 4 W f or t he first 
3 d o ses, t he n 1 4 0 0 mg I V Q 4 W , base d o n o bser vati o n of 2 cases o f s y m pt o mat ic A RI A o bser ve d 
wi t hi n t he first 3 d oses i n a n o n g oi n g d o na ne ma b st u d y.
4. 4.
E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m p lete d t he st u d y if he/s he has c o m p lete d all re q uire d 
p hases of t he p arts (as descri be d i n Secti o n 4. 1 ) of  t he st u d y t he partici pa nt e nr olle d i n, i ncl u di n g 
t he last visit or t he last sc he d ule d pr oce d ure s h o w n i n t he S o A.
T he e n d o f t he st u d y is defi ne d as t he date of last sc he d ule d assess me nt s h o w n i n t he S o A f or t he
last partici pa nt i n t he trial.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 6
5.
St u d y P o p ul ati o n
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, is n ot per mitte d.
5. 1.
I ncl usi o n Criteri a
P art A:
1.
Ha ve part ici pate d i n a d o u ble-bli n d treat me nt peri o d of  a s p o ns or-a p pr o ve d ori gi nati n g
d o na ne ma b trial .
2.
Ha ve a st u d y  part ner w h o will pr o vi de writte n i nf or me d c o nse nt t o partici pate, is i n 
fre q ue nt c o ntact wit h t he partici pa nt ( defi ne d as at least 1 0 h o urs per wee k), a n d will 
acc o m pa n y t he partici pa nt t o st u d y visits or be a vailable b y  vi de o/tele p h o ne at desig nate d 
ti mes. 
A sec o n d st u d y  part ner ma y ser ve as bac k u p.
3.
T he st u d y  part ner(s) is/are re q uire d t o acc o mpa n y  t he parti ci pa nt f or sig ni n g c o nse nt . 
O ne st u d y  part ner is re q ueste d t o be prese nt o n all da ys t he C-S S R S/ Self -Har m  
S u p pl e me nt F or m is a d mi nistere d a n d m ust be prese nt o n all da ys t he c o g nit i ve a n d 
f u ncti onal scales are a d mi nistere d. If a parti ci pa nt has a sec o n d st u d y  part ner, it is 
preferre d t hat 1 stu d y part ner be pri maril y res p o nsi ble f or t he C D R -S B a n d t he 
A D C S -A D L a ssess me nts. Vi sits n ot re q uirin g efficac y  assess me nts must ha ve a st u d y  
part ner a vaila ble b y tele p h o ne if n ot acc o m pa n yi n g partici pa nt at a visit for t he f oll o wi n g 
assess me nts: 

A Es a n d c o nc o mit a nt me dicat i ons

Rele va nt p orti o ns of t he C -S S R S/ Self -Har m  S u p ple m e nt F or ms
If a st u d y part ner must wi t hdra w fr o m  st u d y p artici pat i on, a re place me nt ma y be all o we d 
at t he i n vesti gat or’s discret i on . T he re pl ace me nt will nee d t o si g n a se parate i nf or me d 
c o nse nt o n t he first visit t hat he or s he acc o m pa nies t he parti ci pa nt . 
4.
Ha ve a de q uate literac y, visi o n, a n d heari n g f or ne ur o ps y c h o l ogi cal testi n g i n t he o pi ni on 
of  t he i n vesti gat or at  t he ti me of scree ni n g.
5.
Are relia ble a n d willi n g t o ma ke t he msel ves a vaila ble f or t he d urati o n of t he st u d y  a n d 
are willi n g t o f o ll ow s t u d y pr oce d ures.
6.
Sta bl e s y m pt o mat ic A D me dicat i ons a n d ot her me dicat i on t hat m a y i m pact c o g nit i on f or 
at least 3 0 da ys pri or t o ra n d o mizat i on i nto Part A ( d oes n ot a p pl y t o as nee de d or 
di sc o nti n ue d me dicati ons).
7.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt a s descri be d i n Secti on 1 0. 1. 3 w hic h i ncl u des 
c o mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he I C F a n d i n t his pr ot oc ol.
P art B:
If t he parti ci pa nt’s treat me nt assig n me nt is k n o w n at t he ti me of scree ni n g, o nl y e val uate Part B 
i ncl usi on crit eria if t he partici pa nt recei ve d place b o i n t he ori gi nat i n g st u d y. 
8.
Males a n d fe males of  n o nc hil d beari n g p ote ntial will  be eli gi ble f or Part B .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 7
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulat i ons re gar di n g t he 
met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies.
Male parti ci pa nts:
i.
Me n, re gar dless of t heir fertilit y stat us, wit h n o n-pre g na nt W O C B P part ners
m ust a gree t o eit her re mai n a bst i ne nt (if t his is t heir preferre d a n d us ual 
lifestyle) or use c o n d o ms as well as 1 a d dit i onal hi g hl y  effecti ve (less t ha n 
1 % fail ure rate) met h o d of c o ntrace pti o n (s uc h as c o m bi nati on oral  
c o ntrace pti ves, i m pla nte d c o ntrace pt i ves, or i ntra uteri ne de vices) or effecti ve 
met h o d of c o ntrace pti o n (s uc h as dia p hra g ms wit h s per mici de or cer vical 
s p o n ges) f or t he d urati o n of st u d y Part B a n d u ntil t heir plas ma c o nce ntrati o ns 
are bel o w t he le vel t hat c o ul d res ult i n a rele va nt p ote nt ial e x p os ure t o a 
p ossi ble fet us, pre dicte d t o be 9 0 d a y s fol l owi n g last d ose of I P.
A.
Me n a n d t heir part ners ma y  c h o ose t o use a d o u ble-barri er met h o d of 
c o ntrace pti o n. Barrier -pr otecti o n met h o ds wi t ho ut c o nc o mi ta nt use of 
a s per mici de are n ot a n effect i ve or acce pta ble met h o d of 
c o ntrace pti o n. T h us, eac h barrier met h o d m ust i ncl u de use of a 
s per mici de. It s h o uld be n ote d, h o we ver, t hat t he use of male a n d 
fe male c o n d oms as a d o u ble -barrier m et h o d is n ot c o nsi dere d 
acce pta ble d ue t o t he hi g h fail ure rate w he n t hese barrier met h o ds are 
c o m bi ne d.
B.
P eri o dic a bst i ne nce (e. g., cale n dar, o v ulati on, s y m pt ot her mal, 
p ost -o v ul at i on met h o ds), decl aratio n of  a bsti ne nce j ust f or t he d urati o n 
of  a trial, a n d wit hdra wal  are n ot acce pta ble met h o ds of c o ntrace pti o n.
ii.
Me n wi t h pre g na nt part ners s h o ul d use c o n d o ms d uri n g i nterc o urse f or t he 
d urati o n of  t he st u d y a n d u ntil t he e n d of esti mate d rele va nt p ote ntial e x p os ure 
i n W O C B P ( 9 0 da y s).
iii.
Me n s h o ul d refrai n fr o m s per m d o nati on f or t he d uratio n of  t he st u d y a n d 
u nt il t heir plas ma c o nce ntratio ns are bel o w t he le vel t hat c o ul d res ult i n a 
r ele va nt p ote ntial e x p os ure t o a p ossi ble fet us, pre dicte d t o be 9 0 da ys 
f oll owi n g last d ose of I P.
i v.
Me n w h o are i n e xcl usi vel y sa me se x relat i ons hi ps (as t heir preferre d a n d 
us ual lifest yle) are n ot re q uire d t o use c o ntrace pti o n.
Fe male partici pa nts:
i.
W o me n n ot of c hil d beari n g p ote ntial ma y partici pate a n d i ncl u de t h ose w h o 
are:
A.
i nfertile d ue t o s ur gical sterilizati on ( h ysterect o m y, bilateral 
o o p h orect o m y , or t u bal li gati on), c o n ge nital a n o mal y s uc h a s 
M ulleria n a ge nesis; or
B.
p ost m e n o pa usal – defi ne d as eit her
a. A w o ma n at l east 4 0 years of a ge wit h a n i ntact uter us, n ot o n 
h or m o ne t hera p y , w h o has cessati on of me nses f or at least 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 8
1 year wit h o ut a n alter nat i ve me d ical ca use, A N D a 
f ollicle-sti m ulati n g h or m o ne > 4 0 mI U/ m L; or
b. A w o ma n 5 5 or ol der n ot o n h or m o ne t hera p y , w h o has ha d at 
least 1 2 mo nt hs of s p o nta ne o us a me n orr hea; or
c. A w o ma n at l east 5 5 years of a ge wit h a dia g n osis of 
me n o pa use pri or t o starti n g h or m o ne re place me nt t hera p y.
5. 2.
E xcl usi o n Criteri a
P art A:
9.
C urre nt seri o us or u nsta ble ill nesses i ncl u di n g car di o vasc ular, he pat ic, re nal, 
gastr oe nter ol o gic, res pirat or y , e n d ocri n ol ogi c, ne ur olo gic ( ot her t ha n A D), ps y c hiatric, 
i m m u n ol ogic, or he mat ol o gic disease a n d ot her c o n dit i ons t hat, i n t he i n vest i gat or’s 
o pi ni o n, c o ul d i nterfere wi t h o ut c o m e assess me nts or t he a nal yses i n t his st u d y.
1 0. Are i n vest i gat or site pers o n nel directl y affiliate d with t his st u d y  a n d/ or t heir i m me diate 
fa milies. I mme diate fa mil y is defi ne d as a s p o use, pare nt, c hil d, or si bli n g, w het her 
bi o l ogical  or le gall y a d o pte d.
1 1. Are Lill y  e m plo y ees or are e mpl o y ees of t hir d-part y  or ga nizatio ns i n v ol ve d i n st u d y  
w h ic h re q uir es e xclusi o n  of t h eir e m plo y ees, or ha ve st u d y part ners w h o are 
Lill y e m plo y ees or are e mpl o y ees o f t hir d-part y  or ga nizati ons i n v ol ve d i n a st u d y w hic h
re q uir es e xcl usi o n of t heir e m pl o yees.
P art B:
If t he partici pa nt’s treat me nt assi g n me nt is k n o w n at t he ti me of scree ni n g, o nl y e val uate Part B 
e xcl usi o n criteria if t he partici pa nt recei ve d place b o i n t he ori gi nati n g st u d y. 
1 2. Life e x pecta nc y  < 2 4 mo n t hs per t he i n vesti gat or’s j u d g me nt.
1 3. K n o w n cli nicall y  i m p orta nt a b n or malit y, as deter mi ne d b y t he i n vesti gat or, i n p h ysical or 
ne ur o l ogi cal e xa mi natio n, vi tal si g ns, E C G, or cli nical la b orat or y test res ults fr o m t he 
ori gi nati n g st u d y  t hat c o uld be detri me ntal  t o t he parti ci pa nt or c o ul d c o m pr o mise t he 
st u d y.
1 4. Are, i n t he j u d g me nt of t he i n vest i gat or, acti vel y s uici dal, a n d t heref ore , dee me d t o be at 
sig nifica nt ris k f or s ui ci de.
1 5. P o or ve n o us access.
1 6. Ha ve a n y c o ntrai n dicati o ns f or M RI, i ncl u di n g cla ustr o p h o bia or t he prese nce of 
c o ntrai n dicate d metal (ferr o ma g net ic) i m pla nts/car diac pace ma ker.
1 7. Se nsit i vity t o flor beta pi r F 1 8, prese nt or pla n ne d e x p os ure t o i o nizi n g ra dia tio n t hat, i n 
c o m bi nat i on wi t h t he pla n ne d a d mi nistratio n of  st u d y P E T li ga n ds, w o ul d res ult i n a 
c u mulat i ve e x p os ure t hat e xcee ds l ocal rec om me n de d e x p os ure li mit s, or ot her 
c o ntrai n dicat i on t o P E T i ma gi n g.
1 8. Ha ve recei ve d treat me nt wit h a passi ve a nt i-a m yloi d i m m u n ot hera p y  aft er c o mpleti o n of  
ori gi nati n g d o na ne ma b st u d y .
1 9. Ha ve recei ve d act i ve i m m u nizati o n a gai nst A β i n a n y ot her st u d y. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
3 9
2 0. Ha ve k n o w n aller gies t o d o na ne ma b , r elate d c o mp o u n ds, or a n y  c o mp o ne nts of t he 
f or mulat i on.
2 1. Di sc o nti n uatio n of  a d mi nistratio n of  I P i n t he origi nat i n g st u d y d ue t o a n A E if, i n t he 
o pi ni o n of t he i n vest i gat or, t he A E ma y i m pact t he partici pa nt ’s a bility t o s afel y 
parti ci pate i n t he st u d y.
2 2. Are c urre nt l y e nr olle d i n a n y ot her i nter ve nt i onal cli nical trial i n v o l vi n g a n I P or a n y 
ot her t y pe of me dical researc h j u d ge d n ot t o be scie ntificall y or me d icall y c om pat i ble 
wi t h t his st u d y.
2 3. Ha ve part ici pate d, wit hi n t he last 3 0 da ys ( 4 m o nt hs f or st u dies c o n d ucte d i n Ja pa n; 
3 m o nt hs f or st u dies c o n d ucte d i n t he U nite d Ki n g d o m), i n a cli nica l trial in v o l vi n g a n 
I P. If t he pre vi o us I P is scie ntificall y or me dicall y i nc om pat i ble wit h t his st u d y a n d has a 
l on g half -life, 3 m o nt hs or 5 half-li ves ( w hic he ver is l on ger) s h o ul d ha ve passe d pri or t o 
scree ni n g ( partici pati o n i n o bser vati o nal st u dies ma y be per mitte d u p o n re vie w of t he 
o bser vat i onal st u d y  pr ot oc ol a n d a p pr o val b y t he s p o ns or).
P art C
If t he partici pa nt’s treat me nt assi g n me nt is k n o w n at t he ti me of scree ni n g, o nl y e val uate Part C 
e xcl usi o n if t he partici pa nt recei ve d d o na ne ma b i n t he ori gi nati n g st u d y a n d pla ns t o partici pate 
i n Part C. 
2 4. F or parti ci pat i on i n P E T assess me nt: P rese nt or pla n ne d e x p os ure t o i o nizi n g ra diati on 
t hat, i n c o m bi nat i on wi t h t he pla n ne d a d mi nistrati o n of st u d y P E T li ga n ds, w o ul d res ult 
i n a c u mulat i ve e x p os ure t hat e xcee ds l ocal rec o m me n de d e x p os ure li mit s, or ot her 
c o ntrai n dicat i on t o P E T i ma gi n g.
a.
F or parti ci pat i on i n fl or bet a pir P E T i ma gi n g: Ha ve se nsit i vity t o fl or beta pir F 1 8.
b.
F or parti ci pat i on i n fl ort a u cipi r P E T i ma gi n g: Ha ve se nsit i vity t o fl orta uci pir 
F 1 8.
2 5. Ha ve recei ve d treat me nt wit h a passi ve a nt i-a m yl o i d i m m u n ot hera p y aft er c o mpleti o n of  
ori gi nati n g d o na ne ma b st u d y .
2 6. Ha ve recei ve d act i ve i m m u nizati o n a gai nst A β i n a n y ot her st u d y.
2 7. Are c urre nt l y e nr olle d i n a n y ot her i nter ve nt i onal cli nical trial i n v o l vi n g a n I P or a n y 
ot her t y pe of me dical researc h j u d ge d n ot t o be scie ntificall y or me dicall y c om pat i ble 
wi t h t his st u d y.
5. 3.
Lifest yle C o nsi der ati o ns
P arti cipa nt s partici pat i n g i n Part B s h o ul d refrai n fr o m d o nati n g bl o o d or bl o o d pr o d ucts fr o m 
t he ti me o f t heir e ntr y int o Part B u nt il 6 m o nt hs f oll o wi n g t he last d ose of I P.
P articipa nt s s h o ul d a v oi d e xcessi ve use of alc o h ol fr o m t he scree ni n g visit u nt il t he st u d y e n ds. 
E xcessi ve alc o h o l c o ns u m pti o n is defi ne d f or me n as c o ns u mi n g a n a vera ge of m ore t ha n 
3 dri n ks per da y, or m ore t ha n 2 1 dri n ks per wee k. F or w o me n, e xcessi ve use of alc o h o l is 
defi ne d as c o ns u mi n g a n a vera ge of m ore t ha n 2 dri n ks per da y , or more t ha n 1 4 dri n ks per 
wee k.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 0
5. 4.
Sc ree n F ail ures
Scree n fail ures are defi ne d as part ici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y e nr olle d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o 
e ns ure tra ns pare nt re p orti n g of scree n fai l ure partici pa nt s t o meet t he C O N S O R T p u blis hi n g 
re q uire me nts a n d t o res p o n d t o q ueries fr om re g ulat or y a ut h orities. Mi ni mal i nf or mati on 
i ncl u des de m o gra p h y, scree n fail ure details, eli gi bility criteria, a n d a n y S A E.
P arti cipa nts ma y  rescree n o nce if scree n fail ure was d ue t o lac k of sta ble s y m pt o mat ic A D 
me dicat i ons or ot her m e dicat i on t hat ma y i m pact c o g nit i on . T he s p o ns or m ust be c o ntacte d f or 
ot her e xce pt i onal reas o ns f or rescree ni n g.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 1
6.
St u d y I nter ve nti o n
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol . F or t hi s st u d y, I P is use d i nterc ha n gea bl y with st u d y  
i nter ve nt i on.
6. 1.
St u d y I nter v e nti o n(s) A d mi nistere d
T he I P use d i n t his st u d y  is:

D o na ne ma b
I P is a d mi nistere d o nl y d uri n g t he o pe n-lab el  d o na ne ma b p eri o d ( Part B). Parti ci pa nts d o n ot 
recei ve I P d uri n g P art A or Part C . 
T he f o ll owi n g cli nical a n d i ma gi n g assess me nts are t o be perf or m e d prior t o a d mi nistrati o n of I P 
at Part B Visit 1:

V isit 1 p h ysical a n d ne ur o l ogi cal e xa mi natio n, vi t al si g ns, a n d E C G

If > 6 m o nt hs bet wee n t he fi nal cli nical la b orat or y assess me nt fr om t he origi nati n g 
st u d y a n d Visit 1, cli nical la b orat or y  assess me nt ( See S o A ; Secti o n 1. 3 )

If > 1 2 m o nt hs bet wee n t he fi nal ce ntrall y rea d M RI fr o m t he ori gi nati n g st u d y 
a n d V isit 1, M RI assess me nt ( See S o A ; Secti on 1. 3 )
See Secti o n 7 f or details re gar di n g disc o nti n uati on cri teria.
I P is a d mi nistere d b y I V i nf usi on o ver a mi ni m u m of 3 0 mi n utes . Detaile d i nstr ucti o ns f or 
a d mi nistrati o n, i ncl u di n g i nf usi o n rate, ca n be f o u n d i n t he p har mac y ma n ual. 
N ote t hat at visits w hic h re q uire c o g nit i ve assess me nts t o be perf or me d, all c o g nit i ve scales are 
t o be a d mi nistere d bef ore I P is a d mi nistere d. 
I P is t o be a d mi nistere d o nce Q 4 W. I P m ust n ot be a d mi nistere d at a d osi n g i nter val o f < 2 1 da ys 
at a n y ti me i n t he st u d y. Base d o n per mitte d visit wi n d o ws, it w o ul d a p pear t hat st u d y  
me dicat i on c o ul d t he oreti call y be a d mi nistere d at a 2 -wee k i nter val . H o we ver, a d mi nistrati o n of 
2 d oses wit hi n < 2 1 da ys of eac h ot her will be a pr ot oc ol de viati o n.
See Secti o n 6. 5. 2 f or i nf usi on- relate d reactio ns a n d pre m e dicatio n i nstr ucti o ns, if a p plica ble . 
Si t es must ha ve res uscitat i on e q ui p me nt a vaila ble. 
P ac k a gi n g a n d L a beli n g
Cli nical trial materials will be la bele d acc or di n g t o t he c o u ntr y ’s re g ulat or y re q uire me nts. All I Ps 
will be st ore d, i n ve nt orie d, rec o ncile d, a n d destr o ye d acc or di n g t o a p plica ble re g ulat i ons . 
Cli nical trial materials are ma n ufact ure d i n acc or da nce wit h c urre nt G o o d Ma n ufact uri n g 
Practi ces.
I P will be s u p plie d i n a vial. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 2
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c on dit i ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all I P recei ve d a n d a n y discre pa ncies are re p orte d a n d 
res ol ve d bef ore use of t he I P.
2.
O nl y partici pa nts e nr o lle d i n Part B of t he st u d y ma y recei ve I P a n d o nl y a ut h orize d sit e 
staff ma y s u p pl y or a d mi nister I P. All I P m ust be st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce wit h t he la bele d 
st ora ge c o n diti ons wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff.
3.
T he i n vest i gat or, i nstit uti o n, or t he hea d of t he me dical i nst ituti o n ( w here a p plica ble) is 
res p o nsi ble f or I P acc o u nta bility, rec o nciliat i on, a n d rec or d mai nte na nce (i.e., recei pt, 
rec o nciliati on, a n d fi nal dis p osit i on rec or ds).
4.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p osit i on of u n use d I Ps are pr o vi de d b y 
t he s p o ns or.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
P art A
F or t he vi de o assess me nt peri o d, partici pa nts will be ra n d o mize d 1: 1 t o eit her

Gr o u p 1 : C o g nitive/f u ncti o nal scale assess me nt perf or me d o n -sit e, f oll owe d b y  
at -h o me ( V T C ) assess me nt, or

