Conditions: Alzheimer Disease Dementia Brain Diseases Central Nervous System Diseases Cognitive Impairment
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 95
Healthy volunteers: no

Brief summary:
The main goals of this study are to further determine whether the study drug donanemab is safe and effective in participants with Alzheimer's disease and to validate neuropsychological assessments administered over videoconferencing

Detailed description:

Arms:
arm 1: Participants from the originating trials did not receive any drug in Part A. Participants were randomized 1:1 into two groups to have their cognitive and functional scales assessed.

Group 1: Cognitive/functional scale assessment at the study site (on-site), followed by an at-home assessment (VTC; video teleconference), or Group 2: Cognitive/functional scale assessment at home (VTC), followed by assessment on-site.

Total time in Part A was up to 24 weeks. arm 2: Participants who had received placebo in the originating trials received 700 milligrams (mg) donanemab administered intravenously (IV) every 4 weeks (Q4W) for 3 doses, then 1400 mg donanemab administered IV Q4W for up to 48 weeks.

Interventions: intervention 1: No Intervention intervention 2: donanemab
Intervention descriptions: intervention 1: No intervention intervention 2: Administered IV

Protocol document:
Prot_000.pdf: 
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
Pr ot oc ol  n u m ber I 5 T-M C -A A C H ( b)
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)
6 9
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
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9 9
1 1.
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S a m ps o n H A, M u ñ o z -F url o n g A, Ca m p bell R L, et al. Sec o n d s y m p osi u m o n t he defi nit i on a n d 
ma na ge me nt of a na p h yla xis: s u m mar y re p ort — Sec o n d Nati o nal I nst itute of Aller g y  a n d 
I nfecti o us Disease/ F o o d Aller g y a n d A na p h yla xis Net w or k s y m p osi u m. J Aller gy Cli n 
I m m u n ol. 2 0 0 6; 1 1 7( 2): 3 9 1 -3 9 7. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.jaci. 2 0 0 5. 1 2. 1 3 0 3
Si e mers E R, S u n dell K L, Carls o n C, et al. P hase 3 s ola nez u ma b trials: sec o n dar y  o ut c o mes i n 
mil d Alz hei mer's disease pat ient s. Alz hei mers De me nt . 2 0 1 6; 1 2( 2): 1 1 0-1 2 0. 
ht t ps:// d oi. or g/1 0. 1 0 1 6/j.jalz. 2 0 1 5. 0 6. 1 8 9 3
Wessels A M, Sie mers E R, Y u P, et al. A c o m bi ne d meas ure of c o g nit i on a n d f u ncti o n f or 
cli nical trials: t he i nte grate d Alz hei mer’s Disease Rati n g Scale (i A D R S). J Prev Alz hei mers 
Dis . 2 0 1 5; 2( 4): 2 2 7-2 4 1. htt ps: //d oi . or g/1 0. 1 4 2 8 3/j pa d. 2 0 1 5. 8 2
Willia ms M M, St ora n dt M, R oe C M, M orris J C. Pr o gressi o n of Alz hei mer's disease as meas ure d 
b y Cli nical De me ntia Rati n g S u m o f B o xes sc ores. Alz hei mers De me nt . 2 0 1 3; 9( 1 
S u p pl ): S 3 9-S 4 4. htt ps:// d oi . or g/1 0. 1 0 1 6/j.jalz. 2 0 1 2. 0 1. 0 0 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)
1 0 1
Y os hi da K, Ya ma o ka Y, E g uc hi Y, et al . Re m ote ne ur o ps y c h o l ogi c al assess me nt of elderl y  
Ja pa nese p o p ulati on usi n g t he Alz hei mer's Disease Assess me nt Scale: a vali dati o n st u d y . 
J Tele me d Telec are . 2 02 0; 2 6( 7 -8): 4 8 2 - 4 87. htt ps:// d oi. or g/ 1 0. 1 1 7 7/ 1 3 5 7 6 3 3 X 1 9 8 4 5 2 7 8


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

SAP_001.pdf: 
Statistical A nal ysis Pla n I 5 T- M C- A A C H ( Versi o n 2) 
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 3- D E C- 2 0 2 2


I 5 T-M C -A A C H  S A P  V er si o n 2  
P a g e 1  
L Y 3 0 0 2 8 1 3  
A p pr o v al D at e: 
1.
St ati sti c al A n al y si s Pl a n:
I 5 T-M C -A A C H :  D o n a n e m a b F oll o w -O n St u d y:  S af et y, 
T ol er a bilit y a n d Effi c a c y i n S y m pt o m ati c Al z h ei m er’ s Di s e a s e  
wit h V ali d ati o n of R e m ot e N e ur o p s y c h ol o gi c al A s s e s s m e nt s   
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 n i 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 a l i n v e sti g ati o n of 
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 el 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.  
L Y 3 0 0 2 8 1 3  
I 5 T-M C -A A C H  i s a multi c e nt er, r a n d o mi z e d, o p e n -l a b el, P h a s e 2 st u d y u p t o 1 2 4  w e e k s i n 
a p pr o xi m at el y 2 0 0  p ati e nt s wit h e arl y s y m pt o m ati c A D  w h o h a v e c o m pl et e d st u d y I 5 T -M C -
A A C G.  
Eli Lill y a n d C o m p a n y  
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5 
Pr ot o c ol I 5 T-M C -A A C H  
P h a s e 2  
S A P  v er si o n 2  w a s  a p pr o v e d o n d at e pr o vi d e d b el o w:  
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 2  
L Y 3 0 0 2 8 1 3  
2.  
T a bl e of C o nt e nt s   
S e cti o n  
P a g e   
1.  
Statistical A nal ysis Pla n:   I 5 T -M C -A A C H:  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  ..................................1  
2.  
Ta ble of C o nte nts  ....................................................................................................................2  
3.  
Re visi o n Hist or y  ......................................................................................................................5  
4.  
St u d y O bjecti ves  ......................................................................................................................6  
5.  
A nal ysis P o p ulati o ns  ...............................................................................................................8  
5. 1.  
D escri pti o ns of A nal ysis Datasets  ......................................................................................8  
5. 2.  
Patie nt Dis p ositi o n ..............................................................................................................8  
5. 3.  
I nteri m A nal yses .................................................................................................................8  
6.  
Part A A nal yses  .......................................................................................................................9  
6. 1.  
Ge ner al C o nsi derati o ns  ......................................................................................................9  
6. 2.  
A dj ust me nts f or C o variat es  ................................................................................................9  
6. 3.  
Ha n dli n g of Dr o p o uts or Missi n g Data  ..............................................................................9  
6. 4.  
Baseli ne De m o gra p hi cs  ......................................................................................................9  
6. 5.  
Pri mar y O bj ecti ve  ...............................................................................................................9  
6. 6.  
L o n git u di nal Assess me nts  ................................................................................................1 0  
6. 7.  
Safet y Assess me nts  ..........................................................................................................1 1  
7.  
P art B A nal ys es  .....................................................................................................................1 2  
7. 1.  
Ge neral C o nsi derati o ns  ....................................................................................................1 2  
7. 2.  
Baseli ne De m o gra p hi cs  ....................................................................................................1 2  
7. 3.  
C o nc o mita nt Me dicati o ns  .................................................................................................1 2  
7. 4.  
E xte nt of E x p os ure  ...........................................................................................................1 2  
7. 5.  
Efficac y Scales  .................................................................................................................1 2  
7. 6.  
Safet y A nal yses  ................................................................................................................1 2  
7. 6. 1.  
A d verse E v e nts  ........................................................................................................1 2  
7. 6. 2.  
Cli nical La b orat or y E val uati o ns  ..............................................................................1 3  
7. 6. 3.  
Electr ocar di o gra m Para meters  .................................................................................1 4  
7. 6. 4.  
Vital Si g ns a n d Wei g ht  ............................................................................................1 5  
7. 6. 5.  
C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S)  ................................................1 5  
7. 6. 6.  
I m m u n o ge nicit y .......................................................................................................1 5  
7. 6. 7.  
A m yl oi d -Relate d I m a gi n e A b n or malities ( A RI A)  ..................................................1 6  
7. 7.  
S u b gr o u p A n al ys es  ...........................................................................................................1 6  
8.  
Part C A nal ys es  .....................................................................................................................1 7  
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P a g e 3  
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8. 1.  
Ge neral C o nsi derati o ns  ....................................................................................................1 7  
8. 2.  
A dj ust me nts f or C o variat es  ..............................................................................................1 7  
8. 3.  
Ha n dli n g of Dr o p o uts or Missi n g Data  ............................................................................1 7  
8. 4.  
Patie nt De m o gra p hics  .......................................................................................................1 7  
8. 5.  
Ti me Bet w ee n Cli nical, I ma gi n g, a n d Bi o mar ker Assess me nts  ......................................1 8  
8. 6.  
Cli nical O utc o mes  ............................................................................................................1 8  
8. 7.  
P E T I ma gi n g O utc o m es  ...................................................................................................1 8  
8. 8.  
Plas ma Bi o mar ker O utc o mes  ...........................................................................................1 9  
9.  
Refere n ces  .............................................................................................................................2 0  
1 0.  A p pe n dices  ............................................................................................................................2 1  
 
