Assessment of Safety, Tolerability, and Efficacy of LY3303560 in Early Symptomatic Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease (AD)
Sponsor: Eli Lilly and Company

 
 
 
Pr ot oc ol : I 8 G- M C- L M D C(c)  
 
 
Assess me nt of Safet y, T olera bilit y, a n d Efficac y of L Y 3 3 0 3 5 6 0 i n Earl y 
S y m pt o matic Alz hei mer’s Disease  
 
 
N C T 0 3 5 1 8 0 7 3  
 
 
A p pr o val Date: 2 9 -Mar -2 0 2 1  

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 3 0 3 5 6 0
Pr ot o c ol I 8 G-M C -L M D C ( c)
A s s e s s m e nt of S af et y , T ol er a bilit y, a n d Effi c a c y  of 
L Y 3 3 0 3 5 6 0 i n E arl y  S ym pt o m ati c A l z h ei m er’ s Di s e a s e
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 
L Y 3 3 0 3 5 6 0, 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 3 0 3 5 6 0
M ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, P h a s e 2 st u d y c o m p ari n g u p t o 
5 6 0 0 m g of  L Y 3 3 0 3 5 6 0 wit h pl a c e b o o v er 8 0 w e e k s i n a p pr o xi m at el y 2 2 5 p ati e nt s wit h 
e arl y s y m pt o m ati c A D .
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 El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 1 9 F e br u ar y 2 0 1 8
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 1 8 M a y 2 0 1 8
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y: 2 6 A u gu st 2 0 1 9
A m e n d m e nt ( c) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d 
b el o w .
A p pr o v al D at e: 2 9- M ar- 2 0 2 1 G M T

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2
L Y 3 3 0 3 5 6 0
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 me n d me nt ( b)
2 6 -A u g -2 0 1 9
A me n d me nt (a)
1 8- M a y - 2 0 1 8
Ori gi nal P r ot oc ol
1 9- Fe b - 2 0 1 8
A me n d me nt [ c]
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 i ncl u des c ha n ges t o t he statist ical mo d el  use d i n a nal yses of pri mar y a n d 
sec o n dar y o ut c o mes, a n d m o dificat i on t o t he sc o pe of t he t hir d i nteri m a nal ysis.
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
Secti o n 1. S y n o psis
C ha n ge d t he statistical m o del use d 
i n a nal yses of pri mar y a n d 
sec o n dar y o utc o mes
Base d o n rece nt data assess me nts of n o n -
L M D C datasets, disease pr o gressi o n m o del 
(D P M ) offers r ed uce d varia bilit y a n d he nce
i m pr o ve d p o wer f or detecti o n of 
l o n git u di nal treat me nt effect sizes i n 
cli nical meas ures
Secti o n 7. 3. 
Bli n di n g
Secti o n 1 0. 3. 6. 
I nteri m A nal yses
A me n de d a nal yses perf or me d b y 
t he e xter nal D M C
Re m o ve d t he r e q uire me nt f or 
efficac y a n d/ or f utilit y assess me nts
i n t hird i nteri m a nal ysis
1) C urre nt u n dersta n d i n g of safet y pr ofile 
d oes n ot s u g gest c o nti n ue d treat me nt t o 
e n d of st u d y a d ds si g nifica nt ris k t o 
partici pa nts. 
2) A me n d me nt ( b) le n gt he ne d st u d y fr o m 
1 8 m o nt hs t o 2 4 m o nt hs base d o n t he 
pre mise t hat t here ma y be dela ye d 
efficac y bet wee n 1 8 a n d 2 4 m o nt hs. 
T her ef or e, a f utilit y a nal ysis at 1 8 
m o nt hs ma y n ot acc uratel y re prese nt 
p ote nt ial ef ficac y at 2 4 mo nt hs .
3) Base d o n t he ti mi n g of last patie nt visit, 
st o p pi n g st u d y f or f utilit y at I nteri m 3
w o ul d res ult i n st u d y cl os ure wit hi n a 
fe w m o nt hs of pla n ne d last st u d y visit.
Secti o n 9. 1. 2. 2. 
Alz hei mer ’s Disease 
C o o perati ve St u d y -
Act i vities of Dail y 
Li vi n g I n ve nt or y 
( A D C S-A D L)
A d de d It e m 6a t o A D C S -A D L 
s u bset of ite ms
C orrect e d u p per li mit i n t he ra n ge
f or t he i A D L sc ore
C orrecte d u p per li mit i n t he ra n ge 
f or t he b A D Ls
C orrecti o n
Secti o n 1 0. 1. 
S a m ple Size 
Det er mi nati o n
A d de d la n g ua ge t o descri be p o wer 
calc ulati o ns a n d t h e false-p ositi ve
rate f or t he u p date d statistical 
m o del
Base d o n rece nt data assess me nts of 
n o n- L M D C datasets, D P M offers 
re d uce d varia bilit y a n d he nce i m pro ve d 
p o wer f or detecti o n of l o n git u di nal 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3
L Y 3 3 0 3 5 6 0
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
treat me nt effect sizes i n cli nical 
meas ures
Secti o n 1 0. 3. 1. 
Ge neral Statistical 
C o nsi derati o ns
Re m o ve d e x plicit refere nce t o 
Bretz’ s gra p hical a p pr oac h
Wit h c ha n gi n g t he pri mar y a nal yses t o 
D P M, a m ore ge neral a p pr oac h ma y be 
re q uire d t o c o ntr ol T y pe I err or
Secti o n 1 0. 3. 1. 
Ge neral Statistical 
C o nsi derati o ns
Secti o n 1 0. 3. 6. 
I nteri m A nal yses
M o dificati o n t o t he sc o pe of t he 
t hird i nteri m a nal ysis
Base d o n rece nt data assess me nts of n o n -
L M D C datasets, D P M offers r ed uce d
varia bilit y a n d he nce i m pr o ve d p o wer f or 
detecti o n of l o n g it u di nal treat me nt effect 
sizes i n cli nical meas ures
Secti o n 1 0. 3. 1. 1. 
Ha n dli n g of Missi n g 
Ite ms f or Scales
C ha n ge d re q uire me nts relate d t o 
sc ori n g of t he A D A S -C o g 1 3 scale
C orrecti o n
Secti o n 1 0. 3. 3. 1.
Pri mar y A nal yses
M o difi e d sc o pe of t he pri m ar y
a nal ysis
Base d o n rece nt data assess me nts of n o n -
L M D C datasets, D P M offers r ed uce d
varia bilit y a n d he nce i m pr o ve d p o wer f or 
detecti o n of l o n git u di nal treat me nt effect 
sizes i n cli nical meas ures
Secti o n 1 0. 3. 3. 2 . 
Sec o n dar y Efficac y 
A nal yses
M o dificati o n t o t he sc o pe of t he 
sec o n dar y a nal ysis
Base d o n rece nt data assess me nts of n o n -
L M D C datasets, D P M offers r ed uce d
varia bilit y a n d he nce i m pr o ve d p o wer f or 
detecti o n of l o n git u di nal treat me nt effect 
sizes i n cli nical meas ures
Secti o n 1 0. 3. 4 . 4. 
Electr ocar di o gra ms
U p date d a nal ysis of E C G data fr o m 
M M R M t o A nal ysis of c o varia nce 
(A N C O V A )
U p date d a nal ysis of E C G data o ver ti me t o 
c urre nt sta n dar d ( A N C O V A b y visit)
Secti o n 1 0. 3. 6.
I nteri m A nal yses
A d de d lan g ua ge t o pr o vi de 
fle xi bilit y t o efficac y a nal yses 
perf or me d b y e xter nal D M C
Clarificati o n
T hr o u g h o ut t he 
pr ot oc ol
Mi n or f or matti n g a n d e dit orial 
c ha n ges
Mi n or, t heref ore n ot detaile d

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4
L Y 3 3 0 3 5 6 0
T a bl e of C o nt e nt s
S e cti o n
P a g e
Pr ot oc ol  I 8 G-M C -L M D C(c) Assess me nt of Safet y, T olera bilit y,  a n d 
Efficac y of L Y 3 3 0 3 5 6 0 i n Earl y  S y m pt o mat ic Alz hei mer’s Disease...................................1
Pr ot oc ol  A me n d me nt S u m mar y of C ha n ges Ta ble....................................................................2
Ta ble of C o nte nts ........................................................................................................................4
1.
S y n o psis ...........................................................................................................................1 1
2.
Sc he d ule of Act i vities .......................................................................................................1 6
3.
I ntr od ucti o n ......................................................................................................................2 8
3. 1.
St u d y  Ratio nale ............................................................................................................2 8
3. 2.
Bac k gr o u n d ..................................................................................................................2 9
3. 2. 1.
N o ncli nical St u dies ..............................................................................................3 0
3. 2. 2.
P hase 1 St u dies ....................................................................................................3 1
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................3 2
3. 3. 1.
Be nefit .................................................................................................................3 2
3. 3. 2.
Ris ks ....................................................................................................................3 2
3. 3. 3.
Be nefit/ Ris k Assess me nt S u m mar y ......................................................................3 3
4.
O bject i ves a n d E n d p oi nts ..................................................................................................3 4
5.
St u d y  Desi g n.....................................................................................................................3 6
5. 1.
O verall Desi g n .............................................................................................................3 6
5. 1. 1.
Scree ni n g Peri o d ( Visit 1) ....................................................................................3 8
5. 1. 1. 1.
Scree ni n g Pr oce d ures .....................................................................................3 9
5. 1. 1. 1. 1.
Mi ni -Me ntal  State E xa mi nati on ................................................................3 9
5. 1. 1. 1. 2.
C o g State Brief Batter y ..............................................................................3 9
5. 1. 1. 1. 3.
Di gi t al Cloc k Dra wi n g Test ......................................................................3 9
5. 1. 1. 1. 4.
C ol u m bia S uici de Se veri t y Rati n g Scale — A d ult 
Versi o n .....................................................................................................3 9
5. 1. 1. 1. 5.
Alz hei mer’s Disease Bi o mar kers ..............................................................4 0
5. 1. 1. 1. 6.
Scree ni n g P ositr o n E missi o n T o m o gra p h y  a n d 
Ma g net ic Res o na nce I ma gi n g ...................................................................4 0
5. 1. 1. 1. 6. 1.
Scree ni n g Fl orta uci pir F 1 8 P E T Sca n .................................................4 0
5. 1. 1. 1. 6. 2.
Scree ni n g M RI ....................................................................................4 0
5. 1. 2.
D o u bl e- Bli n d Peri o d ( Visit 2 t hr o u g h Visit 2 8) ....................................................4 1
5. 1. 3.
I mm u n o ge nicit y a n d Safet y F o ll ow- U p Vi sit ( Visit 8 0 1)......................................4 1
5. 2.
N u m ber of Partici pa nts ................................................................................................. 4 1
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................4 1
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................4 1

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 5
L Y 3 3 0 3 5 6 0
5. 5.
J ustificati o n f or D ose ...................................................................................................4 2
6.
St u d y  P o p ulat i on ...............................................................................................................4 4
6. 1.
I ncl usi on Cri t eria ..........................................................................................................4 4
6. 2.
E xcl usi o n Cri t eria ........................................................................................................4 6
6. 2. 1.
Rati o nale f or E xcl usi o n  of Certai n St u d y Ca n di dates ...........................................4 9
6. 3.
Lifest yle Restrict i ons ....................................................................................................4 9
6. 4.
Scree n Fail ures .............................................................................................................4 9
7.
Treat me nts ........................................................................................................................5 0
7. 1.
Treat me nts A d mi nistere d .............................................................................................5 0
7. 1. 1.
Pac ka gi n g a n d La beli n g .......................................................................................5 0
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................5 1
7. 2. 1.
S el ect i on a n d Ti mi n g o f D oses .............................................................................5 1
7. 3.
Bli n di n g .......................................................................................................................5 2
7. 4.
D osa ge M o dificati o n ....................................................................................................5 3
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................5 3
7. 6.
Treat me nt C o m plia nce ................................................................................................. 5 3
7. 7.
C o nc o mita nt T hera p y ...................................................................................................5 3
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................5 5
7. 8. 1.
Treat me nt after St u d y  C o mplet i on ........................................................................5 5
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................5 6
8. 1.
Di sc o nti n uatio n f r o m St u d y Treat me nt .........................................................................5 6
8. 1. 1.
T e m p orar y  Disc o nti n uati on fr om St u d y  Treat me nt ...............................................5 7
8. 1. 2.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d S u bjects ..............................................5 7
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................5 7
8. 3.
L ost t o F oll o w -U p ........................................................................................................5 8
9.
St u d y  Assess me nts a n d Pr oce d ures ...................................................................................5 9
9. 1.
Efficac y Assess me nts ...................................................................................................5 9
9. 1. 1.
Pri mar y Efficac y  Assess me nts .............................................................................5 9
9. 1. 2.
Sec o n dar y  Efficac y Assess me nts..........................................................................6 0
9. 1. 2. 1.
Alz hei mer’s Disease Assess me nt Scale — C o g ni tive 
s u bscale ( A D A S-C o g 1 3 ) ................................................................................6 0
9. 1. 2. 2.
Alz hei mer’s Disease C o o perati ve St u d y — Act i vities of 
Dail y Li vi n g I n ve nt or y  ( A D C S-A D L) ............................................................6 0
9. 1. 2. 3.
Cli nical De me nt ia Rati n g Scale— S u m  of B o xes ( C D R-
S B) .................................................................................................................6 1
9. 1. 2. 4.
Mi ni -Me ntal  State E xa mi nati on ( M M S E) .......................................................6 1
9. 1. 2. 5.
Bi o m ar ker Efficac y Meas ures.........................................................................6 1
9. 1. 2. 5. 1.
Fl ort a u ci pir F 1 8 P E T Sca n .......................................................................6 1

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 6
L Y 3 3 0 3 5 6 0
9. 1. 2. 5. 2.
V ol u metric M RI .......................................................................................6 1
9. 1. 3.
E x pl or at or y  Efficac y Meas ures ............................................................................6 1
9. 1. 3. 1.
C o g State Brief Batter y  ( C B B) ........................................................................6 1
9. 1. 3. 2.
Di gi t al Cloc k Dra wi n g Test ( D C T Cl oc k) ........................................................6 1
9. 1. 3. 3.
Pl as ma Ta u, P h os p h o 1 8 1 Ta u, a n d Ne ur ofila me nt Li g ht ................................6 2
9. 1. 4.
A p pr o priate ness of Efficac y  Assess me nts ............................................................6 2
9. 2.
A d verse E ve nts ............................................................................................................6 2
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................6 3
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................6 4
9. 2. 2.
C o m plai nt Ha n dli n g .............................................................................................6 4
9. 3.
Tr e at me nt of O ver d ose ................................................................................................. 6 4
9. 4.
S af et y ...........................................................................................................................6 5
9. 4. 1.
P h ysical a n d Ne ur ol o gical E xa mi nat i ons ..............................................................6 5
9. 4. 2.
Electr ocar di o gra ms ..............................................................................................6 5
9. 4. 3.
Vi t al Si g ns........................................................................................................... 6 6
9. 4. 3. 1.
Bl o o d Press ure ................................................................................................6 6
9. 4. 3. 2.
H eig ht, Wei g ht, a n d B o d y  T e mperat ure ..........................................................6 6
9. 4. 4.
La b orat or y  Tests..................................................................................................6 7
9. 4. 5.
I mm u n o ge nicit y Assess me nts ..............................................................................6 7
9. 4. 6.
Ot her Tests ...........................................................................................................6 7
9. 4. 6. 1.
C ol u m bia S uici de Se veri t y Rati n g Scale .........................................................6 7
9. 4. 6. 2.
Ma g net ic Res o na nce I ma gi n g.........................................................................6 8
9. 4. 7.
S af et y M o ni t ori n g ................................................................................................6 8
9. 4. 7. 1.
I nf usi on React i ons ..........................................................................................6 9
9. 4. 7. 2.
I mm u n o ge nicit y ..............................................................................................6 9
9. 4. 7. 3.
He pati c Safet y M o ni t ori n g..............................................................................6 9
9. 4. 8.
A p pr o priate ness of Safet y Assess me nts ................................................................7 0
9. 5.
P har mac o ki net ics .........................................................................................................7 0
9. 6.
P har mac o d y na mics ......................................................................................................7 1
9. 6. 1.
C ha n ge i n A g gre gate d Ta u De p osit i on as Esti mate d b y 
Fl ort a u ci pir F 1 8 ..................................................................................................7 1
9. 7.
P har mac o ge n o mics [ O R] Ge netics ...............................................................................7 1
9. 7. 1.
A p o li p o pr otei n E Ge n ot y pi n g...............................................................................7 1
9. 7. 2.
W h o le Bl o o d Sa m ples f or P har mac o ge netic Researc h..........................................7 1
9. 8.
Bi o m ar kers ...................................................................................................................7 2
9. 9.
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics ...................................................7 2
1 0.
Stati stical C o nsi derati o ns ..................................................................................................7 4
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................7 4

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7
L Y 3 3 0 3 5 6 0
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................7 5
1 0. 3.
Stati stical A nal yses ......................................................................................................7 5
1 0. 3. 1.
Ge neral Statist ical C o nsi derat i ons ........................................................................7 5
1 0. 3. 1. 1.
Ha n dli n g of Missi n g Ite ms f or Scales .............................................................7 6
1 0. 3. 2.
Treat me nt Gr o u p C o m para bilit y ...........................................................................7 6
1 0. 3. 2. 1.
S u bject Dis p osit i on .........................................................................................7 6
1 0. 3 . 2. 2.
S u bject C haracterist ics....................................................................................7 7
1 0. 3. 2. 3.
Pri or a n d C o nc o mi ta nt T hera p y......................................................................7 7
1 0. 3. 2. 4.
Treat me nt C o m plia nce ....................................................................................7 7
1 0. 3. 3.
Efficac y A nal yses ................................................................................................7 7
1 0. 3. 3. 1 .
Pri mar y A nal yses ...........................................................................................7 7
1 0. 3. 3. 2.
Sec o n dar y  Efficac y A nal yses..........................................................................7 8
1 0. 3. 4.
S af et y A nal yses ....................................................................................................7 9
1 0. 3. 4. 1.
A d verse E ve nts ...............................................................................................7 9
1 0. 3. 4. 2.
Vi t al Sig ns a n d Wei g ht ...................................................................................8 0
1 0. 3. 4. 3.
La b orat or y  A nal yses.......................................................................................8 0
1 0. 3. 4. 4.
Electr ocar di o gra ms .........................................................................................8 0
1 0. 3 . 4. 5.
E val uat i on of I m m u n o ge nicit y ........................................................................8 1
1 0. 3. 4. 6.
S ui ci dal I deati on a n d Be ha vi or .......................................................................8 1
1 0. 3. 5.
P har mac o ki net ic/ P har mac o d y na mic A nal yses......................................................8 2
1 0. 3. 6.
I nteri m A nal yses ..................................................................................................8 2
1 1.
Refere nces ........................................................................................................................8 4
1 2.
A p pe n dices .......................................................................................................................8 8