Gr o u p 2 : C o g niti ve/f u ncti o nal scale assess me nt at h ome ( V T C ), foll o we d b y 
o n -sit e assess me nt . 
T o mi ni mize bias, partici pa nts f o ll ow a cr oss o ver desi g n, alter nati n g bet wee n assess me nt 
l ocat i on s, st artin g wit h t heir ra n d omize d i nit ial l oc atio n . 
P art B
Part B i s a n o pe n-label d o na ne ma b p hase . 
P art C
P arti cipa nts d o n ot recei ve I P i n Part C . Ra n d o mizati o n a n d bli n di n g are n ot a p plica ble.
6. 4.
St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts are d ose d at t he site, t he y  will recei ve I P direct l y fr o m t he i n vesti gat or or 
desi g nee, u n der me dical s u per visi o n . T he date , ti me, a n d v ol ume of  eac h d ose a d mi nistere d i n 
t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he electr o nic C R F . 
A n y i nf usi o n at w hic h 7 5 % (a p pr o xi matel y 1 0 5 m L) or m ore of t he i nf usi o n s ol ut i on is gi ve n 
will be c o nsi dere d a c o m plete i nf usi o n.
If a p artici pa nt atte n ds a visit b ut d oes n ot recei ve a c o m plete i nf usi o n (e. g., d ue t o tec h nical 
c o mplicat i ons), e ver y eff ort s h o ul d be ma de t o c o m plete t he i nf usi o n wi t hi n 2 4 h o urs if p ossi ble. 
If less t ha n 7 5 % of t he i nf usi on s ol ut i on is gi ve n, t his m ust be rec or de d as a n i nc o m p lete i nf usi on 
o n t he C R F.
Misse d i nf usi o ns s h o ul d be rec or de d o n t he C R F.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 3
If at a n y time it is disc o vere d t hat t he partici pa nt has n ot c o m plete d pr o per d osi n g d uri n g t he 
titr atio n p hase, t he s p o ns or s h o ul d be c o ntacte d pri or t o t he s u bs e q ue nt i nf usi o ns t o disc uss t he 
p ossi bilit y of c o m p leti n g a pr o per titrati o n p hase, if nee de d.
6. 5.
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he- c o u nter or prescri pt i on me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves 
d uri n g t he st u d y  must be rec or de d i n t he C R F, al o n g wit h a n y c ha n ges t o d ose. 
T he m e dical mo ni t or s h o uld be c o ntacte d if t here are a n y  q uestio ns re gar di n g c o nc o mita nt or 
pri or t hera p y .
P arti cipa nt s a n d t heir st u d y part ners will be i nstr ucte d t o c o ns ult t he i n vesti gat or or ot her 
a p pr o priate st u d y pers o n nel at t he site bef ore i nitiatio n of  a n y ne w me dicat i ons or s u p ple me nts 
a n d bef ore c ha n gi n g d ose of a n y c urre nt c o nc o mit a nt me dicat i ons or s u p ple me nts.
6. 5. 1.
St a n d ar d of C are f or Alz hei mer’s Dise ase
T o e ns ure sta n dar d of care f or A D, use of a p pr o ve d s y m pt o mat ic treat me nts f or A D is per mitte d 
i n t his st u d y. T he sect i on bel o w pr o vi des a d dit i onal g ui da nce o n ma na gi n g c o nc o mit a nt 
me dicat i on use.
Use of a p pr o ve d or sta n dar d of  care s y m pt o mat ic treat me nts f or A D is per mitte d d uri n g t he 
st u d y, pr o vide d t hat t he d ose has bee n u nc ha n ge d f or 3 0 da y s bef ore Visit 6 0 2 . D oses of t hese 
me dicat i ons s h o ul d re mai n c o nsta nt w he n p ossi ble t hr o u g h t he st u d y. W he n me dicall y i n dicate d, 
i nitiati on, i ncrease , or disc o nt i n uati on of s y m pt o matic treat me nts f or A D is per mitte d.
N o n m e dicat i on treat m e nts f or A D , s uc h as be ha vi oral ma na ge me nt, are per mitte d b ut are s u bject 
t o t he sa me restricti ons as me dicat i on treat me nt ta ke n f or A D.
6. 5. 2.
Me dic ati o ns f or
I nf usi o n Re acti o ns
If a n i nf usi on react i on occ urs, me dicat i ons ma na gi n g t he reacti o n ma y  be a d mi nistere d at t he 
di scretio n of  t he i n vesti gat or, acc or di n g t o l ocal practice g ui deli nes. If t he nee d f or c o nc o mita nt 
me dicat i on arises, i ncl usi o n or c o n ti n uatio n of  t he parti ci pa nt ma y be at t he discret i on of t he 
i n vesti gat or after c o ns ultati o n wit h a Lill y me dical m o ni t or. C o nc o mita nt t hera p y a d mi nistere d 
t o treat a n i nf usi on react i on or as p re me dicati o n f or i nf usi ons s h o ul d be d oc u me nte d.
6. 5. 3.
E xcl u de d Me dic ati o ns
I mm u n o gl o b uli n G t hera p y  (als o k n o w n as ga m ma gl o b uli n or I V i m m u n o gl o b uli n [I VI G]) is 
n ot all o we d d uri n g t he st u d y . Ot her disease -m o dif yi n g t hera pe utic a ge nts ma y als o be e xcl u de d 
me dic at i ons (see Secti o n 7. 2 f or a d ditio nal details).

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 4
6. 6.
D ose M o dific ati o n
T he d osi n g g oal  is for t he parti ci pa nt t o be titrate d t o t he tar get d ose of  1 4 0 0 mg . 
F or partici pa nts w h o de vel o p A RI A d uri n g t he titrati o n peri o d ( t hat is, bef ore t he f ourt h i nf usi o n 
of  st u d y dr u g), t he i n vest i gat or ma y deci de t o 

te m p oraril y s us pe n d d osi n g as descri be d i n Sect i on 7. 1. 1. 1 , t he n deter mi ne if t he 
parti ci pa nt s h o uld r e m ai n o n 7 0 0 m g eit her te mp oraril y  be yo n d t he first 3 d oses 
or t hr o u g h o ut t he re mai n der of t he treat me nt peri o d ,

c o nti n ue t he 7 0 0 m g d ose eit her te m p oraril y  be yo n d t he fi rst 3 d oses or 
t hr o u g h o ut t he re mai n der of t he treat me nt peri o d, or

c o nti n ue t he d osi n g sc he d ule as o utli ne d i n Sect i on 4. 1 . 
6. 7.
I nter ve nti o n after t he E n d of t he St u d y
N ot a p plica ble . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 5
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1.
Disc o nti n u ati o n of St u d y I nter ve nti o n
I P ma y be disc o nt i n ue d for a parti ci pa nt f or t he f oll o wi n g reas o ns ( details gi ve n bel o w) : 

B y  re q uest of t he partici pa nt or partici pa nt’s desi g nee (f or e xa m ple, le gal g uar dia n) 

Cli nical j u d g me nt 

A he pat ic e ve nt or li ver test a b n or mality

C- S S R S res ults

A RI A

S y ste mic h y perse nsiti vity react i on

Se vere n o nc o m p lia nce 

T he parti ci pa nt re q uires a n e xcl u de d t hera pe utic a ge nt

Pl ace me nt of de vice i nc o m pat i ble wit h M RI
I n rare i nsta nces, it ma y be necessar y for a parti ci pa nt t o per ma ne nt l y disc o nti n ue ( defi niti ve 
di sc ont i n uati on) I P . If I P is defi niti vel y disc o nti n ue d, t he partici pa nt will re mai n i n t he st u d y 
(f oll owi n g t he S o A, e xce pt as n ote d bel o w) t o be e val uate d f or safety a n d efficac y. 
If I P i nf usi on is per ma ne ntl y disc o nti n ue d a n d t he parti ci pa nt re mai ns i n t he st u d y, 1 P K sa m ple 
s h o uld be c ollecte d at t he s o o nest sc he d ule d visit re gar dless if P K c o llecti on is o n t he S o A at t hat 
visit . D osi n g dates a n d ti mes s h o ul d be c ollecte d . S u bse q ue nt P K sa m ple c o llecti on s h o ul d 
f oll ow t he pr ot oc ol S o A u nless t he sc he d ule d visit e xcee ds 6 m o nt hs si nce disc o nti n uati o n o f 
i nf usi ons . N o a d di tio nal  P K  c o llecti on is re q uire d o nce t he partici pa nt e xcee ds 6 m o nt hs si nce 
di sc o nti n uati on of d o na ne ma b i nf usi o ns.
Cli nical J u d g me nt
A E or cli nicall y si g nifica nt la b orat or y  val ue, E C G res ult, p h ysical e xa mi nati on fi n di n g, M RI 
fi n di n g (s uc h as s y m pt o matic isc he mic str o ke), C-S S R S res ult, or vital si g n meas ure me nt of s uc h 
se verity t hat, i n t he o pi ni o n o f t he i n vest i gat or or Lill y-desi g nate d me dical m o nit or, c o nti n ue d 
treat me nt is n ot i n t he best i nterest of t he parti ci pa nt .
He pati c E ve nt or Li ver Test A b n or malit y
P arti cipa nts w h o are di sc o nti n ue d fr om I P d ue t o a he patic e ve nt or li ver test a b n or mality s h o uld 
ha ve a d dit i onal he patic safet y  data c ollecte d via t he C R F .
Di sc o nti n uatio n of  t he I P f or a b n or mal li ver tests s h o ul d be c o nsi dere d b y t he i n vest i gat or w he n 
a partici pa nt meets 1 of t he f o ll owi n g c o n di tio ns after c o ns ultat i on wi t h t he s p o ns or-desi g nate d 
me dical m o nit or : 

A L T or A S T > 8 X U L N

A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks

A L T or A S T > 3 X U L N a n d T B L > 2 X U L N or I N R > 1. 5

A L T or A S T > 3 X U L N wit h t he a p peara nce of fat i g ue, na usea, v omit i n g, ri g ht 
u p per -q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)

A L P > 3 X U L N

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 6

A L P > 2. 5 X U L N a n d T B L > 2 X U L N

A L P > 2. 5 X U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht q ua dra nt pai n or 
te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)
C- S S R S 
I n a d diti on, I P m a y be disc o nti n ue d if partici pa nts:

A ns wer “ yes” t o Q uesti o n 4 or Q uesti o n 5 o n t he “ S uici dal I deat i on” p orti o n of t he 
C- S S R S, or

A ns wer “ yes” t o a n y  of t he s uici de-r elate d be ha vi o rs o n t he S uici dal Be ha vi or p orti o n of 
t he C-S S R S.
A ps yc hiatrist or a p pr o priatel y trai ne d pr ofessi o nal ma y  assist i n t he decisi o n t o disc o nt i n ue t he 
parti ci pa nt . 
E C G
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges fr o m 
baseli ne i n Q T i nter val c orrecte d usi n g Q Tc F) after e nr oll me nt, t he i n vesti gat or or q ualifie d 
desi g nee will deter mi ne if t he parti ci pa nt ca n c o nti n ue i n t he st u d y a n d if a n y c ha n ge i n 
parti ci pa nt ma na ge me nt is nee de d. T hi s re vie w of t he E C G pri nte d at t he ti me of c ollect i on m u st 
be d oc u m e nte d. A n y ne w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as a n A E.
A RI A
Treat me nt wit h I P ma y be per ma ne ntl y disc o nt i n ue d i n parti ci pa nt s wit h T E A RI A -E a n d/ or 
A RI A- H at t he discret i on of t he PI de pe n di n g o n se verit y of  cli nical a n d ra diol o gi c fi n di n gs (see 
Ma n ual o f O perati o ns f or p er m a ne nt disc o nt i n uati o n g ui da nce). F or te m p orar y  disc o nti n uat i on 
f or A RI A-relate d reas o ns, see Secti o n 7. 1. 1. 1 .
S y ste mic H y perse nsit i vity R e a ctio n
If t he i n vesti gat or, after c o ns ultati o n wit h t he s p o ns or-desi g nate d me dical m o nit or, deter mi nes 
t hat a s yste mic h y perse nsiti vity r e a ctio n has occ urre d relate d t o I P a d mi nistrati o n, t he partici pa nt 
s h o uld be per m a ne ntl y disc o nt i n ue d fr om t he i n vesti gat i onal dr u g.
Se vere N o nc o m p lia nce
Se vere n o nc o m p lia nce t o t he st u d y pr ot oc ol, t hat res ults i n a safet y c o ncer n, i n t he j u d g me nt of 
t he i n vest i gat or, ma y be reas o n f or disc o nt i n ui n g I P.
E xcl u de d T hera pe ut ic A ge nt
T he parti ci pa nt , for a n y  reas o n, re q uires a treat me nt wit h a n e xcl u de d t hera pe utic a ge nt
( Sectio n 6. 5. 3 ) a n d te m p orar y disc o nt i n uati on cri t eria ca n n ot be met (see Secti o n 7. 1. 1. 2 ).
Pl ace me nt of De vice I nc om pat i ble wit h M RI
P arti cipa nts w h o re q ui r e a ferr o ma g net ic i m pla nt or i nserti o n of a car diac pace ma ker t hat is n ot 
M RI -c o mpat i ble will be per ma ne ntl y disc o nti n ue d fr om I P a n d s h o ul d ha ve n o M RIs. If t he 
parti ci pa nt disc o nt i n ues fr om t he st ud y, wit h t he e xce pt i on of a n M RI, t he partici pa nt s h o ul d 
ha ve e n d -of -t hera p y a nd/ or e n d -of -st u d y pr oce d ures perf or me d as s h o w n i n t he S o A.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 7
7. 1. 1. 
Te m p or ar y Disc o nti n u ati o n
7. 1. 1. 1.
D ue t o A RI A
T he de vel o p me nt of A RI A -E a n d/ or A RI A -H ( micr o he m orr ha ges a n d/ or c ortical s u per ficial 
sid er osi s) are e x pecte d e ve nts f or s o me partici pa nt s d ue t o t he treat me nt wit h d o na ne ma b. T he 
sit e PI ma y t e mp oraril y  disc o nti n ue I P if t he parti ci pa nt de vel o ps T E A RI A -H or A RI A -E t o a n 
e xte nt dee me d cli nicall y sig nifica nt b y  t he sit e PI (see Ma n ual of O perati ons f or t e mp or ar y
di sc o nti n uati on g ui da nce) . Rei nitiati n g I P ca n be c o nsi dere d after res ol uti on of A RI A -E a n d 
sta bilizati o n of A RI A- H i ma gi n g fi n di n gs a n d t he res ol ut i on of a n y  ass ociate d s y m pt o ms. B ot h 
di sc o nti n uati on a n d re -i nitiatio n decisi o n s ma y be di sc usse d wit h t he s p o ns or. D o se m o dificati o n 
c o nsi derati o ns are descri be d i n Secti on 6. 6 .
I n t he e ve nt of a fi n di n g of A RI A-E o n M RI, t he i n vesti gat or is t o c o m plete t he C R F re gar di n g 
t he prese nce or a bse nce of s y m pt o ms relate d t o t he A RI A -E.
I n cases of ne w A RI A- E or A RI A -H, gi ve n t he c o nte xt of t he se verit y of  t he i ma gi n g fi n di n gs 
a n d s y m pt o ms, t he site PI, at his/ her cli nical discr etio n, ca n elect t o rec o m me n d disc o nt i n ui n g I P 
a n d t he n f o ll ow t he parti ci pa nt wit h serial M RIs e ver y  4 t o 6 wee ks (fl ui d atte n uatio n i n versi o n 
rec o ver y [F L AI R ] a n d T 2 * gra die nt -recall ec h o) a n d m o nit or s y m pt o ms, t o mo ni t or sta bilizati o n 
or res ol ut i on . U p o n res olut i on of A RI A -E a n d sta bilizati on of  ARI A -H a n d t he res olut i on of  a n y 
ass ociate d s y m pt o ms, t he parti ci pa nt ca n be c o nsi dere d f or re -i nitiati n g I P. T here is n o defi ne d 
ti me d urati o n f or t his m onit ori n g peri o d w hile off I P a n d will be base d o n cli n ical j u d g me nt. See 
t he Ma n ual of O perat i ons f or t e mp orar y  a n d per ma ne nt disc o nt i n uati on g ui da nce.
7. 1. 1. 2.
D ue t o Re as o ns Ot her t h a n A RI A
T e m p orar y  disc o nti n uati on fr om I P treat me nt is all o we d if a s h ort-t er m treat me nt wit h a n 
e xcl u de d me dicat i on is necessar y, sec on dar y  t o h os pitalizatio n, pers o nal  circ u msta nces or t o 
e val uate t he I P i m pact o n a n u ncertai n A E. 
I P ma y be restarte d at t he ne xt sc he d ule d visit, at t he i n vest i gat or’s discreti o n. 
If te mp orar y  disc o nti n uati on is d ue t o a n A E, it s h o ul d be re p orte d t o t he Lill y m e dical m o ni t or. 
T e m p orar y  treat me nt disc o nti n uati on a n d restarti n g s h o ul d be d oc u me nte d . Restarti n g treat me nt 
after a disc o nti n uati on peri o d t hat is greater t ha n 1 2 wee ks s h o ul d be disc usse d bet wee n t he 
i n vesti gat or a n d Lill y m e dical m o ni t or.
7. 2.
P art ici p a nt Disc o nti n u ati o n/Wit h dr a w al fr o m t he St u d y
A partici pa nt ma y wit h dra w fr o m t he st u d y: 

at a n y ti me at his/ her o w n re q uest 

at t he re q uest of his/ her desi g nee (f or e xa m ple, pare nts or le gal g uar dia n)

at t he discreti o n of t he i n vest i gat or f or safety,  be ha vi or al , c o mplia nce, or a d mi nistrati ve 
reas o ns

if t he partici pa nt bec ome s pre g na nt d uri n g t he st u d y 

if t he partici pa nt e nr olls i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vesti gati onal 
me dici nal pr o d uct or e nr oll me nt i n a n y  ot her t yp e of  me dical researc h j u d ge d n ot t o be 
scie ntificall y or me dicall y c om pati ble wit h t his st u d y

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 8

if t he partici pa nt, f or a n y reas o n, re q uires treat me nt wit h a n ot her disease-m o dif yi n g 
t hera pe utic a ge nt t hat has bee n de m o nstrate d t o be effect i ve f or treat me nt of t he st u d y 
in dicat i on, di sc o nti n uati on fr om t he st u d y occ urs prior t o i ntr o d ucti o n of  t he ne w a ge nt

parti ci pat i on i n t he st u d y nee ds t o be st o p pe d f or me dical, safety,  re g ulat or y, or ot her 
reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G C P
o
i ncl u des fi n di n gs of  e xcl us or y M RI, he mat olo g y , or cli nical c he mistr y at a n 
u nsc he d ule d p r oce d ure pri or t o t he partici pa nt starti n g Part B. 
N O T E: If a cli nicall y i m p orta nt a b n or mality, as deter mi ne d b y t he i n vest i gat or, i n 
p h ysical or ne ur ol o gical e xa mi nat i on, vital si g n, E C G, or cli nical la b orat or y  test res ults 
c o uld be detri me ntal  t o t he partici pa nt or c o ul d c o m pr o mise t he st u d y , t he n t he 
parti ci pa nt s h o uld n ot recei ve I P i n Part B.
P arti cipa nts m ust n ot e nter Part B if t he fi nal ce ntrall y  rea d M RI fr o m t he origi nat i n g 
st u d y or u nsc he d ule d M RI perf or me d i n St u d y  A A C H pri or t o Part B de m o nstrat e
prese nce of A RI A -E, > 4 cere bral micr o he m orr ha ges, m ore t ha n 1 area of s u perficial 
sid er osi s, a n y macr o he m orr ha ge, se vere w hite matter disease, sig nifica nt a b n or m alit y t hat 
w o ul d s u g gest a n ot her p ote ntial et i ol og y  for pr o gressi ve de me nt ia, or a cli nicall y 
sig nifica nt fi n di n g t hat ma y  i m pact t he partici pa nt ’s a bility t o s afel y p artici pate i n t he 
st u d y.
At  t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati on visit s h o ul d be 
c o n d ucte d if partici pa nt c o m plete d Visit 1 a n d recei ve d I P ( Part B o nl y), as s h o w n i n t he S o A. 
See S o A f or data t o be c ollecte d at t he ti me of st u d y  disc o nti n uati on a n d f o ll ow- u p a n d f or a n y  
f urt her e val uati ons t hat nee d t o be c o m plete d . T h e partici pa nt will be per ma ne nt l y disc o nti n ue d 
b ot h fr o m t he I P a n d fr o m t he st u d y at t hat ti me.
If t he partici pa nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati on, t he s p o ns or ma y  retai n 
a n d c o nt i n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt. If a partici pa nt 
wi t hdra ws fr o m t he st u d y, he/s he ma y re q uest destr uctio n of  a n y sa mples ta ke n a n d n ot teste d, 
a n d t he i n vest i gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.
7. 2. 1.
Disc o nti n u ati o n of I n a d verte ntl y E nr olle d P artici p a nts
If t he sp o ns or or i n vest i gat or i de ntif y a partici pa nt w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, disc ussi on s h o ul d occ ur bet wee n t he s p o ns or a n d i n vest i gat or. If t he 
i n vesti gat or a n d t he Lill y m e dical mo ni t or a gree it is me dicall y a p pr o pr iate t o c o nti n ue, t he 
i n vesti gat or m ust o btai n d oc u me nte d a p pr o val fr o m t he Lill y m e dical m o ni t or t o all o w t he 
i na d verte ntl y e nr olle d partici pa nt t o c o nti n ue i n t he st u d y wit h or wit h o ut treat me nt wit h I P. 
S af et y f oll ow- u p i s as o utli ne d i n Secti on 1. 3 ( S o A), Secti o n 8. 2 ( Safet y Assess me nts), a n d 
Secti o n 8. 3 ( A Es a n d S A Es) of t he pr ot oc ol.
7. 3.
L ost t o F oll o w - U p
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if  he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e. Si te pers o n nel are e x pecte d t o 
ma ke dili ge nt atte m pts t o c o ntact partici pa nts w h o fail t o ret ur n f or a sc he d ule d visit or were 
ot her wi se u na ble t o be f oll owe d u p b y t he site.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
4 9
Si te pers o n nel, or a n i n de pe n de nt t hir d part y, will att e mpt t o c ollect t he vital stat us of t he 
parti ci pa nt wit hi n le gal a n d et hical b o u n daries f or all partici pa nts ra n d o mize d, i ncl u di n g t h ose 
w h o di d n ot get I P . P u blic s o urces ma y be searc he d f or vital stat us i nf or mat i on . If vit al st at us is 
deter mi ne d t o be decease d, t his will be d oc u me nte d, a n d t he partici pa nt will n ot be c o nsi dere d 
l ost t o f ollo w - u p. S p o ns or pers o n nel will n ot be i n v ol ve d i n a n y atte m pts t o c ollect vital stat us 
i nf or mat i on.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of re g ulat or y, 
et hical, a n d trial o versi g ht c o nsi derat i ons i n Secti on 1 0. 1. 8 .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 0
8.
St u d y Assess me nts a n d Pr oce d ures
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. Pr ot oc ol wai vers or e xe m pt i ons 
are n ot all o we d.
I mme diate safet y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nt i n ue or disc o nti n ue I P.
A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse nt ial 
a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote ntial part ici pa nts 
meet all eli gi bilit y crit eri a. T he i n vest i gat or will mai ntai n a scree ni n g l o g t o rec or d details of all 
parti ci pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as 
a p plica ble.
8. 1.
Effic ac y Assess me nts
8. 1. 1.
C o g niti ve a n d F u ncti o n al Me as ures
T he f oll owi n g c o g ni tive a n d f u nct i onal meas ures will be i ncl u de d i n t his st u d y: 