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I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 4  
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I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 5  
L Y 3 0 0 2 8 1 3  
3.  
R e vi si o n Hi st or y   
T he ori gi nal  versi o n of t h e statistical a nal ysis pla n was a p pr o ve d 1 5 -Oct -2 0 1 8, pri or t o first 
patie nt visit .  Versi o n 2 i ncl u de d m o dificati o ns t o t he des cri pti o n of Part C a nal ys es t hat 
i nc or p orate d ata acr oss b ot h t he fee der st u d y a n d t his f oll o w-o n st u d y.   A d diti o nall y, v ersi o n 2 
u p dates t he fee der st u dies t o i ncl u de I 5 T -M C -A A C C . 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 6  
L Y 3 0 0 2 8 1 3  
4.  
St u d y O bj e cti v e s   
T a bl e A A C H .4 .1 . 
O bj e cti v e s a n d E n d p oi nt s   
P ri m ar y O bjecti ve  
P ri m ar y E n d p oi nt  
P art A  
T o e val uate t he relia bilit y  of V T C c o m pare d 
wit h o n -site a d mi nistere d c o g niti ve a n d 
f u ncti o nal meas ur es 
 
T he i ntraclass c orrelati o n 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 bilit y 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 tests  
 Vital 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 nati o ns  
M RI ( A RI A a n d e m er ge nt ra di ol o gical fi n di n gs)  
I nf usi o n-relat e d reacti o ns 
C -S S R S   
Sec o n d ar y O bjecti ves  
Sec o n d ar y E n d p oi nts  
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  
C ha n ge fr o m bas eli 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 s c 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 oi d 
de p ositi o n  
C ha n ge i n brai n a m yl oi d pla q ue de p ositi o n fr o m baseli ne at 
Wee k 3 6 of P art 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 re gi o n 
v ol u mes  
C ha n ge i n v ol u metri c M RI meas ures fr o m 
baseli ne t o Wee k 7 2 i n Part B  
 
 
 
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I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 7  
L Y 3 0 0 2 8 1 3  
 
T o assess peri p heral P K a n d prese nce of 
a nti -d o na ne ma b a nti 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 n e 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 nti b o dies 
A b bre viati o ns: 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 he i mer’s Diseas e 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 yl 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 = elect r 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  
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I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 8  
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5.  
A n al y si s P o p ul ati o n s   
5. 1.  D e s cri pti o n s of A n al y si s D at a s et s   
F or p ur p os es of a n al ysis, Parts A, B, a n d C o f t he st u d y will be a nal ys e d se paratel y as t h e data 
f or eac h bec o mes a vaila ble.  T he ta ble bel o w d efi n es s u bject p o p ulati o ns w hic h are d efi ne d 
pri maril y b y p artici pati o n a n d data creati o n i n t he a p plica ble part of t he st u d y.  W he n c h a n ge 
fr o m baseli ne is assess e d, patie nts will be i ncl u de d i n t he a nal ysis o nl y if b ot h a baseli ne a n d at 
least 1 vali d p ost-b aseli n e meas ur e are a vaila bl e.  
P o p ul ati o n  
Descri pti o n  
Ra n d o mize d P o p ulati o n  
S u bjects fr o m Part A ra n d o mize d t o recei ve 
o n -site assess me nts first or re m ote ass ess me nt 
first. 
Part A:  Vi de o Assess me nt  
Ra n d o mize d s u bjects t hat pr o vi de at least 1 
pair ( o n -site a n d re m ote) of c o m plete cli nical 
assess me nts fr o m Part A.  P o p ulati o n will be 
scale-d e pe n de nt.  
Part B: Safet y P o p ulati o n  
S u bjects w h o are d os e d wit h d o na ne ma b 
d uri n g Part B.  
Part  C: I ma gi n g a n d Cli nical F oll o w-u p  
S u bject w h o pr o vi de cli nical a n d/ or i ma gi ni n g 
data fr o m Visit 2 0 1.  
 