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P a g e 8
L Y 3 3 0 3 5 6 0
Li st of T a bl e s
T a bl e
P a g e
Ta ble L M D C. 2. 1.
Sc he d ule of Act i vities.............................................................................1 7
Ta ble L M D C. 4. 1.
O bject i ves a n d E n d p oi nts .......................................................................3 4
Ta ble L M D C. 7. 1.
Treat me nt Re gi me ns, D o u ble -Bli n d Treat m e nt Peri o d ............................5 0

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 9
L Y 3 3 0 3 5 6 0
Li st of Fi g ur e s
Fi g ur e
P a g e
Fi g ure L M D C. 5. 1.
Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol I 8 G-M C -L M D C. .........3 7

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 0
L Y 3 3 0 3 5 6 0
Li st of A p p e n di c e s
A p p e n di x
P a g e
A p pe n di x 1.
A b bre viat i ons a n d Defi nit i ons ................................................................8 9
A p pe n di x 2.
Cli nical La b orat or y  Tests........................................................................9 4
A p pe n di x 3.
St u d y  G o ver na nce C o nsi derati ons ..........................................................9 5
A p pe n di x 4.
He pati c M o nit orin g Tests f or Treat me nt -E m er ge nt A b n or malit y ............9 9
A p pe n di x 5.
Fl ort a u ci pir F 1 8 Ta u P E T I m a gi n g ......................................................1 0 0

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 1
L Y 3 3 0 3 5 6 0
1.
S y n o p si s
Title of St u d y:
Pr ot oc ol  I 8 G-M C -L M D C ( c).  Assess me nt of Safet y, T olera bilit y, a n d Efficac y of L Y 3 3 0 3 5 6 0 i n 
Earl y S y m pt o mat ic Alz hei mer’s Disease
R ati o n ale:
Eli Lill y a n d C o mp a n y  (Lill y ) is de vel o pi n g L Y 3 3 0 3 5 6 0 , a h u ma nize d m o n ocl o nal a nt i b o d y,
w hic h tar gets e xtracell ular a g gre gat e d ta u f or t he treat me nt of Alz hei mer’s disease ( A D ).
A P hase 1 st u d y  (I 8 G-M C -L M D A [ L M D A]) is c urre nt l y o n g oi n g t o e val uate the safet y,  
t olera bilit y, a n d p har mac o ki net ics ( P K) of L Y 3 3 0 3 5 6 0 i n healt h y s u bjects a n d pat ient s wit h A D. 
S af et y a n d t olera bilit y e val uat i ons are bei n g c o n d ucte d o ver a wi de ra n ge o f si n gle d oses, a n d 
d ose escalat i on d oes n ot occ ur u n til safety data fr o m  pre vio us d oses ha ve bee n re vie we d.  St u d y  
L M D A ai ms t o assess w het her a ma xi m u m -t olerate d d ose ca n be esta b lis he d or t o de m o nstrate 
t he t olera bilit y of  a d ose greater t ha n t he e x pecte d t hera pe utic d ose.
A P hase 1 m ult i ple-d ose, d ose -escalati o n st u d y (I 8 G-M C -L M D D [ L M D D]) is c urre nt l y als o 
o n g oi n g t o assess t he safet y,  t olera bilit y, P K , a n d p har mac o d y na mics ( P D) of  L Y 3 3 0 3 5 6 0 i n 
pati e nts wit h mil d c o g niti ve i m pair me nt d ue t o A D or mil d -t o-m o derate Al z hei mer’s De me nt ia.
St u d y  I 8 G-M C -L M D C ( L M D C) is a 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 valuate 
t he safet y a n d efficac y of ta u a nti b o d y ( L Y 3 3 0 3 5 6 0) i n patie nts wit h l ow- t o-me d i u m ta u b ur de n 
as meas ure d b y fl orta uci pir wit hi n a p o p ulat i on w h o ha ve earl y s y m pt o mat ic A D ( pr o dr o mal A D 
a n d mil d de me nt ia d ue t o A D).  St u d y L M D C will assess w het her bi n di n g a n d cleara nce of 
a g gre gate d ( misf ol de d) t a u ca n sl o w t he pr o gressi o n of disease as assesse d b y cli nical meas ures 
a n d bi o mar kers of disease pat h ol o g y  a n d ne ur o de ge nerati on o ver 1 0 0 wee ks of treat me nt
( 2 6 d oses, a d mi nistere d as a n i ntra ve n o us [I V] i nf usi o n o nce e ver y  4 wee ks [Q 4 W ], starti n g at 
Vi sit 2 [Wee k
0 ] a n d e n di n g at Visit 2 7 [Wee k
1 0 0], wit h e n d p o i nt c o g niti ve assess me nts carrie d 
o ut at  Visit 2 8 [ Wee k
1 0 4] ).
P r o gressi o n of cere bral ta u o pat h y ass ociate d wit h A D will be assesse d b y p osi tr o n e missi o n 
t o mo gra p h y (P E T ) sca n usi n g fl orta uci pir F 1 8 , a mar ker of a g gre gate d ( misf ol de d) t a u.  
F l orta ucipir is a n F -1 8- labele d s mall m o lec ule t hat bi n ds wit h hi g h affi nity a n d select i vity t o 
a g gre gate d ta u pat h ol o g y ( b ut n ot n or mal mo n o m eric ta u) i n e x vi v o h u ma n brai n sect i ons. T hi s 
bi o mar ker is belie ve d t o pr o vi de a q ualitat i ve a n d q ua ntitati ve meas ure me nt of de p osite d 
a g gre gate d ta u a n d its a nat o mical distri b ut i on i n t he brai n.  A bse nce of si g nifica nt ne oc ortical 
flort a u ci pir F 1 8 P E T si gnal is belie ve d t o i n dicate t hat, alt h o u g h patie nts ma y be cli nicall y 
ma nifes tin g c o g nit i ve i m pair me nt, levels of a g gre gate d ta u de p osits are l o w a n d ma y n ot ha ve 
s prea d be y on d t he m e dial/a nterior t e m p or al  c orte x, a n d at t he gr o u p le vel ma y be ass ociate d wit h 
a relati vel y sl o w rate of c o g nit i ve deteri orati o n. H i g h a n d wi des prea d fl ort a u cipi r F 1 8 si g nal  
i n dicates t hat a g gre gate d ta u de p osits ha ve alrea d y s prea d t hr o u g h mu c h of  t he brai n, a n d at t he 
gr o u p l e vel ma y be ass ociat e d wit h a more ra pi d rate of c o g ni tive deteri orati o n . T h us, 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 2
L Y 3 3 0 3 5 6 0
im ple me ntati o n of fl ort a u cipi r F 1 8 sca ns ai ms t o facilitate sele ctio n of parti ci pa nts wit h a 
l ow- t o-me d i u m t a u acc u m ulati o n f or e ntr y int o t he cli nical trial .
Alz hei mer’s disease is als o ass ociate d wit h pr o n o u nce d brai n atr o p h y, reflecti n g b ul k 
ne ur o de ge nerat i ve l oss of gr a y  a n d w hite matter.  Pr o gre ssi o n of brai n atr o p h y will be assesse d 
b y v o l um etri c ma g net ic res o na nce i ma gi n g ( v M RI), pr o vi di n g re gi o nal q ua ntificati o n of v o l ume 
l oss.
T he patie nt p o p ulat i on selecte d f or t he cli nical trial is pati e nts wi t h AD ha vi n g earl y
s y m pt o mat ic disease (t hat is, pr o dr o m al-t o-mil d A D de me nt ia) a n d l ow- t o-me d i u m ta u b ur de n as 
meas ure d b y fl orta uci pir F 1 8 P E T sca ns.  Cli nical– pat h ol o gi cal c orrelat i ons s u g gest t hat 
baseli ne i ma gi n g t hat all o ws sta gi n g base d o n ne ur ofi brillar y  ta n gles c o uld s u bsta nt iall y i m pr o ve 
t he p o wer of cli nical trials ai me d at c ha n gi n g t he rate of pr o gressi o n of t he disease ( Qia n et al. 
2 0 1 7).  A n earl y  AD p o p ul at i on defi ne d cli nicall y a n d pat h o l ogi call y ( usi n g ta u P E T i ma gi n g) is 
a nt ici pate d t o be m ore h o m o ge ne o us t ha n p o p ulati o ns defi ne d b y cli nical s y m pt o ms al one.  It is 
p ost ul ate d t hat t he earl y A D, l ow- t o-me d i u m ta u b ur de n p o p ulati on will be s ufficie nt l y earl y i n 
t heir disease c o urse t o res p o n d t o treat me nts pri or t o m ore a d va nce d disease w he n e xte nsi ve 
irre versi ble ne ur o nal l oss occ urs.  C o nfir mat i on of a m yl o i d stat us is n ot re q uire d beca use t he 
flort a u ci pir F 1 8 P E T st u d y  e ntr y crit eria c o nfir m t he prese nce of ta u o pat h y of AD a n d t he 
a nt i b o d y tar get, a n d is hi g hl y ass o ciat e d wit h a m yl oid p osi ti vity ( Lill y, data o n file, A 0 5 st u d y ).

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 3 3 0 3 5 6 0
O bjecti ve(s)/ E n d p oi nts:
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nt
T o test t he h y p ot hesis t hat L Y 3 3 0 3 5 6 0 a d mi nistere d 
f or 1 0 0 wee ks will decrease t he decli ne i n c o g niti ve 
a n d/ or f u ncti o nal o utc o mes i n p atie nts wit h earl y 
s ym pt o matic A D relati ve t o place b o.
C ha n ge i n c o g niti o n a n d f u ncti o n as meas ure d b y t he 
i nte grate d Alz hei mer’s Disease Rati n g Scale (i A D R S) sc ore 
fr o m baseli ne t o 1 0 4 wee ks.
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 L Y 3 3 0 3 5 6 0 v ers us place b o o n 
cli nical pr o gr essi o n i n patie nts wit h earl y 
s ym pt o matic A D .
C ha n ge i n c o g nit i on a n d/ or f u nct i on fr o m baseli ne 
t o 1 0 4 wee ks as meas ure d b y t he c ha n ge i n:

Alz hei mer’s Disease Assess me nt Scale —
C o g ni tive s u bscale ( A D A S -C o g 1 3) sc ore

Alz hei mer’s Disease C o o perati ve St u d y —
i nstr u me nt al Acti vit ies of Dail y Li vi n g 
scale ( A D C S-i A D L) sc ore

Cli nical De me nt ia Rati n g Scale— S u m  of 
B o xes ( C D R -S B) sc ore

Mi ni -Me ntal  State E xa mi nati on ( M M S E) 
sc ore
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
br ai n a g gre gate d ta u de p ositi o n.
C ha n ge i n brai n a g gre gate d ta u de p ositi o n fr o m baseli ne 
t hr o u g h 1 0 4 wee ks as meas ure d b y fl orta uci pir F 1 8 P E T 
sca n.
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
atte n uati n g d o w nstrea m ma rkers of t he 
ne ur o de ge nerati ve pr ocess i n A D .
C ha n ge i n brai n v o l u metric meas ures fr o m baseli ne t hr o u g h 
1 0 4 wee ks as meas ure d b y v ol u metric ma g netic res o na nce 
i ma gi n g (v M RI ).
S afet y O bjecti ve
S afet y E n d p oi nts
T o e val uate safet y a n d t olera bilit y of L Y 3 3 0 3 5 6 0 .

Safet y assess me nts:
o
S p o nta ne o usl y re p orte d A Es
o
C li nical la b orat or y tests
o
V ital si g n a n d b o d y wei g ht meas ure me nts
o
1 2- lea d E C Gs
o
P h y sical a n d ne ur ol o gical e xa mi nati o ns
o
A nti -dr u g a nti b o dies

Ma g netic res o na nce i ma gi n g (M RI ) (treat me nt-
e mer ge nt ra di ol o gical fi n di n gs)

C ol u m bia S uici de Se verit y Rati n g Scale ( C-S S R S)

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 3 3 0 3 5 6 0
S u m m ar y of St u d y Desi g n:
St u d y  L M D C is a m ult ice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, P hase 2 st u d y  of 
L Y 3 3 0 3 5 6 0 i n s u bjects wit h earl y s y m pt o matic A D wi t h lo w -t o-me d i u m cere bral ta u b ur de n.  
T he ma xi m u m p ossi ble d urati o n of  t he st u d y is 1 2 1 wee ks t hat i ncl u des a scree ni n g peri o d of u p 
t o 8 wee ks, a t reat me nt p eri o d of  1 0 0 wee ks, a 4 -wee k p ost last d ose assess me nt, a n d a n 
i m m u n o ge nicity a n d safet y f oll ow- u p peri o d of  u p t o 1 3 wee ks f o ll owi n g t he l ast d ose of  st u d y 
dr u g at  Wee k 1 0 0.
Tre at me nt Ar ms a n d D ur ati o n:
P ati e nts will recei ve o ne of t he fol l owi n g treat m e nts for 1 0 0 wee ks:

1 4 0 0 m g L Y 3 3 0 3 5 6 0 :  L Y 3 3 0 3 5 6 0 1 4 0 0 m g I V i nf usi on Q 4 W f or 1 0 0 wee ks
( Visit 2 [ Wee k 0] t o Visit 2 7 [ Wee k 1 0 0 ]).

5 6 0 0 m g L Y 3 3 0 3 5 6 0 :  L Y 3 3 0 3 5 6 0 5 6 0 0 m g I V i nf usi on Q 4 W f or 1 0 0 wee ks
( Visit 2 [ Wee k 0] t o Visit 2 7 [ Wee k 1 0 0 ]).

Pl ace b o :  I V place b o i nf usi on Q 4 W f or 1 0 0 wee ks ( Visit 2 [ Wee k 0] t o Visit 2 7
[ Wee k 1 0 0 ]).
N u m ber of P atie nts ( A p pr o xi m ate):

Scree ne d – a p pr o xi matel y 1 4 0 0

Ra n d o mize d – 2 8 5 ( 3 0 ra n d o mize d f or Gr o u p 1 [ patie nts i ncl u de d i n t he first 
i nteri m safet y a nal ysis] a n d 2 55 ra n d omize d f or Gr o u p 2)

E val ua ble ( C o mpleters) – 2 2 5 (a p pr o xi matel y 7 5 per treat me nt gr o u p)
St atistic al A n al ysis:
All efficac y a nal yses will f o ll ow t he i nte nt -t o-treat (I T T) pri nci ple u nless ot her wise s pecifie d. 
A n I T T a nal ysis is a n a nal ysis of data b y  t he gr o u ps t o w hic h s u bjects are assi g ne d b y ra n d o m 
all ocat i on, e ve n if t he s u bject d oes n ot ta ke t he assi g ne d trea t me nt, d oes n ot recei ve t he c orrect 
treat me nt, or ot her wise d oes n ot f oll ow t he pr ot oc ol . U nless ot her wise n ote d, all pair wise tests 
of  treat me nt effects will be c o n d ucte d at a 2 -si de d alp ha le vel  of 0. 0 5; 2 -side d c o nfi de nce 
i nter vals ( CIs) will be dis pla ye d wit h a 9 5 % CI.
Effic ac y :
T he pri mar y  o bjecti ve of t his st u d y is t o test t he h y p ot hesis t hat I V i nf usi on of L Y 3 3 0 3 5 6 0 will 
slo w t he decli ne of A D as meas ure d b y t he i nte grate d Alz hei mer’s Disease Rat i n g Scale 
(i A D R S), w hic h is a c o m p osite c o g nit i ve a n d f u nctio n al meas ure, c o mpare d wi t h place b o i n 
pati e nts wit h earl y s y m pt o mat ic A D.  T he slo wi n g i n disease pr o gressi o n o n i A D R S will be 
e valuate d usi n g a disease pr o gressi o n m o del ( D P M) as a pri mar y assess me nt m o d el . T o test t he 
h y p ot hesis of a disease pr o gressi o n be nefit , we calc ulate t he p osteri or pr o ba bilit y of  s u periori t y 
i n c o g nitive /f u ncti onal slo wi n g , a n d if it is a b o ve a pre-s pecifie d t hres h ol d ( w hic h c o ntr ols t he 
e x peri me nt -wi se ty pe I err or at 2. 5 %) , t he n a clai m of c o g nit i ve sl o wi n g will be ma de.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 5
L Y 3 3 0 3 5 6 0
Eac h of t he sec o n dar y  efficac y o utc o mes will be assesse d usi n g D P M, mi xe d m o del re peate d 
meas ure s (M M R M ), a n d nat ural c u bic s pli ne ( N C S ) a nal yses. T hese sec o n dar y efficac y 
o utc o m es i ncl u de Alz hei mer’s Disease Assess me nt Scale — C o g ni tive s u bscal e ( A D A S -C o g 1 3 ), 
Alz hei mer’s Disease C o o perati ve St u d y — i nstr u me ntal Act i vities of Dail y Li vi n g I n ve nt ory 
( A D C S-i A D L), Cli nical De me nt ia Rati n g Scale— S u m  of B o xes ( C D R-S B), a n d Mi ni -Me ntal  
State E xa mi nat i on ( M M S E) . i A D R S will als o be assesse d usi n g M M R M a n d N C S a nal yses.
A d dit i onal d etails are descri be d i n t he statistical anal ysis p la n (S A P ).
S afet y:
S af et y will be assesse d b y s u m marizi n g a n d c o m p ari n g bet wee n treat me nt ar m a d verse e ve nts 
(A Es ), la b orat or y a nal ytes, vit al si g ns, ma g neti c res o na nce i ma gi n g (M RI ) sca ns, 
electr ocar dio gr a m s ( E C Gs), a n d i m m u n o ge nicity f or eac h defi ne d st u d y p erio d:  a treat me nt 
p eri o d of  1 0 0 wee ks, a 4- wee k p ost last d ose assess me nt, a n d a n i m m u n o ge nicity a n d safet y 
f oll ow -u p peri o d of u p t o 1 3 wee ks f o ll owi n g t he last d ose of st u d y  dr u g at Wee k 1 0 0.
P h ar m ac o ki netics/ P h ar m ac o d y n a mics:
C o m part me nt al mo deli n g of  L Y 3 3 0 3 5 6 0 P K data usi n g n o nli near mi xe d effects m o deli n g or 
ot her a p pr oac hes ma y be e x pl ore d, a n d p o p ulat i on esti mates f or cleara nce a n d ce ntral vol u me of 
di stri b uti on ma y be re p orte d. De pe n di n g o n t he m o del selecte d, ot her P K para meters ma y als o 
be re p orte d. E x pl or at or y  gra p hical a nal yses of t he effect of d ose le vel or de m o gra p hic fact ors o n 
P K para meters ma y be c o n d ucte d. If a p pr o priate, data fr o m ot her st u dies of L Y 3 3 0 3 5 6 0 ma y be 
use d i n t his a nal ysis.
P har mac o ki net ic/ p har mac o d y na mic r elat i ons hi ps bet wee n plas ma L Y 3 3 0 3 5 6 0 c o nce ntrati o n a n d
flort a u ci pir F 1 8 sta n dar dize d u pta ke val ue rati o (S U Vr ), v M RI meas ures, c o g nitive e n d p o i nts, 
or o t her mar kers of P D acti vit y ma y be e x pl ore d gra p hicall y.  T he rel at i ons hi p bet wee n t he 
prese nce of a nti b o dies a gai nst L Y 3 3 0 3 5 6 0 a n d P K, P D, safet y, a n d/ or efficac y ma y be assesse d 
gra p hicall y .  If warra nte d, a d diti onal a nal ysis ma y be e x pl ore d t o e val uate p ote ntial i nteract i ons 
f or a nt i-dr u g a nti b o dies ( A D A ), P D, a n d ot her e n d p oi nts ( P E T or M RI meas ures , safety , etc.).  
A d di tio n al mo deli n g ma y  be p erf or m e d base d o n t he res ults of t he gra p hical a nal yses.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 6
L Y 3 3 0 3 5 6 0
2.
S c h e d ul e of A c ti viti e s