A D A S -C o g 1 3

A D C S -A D L

M M S E

C D R -S B
T hese meas ures are utilize d i n P arts A , B, a n d C . F o r differe nces i n a d mi nistrati o n of t he 
meas ures, see Secti o n 8. 1. 2 . 
8. 1. 1. 1.
C D R -S B
T he C D R -S B ( H u g hes et al . 1 9 8 2; M orris 1 9 9 3) is a glo bal assess me nt t o ol t hat ca n be use d t o 
effect i vel y e val uate b ot h c o g niti o n a n d f u ncti on. T he t o ol  was i nitiall y d e v elo pe d t o m eas ure 
d e m e nt ia se verity a n d c o vers 6 cate g ories or “ b o xes”: Me m or y , Orie ntatio n, J u d g m e nt a n d 
Pr o ble m S o l vi n g, C om m u nit y Affairs, H o me a n d H o b bies, a n d Pers o nal Care . 
T he C D R gl o b al  rati n gs, calc ulate d usi n g a n al g orit h m, ra n ge fr o m 0 ( n o de me nt ia) t o 3 (se vere 
d e m e nt ia) w hile C D R-S B sc ores, calc ulate d b y a d di n g t he b o x sc ores, ra n ge fr o m 0 t o 1 8 ( wi t h 
hi g her sc ores i n dicat i ve of m ore i m pair me nt). Sc ori n g is deter mi ne d b y a cli nicia n t hr o u g h a 
se mistr uct ure d a n d i n-de pt h i nter vie w wit h b ot h t he affecte d i n di vi d ual a n d t heir st u d y part ner. 
T he st u d y  part ner a n d parti cipa nt m ust be i nter vie we d se paratel y.
T his scale de m o nstrates acce pta ble ps yc h o met ric c haracterist ics (C ol e y et al. 2 0 1 1; Ce dar ba u m 
et al. 2 0 1 3) a n d has bee n s h o w n t o be se nsiti ve e n o u g h t o detect disease pr o gressi o n, e ve n i n 
p o p ul at i ons wit h less a d va nce d cli nical disease (Willia ms et al. 2 0 1 3; Wessels et al. 2 0 1 5).
8. 1. 1. 2.
M M S E
T he M M S E is a brief i nstr u me nt use d t o assess c o g nit i ve f u ncti on i n patient s ( F olstei n et al. 
1 9 7 5) . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 1
T he i nstr u me nt meas ures orie ntati o n, me m or y , a n d atte ntio n ; t he a bilit y of t he parti ci pa nt t o 
na me o bjects ; f oll ow ver bal a n d writte n c o m ma n ds ; wri te a se nte nce; a n d c o p y fi g ures. T he 
ra n ge f or t he t otal M M S E sc ore is 0 t o 3 0, wit h l o wer sc ores i n dicati n g greater level o f 
i m pair me nt.
8. 1. 1. 3.
A D A S -C o g 1 3
T he A D A S -C o g 1 3 is a rater- a d mi nistere d i nstr u me nt t hat was desi g ne d t o assess t he se verit y of  
d y sf u ncti on i n t he c o g niti ve a n d n o nc o g niti ve be ha vi ors c haracteristic of pers o ns with A D 
( R ose n et al. 1 9 8 4). 
T he c o g nit i ve s u bscale of t he A D A S, t he A D A S-C o g 1 3, c o nsists of 1 3 ite ms assessi n g areas of 
c o g nitive f unct i on t hat are t he m o st t ypicall y  i m paire d i n A D: ori e ntatio n, ver bal me m or y , 
la n g ua ge, pra xis, dela ye d free recall, di git ca ncellati o n, a n d maze-c o m p leti o n meas ures ( M o hs et 
al. 1 9 9 7). T he A D A S -C o g 1 3 scale ra n ges fr o m 0 t o 8 5, wit h hi g her sc ores i n dicati n g greater 
di sease se verit y.
8. 1. 1. 4.
i A D R S
T he i A D R S ( Wessels et al. 2 0 1 5) re prese nts a c o m p osite t hat was de vel o pe d usi n g b ot h a 
t he or y-dri ve n a p pr oac h (i nc or p orati n g meas ures of b ot h c o g nit i on a n d f u ncti o n) a n d a 
data -mi ni n g a p pr oac h (i de nt if yi n g t he m ost se nsiti ve c om bi nat i on of s cales t hr o u g h a nal ysis of 
data fr o m  t he A D Ne ur oi ma gi n g I nit iati ve a n d t he E X P E DI TI O N, E X P E DI TI O N 2, a n d 
E X P E DI TI O N 3 st u dies). 
T he i A D R S is a si m ple li near c o m bi nat i on of sc ores fr o m 2 well -esta blis he d, t hera pe uticall y 
se nsiti ve, widel y acce pte d m eas ures in A D, t he A D A S -C o g 1 3 a n d t he A D C S -i A D L, meas uri n g 
t he c ore d o mai ns o f A D . All i te ms of t hese 2 scales are i ncl u de d wit h o ut a d diti onal wei g ht i n g of 
ite ms, yiel di n g face vali dit y a n d ease of i nter pretati o n of t he c o m p osite relat i ve t o its 
c o mp o ne nts.
T he i A D R S sc ore will be deri ve d fr o m t he A D A S -C o g 1 3 a n d t he A D C S -i A D L. T he 
A D A S -C o g 1 3 a n d t he A D C S -A D L will be t he act ual scales a d mi nistere d t o partici pa nt s.
8. 1. 1. 5.
A D C S -A D L
T he A D C S -A D L is a 2 3 -ite m i n ve nt or y de vel o pe d as a rater-a d mi nistere d q uest i on naire t hat is t o 
be a ns were d b y t he parti ci pa nts st u d y part ner ( Galas k o et al. 1 9 9 7, 2 0 0 4). 
F or eac h of t he s pecific ite ms, t he st u d y  part ner is first as ke d if t he partici pa nt atte mpte d t he 
A D L d uri n g t he past 4 wee ks . If t he partici pa nt di d atte m pt t he A D L, t he st u d y part ner is as ke d 
t o rate t he perf or ma nce le vel base d o n a set of perf or ma nce descri pt i ons . Sc ores f or eac h ite m 
a n d t he o verall sc ore f or t he t o ol are calc ulate d . T he ra n ge f or t he t otal A D C S -A D L sc ore is 0 t o 
7 8, wi t h l ower sc ores i n dicati n g greater le vel of i m pair me nt ( Galas k o et al. 1 9 9 7, 2 0 0 4). 
8. 1. 2.
Or der of Assess me nts a n d R ater R oles
Assess me nts a d mi nistere d t o t he partici pa nt are t he M M S E, A D A S -C o g 1 3 , C D R, a n d C-S S R S 
( C-S S R S i s i n Part B o nl y) . As sess me nt s a d mi nistere d t o t he st u d y part ner are t he C D R a n d 
A D C S -A D L.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 2
Refer t o t he ta ble bel o w f or t he se q ue nce of  tests f or b ot h partici pa nt a n d st u d y part ner.
Ps yc h o metric R ater
Gl o b al R ater
P a rtici p a nt
St u d y P art ner
1: M M S E
2: A D A S -C o g 1 3
1: A D C S -A D L 
2: C D R a
P artici p a nt
4: C -S S R S ( Part B o nl y)
3: C D R a
A b bre viati o ns: 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 ; 
A D C S -A D L = 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; 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; M M S E = Mi ni Me ntal State 
E xa mi nati o n ; V T C = vi de o telec o nfere nce.
a
T he C D R m ust al wa ys be a d mi nistere d t o t he st u d y part ner first a n d t he n t o t he partici pa nt. It is rec o m me n de d 
t hat b ot h secti o ns are a d mi nistere d o n t he sa me da y. F or V T C assess me nt; t he partici pa nt a n d t he st u d y part ner 
ca n n ot be prese nt d uri n g t he ot her part y’s i nter vie w.
N ote t hat , i n Parts B a n d C, t he A D A S-C o g 1 3 a n d M M S E s h o ul d be a d mi nistere d b y a differe nt rater t ha n t he 
A D C S -A D L a n d C D R. 
I n Part A , for Pair 1 wi t hi n eac h s u bject, t he V T C assess me nt a n d t he o n-site assess me nt must be 
c o n d ucte d b y 2 se parate raters. I n s u bse q ue nt pairs, e ver y eff ort s h o uld be ma de t o ha ve se pa rate 
raters c o n d uct t he V T C assess me nt a n d t he o n-site assess me nt.
I n Part B, t he gl o bal a n d ps yc h o met ric raters s h o ul d a d mi nister t he sa me scale t o t he sa me 
parti ci pa nt t hr o u g h o ut t he st u d y w he ne ver p ossi ble . T he PI has t he res p o nsi bilit y of selecti n g t he
raters w h o will a d mi nister t he i nstr u me nts at t he site, a n d e ns uri n g all trai ni n g re q uire me nts ha ve 
bee n met b y  t h ose raters.
W he n a d mi nistere d, c o g nit i ve a n d f u ncti onal test i n g s h o ul d be perf or me d bef ore me dical 
pr oce d ures t hat c o ul d be stressf ul f or t he parti ci pa nt (e. g., bl o o d dra ws). N ote t hat s o me 
pr oce d ures ( M RI, fl orta uci pir F 1 8 P E T ta u i ma gi n g, fl or beta pir F 1 8 P E T a m yl o i d i ma gi n g) ca n 
be c o n d ucte d o n ot her da y s wit hi n t he visit wi n d o w. T he C D R rater s h o ul d be bli n de d t o A Es t o 
a v o i d bias i n t he C D R assess me nt . 
C o g ni tive a n d f u nct i onal testi n g will be a d mi nistere d usi n g a n e C O A ta blet . T he a u di o v oice 
rec or di n gs of t he rater’s q uesti o ns a n d t he parti ci pa nt ’s a n d st u d y part ner’s res p o nses will als o be 
c ollecte d via t he e C O A ta blet d uri n g a d mi nistratio n of  t he c o g nitive a n d f u nct i onal testi n g f or 
ce ntral mo ni t orin g of rater scale a d mi nistrati o n . C o g ni tive a n d f u nct i onal test i n g f or eac h 
parti ci pa nt s h o uld be perf or m e d at a p pr o xi matel y t he sa me ti me o n eac h da y, w he ne ver p ossi ble, 
t o re d uce p ote ntial varia bilit y.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 3
8. 1. 3.
Bi o m ar ker Effic ac y Me as ures
Bi o m ar ker efficac y meas ures c ollecte d i n t his st u d y are descri be d i n t he res pecti ve secti ons 
bel o w:

Fl or beta pi r F 1 8 P E T sca n – Secti o n 8. 6. 1

Fl ort a u ci pir F 1 8 P E T sca n – Secti o n 8. 8

V ol u metric M RI – Secti o n 8. 8
8. 2.
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A.
8. 2. 1.
P h ysic al a n d Ne ur ol o gic al E x a mi n ati o ns
C o m plete a n d bri ef p h ysical e xa mi nati ons will be perf or me d as i n dicate d i n t he S o A 
( Sectio n 1. 3 ). 
T he c o m plete p h ysical e xa mi nat i on will i ncl u de assess me nt of t he f o ll owi n g : 

ge neral a p peara nce; 

s ki n, hea d, a n d nec k; 

l y m p h n o des; 

t h yr oid;

a b d o me n ( b o wel s o u n ds, li ver a n d s plee n pal pat i on) ; 

bac k (c ost o verte bral a n gle te n der ness); a n d

m usc ul os keletal, car di o vasc ular, a n d res pirat or y  s yste ms. 
T he brief p h ysical e xa mi nat i on will  incl u de assess me nts of t he f o ll owi n g:

s ki n, 

l u n gs, 

car dio vasc ular s yste m , a n d 

a b d o me n ( b o wel s o u n ds, li ver a n d s plee n pal pat i on).
C o m plete ne ur ol o gical  e xa mi nati ons will be perf or me d as i n dicate d i n t he S o A ( Secti o n 1. 3 ). 
T he e xa mi nat i ons will i ncl u de a t h or o u g h assess me nt of t he f o ll owi n g:

g ai t, 

bala nce, 

c o or di nat i on, 

cra nial ner ves, 

se ns or y a n d mot or s yste m s, a n d

refle xes. 
If necessar y, gi ve n t he tra i ni n g of t he PI, a ne ur ol o gist ma y be c o ns ulte d i n t he e ve nt of 
sig nifica nt ne w fi n di n gs. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 4
If a cli nicall y mea ni n gf ul c ha n ge i n an M RI is n ote d d uri n g t he st u d y , a n a d ditio nal f ull 
ne ur o l ogi cal e xa m s ho ul d be perf or m e d as s o o n as p ossi ble, al o n g wit h a n y o t her me dical 
f oll ow- u p dee m e d necessar y b y t he i n vesti gat or.
8. 2. 2.
Vit al Si g ns
Vi t al si g ns, i ncl u di n g te m perat ure, will be meas ure d as i n dicate d i n t he S o A ( Secti o n 1. 3 ). 
Vi t al si g ns s h o uld be ta ke n bef ore a d mi nistrati o n of I P . Vi t al sig ns m a y be re peate d as nee de d . 
8. 2. 2. 1.
Bl o o d Press ure
Si tti n g blo o d press ure a n d p ul se will be meas ure d after 5 mi n utes i n t he sitti n g p osit i on at all 
visit s. I n a d diti on, ort h ostatic bl o o d press ure a n d p ulse will be meas ure d s u pi ne a n d sta n di n g at 
desi g nate d visits, as detaile d i n t he S o A ( Secti o n 1. 3 ).
F or ort h ostati c bl o o d press ure m o nit ori n g, partici pa nts s h o ul d be s u pi ne f or at least 5 mi n utes 
a n d t he n sta n d f or at least 3 mi n utes pri or t o ta ki n g t he res pect i ve meas ure me nts . If t he s u bject 
feels u na ble t o sta n d, o nl y s u pi ne vital si g ns will be rec or de d.
U nsc he d ule d ort h ostatic vital si g ns s h o ul d be assesse d, if p ossi ble, d uri n g a n y A E of dizzi ness or 
p ost ure -i n d uce d s y m pt o ms.
A n y cli nicall y  sig nifica nt fi n di n gs fr o m vital si g n meas ure me nts t hat res ult i n a dia g n osis a n d 
t hat occ ur after t he partici pa nt recei ves t he first d ose of st u d y treat me nt s h o uld be re p orte d t o 
Lill y or i ts desig nee as a n A E via C R F/electr o nic data e ntr y .
8. 2. 2. 2.
Hei g ht, Wei g ht, a n d B o d y Te m per at ure
H ei g ht a n d b o d y  wei g ht will be meas ure d. Meas ure m e nts s h o uld be ta ke n, w he n p ossi ble, wit h 
the sa me scale f or all meas ure me nts . B o d y  mass i n de x will be calc ulate d fr o m t he hei g ht a n d 
b o d y  wei g ht. 
T e m perat ure will be rec or de d usi n g a n oral or t y m pa nic ( or ot her acce pta ble r o ute) t her m o meter.
A n y b o d y  w eig ht data e ntere d i nt o t he C R F will be use d f or t he o verall data a nal ysis.
8. 2. 3.
Electr oc ar di o gr a ms
1 2- lea d di gital E C Gs will be c ollecte d acc or di n g t o t he S o A ( Secti o n 1. 3 ). Partici pa nt s must be 
s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G c ollecti on a n d re m ai n s u pi ne b ut a wa ke 
d uri n g E C G c ollect i on.
E C Gs ma y be o btai ne d at a d dit i onal t i mes, w he n dee me d cli nicall y necessar y. C o llecti on of 
m o re E C Gs (re plicates) t ha n e x pecte d at a ti me p oi nt is all o we d w he n nee de d t o e ns ure 
hi g h -q ualit y rec or ds.
E C Gs will i nit iall y be i nter prete d b y a q ualifie d p h ysicia n (t he i n vesti gat or or q ualifie d desi g nee) 
at t he site as s o o n after t he ti me of E C G c ollect i on as p ossi ble, a n d i deall y w hile t he parti ci pa nt
is still prese nt, t o deter mi ne w het her t he s u bject meets e ntr y crit eria at t he rele va nt visit(s) a n d 
f or i m me diate partici pa nt ma na ge me nt, s h o ul d a n y cli nicall y rele va nt  fi n di n gs be i de ntifie d.
After e nr o ll me nt, if a cli nicall y si g nifica nt i ncrease i n t he Q T/ Q Tc i nter val fr om baseli ne or 
ot her cli nicall y si g nifica nt q ua ntitati ve or q ualitat i ve c ha n ge fr om baseli ne is i de ntifie d, t he 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 5
parti ci pa nt will be assesse d b y t he i n vesti gat or f or s y m pt o ms (e. g., pal pitat i ons, near s y nc o pe, 
s y nc o pe) a n d t o deter mi ne w het her t he partici pa nt ca n c o nt i n ue i n t he st u d y. T he i n vesti gat or or 
q ualifie d desi g nee is res p o nsi ble f or deter mi ni n g if a n y c ha n ge i n parti ci pa nt ma na ge me nt i s 
nee de d . T he i n vest i gat or or q ualifie d desi g nee m ust d oc u me nt his/ her re vie w of t he E C G pri nte d 
at t he ti me of e val uat i on.
All di gital E C Gs will be electr o nicall y  tra ns mitte d t o a desig nate d ce ntral E C G la b orat or y . A 
car diol o gi st at t he ce ntral E C G la b orat or y will t he n c o n d uct a f ull o verrea d. A re p ort base d o n 
data fr o m  t his o verrea d will be iss ue d t o t he i n vesti gati ve site. T hese data are n ot r o uti nel y 
re p orte d bac k t o t he i n vesti gati ve site. All data fr o m t he o verrea ds will be place d i n t he Lill y  
data base f or a nal yt ical a n d st u d y re p ort p ur p oses.
W he n t here are differe nces i n E C G i nter pretati o n bet wee n t he i n vest i gat or ( or q ualifie d 
desi g nee) a n d t he car di o l ogi st at t he ce ntral E C G la b orat or y, t he i n vesti gat or’s ( or q ualifie d 
desi g nee’s) i nter pretati o n will be u s e d for s t u d y e ntr y a n d i m me diate partici pa nt ma na ge me nt . 
I nter pretati o ns fr o m t he car di ol ogi st at t he ce ntral E C G la b orat or y will be use d f or data a nal ysis 
a n d re p ort writ i n g p ur p oses.
T he i n vest i gat or ( or q ualifie d desi g nee) m ust d oc u me nt his/ her re vie w of  t he E C G pri nte d at t he 
ti me of c ollecti on, t he fi nal o verrea d E C G re p ort iss ue d b y t he ce ntral E C G la b orat or y , a n d a n y 
alert re p orts.
8. 2. 4.  
Cli nic al S afet y L a b or at or y Assess me nts
See Secti o n 1 0. 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he S o A f or t he 
ti mi n g a n d fre q ue nc y.
T he i n vest i gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F . T he 
la b orat or y re p orts must be file d wit h t he s o urce d oc u me nts . Cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d 
b y t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt's c o n dit i on.
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g partici pat i on 
i n t he st u d y, or wit hi n t he fol l ow- u p peri o d aft er t he last d ose of I P, s h o ul d be re peate d u ntil t he 
val ues ret ur n t o n or mal, baseli ne, or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y  t he 
i n vesti gat or or me dical m onit or.
1.
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne withi n a perio d of  ti me j u d ge d reas o na ble b y 
t he in vest i gat or, t he eti ol og y  s h o uld be i de ntifie d a n d t he s p o ns or n otifie d.
2.
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n Secti on 1 0. 2 , mus t be c o n d ucte d 
i n acc or da nce wit h t he la b orat or y  ma n ual a n d t he S o A.
3.
If la b orat or y val ues fr o m n o n pr ot oc ol -s pecifie d la b orat or y assess me nts perf or me d at t he 
i nstituti o n’s l o c al  la b orat or y r e q uire a c ha n ge i n partici pa nt ma na ge me nt or are c o nsi dere d 
cli nica ll y si g nifica nt b y t he i n vestigat or (f or e xa m pl e, S A E, A E, or d ose m o dificat i on), t he n 
t he res ults must be rec or de d i n t he C R F.
Lill y or i ts desig nee will  pr o vi de t he i n vestig at or wi t h t he res ults of la b orat or y tests a nal yze d b y 
a ce ntral ve n d or, if a ce ntr al ve n d or is use d f or t he cli nical trial. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 6
A n y cli nicall y  sig nifica nt fi n di n gs fr o m la b orat or y tests t hat res ult i n a ne w dia g n osis a n d t hat 
occ ur after t he partici pa nt recei ves t he first d ose of I P s h o ul d be re p orte d t o Lill y or its desi g nee 
as a n A E via C R F/electr o ni c data e ntr y.
8. 2. 5.
M a g netic Res o n a nce I m a gi n g
M RI
of  t he brai n will be perf or me d acc or di n g t o t he S o A ( Secti o n 1. 3 ) a n d as cli nicall y 
i n dicate d. U nsc he d ule d M RIs ma y be perf or me d at t he discreti o n of i n vest i gat or.
T his tec h n o l og y  will be use d t o c hec k f or e vi de nce of A RI A-H or A RI A - E a n d safet y fi n di n gs 
( vol u metri c M RI will als o be use d t o calc ulate brai n v o l umes, as n ote d i n Sect i on 8. 8 ).
T he M RI sca ns will be re vie we d b y  t he i n vesti gat or or q ualifie d desi g nee f or i m me diate 
parti ci pa nt ma na ge me nt . A n y cli nicall y si g nifica nt fi n di n gs n ote d t hat res ult i n a ne w or u p date d 
di a g n osis s h o uld be rec or de d as a n A E . After t he M RI sca n is rea d l ocall y, t he M RI sca ns will be 
se nt f or a nal ysis t o a ce ntralize d M RI ve n d or desi g nate d b y Lill y. T he ce ntralize d M RI ve n d or’s 
i nter pretatio n of  t he partici pa nt’s fi nal M RI fr o m t he ori gi nat i n g st u d y or u nsc he d ule d M RI 
perf or m e d i n St u d y A A C H prior t o Part B will deter mi ne fi nal M RI eli gi bilit y f or Part B.
S pecific a nal yses of t he sca ns, i ncl u di n g assess me nts of A RI A- H a n d A RI A -E a n d calc ulat i ons 
of  brai n v ol umes, will be i nter prete d b y  t he ce ntralize d M RI ve n d or f or data a nal ysis a n d re p ort 
wri ti n g p ur p oses. 
Res ults of ce ntrall y  rea d M RIs re gar di n g parti ci pa nt care/safet y will be re p orte d bac k t o sites.
8. 2. 6.
He p atic S afet y M o nit ori n g
Cl ose H e pat ic M o ni t ori n g
La b orat or y  tests ( Sectio n 1 0. 4 ), i ncl u di n g A L T, A S T, A L P, T B L, direct bilir u bi n, G G T, a n d C K, 
s h o uld be re peate d wi t hi n 4 8 t o 7 2 h o urs t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is 
i ncreasi n g or decreasi n g, if 1 or mor e of  t hese c o n diti ons occ ur:
If a p artici p a nt wit h b aseli ne res ults of ... 
de vel o ps t he f oll o wi n g ele v ati o ns:
A L T or A S T < 1. 5 x U L N
A L T or A S T ≥3 x U L N
A L P < 1. 5 x U L N
A L P ≥2 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or partici pa nt s wit h Gil bert’s s y ndr o me)
A L T or A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥2 x baseli ne (e xce pt f or pa rtici pa nts wit h Gil bert’s 
s yn dr o me)
A b bre viati o ns : A L P = al kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; 
T B L = t otal bilir u bi n le vel; U L N = u p per li mit of n or mal.
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultat i on wi t h 
t he Lill y-desi g nate d m e dical m o nit or . At a mi ni m u m, t his e val uat i on s h o ul d i ncl u de p h ysical 
e xa mi nat i on a n d a t h or o u g h me dical hist or y , i ncl u di n g s y m pt o ms, rece nt ill nesses (f or e xa m ple:
heart fail ure, s yste mic i nfect i on, h y p ote ns i on, or seiz ures), rece nt tra vel, hist or y  of c o nc o mit a nt 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 7
me dicat i ons (i ncl u di n g o ver -t he- c o u nter), her bal a n d dietar y s u p ple me nts, a n d hist or y of alc o h ol 
dri n ki n g a n d ot her s u bsta nce a b use. 
I nitiall y, mo ni t ori n g of s y m pt o ms a n d he patic bi oc he mical tests s h o ul d be d o ne at a fre q ue nc y o f 
1 t o 3 ti mes wee kl y, base d o n t he partici pa nt’s cli nical c o n dit i on a n d he pat ic bi oc he mical tests. 
S u bse q ue ntl y, t he fre q ue nc y  of mo ni t orin g m a y be lo were d t o o nce e ver y  1 t o 2 wee ks if t he 
parti ci pa nt’s cli nical c o n dit i on a n d l a b orat or y res ults sta bilize. M o ni t ori n g of A L T, A S T, A L P, 
a n d T B L s h o ul d c o nti n ue u nt il le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
C o m pre he nsi ve H e pat ic E val uat i on  
A c o m pre he nsi ve e val uat i on s h o ul d be perf or m e d t o searc h f or p ossi ble c a uses of li ver i nj ur y if 
1 or m ore of t hese c o n dit i ons occ ur:
If a p artici p a nt wit h b aseli ne res ults of... 
de vel o ps t he f oll o wi n g ele v ati o ns:
A L T or A S T < 1. 5 x U L N
A L T or A S T ≥3 x U L N wit h he patic si g ns/s y m pt o ms *, or
A L T or A S T ≥5 x U L N
A L P < 1. 5 x U L N
A L P ≥3 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or partici pa nt s wit h Gil bert’s s y n dr o me)
A L T or A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne wit h he patic si g ns/s y m pt o ms *, or
A L T or A S T ≥3 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥1. 5 x baseli ne (e xce pt f or partici pants wit h Gil bert’s 
s yn dr o me) 
A b bre viati o ns : A L P = al kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; 
T B L = t otal bilir u bi n le vel; U L N = u p per li mit of n or mal.
*
He patic si g ns/s y m pt o ms are se vere f ati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, fe ver, ras h, 
a n d/ or e osi n o p hilia > 5 %.
At  a mi ni m u m, t his e val uati on s h o ul d i ncl u de p h ysical e xa mi nat i on a n d a t h or o u g h me dical 
hist or y , as o utli ne d a b o ve, as well as tests f or Pr ot hr o m bi n ti me a n d I N R; tests f or viral 
he pat itis A, B, C, or E; tests f or a ut oi m m u ne he patit is; a n d a n a b d omi nal i ma gi n g st u d y (for 
e xa m ple, ultras o u n d or C T sca n). 
Base d o n t he partici pa nt ’s hist or y a n d i nitial r es ults, furt her testi n g s h o ul d be c o nsi dere d i n 
c o ns ultati o n wit h t he Lill y -desi g nate d m e dical mo ni t or, i ncl u di n g tests f or he patitis D vir us, 
c yt o me galo vir us, E pstei n -Barr vir us, aceta mi n o p he n le vels, aceta mi n o p he n pr otei n a d d ucts, 
uri ne t o xic o l og y  scree n, Wils on’s disease, bl o o d alc o h ol le vels, uri nar y et h yl gl uc ur o nide, a n d 
ser u m p h os p hati dylet ha n o l. Base d o n t he circ u msta nces a n d t he i n vest i gat or’s assess me nt of t he 
parti ci pa nt’s cli nical c o n dit i on, t he i n vest i gat or s h o ul d c o nsi der referri n g t he partici pa nt f or a 
he pat ol o gi st or gastr oe nter ol o gist c ons ultati o n, ma g net ic res o na nce c h olan gi o pa ncreat o gra p h y , 
e n d osc o pic retr o gra de c h ola n gi o pa ncreat o gra p h y, c ar diac ec h ocar dio gr a m , or a li ver bi o ps y. 
8. 2. 7.
S uici d al I de ati o n a n d Be h a vi or Ris k M o nit ori n g
P arti cip a nts bei n g treate d wit h d o na ne ma b s h o uld be m o ni t or ed a p pr o priatel y a n d o bser ve d 
clos el y  for s ui ci dal i deat i on a n d be ha vi or or a n y  ot her u n us ual c ha n ges i n be ha vi or, es peciall y at 
t he be gi n ni n g a n d e n d of t he c o urse of i nter ve nt i on or at t he ti me of d ose c ha n ges, eit her 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 8
i ncreases or decreases. C o nsi derat i on s h o uld be gi ve n t o di sc o nti n ui n g t he st u d y me dicat i on i n 
s u bjects w h o e x perie nce si g ns of s uici dal i deati on or be ha vi or, f o ll owi n g a ris k assess me nt.
Fa milies a n d care gi vers of parti ci pa nts bei n g treate d wit h d o na ne ma b s h o uld be alerte d a b o ut t he 
nee d t o m o nit or partici pa nts f or t he e mer ge nce of u n us ual c ha n ges i n be ha vi or, as well as t he 
e mer ge nce of s uici dal i deat i on a n d be ha vi or a n d t o re p ort s uc h s y m pt o ms i m me diatel y t o t he 
st u d y in vest i gat or.
Baseli ne assess me nt of s uici dal i deati o n a n d be ha vi or a n d i nter ve ntio n -e mer ge nt s uici dal 
i deati on a n d be ha vi or will be m o nit ore d d uri n g Part B of St u d y  A A C H usi n g t he C-S S R S. 
C- S S R S
T he C -S S R S is a scale t hat ca pt ures t he occ urre nce, se verity,  a n d fre q ue nc y of s uici dal i deati o n 
a n d be ha vi or d uri n g t he assess me nt peri o d via a q uesti o n naire . T he scale was de vel o pe d b y t he 
NI M H trial gr o u p f or t he p ur p ose of bei n g c o u nter part t o t he C ol u m bia Class ificati on Al g ori t h m 
of  S uici de Assess me nt ( C -C A S A) cate g orizati o n of s uici dal e ve nts.
8. 3.
A d verse E ve nts a n d Seri o us A d verse E ve nts
A E s will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, st u d y part ner, 
s urr o gate, or t he partici pa nt's legall y a ut h ori ze d re prese ntati ve).
T he i n vest i gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti on of a n A E or S A E, a n d re mai n res p o nsi ble f or f o ll owi n g 
u p o n A Es t hat are seri o us, c o nsi dere d rel ate d t o t he I P or st u d y pr oce d ures, or t hat ca use d t he 
parti ci pa nt t o disc o nti n ue t he I P (see Secti o n 7 ).
8. 3. 1.
Ti me Peri o d a n d Fre q ue nc y f or C ol lecti n g A E a n d S A E I nf or m ati o n
All S A Es will be c o llecte d fr om t he sig ni n g of t he I C F t hr o u g h t he ti me p oi nts s pecifie d i n t he 
S o A ( Secti o n 1. 3 ).
All A Es will be c o llecte d fr om t he sig ni n g of t he I C F t hr o u g h t he ti me p oi nts s pecifie d i n t he 
S o A .
Me dical occ urre nces t hat be gi n bef ore t he start of I P b ut after si g ni n g of t he I C F will b e rec or de d 
o n t he A E C R F.
Alt h o u g h all A Es after si g ni n g t he I C F are rec or de d b y t he site i n t he C R F/electr o nic data e ntr y, 
S A E re p orti n g t o s p o ns or be gi ns after t he partici pa nt has si g ne d t he I C F a n d has recei ve d I P or 
P E T tracer . H o we ver, if a n S A E occ ur s after si g ni n g t he I C F, b ut pri or t o recei vi n g I P or P E T 
tracer, it nee ds t o be re p orte d O N L Y if it is c o nsi dere d reas o na bl y p ossi bl y relate d t o st u d y 
pr oce d ures.
All S A Es will be rec or de d a n d re p orte d t o t he s p o ns or or desi g nee i m me diatel y a n d u n der n o 
c irc u msta nce s h o uld t hi s e xcee d 2 4 h o urs, as i n dicate d i n Secti o n 1 0. 3 . T he i n vest i gat or will 
s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g a vaila ble . 
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A Es or S A Es aft er c o nclusi o n  of st u dy 
parti ci pat i on . H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after 
a partici pa nt has bee n disc har ge d fr o m t he st u d y , a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y 
r elate d t o t he I P or st u d y p artici pat i on, t he i n vest i gator m ust pr o m ptl y n otif y t he s p o ns or.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
5 9
8. 3. 1. 1.
A d verse E ve nt M o nit ori n g wit h a S yste m atic Q uesti o n n aire
N o nl ea di n g A E c ollect i on s h o ul d occ ur pri or t o t he c ollect i on of t he C -S S R S . 
If a s uici de-relate d e ve nt is disc o vere d d uri n g t he C-S S R S b ut was n ot ca pt ure d d uri n g t he 
n o nlea di n g A E c ollect i on, si tes s h o uld n ot c ha n ge t he A E f or m . 
If a n A E is serio us or l ea ds t o disc o nt i n uati on, it nee ds t o be i ncl u de d o n t he A E f or m a n d t he 
pr ocess f or re p orti n g S A Es is f o ll owe d.
8. 3. 2.
Met h o d of Detecti n g A Es a n d S A Es
T he m et h o d of rec or di n g, e val uat i n g, a n d assessi n g ca usality of A E a n d S A E a n d t he pr oce d ures 
f or c o mplet i n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n Sect i on 1 0. 3 .
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut A E
occ urre nc es.
8. 3. 3.
F oll o w - Up of A Es a n d S A Es
After t he i nit ial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll ow eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es, a n d A Es of s pecial i nterest (as defi ne d i n Sect i on 8. 3. 8 ), 
will be f o ll owe d u nt il res ol uti on, sta bilizat i on, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt 
is l ost t o f oll o w-u p (as defi ne d i n Sect i on 7. 3 ). F urt her i nf or mati on o n f o ll ow- u p pr oce d ures i s 
pr o vi de d i n Sect i on 1 0. 3 . 
8. 3. 4.
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es
Pr o m pt n otificat i on b y t he i n vest i gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le g al 
o bli gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of  partici pa nts a n d t he safet y of  a n I P 
u n der cli nical i n vest i gati on are m et.
T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he lo c al  re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of  a n I P u n der cli nical i n vesti gati o n. T he s p o ns or will 
c o mpl y  wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relat i n g t o safety re p orti n g t o t he 
re g ulat or y a ut h orit y, I R Bs/I E Cs, a n d i n vesti gat ors.
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her s pecific 
safet y i nf or mati on ( f or e xa m ple, s u m mar y or listi n g of S A Es) fr om t he s p o ns or will re vie w a n d 
t he n file it al o n g wit h t he I B, a n d will n otif y t he I R B/I E C if a p pr o priate acc or di n g t o l ocal 
re q uire me nts.
8. 3. 5.
Pre g n a nc y
W O C B P are e xcl u de d fr o m St u d y  A A C H . T heref ore, pre g na nc y is n ot e x pecte d t o occ ur . 
H o we ver, if pre g na nc y d oes occ ur, f o ll ow t he i nstr ucti o ns bel o w.
Details o f all pre g na ncies i n fe male partici pa nts a n d, if i n dicate d, fe male part ners of male 
parti ci pa nts will be c o llecte d after t he start of I P a n d u ntil 9 0 da ys after t he last d ose of I P 
recei ve d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 0
If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of  lear ni n g 
of  t he pre g na nc y.
A b n or m al pre g na nc y o utc o mes ( f or e xa m ple, s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n genit al a n o malies, ect o pic pre g na nc y) are c o nsi dere d S A Es.
8. 3. 6.
H y perse nsiti vit y, I ncl u di n g I nf usi o n -Rel ate d Re acti o ns
8. 3. 6. 1.
M a n a ge me nt of I nf usi o n -Rel ate d Re acti o ns
Ma n y  dr u gs, b ut partic ularl y bi o l ogic a ge nts, carr y t he ris k of s yste mic h y perse nsit i vity 
reactio ns . If s uc h a reacti o n occ urs, a d dit i onal data descri bi n g eac h s y m pt o m s h o ul d be pr o vi de d 
t o t he s p o ns or i n t he C R F.
Si tes s h o uld ha ve a p pr o pri atel y trai ne d me dical staff a n d a p pr o priate me dical e q ui p me nt 
a vaila ble w he n st u d y p artici pa nts are recei vi n g I P. It is rec om me n de d t hat partici pa nts w h o 
e x perie nce a s yste mic h y perse nsit i vity reacti on be treate d per t he l ocal sta n dar d of care.
I n t he case of ge neralize d urticaria or s us pecte d a na p h yla xis, a d dit i on al  blo o d a n d uri ne sa m ples 
s h o uld be c ollecte d as descri be d i n Sect i on 1 0. 2 . La b orat or y res ults are pr o vi de d t o t he s p o ns or 
via t he ce ntral la b orat or y .
8. 3. 6. 2.
D osi n g Rec h alle n ge a n d Pre me dic ati o n f or I nf usi o ns
Pr e m e dicat i on f or d osi n g is n ot pla n ne d. 
H o we ver, if a n i nf usi o n reacti o n occ urs, a p pr o priate me dicat i on ma y be use d f or t he ac ute e ve nt 
as deter mi ne d b y t he st u d y in vest i gat ors (see Secti o n 6. 5. 2 ). T he me dicati o ns use d s h o ul d be 
d oc u m e nte d.
T he parti ci pa nt ma y be pre me dicate d f or s u bse q ue nt i nf usi o ns . If i nf usi on react i ons are 
o bser ve d, b ut re vie w of t he data s u g gests t hat d osi n g ma y  c o nti n ue, a d mi nistr atio n of  me dici nes 
ma na gi n g t he reacti o n ma y  be a d mi nistere d bef ore starti n g s u bse q ue nt i nf usi o ns at t he discret i on 
of  t he i n vesti gat or, acc or di n g t o l ocal practice g ui deli nes.
D osi n g rec halle n ge is c o ntrai n dicate d i n partici pa nts t hat ha ve e x perie nce d a s us pecte d or 
p ossi ble a na p h ylact ic reacti o n (e. g., reactio n i n v o l vi n g 2 or m ore or ga n s y ste ms [f or e xa mple, 
m uc oc uta ne o us, res pirat or y , car dio vasc ular, or gastr oi nt est i nal s yste ms] occ urri n g i n cl o se 
pr o xi mit y t o d osi n g), i n a pri or d ose ( Sa m ps o n et al. 2 0 0 6). F or i nf usi o n -relate d reactio ns w hic h 
are n ot s us pici o us f or a na p h yla xis, after re vie w o f t he data, a n d at t he i n vest i gat or’s discreti o n, 
t he partici pa nt ma y be rec halle n ge d. If rec halle n ge is pla n ne d, t he partici pa nt ma y be 
pr e m e dicate d f or s u bse q ue nt d oses at t he i n vesti gat or’s discreti o n a n d acc or di n g t o l ocal pract ice 
g ui deli nes. 
Pri or t o i ni tiati n g pre me dicat i on, t he i n vest i gat or m ust c o ns ult wit h t he s p o ns or. 
A n y pre me dicat i on gi ve n will be d oc u me nte d as a c o nc o mita nt t hera p y ( Sect i on 6. 5. 2 ).
8. 3. 7.
A m yl oi d - Rel ate d I m a gi n g A b n or m alities ( A RI A-E a n d A RI A -H)
W hile m ost cases of A RI A -E are as y m pt o mat ic, s erio us cases ha ve bee n re p orte d. A vaila ble data 
s u g gest seri o us cases are m ost li kel y t o occ ur earl y i n d osi n g, after t he first, sec o n d, or t hir d 
i nf usi on.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 1
W he n s y m pt o ms d o occ ur, t he y  are re p orte d t o be m ost c o m m o nl y: 

hea dac he, 

w orse ni n g of c o g nit i ve f u ncti on, 

alt er atio n of  c o nsci o us ness, 

seiz ures, 

u nstea di ness, a n d 

v o mit i n g. 
If a parti ci pa nt si m ulta ne o usl y de vel o ps m ore t ha n 1 of t he s y m pt o ms s u g gest i ve of A RI A-E, 
t he n a n u nsc he d ule d M RI s h o ul d be perf or me d . A si n gle s y m pt o m s u g gesti ve of A RI A-E of  
s ufficie nt se verity ma y als o warra nt a n M RI.
If t he a b o ve-me nt i one d s y m pt o ms are re p orte d, a n d: 

A RI A- E i s s us pecte d, t he n t he a b n or malit y is best detecte d b y  F L AI R se q ue nces o n 
M RI, w hile

A RI A- H is best detecte d wit h t he T 2 * gra die nt -recalle d ec h o o n M RI.
A n u nsc he d ule d M RI wit h t hese i ma gi n g se q ue nces s h o ul d be o btai ne d u p o n s us pici o n o f A RI A . 
If A RI A is prese nt, it is rec om me n de d t o re peat M RIs wit h t hese se q ue nces e ver y 4 t o 6 wee ks 
u nt il res ol uti on of A RI A -E or sta bilizat i on of A RI A -H is d oc u m e nte d. F or as y m pt o mat ic or mil d 
s y m pt o ms, t he parti ci pa nt ca n be o bser ve d . For m o derate s y m pt o m s ass ociate d wit h A RI A-E, 
t he use of oral or I V ster oi ds ca n be c o nsi dere d . I n t he case of se vere s y m pt o ms ass ociate d wit h 
A RI A- E, i t is rec o m me n de d t o h os pitalize t he partici pa nt f or close o bser vat i on a n d c o nsi der t he 
use of I V ster oi ds s uc h as hi g h -d ose de xa met has o ne or a si milar a ge nt.
T he u nsc he d ule d M RI s h o ul d be perf or me d i n t he sa me ma n ner as t he c urre nt l y sc he d ule d M RIs 
i n t he pr ot oc ol, w hic h i ncl u des se n di n g t he i ma ges f or ce ntral re vie w ( Secti o n 8. 2. 5 ). 
F or pr oce d ure s t o f oll ow i n t he e ve nt of A RI A -E or A RI A -H, see Secti o n 7. 1. 1. 1 . 
8. 3. 8.
A d verse E ve nts of S peci al I nterest 
S pecific safet y t o pics of int erest f or t his st u d y incl u de, b ut are n ot li mite d t o, t he f o ll owi n g : 