5. 2.  P ati e nt Di s p o siti o n   
T he pr ot oc ol f or t his st u d y ma k es t he disti ncti o n bet w ee n p atie nt wit h dra wal fr o m st u d y a n d 
patie nt disc o nti n uati o n of st u d y treat me nt.  Patie nt wit h dra wal occ urs w h e n a patie nt will n o 
l o n ger partici pate i n t he st u d y ( n o l o n ger ta ki n g st u d y treat me nt a n d n o l o n ger bei n g assess e d).  
Patie nt disc o nti n uati o n of  st u d y tr eat me nt occ urs w he n a patie nt a grees t o c o nti n ue bei n g 
assesse d b ut will n o l o n ger ta ke st u d y treat me nt s.  Patie nt dis p ositi o n s u m marizes t he reas o ns f or 
patie nt wit h dra wal fr o m st u d y a n d p atie nt disc o nti n uati o n of st u d y treat me nt.  
T he perce nta ge of patie nts  wit h dra wi n g  fr o m st u d y a n d dis c o nti n ui n g treat me nt acr oss all parts 
of t he st u d y  will be s u m mariz e d .   
5. 3.  I nt eri m A n al y se s   
St u d y A A C H is a n o pe n -la bel st u d y, wit h n o st u d y dr u g tr eat me nt d uri n g Parts A a n d C, a n d 
d o na ne ma b treat me nt d uri n g Part B.  N o i nteri m a nal yses are pl a n ne d f or t his st u d y.  Parts A, 
B, a n d C will be a n al ys e d as s u bjects c o m plete t h ose parts of t he st u d y a n d data bec o m es 
a vaila ble. Treat me nt is u n bli n de d i n t his st u d y a n d data is a vaila ble f or s p o ns or use o n a 
c o nti n ual basis.  
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6.  
P art A A n al y s e s   
6. 1.  G e n er al C o n si d er ati o n s   
Statistical a nal yses of t his st u d y will be t he res p o nsi bilit y of t he s p o ns or or its desi g nee.  
U nless ot her wise n ote d, statistical tests will be c o n d ucte d at a 2 -si d e d al p ha le vel of 0. 0 5 a n d 
9 5 % c o nfi de n ce i nter vals will be dis pla ye d a s 2-si de d. 
N o a dj ust me nts f or m ulti ple c o m paris o ns are pla n ne d.  
All a nal ys es i n v ol vi n g calc ulati o n of I C Cs will be li mite d t o t he Part A: Vi de o Assess me nt 
p o p ulati o n, re q uiri n g p artic pa nts t o c o ntri b ute c o m plete pairs of o n -site a n d re m ote cli nical 
assess m e nts t o be i ncl u de d.  T he I C C will be cal c ulate d as 2 -wa y mi x e d -effect m o del l o o ki n g f or 
a bs ol ute a gree me nt acr oss raters, wit h r aters defi ne d as o n -site ass ess me nt a n d V T C assess me nt. 
A data base l o c k is e x pecte d t o occ ur after all ra n d o mize d partici pa nts ha ve c o m plete d 
partici pati o n i n Part A of t he st u d y.  A nal ys es relate d t o t he vali dati o n of re m ote assess me nts 
c o m pare d t o o n -site assess me nts will be c o n d ucte d.  As n o st u d y dr u g is a d mi nistere d d uri n g 
Part A, safet y a nal yes will be li mite d.   
A d diti o nal e x pl orat or y a nal yses of t he data will be c o n d ucte d as dee m e d a p pr o priate.  
6. 2.  A dj u st m e nt s f or C o v ari at e s   
M o dels f or eac h of t he cli nical  e n d p oi nts are s pecifie d i n t he rele va nt secti o ns bel o w. 
6. 3.  H a n dli n g of Dr o p o ut s or Mi s si n g D at a   
Beca use t he I C C c o m p ut ati o n re q uires a c o m plete o n -site assess me nt a n d a c o m plete virt ual 
assess me nt, n o i m p utati o n of missi n g val ues will occ ur i n efficac y a n al ys es f or Part A .  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 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 ass ess me nts will res ult i n m ore missi n g ite m sc ores 
relati ve t o t he o n-site ass ess me nt is of i nterest.  T o a d dress t his q uesti o n, t he n u m ber of s cale 
assess me nts wit h missi n g val ues f or eac h of t he cli nical scales will be s u m marize d b y m o dalit y. 
6. 4.  B a s eli n e D e m o gr a p hi c s   
Baseli ne d e m o gra p hics, cli nical rati n g scales, dis ease c h aracteristics, select c o nc o mita nt 
me dicati o ns, a n d i ma gi n g para meters will be s u m marize d f or t he Part A: Vi de o Assess me nt  
p o p ulati o n.  
6. 5.  Pr i m ar y O bj e cti v e  
T he pri mar y o bje cti ve of Part A of t his st u d y is t o e val uate t he relia bilit y of V T C c o m pare d wit 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 wi ll be assesse d b y esti mati n g t he 
i ntra-class c orrel ati o n (I C C) a n d t he ass ociate d 9 5 % c o nfi de n ce i nter val f or t he first pair of 
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o bser v ati o ns fr o m partici 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 bilit y. 
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 i nterest f or t his st u d y is a 2-wa y mi x e d m o del, i nteracti o n a bse nt, wit h si n gle 
meas ure me nts fr o m eac h m o dalit y o n partici pa nts, l o o kin 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 ‘rat ers’ are t he t w o m o dalities b y w hic h t h e cli nical sc ales are assesse d, o n -
site a n d V T C.  As we are i ntereste d i n c o m pari n g t hese s pecifi c m o dalities, m o dalit y is 
c o nsi dere d a fi x e d effect.  
F or A D A S -C o g 1 3 t otal sc ore, A D C S -A D L  t otal sc ore, i A D R S t otal sc ore, C D R S u m of B o x es, 
a n d M M S E t otal sc ore, i n di vi d ual mi x e d  m o dels will be fit t o t he data wit h fi x e d effects of 
m o dalit y, ti me effect, a ge, years of e d ucati o n, a n d prese nce/a bse n ce of a nti -de me ntia dr u gs  a n d a 
ra n d o m effect f or s u bject.  I C Cs will be esti mate d usi n g t he mea n s q u ares fr o m t hese  m o del s a n d 
defi ne d as:  
A bs ol ute A gree m e nt: I C C ( A, 1) = ( M Ss u bj –  M S
err or) / (M S
s u bj + M S err or + 1/ n ( M Sm o dalit y  –  M S
err or)) 
C o nsista nc y: I C C (C , 1) = ( M Ss u bj –  M S
err or) / ( M Ss u bj + M S err or) 
9 5 % C o nfi de nce i nter vals f or t hese q ua ntities will be c o nstr ucte d as s pecifi e d i n Ta ble 7 of 
Mc Gra w a n d W o n g ( 1 9 9 6).  
Si milar a nal yses will als o be c o n d ucte d f or pairs 2 a n d 3 of eac h of t he cli nical o utc o mes 
s pecifie d a b o v e.  As t he n u m ber of s u bjects c o ntri b uti n g a d diti o nal pairs m a y b e li mite d, n o 
s pecific h y p ot hesis/test is s pecifie d.  
6. 6.  L o n git u di n al A s s e s s m e nt s   
T o c o m pare dise ase 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 vati o ns will be gr o u pe d b y test m o dalit y ( V T C a n d o n -site). 
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 dalit y i nteracti o n, a ge, year s of 
e d ucati o n, a n d prese n ce/ a bse nce of a nti -de m e ntia dr u gs. Visit will be c o nsi dere d a cate g orical 
varia ble. T h e n ull h y p ot h esis 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 -site 
m o dalit y at eac h visit e q uals 0. A n u nstr uct ure d c o varia nce m atri x will be use d t o m o del t he 
wit hi n -s u bject varia nce-c o varia nce err ors. If t h e u nstr uct ure d c o v aria n ce str uct ure matri x res ults 
i n a lac k of c o n v er ge nce, t he f oll o wi n g tests will be use d i n se q ue n ce: 
 