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 7
L Y 3 3 0 3 5 6 0
T a bl e L M D C . 2. 1.
S c h e d ul e of A cti viti e s
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C Vi sit 1 ( S cr e e ni n g P eri o d)
Peri o d:
Pr oce d ure
Visit N o.:
V 1
E n d of Wee k Relati ve t o St u d y Me dicati o n Start
a
W k - 8 t hr o u g h W k - 1
T olera nce I nter val f or Visit ( da ys)
a, b
- 5 6 t o 0
P R E LI MI N A R Y S C R E E NI N G
E ntr y a n d A d mi nistr ati ve
A b bre viate d ( or f ull) I nf or me d C o nse nt – partici pa nt a n d st u d y part ner
c
X
  Patie nt n u m ber assi g ne d via I W R S
X
  De m o gra p hics a n d ha bits
X
  Me dical hist or y
X
E ntr y Di a g n o stics
  M M S E
d ,o
X
  C B B
X
  D C T Cl oc k
X
S C R E E NI N G
F ull I nf or me d C o nse nt – partici pa nt a n d st u d y part ner
d
X
  I ncl usi o n/e xcl usi o n re vie w
X
  P h ysical/ ne ur ol o gical e xa mi nati o n
e
X
  Pr e vi o us/c o nc o mita nt me dicati o ns
X
  Pr ee xisti n g c o n diti o ns
X
E ntr y Di a g n o stics
S afet y Assess me nts
   Vital si g ns
f
X
   Hei g ht a n d wei g ht
g
X
   E C G i n tri plicate
h
X
   C-S S R S
i
X
   Self -Har m S u p ple me nt F or m
X
j
   Self -Har m F oll o w -u p F or m
X
j
L a b or at or y S peci me ns
   Cli nical c he mistr y, he mat ol o g y
X b
   Hi g h se nsiti vit y C -reacti ve pr otei n
X
   H Bs A g
k
X
   H C V R N A P C R
l
X
  Ur i nal ysis
X
   Plas ma ta u
X
   Plas ma p h os p h o 1 8 1ta u a n d Nf L
X
   Bi o mar ker st ora ge
X
Scree ni n g P E T Sc a n s a n d M RI
   Fl orta uci pir F 1 8 P E T Sca n
m
X
   M RI
n
X

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 8
L Y 3 3 0 3 5 6 0
Sc he d ule of Acti vities , Pr ot oc ol I 8 G-M C -L M D C , Visit 1 ( Scree ni n g Peri o d) A b bre vi ati o ns a n d F o ot n otes
A b bre viati o ns:  C B B = C o g State Brief Batter y; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; D C T Cl oc k = 
Di gital Cl oc k Dra wi n g Test; E C G = electr ocar di o gra m; H Bs A g = h e patitis B s urface a nti ge n ; H C V = h e patitis C 
vir us ; I C F = i nf or me d c o nse nt f or m; 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 = m a g netic res o na nce ima gi n g; Nf L = ne ur ofila me nt li g ht; N o. = n u m ber; P C R = p ol y merase
c hai n reacti o n ; P E T = p ositr o n e missi o n t o m o gra p h y; R N A = ri b o n ucleic aci d; V = visit; W k = wee k.
a
T he i nter val bet wee n t he si g ni n g of t he f ull I C F at V 1 a n d V 2 ma y be u p t o 5 6 da ys t o all o w f or c o m pleti o n of 
V 1 scree ni n g pr oce d ures, assess me nts, a n d e val uati o n of res ults fr o m la b orat or y tests a n d E C Gs.  V 1 is n ot 
c o nsi dere d c o m plete u ntil all scree ni n g pr oce d ures ha ve bee n c o m plete d a n d res ults re vie we d b y t he i n vesti gat or 
t o deter mi ne patie nt eli gi bilit y.
b
Patie nts w h ose scree ni n g res ults are n ot a vaila ble wit hi n t he 5 6 -da y  scree ni n g wi n d o w fr o m t he ti me of si g ni n g 
t he f ull I C F will re ma i n eli gi ble wit hi n V 1 u ntil t hese res ults bec o me a vaila ble if all ot her eli gi bilit y criteria ha ve 
bee n met .  N ote: If all scree ni n g res ults c o nfir mi n g eli gi bilit y f or t he st u d y ha ve n ot bee n recei ve d b y t he site b y 
Da y 5 6 of t he scree ni n g peri o d, it will n ot be c o nsi dere d a pr ot oc ol de viati o n, b ut cli nical la b orat or y tests (bl o o d 
he mat ol o g y, c he mistr y, a n d uri nal ysis are t o be re peate d f or t hat patie nt.   Res ults of t he re peate d la bs are t o be 
re vie we d b y t he i n vesti gat or or q ualifie d desi g nee f or assess me nt of t he patie nt’s c o nti n ue d eli gi bilit y.  Re peat 
scree ni n g f or M M S E,
C B B , D C T Cl oc k, C- S S R S, E C G, fl orta uci pir F 1 8 P E T, M RI , sa m ple c ollecti o n f or 
plas ma ta u, plas ma p h os p h o 1 8 1 ta u, a n d bi o mar ker st ora ge, a n d la b orat or y testi n g f or H Bs A g, a n d H C V R N A 
P C R ar e n ot re q uire d.  
c
A preli mi nar y scree ni n g i nf or me d c o nse nt ma y be o btai ne d t o c ollect de m o gra p hics data a n d a d mi nister t he 
M M S E,
C B B , a n d t he D C T Cl oc k . Patie nts w h o d o n ot meet t he M M S E
scree ni n g criteria will pr ocee d t o 
c o m plete t he C B B a n d D C T Cl oc k, b ut are n ot t o ha ve a n y ot her scree ni n g pr oce d ures perf or me d.  T he y ma y be 
rescree ne d o nce f or t he M M S E 8 wee ks or m ore after t he first scree n.  St u d y part ners are n ot re q uire d t o 
c o m plete t he preli mi nar y scree ni n g i nf or me d c o nse nt.   Patie nts w h o scree n faile d o n t he C B B i n t he pre vi o us 
versi o n of t his pr ot oc ol ma y be rec o nse nte d a n d i m me diatel y rescree ne d usi n g t he M M S E .  If t he patie nt has a
hist orical Lill y or A vi d fl orta uci pir P E T sca n res ult s ho w i n g l o w t o me di u m ta u, t he n t he sca n ma y be s u b mitte d 
t o t he P E T i ma gi n g ce ntral rea der t o deter mi ne eli gi bilit y. If t he hist orical P E T sca n is verifie d as eli gi ble, t he n 
t he patie nt d oes n ot nee d t o meet scree ni n g M M S E eli gi bilit y criteria (see Secti o n 5. 1. 1. 1. 1 a n d 
Secti o n 5. 1. 1. 1. 6. 1 ), alt h o u g h t he M M S E data will be c ollecte d f or statistical a nal ysis.
d
Patie nts w h o sc ore 2 0 t o 2 8 o n t he M M S E
at Visit 1 or  ha ve a hist orical Lill y  or A vi d fl orta uci pir F 1 8 P E T sca n 
t hat meets eli gi bilit y m a y  pr ocee d t o t he re mai ni n g scree ni n g pr oce d ures be y o n d t he C B B a n d D C Tcl oc k o nce 
t he y ha ve gi ve n si g ne d/ date d i nf or me d c o nse nt f or t he f ull st u d y a n d t heir st u d y part ner has gi ve n si g ne d/ date d 
i nf or me d c o nse nte d t o partici pate as a st u d y part ner.
e
C o m plete p h ysical a n d ne ur ol o gical e xa m i nati o ns are t o be perf or me d at t his visit.  A d diti o nal details are 
pr o vi de d i n Secti o n 9. 4. 1 .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 9
L Y 3 3 0 3 5 6 0
f
Bl o o d press ure a n d p ulse will be meas ure d i n t he sitti n g p ositi o n o nl y.  Te m perat ure will be c ollecte d wit h vital 
si g ns.
g
Hei g ht a n d w ei g ht will be meas ure d , wit h s h oes re m o ve d at least for  t he hei g ht meas ure me nt at t he scree ni n g 
visit .
h
E C Gs s h o ul d be ta ke n i n tri plicate at a p pr o xi matel y 1 -mi n ute i nter vals.  E C Gs s h o ul d be c ollecte d at 
a p pr o xi matel y t he sa me ti me of da y, as m uc h as p ossi ble, t o mi ni mize di ur nal variati o n.
i
T he baseli ne versi o n of t he C -S S R S is t o be a d mi nistere d at V 1. Patie nts at i m mi ne nt ris k of s uici de ( p ositi ve 
res p o nse t o Q uesti o n 4 or 5 o n t he C -S S R S) will be e xcl u de d fr o m partici pati n g i n t he st u d y.
j
T he Self -Har m S u p ple me nt F or m is c o m plete d after eac h C -S S R S a d mi nistrati o n t o e nter t he n u m ber of discrete 
e ve nts of s uici dal be ha vi or i de ntifie d. If, base d o n a d mi nistrati o n of t he C- S S R S, it is deter mi ne d t hat 
s uici de-relate d be ha vi ors ha ve occ urre d, t he n c o m pleti o n of t he Self -Har m F oll o w -U p F or m is re q uire d t o c ollect 
a d diti o nal i nf or mati o n t o all o w f or a m ore c o m plete assess me nt of t hese be ha vi ors.
k
Patie nts wit h a hist or y of h e patitis B are t o ha ve a ser u m H Bs A g test at scree ni n g V 1 a n d are e xcl u de d if t he 
H Bs A g test is p ositi ve.
l
Patie nts w h o are H C V -a nti b od y  p ositi ve s h o ul d ha ve f oll o w- u p H C V R N A P C R testi n g at scree ni n g V 1 a n d are 
e xcl u de d if H C V R N A P C R is p ositi ve.
m
F or patie nts w h o d o n ot ha ve a n acce pta ble hist orical Lill y or A vi d fl orta uci pir P E T sca n, a scree ni n g fl orta uci pir 
F 1 8 P E T sca n will be p erf or me d as part of t he st u d y eli gi bilit y criteria at all sites t o deter mi ne patie nt eli gi bilit y 
f or partici pati o n i n St u d y L M D C (see A p pe n di x 5 ).  Wit h t he e xce pti o n of a n M RI, a patie nt m ust meet all ot her 
V 1 eli gi bilit y criteria bef ore ha vi n g a scree ni n g fl orta uci pir F 1 8 P E T sca n.  T he fl orta uci pir F 1 8 P E T sca n will 
be s u b mitte d t o a ce ntralize d P E T i ma gi n g ve n d or desi g nate d b y Lill y f or a n assess me nt of patie nt’s eli gi bilit y.  
T he fl orta uci pir F 1 8 P E T scree ni n g criteria s ho ul d be met (sca n res ults c o nsiste nt wit h s p o ns or -deri ve d 
eli gi bilit y li mits f or fl orta uci pir F 1 8 P E T ) bef o r e t he patie nt ca n u n der g o t he M RI .  A hist orical fl orta uci pir F 1 8
P E T sca n ma y be s u b mitte d t o be c o nsi dere d f or eli gi bilit y if perf or me d wit hi n 6 m o nt hs of V 1 . If t he hist orical 
sca n meets eli gi bilit y criteria b ut is perf or me d m ore t ha n 6 m o nt hs pri or t o Visit 2, t he n a n ot her fl orta uci pir sca n 
m ust be perf or me d a n d use d as t he baseli ne sca n (see Secti o n 5. 1. 1. 1. 6. 1 ) f or a nal ysis.
n
A scree ni n g M R I will be perf or me d at V 1 as part of t he st u d y eli gi bilit y criteria.  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 patie nt ma na ge me nt.  After t he M RI sca n is 
rea d l ocall y, t he sca n is t o be s u b mitte d t o t he ce ntralize d M RI ve n d or desi g nate d b y Lill y f or fi nal deter mi nati o n 
of M RI eli gi bilit y.  Res ults of ce ntrall y rea d M RIs will be use d f or data a nal ysis a n d re p ort-wr iti n g p ur p oses a n d 
patie nt safet y a n d eli gi bilit y will be re p orte d bac k t o sites .
o   Assess me nt i ncl u de s 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 patie nt a n d care gi ver res p o nses.   

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 0
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 2 t hr o u g h Vi sit 1 4 ( D o u bl e- Bli n d P eri o d)
Peri o d:  
Pr oce d ure
R a n d
Visit N o.:
V 2
a, b
V 3  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9
V 1 0
V 1 1
V 1 2
V 1 3
V 1 4
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
0 
4 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
T oler a nce I nter v al f or Visit ( d a ys)
0
7
7
7
7
7
7
7
7
7
7
7
7
   I ncl usi o n/e xcl usi o n re vie w
X
   C o ntact I W R S – dis pe nsati o n of st u d y me dicati o n   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
   P h ysical/ ne ur ol o gical e xa mi nati o n
e
X f
X g
X g
X g
   Pr e vi o us/c o nc o mita nt me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
   Pr ee xisti n g c o n diti o ns/a d verse e ve nts
e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
   St u d y me dicati o n a d mi nistere d
h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
   Patie nt dis p ositi o n
Effic ac y Me as ures
   A D A S -C o g 1 3
i, a a
X
X
X
X
   A D C S -A D L i, a a
X
X
X
X
   C D R -S B i, a a
X
X
X
X
   MM S E
i, a a
X
X
X
   C B B
   D C T Cl oc k i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
S afet y Assess me nt
   C-S S R S
j
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
k
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 k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 2 t hr o u g h Vi sit 1 4 ( D o u bl e- Bli n d P eri o d)
Peri o d:  
Pr oce d ure
R a n d
Visit N o.:
V 2
a, b
V 3  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9
V 1 0
V 1 1
V 1 2  
V 1 3
V 1 4
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
0 
4 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8
T oler a nce I nter v al f or Visit ( d a ys)
0
7
7
7
7
7
7
7
7
7
7
7
7
L a b or at or y S peci me ns l
   Cli nical c he mistr y, he mat ol o g y
m
X  
X  
X
X
X
X
   Hi g h se nsiti vit y C -reacti ve pr otei n
m
X  
X  
X
X
X
X
   Ur i nal ysis
m
X
   Ser u m f or a nti -L Y 3 3 0 3 5 6 0 a nti b o d y
m
X
X  
X  
X
X 
X
X
   Ser u m L Y 3 3 0 3 5 6 0
n, o
X n
X n
X n
X n
X o
X n 
X o
  Plas ma t otal ta u m
X  
X  
X  
X  
X  
X
X
  Plas ma p h os p h o 1 8 1ta u a n d Nf L
m
X
X  
X  
X  
X  
X
X
   Bl o o d f or assess me nt of A P O E ge n ot y pe
m, p
X
   W h ole bl o o d, plas ma a n d ser u m f or bi o mar ker st ora ge
m, q
X
X  
X
X
   Bl o o d f or p har mac o ge n o mics
m, q,r
X
Ot her S afet y Me as ures
   Wei g ht
X
X
X
X
   Vital si g ns a n d b o d y te m perat ure
s,t
X t
X  
X  
X t
X  
X  
X t
X  
X  
X t
X  
X  
X
   E C G i n tri plicate
u
X
X  
X
X
X
X
   M RI
v
w
X
A d diti o n al Effic ac y Me as ures
   Fl orta uci pir F 1 8 P E T Sca n
x
w

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 2
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 1 5 t hr o u g h Vi sit 22 ( D o u bl e-Bli n d P eri o d)
Peri o d:  
Pr oce d ure
Visit N o.:
V 1 5
V 1 6  
V 1 7  
V 1 8  
V 1 9  
V 2 0  
V 2 1  
V 2 2
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
8 0
T oler a nce I nter v al f or Visit ( d a ys)
7
7
7
7
7
7
7
7
   I ncl usi o n/e xcl usi o n re vie w
   C o ntact I W R S – dis pe nsati o n of st u d y me dicati o n
X  
X  
X  
X  
X  
X  
X  
X
   P h ysical / Ne ur ol o gical e xa mi nati o n
e
X g
X g
X f
   Pr e vi o us/c o nc o mita nt me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X
   Pr ee xisti n g c o n diti o ns/a d verse e ve nts
e
X  
X  
X  
X  
X  
X  
X  
X
   St u d y me dicati o n a d mi nistere d
h
X  
X  
X  
X  
X  
X  
X  
X
   Patie nt dis p ositi o n
X
Effic ac y Me as ures
   A D A S -C o g 1 3
i, a a
X
X
X
   A D C S -A D L i, a a
X
X
X
   C D R -S B i, a a
X
X
X
   MM S E
i, a a
X
X
X
   C B B i
X
   D C T Cl oc k i
X  
X  
X  
X  
X  
X  
X  
X
S afet y Assess me nt
   C-S S R S j
X  
X  
X  
X  
X  
X  
X  
X
   Self -Har m S u p ple me nt F or m
k
X  
X  
X  
X  
X  
X  
X  
X
   Self -Har m F oll o w -u p F or m
X k
X k
X k
X k
X k
X k
X k
X k