A RI A- E

A RI A- H

H y perse nsi tivi t y, i m me diate a n d n o n- i m me diate, i ncl u di n g i nf usi on- relate d reactio ns 
a n d a na p h yla xis
T he t o pi cs liste d a b o ve, as well as ot her t o pics w hic h ma y be s u bse q ue nt l y deter mi ne d b y t he 
s p o ns or, will be s u bject t o e n ha nce d s ur veilla nce acti vit ies. A d dit i onall y , t he t o pics a b o ve will be 
a nal yze d f or prese ntati o n i n t he c li nical st u d y re p ort i n acc or da nce wit h t he S A P.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 2
8. 3. 9.
Pr o d uct C o m pl ai nts
A pr o d uct c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicat i on t hat alle ges deficie ncies 
r elate d t o t he i de ntit y,  q uality, d ura bilit y,  relia bility,  s afet y,  effecti ve ness, or perf or ma nce of a 
trial int er ve nt i on. 
S p o ns or c ollects pr o d uct c o m plai nts o n I Ps use d i n cli nical st u dies i n or der t o e ns ure t he safet y 
of  st u d y p artici pa nts, mo ni t or q ualit y, a n d t o facilitate pr ocess a n d pr o d uct i m pr o ve ment s.
P arti cip a nts will be i nstr ucte d t o c o ntact t he i n vest i gat or as s o o n as p ossi ble if he or s he has a 
c o mplai nt or pr o bl e m wit h t he I P s o t hat t he sit uati o n ca n be assesse d.
N O T E: A E s/ S A Es t hat are ass ociate d wit h a pr o d uct c o m plai nt will als o f o ll ow t he pr ocesses 
o utli ne d i n Sect i on 8. 3. 3 a n d Secti o n 1 0. 3 of  t he pr ot oc ol.
8. 3. 9. 1.
Ti me Peri o d f or Detecti n g Pr o d uct C o m pl ai nts
Pr o d uct c o m plai nts t hat res ult i n a n A E will be detecte d, d oc u me nte d, a n d re p orte d t o t he 
s p o ns or d uri n g all peri o ds of t he st u d y i n w hic h t he dr u g is use d.
If t he i n vestigat or l ear ns of a n y pr o d uct c o m plai nt at a n y ti me after a partici pa nt has bee n 
di sc har ge d fr o m t he st u d y, a n d s uc h i nci de nt is c o nsi dere d reas o na bl y relate d t o a dr u g pr o vi de d 
f or t he st u d y, t he i n vesti gat or will pr o m ptl y n otif y t he s p o ns or.
8. 3. 9. 2.
Pr o m pt Re p orti n g of Pr o d uct C o m pl ai nts t o S p o ns or
Pr o d uct c o m plai nts will  be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs aft er t he i n vest i gat or bec o mes 
a ware of t he c o m plai nt .
8. 3. 9. 3.
F oll o w - Up of Pr o d uct C o m pl ai nts
F o ll ow- u p a p plies t o all partici pa nts, i ncl u di n g t h ose w h o disc o nt i n ue I P.
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t hat f oll o w-u p i ncl u des a n y s u p ple me ntal 
i n vesti gati ons as i n dicate d t o el uci date t he nat ure a n d/ or ca usalit y of  t he pr o d uct c o m plai nt .
Ne w or u p date d i nf or mat i on will be rec or de d o n t he ori gi nall y c o m p lete d f or m with all c ha n ges 
sig ne d a n d date d b y t he i n vest i gat or a n d s u b mitte d t o t he s p o ns or.
8. 4.
Tre at me nt of O ver d ose
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or or treati n g p h ysicia n s h o uld:
1.
C o nta ct  t he m e dical m o ni t or i m me diatel y.
2.
Cl os el y  mo ni t or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities.
3.
O btai n a plas ma sa m ple f or P K a nal ysis o f I P if re q ueste d b y t he m e dical mo ni t or 
( deter mi ne d o n a case- b y-case basis).
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vest i gat or i n 
c o ns ultati o n wit h t he m e dical m o ni t or base d o n t he cli nical e val uati o n of t he partici pa nt.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 3
8. 5.
P h ar m ac o ki netics
At  t he visits a n d ti mes s pecifie d i n t he S o A ( Sectio n 1. 3 ), ve n o us bl o o d sa m ples will be c o llecte d 
t o deter mi ne t he ser u m c o nce ntrati o ns of d o na ne ma b . I nstr uctio ns f or t he c ollect i on a n d ha n dli n g 
of  blo o d s a m ples will  b e pr o vide d b y t he s p o ns or . T he act ual  date a n d ti me ( 2 4-h o ur cl oc k ti me) 
of  eac h sa m pli n g will be rec or de d.
A ma xi m u m of 3 bl o o d sa m ples per partici pa nt ma y be dra w n at a d dit i onal ti me p o i nts d uri n g 
t he st u d y, if warra nte d a n d a gree d u p o n bet wee n b ot h t he i n vest i gat or a n d s p o ns or. I nstr ucti o ns 
f or t he c ollecti o n a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or.
If I P i nf usi on is per ma ne ntl y disc o nti n ue d b ut t he parti ci pa nt re mai ns i n t he st u d y, 1 P K sa m ple 
s h o uld be c ollecte d at t he s o o nest sc he d ule d visit re gar dless if assess me nt is o n t he S o A at t hat 
visit . D osi n g dates a n d ti mes s h o ul d be c ollecte d . S u bse q ue nt P K sa m ple c o llecti on s h o ul d 
f oll ow t he pr ot oc ol S o A f or ser u m d o na ne ma b c o llecti o n u nless t he sc he d ule d visit e xcee ds 
6 m o nt hs si nce disc o nt i n uati on of i nf usi o ns . N o a d dit i onal c o llecti o n f or d o na ne ma b is re q uire d 
o nce t he partici pa nt e xcee ds 6 m o nt hs si nce disc o nti n uat i on of d o na ne ma b i nf usi o ns.
Bi oa nal yt ical sa m ples c ollecte d t o meas ure d o na ne ma b c o nce ntrati o ns will be retai ne d f or a 
ma xi m u m of 1 year f oll owi n g last s u bject visit f or t he stu d y . D uri n g t his ti me, sa m ples re mai ni n g
after t he bioa nal yses m a y be use d f or e x pl orat or y a nal yses s uc h as meta b o lis m, pr otei n bi n di n g, 
or bi oa nal y tical met h o d de vel o p me nt/ va li dati o n w or k.
8. 6.
P h ar m ac o d y n a mics
8. 6. 1.
Cle ar a nce of A m yl oi d De p osits 
Fl or beta pi r F 1 8 P E T pr o vi des q ua nti tati ve assess me nt of a m yl oi d pla q ue de p ositi on i n t he brai n 
a n d ca n ser ve as a P D bi o mar ker of cleara nce of a m yl o i d de p osits.
Cl eara nce of a m yl o i d de p osits (as assesse d b y flor b et a pir F 1 8 P E T si g nal) will be a ssesse d at 
ti me p oi nts descri be d i n Part B a n d C of t he S o A ( Secti o n 1. 3 ).
8. 7.
Ge netics
Ge net ics are n ot e val uate d i n t his st u d y.
8. 8.
Bi o m ar kers
Bl o o d - Base d Bi o m ar kers
Bi o m ar ker researc h is perf or me d t o a d dress q uesti o ns of rele va nce t o dr u g dis p osit i on, tar get 
e n ga ge me nt, P D, mec ha nis m of act i on, varia bilit y of  parti ci pa nt res p o nse (i ncl u di n g safety) , a n d 
cli nical o utc o me . S a mple c ollecti o n is i nc or p orate d i nt o cli nical st u dies t o e na ble e xa mi nat i on of 
t hese q uest i ons t hr o u g h meas ure me nt of bi o m o lec ules i ncl u di n g R N A, pr otei ns, li pi ds, a n d ot her 
cell ular ele me nts.
S er u m, pl as ma, a n d w h o le bl o o d R N A sa m ples f or e x pl orat or y bi o mar ker researc h will be 
c ollecte d at t he ti mes s pecifie d i n t he S o A ( Secti o n 1. 3 ) w here l ocal re g ulat i ons all o w.
S a m ples will  be use d f or researc h o n t he dr u g tar get, disease pr ocess, varia ble res p o nse t o 
d o na ne ma b , pat h wa ys ass ociat e d wit h A D, mec ha nis m of act i on of d o na ne ma b , a n d/ or researc h 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 4
met h o d or i n vali dat i n g dia g n ostic t o ols or assa y(s) relate d t o A D or ot her ne ur ol o gical 
c o n ditio ns.
All sa m ples will be c o de d wit h t he partici pa nt n u m ber . T hese sa m ples a n d a n y data ge nerate d 
ca n be li n ke d bac k t o t he parti ci pa nt o nl y  b y t he i n vestigat or si te pers o n nel.
S a m ples will  be retai ne d at a facilit y selecte d b y Lill y or its desi g nee f or a ma xi m u m of 1 5 years 
after t he last partici pa nt visit f or t he st u d y , or for a s h orter peri o d if l o c al  re g ulati ons a n d E R Bs 
i m p ose s h orter ti me li mits. T his rete nt i on peri o d e na bles use of ne w tec h n ol o gies, res p o nse t o 
re g ulat or y q uestio ns, a n d i n vest i gati on of varia ble res p o nse t hat ma y n ot be o bser ve d u nt il later 
i n t he de vel o p me nt of d o na ne ma b or af t er d o na ne ma b bec o mes c o m merciall y a vaila ble.
Acc u m ul ati o n of T a u De p osits
Fl ort a u ci pir F 1 8 P E T pr o vi des q ua nti tati ve assess me nt of ta u de p ositi o n i n t he brai n a n d ca n 
ser ve as a P D bi omar ker of acc u m ulat i on of ta u de p osits as A D pr o gresses.
Acc u m ulat i on of  ta u de p osits (as assesse d b y fl orta uci pir F 1 8 P E T si g nal) will be assesse d at t he 
ti me p oi nt descri be d i n Part C of t he S o A ( Secti o n 1. 3 ).
V ol u metric M RI
Effects o n re gi o nal brai n v o l umes, as assesse d b y v o l umetric M RI , will be perf or med acc or di n g 
t o t he S o A ( Secti o n 1. 3 ). D o na ne ma b effects o n vol u metric M RI will be assesse d t o e val uate t he 
l oss of brai n v olu me t hat occ urs i n A D pat ient s.
8. 9.
I m m u n o ge nicit y Assess me nts
W here l ocal re g ulat i ons a n d E R Bs all o w, at t he visits a n d ti mes s pecifie d i n t he S o A 
( Sectio n 1. 3 ), ve n o us bl o od sa m ples will be c ollecte d t o deter mi ne a nti b o d y  pr o d uctio n a gai nst 
d o na ne ma b . T o i nter pret t he res ults of i m m u n o ge nicit y,  a ve n o us blo o d s a m ple will be c ollecte d, 
if warra nte d, at t he sa me ti me p oi nts t o deter mi ne t he ser u m c o nce ntrati o ns of d o na ne ma b . A ll 
sa m ples f or i m m u n o ge nicit y s h o ul d be ta ke n pre d ose w he n a p plica ble a n d p ossi ble.
I mm u n o ge nicit y will  be assesse d b y a vali date d assa y desi g ne d t o detect A D As i n t he prese nce 
of  d o na ne ma b at a la b orat or y a p pr o ve d b y t he s p o ns or. A nt i b o dies ma y be f urt her c haracterize d 
a n d/ or e val uate d f or t heir a bilit y t o ne utralize t he acti vity of  d o na ne ma b . 
T E A D As are defi ne d i n Sect i on 9. 4. 6. 1 . If t he i m m u n o ge nicity sa m ple at t he last sc he d ule d 
assess me nt or disc o nt i n uati on visit is T E A D A p osit i ve, a d diti onal sa m ples ma y be ta ke n f or u p 
t o 1 year after last d ose . 
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last partici pa nt visi t, or for a 
s h orter peri o d if l ocal re g ulat i ons a n d E R Bs all o w, at a facilit y selecte d b y  t he s p o ns or. T he 
d urati o n all o ws t he s p o ns or t o res p o n d t o f ut ure re g ulat or y  re q uests relate d t o d o na ne ma b . A n y 
sa m ples re mai ni n g after 1 5 years will be destr o ye d.
8. 1 0.
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics
N ot a p plica ble.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 5
9. 
S t atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
P art A :
T he I C C c o m pari n g V T C a d mi nistrati o n of t he A D A S -C o g 1 3, t he A D C S-A D L, t he M M S E , a n d 
t he C D R -S B will s h o w at a mi ni m u m ‘acce pta ble ’ a gree me nt wit h t he o n-site assess me nt of  t he 
sa me scales. Acce pta ble a gree me nt is defi ne d as a n I C C val ue of 0. 7 0 or greater ( K o o a n d Li 
2 0 1 6 ; C o o ns 2 0 09).
T he I C C will re mai n c o nsiste nt acr oss m u lti ple pairs of  V T C a n d o n-site assess me nts.
Di sease pr o gressi o n meas ure d b y V T C a d mi nistrati o n will be n o differe nt t ha n disease 
pr o gressi o n meas ure d b y  o n-site assess me nts.
P art B :
N o stati stical h y p ot heses f or Part B of t he st u d y .
9. 2.
S a m ple Size Deter mi n ati o n
A p pr o xi matel y  2 0 0 parti ci pa nts will be e nr olle d a n d ra n d o mize d i n a 1: 1 rati o t o t he 2 gr o u ps 
(Gr o u p 1: C o g nit i ve/f u ncti onal scale assess me nt o n- sit e, fol l owe d b y V T C assess me nt; or 
Gr o u p 2: C o g nit i ve/f u ncti o nal scale assess me nt b y V T C, f oll owe d b y  assess me nt o n -sit e). It is 
e x pecte d t hat a p pr o xi matel y 1 8 0 parti ci pa nts will c o m plete Pair 1 of Part A . A p pr o xi matel y 1 5 0 
parti ci pa nts are e x pecte d t o c o m plete t he st u d y. 
A c orrelat i on c oefficie nt of 0. 8 0 bet wee n o n -site a n d V T C assess me nt is ass u me d.
F urt her m or e, i t is ass u me d t hat t he 2 m o dalities will yiel d similar mea ns b ut differe nt sta n dar d 
de viat i ons. A m ea n A D A S -C o g 1 3 t otal sc ore of 2 7. 2 a n d a S D of 8 a n d 9 were use d f or t he p o wer 
calc ulat i on. T hese est i mates were deri ve d fr om S t udi es I 8 D-M C -A Z E S , I 8 D-M C -A Z E T , a n d 
H 8 A -M C -L Z A X , all reflecti n g a n earl y or mil d A D p o p ulati o n.
T his sa m ple size will pr o vi de a p pr o xi matel y 8 1 % p o w er t o de mo nstrate ‘acce pta ble’ relia bility , 
defi ne d as t he l o wer li mit of t he 9 5 % c o nfi de nce i nter val f or I C C a b o ve 0. 7 0.
T his p o wer calc ulat i on is base d o n t he A D A S-C o g 1 3 , as t his is t he scale a nt ici pate d t o ha ve m o st
scale a da ptati o ns a n d m ost varia bilit y fr om o n -site t o V T C assess me nt. Ot her scales s h o uld 
t heref ore de m o nstrate e q ual or greater p o wer f or t hese c o m paris o ns.
Si m ulati o ns ( c arrie d o ut i n R) wi t h 1 0 0 0 it er atio ns , utilizi n g a b o ve descri be d ass u m pti o n, yiel ds 
a n a vera ge I C C of 0. 7 9 3 a n d a vera ge 9 5 % c o nfi de nce i nter val of  0. 73 2 t o 0. 8 4 1.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 6
9. 3.
P o p ul ati o ns f or A n al yses
T he f oll owi n g p o p ul at i ons are defi ne d:
P o p ul ati o n
Descri pti o n
E nr olle d
Part A: All partici pa nts ra n d o mize d . Partici pa nts will be a nal yze d acc or di n g t o 
t he assess me nt or der act uall y c o m plete d .
Part B: All partici pa nts gi ve n I P d uri n g Part B.
Part C: All partici pa nts partici pati n g i n a Part C f oll o w-u p assess me nt .
Efficac y E v al ua ble
(scale-de pe n de nt)
Part A: All partici pa nts wit h a t least 1 c o m plete pair of assess me nts f or t he 
c o nsi dere d scale.
Part B: All partici pa nts wit h a n y Part B efficac y assess me nt.
Part C: All partici pa nts wit h a n y Part C efficac y assess me nt.
Safet y
All partici pa nts w h o recei ve at least 1 d ose of I P d uri n g Part B .
P har mac o ki netic A nal ysis
All e nr olle d partici pa nts w h o recei ve d at least 1 d ose of I P d uri n g Part B a n d 
ha ve at least 1 e val ua ble P K sa m ple.
A b bre viati o ns: I P = i n vesti gati o nal pr o d uct; P K = p har mac o ki netics.
9. 4.
St atistic al A n al yses
9. 4. 1.
Ge ner al C o nsi der ati o ns
Stati stical a nal ysis of  t his st u d y will  be t he res p o nsi bilit y of  t he sp o ns or or i ts desig nee.
U nless ot her wise n ote d, stat istical tests will be c o n d ucte d at a 2-si de d al p ha le vel of  0. 0 5 a n d 
9 5 % c o nfi de nce i nter v als will be dis pla ye d as 2-si ded.
N o a dj ust me nt s for m ul tipl e c o m paris o ns are pla n ne d . 
All a nal yses i n v o l vi n g calc ulati on of I C Cs will be li mi te d t o t he Efficac y E val ua ble p o p ulati on, 
re q uirin g partici pa nts t o c o ntri b ute c o m plete pairs of o n -site a n d re mo te cli nical assess me nts t o 
be i ncl u de d. T he I C C will be calc ulate d as 2 -wa y  mi xe d-effect mo d el  lo o ki n g f or a bs ol ute 
a gree me nt acr oss mul tiple raters, wit h raters defi ne d as o n -site assess me nt a n d V T C assess me nt. 
See Secti o n 9. 4. 2 bel o w a n d t he S A P f or f urt her s pecificat i on of t he a nal ysis.
If either A D A S -C o g 1 3 or A D C S -i A D L is missi n g, i A D R S sc ore will be c o nsi dere d missi n g.
Baseli ne defi nit i ons are de pe n de nt o n t he q ua ntit y bei n g assesse d. F or T E safety a nal yses, o nl y 
parti ci pa nt s w h o ha ve b ot h a baseli ne o bser vat i on a n d a p ost baseli ne o bser vat i on will  be 
i ncl u de d i n t he a nal ysis f or eac h a nal yte or para meter, res pecti vel y. T he S A P wi ll defi ne 
baseli nes w here nee de d.
A data base l oc k is e x pecte d t o occ ur aft er all ra n d o mize d parti ci pa nt s ha ve c o mplete d 
parti ci pat i on i n Part A of t he st u d y. A nal yses relate d t o t he vali dat i on of re m ote assess me nts 
c o mpare d t o o n -site assess me nts will be co n d ucte d . As n o I P is a d mi nistere d d uri n g Part A, 
safety a nal yses will be li mite d.
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt 
o nl y  if it c ha n ges a pri nci ple feat ure of t he pr ot oc ol. A n y ot her c ha n ge ma de t o t he data a nal ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ust ificati o n f or ma ki n g t he c ha n ge, will be descri be d 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
6 7
i n t he S A P a n d t he cli nical st u d y re p ort. A d diti onal e x plor at or y  a nal yses of  t he data will be 
c o n d ucte d as dee me d a p pr o priate.
T he S A P wi ll be fi nalize d pri or t o first parti ci pa nt visit a n d will i ncl u de a m ore tec h nical a n d 
detaile d descri pt i on of t he statistical a nal yses descri be d i n t hese sect i ons.
H a n dli n g of missi n g ite ms f or sc ales
Beca use t he I C C c o mp utati o n re q uires eac h it e m i n its calc ulati on, n o i m p utati o n will occ ur i n 
I C C a nal yses. If a n y of t he i n di vi d ual ite ms f or a n y scale are missi n g or u n k n o w n, t he t otal sc ore 
f or t hat scale for t hat vi sit will be c o nsi dere d missi n g.
W het her virt ual a d mi nistrati o n of  t he cli nical assess me nts will res ult i n m ore missi n g ite m sc ores 
r elat i ve t o t he o n-site assess me nt is als o of i nterest. T o a d dress t his q uest i on, t he n u m ber of 
missi n g i t e ms acr oss t he a d mi nistrati o n of eac h of t he cli nical scales will s u m marize d b y 
m o dali t y.
F or t he M M R M o bject i ve i n P art A a n d all a nal yses i n Part B relate d t o A D A S -C o g 1 3 a n d 
A D C S -A D L, if a li mite d n u m ber of i n di vi d ual test ite ms are missi n g, i m p utati o n usi n g pr orati n g 
will be i m ple me nte d t o o btai n a t otal sc ore . Details of t his pr orat i n g a n d t he circ u msta nces i n 
w hic h it will be use d are i ncl u de d i n t he S A P .
W het her virt ual a d mi nistrati o n o f t he cli nical assess me nts will res ult i n m ore missi n g ite m sc ores 
r elat i ve t o t he o n-site assess me nt is als o of i nterest. T o a d dress t his q uest i on , t he n u m ber of 
missi n g i t e ms acr oss t he a d mi nistrati o n of eac h of t he cli nical scales will s u m marize d b y 
m o dali t y.
9. 4. 2.
Pri m ar y E n d p oi nt (s)
P art A
T he pri mar y  o bjecti ve f or Part A of t his st u d y is t o e val uate t he relia bility of  V T C c o mpare d 
wi t h o n-site a d mi nistere d c o g niti ve a n d f u ncti o nal meas ures. T his will be assesse d b y est i mati n g 
t he I C C a n d t he ass ociate d 9 5 % c o nfi de nce i nter val f or t he first pair of o bser vati o ns fr o m 
parti ci pa nts a n d c o m pari n g t he l o wer b o u n d of t he c o nfi de nce i nter val t o 0. 7 0 , t he I C C c ut -off 
f or acce pta ble relia bility.
Usi n g t he g ui deli nes a n d n otati o n f or defi ni n g I C Cs p u blis he d b y Mc Gra w a n d W o n g ( 1 9 9 6), t he 
I C C of pri mar y int erest f or t his st u d y is a 2- wa y  mi xe d mo d el , i nteractio n a bse nt, wi t h si n gle 
meas ure me nts fr o m eac h mo dali t y o n p arti ci pa nts, l o o ki n g at a bs ol ute a gree me nt – I C C( A, 1). I n 
t he prese nt st u d y, t he ‘raters’ are t he 2 m o dalit ies b y w hic h t he cli nical scales are assesse d, 
o n -site a n d V T C. As we are i ntereste d i n c o m par i n g t hese s pecific m o dalities, mo dali t y is 
c o nsi dere d a fi xe d effect.
A n A N O V A m o del will be fit t o t he data wit h fi xe d effects of m o dalit y, ti me effect, a ge, y ears of 
e d ucati o n, a n d prese nce/a bse nce of a nt i-d e m e nt ia dr u gs . T o esti mate t he I C C a n d t he ass ociate d 
c o nfi de nce i nter val, t he a p pr o priate mea n s q uares fr o m t his m o del will be use d f or t hese 
esti mates. Refer t o t he S A P f or more details .