heter o ge n e o us T oe plitz c o varia nce str uct ur e  
 
heter o ge n e o us a ut ore gressi ve c o varia n ce str u ct ure  
 
heter o ge n e o us c o m p o u n d s y m metr y c o v aria n ce str uct ure  
 
c o m p o u n d s y m metr y c o v aria nce str uct ur e  
T he Ke n w ar d -R o ger a p pr o xi mati o n will be use d t o esti mate t he de n o mi nat or de grees of 
free d o m. 
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6. 7.  S af et y A s s e s s m e nt s   
Alt h o u g h n o st u d y me dicati o n is gi ve n t o s u bjects d uri n g Part A of st u d y A A C H, a d verse e ve nts 
are r o uti nel y c ollecte d.  A s u m mar y of a d v erse e ve nts, re p orte d b y M e d D R A preferre d ter m, will  
be dis pla ye d b y decreasi n g fre q ue n c y.  A list of a d verse e v e nts dee me d s eri o us will als o be 
creat e d.  
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7.  
P art B A n al y s e s   
7. 1.  G e n er al C o n si d er ati o n s   
All a nal ys es will be li mite d t o partici pa nts w h o recei ve d st u d y dr u g a n d pr o vi de d cli nical, 
i ma gi n g, a n d/ or bi o mar ker data fr o m Part B of A A C H. 
Baseli ne d efi niti o ns are d e pe n de nt o n t he q u a ntit y bei n g assesse d. F or safet y a n al ys es, bas eli ne 
will be defi ne d as t he l ast assess me nt c ollecte d pri or t o t he first d ose of d o n a ne ma b, ge n erall y 
Visit 1 fr o m Part B.  F or treat me nt-e mer ge nt  safet y a n al ys es, o nl y partici pa nt s w h o ha ve b ot h a 
baseli ne o bser vati o n a n d a p ost baseli ne o bser vati o n will be i ncl u de d i n t he a nal ysis f or eac h 
a nal yt e or para meter, res pecti vel y.  W here f urt her clarificati o n o n baseli ne defi niti o ns is nee de d, 
t he rele va nt s u bsecti o ns will s pecif y t h e defi niti o ns. 
7. 2.  B a s eli n e D e m o gr a p hi c s   
Baseli ne d e m o gra p hics, cli nical rati n g scales, dis ease c h aracteristics, select c o nc o mita nt 
me dicati o ns, a n d i ma gi n g para meters will be s u m marize d f or t he safet y p o p ul ati o n.  
7. 3.  C o n c o m it a nt M e di c ati o n s   
Pri or me dicati o ns are d efi ne d as t h ose t hat st o p bef ore st u d y dr u g a d mi nistrati o n.  C o nc o mita nt 
me dicati o ns are d efi ne d as t h ose be i n g ta ke n o n or after i nitiati o n of st u d y dr u g.  A s u m mar y of 
c o nc o mita nt me dicati o ns will be prese nte d as fre q ue ncies a n d p erce nta ges . 
7. 4.  E xt e nt of  E x p o s ur e   
S u m mar y statistics  will be pr o vi de d f or t he t otal n u m ber of c o m plete i nf usi o ns recei v e d  b y 
partici pa nts d uri n g Part B of t he st u d y .  
7. 5.  Effi c a c y S c al e s   
L o n git u di nal assess me nt acr oss sc h e d ule d visits will be s u m marize d f or Part B  partici pa nts f or 
A D A S -C o g 1 3, A D C S-i A D L, i A D R S T otal Sc ore, C D R S u m of B o x es, a n d M M S E T otal Sc ore. 
7. 6.  S af et y A n al y s e s   
T he f oll o wi n g s u bs ecti o ns descri be t he s u m mari es of safet y i nf or mati o n t hat will be prese nte d 
f or t he Part B  data b ase l o c k.  All a nal yses c o nt ai ne d i n t he s u bsecti o ns bel o w will be base d o n 
t he safet y p o p ulati o n of t he st u d y. 
7. 6. 1.  A d v er s e E v e nt s   
A treat me nt -e mer ge nt a d verse e v e nt ( T E A E) is defi ne d as a n e ve nt t hat first occ urre d or 
w orse ne d after t h e first d o na ne ma b i nf usi o n.  T he Me dical Dicti o nar y f or R e g ul at or y Acti vities 
( Me d D R A) L o w est Le vel Ter m ( L L T) will be us e d i n t he treat me nt-e mer ge nt c o m p utati o n.  T he 
versi o n of Me d D R A t hat will be use d is t he m ost rece nt versi o n a vaila ble at t he ti me of data bas e 
l oc k.  T he ma xi m u m se verit y f or eac h L L T d uri n g t he baseli ne peri o d will be use d as bas eli ne.  
T he treat me nt pe ri o d will be i ncl u de d as p ost-bas eli ne f or t he a n al ysis.  W hile u n us ual, it is 
p ossi ble t o ha ve a missi n g se v erit y f or e ve nts.  F or e ve nts wit h a missi n g s e verit y d uri n g t he 
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baseli ne peri o d, it will be treate d as “ mil d” i n se verit y f or d eter mi ni n g treat me n t e mer ge n ce.  
E ve nts wit h a missi n g se verit y d uri n g t h e p ost bas eli ne peri o d will be treate d as “se vere” a n d 
treat me nt e mer ge nce will be deter mi ne d b y c o m pari n g wit h bas eli ne se verit y.  
T he pla n ne d s u m maries f or a d vers e e ve nts ( A Es) are pr o vi d e d i n t he ta bl e bel o w.  
 
T a bles a n d Fi g ures Rel ate d t o A d verse E ve nts  
A n al ysis  
Det ails  
A n al ysis Set/ P o p ul ati o n  
O ver vie w of A Es  
N u m ber a n d perce nta ge of partici pa nts w h o 
e x perie nce d 
 
T E A E  
 
S A E  
 
deat h, a n d  
 
disc o nti n uati o n fr o m st u d y treat me nt d ue t o 
a n A E. 
 