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 3
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 1 5 t hr o u g h Vi sit 2 2 ( D o u bl e-Bli n d P eri o d)
Peri o d:  
Pr oce d ure
Visit N o.:
V 1 5
V 1 6  
V 1 7  
V 1 8  
V 1 9  
V 2 0  
V 2 1  
V 2 2
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
5 2 
5 6 
6 0 
6 4 
6 8 
7 2 
7 6 
8 0
T oler a nce I nter v al f or Visit ( d a ys)
7
7
7
7
7
7
7
7
L a b or at or y S peci me ns l
   Cli nical c he mistr y, he mat ol o g y
m
X
X
X
   Hi g h se nsiti vit y C -reacti ve pr otei n
m
X
X
X
   Ur i nal ysis
m
X
X
X
   Ser u m f or a nti -L Y 3 3 0 3 5 6 0 a nti b o d y
m
X
X
X
   Ser u m L Y 3 3 0 3 5 6 0
n, o
X o
X o
X o
   Plas ma t otal ta u m
X
X
X
   Plas ma p h os p h o 1 8 1ta u a n d Nf L
m
X
X
X
   Bl o o d f or assess me nt of A P O E ge n ot y pe
m, p
   W h ole bl o o d, plas ma a n d ser u m f or bi o mar ker
   st ora ge
m, q
X
X
X
   Bl o o d f or p har mac o ge n o mics
m, q,r
Ot her S afet y Me as ures
   Wei g ht
X
X
X
   Vital si g ns a n d b o d y te m perat ure
s,t
X t
X  
X
X t
X  
X  
X
X t
   E C G i n tri plicate
u
X
X
X
   M RI v
X
A d diti o n al Effic ac y Me as ures
   Fl orta uci pir F 1 8 P E T Sca n
x
X x

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 4
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 2 3 t hr o u g h Vi sit 2 8 ( D o u bl e-Bli n d P eri o d) a n d Vi sit 8 0 1 (I m m u n o g e ni cit y a n d 
S af et y F oll o w -U p)
Peri o d:  
Pr oce d ure
Visit N o.:
V 2 3  
V 2 4  
V 2 5  
V 2 6  
V 2 7
V 2 8
E D
c
V 8 0 1
d
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4
1 1 3
T oler a nce I nter v al f or Visit ( d a ys)
7
7
7
7
7
7
1 4
   I ncl usi o n/e xcl usi o n re vie w
   C o ntact I W R S – dis pe nsati o n of st u d y me dicati o n
X  
X  
X  
X  
X
   P h ysical / Ne ur ol o gical e xa mi nati o n
e
X g
X f
X f
   Pr e vi o us/c o nc o mita nt me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X
   Pr ee xisti n g c o n diti o ns/a d verse e ve nts
e
X  
X  
X  
X  
X  
X  
X  
X
   St u d y me dicati o n a d mi nistere d
h
X  
X  
X  
X  
X
   Patie nt dis p ositi o n
X  
X  
X
Effic ac y Me as ures
   A D A S -C o g 1 3
i, a a
X
X  
X
   A D C S -A D L i, a a
X
X  
X
   C D R -S B i, a a
X
X  
X
   MM S E
i, a a
X
X  
X
   C B B i
X  
X
   D C T Cl oc k i
X  
X  
X  
X  
X  
X  
X
S afet y Assess me nt
   C-S S R S j
X  
X  
X  
X  
X  
X  
X  
X
   Self -Har m S u p ple me nt F or m
k
X  
X  
X  
X  
X  
X  
X  
X
   Self -Har m F oll o w -u p F or m
X k
X k
X k
X k
X k
X k
X k
X k

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 5
L Y 3 3 0 3 5 6 0
S c h e d ul e of A cti viti e s , Pr ot o c ol I 8 G-M C -L M D C , Vi sit 2 3 t hr o u g h Vi sit 2 8 ( D o u bl e-Bli n d P eri o d) a n d Vi sit 8 0 1 (I m m u n o g e ni cit y a n d 
S af et y F oll o w -U p)
Peri o d:  
Pr oce d ure
Visit N o.:
V 2 3  
V 2 4  
V 2 5  
V 2 6  
V 2 7
V 2 8
E D
c
V 8 0 1
d
E n d of Wee k Rel ati ve t o St u d y Me dic ati o n St art
8 4 
8 8 
9 2 
9 6 
1 0 0 
1 0 4
1 1 3
T oler a nce I nter v al f or Visit ( d a ys)
7
7
7
7
7
7
1 4
L a b or at or y S peci me ns l
   Cli nical c he mistr y, he mat ol o g y
m
X
X
X
   Hi g h se nsiti vit y C -reacti ve pr otei n
m
X
X
X
   Ur i nal ysis
m
X
X
X
   Ser u m f or a nti -L Y 3 3 0 3 5 6 0 a nti b o d y
m
X
X  
X
X
   Ser u m L Y 3 3 0 3 5 6 0
n, o
X o
X o
X o
X o
   Plas ma t otal ta u m
X
X  
X
   Plas ma p h os p h o 1 8 1ta u a n d Nf L
m
X
X  
X
   Bl o o d f or assess me nt of A P O E ge n ot y pe
m, p
   W h ole bl o o d, plas ma a n d ser u m f or bi o mar ker
   st ora ge
m, q
X
X  
X
   Bl o o d f or p har mac o ge n o mics
m, q,r
Ot her S afet y Me as ures
   Wei g ht
X
X  
X
   Vital si g ns a n d b o d y te m perat ure
s,t
X
X  
X t
X
X
X t
X t
X
   E C G i n tri plicate
u
X
X  
X
   M RI v
X  
X
A d diti o n al Effic ac y Me as ures
   Fl orta uci pir F 1 8 P E T Sca n
x
X x
X x, y

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 6
L Y 3 3 0 3 5 6 0
Sc he d ule of Acti vities, Pr ot oc ol I 8 G-M C -L M D C , Visit 2 t hr o u g h Visit 8 0 1, A b bre vi ati o ns a n d F o ot n otes
A b bre viati o ns:  A D A = a nti -dr u g a nti b o dies; A D A S -C o g 1 3 = 1 3- ite m Alz hei mer’s Disease Assess me nt Scale —
C o g niti ve s u bsc ore; 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 P O E = ap oli p o pr otei n s u bt y pe E; C B B = C o g State Brief Batter y; C D R -S B = Cli nical De me ntia 
Rati n g — S u m of B o xes; C R F = case re p ort f or m; C- S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; D C T Cl oc k
= Di gital Cl oc k Dra wi n g Test; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; I V = i ntra ve n o us; 
I WR 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 = m a g netic res o na nce 
i ma gi n g; Nf L = ne ur ofila me nt li g ht; N o. = n u m ber ; P E T = p ositr o n e missi o n t o m o gra p h y; T E = treat me nt -
e mer ge nt; Ra n d = ra n d o mizati o n; V = visit.
a
C o nfir m t hat t he patie nt has met all V 1 eli gi bilit y criteria bef ore pr ocee di n g wit h V 2 pr oce d ures.
b
At V 2, a p p o i nt me nts 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 cl ose as p ossi ble t o t he 
tar get date, relati ve t o V2.  Pr oce d ures f or s o me visits ma y ta ke m ore t ha n 1 da y.
c
If a patie nt disc o nti n ues bef ore t he d o u ble-bli n d peri o d e n d p oi nt ( V 2 8 at Wee k 1 0 4 ), t he E D pr oce d ures a n d 
C R Fs s h o ul d be c o m plete d.  T he patie nt s h o ul d be e nc o ura ge d t o ret ur n t o t he site 13 wee ks after t he E D visit f or 
a n i m m u n o ge nicit y f oll o w-u p visit ( V 8 0 1).
d
Patie nts are t o ret ur n t o t he site f or c ollecti o n of bl o o d sa m ples a n d safet y assess me nts f or assess me nt of 
i m m u n o ge nicit y stat us at V 8 0 1 ( Wee k 1 1 3 ).  F oll o w-u p f or patie nts e x perie nci n g cli nicall y si g nifica nt e ve nts 
ass ociate d wit h T E -A D A stat us is descri be d i n Secti o n 9. 4. 7. 2 .
e
A n y  cli nicall y si g nifica nt c ha n ges fr o m baseli ne o n f oll o w-u p 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 pa ge.
f
C o m plete p h ysical a n d ne ur ol o gical e xa m i nati o ns are t o be perf or me d at t his visit pr i or t o st u d y dr u g 
a d mi nistrati o n .  A d diti o nal details are pr o vi de d i n Secti o n 9. 4. 1 .
g
B rief p h ysical a n d ne ur ol o gical e xa mi nati ons are t o be perf or me d at t his visit pr i or t o st u d y dr u g a d mi nistrati o n.  
A d diti o nal details are pr o vi de d i n Secti o n 9. 4. 1 .
h
St u d y dr u g will be a d mi nistere d b y I V a d mi nistrati o n at i n vesti gati ve st u d y site. Patie nts s h o ul d be o bser ve d f or 
a mi ni m u m of 2 h o urs f oll o wi n g eac h i nf usi o n for  t he first 3 i nf usi o ns.  After t he first 3 d oses, a mi ni mal p ost -
i nf usi o n o bser vati o n ti me of 6 0 mi n utes will be re q uire d f or all s u bse q ue nt i nf usi o ns.
i
W he n a d mi nistere d, c o g niti ve a n d f u ncti o nal assess me nts ( A D A S -C o g 1 3 , A D C S-A D L, C D R, M M S E , C B B , a n d 
D C T Cl oc k ) s h o ul d be perf or me d first bef ore me dical pr oce d ures t hat c o ul d be stressf ul f or t he patie nt (f or 
e xa m ple, bl o o d dra ws).
j
T he “si nce last visit” versi o n of t he C -S S R S will be a d mi nistere d at all visits after V 1 ( Wee ks -8 t hr o u g h - 1) t o 
t he patie nt wit h t he st u d y part ner/st u d y i nf or ma nt prese nt, after t he c o g niti ve a n d f u ncti o nal assess me nts.
k
T he Self -Har m S u p ple me nt F or m is c o m plete d after eac h C -S S R S a d mi nistrati o n t o e nter t he n u m ber of discrete 
e ve nts of s uici dal be ha vi or i de ntifie d. If, base d o n a d mi nistrati o n of t he C- S S R S, it is deter mi ne d t hat s uici de -
relate d be ha vi ors ha ve occ urre d, t he n c o m pleti o n of t he Self -Har m F oll o w -U p F or m is re q uire d t o c ollect 
a d diti o nal i nf or mati o n t o all o w f or a m ore c o m plete assess me nt of t hese be ha vi ors.
l
U n sc he d ule d la b orat or y tests ma y be perf or me d at t he discreti o n of t he i n vesti gat or.
m
La bs are t o be c ollecte d pri or t o a d mi nistrati o n of t he I V st u d y me dicati o n.  Rec or d t he date a n d ti mes of sa m ple 
c ollecti o n o n t he La b Re q uisiti o n F or m.
n
Pre d ose ( bef ore be gi n ni n g t he i nf usi o n) a n d p ost d ose ( wit hi n 3 0 mi n utes of c o m pleti o n of t he i nf usi o n) sa m ples 
f or I V st u d y me dicati o n  s h o ul d be c ollecte d fr o m t he ar m t hat di d n ot recei ve t he i nf usi o n . ( N ote:  Sites are 
per mitte d t o c ollect t he pre d ose sa m ple fr o m t he i n d welli n g cat heter pri or t o start of i nf usi o n) . T hese sa m ples 
will be c ollecte d at V 2 ( Wee k 0), V 3 ( Wee k 4 ), V 4 ( Wee k 8), V 5 ( Wee k 1 2), a n d V 8 ( Wee k 2 4). At V 2, o nl y 
t he p ost d ose sa m ple will be c ollecte d.
o
A si n gle pre d ose L Y 3 3 0 3 5 6 0 sa m ple s h o ul d be c ollecte d bef ore be gi n ni n g t he i nf usi o n at V 6 ( Wee k 1 6), V 1 1 
( Wee k 3 6), V 1 5 ( Wee k 5 2) , V 1 8 ( Wee k 6 4 ), V 2 2 ( Wee k 8 0), V 2 5 ( Wee k 9 2), a n d V 2 8 ( Wee k 1 0 4).  I n a d diti o n, 
a si n gle sa m ple f or ser u m L Y 3 3 0 3 5 6 0 s ho ul d be c ollecte d at E D (a visit at w hic h t he patie nt ma y n ot recei ve a 
st u d y dr u g i nf usi o n).  Rec or d t he act ual date a n d ti mes of sa mple c ollecti o n o n t he La b Re q uisiti o n F or m.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 7
L Y 3 3 0 3 5 6 0
p
A bl o o d sa m ple will be c ollecte d t o deter mi ne A P O E ge n ot y pe.  T he A P O E m a y  be c ollecte d at a n alter nati ve 
visit if it ca n n ot be c ollecte d at V 2.
q
Bl o o d f or bi o mar ker st ora ge, a n d bl o o d f or p har mac o ge n o mic sa m ples are t o be c ollecte d u nless n ot all o we d or 
u nfeasi ble d ue t o l ocal re g ulati o ns pr o hi biti n g sa m ple tra ns p ort o utsi de of t he c o u ntr y.
r
P har mac o ge n o mic sa m ples ma y be c ollecte d at a n alter nati ve visit if t he y ca n n ot be c ollecte d at V 2.  It will n ot 
be a pr ot oc ol de viati o n if a bi o mar ker st ora ge sa m ple ca n n ot be c ollecte d f or tec h nical reas o ns (f or e xa m ple, if 
t he site is u na ble t o c ollect e n o u g h bl o o d via ve ni p u nct ure).
s
Sitti n g bl o o d press ure a n d p ulse will be meas ure d after 5 mi n utes i n t he sitti n g p ositi o n at all visits pri or t o 
a d mi nistrati o n of st u d y dr u g .  Te m perat ure will be c ollecte d wit h sitti n g vital si g ns.
t
I n a d diti o n, ort h ostatic bl o o d press ure a n d p ulse will be meas ure d at V 2 ( Wee k 0), V 5 ( Wee k 1 2), V 8 ( Wee k 2 4), 
V 1 1 ( Wee k 3 6), V 1 5 ( Wee k 5 2), V 1 8 ( Wee k 6 4 ), V 2 2 ( Wee k 8 0), V 2 5 ( Wee k 9 2), a n d V 2 8 ( Wee k 1 0 4) , or E D, 
a n d at u nsc he d ule d visits after 5 mi n utes i n t he s u pi ne p ositi o n a n d after 3 mi n utes sta n di n g.
u
Electr ocar di o gra ms s h o ul d be ta ke n i n tri plicate at a p pr o xi matel y 1 -mi n ute i nter vals.  Electr ocar di o gra ms s h o ul d 
be c ollecte d at a p pr o xi matel y t he sa me ti me of da y, as m uc h as p ossi ble, t o mi ni mize di ur nal variati o n.  
Electr ocar di o gra ms are t o be perf or me d pr i or t o t he a d mi nistrati o n of I V st u d y me dicati o n ( L Y 3 3 0 3 5 6 0 a n d I V 
place b o) .
v
If M RI is perf or me d o n t he sa me da y as c o g niti ve a n d f u ncti o nal assess me nts, t he n it s h o ul d be perf or me d after 
c o g niti ve a n d f u ncti o nal tests.  M a g netic res o na nce ima gi n g m a y be perf or me d b ef ore ot her visit pr oce d ures, 
i ncl u di n g c o g niti ve a n d f u ncti o nal tests, b ut i n t hat case it m ust be perf or me d at least 1 da y bef ore ot her visit 
pr oce d ures.
w
T he scree ni n g fl orta uci pir F 1 8 P E T sca n a n d M RI perf or me d at V 1 (or acce pte d fr o m a per mitte d hist orical 
sca n) ser ve as t he baseli ne fl orta uci pir F 1 8 P E T sca n a n d M RI .
x
Bef ore t he fl orta uci pir F 1 8 P E T sca n is perf or me d, t he i n vesti gat or s h o ul d re vie w t he patie nt’s me dical hist or y 
t o verif y t here is n o ris k fact or f or T orsa des de P oi ntes a n d re vie w t he m ost rece nt E C G.   If cli nicall y mea ni n gf ul 
a b n or malities are n ote d o n t he E C G, t he a d visa bilit y of t he fl orta uci pir sca n s h o ul d be c o nsi dere d b y t he 
i n vesti gat or i n c o ns ultati o n wit h t he Lill y-desi g nate d me dical m o nit or .
y
Patie nts w h o disc o nti n ue fr o m t he st u d y earl y will ha ve a fl orta uci pir sca n perf or me d at t he E D visit o n l y if t he y 
ha ve c o m plete d V 1 1 a n d it has bee n at least 6 m o nt hs si nce t heir pre vi o us sca n .  
z
F o ot n ote z was delete d.
aa
Assess me nt i ncl u de s 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 patie nt a n d care gi ver res p o nses t o 
assess me nt q uesti o ns.    