C O N FI D E N TI A L
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6 8
P art B
T he pri mar y  o bjecti ve f or Part B of t he st u d y is t o c haracterize t he safety a n d t olera bilit y of 
d o na ne ma b . F or Part B of t he st u d y , safety will be ass esse d b y s u m marizi n g s p o nta ne o usl y 
re p orte d A Es (i ncl u di n g i nf usi o n-relate d reactio ns), l a b orat or y a nal yt es, vit al sig ns a n d b o d y  
w ei g ht meas ure me nts, E C Gs, p h y sical a n d ne ur olo gi cal e xa mi nat i ons, M RI sca ns, a n d C -S S R S 
assess me nts.
9. 4. 3.
Sec o n d ar y E n d p oi nt (s)
T o assess t he effect of d o na ne ma b o n cli nical pr o gressi o n i n partici pa nts wit h s y m pt o matic A D, 
M M R M s will be fit t o t he Part B data u p t o Wee k 7 2 f or A D A S-C o g 1 3, A D C S-A D L, i A D R S, 
M M S E, a n d C D R -S B . T he m o d el s will i ncl u de ter ms f or visit, a ge, years of e d ucat i on, a n d 
prese nce/a bse nce of a nt i-d e m e nt ia dr u gs. Vi sit will be c o nsi dere d a cate g orical varia ble. 
O bser ve d case a nal yses will als o be c o n d ucte d f or eac h scale. A d dit i onall y , if particip a nt 
n u m bers are a de q uate, A D pr o gressi o n fr o m t hese m o dels ca n be c o m p are d t o a ntici pate d 
pr o gressi o n ha d t he patie nt re mai ne d u ntreate d. Details of s uc h a c o m paris o n are c o ntai ne d i n t he 
S A P.
C ha n ge fr o m baseli ne i n brai n a m yl o i d de p ositio n at Wee k 3 6 a n d Wee k 7 2 of Part B will be 
assesse d usi n g a n M M R M . T he m o d el  will in cl u de ter ms f or vi sit, a ge, years of e d ucati on, a n d 
prese nce/a bse nce of a nt i-d e m e nt ia dr u gs. Vi sit will be c o nsi dere d a cate g orical varia ble. A n 
o bser ve d case a nal ysis will als o be c o n d ucte d.
C ha n ge fr o m baseli ne i n brai n re gi o n v o l umes at Wee k 7 2 f or Part B will be assesse d usi n g a n 
A N C O V A m o del . T he m o d el  will incl u de ter m s for a ge, y ears of e d ucat i on, a n d 
prese nce/a bse nce of a nt i-d e m e nt ia dr u gs. A n o bser ve d case a nal ysis will als o be c o n d ucte d . T he 
brai n re gi o ns o f i nterest will be defi ne d i n t he S A P.
P K a nal yses will be defi ne d b y t he P K scie nt ist a n d will be s pecifie d i n t he P K a nal ysis pla n.
Cate g orical dis pla ys o f A D A s a gai nst d o na ne ma b a n d ne utralizi n g a nt i b o dies will be prese nte d.
9. 4. 4.
Terti ar y/ E x pl or at or y E n d p oi nt (s)
As a se nsit i vity a nal ysis f or t he pri m ar y e nd p oi nt of Part A, t o assess w het her t he V T C cli nical 
assess me nt i ncl u des a n y bias relat i ve t o t he o n-site cli nical assess me nt, a n I C C lo o ki n g at t he 
c o nsiste nc y of t he 2 meas ures will be calc ulate d – I C C( C, 1) per Mc Gra w a n d W o n g ( 1 9 9 6). B y 
defi nit i on, t he c o nsiste nc y I C C will be e q ual t o or lar ger t ha n t he I C C f or a bs ol ute a gree me nt . 
Lar ge differe nces bet wee n t he a bs o l ute a gree me nt a n d c o nsiste nc y I C Cs s u g gest a s hift ( u p war d 
or d o w n war d) i n t he V T C relati ve t o t he o n -site assess me nt. 
Usi n g t he sa me A N O V A m o del s pecifie d i n Secti o n 9. 4. 2 , t he I C Cs a n d 9 5 % c o nfi de nce 
i nter vals f or t he sec o n d pair a n d t hir d pair of o n -site a n d re mote cli nical asses s me nts will be 
esti mate d. C o m paris o ns bet wee n t he I C C s fr om t he first pair of assess me nts a n d t he sec o n d a n d 
t hir d p airs of assess me nts will be ma de t o meas ure c o nsiste nc y a cr oss meas ures. If fe wer t ha n 
5 0 p ai rs of cli nical assess me nts are c ollecte d f or P airs 2 or 3, o nl y descri pti ve statistics will be 
re p orte d. See t he S A P f or furt her details.
T o c o m pare disease pr o gressi o n as meas ure d b y V T C vers us o n -site, a n M M R M will be fit t o t he 
cli nical assess me nt meas ures . O bser vat i ons will be gr o u pe d b y  test mo d a lity ( V T C a n d o n-sit e). 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
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T he M M R M will i ncl u de ter ms f or m o dalit y,  visit, visit- b y-m o dali t y int eract i on, a ge, y ears of 
e d ucati o n, a n d prese nce/a bse nce of a nt i-d e m e nt ia dr u gs . Visit will be c o nsi dere d a cate g orical 
varia ble . T he n ull h y p ot hesis is t hat t he c o ntrast bet wee n t he V T C m o dalit y vers us t he o n -sit e 
m o dali t y at eac h visit e q uals 0. A n u nstr uct ure d c o varia nce matri x will be use d t o m o del t he 
wi t hi n-s u bject 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 f oll o wi n g tests will be use d i n se q ue nce:

heter o ge ne o us T oe plitz c o varia nce str uct ure

heter o ge ne o us a ut ore gressi ve c o varia nce str uct ure

heter o ge ne o us c o m p o u n d s y m metr y  c o varia nce str uct ure 

c o mp o u n d s y m metr y  c o varia nce str uct ure
T he Ke n wa r d-R o ger a p pr o xi mat i on will  be use d t o esti mate t he de n o mi nat or de grees of 
free d om.
C ha n ges i n t he bl o o d -base d bi o mar kers of Nf L, P- ta u, a n d A β d uri n g Part B will be s u m marize d 
wi t h o bser ve d case a nal yses. 
F or partici pa nt s i n Part C of t he st u d y, t he i nterest is w het her t he c ha n ges i n brai n a m yl oi d 
de p osi tio n, brai n ta u de p osi tio n, a n d cli nical pr o gressi o n of A D f or partici pa nt s w h o recei ve d 
d o na ne ma b i n t he ori gi nat i n g st u d y ar e mai ntai ne d after d o na ne ma b treat me nt is re m o ve d . F or 
eac h of t hese e n d p oi nts, c ha n ge fr o m t he last o bser vat i on of t he ori gi nat i n g st u d y will be fit 
usi n g a n A N C O V A m o del i ncl u di n g ter ms f or a ge, years of e d ucat i on, a n d prese nce/a bse nce of 
a nt i-de me nt ia dr u gs. O bser ve d case a nal yses will als o be prese nte d.
9. 4. 5.
Ot her S afet y A n al yse (s)
A d dit i onal safety s u m maries will be perf or me d if warra nte d u p o n re vie w of t he data.
9. 4. 6.
Ot her A n al yse (s)
9. 4. 6. 1.
E v al u ati o n of I m m u n o ge nicit y
T he fre q ue nc y a n d perce nta ge of s u bjects wit h pree xist i n g ( baseli ne) A D As, A D As at a n y ti me 
after baseli ne, a n d T E A D As t o d o na ne ma b will be ta b ulate d.  If n o A D As are detecte d at 
baseli ne, T E A D As are defi ne d as t h ose wit h a titer 2 -f ol d ( 1 dil uti on) greater t ha n t he mi ni mal 
re q uire d dil uti on of t he assa y.  F or sa m ples wit h A D As detecte d at baseli ne, T E A D As are
defi ne d as t h os e wi t h a 4-f ol d ( 2 dil uti ons) i ncrease i n titer c o m pare d t o baseli ne.  F or t he T E 
A D A s u bjects, t he distri b ut i on of ma xi m u m t iters will be descri be d.  T he fre q ue nc y of 
ne utralizi n g a nt i b o dies ma y als o be ta b ulate d.  T he relati ons hi p bet wee n t he prese nce of  
a nt i b o dies t o d o na ne ma b a n d P K, P D, safet y,  a n d/ or efficac y assess me nt ma y be assesse d.
Ot her a nal yses are descri be d i n t he S A P.
9. 5.
I nteri m A n al yses 
N o i nt eri m a nal yses are pla n ne d f or t his st u d y. All data i s u n bli n de d f or sp o ns or use o n a 
c o nti n ual basis.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 0
9. 6.
D at a M o nit ori n g C o m mittee ( D M C)
N ot a p plica ble . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 1
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns
1 0. 1.
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns
1 0. 1. 1.
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wi t h t he pr ot oc ol a n d wit h t he f oll owi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nat i onal Et hical G ui deli nes

A p plica ble I C H G C P G ui deli nes

A p plica ble la ws a n d re g ulati o ns
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) 
m ust be s u b mitte d t o a n I R B/I E C b y  t he i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he I R B/I E C
bef ore t he st u d y  is i nitiate d.
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val b efore i m ple me ntati o n of  
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate 
hazar d t o st u d y  p artici pa nts.
T he i n vest i gat or will be res p o nsi ble f or t he f oll owi n g:

Pr o vi di n g wri tte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or mor e 
fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C.

N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures.

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y  at t he site a n d a d here nce t o re q uire me nts 
of  2 1 C F R, I C H g uideli nes, t he I R B/I E C, E ur o pea n re g ulat i on 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulat i ons.
I n vesti gat or sites are c o mpe nsate d f or parti ci pat i on i n t he st u d y as detaile d i n t he C T A .
1 0. 1. 2.
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati on o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y  a n d f or 
1 year after c o m plet i on of t he st u d y.
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess
T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y, i ncl u di n g t he ris ks 
a n d be nefits, t o t he partici pa nt or his/ her l e gall y a ut h orize d re prese ntative a n d a ns wer all
q uesti o ns re gar di n g t he st u d y.
P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y. Participa nts or t hei r le gall y 
a ut h orize d re prese ntati ve will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 2
re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H g ui deli nes, HI P A A re q uire me nts, w here 
a p plica ble, a n d t he I R B/I E C or st u d y ce nter.
As use d i n t his pr ot oc ol, t he ter m “i nf or me d c o nse nt” i ncl u des all c o nse nt a n d asse nt gi ve n b y 
t he partici pa nt or t heir le gal re prese ntati ves a n d b y st u d y  part ners.
T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nter e d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.
P arti cip a nt s m ust be re-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t h eir 
parti ci pat i on i n t he st u d y.
A c o p y  of t he I C F(s) must be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y a ut h orize d 
re prese ntative a n d is ke pt o n file. 
P arti cipa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
1 0. 1. 4.
D at a Pr otecti o n
P arti cipa nts will be assi g ne d a u ni q ue i de nt ifier b y t he s p o ns or. A n y partici pa nt rec or ds, datasets
or ti ss ue sa m ples t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; p artici pa nt 
na mes or a n y  inf or m at i on w hic h w o ul d ma ke t he partici pa nt i de nt ifia ble will n ot be tra nsferre d.
T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-r elate d data will be use d b y t he 
s p o ns or i n acc or da nce with l ocal data pr otectio n la w. T he le vel o f di s clos ure m ust als o b e 
e x plai ne d t o t he partici pa nt w h o will be re q uire d t o gi ve c o nse nt f or t heir data t o be use d as 
descri be d i n t he i nf or me d c o nse nt .
T he parti ci pa nt m ust be i nf or me d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y Cli nical
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p o i nte d b y t he s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y  a ut h orities.
T he sp o ns or has pr ocesses i n place t o e ns ure data pr otecti o n, i nf or mat i on sec urit y, a n d data 
i nte grit y. T hese pr ocesses i ncl u de a p pr o priate c o nti n ge nc y pla n(s) f or a p pr o priate a n d ti mel y 
res p o nse i n t he e ve nt of a data sec urity breac h.
1 0. 1. 5.
Disse mi n ati o n of Cli nic al St u d y D at a
Re p orts 
T he s p o ns or will discl ose a s u m mar y o f st u d y inf o r mat i on, i ncl u di n g ta b ular st u d y res ults, o n 
p u blicl y  a vaila ble we bsites w here re q uire d b y lo c al  la w or re g ulat i on.    
D at a  
T he s p o ns or pr o vi des access t o all i n di vi d ual part ici pa nt data c ollecte d d uri n g the trial a n d after 
a n o n y mizat i on, wi t h t he e xce ptio n of  P K or ge netic data. Data are a vaila ble f or re q uest 6 m o nt hs 
after t he i n dicati on st u die d has bee n a p pr o ve d i n t he U S a n d E U, a n d after pri mar y p u blicat i on 
acce pta nce, w hic he ver is later . N o e x pirat i on date of data re q uests is c urre nt l y set o nce data are 
ma de a vaila ble.    
Access i s pr o vid e d af ter a pr o p osal has bee n a p pr o ve d b y a n i n de pe n de nt re vie w c o m mittee 
i de ntifie d f or t his p ur p ose a n d after recei pt of a si g ne d data s hari n g a gree me nt. Data a n d 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 3
d o c u me nts, i ncl u di n g t he st u d y  pr ot oc ol, S A P, cli nical st u d y re p ort, a n d bla n k or a n n otate d 
C R Fs, will be pr o vi de d i n a sec ure data -s hari n g e n vir o n me nt f or u p t o 2 years per pr o p osal.    
F or details o n s u b mitti n g a re q uest, see t he i nstr ucti o ns pr o vi de d at 
w w w.cli nicalst u d y datare q uest.c o m .
1 0. 1. 6.
D at a Q u alit y Ass ur a nce
All partici pa nt data relat i n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T he i n vesti gat or is 
res po nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y  p h ysicall y or electr o nicall y 
sig ni n g t he C R F.
T he i n vest i gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he C R F.
T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
a ge nc y ins pect i ons a n d pr o vi de direct a ccess t o s o urce data d oc u me nts.
M o ni t ori n g details descri bi n g strate g y ( e.g. , ris k-base d i nit iati ves i n o perati o ns a n d q uality s uc h 
as Ris k Ma na ge me nt a n d Mitigat i on Strate gies a n d A nal yt ical Ris k -Base d M o nit ori n g), met h o ds, 
res p o nsi bilities, a n d re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m p lia nce iss ues a n d m o nit ori n g 
tec h ni q ues are pr o vi de d i n t he M o ni t ori n g Pla n.
T he s p o ns or or desi g nee is res p o nsi b le f or t he data ma na ge me nt of t his st u d y incl u di n g q ualit y 
c hec ki n g o f t he data.
T he s p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals (e . g., co ntract 
researc h o r ga nizati ons).
St u d y  mo ni t ors will perf or m o n g oi n g s o urce data verificatio n t o c o nfir m  t hat data e ntere d i nt o 
t he C R F b y a ut h orize d site pers o n nel are acc urate, c o mplete, a n d verifia ble fr o m s o urce 
d oc u m e nts; t hat t he safet y a n d rig hts of  partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y  is 
bei n g c o n d ucte d i n acc or da nce wi t h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, I C H G C P, a n d all a p plica ble re g u lator y  re q uire me nts.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y  must be 
retai ne d b y t he i n vesti gat or f or t he ti me p eri o d o utli ne d i n t he C T A u nless l ocal re g ulat i ons or 
i nstituti o nal  p olicies re q uir e a lo n ger rete nti o n peri o d. N o rec or ds ma y be destr o y e d d uri n g t he 
rete ntio n peri o d wi t ho ut t he wri tte n a p pr o val of t he s p o ns or. N o rec or ds ma y be tra nsferre d t o 
a n ot her lo c ati o n or part y  wit ho ut wri tte n n otificati o n t o t he s p o ns or.
I n a d diti on, sp o ns or or i ts re prese ntati ves will peri o dicall y c hec k a sa m ple of t he parti ci pa nt data 
rec or de d a gai nst s o urce d oc u me nts at t he st u d y sit e. T he st u d y  ma y be a u dite d b y sp o ns or or i ts 
re prese ntati ves, a n d/ or re g ulat or y a ge ncies at a n y ti me. I n vesti gat ors will be gi ve n n otice bef ore 
a n a u dit occ urs.
D at a C a pt ure S yste m
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bility,  a n d ti meli ness 
of  t he data re p orte d t o t he s p o ns or. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 4
A n E D C s yste m will be use d i n t his st u d y  for t he c ollect i on of C R F data . T he i n vesti gat or 
mai ntai ns a se parate s o urce f or t he data e ntere d b y t he i n vesti gat or or desi g nee i nt o t he 
s p o ns or-pr o vi de d E D C s yste m . T he i n vest i gat or is res p o nsi ble f or t he i de ntificati on of a n y  d at a 
t o be c o nsi dere d s o urce a n d f or t he c o nfir mat i on t hat data re p orte d are acc urate a n d c o m plete b y  
si gni n g t he C R F .
A d dit i onall y , C O A data ( partici pa nt -f oc use d o utc o me i nstr u me nt) will be c o llecte d b y t he 
parti ci pa nt a n d/ or i n vesti gat or site pers o n nel via a pa per s o urce d oc u me nt a n d will be tra nscri be d 
b y t he i n vesti gat or site pers o n nel i nt o t he E D C s yst e m.
A d dit i onall y , e C O A data ( partici pa nt -f oc use d o utc o me i nstr u me nt) will be direct l y rec or de d b y 
t he i n vesti gat or site pers o n nel i nto a n i nstr u m e nt ( f or e xa m ple, ta blet). T he e C O A data will ser ve 
as t he s o urce d oc u me ntati o n a n d t he i n vest i gat or will n ot mai ntai n a se parate, writte n or 
ele ctr o nic, rec or d of t hese data . 
Data c ollecte d via t he s p o ns or- pr o vi de d data ca pt ure s yste m will be st ore d at a t hird- part y . T he 
i n vesti gat or will ha ve c o nti n u o us access t o t he data d uri n g t he st u d y a n d u ntil dec om missi o ni n g 
of  t he data ca pt ure s yst e m. Pri or t o dec o m missi o ni n g, t he i n vest i gat or will recei ve a n arc hi val 
c o p y of perti ne nt data f or rete nti o n.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data, will be st ore d electr o nicall y in 
t he ce ntral ve n d or’s data base s yste m a n d re p orts will be pr o vi de d t o t he i n vesti gat or f or re vie w 
a n d rete nti o n. Data will s u bse q ue nt l y be tra nsferre d fr o m t he ce ntral ve n d or t o t he s p o ns or data 
ware h o use.
Data fr o m c o m p lai nt f or ms s u b mitte d t o t he s p o ns or will be e nc o de d a n d st ore d i n t he gl o bal 
pr o d uct c o m plai nt ma na ge me nt s y st e m.
1 0. 1. 7.
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or d s, de pe n di n g o n t he 
st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
1 0. 1. 8.
St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uitme nt  of 
parti ci pa nts.
T he first act of recr uit me nt is t he first site o pe n a n d will be t he st u d y start date.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n at t he s ole discret i on of t he s p o ns or. St u d y  sites will b e close d u p o n st u d y  
c o mplet i on. A st u d y site is c o nsi dere d close d w he n all re q uire d d oc u me nts a n d st u d y  s u p plies 
ha ve bee n c o llecte d a n d a st u d y-sit e clos ure visi t has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y-sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble ca use 
a n d s ufficie nt n oti ce is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 5
Reas o ns f or t he earl y cl os ure of a st u d y  site b y t he s p o ns or or i n vesti gat or ma y incl u de b ut are 
n ot li mite d t o:

Fail ure of t he i n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uitme nt  of p artici pa nts b y t he i n vestigat or

Di sc o nti n uatio n of  furt her I P de vel o p me nt
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
in vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y  a ut h orities, a n d a n y c o ntract researc h or ga nizati on(s) 
use d i n t he st u d y  of t he reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y r e q uire me nts. T he in vesti gat or s hall pr o m pt l y i nf or m t he parti ci pa nt a n d ass ure s
a p pr o priate partici pa nt t hera p y a n d/ or f ollo w - u p.
1 0. 1. 9.
P u blic ati o n P olic y
I n acc or da nce wit h t he s p o ns or’s p u blicati o n p olic y, t he res ults of t his st u d y will be s u b mitte d 
f or p u blicati on b y a peer -re vie we d j o ur nal.
1 0. 1. 1 0.
I n vesti g at or I nf or m ati o n
P h ysicia ns wit h a s pecialty i n ne ur o l og y , geriatrics, or ps yc hiatr y will  p artici pate as i n vest i gat ors 
i n t his cli nical trial. I n a d diti on, lice nse d cli nicia ns w h o ha ve clearl y d oc u me nte d e x peri e nce i n 
A D ma y part ici pate as i n vesti gat ors i n t his cli nical st u d y.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 6
1 0. 2.
A p pe n di x 2: Cli nic al L a b or at or y Tests

T he tests detaile d i n t he ta ble bel o w will be perf or me d b y t he ce ntral la b orat or y  ( u nless 
s pecifie d ot her wise bel o w).

Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e xcl usi o n of partici p a nts are detaile d i n 
Secti o n 5 of  t he pr ot oc ol.