Safet y P o p ulati o n  
 
T E A Es b y P T 
wit hi n S O C  
N u m ber a n d perce nta ge of partici pa nts wit h 
T E A Es usi n g Me d D R A P T  neste d wit hi n  S O C  
 
Safet y P o p ulati o n  
S A Es b y P T  
T he n u m ber a n d perce nta ge of partici pa nts w h o 
e x perie nce d a n  S A E (i ncl u di n g deat hs a n d S A Es 
te m p orall y ass ociate d or prece di n g deat hs) usi n g 
Me d D R A P T  
 
Safet y P o p ulati o n  
A Es Re p orte d as 
Reas o n f or  
Treat me nt 
Disc o nti n uati o n  
b y P T  
N u m ber a n d perce nta ge of partici pa nts re p orti n g 
a n A E as t he reas o n f or disc o nti n ui n g st u d y 
treat me nt usi n g Me d D R A P T  
 
Safet y P o p ulati o n  
 A b bre viati o ns:  A E = a d verse e ve nt; S A E = seri o us a d verse e ve nt; Me d D R A = Me dical Dicti o nar y f or Dr u g 
Re g ulat or y Acti vities; P T = preferre d ter m; S O C = S yste m Or ga n Class; T E A E = treat me nt -e mer ge nt a d ver se e ve nt. 
7. 6. 2.  Cli ni c al L a b or at or y E v al u ati o n s   
La b orat or y me as ure m e nts will be a nal yze d usi n g c o nti n u o us data (c h a n ge fr o m baseli ne) a n d 
cate g orical or or di nal d ata ( pr o p orti o n of tr eat me nt-e mer ge nt a b n or malities).  If t here are 
m ulti ple rec or ds of la b orat or y m eas ur e me nts at baseli ne or p ost baseli ne visit, t he last rec or d will 
be use d.  S u m maries a n d a nal ys es of c o nti n u o us data (c h a n ge fr o m baseli n e) will be perf or me d 
usi n g b ot h c o n ve nti o nal a n d I nter n ati o nal S yste m of U nits  (SI u nits).  
Mea n c ha n ge s fr o m b aseli ne t o sc he d ule d p ost -baseli ne visit s will be s u m marize d f or c he mistr y 
a n d he mat ol o g y la b para meters.   
T he n u m ber a n d p erce nta ges f or he mat ol o g y a n d c he mistr y la b orat or y o bser vati o ns t hat fall 
o utsi de of refere n ce li mits will be s u m marize d.  T he refere n ce li mits fr o m t he perf or mi n g 
la b orat or y will be use d t o defi ne l o w a n d hi g h.  F or a gi ve n la b para meter, a val ue is c o u nte d as 
treat me nt-e mer ge nt l o w if t he mi ni m u m p ost -ba seli ne val ue is cate g orize d as l o w a n d t he 
baseli ne val ue was classifie d as eit her n or mal or hi g h.  Si milarl y, a v al ue is c o u nte d as treat me nt -
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e mer ge nt hi g h if t he ma xi m u m p ost -baseli ne val ue is cate g orize d as hi g h a n d t he baseli ne val ue 
was classifie d as eit her n or mal or l o w.  All p ost -baseli ne la b assess me nts will be i ncl u de d i n t he 
a nal ys es, w het h er sc h e d ule d or u nsc he d ule d.  
I n a d diti o n, f or he patic l a b val ues, cli nicall y si g nifica nt c ha n ges of i nterest at a n y ti me are:  A L T 
≥3 x u p per li mit of n or mal ( U L N), A S T ≥3 x U L N, A L T ≥5 x U L N, A L T ≥1 0 x U L N, a n d t otal 
bilir u bi n ≥2 x U L N.  A d diti o nall y, H y’s La w a nal ysis will be c o n d uct e d b y c o m pari n g treat me nt 
gr o u ps wit h re gar d t o t he pr o p orti o n of patie nts wit h ( A L T ≥3 x U L N O R A S T ≥3 x U L N) A N D 
t otal bilir u bi n ≥2 x U L N at a n y ti me. 
 
 
7. 6. 3.  El e ctr o c ar di o gr a m P ar a m et er s   
E C G meas ure me nts will be a nal yz e d usi n g c o nti n u o us data (c h a n ge fr o m baseli ne) a n d 
cate g orical data ( pr o p orti o n of treat me nt -e mer ge nt a b n or malities).  
A nal ysis will be d o ne f or t he f oll o wi n g E C G meas ure me nts:  heart rate, P R, Q T, Q Tc, a n d R R 
i nter vals a n d Q R S d urati o n.  All a nal ys es of Q T c will be carri e d o ut usi n g t he Fri dericia 
c orrecti o n ( Q Tc F) met h o d.  T hese s u m maries will i ncl u de data fr o m eac h  sc he d ule d visit at 
w hic h E C G meas ur es are perf or me d.  M ea n c ha n ge fr o m baseli ne t o eac h p ost -baseli ne visit at 
w hic h E C G meas ur e me nts are ta ke n will be s u m marize d. 
I n ci de nce of treat me nt-e mer ge nt a b n or m al E C Gs will be assesse d b y c o m p aris o ns at ( 1) a n yti me 
a n d ( 2) eac h p ost -b aseli ne visit .  A b n or mal E C G criteria a n d c riteria f or a b n or mal Q Tc F 
pr ol o n gati o n are prese nte d bel o w:  
E C G P ar a meter  
L o w Criteri a  
Hi g h Criteri a  
Heart Rate  
< 5 0 b p m  
> 1 0 0 b p m  
P R I nter val  
< 1 2 0 msec  
2 2 0 msec  
Q R S D urati o n  
< 6 0 msec  
1 2 0 msec  
Q T c F I nter val  
            Males  
            Fe males  
       Males a n d fe males  
 