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 8
L Y 3 3 0 3 5 6 0
3.
I ntr o d u cti o n
Alz hei mer’s disease ( A D) is a n a ge -relate d ne ur o de ge nerati ve dis or der c haracterize d b y a
pr o gressi ve decli ne i n c o g nit i ve f u ncti o n a n d a bility t o p erfor m  acti vities of dail y li vi n g, a n d
ul timatel y ca n lea d t o deat h d ue t o c o m plicat i ons of t he disease. Pat h ol o gic hall mar ks of A D
i de ntifie d at a ut o ps y i ncl u de t he prese nce of ne uritic a m yl oi d-β ( A β) pla q ues, ne ur o fibr illar y 
ta n gles ( N F Ts) ( H y ma n et al. 2 0 1 2), a n d ne ur o nal l oss i n brai n re gi o ns i m p orta nt f or c o g niti on, 
s uc h as t he hi p p oca m p us a n d te m p oral c orte x ( Sel k oe 1 9 9 1).
Ta u is a n a x o nal micr ot u b ul e- bi n di n g pr otei n t hat n or m all y pr o m ot es micr ot u b ule asse m bl y a n d
sta bility .  I n A D a n d ot her ne ur o de ge nerati ve diseases , c ollect i vel y ter me d ta u o pat hies, 
h y per p h os p h or ylate d misf o l de d ta u ca uses ta u a g gre gati o n, ta u see di n g, N F T f or mat i on, 
micr ot u b ule desta bilizat i on, a n d ne ur o nal t o xicit y ( Wa n g a n d Ma n del k o w 2 0 1 6).   O ver ti me, ta u 
acc u m ulates i n t he brai ns of patie nts wit h A D, a n d f or ms i ntra ne ur o nal N F Ts, wit h ta u pat h ol o g y 
s prea di n g i n se q ue nce fr om tra nse nt or hi nal, t o li m bic, t o ne oc ortical re gi o ns ( Braa k a n d Braa k 
1 9 9 1 ; Delac o urte et al. 1 9 9 9).  T he s prea d of ta u p at h olo g y  is c orrelate d wit h ne ur o nal l oss, 
cli nical s y m pt o ms, a n d pr o gressi o n i n A D a n d ot her ne ur o de ge nerati ve diseases , s uc h as 
pr o gressi ve s u pra n uclear pals y ( P S P) ( D u yc kaerts et al. 1 9 8 7 ).
L Y 3 3 0 3 5 6 0 is a h u ma nize d m o n ocl o nal a nt i b o d y t hat bi n ds t o e xtr acell ular a g gre gat e d ta u i n 
pati e nts wit h A D a n d ot her ta u o pat hies, s uc h as P S P.  I n precli nical i n vitr o a n d i n vi v o st u di es, 
L Y 3 3 0 3 5 6 0 re d uces tra nscell ular s prea d of t a u see ds a n d ta u pat h ol o g y pr o pa gati o n.  B y  bi n di n g 
t o a g gre gate d ta u, L Y 3 3 0 3 5 6 0 is h y p ot hesize d t o bl o c k or dela y tra ns cell ular s prea d of 
a g gre gat e d ta u, N F T f or mat i on, a n d ne ur o nal l oss, a n d ma y ha ve t he p ote ntial t o slo w t he 
cli nical a n d pat h ol o gical pr o gressi o n of  t a u-relate d diseases.
3. 1.
St u d y R ati o n al e
Eli Lill y a n d C o mp a n y  (Lill y ) is de vel o pi n g L Y 3 3 0 3 5 6 0 , a h u ma nize d m o n ocl o nal a nt i b o d y,
w hic h tar gets e xtracell ular a g gre gat e d ta u f or t he treat me nt of A D.
A P hase 1 st u d y  (I 8 G-M C -L M D A [ L M D A]) is c urre nt l y o n g oi n g t o e val uate the safet y,  
t olera bilit y, a n d p har mac o ki net ics ( P K) of L Y 3 3 0 3 5 6 0 i n healt h y s u bjects a n d pat ient s wit h A D. 
S af et y a n d t olera bilit y e val uat i ons are bei n g c o n d ucte d o ver a wi de ra n ge o f si n gle d oses, a n d 
d ose escalat i on d oes n ot occ ur u n til safety data fr o m  pre vio us d oses ha ve bee n re vie we d.  
St u d y L M D A ai ms t o assess w het her a ma xi m u m-t olerate d d ose ca n be esta blis he d or t o 
d e m o nstrate t he t ol era bilit y of a d ose greater t ha n t he e x pecte d t hera pe utic d ose.
A P hase 1 m ult i ple-d ose, d ose -escalati o n st u d y (I 8 G-M C -L M D D [ L M D D]) is c urre nt l y als o 
o n g oi n g t o assess t he safety,  t olera bilit y, P K , a n d p har mac o d y na mics ( P D) of  L Y 3 3 0 3 5 6 0 i n 
pati e nts wit h mil d c o g niti ve i m pair me nt d ue t o A D or mil d -t o-m o derate Al z hei mer’s d e me nt ia.
St u d y  I 8 G-M C -L M D C ( L M D C) is a 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 valuate 
t he safet y a n d efficac y of ta u a nti b o d y ( L Y 3 3 0 3 5 6 0) i n patie nts wit h l ow -t o-me d i u m ta u b ur de n 
as meas ure d b y fl orta uci pir wit hi n a p o p ulat i on w h o ha ve earl y s y m pt o mat ic A D ( pr o dr o mal A D 
a n d mil d de me nt ia d ue t o A D).  St u d y L M D C will assess w het her bi n di n g a n d cleara nce of 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 2 9
L Y 3 3 0 3 5 6 0
a g gre gate d ( misf ol de d) t a u ca n sl o w t he pr o gressi o n of disease as assesse d b y cli nical meas ures 
a n d bi o mar kers of disease pat h ol o g y  a n d ne ur o de ge nerati on o ver 1 0 0 wee ks of treat me nt
( 2 6 d oses, a d mi nistere d as a n i ntra ve n o us [I V] i nf usi o n o nce e ver y 4 wee ks [Q 4 W ] starti n g at 
Vi sit 2 [ Wee k 0] a n d e n di n g at Visit 2 7 [ Wee k 1 0 0 ], wit h e n d of  tr e at me nt c o g nit i ve assess me nts 
carrie d o ut at Visit 2 8 [ Wee k 1 0 4] ).
P r o gressi o n of cere bral ta u o pat h y ass ociate d wit h A D will be assesse d b y p osi tr o n e missi o n 
t o mo gra p h y (P E T ) sca n usi n g fl orta uci pir F 1 8 , a mar ker of a g gre gate d ( misf ol de d) t a u.  
F l orta ucipir is a n F -1 8 -labele d s mall m o lec ule t hat bi n ds wit h hi g h affi nity a n d select i vity t o 
a g gre gate d ta u pat h ol o g y ( b ut n ot n or mal mo n o m eric ta u) i n e x vi v o h u ma n brai n sect i ons. T hi s 
bi o mar ker is belie ve d t o pr o vi de a q ualitat i ve a n d q ua ntitati ve meas ure me nt of de p osite d 
a g gre gate d ta u a n d its a nat o mical distri b ut i on i n t he brai n.  A bse nce of si g nifica nt ne oc ortical 
flort a u ci pir F 1 8 P E T si gnal is belie ve d t o i n dicate t hat, alt h o u g h patie nts ma y be cli nicall y 
ma nifest i n g c o g niti ve i m pair me nt, le vels of  a g gre gate d ta u de p osits are lo w a n d m a y n ot ha ve 
s prea d be y on d t he m e dial/a nterior t e m p or al  c orte x, a n d at t he gr o u p le vel ma y be ass ociate d wit h 
a relati vel y sl o w rate of c o g nit i ve deteri orati o n. H i g h a n d wi des prea d fl orta uci pir F 1 8 si g nal  
i n dicates t hat a g gre gate d ta u de p osits ha ve alrea d y s prea d t hr o u g h mu c h of  t he brai n, a n d at t he 
gr o u p l e vel ma y be ass ociat e d wit h a more ra pi d rate of c o g ni tive deteri orati o n. T h us, 
im ple me ntati o n of fl ort a u cipi r F 1 8 sca ns ma y facilitate selecti on of partici pa nt s wit h a 
l ow- t o-me d i u m ta u acc u mulati o n f or e ntr y int o t he cli nical trial .
Alz hei mer’s disease is als o ass ociate d wit h pr o n o u nce d brai n atr o p h y, reflecti n g b ul k 
ne ur o de ge nerat i ve l oss of gr a y  a n d w hite matter. Pr o gressi o n of brai n atr o p h y will be assesse d 
b y v o l um etri c ma g net ic res o na nce i ma gi n g ( v M RI), pr o vi di n g re gi o nal q ua ntificati o n of v o l ume 
l oss.
T he patie nt p o p ulat i on selecte d f or t he cli nical trial is pati e nts wi t h A D ha vi n g earl y
s y m pt o mat ic disease (t hat is, pr o dr o mal-t o-mil d A D d e m e nt ia) a n d with l ow- t o-me d i u m ta u 
b ur de n as meas ure d b y flort a u ci pir F 1 8 P E T sca ns.  Cli nical– pat h o l ogi cal c orr elat i ons als o 
str o n gl y s u g gest t hat baseli ne i ma gi n g t hat all o ws sta gi n g base d o n ne ur ofi brillar y ta n gles c o ul d 
s u bsta ntiall y i m pr o ve t he p o wer of cli nical trials ai me d at c ha n gi n g t he rate of pr o gressi o n of t he 
di sease ( Qia n et al. 2 0 1 7).  A n earl y A D p o p ulati on defi ne d cli nicall y a n d pat h ol o gicall y ( usi n g 
ta u P E T i ma gi n g) is a ntici pate d t o be m ore h o m o ge ne o us t ha n p o p ulati ons defi ne d b y cli ni c al 
s y m pt o ms al o ne. It is p ost ulate d t hat t he earl y AD, l ow -t o-me d i u m ta u b ur de n p o p ulati on will 
be s ufficie nt l y earl y i n t heir disease c o urse t o res p o n d t o treat me nts pri or t o m ore a d va nce d 
di sease w he n e xte nsi ve irre versi ble ne ur o nal l o ss occ urs.  C o nfi r mat i on of a m yl o i d stat us is n ot 
re q uire d beca use t he fl orta uci pir F 1 8 P E T st u d y e ntr y criteria c o nfir m t he prese nce of ta u o pat h y 
of  A D a n d t he a nti b o d y tar get, a n d is i n varia bl y ass o ciate d wit h a m yloi d p osi tivit y ( Lill y, data 
o n file, A 0 5 st u d y ).
3. 2.
B a c k gr o u n d
L Y 3 3 0 3 5 6 0 is a h u ma nize d m o n ocl o nal a nt i b o d y e n gi neere d fr om t he M C - 1 a nt i b o d y, w hic h 
was i de nt ifie d a m o n g a pa nel of m o use m o n o cl o n al  a nti b o dies as t he best a nti b o d y t o tar get ta u 
pr o pa gati o n i n vi tr o a n d i n vi v o.  L Y3 3 0 3 5 6 0 b i n ds prefere ntiall y t o a g gre gate d ta u, wit h 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 0
L Y 3 3 0 3 5 6 0
mi ni mal bi n di n g t o m o n o meric ta u as deter mi ne d b y a n e nz y me-li n ke d i m m u n os or be nt assa y
a n d Biac ore meas ure me nts ( > 1 0 0- f ol d selecti vity f or a g gre gate d ta u o ver m o n o mer ic Ta u).
I n vitr o, L Y3 3 0 3 5 6 0 i n hi bits cell-bas e d ta u pr o pa gatio n, bi n ds t o brai n sect i ons deri ve d fr o m 
pati e nts wit h A D or ta u o pat h y, a n d d oes n ot int erfere wit h t he bi n di n g of t he ta u P E T tracer 
flort a u ci pir t o N F Ts .  I n vi v o, L Y3 3 0 3 5 6 0 i n hi bits ta u pr o pa gati o n w he n c o-i njecte d wit h ta u 
see ds i n mice.  T he hi g h affi nity s urr o gate muri ne a nt i b o d y ( M C- 1-3 C 9) re d uce d ta u pat h ol o g y ,
f oll owi n g s yste mic d osi n g i n 2 ta u tra ns ge nic m o use m o dels (J N P L 3 a n d T g 4 5 1 0).
3. 2. 1.
N o n cli ni c al St u di e s
T he safet y of  L Y 3 3 0 3 5 6 0 was e val uate d i n tra ns ge nic T g 4 5 1 0 mice b y s u bc uta neo us (S C )
i njecti on of 0, 2, 2 0, or 2 0 0 m g/ k g o nce wee kl y f or 5 d oses or o nce wee kl y f or 2 6 d oses .  I n t he 
6- m o nt h st u d y, mi n or test article-relate d cli nical c he mistr y fi n di n gs i n a ni mals a d mi nistere d 
2 0 0 m g/ k g i ncl u de d mi ni mall y hi g her gl o b uli n c o nce ntrati o n res ul tin g i n hi g her t otal pr otei n 
c o nce ntrati o n a n d l o wer al b u mi n: gl o b uli n rat i o.  T hese c ha n ges were s u g gesti ve of i nfla m mat or y 
res p o nse; h o we ver, i nfla m mati on was n ot e vi de nt i n le u k oc y te c o u nts, a n d n o c orrelat i ve 
fi n di n gs of i nfla m mati on were n ote d micr osc o picall y. T his i ncrease d gl o b uli n c o nce ntrati o n 
ma y ha ve bee n d ue t o t he prese nce of t he test article (a n i m m u n o gl o b uli n [I g]).  At t he hi g hest 
d ose teste d ( 2 0 0 m g/ k g/ wee k), t here were n o -o bser va ble -a d verse-effect s i n t he m o use a n d 
m o n ke y i n b ot h t he 5-wee k a n d 6 -m o nt h st u dies. T his was defi ne d as N O A E L.
T he safety of  L Y 3 3 0 3 5 6 0 was als o e val uate d i n c y n om o l g us m o n ke ys b y S C ( 0, 2, 2 0 m g/ k g) or 
I V ( 2 0 0 m g/ k g) i nject i ons o nce wee kl y f or 5 d oses or o nce wee kl y f or 2 6 d oses.  I n a d dit i on t o 
tra ditio n al G o o d La b orat or y  Practice t o xic olo g y  st u d y assess me nts, safet y p har mac olo g y  
assess me nts were perf or me d d uri n g t he 5 -wee k m o n ke y  st u d y, i ncl u di n g t he e val uati on of b o d y  
t e mperat ure, car di o vasc ular safet y,  o bser vati ons f or ce ntral ner v o us s yste m ( C N S) sig n s wit h 
ne ur o l ogi cal e xa mi natio n, a n d q ualitat i ve assess me nt of res pirat or y de pt h wit h q ua ntitati ve 
esti mates of res pirat or y rate.  Car dio vasc ular assess me nt was als o c o n d ucte d i n t he 6 -m o nt h 
m o n ke y st u d y  o n Da y 8, 8 5, or 1 6 9 of t he d osi n g p hase.  N o dr u g -relate d c ha n ges occ urre d i n 
a n y para meters.  O ne m o n ke y gi ve n t he hi g hest d ose of 2 0 0 m g/ k g I V f or 5 wee ks was o bser ve d 
wi t h p erior bi t al s welli n g after t he last d ose.  T he m o n ke y was gi ve n dip he n h y dra mi ne a n d t he 
s welli n g was si g nifica ntl y re d uce d withi n 1 h o ur of di p he n h y dra mi ne a d mi nistrati o n a n d 
res ol ve d t he f oll owi n g da y .  It is n ot clear if t he perior bi t al s welli n g was c o mp o u n d- r elate d; 
n ota bl y  no o bser vat i ons of peri or bi t al s welli n g were o bser ve d i n t he 6-m o nt h st u d y .  I n t he 
6- m o nt h st u d y , t he onl y test article -relate d fi n di n g i n a ni mals a d mi nistere d 2 0 0 m g/ k g I V was 
mil dl y  increase d gl o b uli n c o nce ntrati o n, res ul ti n g i n decrease d al b u mi n: gl ob uli n rat i o, o n 
Da ys 7 8 a n d 1 8 3.  E vi de nce of i nfla m mat i on was n ot o bser ve d i n ot her cli nical pat h o l og y  data.  
I n t he a bse nce of i nfla m mati on or e vi de nce of i m m u ne st i m ulati on, t his i ncrease i n gl o b uli n 
c o nce ntrati o n ma y ha ve bee n d ue t o t he prese nce of t he test article ( I g).  I n t he 6-m o nt h st u d y , 
s p o nta ne o us mi ni mal li ver c ha n ges were o bser ve d i n 2 a ni mals a d mi nistere d L Y 3 3 0 3 5 6 0.  O ne 
fe male a d mi nistere d wi t h 2 0 0 m g/ k g ha d a mi ni mall y i ncrease d n u m ber of i n di vi d ual 
necr oti c/a p o pt otic he pat oc ytes i n 1 s mall s u bca ps ular re gio n i n 1 of  2 e xa mi ne d li ver secti o ns; 
t he li ver secti o ns were ot her wi se micr osc o picall y unre mar ka ble.  Base d o n t he li mite d 
s u bca ps ular distri b uti on a n d l a c k of cli nical c he mistr y c ha n ges, i n dicati ve of a m ore ge neralize d 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 1
L Y 3 3 0 3 5 6 0
li ver i n v ol ve me nt, t he c ha n ge i n t his a ni mal was c o nsi dere d s p o nta ne o us, rat her t ha n test art icle-
r elate d.  O ne male a d mi nistere d wi t h 2 0 m g/ k g ha d a mi ni mall y i ncrease d n u m ber of i n di vi d ual 
necr oti c/a p o pt otic he pat oc ytes scattere d ra n d o ml y in occasi o nal micr osc o pic fiel ds i n e xa mi ne d 
secti ons of li ver; li ver secti o ns i n t his a ni mal were ot her wise micr osc o picall y u nre mar ka ble, a n d 
n o differe nces i n li ver wei g ht or i n li ver -relate d cli nical c he mistr y para meters were n ote d 
c o mpare d wi t h c o ntr ol.  T his less-r estricte d patter n of i n di vi d ual he pat oc yte necr osis/a p o pt osis 
was li mite d t o 1 a ni mal a n d lac ke d e vi de nce of a d ose res p o nse ; t heref ore, it was c o nsi dere d n ot 
test article-r elate d.  T he N O A E L i n b ot h t he 5 -wee k a n d 6 -m o nt h st u dies was 2 0 0 m g/ k g/ wee k 
(I V).
C o m para ble L Y 3 3 0 3 5 6 0 bi n di n g was o bser ve d i n a sta n dar d pa nel of n or mal h u ma n a n d 
c y n o m o l g us m o n ke y t iss ues as e val uate d b y tiss ue cr oss-reacti vity a nal ysis.  T h us, t he m o n ke y  
t o xic o l og y  st u d y is c o nsi dere d t o ha ve a de q uatel y assesse d t he p ote ntial f or a d verse effects t hat 
ma y ha ve bee n ass ociate d wit h a n y bi n di n g t o tiss ues i n vi v o.
T he n o ncli nical safet y pr ofile of L Y 3 3 0 3 5 6 0 i n m o n ke ys a n d tra ns ge nic T g 4 5 1 0 mice s u p p orts 
cli nical de vel o p me nt.  Pl ease see t he I n vest i gat or’s Br oc h ure (I B) f or details re gar di n g 
n o ncli nical L Y 3 3 0 3 5 6 0 st u dies.
3. 2. 2.
P h a s e 1 St u di e s
C CI