A d dit i onal tests ma y be perf or me d at a n y  time d uri n g t he st u d y  as deter mi ne d necessar y 
b y t he i n vesti gat or or as re q uire d b y l ocal re g ulati ons.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.
La b orat or y  a nal yte res ults de n ote d belo w t hat c o uld u n bli n d t he st u d y  will not be re p orte d t o 
i n vesti gati ve sites or ot her bli n de d pers o n nel.
Cli nic al L a b or at or y Tests
C o m me nts  
He m at ol o g y
Assa y e d b y Lill y-desi g nate d la b orat or y
He m o gl o bi n
He mat ocrit
Er y t hr oc yte c o u nt ( R B Cs)
Mea n cell v ol u me 
Mea n cell he m o gl o bi n
Mea n cell he m o gl o bi n c o nce ntrati o n 
Le u k oc ytes ( W B Cs) 
Differe ntial
   Ne utr o p hils, se g me nte d
   L y m p h oc y tes
   M o n oc ytes
   E osi n o p hils
   Bas o p hils
Platelets
Cell m or p h ol o g y ( R B C a n d W B C)
Cli nic al C he mistr y
Assa y e d b y Lill y-desi g nate d la b orat or y
S o di u m
P otassi u m
C hl ori de
Bicar b o nate
T otal bilir u bi n
Direct bilir u bi n
A L P
A L T
A S T
G G T
B U N
Creati ni ne 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 7
Cli nic al L a b or at or y Tests
C o m me nts  
C K
Ur ic aci d
Al b u mi n
Calci u m
Gl uc ose
C h olester ol 
P K S a m ples – D o na ne ma b C o n ce ntrati o n
Assa y e d b y Lill y-desi g nate d la b orat or y . Res ults will n ot 
be pr o vi de d t o t he i n vesti gati ve sites.
Bi o m ar kers
Assa y e d b y Lill y-desi g nate d la b orat or y . Res ults will n ot 
be pr o vi de d t o t he i n vesti gati ve sites.
Nf L
P-t a u
A 
St ore d S a m ples
Assa y e d b y Lill y-desi g nate d la b orat or y . Res ults will n ot 
be pr o vi de d t o t he i n vesti gati ve sites.
E x pl o rat or y st ora ge sa m ples: 
Ser u m
Plas ma ( E D T A)
Pa x ge ne R N A t u be
I m m u n o ge nicit y S a m ples
Assa y e d b y Lill y-desi g nate d la b orat or y . Res ults will n ot 
be pr o vi de d t o t he i n vesti gati ve sites.
   A n ti-d o na ne ma b a nti b o dies 
   A n ti-d o na ne ma b a nti b o dies ne utralizati o n
H y perse nsiti vit y Tests
Selecte d test s m a y  be o btai ne d i n t he e ve nt of 
a na p h yla xis or  s yste mic aller gic/ h y perse nsiti vit y 
reacti o ns. T hese s h o ul d be c ollecte d as s o o n after t he 
e ve nt as p ossi ble. Assa ye d b y Lill y -desi g nate d 
la b orat or y. Res ults will n ot be pr o vi de d t o t he 
i n vesti gati ve sites.
A nti -d o na ne ma b a nti b o dies (I m m u n o ge nicit y)
D o na ne ma b co nce ntrati o ns ( P K)
Tr y ptase
D o n ot c ollect i f > 1 2 h o urs ha ve passe d si nce t he 
h y perse nsiti vit y e ve nt.
N M H
O btai n o nl y if tr y ptase sa m ple was c ollecte d > 2 h o urs 
after t he h y perse nsiti vit y e ve nt . O btai n a f oll o w - u p 
sa m ple at t he ne xt sc he d ule d visit or after 4 wee ks, 
w h ic he ver is later.
Dr u g -specific I g E
Will be perf or me d if a vali date d assa y is a vaila ble.
Bas o p hil Acti vati o n Test
Will be perf or me d if a vali date d assa y is a vaila ble.
C o m ple me nt ( C 3, C 3 a, a n d C5a)
C yt o ki ne Pa nel

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 8
A b bre viati o ns : A = a m yl oi d beta; A L P = al kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate 
a mi n otra nsferase; B U N = bl o o d urea nitr o ge n; C K = creati ne ki nase; E D T A = Et h yle ne dia mi netetraacetic aci d ;
G G T = ga m ma -gl uta m yl tra nsferase; I g E = i m m u n o gl o b uli n E ; Nf L = ne ur ofila me nt li g ht c hai n; 
N M H = N met h y l hista mi ne; R B C = re d bl o o d cell; P K = p har mac o ki netics; P -ta u = p h os p h or ylate d ta u; 
R N A = ri b o n ucleic aci d; W B C = white b l o o d cell .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
7 9
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w - Up, a n d Re p orti n g
1 0. 3. 1.
Defi niti o n of A E
A E Defi niti o n

A n A E i s a n y u nt o war d me dical occ urre nce i n a parti ci pa nt or cli nical st u d y  
parti ci pa nt, te mp orall y ass oci ate d wit h t he use of I P, w het her or n ot c o nsi dere d relate d 
t o t he I P.

N O T E: 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), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y 
ass ociat e d wit h t he use of I P. 
E ve nts Meeti n g
t he A E Defi niti o n

A n y a b n or mal la b orat or y  test res ults ( he mat olo g y , cli nical c he mistr y, or urinal ysis) or 
ot her safet y assess me nts (e . g., E C G, ra di ol ogical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr om baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he 
me dical a n d scie nt ific ju d g me nt of t he i n vesti gat or (i .e. , n ot relate d t o pr o gressi o n of 
u n derl yi n g disease).

E xacer bat i on of a c hr o nic or i nter mitte nt pree xisti n g c o n dit i on i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsity of  t he c o n ditio n .

Ne w c o n dit i ons detecte d or di a g n ose d after I P a d mi nistrati o n e ve n t h o u g h it ma y ha ve 
bee n prese nt bef ore t he start of t he st u d y .

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her I P or a 
c o nc o mita nt me dicat i on. O ver d ose per se will n ot be re p orte d as a n A E/ S A E u nless it 
is a n i nte nti onal o ver d ose ta ke n wit h p ossi ble s uici dal/self- har mi n g i nte nt. S uc h 
o ver d ose s h o ul d be re p orte d re gar dless of se q uelae . 

“Lac k of efficac y ” or “fail ure of e x pecte d p har mac ol o gical acti on” per se will n ot be 
re p orte d as a n A E or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts. 
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ult i n g fr om lac k of efficac y 
will be re p orte d as A E or S A E if t he y f ulfil l t he defi nit i on of a n A E or S A E .
E ve nts N O T Meeti n g t he A E D efi niti o n

A n y cli nicall y  sig nifica nt a b n or mal la b orat or y  fi n di n gs or ot her a b n or mal safety 
assess me nts, w hic h are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti on.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o m s of t he 
di sease/ dis or der bein g st u die d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n ditio n.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 0

Me dical or s ur gical pr oce d ure (e . g., e n d osc o p y, a p pe n dect o m y): t he c o n diti on t hat 
lea ds t o t he pr oce d ure is t he A E.

Si t u atio ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A nt ici pate d da y-t o-da y fl uct uati o ns of pree xisti n g disease(s) or c o n ditio n(s) prese nt or 
detecte d at t he start of t he st u d y  t hat d o n ot w orse n. 
1 0. 3. 2.
Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi nit i on a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us c o n dit i ons 
are met (e. g., h os pitalizati on f or sig ns/s y m pt o ms of t he disease u n der st u d y , deat h d ue t o 
pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose :
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m  'life-t hreate ni n g' i n t he defi niti on of 'seri o us' refers t o a n e ve nt i n w hic h t he 
parti ci pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heti call y mi g ht ha ve ca use d deat h, if it were m ore se vere.
c.
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n

I n ge neral, h os pitalizati on si g nifies t hat t he partici pa nt has bee n a d mitte d t o h os pi t al
f or o bser vati on a n d/ or treat me nt t hat w o ul d n ot h a ve bee n a p pr o priate i n t he 
p h ysicia n’s office or o ut patie nt setti n g. C o m plicat i o ns t hat occ ur d uri n g h os pitalizati o n 
are A Es. If a c o m plicat i on pr ol o n gs h os pi talizatio n or f ulfills a n y  ot her serio us cri t eria, 
t he e ve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o uld be c o nsi dere d seri o us.

H os pitalizati o n f or elect i ve treat me nt of a pree xisti n g c o n diti on t hat di d n ot w orse n 
fr om baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y

T he ter m disa bili t y mea ns a s u bsta nt ial disr u pt i on of a pers o n’s a bilit y t o c o n d uct 
n or m al lif e fu nct i ons.

T his defi nit i on is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
sig nifica nce s uc h as u nc o m p licate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, 
a n d acci de ntal tra u ma (e . g., s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt 
e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pt i on .
e.
Is a c o n ge nit al a n o m al y/ birt h defect

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 1
f.
Ot her sit u ati o ns:

Me dical or scie nt ific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g 
is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
parti ci pa nt or ma y re q uir e me dical or s ur gical i nter ve nt i on t o pre ve nt o ne of t he ot her 
o utc o m es liste d i n t he a b o ve defi nit i on. T hese e ve nts s h o ul d us uall y be c o nsi dere d 
serio us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n 
a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizat i on, or de vel o p me nt of dr u g de pe n de nc y or 
dr u g a b use . 
1 0. 3. 3.
Rec or di n g a n d F oll o w - Up of A E a n d/ or S A E
A E a n d S A E Rec or di n g

W he n a n A E/ S A E occ urs, it is t he res p o nsi bility of t he i n vesti gat or t o re vie w all 
d oc u m e nt atio n (e . g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics 
re p orts) relate d t o t he e ve nt.

T he i n vest i gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati on i n t he C R F.

It is n ot acce pta ble f or t he i n vest i gat or t o se n d p h ot oc o pies of t he partici pa nt’s me dical 
rec or ds t o sp o ns or or desi g nee i n lie u of c om p leti o n of t he A E/ S A E C R F pa ge.

T here m a y be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d 
b y sp o ns or or desi g nee . I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti on of t he 
parti ci pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore 
s u b missi on t o sp o ns or or desi g nee .

T he i n vest i gat or will atte m pt t o esta blis h a dia g n osis of  t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati on. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
Assess me nt of I nte nsit y
T he i n vest i gat or will ma ke a n assess me nt of i nte nsit y for eac h A E a n d S A E re p orte d d uri n g 
t he st u d y a n d assi g n it t o 1 of t he f oll owi n g cate g ori es:

Mil d: A n e ve nt t hat is easil y t olerate d b y t he partici pa nt, ca usi n g mi ni mal disc o mf o rt 
a n d n ot i nterferi n g wit h e ver y da y act i vities.

M o derate: A n e ve nt
t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or m al 
e ver y da y act i vities.

Se vere: A n e ve nt t hat pre ve nts n or mal e ver y da y acti vi ties. A n A E t hat is assesse d as 
se vere s h o ul d n ot be c o nf use d wit h an S A E. Se vere is a cate g or y  utilize d f or rati n g t he 
i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.
A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi nit i on o f a n S A E, N O T w he n it is rate d as se vere . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 2
Assess me nt of C a us alit y

T he i n vest i gat or is o bli gate d t o assess t he relati o ns hi p bet wee n I P a n d eac h occ urre nce 
of  eac h A E/ S A E.

A “reas o na ble p ossi bility” of  a r elat i ons hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca usal relat i ons hi p, rat he r t ha n a relati ons hi p ca n n ot be 
r ule d o ut.

T he i n vest i gat or will use cli nical j u d g me nt t o deter mi ne t he relati ons hi p.

Alt er nat i ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o I P a d mi nistrati o n will be 
c o nsi dere d a n d i n vest i gate d.

T he i n vest i gat or will als o c o ns ult t he I B a n d/ or Pr o d uct I nf or mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.

F or eac h A E/ S A E, t he i n vest i gat or m ust
d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usality.

T here m a y be sit u atio ns i n w hic h a n S A E has occ urre d a n d t he i n vest i gat or has 
mi ni mal i nf or mat i on t o i ncl u de i n t he i nit ial re p ort t o sp o ns or or desi g nee . H o we ver, it 
is ver y  i m p orta nt t hat t he i n vesti gat or al wa ys ma ke a n assess me nt of ca usality f or 
e ver y e ve nt bef ore t he i nit ial tra ns missi on of t he S A E data t o sp o ns or or desi g nee .

T he i n vest i gat or ma y c ha n ge his/ her o pi ni on of ca usalit y i n li g ht of  fol l ow- u p 
i nf or mat i on a n d se n d a n S A E f oll o w -u p re p ort wi t h t he u p date d ca usality assess me nt.

T he ca usalit y assess me nt is o ne of t he crit eria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts. 
F oll o w - Up of A Es a n d S A Es

T he i n vest i gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uat i ons as me dicall y i n dicate d or as re q ueste d b y sp o ns or or 
desi g nee t o eluci date t he nat ure a n d/ or ca usalit y of  t he A E or S A E as f ull y as p ossi ble. 
T his m a y i ncl u de a d dit i on al  la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical 
e xa mi nat i ons, or c o ns ultati o n wit h ot her healt hcare pr ofessi o nals.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll ow- u p 
p eri o d, t he i n ve sti gat or will pr o vi de sp o ns or or desi g nee wi t h a c o p y of a n y 
p ost m ort e m  fi n din gs i ncl u di n g hist o pat h ol o g y .

Ne w or u p date d i nf or mat i on will be rec or de d i n t he ori gi nall y c o m p lete d C R F.

T he i n vest i gat or will s u b mit a n y u p date d S A E data t o sp o ns or or desi g nee wi t hi n 
2 4 h o urs of recei pt of t he i nf or mati o n . 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 3
1 0. 3. 4.
Re p orti n g of S A Es
S A E Re p orti n g vi a a n Electr o nic D at a C ollecti o n T o ol

T he pri mar y  mec ha nis m for re p orti n g a n S A E will be t he electr o nic data c ollect i on 
t o ol.

If t he electr o nic s yste m is u na vaila ble, t he n t he site will use t he pa per S A E data 
c ollect i on t o ol  (see ne xt sectio n) i n or der t o re p ort t he e ve nt wit hi n 2 4 h o urs.

T he site will e nter t he S A E data i nt o t he electr o nic s y st e m as s o o n as it bec o mes 
a vaila ble.

After t he st u d y  is c o mplete d at a gi ve n site, t he electr o nic data c ollect i on t o ol  will be 
ta ke n off-li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xist i n g data.

If a site recei ves a re p ort of a ne w S A E fr om a st u d y partici pa nt or recei ves u p date d 
da ta o n a pre vio usl y  re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n 
ta ke n off-li ne, t he n t he site ca n re p ort t his i nf or mati on o n a pa per S A E f or m (see ne xt 
secti on) or t o t he me d ical m o nit or b y tele p h o ne.

C o ntacts f or S A E re p orti n g ca n be f o u n d i n e C R F. 
S A E Re p orti n g vi a P a per C R F

Facsi mile tra ns missi o n of t he S A E pa per C R F is t he preferre d met h o d t o tra ns mit t his 
i nf or mat i on t o t he me dical m o nit or .

I nitial notificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vest i gat or t o 
c o mplete a n d si g n t he S A E C R F pa ges wit hi n t he desi g nate d re p orti n g ti me fra mes.

C o ntacts f or S A E re p orti n g ca n be f o u n d i n e C R F. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 4
1 0. 4.
A p pe n di x 4 : Li ver S afet y: S u g geste d Acti o ns a n d F oll o w-U p 
Assess me nts
He p atic E v al u ati o n Testi n g
T he Lill y -desi g nate d ce ntral la b orat or y m ust c o m plete t he a nal ysis of all selecte d testi n g e xce pt 
f or micr o biol o g y  testi n g.
L ocal  testi n g ma y be perf or me d i n a d diti on t o ce ntral testi n g w he n necessar y f or i m me diate 
parti ci pa nt ma na ge me nt.
Res ults will be re p orte d if a vali date d test or calc ulati o n is a vaila ble.
He m at ol o g y
Cli nic al C he mistr y
He m o gl o bi n
T otal bilir u bi n
He mat ocrit
Direct bilir u bi n
Er y t hr oc ytes ( R B Cs - re d bl o o d cells)
Al kali ne p h os p hatase ( A L P)
Le u k oc ytes ( W B Cs - w h ite bl o o d cells)
Ala ni ne a mi n otra nsferase ( A L T)
Differe ntial:
As partate a mi n otra nsferase ( A S T)
    Ne utr o p hils, se g me nte d
Ga m ma -gl uta m yl tra nsferase ( G G T)
    L y m p h oc ytes
Creati ne ki nase ( C K)
    M o n oc yt es
Ot her C he mistr y
    Bas o p hils
Aceta mi n o p he n
    E osi n o p hils
Aceta mi n o p he n pr otei n a d d ucts
Platelets
Al kali ne p h os p hatase is oe nz y mes
Cell m or p h ol o g y ( R B C a n d W B C)
Cer ul o plas mi n
C o a g ul ati o n
C o p per
Et h y l alc o h ol ( Et O H)
Pr ot hr o m bi n ti me, I N R ( P T -I N R)
Ha pt o gl o bi n
Ser ol o g y
I m m u n o gl o b uli n A ( I g A) ( q ua ntitati ve)
He patitis A vir us ( H A V) testi n g:
I m m u n o gl o b uli n G ( I g G) ( q ua ntitati ve)
    H A V t otal a nti b o d y
I m m u n o gl o b uli n M ( I g M) ( q ua ntitati ve)
    H A V I g M a nti b o d y
P h os p hati d ylet ha n ol ( P Et h)
He pat itis B vir us ( H B V) testi n g:
Uri ne C he mistr y
    He patitis B s urface a nti ge n ( H Bs A g)
Dr u g scree n
    He patitis B s urface a nti b o d y (a nti -H Bs)
Et h y l gl uc ur o ni de ( Et G)
    He patitis B c ore t otal a nti b o d y (a nti -H Bc)
Ot her Ser ol o g y
    He patitis B c ore I g M a nti b o d y
A nti- n uclear a nti b o d y ( A N A)
    He patitis B c ore I g G a nti b o d y
A nti- s m o ot h m uscle a nti b o d y ( A S M A) a
    H B V D N A b
A nti- acti n a nti b o d y c