< 3 3 0 msec  
< 3 4 0 msec  
 
4 5 0 msec  
4 7 0 msec  
> 5 0 0 msec  
A b bre viati o ns:  b p m = beats per mi n ute; E C G = el ectr ocar di o gra m; Q Tc F = Fri deri cia -c orrecte d 
Q T i nter val.  
Treat me nt -e mer ge nt hi g h E C G para meters ( heart rate, P R i nter val, Q R S d urati o n, Q T a n d Q Tc F 
i nter vals) are t he val ues w hic h are l o w or n or mal at all baseli ne visits a n d fall i nt o t he hi g h 
a b n or mal cat e g ories p ost -baseli ne.  Si milarl y, tr eat me nt -e mer ge nt l o w  E C G para met ers ( h eart 
rate, P R i nter val, Q R S d urati o n) are t he val ues w hic h are hi g h or n or mal at all baseli ne visits a n d 
fall i nt o t he l o w a b n or mal cate g ories a b o ve.  
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7. 6. 4.  Vit al Si g n s a n d W ei g ht   
Vitals si g ns a n d w ei g ht will be a nal yze d usi n g c o nti n u o us data (c ha n ge fr o m baseli ne) a n d 
cate g orical data ( pr o p orti o n of treat me nt -e mer ge nt a b n or malities).  
A nal ysis will be d o ne f or all c ollecte d vital si g ns a n d wei g ht p ara met ers.   T hese s u m maries will 
i ncl u de data fr o m eac h sc he d ule d visit at w hic h vital  si g ns are perf or me d.  Mea n c ha n ge fr o m 
baseli ne t o eac h p ost -bas eli ne visit at w hic h vital si g ns  are ta ke n will be s u m marize d.  
T he n u m ber a n d p erce nta ge of partici p a nts wit h o bser vati o ns e x c ee di n g defi ne d li mits o n vital 
si g ns a n d wei g ht will be s u m marize d.  T he meas ures of i nterest a n d t heir c orres p o n di n g li mits 
are as f oll o ws:  
Vit al Si g n P ar a meter ( U nit)  
P ost b aseli ne L o w Criteri a  
P ost b aseli ne Hi g h Criteri a  
Sitti n g s yst olic bl o o d press ure 
( m m H g) 
A bs ol ute val ue 9 0 a n d 2 0 decrease 
fr o m baseli ne 
A bs ol ute val ue 1 6 0 a n d 2 0 i ncrease 
fr o m baseli ne 
Sitti n g diast olic bl o o d press ur e 
( m m H g) 
A bs ol ute val ue 5 0 a n d 1 0 decrease 
fr o m baseli ne 
A bs ol ute val ue 1 0 0 a n d 1 0 i ncrease 
fr o m baseli ne 
Sitti n g p ulse ( b p m)  
A bs ol ute val ue < 5 0 a n d 1 5 decrease 
fr o m baseli ne 
A bs ol ute val ue > 1 0 0 a n d 1 5 i ncrease 
fr o m baseli ne 
W ei g ht  
7 % decrease  
7 % i ncrease  
 