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 2
L Y 3 3 0 3 5 6 0
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
3. 3. 1.
B e n efit
T here i s a lar ge u n met me dical nee d f or disease-m o dif yi n g treat me nts f or A D.   A ni mal m o dels 
s u g gest t hat a n a nti-ta u a nti b o d y will re d uce pr o gressi o n/s prea d of t he a g gre gate d f or ms of ta u.  
I n a d diti on t o assess me nt of safety a n d t olera bilit y of L Y 3 3 0 3 5 6 0 , t his st u d y will als o assess 
w het her bi n di n g a n d cleara nce of e xtracell ular a g gre gate d ta u ca n sl o w t he pr o gressi o n of t he 
di sease as assesse d b y cli nical meas ures a n d bi o mar kers of disease pat h ol o g y  a nd 
ne ur o de ge nerat i on r elat i ve t o place b o treat me nt.
3. 3. 2.
Ri s k s
T he t ol era bilit y a n d safety of  a n y ne w a ge nt are u n k n o w n u ntil s ufficie nt cli nical e x perie nce is 
o btai ne d u n der c o ntr olle d c o n dit i ons.  As o f 0 8 Fe br uar y 2 0 1 8, safety data ha ve bee n re vie we d 
f or 6 3 s u bjects w h o ha ve parti ci pate d i n a cli nical trial e xa mi ni n g L Y 3 3 0 3 5 6 0.   F ort y -ei g ht 
h ealt hy s u bjects ha ve recei ve d L Y 3 3 0 3 5 6 0 as si n gle I V d oses ( 7 t o 5 6 0 0 m g) a n d 1 6 ha ve 
recei ve d I V pl ace b o . Si x patie nts wit h A D ha ve recei ve d bet wee n 6 a n d 9 d oses of   L Y 3 3 0 3 5 6 0
I V Q 4 W a n d 3 patie nts ha ve recei ve d place b o. Wit h a n y n o vel tar get or t hera p y t here ma y be 
u nf oreseea ble ris ks , a n d s u bjects s h o ul d be m o nit ore d cl osel y d uri n g cli nical trials.
P ote nti al A D p har mac o l ogi cal class effects f or L Y 3 3 0 3 5 6 0 c o mprise of , b ut are n ot li mite d t o:  
( 1) L Y 3 3 0 3 5 6 0 – f or mat i on of a nt i-dr u g a nt i b o dies ( A D As), a n d (2) i m me diate h y perse nsiti vity 
(im me diate a n d n o ni m me diate, i ncl u di n g i nf usi o n- r elate d reactio ns).
L Y 3 3 0 3 5 6 0 – A nti -Dr u g A nti b o dies : T reat me nt-e mer ge nt a nti-dr u g a nt i b o dies ( T E-A D As) ma y 
be o bser ve d i n cli nical st u dies wit h L Y 3 3 0 3 5 6 0 .  A nt i-dr u g a nt i b o dy levels ma y als o affect P K 
a n d dr u g effect.  I nf usi on reacti o ns a n d A D As are p ote ntial ris ks c o m m o n t o all lar ge m o lec ules.
A lth o u g h mi ni mal A D As ha ve bee n o bser ve d i n St u d y  L M D A , a ris k ma na ge me nt pla n for 
i m m u ne safety will be i nc or p orate d i nt o t he cli nical trial incl u di n g a pr ot oc ol  for m a na ge me nt of 
i nf usi on reactio ns, a n d sta n dar dize d data c ollecti o n f or i nf usi o n react i on A Es. I n St u d y L M D C, 
C CI

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 3
L Y 3 3 0 3 5 6 0
A D As will be asses se d t hr o u g h o ut t he st u d y a n d at a fi nal safety visit 1 3 wee ks after t he fi nal 
d ose of L Y 3 3 0 3 5 6 0 .
L Y 3 3 0 3 5 6 0 – Hy perse nsitivity (I m me di ate a n d N o ni m me di ate), i ncl u di n g i nf usi o n -rel ate d 
re acti o ns):  T here is a ris k of a n i nf usi o n- r elate d reactio n wi t h L Y 3 3 0 3 5 6 0 t hera p y .  I n 
St u d y L M D A, si n gle d oses u p t o 5 6 0 0 m g I V L Y 3 3 0 3 5 6 0 a n d m ult i ple d oses of 7 0 m g I V Q 4 W 
ha ve bee n ge nerall y  w ell t ol erate d i n healt h y s u bjects, a n d preli mi nar y res ults s h o w n o i nf usi on 
reactio ns.  T o mit i gate t he p ote ntial ris k of h y perse nsit i vity (i m me diate a n d n o ni m me diate), 
i ncl u di n g i nf usi on- relate d reacti o ns, specific st u d y e xcl usi o n cri t eria relate d t o aller g y are 
defi ne d i n t he cli nical pr ot oc ol , a n d a pr ot oc ol  for ma na ge me nt of i nf usi o n reacti o ns is i ncl u de d 
i n t he trial Ma n ual
of  O peratio ns.
3. 3. 3.
B e n efit/ Ri s k A s s e s s m e nt S u m m ar y
T o mit i gate t he p ote ntial ris ks descri be d i n Secti on 3. 3. 2 , the c urre nt st u d y will i ncl u de sta n dar d 
safety assess me nts: A Es, cli nical la b orat or y  tests, i m m u n o ge nicity assess me nts, vit al sig n a n d 
b o d y  wei g ht meas ure me nts, 1 2-lea d E C Gs, a n d p h ysical e xa mi nat i ons.
A d dit i onal safety assess me nts will i ncl u de ne ur o l ogi cal e xa mi nat i ons (as part of eac h p h ysica l 
e xa mi nat i on), M RI e xa mi nat i ons, a n d s uici dalit y e val uat i ons usi n g t he C o l um bia S uici de 
Se verit y Rati n g Scale ( C -S S R S).  T he c urre nt st u d y  will use a n in de pe n de nt e xter nal Data 
M o ni t ori n g C o m mittee ( D M C) t o m o nit or data o n a n o n g oi n g basis t o e ns ure t he co nti n ui n g 
safety of  p atie nts e nr olle d i n t his st u d y. T he D M C will c o n d uct a n i nit ial safety re vie w w he n t he 
first a p pr o xi matel y 3 0 pat ient s ha ve c om p lete d 3 m ont hs of e x p os ure t o st u d y  treat me nt (t hat is, 
after c o mplet i n g 4 wee ks f o ll owi n g t he t hi r d d ose of  st u d y tr e at me nt).  N o ne w pati e nts will be 
d ose d u ntil t he D M C re vie w has bee n c o m p lete d a n d t he rec o m me n dati on is t o c o nti n ue t he 
st u d y.
I n the c urre nt st u d y , a p pr o xi matel y 3 3 % of  t he patie nts will be ra n d o mize d t o place b o.  I n 
a d ditio n , all patient s p artici pat i n g i n t he st u d y will ha ve a desi g nate d st u d y part ner w h o will ha ve 
re g ular c o ntact wit h t he patie nt, acc o mp a n y  t he patie nt t o st u d y visits, a n d liaise wit h t he st u d y 
staff bet wee n visits as nee de d (see Secti on 6. 1 f or a d ditio nal  inf or m atio n a b o ut t he r ol e of t he 
st u d y part ner).
I n c o ncl usi on, t he a vaila ble n o ncli nical a n d cli nical data s u p p ort t he I V a d mi nistrati o n of 
L Y 3 3 0 3 5 6 0 t o t he i nte n de d st u d y p op ulati o n acc or di n g t o t he pr o p ose d cli nical i n vest i gati on 
pl a n, a n d als o pr o vi de a s ufficie nt mar gi n o f safety f or t he pr o p ose d desi g n a n d d oses.  T here are 
c urre ntl y n o disease -m o dif yi n g treat me nts f or A D. T he p ote ntial be nefits of L Y 3 3 0 3 5 6 0 
s h o wi n g disease-m o dif yi n g pr o perties i n patie nts wit h A D are c o nsi dere d t o o ut wei g h t he 
p ote nti al ris ks.
M ore 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, ris ks, S A Es , a n d reas o na bl y 
a nt ici pate d A Es of L Y 3 3 0 3 5 6 0 are t o be f o u n d i n t he I B.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 4
L Y 3 3 0 3 5 6 0
4. O bj e cti v e s a n d E n d p oi nt s
Ta ble L M D C . 4. 1 s h o ws t he o bjecti ves a n d e n d p o i nts of t he st u d y.
T a bl e L M D C .4. 1.
O bj e cti v e s a n d E n d p oi nt s
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nt
T o test t he h y p ot hesis t hat L Y 3 3 0 3 5 6 0 a d mi nistere d 
f or 1 0 0 wee ks will decrease t he decli ne i n c o g niti ve 
a n d/ or f u ncti o nal o utc o mes i n p atie nts wit h earl y 
s ym pt o matic A D relati ve t o place b o.
C ha n ge i n c o g niti o n a n d f u ncti o n as meas ure d b y t he 
i nte grate d Alz hei mer’s Disease Rati n g Scale (i A D R S) sc ore 
fr o m baseli ne t o 1 0 4 wee ks .
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 L Y 3 3 0 3 5 6 0 v ers us place b o o n 
cli nical pr o gressi o n i n patie nts wit h earl y 
s ym pt o matic A D .
C ha n ge i n c o g nit i on a n d/ or f u nct i on fr o m baseli ne 
t o 1 0 4 wee ks as meas ure d b y t he c ha n ge i n:

Alz hei mer’s Disease Assess me nt Scale —
C o g ni tive s u bscale ( A D A S -C o g 1 3) sc ore

Alz hei mer’s Disease C o o perati ve St u d y —
i nstr u me nt al Acti vit ies of Dail y Li vi n g 
scale ( A D C S-i A D L) sc ore

Cli nical De me nt ia Rati n g Scale— S u m  of 
B o xes ( C D R -S B) sc ore

Mi ni -Me ntal  State E xa mi nati on ( M M S E) 
sc ore
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
br ai n a g gre gate d ta u de p ositi o n.
C ha n ge i n brai n a g gre gate d ta u de p ositi o n fr o m baseli ne 
t hr o u g h 1 0 4 wee ks as meas ure d b y fl orta uci pir F 1 8 P E T 
sca n.
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
atte n uati n g d o w nstrea m ma rkers of t he 
ne ur o de ge nerati ve pr ocess i n A D .
C ha n ge i n brai n v ol u me tric meas ures fr o m baseli ne t hr o u g h 
1 0 4 wee ks as meas ure d b y v ol u metric ma g netic res o na nce 
i ma gi n g (v M RI ).
S afet y O bjecti ve
S afet y E n d p oi nts
T o e val uate safet y a n d t olera bilit y of L Y 3 3 0 3 5 6 0 .

Safet y assess me nts:
o
S p o nta ne o usl y re p orte d A Es
o
C li nical la b orat or y tests
o
V ital si g n a n d b o d y wei g ht meas ure me nts
o
1 2- lea d E C Gs
o
P h y sical a n d ne ur ol o gical e xa mi nati o ns
o
A nti -dr u g a nti b o dies

M a g netic res o na nce i ma gi n g (M RI ) (treat me nt-
e mer ge nt ra di ol o gical fi n di n gs)

C ol u m bia S uici de Se verit y Rati n g Scale ( C-S S R S)

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 5
L Y 3 3 0 3 5 6 0
E x pl or at or y O bjecti ves
E x pl or at or y E n d p oi nts
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
cli nical pr o gressi o n i n patie nts wit h earl y 
s ym pt o matic A D .
C ha n ge i n de pe n de nce le vel deri ve d fr o m A D C S -A D L scale 
sc ores fr o m baseli ne t o 1 0 4 wee ks .
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
cli nical pr o gressi o n i n patie nts wit h earl y 
s ym pt o matic A D .
C ha n ge i n c o g nit i on fr om baseli ne t o 1 0 4 wee ks as 
meas ure d b y t he c ha n ge i n:

C o g State Brief Batter y  ( C B B)
T o assess peri p heral P K a n d prese nce of 
a nti -L Y 3 3 0 3 5 6 0 a nti b o dies o ver 1 0 0 wee ks .

Ma xi m u m ser u m c o nce ntrati o n of
L Y 3 3 0 3 5 6 0 at 
stea d y state ( Cma x,ss ).

A nti -dr u g a nti b o dies (A D A ) a gai nst L Y 3 3 0 3 5 6 0 
i ncl u di n g treat me nt-e mer ge nt A D A a n d 
ne utralizi n g a nti b o dies.
T o assess t he effect of L Y 3 3 0 3 5 6 0 v ers us place b o o n 
cli nical pr o gressi o n as meas ure d b y Di gital Cl oc k 
Dra wi n g test (D C T Cl oc k ) i n patie nts wit h earl y 
s ym pt o matic A D .
C ha n ge i n D C T Cl oc k res ults fr o m baseli ne t hr o u g h 
1 0 4 wee ks .
T o assess ti me -de pe n de nt effects of L Y 3 3 0 3 5 6 0 
vers us place b o o n p las ma ta u, p h os p h o 1 8 1ta u, a n d 
ne ur ofila me nt li g ht ( Nf L) le vels i n patie nts wit h 
earl y s ym pt o matic A D.
C ha n ge i n plas ma ta u, p h os p h o 1 8 1ta u, a n d Nf L le vels fr o m 
baseli ne t hr o u g h 1 0 4 wee ks.
T o assess t he utilit y of D C T Cl oc k a n d plas ma 
p h os p h o 1 8 1ta u i n scree ni n g p hase efficie nc y f or 
trials of patie nts wit h earl y s y m pt o matic A D.
Ass ociati o ns of D C T Cl oc k a n d plas ma p h os p h o 1 8 1ta u wit h 
M M S E,
C B B, scree n fail ure cate g ories , a n d baseli ne data 
fr o m e nr olle d s u bjects.

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L Y 3 3 0 3 5 6 0
5.
St u d y  D e si g n
5. 1.
O v er all D e si g n
St u d y  L M D C is a m ult ice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, P hase 2 st u d y  of 
L Y 3 3 0 3 5 6 0 i n patie nts wit h earl y  s y m pt o matic A D a n d l o w-t o-me di u m cere bral ta u b ur de n.
T he ma xi m u m p ossi ble d urati o n of  t he st u d y is 1 2 1 wee ks t hat i ncl u des a scree ni n g peri o d of u p 
t o 8 wee ks, a t reat me nt p eri o d of  1 0 0 wee ks, a 4 -wee k p ost last d ose assess me nt, a n d a n 
i m m u n o ge nicity a n d safet y f oll ow- u p peri o d of  u p t o 1 3 wee ks , f oll owi n g t he l ast d ose of  t he 
st u d y dr u g at Wee k 1 0 0.  S u bject s w h o meet e ntr y criteria will be ra n d o mize d i n a 1: 1: 1 r atio t o 
o ne of t he f o ll owi n g treat m e nts:

1 4 0 0 m g L Y 3 3 0 3 5 6 0 :  L Y 3 3 0 3 5 6 0 1 4 0 0 m g I V i nf usi on Q 4 W f or 1 0 0 wee ks
( Visit 2 [ Wee k 0] t o Visit 2 7 [ Wee k 1 0 0 ]).

5 6 0 0 m g L Y 3 3 0 3 5 6 0 :  L Y 3 3 0 3 5 6 0 5 6 0 0 m g I V i nf usi on Q 4 W f or 1 0 0 wee ks
( Visit 2 [ Wee k 0] t o Visit 2 7 [ Wee k 1 0 0 ]).