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 5
He patitis C vir us ( H C V) testi n g:
E pstei n -Barr vir us ( E B V) testi n g:
    H C V a nti b o d y
    E B V a nti b o d y
    H C V R N A b
    E B V D N A b
He patitis D vir us ( H D V) testi n g:
C y t o me gal o vir us ( C M V) testi n g:
    H D V a nti b o d y
    C M V a nti b o d y
He patitis E vir us ( H E V) testi n g:
    C M V D N A b
    H E V I g G a nti b o d y
Her pes si m ple x vir us ( H S V) testi n g:
    H E V I g M a nti b o d y
    H S V ( T y pe 1 a n d 2) a nti b o d y 
    H E V R N A b
    H S V ( T y pe 1 a n d 2) D N A b
Micr o bi ol o g y
d
Li ver ki d ne y micr os o mal t y pe 1 ( L K M -1) a nti b o d y
C ult ure:
    Bl o o d
A b bre viati o ns: I N R = i nter nati o nal n or malize d rati o; R N A = ri b o n ucleic aci d.
a
N ot re q uire d if a nti -acti n a nti b o d y is teste d.
b
Refle x/c o nfir mati o n de pe n de nt o n re g ulat o r y re q uire me nts, testi n g a vaila bilit y, or b ot h.
c
N ot re q uire d if A S M A is teste d.
d
Assa y e d O N L Y b y i n vesti gat or -desi g nate d l ocal la b orat or y; n o ce ntral testi n g a vaila ble.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 6
1 0. 5.
A p pe n di x 5 : Fl or bet a pir F 1 8 A m yl oi d P E T I m a gi n g
Fl or beta pi r F 1 8 P E T sca ns will be perf or m e d as part of t he st u d y as i n dicate d i n t he S o A 
( Sectio n 1. 3 ).
Si te i n vesti gat ors, partici pa nt s, a n d st u d y part ners will n ot be i nf or me d of sca n res ults o btai ne d . 
A n y si g nifica nt fi n di n gs t hat ma y be of p ote ntial me dical c o ncer n will be pr o vi de d f or 
a p pr o priate f o ll ow- u p.
P E T Sc a n -S pecific I nf or m ati o n
P E T Sc a n Pr oce d ures
S pecific i ma gi n g ac q uisit i on pr ot oc ols desi g ne d t o e ns ure c o nsiste nc y a cr oss sites will be 
pr o vi de d i n a P E T I ma gi n g Ma n ual. 
P E T Sc a n S afet y
T he pri mar y  ris k relate d t o flor b et a pir F 1 8 P E T i s r a diat i on e x p os ure . Details o n t he a m o u nt of 
e x p os ure esti mate d t o occ ur o n eac h i ma gi n g occasi o n a n d c u m ulati vel y are prese nte d i n t he 
ta bles bel o w a n d will be pr o vi de d i n t he I C F. Details o n t he cli nical i nf or mati o n t o date 
re gar di n g fl or beta pir F 1 8 e x p os ure will be pr o vi de d i n t he I C F . M ore detaile d i nf or mat i on a b o ut 
t he k n o w n a n d e x pecte d be nefits a n d ris ks of fl or beta pir F 1 8 ca n be f o u n d i n t he U S Pac ka ge 
I nsert f or fl or beta pir F 1 8 I njecti on ( A m y vi d T M pac ka ge i nsert, 2 0 1 2).
P arti cipa nt s m ust mi ni mize m o ve me nt d uri n g eac h P E T pr oce d ure, w hic h ca n last 2 0 t o 
3 0 mi n utes f or eac h sca n . M ost state -of -t he-art i ma gi n g s yste ms are d esig ne d t o re d uce hea d 
m o tio n a n d partici pa nt disc o mf ort.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 7
P A R T B: T he ta ble bel o w s h o ws t he effecti ve ra diati o n d ose of t he St u d y A A C H’s P E T sca ns.
Effect i ve 
D ose 
( mS v) per 
Sca n *
N u m ber 
of  Sca ns 
i n First 
Year * *
Effect i ve 
D ose 
( mS v) f or 
Sca ns i n 
Fi rst Year
N u m ber 
of  Sca ns 
i n 
Sec o n d 
Year
Effect i ve 
D ose ( m S v ) 
f or Sca ns i n 
Sec o n d 
Year
S u m  of 
Effect i ve 
D ose ( m S v ) 
f or Years 1 
a n d 2
Fl or beta pi r F 
1 8 Sca n 
( 1 0 m C i I V)
7. 4 3
1
7. 4 3
0 
0
7. 4 3
T ot al s
1
7. 4 3
0 
0
7. 4 3
A b bre viati o ns: C T = c o m p ute d t o m o gra p h y; E D = earl y disc o nti n uati o n; I V = i ntra ve n o us; P E T = p ositr o n e missi o n 
t o m o gra p h y.
* D ose s h o w n i ncl u des ra diati o n e x p os ure fr o m t he ra di otracer a n d ass u mes a n o ncli nical C T sca n is o btai ne d 
(esti mate d at 0. 4 m S v) as part of t he P E T sca n atte n uati o n c orrecti o n process w he n t he sca n is d o ne o n a 
P E T/ C T sca n ner. A cli nical C T sca n is n ot nee de d d uri n g t he P E T sca n sessi o n a n d, beca use it will a d d 
a d diti o nal ra diati o n e x p os ure, it is n ot rec o m me n de d.
N ote : I n t he e ve nt a re peat sca n is re q uire d (f or e xa m ple., t he scan is n ot a nal yza ble), 1 a d diti onal fl or beta pir F 1 8 
sca n ma y be recei ve d. If a n E D visit is perf or me d, c ollect fl or beta pir F 1 8 P E T sca n o nl y if a fl or beta pir F 1 8
P E T sca n has n ot yet bee n perf or me d a n d partici pa nt has recei ve d at least 3 d oses of d o na ne m a b.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 8
P A R T C: T he ta ble bel o w s h o ws t he effect i ve ra diati on d ose of t he St u d y  A A C H’s P E T sca ns.
Effect i ve D ose 
( mS v) per Sca n *
N u m ber of Sca ns 
i n Part C
Effect i ve D ose 
( mS v) f or Part C
Fl ort a u ci pir F 1 8 Sca n 
( 1 0 m C i I V)
9. 1 0
1
9. 1 0
Fl or beta pi r F 1 8 Sca n 
( 1 0 m C i I V)
7. 4 3
1
7. 4 3
T ot al s
2
1 6. 5 3
A b bre viati o ns: C T = c o m p ute d t o m o gra p h y; I V = i ntra ve n o us; P E T = p ositr o n e missi o n t o m o gra p h y.
* D ose s h o w n i ncl u des ra diati o n e x p os ure fr o m t he ra di otracer a n d ass u mes a n o n -cli nical C T sca n is o btai ne d 
(esti mate d at 0. 4 m S v) as part of t he P E T sca n atte n uati o n c orrecti o n pr ocess w he n t he sca n is d o ne o n a 
P E T/ C T sca n ner. A cli nical C T sca n is n ot nee de d d uri n g t he P E T sca n sessi o n a n d, beca use it will a d d 
a d diti o nal ra diati o n e x p os ure, it is n ot rec o m me n de d.
N ote : I n t he e ve nt a re peat sca n is re q uire d (f or e xa m ple, t he sca n is n ot a nal yza ble), 1 a d diti o nal fl or beta pir F 1 8 
sca n ma y be recei ve d. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
8 9
1 0. 6.
A p pe n di x 6 : Fl ort a uci pir F 1 8 T a u P E T I m a gi n g 
Fl ort a u ci pir F 1 8 P E T sca ns will be perf or me d as part of t he st u d y  as i n dicate d i n t he S o A 
( Sectio n 1. 3 ).
Si te i n vesti gat ors, partici pa nt s, a n d st u d y part ners will not be i nf or me d of sca n res ults o btai ne d . 
A n y si g nifica nt fi n di n gs t hat ma y be of p ote ntial me dical c o ncer n will be pr o vi de d f or 
a p pr o priate f o ll ow- u p . 
P E T Sc a n -S pecific I nf or m ati o n
P E T Sc a n Pr oce d ures
S pecific i ma gi n g ac q uisit i on pr ot oc ols desi g ne d t o e ns ure c o nsiste nc y  acr oss sites will be 
pr o vi de d i n a P E T I ma gi n g Ma n ual. 
Sc a n S afet y
T he pri mar y  ris k relate d t o flort a u ci pi r F 1 8 P E T i s ra diat i on e x p os ure . Details o n t he a m o u nt of 
e x p os ure esti mate d t o occ ur o n eac h i ma gi n g occasi o n a n d c u m ulati vel y are s h o w n i n t he ta ble 
a b o ve (Secti o n 1 0. 5 ) a n d will be pr o vi de d i n t he I C F. Details o n t he cli nical i nf or mat i on t o date 
re gar di n g fl orta uci pir F 1 8 e x p os ure will be pr o vi de d i n t he I C F . M ore detaile d i nf or mat i on 
a b o ut t he k n o w n a n d e x pecte d be nefit s a n d ris ks of fl orta uci pir F 1 8 ca n be f o u n d i n t he I B.
P arti cipa nt s m ust mi ni mize m o ve me nt d uri n g eac h P E T pr oce d ure, w hic h ca n last 2 0 t o 
3 0 mi n utes f or eac h sca n . M ost state -of -t he- art i ma gi n g s yste ms are desi g ne d t o re d uce hea d 
m o tio n a n d partici pa nt disc o mf ort.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 0
1 0. 7.
A p pe n di x 7 : A b bre vi ati o ns
T er m
D efi niti o n
A β
a m yl oi d beta
A D
Alz hei mer’s disease
A D A
anti 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
A D C S -A D L
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
A D C S -i A D L
Alz hei mer’s Disease C o o perati ve St u d y – i nstr u me ntal Acti vities of Dail y Li vi n g
A E
a d verse e ve nt
A L P
a l 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 N O V A
anal y sis of varia nce
A RI A
a m y l oi d-relate d i ma gi n g a b n or mality
A S T
as partate a mi n otra nsferase
C DI S C
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
C D R -S B
Cli nical De me ntia Rati n g Scale – S u m of B o xes
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical
Scie nces
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all st u d y -relate d, g o o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts.
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C R F
case re p ort f or m
C K
creati n e ki nase
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
C T
c o m p ute d t o m o gra p h y
C T A
cli nical trial a gree me nt

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 1
D M C
data m o nit ori n g c o m mittee
E C G
electr ocar di o gra m
e C O A
electr o nic C li nical O utc o me A ssess me nt
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
e nr oll
T he act of assi g ni n g a partici pa nt t o a treat me nt. Partici pa nts w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt.
e nt er
Partici pa nts e n tere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or  t hr o u g h t heir le gall y acce pta ble re prese ntati ves.
E R B
Et hical Re vie w B oar d
F L AI R
fl ui d atte n uati on i n versi o n rec o ver y
G C P
g o o d cli nical practice
G G T
ga m ma gl uta m yl tra nsferase
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
i A D R S
i nte grate d Alz hei mer’s Disease Rati n g Scale
I B
I n vesti gat or’s Br oc h ure
I C C
intraclass c orrelati o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I nf or m e d c o n s e nt
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms his or her willi n g ness t o 
partici pate i n a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y 
t hat are rele va nt t o t he partici pa nt’s decisi o n t o partici pate . I nf or me d c o nse nt is 
d oc u me nte d b y mea ns of a writte n, si g ne d, a n d date d i nf or me d c o nse nt f or m .
I N R
i nter nati onal n o r malize d rati o
I P
i n vesti gati o nal pr o d uct; a p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g 
teste d or use d as a refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket 
w h e n use d or asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he 
a ut h orize d f or m, or mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d 
pr o d ucts use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
I R B
I nstit uti onal Re vie w B oar d
I V
i ntra ve n o us(l y)

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 2
I W R S
i nteracti ve we b-res p o nse s yste m
M CI
mil d c o g niti ve i m pair me nt
M M R M
mi xe d -effect m o del f or re peate d meas ure me nts
M M S E
Mi ni Me ntal State E xa mi nati o n
M RI
m a g netic res o na nce i ma gi n g 
Nf L
ne ur ofila me nt li g ht c hai n
NI M H
Nati o nal I nstit ute of Me ntal Healt h
P AI R
A c o m plete cr oss o ver c o m prisi n g a n at h o me assess me nt a n d a n o n -site assess me nt. 

Pair 1 c o m prises V isits 6 0 2 a n d 6 0 3

Pair 2 c o m prises V isits 6 0 4 a n d 6 0 5

Pair 3 c o m prises V isits 6 0 6 a n d 6 0 7
p arti ci p a nt
E q ui vale nt t o C DI S C ter m “s u bject”: a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol
P D
p har mac o d y na mics
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 netics
P R O/ e P R O
patie nt -re p orte d o utc o mes/electr o nic patie nt-re p orte d o utc o mes
Q 2 W
e ver y 2 wee ks
Q 4 W
e ver y 4 wee ks
Q T c
c orrecte d Q T i nter val
Q T c F
Fri dericia’s f or m ula
R N A
ri b o n ucleic aci d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
s cr e e n
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y. 
S o A
Sc he d ule of A cti vities
S U Vr
Sta n dar dize d u pta ke val ue rati o

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 3
T B L
t otal bilir u bi n le vel
T E
treat me nt-e mer ge nt
U L N
u p per li mit of n or mal
V T C
v i de o telec o nfere nce
W O C B P
w o me n of c hil d beari n g p ote ntial

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 4
1 0. 8.
A p pe n di x 8: Pr o visi o ns f or C h a n ges i n St u d y C o n d uct D u ri n g
E xce pti o n al Circ u mst a nces
E xce pt i onal circ u msta nces, s uc h as pa n de mics or nat ural  disasters, ma y ca use disr u pti o ns t o t he 
c o n d uct of t he st u d y. T hese disr u pti o ns ma y li mit t he a bilit y of  t he i n vesti gat ors, partici pa nts, or 
b ot h t o atte n d o n -site visits or t o c o n d uct pla n ne d st u d y pr oce d ures.
I n a n e xce pti onal circ u msta nce, after recei vi n g t he s p o ns or’s writte n a p pr o val, sites ma y  
i m ple me nt c ha n ges if per mitte d b y l ocal re g ulati ons. S uc h c ha n ges are i nte n de d t o mit i gate ris ks 
of  p artici pa nts missi n g visits, all o w parti ci pa nts t o c o nti n ue safel y i n t he st u d y, a n d mai ntai n t he 
data i nte grit y of  t he st u d y. G C P c o mplia nce a n d mi ni mizat i on of ri s k t o st u d y int e grit y are 
i m p orta nt c o nsi derati o ns. E ns uri n g t he safety of  st u d y partici pa nts is t he pre vaili n g 
c o nsi derati o n.
T he c ha n ges t o pr oce d ures descri be d i n t his a p pe n di x are te mp orar y  meas ures i nte n de d t o be 
use d o nl y d uri n g s pecific ti me peri o ds as directe d b y t he s p o ns or i n part ners hi p with t he 
in vesti g at or . 
A d dit i onal wri tt e n g ui da nce , if nee de d, will be pr o vi de d b y  t he s p o ns or i n t he 
e ve nt wri tt e n a p pr o val is gra nte d f or c ha n ges i n st u d y c o n d uct. 
E R Bs , re g ulat or y bo dies , a n d a n y ot her rele va nt lo c al  a ut h orities, as re q uire d, will be n otifie d as 
earl y as p ossi ble t o c o m m u nicate i m ple me ntati o n of c ha n ges i n st u d y c o n d uct d ue 
t o e xce pt i onal circ u msta nces. T o pr otect t he safety of  st u d y partici pa nts, ur ge nt c ha n ges ma y be 
i m ple me nte d bef ore s uc h c om m u nicat i ons are ma de, b ut all c ha n ges will be re p orte d as s o o n as 
p ossi ble f o ll owi n g i m ple me ntati o n. If a p pr o val of E R Bs, re g ulat or y  bo dies, or b ot h i s re q uire d 
per l o c al  re g ulatio ns, c o nfir mat i on of t his a p pr o val will be retai ne d i n t he st u d y rec or ds.
I nf or me d C o nse nt
A d dit i onal c o nse nt fr o m t he participa nt will  be o btai ne d, as a p plica ble, f or:

parti ci pat i on i n re m ote visits, as defi ne d i n t he Re m ote Visit secti on,

a c ha n ge of t he met h o d, l ocatio n, or b ot h, of  I P a d mi nistrati o n,

alter nate deli ver y of st u d y int er ve ntio n a n d a ncillar y  s u p plies, a n d

pr o vi sio n  of t h eir pers o nal or me dical inf or m atio n r e q ui re d prior t o i m ple me ntati o n of 
t hese acti vit ies.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 5
C h a n ges i n St u d y C o n d uct
C ha n ges i n st u d y  c o n d uct n ot descri be d i n t his a p pe n di x, or n ot c o nsiste nt wit h a p plica ble l ocal 
re g ulat i ons, are n ot all o we d.
T he f o ll owi n g c ha n ges i n st u d y  c o n d uct will n ot be c o nsi dere d pr ot oc ol de viati ons. Missi n g data 
will be ca pt ure d as pr ot oc ol de viat i ons.
Re m ote V isits
M o bile healt hcare
I n Part B, healt hcare visits m a y be perf or me d b y a mo bile heal t hcare pr o vider at l o c ati o ns ot her 
t ha n t he st u d y site w he n partici pa nts ca n n ot tra vel t o t he site d ue t o a n e xce pt i onal circ u msta nce 
if wri tte n a p pr o val is pr o vide d b y  t he s p o ns or. Pr oce d ures perf or me d at s uc h visits i ncl u de, b ut 
are n ot li mit e d t o : re vie w of c o nc o mit a nt me dicat i o ns, c ollect i on of bl o o d sa m ples, p h ysical 
assess me nts, a d mi nistrati o n o f P R Os, a d mi nistrati o n of I P, a n d c ollect i on of healt h i nf or mati on . 
Ot her alt er nate lo c ati o ns
Ot her pr oce d ures t hat ma y  be d o ne at a n alter nate l ocati o n i n e xce pti o nal 
circ u msta nces are inf usi o n, l a b orat or y dra ws, etc.
Re gar dless of t he t y p e of  r e mote visits i m ple me nte d, t he pr ot oc o l re q uire me nts re gar di n g t he 
re p orti n g of A Es, S A Es, a n d pr o d uct c o m plai nts re mai n u nc ha n ge d. F urt her m or e, e ver y eff ort 
s h o uld be ma de t o e na ble parti ci pa nts t o ret ur n t o o n-site visits as s o o n as reas o na bl y p ossi ble, 
w hile e ns uri n g t he safet y of b ot h t he partici pa nts a n d t he sit e staff.
I n vesti g ati o n al P r o d uct a n d A ncill ar y S u p plies
W he n a
parti ci pa nt is u na ble t o g o t o t he site t o recei ve st u d y s u p plies d uri n g n or m al o n-sit e 
visit s, t he site s h o ul d w or k wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns. T hese 
actio ns ma y i ncl u de: 

as ki n g t he partici pa nt t o g o t o t he sit e a n d recei ve st u d y s u p plies fr o m site staff with o ut 
c o mplet i on of a f ull st u d y visit ;

as ki n g t he partici pa nt’s d esi g nee t o g o t o t he sit e a n d recei ve st u d y s u p plies o n 
a partici pa nt’s be half ;

arra n gi n g deli ver y of  st u d y s u p plies; a n d

w or ki n g wit h t he s p o ns or t o deter mi ne h o w I P is t o be a d mi nistere d t o t he partici pa nt.  
E xa m ples: A d mi n istr atio n of  I P t o t he participa nt d uri n g a m o bile healt hcare visit or at 
a n alter nate i nf usi on ce nter. T he first 3 i nf usi o ns m ust be a d mi nistere d i n t he cli nic.
T hese re q uire me nts must be met bef ore acti o n is ta ke n:

Alt er nate deli ver y  of I P s h o uld be perf or me d i n a ma n ner t hat d oes n ot c o m pr o mise 
pati e nt c o nfi de nt iality a n d e ns ures pr o d uct i nte grit y. T h e e xist i n g pr ot oc ol re q uire me nts 
f or pr o d uct acc o u nta bility re mai n u nc ha n ge d, i ncl u di n g verificat i on of partici pa nt’s 
receipt of  st u d y s u p plies.

W he n
deli veri n g s u p plies t o a l ocat i on ot her t ha n t he st u d y  sit e (e. g. , partici pa nt’s 
h o me), i n vesti gat or, s p o ns or, or b ot h s h o uld e ns ure o versi g ht of t he s hi p pi n g 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 6
pr ocess t o e ns ure acc o u nta bilit y a n d pr o d uct q ualit y (t hat is, st ora ge 
c o n ditio ns mai ntai ne d a n d i ntact pac ka gi n g u p o n recei pt).

Instr ucti o ns s h o ul d be pr o vi de d t o t he partici pa nt o n h o w t o ret ur n a n y  u n use d or 
c o mplete d st u d y s u p plies.
I n a d diti on, if I P is t o be a d mi nistere d t o t he partici pa nt d uri n g a m o bile healt hcare visit or at a n 
alter nate lo c ati o n, t hese a d dit i onal re q uire me nts m ust be met : 

O nl y a ut h orize d st u d y pers o n nel ma y s u p pl y, pre pare, or a d mi nister I P; a n d

F o ll ow i nf usi o n i nstr ucti o ns descri be d i n Secti on 6. 1 .
A dj ust me nts t o Visit Wi n d o ws
W he ne ver p ossi ble a n d safe t o d o s o,
as deter mi ne d b y t he i n vest i gat or’s discreti o n, partici pa nts 
s h o uld c o m p lete t he us ual S o A . T o ma xi mize t he p ossi bilit y t h at t hese visits ca n be c o n d ucte d 
as o n -site visits, t here b y mi ni mizi n g missi n g data a n d preser vi n g t he i nte n de d c o n d uct of t he 
st u d y, t he wi n d o ws f or visits ma y be a djuste d, u p o n f urt her s pecific g ui da nce fr om t he s p o ns or, 
b ut wit hi n t his ra n ge:
Visit N u m ber
T oler a nce
Part B
Visits 2 t hr o u g h 1 5, a n d 
Visits 8 0 1 a n d 8 0 2
I n e xte n uati n g circ u msta nces, t he visit wi n d o w f or visits i n Part B ma y be e xte n de d 
t o ± 1 0 da ys.
N ote : I P ca n n ot be a d mi nistere d t wice wit hi n 2 1 da ys ( Secti o n 6. 1 ).
A b bre viati o n: I P = i n vesti gati o nal pr o d uct. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 7
D oc u me nt ati o n
D oc u m e nt atio n of C ha n ges i n St u d y C o nd uct
C ha n ges t o st u d y  c o n d uct will be d o c u m e nte d:

Si tes will i de ntif y a n d d oc u me nt t he details of h o w partici pa nts, visits t ypes, 
a n d c o n d ucte d acti vit ies were affecte d b y e xce ptio nal circ u msta nces.
Di s pe nsi n g/s hi p me nt rec or ds of I P a n d rele va nt c o m m u nicat i ons, i ncl u di n g dele gat i on, 
s h o uld be file d wit h site st u d y rec or ds. Als o, i n vesti gat or s h o ul d d oc u me nt w he n st u d y  
c o n d uct ret ur ns t o n or mal.

S o urce d oc u me nts ge nerate d at a l ocati o n ot her t ha n t he st u d y site s h o uld be part of t he 
i n vesti gat or’s s o urce d oc u me ntati o n a n d s h o ul d be tra nsferre d t o t he site i n a sec ure 
a n d ti mel y ma n ner. 
Missi n g D ata a n d O t her P r ot oc ol D e viat i ons
T he st u d y  site s h o uld d o c u m e nt s pecific e x pla nati o ns f or a n y missi n g data a n d ot her pr ot oc ol 
de viat i ons . T his i nf or mat i on will als o be ca pt ure d b y t he m o nit ors i n t he m o nit ori n g s yste m . 
Alt h o u g h pr ot oc ol  de viatio ns ma y  be u na v oida ble i n a n e xce pti o nal circ u msta nce, 
d oc u m e nt atio n of pr ot oc ol de viat i ons a n d missi n g data will be i m p orta nt f or data a nal ysis a n d 
re p orti n g.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 8
1 0. 9.
A p pe n di x 9: Pr ot oc ol A me n d me nt Hist or y
T he Pr ot o c ol  A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
di rectl y bef ore t he Ta ble of C o nte nts ( T O C)
A me n d me nt a ( 2 7 J a n 2 0 2 1)
O ver all R ati o n ale f or t he A me n d me nt
T his a me n d me nt a d ds a titrati o n peri o d t o Part B i n res p o nse t o 2 cases o f s y m pt o mat ic A RI A i n 
a n o n g o i n g d o na ne ma b st u d y.
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1. 1 S y n o psis
1. 2 Sc he ma 
4. 1 O verall Desi g n
A d de d t itrati o n peri o d of 7 0 0 m g 
f or first 3 d oses.
S af et y.
1. 3 Sc he d ule of 
Act i vities ( S o A)
A d de d t olera nce f or M RI at Visit 4.
C orrecte d f o ot n ote a. “ V 6 0 2 ca n n ot 
occ ur ≤3 0 d a y s...”  
T o all o w M RI re vie w pri or t o 
pl a n ne d d ose escalat i on.  
C orrecti o n.
2. 2. 3. 1 D o na ne ma b 
Cli nical St u dies
A d de d i nf or mat i on f or St u d y 
A A CI.
U p date d t o reflect A A CI 
a me n d me nt .
4. 3 J ustificati o n f or 
D ose
A d de d j ust ificati on f or titratio n 
d oses.
A d dit i on of titrati o n sc he d ule.
6. 4 St u d y  I nter ve nti o n 
C o m plia nce
A d de d i nstr ucti o ns f or w he n a 
parti ci pa nt d oes n ot c o m plete t he 
titr atio n p hase.
S af et y.
6. 6 D ose M o dificat i on
A d de d i nstr ucti o ns f or w he n a 
parti ci pa nt de vel o ps A RI A. 
S af et y.  
8. 1. 2 Or der of 
Assess me nts a n d 
Rater R oles
Cl arifie d n ote f or A D A S -C o g 1 3 a n d 
M M S E.
Cl arificat i on.
1 0. 6 A p pe n di x 6: 
Fl ort a u ci pir F 1 8 Ta u 
P E T I m a gi n g
Re m o ve d se nte nce relate d t o 
flort a u ci p ir F 1 8 bei n g i n cli nical 
e val uat i on.  
U S F D A a p pr o val o f 
florta uci pir F 1 8 tracer 
esta blis he d a k n o w n safet y 
pr ofile. 
T hr o u g h o ut 
E di t orial c ha n ges
Mi n or e di t orial c ha n ges, 
t heref ore, n ot descri be d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
9 9
1 1.
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
1 0 1
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L e o  D o c u m e n t  I D  =  3 5 e 2 5 f 8 6 - e 9 c 4 - 4 2 e 2 - b b 9 b - 6 7 d 0 9 c 7 3 0 1 6 1
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 1 - O c t - 2 0 2 1  1 4 : 5 7 : 2 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 1 - O c t - 2 0 2 1  1 5 : 1 7 : 4 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D