 
Vit al Si g n P ar a meter ( U nit)  
P ost b aseli ne Criteri a f or A b n or m alit y  
Ort h ostatic s yst olic bl o o d 
press ure ( m m H g)  
2 0 m m H g decrease i n s yst oli c bl o o d press ure (s u pi ne t o sta n di n g)  
(i.e., s u pi ne mi n us sta n di n g 2 0)  
Ort h ostatic diast olic bl o o d 
press ure ( m m H g)  
≥1 0 m m H g decrease i n diast olic bl o o d press ure (s u pi ne t o st a n di n g)  
(i.e., s u pi ne mi n us sta n di ng ≥1 0 m m H g)  
Ort h ostatic p ulse ( b p m)  
3 0 i ncrease i n b p m (sta n di n g t o s u pi ne) (i.e., sta n di n g mi n us s u pi ne 3 0)  
T e m perat ure  
A bs ol ute val ue 3 8. 3 C a n d 1. 1 C i ncrease fr o m baseli ne  
( A bs ol ute val ue 1 0 1 F a n d 2 F i ncrease fr o m baseli ne)  
A b bre viati o n:  b p m = beats per mi n ute.  
7. 6. 5.  C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)   
S uici dal i deati o n, s uici dal be ha vi or , a n d self-i nj uri o us be ha vi or wit h o ut s uici dal i nte nt, base d o n 
t he C ol u m bia-S uici de Se verit y Rati n g Scal e ( C -S S R S), will be liste d b y patie nt  a n d visit.  O nl y 
patie nt s t hat s h o w s uici dal i deati o n/ be ha vi or or self -i nj uri o us be ha vi or wit h o ut s uici dal i nte nt 
will be dis pla ye d (ie, if a patie nt  a ns wers are all ‘ n o’ f or t he C -S S R S, t he n t hat patie nt  will n ot be 
dis pla ye d).  H o we v er, if a patie nt  re p orte d a n y s ui ci dal i deati o n/ be ha vi or  or self -i nj uri o us 
be ha vi or wit h o ut s uici dal i nte nt  at a n y ti me p oi nt , t he n all t heir i deati o n a n d be ha vi or will be 
dis pla ye d, e ve n if n ot p ositi ve . 
7. 6. 6.  I m m u n o g e ni cit y  
S u bject sa m ples will be a nal yze d usi n g a 4 -tiere d a p pr oac h. All sa m ples will be assesse d i n Tier 
1 (scree ni n g) f or t h e p ossi ble prese nce of A D A. Sa m ples f o u n d t o  pr o d uce a si g nal a b o ve or 
e q ual t o t he scree ni n g c ut p oi nt will be assesse d i n Tier 2 t o c o nfir m s pe cificit y t o L Y 3 0 0 2 8 1 3 
(c o nfir mati o n). A n y s a m ples c o nfir me d as s p ecifi c f or a nti-L Y 3 0 0 2 8 1 3 a nti b o dies will be 
re p orte d as “ dete cte d.” All sa m ples bel o w t he scree ni n g c ut p oi nt ( Tier 1) or n ot c o nfir me d ( Ti er 
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2) will be re p orte d as “ n ot detecte d.” A n y “ detecte d” sa m ple i n Tier 2 will be assesse d i n Tier 3 
(titer assess me nt) a n d Tier 4 ( ne utr alizi n g a nti b o dies). A nti-dr u g a nti b o dies titer val ues will be 
re p orte d fr o m Tier 3 titer assess me nt. A n y sa m ples a b o ve t he Tier 4 assa y c ut p oi nt will be 
re p orte d as “ dete cte d f or ne utralizi n g a nti b o dies”; sa m ples bel o w t he assa y c ut p oi nt i n Tier 4 
will be re p orte d as “ n ot d etecte d f or ne utr alizi n g a nti b o dies.”  
T he fre q u e nc y a n d perce nta ge of s u bjects wit h pree xisti n g ( baseli ne) A D A, A D A at a n y ti me 
after baseli ne, a n d tr eat m e nt -e mer ge nt  A D A ( T E-A D A) t o L Y 3 0 0 2 8 1 3 will be s u m marize d . If 
n o A D As are dete cte d at baseli ne, T E -A D A are defi ne d as t h ose wit h a titer 2 f ol d (1 dil uti o n) 
greater t ha n t he mi ni m u m re q uire d dil uti o n  ( M R D) of t he ass a y (t he M R D f or a nti-L Y 3 0 0 2 8 1 3 
a nti b o d y ass a y is 1 0). F or sa m ples w it h A D A det ecte d at baseli ne T E-A D A are defi ne d as t h ose 
wit h a 4 -f ol d ( 2 dil uti o ns) i ncrease i n titer co m pare d t o ba seli ne. F or s u bjects wit h T E-A D A , t he 
distri b uti o n of ma xi m u m titers d uri n g d o u ble -bli n d treat me nt peri o d will b e descri b e d  via a 
baseli ne t o p ost -baseli ne s hift ta ble . T he fre q ue nc y of ne utralizi n g a nti b o di es ma y als o be 
ta b ulate d. 
7. 6. 7.  A m yl oi d -R el at e d I m a gi n e  A b n or m aliti e s ( A RI A)   
Sc he d ule d a n d u nsc h e d ule d ma g netic res o na nce i ma gi n g ( M RI) will be use d t o prese nt A RI A 
e ve nts.  A n o ver vi e w of A RI A i n ci de nce will be prese nte d usi n g fre q u e n c y a n d p erce nta ge of 
s u bjects wit h a n y A RI A ( A RI A-E or A RI A -H), A RI A -E, a n d A RI A -H as d efi ne d b y safet y 
M RIs or T E A E cl uster. A RI A -E T E A E Cl uster P T are d efi ne d as a m yl oi d -relate d i ma gi n g 
a b n or malit y o e de ma/eff usi o n, brai n oe de ma, vas o ge ni c cere bral oe de ma. A RI A -H T E A E Cl uster 
P T are defi n e d as a m yl oi d -relate d i ma gi n g a b n or malit y-micr o hae m orr h a ge a n d hae m osi deri n 
de p osits, brai n ste m micr o hae m orr h a ge, cere b ellar micr o hae m orr h a ge, cere bral he m osi deri n 
de p osit, cere bral micr o h ae m orr ha ge, s u perfi cial si der os is of t he ce ntral ner v o us s yste m, cere bral 
hae m orr h a ge.  
T he fre q u e nc y a n d perce nta ges of A RI A -E will be f urt her br o ke n o ut b y as y m pt o matic vs. 
s y m pt o matic.  T he fre q u e nc y a n d p erce nta ge of s u bjects wit h A RI A-H mi cr o he m orr h a ge, 
A RI A -H s u perficial si der osis,  a n d A RI A -H macr o he m orr ha ge o n safet y M RI will be re p orte d.  
A ta ble dis pla yi n g t he s hift A RI A -H e v e nt fr o m baseli ne b y visit will be create d base d o n s afet y 
M RI.  A RI A -E s hift ta bl e base d o n safet y M RI will be dis pla ye d usi n g a 5 -p oi nt rati n g scale 
( mil d, mil d +, m o derate, m o derate +, s e vere).  
7. 7.  S u b gr o u p  A n al y s e s   
N o s u b gr o u p a nal yses are pla n ne d f or t he safet y p o p ulati o n . 
 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 1 7  
L Y 3 0 0 2 8 1 3  
8.  
P art C A n al y s e s   
8. 1.  G e n er al C o n si d er ati o n s   
O bjecti ves f or Part C of A A C H will be a d dress e d wit h s u m maries of cli nical , i ma gi n g, a n d 
bi o mar ker  dat a.  Data c ollecte d fr o m t he fee d er st u d y fr o m w hic h t he partici pa nt ca me, a n d data 
fr o m t he first o n-site visit fr o m Part A will be a g gre gate d wit h data fr o m Part C t o all o w f or 
dis pla y of l o n git u di nal c ha n ges .  F or c o m parati ve p u r p oses, s u bjects t hat p artici pate i n Part B 
will als o be dis pla ye d, wit h t heir fee d er st u d y, first Part A o n -site visit, a n d Visit 1 fr o m Part B 
( pre-tr eat me nt) a g gre gate d i n a si milar fas hi o n. 
U nless ot her wise s pecifie d, baseli ne f or cli nical , i ma gi n g, a nd bi o mar ker  e n d p oi nts will be 
defi ne d as t he l ast o bser vati o n pri or t o st u d y dr u g i nitiati o n fr o m t he fee der st u d y. W he n c ha n ge 
fr o m baseli ne is assess e d, patie nts will be i ncl u de d i n t he a nal ysis o nl y if b ot h a baseli ne a n d a 
Part C  meas ure are a v aila ble.  
8. 2.  A dj u st m e nt s f or C o v ari at e s   
M o dels f or eac h of t he cli nical, i ma gi n g, a n d bi o mar ker e n d p oi nts are s pecifie d i n t he rele va nt 
secti o ns bel o w. 
8. 3.  H a n dli n g of Dr o p o ut s or Mi s si n g D at a   
All t otal a n d s u bscale sc ores f or cli nical o utc o mes meas ures will be deri ve d fr o m i n di vi d ual 