Pl ace b o :  I V place b o i nf usi on Q 4 W f or 1 0 0 wee ks ( Visit 2 [ Wee k 0] t o Visit 2 7
[ Wee k 1 0 0 ]).
T he first safet y re vie w b y a Data M o nit orin g C o m mittee will be c o n d ucte d after a p pr o xi matel y 
3 0 pati e nts ha ve recei ve d 3 d oses a n d c o m plete d t he 4- wee k assess me nt peri o d ( t hat is j ust pri or 
t o t heir 4t h d ose). E nr ol me nt will halt after t hese p ati e nts ha ve recei ve d o ne d ose of st u d y 
treat me nt, h o we ver t h ose patie nts alrea d y d ose d will c o nt i n ue t heir all ocate d treat me nt. If a n y of 
t hese pati e nts disc o nt i n ue fr o m st u d y treat me nt f or reas o ns ot her t ha n safety,  t he y ma y be 
r e place d, u p o n disc ussi on bet wee n t he i n vest i gat ors a n d Lill y.     
T he pri mar y  h y p ot hesis bei n g teste d is t hat L Y 3 3 0 3 5 6 0 a d mi nistere d f or 1 0 0 wee ks will res u lt in 
a sig nifica nt sl o wi n g i n c o g nit i ve/f u ncti onal decli ne c o m pare d wit h place b o as meas ure d b y  t he 
c ha n ge fr o m baseli ne t o t he e n d of t he d o u ble-bli n d peri o d ( Wee k
1 0 4) o n t he i nte grate d 
Alz hei mer’s Disease Rat i n g Scale (i A D R S), i n s u bjects wit h earl y s ym pt o m at ic A D ( w here earl y  
s y m pt o mat ic A D refers t o t he c o m bi nat i on of 2 sta ges:  pr o dr o mal A D [ mil d c o g nit i ve 
i m pair me nt (M CI )-A D] a n d mil d de me nt ia d ue t o A D; Ala ka et al. 2 0 1 5) w h o ha ve 
l ow- t o-me d i u m ta u b ur de n.
T he o verall st u d y  desi g n is s h o w n i n Fi g ure L M D C . 5. 1.
A b bre viat i ons a n d defi nit i ons are pr o vi de d i n A p pe n di x 1 ; cli nical la b orat or y tests are descri be d 
i n A p pe n di x 2 ; St u d y  g o ver na nce c o nsi derati ons are descri be d i n detail i n A p pe n di x 3 ; a n d
He pati c mo ni t ori n g tests f or treat me nt -e mer ge nt ( T E) a b n or malit y is pr o vi de d i n A p pe n di x 4 .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
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A b bre viat i ons:  Q 4 W = o nce e ver y  4 wee ks; Q 1 3 W = o nce e ver y  1 3 wee ks; V = visit.
Fi g ur e L M D C . 5. 1.
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol I 8 G-M C -L M D C .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 3 8
L Y 3 3 0 3 5 6 0
5. 1. 1.
S cr e e ni n g P eri o d ( Vi sit 1)
At  or bef ore Visit 1, t he st u d y will be e x plai ne d t o t he patie nt (a n d his or her le gal re prese ntati ve, 
if a p plica ble) a n d t heir st u d y part ner.  Inf 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 s pa ns t he ti me bet wee n Visit 1 t o Vi sit 2.  St u d y  
assess me nts are s h o w n i n t he Sc he d ule of  Act i vities ( Sectio n 2 ).
A preli mi nar y  scree ni n g i nf or me d c o nse nt ma y be o btai ne d t o c o n d uct i nitial scree ni n g t o c ollect 
d e m o gra p hics data a n d a d mi nister t he Mi ni -Me ntal State E xa mi nat i on ( M M S E), t he C o g State 
Bri ef Batter y (C B B ), a n d t he Di gital Cl oc k Dra wi n g test ( D C T Cl oc k ).  Patie nts w h o d o n ot meet 
t he M M S E
scree ni n g criteria are n ot t o ha ve a n y ot her scree ni n g pr oce d ures perf or me d , wit h t he 
e xce pti o n of t he C B B a n d D C T Cl oc k .  T he y  ma y be rescree ne d f or t he M M S E 8 wee ks or m or e 
after t he first scree n (see Secti on 6. 4 ). Patie nts w h o scree n faile d o n t he C B B i n t he pre vi o us 
versi o n of t his pr ot oc ol ma y be rec o nse nte d a n d i m me diatel y rescree ne d usi n g t he M M S E (see 
Secti o n 6. 4 ).
P ati e nts w h o meet t he M M S E
scree ni n g criteria ma y pr ocee d t o t he re mai ni n g scree ni n g 
p r oce d ures o nce t he y ha ve gi ve n si g ne d/ date d i nf or me d c o nse nt f or t he f ull st u d y a n d t heir st u d y 
part ner has gi ve n si g ne d/ date d i nf or me d c o nse nte d t o partici pate as a st u d y part ner .    
F o ll owi n g si g ni n g of t he f ull i nf or me d c o nse nt f or m (I C F), 5 6 da ys are all o we d f or c o m plet i on 
of  Visit 1 scree ni n g assess me nts, pr oce d ures, a n d e val uat i on of res ults fr o m la b orat or y  tests, 
E C Gs, p h ysical a n d ne ur o l ogi cal e xa mi nat i ons , fl orta ucipi r F 1 8 P E T, a n d M RI .
P ati e nts w h ose scree ni n g res ults are n ot a vaila ble u nt il after 5 6 d a y s of  si g ni n g t he f ull I C F will 
r e mai n eli gi ble wit hi n Visit 1 u nt il t hese res ults bec o me a vaila ble.  N ote:   If a patie nt’s scree ni n g 
res ults are recei ve d b y t he site after 5 6 da ys, it will n ot be c o nsi dere d as a pr ot oc ol de viati on, b ut 
cli nical la b orat or y tests ( blo o d h e m at olo g y , c he mistr y, a n d uri nal ysis) are t o be re peate d f or t hat 
pati e nt.  Res ults of t he re peate d lab orat or y  t ests are t o be re vie we d b y t he i n vest i gat or or 
q ualifie d desi g nee f or assess me nt of t he patie nt’s c o nti n ue d eli g i bility.   Re peat scree ni n g f or 
M M S E,
C B B, D C T Cl oc k, C- S S R S, E C G, fl orta uci pir F 1 8 P E T i ma gi n g, a n d M RI, sa m ple 
c ollect i on f or plas ma ta u, plas ma p h os p h o 1 8 1 ta u, an d bi o mar ker st ora ge, lab orat or y  testi n g f or 
h e pat itis B s urface a nti ge n (H Bs A g ), a n d h e p atitis C vir us (H C V ) ri b o n ucleic aci d (R N A ) 
p ol y merase c hai n react i on ( P C R ) are n ot re q uire d.
Vi sit 1 is n ot c o nsidere d c o m plete u ntil all scree ni n g pr oce d ures ha ve bee n c o m plete d, res ults 
ha ve bee n re vie we d b y t he i n vest i gat or or q ualifie d desi g nee, a n d t he i n vest i gat or or q ualifie d 
desi g nee has c o nfir me d t hat t he patie nt is eli gi ble t o be ra n d o mize d. O nl y t he n ca n t he patie nt 
pr ocee d t o Visit 2.
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 bs e 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 usse d at Visit 1.  
P ati e nts must meet eli gi bilit y criteria (Secti o n 6. 1 a n d Sect i on 6. 2 ) t o c o nti n ue t o Visit 2.  
P ati e nts w h o d o n ot meet all i ncl usi o n cri t eria or w h o meet a n y e xcl usio n crit erio n ma y be 
di sc o nti n ue d fr om t he st u d y.

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5. 1. 1. 1.
S cr e e ni n g Pr o c e d ur e s
Scree ni n g , e ntr y a n d a d mi nistrati ve pr oce d ures, c o g niti ve assess me nts, safety assess me nts, a n d 
la b orat or y assess me nts (see Sc he d ule of Acti vities i n Secti o n 2 ) are t o be perf or m e d at Visit 1 
bef ore t he scree ni n g fl ort a u cipir F 1 8 P E T sca n a n d M RI.
5. 1. 1. 1. 1.
Mi ni -M e nt al St at e E x a mi n ati o n
T he M M S E will be a d mi nistere d t o patie nts at Visit 1 t o deter mi ne if t he
pati e nt meets e ntr y 
criteria f or c o g nitive i m pair me nt.  If a hist orical Lill y  or A vid fl ort a u cipir P E T sca n i s dee me d 
eli gi ble f or meet i n g e ntr y criteria (see Secti on 5. 1. 1. 1. 6. 1 ), t he n t he M M S E, w hic h is still t o be 
a d mi nistere d at Visit 1, will ser ve as t he baseli ne M M S E f or data a nal ysis , b ut will n ot be use d 
f or meet i n g e ntr y criteria. 
T he M M S E i s a brief i nstr u me nt use d t o assess c o g nit i ve f u ncti on i n el derl y patient s (F olstei n et 
al. 1 9 7 5).  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 dicat i n g greater 
le vel of i m pair me nt (see f urt her descri pti o n i n Secti on 9. 1. 2. 4 .  F or e ntr y  int o t he st u d y , p atie nts 
m ust ha ve a n M M S E sc ore of 2 0 t o 2 8.
5. 1. 1. 1. 2.
C o g St at e Bri ef B att er y
T he C B B will be a d mi nistere d t o patie nts at Visit 1 , b ut is n ot a n eli gibili t y crit erio n .  P at ient s 
s h o uld first perf or m  a C B B practice r o u n d t o fa miliarize t he msel ves wi t h t he i nstr u me nt , prior t o 
act ual a d mi nistrati o n of t he C B B t o be rec or de d f or t he st u d y.  T he C B B is a brief ( 1 5- t o 
1 8- mi n ute) , c o mp uter -base d c o g nitive test batter y desi g ne d t o m eas ure ps yc h o m o t or f u ncti on,
atte ntio n, w or ki n g m e mor y , a n d me mor y (see f urt her descri pti o n i n Secti o n 9. 1. 3. 1 ).
5. 1. 1. 1. 3.
Di git al Cl o c k Dr a wi n g T e st
T he D C T Cl oc k will be a d mi nistere d t o s u bjects at Visit 1 t o assess t heir perf or ma nce i n relat i on 
t o t he M M S E a n d C B B as well as ot her scree ni n g tests, b ut is n ot a n eli gi bility crit erio n .  T he 
cloc k dra wi n g test has bee n use d f or m ore t ha n 5 0 years as a brief ( 3 - t o 5- mi n ute) scree ni n g t o ol 
t o differe ntiate n or mal i n di vi d uals fr om t hose wi t h c o g niti ve i m pair me nt. T he a nal ysis will 
i ncl u de data fr om s u bjects e nr olle d i nt o t he st u d y as well as t h ose w h o fail scree ni n g.  T he 
D C T Cl oc k uses a n o ve l di gitizi n g ball p oi nt pe n t hat f u nct i ons i n t he s u bject’s ha n d as a n 
or di nar y  ball p oi nt pe n, b ut digi tall y rec or ds its p ositio n  o n t he pa per.  T hese data ca n t he n be 
use d al o n g wit h t he fi nal res ult t o assess t he s u bject ’s c o g niti ve stat us ( S o uillar d-Ma n d ar et al. 
2 0 1 6).
5. 1. 1. 1. 4.
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e — A d ult V er si o n
T he C -S S R S will be a d mi nistere d t o patie nts at Visit 1 t o assess t heir ps yc h o l ogi cal healt h. 
P ati e nts at i m mi ne nt ris k o f s uici de ( p ositi ve res p o nse t o Q uesti o n 4 or 5 o n t he C-S S R S) wi ll be 
e xcl u de d fr o m parti ci pat i n g i n t he st u d y. 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 de-relate d t h o u g hts a n d be ha vi ors d uri n g t he c orres p o n di n g 
assess me nt peri o d.  T he C -S S R S, i ncl u de d here as a scree ni n g ass ess me nt, is descri be d i n detail 
i n Secti o n 9. 4. 6. 1 .  T he C- S S R S “ Baseli ne” versi o n will be use d at scree ni n g, a n d t he fi n di n gs 
will c o nst itut e t he baseli ne assess me nt.  