ite ms.  If a n y of t he i n di vi d ual ite ms are missi n g or u n k n o w n, e ver y eff ort will be ma de t o o btai n 
t he sc ore f or t he missi n g ite m(s).  Si milar t o Part A a nal yses, if a n y ite m is missi n g, a n y t otal or 
s u m i n v ol vi n g t hat ite m will be c o nsi dere d missi n g. 
F or fl ui d bi o mar kers, sa m ples t hat were n ot c ollecte d f or a n y reas o n as w ell as sa m ples t hat were 
n ot q ua ntifia ble (i.e. bel o w t he li mit of q ua ntificati o n) will be c o nsi dere d missi n g f or a nal ysis 
p ur p oses.  
F or P E T i ma gi n g, s ca ns t hat were n ot c ollecte d f or a n y reas o n as well as s ca ns t hat were n ot 
q ua ntifia ble will be c o nsi dere d missi n g f or a n al ysis p ur p oses.  
8. 4.  P ati e nt  D e m o gr a p hi c s   
Baseli ne c haracteristics will be s u m marize d f or Part C partici pa nts.   S u m maries will i ncl u de 
descri pti ve statistics f or c o nti n u o us a n d cate g orical meas ures.  Patie nt  c haracteristics t o be 
prese nte d i ncl u d e:  
 a ge  
 a ge gr o u p:  5 5  t o 6 4, 6 5  t o 7 4, a n d 7 5  t o 8 6, > 8 6  
 ge n d er  
 race 
 et h nicit y 
 hei g ht  
 b o d y w ei g ht  
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 1 8  
L Y 3 0 0 2 8 1 3  
 b o d y mass i n de x ( wei g ht ( k g) / [ hei g ht ( m)] 2)  
 c o u ntr y 
 t o bacc o use 
 alc o h ol use  
 years of e d ucati o n  
 w or k stat us  
 A P O E 4 carrier stat us ( carrier [ε 2/ε 4, ε 3/ε 4, ε 4/ε 4], n o ncarri er [ε 3/ε 3, ε 2/ε 2, 
ε 3/ε 2]) 
 A P O E 4 ge n ot y p e (ε 2/ε 4, ε 3/ε 4, ε 4/ε 4, n o ε 4)  
 ha vi n g 1 or m ore first de gree relati ves wit h A D  
 A C h EI a n d/ or me ma nti n e use at bas eli ne  
 A m yl oi d P E T  
8. 5.  Ti m e B et w e e n Cli ni c al, I m a gi n g, a n d Bi o m ar k er A s s e s s m e nt s   
T o better u n derst a n d t he ti me bet wee n fee der st u d y partici pati o n a n d c ollecti o n of assess me nts i n 
A A C H, wee ks b et wee n b a seli ne fr o m t he fee d er st u d y a n d all s u bse q ue nt p ost-baseli ne 
assess me nts will be s u m marize d f or t he cli nical, i ma gi n g, a n d bi o mar ker o utc o mes . 
8. 6.  Cli ni c al O ut c o m e s   
L o n git u di nal assess me nt  acr oss t he fee d er st u d y a n d st u d y A A C H will be s u m marize d f or Part C 
partici pa nts  f or A D A S-C o g 1 3, A D C S -i A D L, i A D R S T otal Sc ore, C D R S u m of B o x es, a n d 
M M S E T otal Sc ore.  C ha n ge fr o m baseli ne t o eac h sc he d ule d c ollecti o n of t hese meas ures d uri n g 
t he fee d er st u d y, t o t he first o n-site assess me nt fr o m Part A of st u d y A A C H, a n d t o t he Part C 
assess me nt of st u d y A A C H w ill be m o delle d wit h an a nal ysis of c ov aria n ce ( A N C O V A)  m o del 
wit h fact ors f or ba seli ne sc ore, bas eli ne a ge, years of e d ucati o n, prese nce/ a bse nce of a nti -
de me ntia me dicati o ns ( yes/ n o) , a n d A A C G treat me nt gr o u p. 
F or c o m p aris o n p ur p oses  t o a n u ntreate d partici pa nt p o p ulati o n, c ha n ge fr o m baseli ne t o eac h of 
t he sa me visits will be s h o w n f or A A C H s u bjects t hat partici pate d i n Part B of A A C H, wit h t he 
e x ce pti o n t hat t he Part C assess me nt w o ul d be re place d b y t he Part B Visit 1 ( pri or t o treat me nt) 
assess me nt.  
A d diti o nall y, eac h of t hese o utc o me s will be a nal yz e d o n a n a n n ualize d basis.  Ti m e fr o m t he 
base li ne assess me nt t o e ac h p ost-baseli ne ass ess me nt will be deter mi ne d a n d di vi de d b y 3 6 5 t o 
deri ve a c ha n ge p er year val ue.  T hese v al ues will be m o delle d usi n g t he s a me A N C O V A 
a nal ysis s p ecifie d a b o ve.  
8. 7.  P E T I m a gi n g O ut c o m e s   
L o n git u di nal assess me nt acr oss t he fee d er st u d y a n d st u d y A A C H will be s u m marize d f or Part C 
partici pa nts f or fl or beta pir P E T a n d fl orta uci pir P E T res ults. C ha n ge fr o m b aseli ne t o eac h 
sc he d ule d c ollecti o n of t hese meas ur es d uri n g t he fee der st u d y a n d t o t he Part C assess me nt of 
st u d y A A C H will be m o delle d wit h a n a nal ysis of c ovaria n ce ( A N C O V A)  m o del wit h fact ors f or 
baseli ne P E T res ult, baseli ne a ge, years of e d u cati o n, a n d pre se n ce/a bs e nce of a nti-de me ntia 
me dicati o ns ( yes/ n o) . 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 1 9  
L Y 3 0 0 2 8 1 3  
A d diti o nall y, eac h of t hese o utc o mes will be a nal yz e d o n a n a n n ualize d basis.  Ti me fr o m t he 
baseli ne assess me nt t o e ac h p ost -baseli ne ass ess me nt will be deter mi ne d a n d di vi de d b y 3 6 5 t o 
deri ve a c ha n ge p er year val ue.  T hese v al ues will be m o delle d usi n g t he s a me A N C O V A 
a nal ysis s p ecifie d a b o ve.  
8. 8.  Pl a s m a Bi o m ar k er  O ut c o m e s   
L o n git u di nal assess me nt acr oss t he fee d er st u d y a n d st u d y  A A C H will be s u m marize d f or Part C 
partici pa nts f or Pta u -2 1 7 a n d ne ur ofil a m e nt li g ht c hai n ( Nf L) pr otei n . C ha n ge fr o m baseli ne t o 
eac h sc h e d ule d c ollecti o n of t hese meas ures d uri n g t he fee d er st u d y  a n d t o t he Part C assess me nt 
of st u d y A A C H will be m o dell e d wit h a n a nal ysis of c ovaria n ce ( A N C O V A)  m o del wit h fact ors 
f or baseli ne v al ue, bas eli ne a ge, a n d A A C G treat me nt gr o u p .  F or b ot h of t hese bi o mar kers, 
c ha n ges o n t he ori gi n al scale a n d t h e l o g -tra nsf or me d scale will be dis pla ye d. 
F or c o m p aris o n p ur p oses t o a n u ntreate d partici pa nt p o p ulati o n, c ha n ge fr o m baseli ne t o eac h of 
t he sa me visits will be s h o w n f or A A C H s u bjects t hat partici pate d i n Part B of A A C H, wit h t he 
e x ce pti o n t hat t he Part C assess me nt w o ul d be re place d b y t he Part B Visit 1 ( pri or t o treat me nt) 
assess me nt.  
A d diti o nall y, eac h of t hes e o utc o mes will be a nal yz e d o n a n a n n ualize d basis.  Ti me fr o m t he 
baseli ne assess me nt t o e ac h p ost -baseli ne ass ess me nt will be deter mi ne d a n d di vi de d b y 3 6 5 t o 
deri ve a fact or t o b e m ulti plie d b y t he o bser ve d c h a n ge, res ulti n g i n a  c h a n ge p er year val ue.  
T hese val ues will be m o delle d usi n g t he s a me A N C O V A a nal ysis s pecifi e d a b o ve.  
 
 
 
 
 
 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 2 0  
L Y 3 0 0 2 8 1 3  
9.  
R ef er e n c e s   
Mc gra w, Ke n net h & W o n g, S. P.. ( 1 9 9 6). F or mi n g I nfere nces A b o ut S o me I ntr aclass C orrelati o n 
C oefficie nts. Ps yc h ol o gi cal Met h o ds. 1. 3 0 -4 6. 1 0. 1 0 3 7/ 1 0 8 2 -9 8 9 X. 1. 1. 3 0.  
 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 2 1  
L Y 3 0 0 2 8 1 3  
1 0.  A p p e n di c e s   
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


I 5 T-M C -A A C H  S A P  V er si o n 2  
 
P a g e 2 2  
L Y 3 0 0 2 8 1 3  
 
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T


Si g nat ure Pa ge f or V V- C LI N- 0 7 6 5 2 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 7 6 5 2 8 v 1. 0
A p pr o val
1 3- Dec- 2 0 2 2 1 5: 0 2: 0 5 G M T + 0 0 0 0
A p pr o ve d o n 1 3 Dec 2 0 2 2 G M T
P P D