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L Y 3 3 0 3 5 6 0
T he C -S S R S will be a d mi nistere d t o t he s u bject aft er t he c o g nit i ve assess me nts.  Res p o nses fr o m 
s u bjects will be c o nsi dere d w he n a d mi nisteri n g t he scale.  T he Lill y Self -Har m  S u p ple me nt f or m 
( S H S F) will be c o mplete d after eac h C -S S R S a d mi nistrati o n t o e nter t he n u m ber of discrete 
e ve nts of s uici dal be ha vi or i de nt ifie d. If, base d o n a d mi nistrati o n of t he C- S S R S, i t is 
deter mi ne d t hat s uici de -relate d be ha vi ors ha ve occ urre d, t he n c o mplet i on of t he Self -H ar m  
F o ll ow- U p ( S H F U) f or m is re qui re d t o c ollect a d diti o nal i nf or mati o n t o all o w f or a m ore 
c o mplete assess me nt of t hese be ha vi ors .
5. 1. 1. 1. 5.
Al z h ei m er’ s Di s e a s e Bi o m ar k er s
Bl o o d -base d bi o mar kers t o scree n f or A D pat h ol o g y  are u n der de vel o p me nt. A pr o misi n g
ca n di date is p h os p h o 1 8 1 t a u, a n d sa m ple s will be c ollecte d d uri n g Visit 1 .  Res ults of t he test 
ma y be use d t o i m pr o ve t he efficie nc y of t he scree ni n g pr ocess t hr o u g h t he i de nt ificati on of 
s u bjects w h o are li kel y t o ha ve ta u pat h olo g y .  A plas ma ta u a n d a n a d dit i onal bi o mar ker st ora ge 
sa m ple will als o be c ollecte d d uri n g Visit 1 a n d st ore d f or f ut ure a nal ysis t o e na ble bi o mar ker 
assa y de vel o p me nt a n d assess me nt of  cli nical utility f or fut ure tri als.
5. 1. 1. 1. 6.
S cr e e ni n g P o sitr o n E mi s si o n T o m o gr a p h y a n d M a g n eti c R e s o n a n c e 
I m a gi n g
All ot her scree ni ng cri t eria m ust be met i n or der f or t he patie nt t o pr ocee d wit h fl ort a u cipir F 1 8
P E T sca n, f o ll owe d b y a n M RI
sca n.
5. 1. 1. 1. 6. 1.
S cr e e ni n g F l ort a u ci pir F 1 8 P E T S c a n
A scree ni n g fl ort a u cipir F 1 8 P E T sca n will be perf or me d as part of t he st u d y eli gi bilit y cri t eria 
(see A p pe n di x 5 ).  T he fl orta ucipir F 1 8 P E T sca n will be s u b mitte d t o a ce ntralize d P E T 
i ma gi n g ve n d or desi g nate d b y  Lill y for assess me nt of pat ient ’s eli gi bility.   
A hist orical Lill y or A vi d fl ort a u cipi r F 1 8 P E T sca n res ult s h o wi n g lo w t o m e di u m t a u, wit hi n 6 
m o nt hs of V 1, ma y be s u b mitte d t o t he P E T i ma gi n g ce ntral rea der t o be c o nsi dere d f or 
eligi bili t y wi t ho ut re q ui rin g t he scree ni n g M M S E t o meet eli gi bilit y criteria. If t he hist orical 
sca n meets eligi bili t y crit eria b ut is perf or me d more t ha n 6 m o nt hs pri or t o Vi sit 2, t he n a n ot her 
flort a u ci pir sca n m ust be perf or me d a n d use d as t he baseli ne s ca n f or a nal ysis.
T he fl ort a u cipi r F 1 8 P E T scree ni n g criteria s h o uld be met  (sca n res ults c o nsiste nt wit h 
s p o ns or-deri ve d eli gi bilit y li mits f or fl ort a u cipir F 1 8 P E T ) bef ore t he patie nt ca n u n der g o t he 
M RI .
S pecific i nstr ucti o ns f or t he fl ort a u cipi r F 1 8 P E T sca n itself will be pr o vi de d i n t he P E T 
I ma gi n g Ma n ual.
5. 1. 1. 1. 6. 2.
S cr e e ni n g M RI
A l ocal scree ni n g M RI will be perf or me d at Visit 1 as part of t he st u d y eli gi bility criteria.
Trai ni n g a n d s pecific i nstr ucti o ns f or t he M RI pr ot oc ol will be pr o vi de d b y  a ce ntralize d M RI 
ve n d or desi g nate d b y  Lill y. T he M RI sca ns will be re vie we d b y t he i n vest i gat or or q ualifie d 
desi g nee f or i m me diate patie nt ma na ge me nt .  The sca n is t o be s u b mitte d t o t he ce ntralize d M RI 
ve n d or desi g nate d b y  Lill y f or fi nal deter mi nati on o f M RI eli gi bilit y.   Res ults of ce ntrall y  rea d 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 1
L Y 3 3 0 3 5 6 0
M RIs will be use d f or data a nal ysis a n d re p ort-writi n g p ur p oses a n d patie nt safety a n d eli gi bilit y 
will be re p orte d bac k t o sites.
5. 1. 2.
D o u bl e -Bli n d P eri o d ( Vi sit 2 t hr o u g h Vi sit 2 8 )
T he treat me nt peri o d is a d o u ble -bli n d treat me nt p hase be gi n ni n g at Visit 2.  At Visit 2, 
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 cl ose as 
p ossi ble t o t he tar get date, relat i ve t o Visit 2.  Patie nts w h o mee t e ntr y crit eria will be e nr o lle d 
a n d ra n d o mize d t o recei ve 1 0 0 wee ks of treat me nt wit h L Y 3 3 0 3 5 6 0 or place b o.
E ver y  4 wee ks d uri n g t his treat ment  p erio d, all  patie nts will be a d mi nistere d I V st u d y me dicat i on 
(pl ace b o or L Y 3 3 0 3 5 6 0) o nsi te as a n I V i nf usi on u p t o 2 5 0 m L o ver at least 9 0 mi n utes, a n d 
assess me nts will be p erf or m e d.
A fi nal assess me nt visit f or t he d o u ble-bli n d peri o d will be perf or me d at Visit 2 8 ( Wee k 1 0 4),
4 wee ks f oll o wi n g t he patie nt’s last d ose of st u d y  me dicati on.   See t he Sc he d ule of Act i vities 
( Sectio n 2 ) f or t he ti mi n g of e ve nts a n d t he meas ures t o be assesse d.  Pr oce d ures f or s o me visits 
ma y ta ke m ore t ha n 1 da y .
T he st u dy i nvesti g at or a n d site cli nic al st u dy te a m will n ot h ave access t o a ny fl ort a uci pir F 1 8
f oll o w-u p P E T sc a ns, as t he i nvesti g at or a n d site cli nic al st u dy te a m m ust re m ai n bli n de d t o 
a ny p ote nti al c h a n ges i n t a u de p ositi o n .
5. 1. 3.
I m m u n o g e ni cit y a n d S af ety F oll o w -U p Vi sit ( Vi sit 8 0 1)
P ati e nts s h o uld ret ur n t o t he site f or i m m u n o ge nicit y a n d safet y fol l ow - u p, Visi t 8 0 1, at 
Wee k
1 1 3, or 1 3 wee ks after t heir last d ose of st u d y dr u g if t he patie nt disc o nti n ues t he st u d y 
earl y f or c ollectio n of  blo o d s a m ples f or a nt i-dr u g a nt i b o dies (A D A ) (a nt i-L Y 3 3 0 3 5 6 0 
a nt i b o d y), P K m eas ure me nt , assess me nt of A Es , c o nc o mit a nt me dicat i ons , C-S S R S, a n d vital 
sig ns ( see t he Sc he d ule of Act i vities i n Secti on 2 ).
5. 2.
N u m b er of P arti ci p a nt s
A p pr o xi matel y  2 8 5 parti ci pa nts will be ra n d omize d .
5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y  is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule o f 
Act i vities ( Sectio n 2 ) for t he last patie nt.
5. 4.
S ci e ntifi c R ati o n al e f or St u d y D e si g n
C o nti n ui n g St a n d ar d of C are .  Patie nts ma y ta ke A D s y m pt o m at ic me dicat i ons , s uc h as 
c o nc o mita nt A C h EIs a n d/ or me ma nt i ne a n d/ or A x o na , if s uc h me dicatio ns are sta n dar d of care 
i n t he patient ’s c o u ntr y a n d sta ble d osi n g has bee n mai ntai ne d f or at least 2 m o nt hs bef ore Visit 
2.  D uri n g t he d o u ble - bli n d peri o d ( V 2 t o V 2 8 ), c ha n ges i n d oses of a vaila ble s y m pt o matic 
me dicat i ons f or M CI or A D will re q uire re p orti n g t o t he s p o ns or a n d t hese c ha n ges s h o uld occ ur 
o nl y  w he n necessar y  for t he a de q uate o verall care of t he patie nt.  T he effect of L Y 3 3 0 3 5 6 0
treat me nt plus sta n dar d of care will be c o m pare d wit h pl ace b o plus sta n dar d of care.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 2
L Y 3 3 0 3 5 6 0
D osi n g .  As descri be d m ore f ull y i n Secti o n 7. 1 , L Y 3 3 0 3 5 6 0 ( 1 4 0 0 m g or 5 6 0 0 m g) or pl ace b o
will be a d mi nistere d e ver y  4 wee ks as a n I V i nf usi o n of a p pr o xi matel y 2 5 0 m L o ver at least
9 0 mi n utes .
Desi g n .  St u d y  L M D C is a m ult ice nter, ra n d o mize d, patie nt, i n vesti gat or a n d s p o ns or bli n de d , 
pl ace b o -c o ntr olle d st u d y of L Y 3 3 0 3 5 6 0 i n patient s wit h earl y s y m pt o matic A D ( w here earl y 
s y m pt o mat ic A D refers t o t he c o m bi nat i on of 2 sta ges:  M CI -A D a n d mil d A D de me nt ia) ( Ala ka 
et al. 2 0 1 5) a n d l ow- t o-me d i u m ta u b ur de n. T he st u d y  is i nte n de d t o c haracterize t he be nefits 
a n d ris ks of treatme nt  wit h L Y 3 3 0 3 5 6 0 vers us place b o i n patie nts wi t h earl y s y m pt o mat ic A D .
St u d y  L M D C i ncl u des a place b o treat me nt ar m a n d all o ws all patient s t o c o nti n ue t heir A D 
sta n dar d-of -care c o nc o mita nt me dicat i ons.  I ncl usi o n of a place b o treat me nt ar m is acce pta ble i n 
St u d y  L M D C beca use t here are n o a vaila ble disease-m o dif yi n g treat me nts f or A D; t his a p pr oac h 
is i n a gree me nt wit h t he use of place b o descri be d i n t he Declarati o n of Helsi n ki ( W orl d Me dical 
Ass oci at i on 2 0 1 3).  T he use of a place b o c o m parat or i n St u d y  L MD C is nee de d t o deter mi ne t he 
efficac y a nd safet y  of L Y 3 3 0 3 5 6 0 t hera p y.
T he st u d y  incl u des a scree ni n g visit, w hic h ca n last u p t o 5 6 da ys fr om t he ti me of si g ni n g t he 
f ull I C F, at w hic h pat ient s are re q uire d t o ha ve fl ort a u cipir F 1 8 P E T i ma gi n g res ults co nsiste nt 
wi t h l ow- t o-me d i u m ta u i n or der t o be ra n d omize d t o t he d o u ble -bli n d p eri o d.  T he d urati o n of  
t he d o u ble -bli n d peri o d of t he st u d y  is 1 0 4 wee ks a n d i ncl u des 1 0 0 wee ks of treat me nt wit h 
e n d p o i nt meas ures at t he e n d of t he d o u ble -bli n d p eri o d ( Wee k
1 0 4) , t o assess t he safety,  
t olera bilit y , a n d efficac y of L Y 3 3 0 3 5 6 0 vers us place b o .
I n a d diti on t o A E re p orti n g, safety meas ures s uc h as la b orat or y assess me nts, i m m u n o ge nicity 
testi n g, vit al si g ns a n d wei g ht m o nit ori n g, E C G m o nit ori n g, p h ysical e xa mi nat i ons, ne ur o l ogi cal 
e xa mi nat i ons , M RI assess me nt s, a n d assess me nts of  s uici dal i deati on a n d be ha vi or are i ncl u de d 
t o facilitate a c o m pre he nsi ve safety e val uat i on.
5. 5.
J u stifi c ati o n f or D o s e
I n t his st u d y, p atie nts will recei ve eit her 1 4 0 0 m g or 5 6 0 0 m g L Y 3 3 0 3 5 6 0 Q 4 W or pl ace b o , for a 
t otal of 2 6 d oses . All d oses will be a d mi nistere d i ntra ve n o usl y.
S ui ta ble bi omar kers t o hel p select d oses f or t his st u d y  are n ot c urre ntl y a vaila ble. T w o d oses 
were selecte d f or use i n t his st u d y .  T he 5 6 0 0- m g d ose c orres p o n ds wit h t he hi g hest d ose teste d 
i n P hase 1, a n d is belie ve d t o be hi g h e n o u g h t o s u p press s ol u ble ta u a g gre gate c o nce ntrati o ns i n 
t he C N S b y > 9 5 %. 
Gi ve n t he hi g h de gree of s u p pressi o n t hat i s a nticip at e d, i t is t h o u g ht t hat t he 
5 6 0 0- m g Q 4 W d ose le vel will pr o vi de pr o of of c o nce pt t hat a n a nt i b o d y tar geti n g s ol uble ta u 
a g gre gates ca n sl o w t he pr o gressi o n of A D . T o date, m u lti ple d oses of 5 6 0 0 m g Q 4 W ha ve n ot 
bee n a d mi nistere d cli nicall y . H o we ver , base d u p o n t he P K o bser ve d i n t he si n gle a n d m ult i ple 
asce n di n g d ose st u dies, it is a ntici pate d t hat little dr u g acc u m ulati o n will be n ote d f oll owi n g a 
Q 4 W d osi n g re gi me n ( m a xi m u m ser u m c o nce nt rati on of L Y 3 3 0 3 5 6 0 at stea d y  state [ Cma x,ss ] is 
a nt ici pate d t o be a p pr o xi matel y 2 6 % hi g her t ha n t hat f oll o wi n g a si n gle d ose). B eca use t he 
e x p os ures i n t his st u d y are e x pecte d t o be relati vel y si milar t o t h ose i n t he si n gle-d ose st u d y , it is 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 3
L Y 3 3 0 3 5 6 0
a nt ici pate d t hat t he t olera bility of L Y 3 3 0 3 5 6 0 o bser ve d i n t his st u d y  will be si milar t o t hat 
o bser ve d i n t he si n gle-d ose st u d y .
T he l o w er d os e le vel in t his st u d y  (1 4 0 0 m g) will e val uate L Y 3 3 0 3 5 6 0 safet y a n d efficac y at 
e x p os ures t hat ha ve bee n teste d i n t he si n gle-d ose st u d y . T he e xte nt t o w hic h s o l uble ta u 
a g gre gate c o nce ntrati o ns will be s u p presse d at t he 1 4 0 0 m g Q 4 W d ose le vel is u n k n o w n, b ut is 
belie ve d t o be > 9 0 %. Base d o n t he 4 -f ol d differe nce i n t he 2 active d oses , little o verla p i n 
e x p os ure bet wee n t he d ose le vels is a nt ici pate d. Acc or di n gl y , t he use of 2 d oses i s e x pecte d t o 
pr o vi de a n e n ha nce d u n dersta n di n g o f t he e x p os ure – res p o nse relati o ns hi p wit h c o g niti ve, 
f u ncti onal, i ma gi n g , a n d safety e n d p o i nts, w hic h will be usef ul i n t he selecti on of d oses i n 
s u bse q ue nt st u dies. A d dit i onall y , t h e lo wer d ose le vel will pr o vi de t he o p p ort u nit y t o ac hie ve 
t he o verall st u d y o bjecti ves if t he 5 6 0 0- m g d ose le vel is n ot t olerate d i n t his st u d y .
I n t o xic o l og y  st u dies, t he hi g hest d ose le vel teste d ( 2 0 0 m g/ k g Q W f or 2 6 wee ks) i n b ot h 
T g 4 5 1 0 mice a n d c y n o m o l g us m o n ke ys was f o u n d t o be t he N O A E L d ose. Base d o n 
t o xic o ki netics, t he a vera ge ser u m c o nce ntrati o n i n T g 4 5 1 0 mice at t hat d ose le vel pr o vi des a 2. 0
mar gi n o f safety t o t he a nticipate d a vera ge c o nce ntrati o n i n h u ma ns at 5 6 0 0 m g Q 4 W, w hereas 
t he mar gi n of safet y deter mi ne d wi t h t he c y n o m o l g us data is 6. 0 . Base d o n t h ese mar gi ns, t he 
t o xic o l og y  data d o n ot s u g gest a n y p ote ntial safet y c o ncer ns at t he 5 6 0 0 m g L Y 3 3 0 3 5 6 0 Q 4 W 
d ose l e vel.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 4
L Y 3 3 0 3 5 6 0
6. 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 exe m pt i ons, are n ot per mitte d.
6. 1.
I n cl u si o n Crit eri a
P ati e nts are eli gi ble f or e nr oll me nt i n t he st u d y o nl y if t he y meet all of t h e foll o wi n g criteria:
T y pe of P atie nt a n d Dise ase C h ar acteristics
[ 1]
M e n or w o me n ( not of  c hil d beari n g p ote ntial), at least 6 0 t o 8 5 years of a ge .
a.
Fe male pat ient s: w o me n m ust be of n o n -c hil d beari n g p ote ntial. Fe male 
pati e nts are c o nsidere d of n o n -c hil d beari n g p ote ntial if t he y ha ve 
u n der g o ne s ur gical sterilizat i on ( h ysterect o m y  or bilateral o o p h orect o m y 
or t u bal li gati o n), ha ve a c o n ge nital a n o mal y s uc h as m ulleria n a ge nesis, 
or are p ost me n o pa usal as defi ne d b y eit her:
(i).
W o me n a ge d 5 5 year s or ol der n ot o n h or m o ne t hera p y , w h o ha ve 
ha d at least 6 m o nt hs of s p o nta ne o us a me n orr hea; or
(ii).
W o me n at l east 5 5 years o f 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 .
[ 2]
Gra d ual a n d pr o gressi ve c ha n ge i n me m or y fu ncti o n re p orte d b y  patie nts or
i nf or ma nts f or ≥6 m o nt hs .
[ 3]
Cri t erio n [ # 3] was r e place d b y crit erio n  [ # 4 1].
[ 4 1]  A n M M S E sc ore of 2 0 t o 2 8 (i ncl usi ve) at Visit 1 or a n acce pta ble hist ori c al 
flort a u ci pir P E T sca n wi t hi n 6 mo n t hs pri or t o Visit 1 .   
[4]
M eet s fl ort a u cipir F 1 8 sca n (ce ntral rea d) criteria.
P atie nt/ S u bject C h ar acteristics
[5 ]
C o ntrace pti o n
a.
Male
s u bjects
(i).
Male s u bjects, re gar dless of t heir fertilit y stat us, with n o n pre g na nt 
fe male part ners of c hil d beari n g p ote ntial m ust a gree t o eit her 
r e 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 ditio n al  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 pti ves, or i ntra uteri ne de vices) 
or effect i 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 9 0 da ys after st u d y dr u g 
d osi n g.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 5
L Y 3 3 0 3 5 6 0
(ii).
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 ptio n. Barrier pr otecti o n met h o ds wit h o ut c o nc o mita 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 ul d 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.
(iii).
Male s u bjects wit h pre g na nt  part ners s h o ul d use c o n d oms 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 me n o f c hil d beari n g 
p ote nti al, pre dicte d t o be 9 0 da ys f oll o wi n g t he last d ose of st u d y 
dr u g.
(iv).
Male s u bjects s h o u l d refrai n fr o m s per m d o nati on f or t he d urati o n 
of  t he st u d y a n d u ntil 9 0 da ys f oll owi n g t he last d ose of st u d y 
dr u g.
( v).
Male s u bjects w h o are i n e xcl usi vel y sa me se x relati o ns hi ps (as 
t heir pr eferre d a n d us ual lifest yle) are n ot re q uire d t o use 
c o ntrace pti o n.
[ 6]
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 patie 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 patient  t o st u d y visits or be a vaila ble b y t ele p h o ne at 
desi g nate d ti mes.
A sec o n d st u d y  part ner ma y ser ve as bac k u p.  T he st u d y part ner(s) is/are re q uire d t o 
acc o m pa n y t he patient  for si g 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 -H ar m  S u p ple me nt F or m a n d c o g niti ve a n d 
f u ncti on al scales are a d mi nistere d.
If a patie 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 a n d Alz hei mer’s Disease C o o perati ve St u d y — Act i vities of 
Dail y Li vi n g I n ve nt or y  (A D C S -A D L ) assess me nts.  If st u d y part ners are n ot a ble t o 
acc o m pa n y t he patient  i n pers o n, t he y  must be a vaila ble b y  t ele p h o ne f or t he 
f oll owi n g assess me nts:

A Es a n d c o nc o mit a nt me dicat i ons

r ele va nt p ortio ns of t he C -S S R S/ Self -H ar m  S u p ple me nt F or ms
If a st u d y part ner must wi t hdra w fr o m  stu d y part ici pati on, a re place me nt w o ul d be 
all o we d at t he i n vest i gat or’s discreti on.  T he re place me nt(s) 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/s he acc om pa nies t he patie nt t o 
parti ci pate.
St u d y  part ners must be a ble t o c o m m u nicate wi t h site pers o n nel a nd be willi n g t o 
c o mpl y  wit h pr ot o c ol r e q uire me nts, a n d i n t he i n vesti gat or’s o pi ni on m ust ha ve 
a de q uate literac y t o c o m p lete t he pr ot oc ol-s pecifie d q uesti o n naires.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 6
L Y 3 3 0 3 5 6 0
[ 7]
Ha ve gi ve n wri tte n i nf or me d c o nse nt a p pr o ve d b y Lill y a n d t he et hical re vie w
b oar d ( E R B) g o ver ni n g t he site .
[8]
A re 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 oll o w st u d y pr oce d ures.
6. 2.
E x cl u si o n Crit eri a
P ati e nts will be e xcl u de d fr o m st u d y e nr oll me nt if t hey meet a n y  of t he f oll owi n g cri t eria:
Me dic al C o n diti o ns
[9]
L ac k, i n t he i n vesti gat or’s o pi ni on, of  a de q uate pre m or bi d literac y, a de q uate 
visi o n, or a de q uate heari n g t o c o m plete t he re q uire d ps yc h o met ric tests.
[1 0] S i gnifica nt ne ur o l ogical disease affect i n g t he C N S, ot her t ha n A D, t hat ma y 
affect c o g nit i on or a bilit y t o c o mpl ete t he st u d y, i n clu di n g b ut n ot li mite d t o 
ot her de me nt ias, serio us i nfect i on of t he brai n, Par ki ns o n’s disease, m u lti ple 
c o nc ussi o ns, or e pile ps y or rec urre nt seiz ures (e xce pt fe brile c hil d h o o d 
seiz ures).
[ 1 1] Curre nt seri o us or u nsta ble ill nesses i ncl u di n g car di ovasc ular, he pat ic, re nal, 
gastr oe nter ol o gic, res pirat or y , e n d ocri n ol ogi c (i ncl u di n g u nsta ble dia betes) , 
ne ur o l ogi c ( ot her t ha n A D), ps yc hiatric, i m m u n olo gi c, 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 on, c o ul d i nterfere wi t h 
t he a nal yses i n t his st u d y; or has a life e x pecta nc y of < 2 4 m o nt hs .
[ 1 2]
Histor y  of  ca ncer wit hi n t he last 5 years, wit h t he e xce pti on of n o n metastatic 
basal a n d/ or s q ua mo us cell carci n o ma of t he s ki n, i n sit u cer vical ca ncer , 
n o n pr o gressi ve pr ostate ca ncer , or ot her ca ncers with l ow ris k of rec urre nce or 
s prea d.
[1 3] P atie nts wi t h an y c urre nt pri mar y ps yc hiatric dia g n osis ot her t ha n A D if, i n 
t he ju d g me nt of t he i n vest i gat or, t he ps yc hiatric dis or der or s y m pt o m is li kel y 
t o c o nf o u n d i nter pretati o n of dr u g effect, affect c o g niti ve assess me nt, or affect 
t he patie nt’s a bilit y t o co m plete t he st u d y . (Patie nts wit h a hist or y  of 
sc hiz o p hre nia or ot her c hr o nic ps yc hosis are e xcl u de d .)
[ 1 4] Are cli nicall y j u d ge d b y t he i n vest i gat or t o be at seri o us ris k f or s uici de as 
assesse d b y me dical hist or y, e xa mi nati on, or t he C -S S R S.
[1 5]
H istor y  of  alc o h ol or dr u g use di s or der (e xce pt t o bacc o use dis or der ) wit hi n 2 
years bef ore t he scree ni n g visit .
[1 6] Ha ve a hist or y  of cli nicall y si g nifica nt m ulti ple or se vere dr u g aller gies or 
se vere p osttreat me nt h y perse nsiti vity react i ons (i ncl u di n g b ut n ot li mite d t o 
er yt he ma mul tifor m e major, li near i m m u n o gl o b uli n A der m at osis, t o xic 
e pider mal  necr ol ysis, a n d/ or e xf oliati ve der matitis).
[1 7]
K n o w n p osi tive ser o l ogi c fi n di n gs f or h u ma n i m m u n o deficie nc y vir us 
a nt i b o dies.  L o c al la ws a n d re g ulat i ons ma y a p pl y t o w het her testi n g is 
re q uire d.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 7
L Y 3 3 0 3 5 6 0
M a g netic R es o n a nce Im a gi n g , Vit al S i g ns, E lectr oc ar di o gr a m s, L a b or at or y T ests, a n d 
P h ysic al E x a mi n ati o n
[ 1 8]
Ha ve a n y cli nicall y i m p orta nt a b n or malit y at scree ni n g, as deter mi ne d b y t he 
i n vesti gat or, i n p h ysical or ne ur ol o gical e xa mi nati o n, vital si g ns, E C G, or 
cli nical la b orat or y test res ults t hat c oul d be detri me ntal t o t he patie nt, c o ul d 
c o mpr o mise t he st u d y , or s h o w e vide nce of ot her eti o l ogi es f or de me nt ia.
[1 9 ] Scree ni n g M RI t hat s h o ws e vi de nce of si g nifica nt a b n or malit y t hat w o uld 
s u g gest a n ot her p ote ntial eti ol og y  for pr o gressi ve d e m e nt ia or a cli nicall y  
sig nifica nt fi n di n g t hat ma y  i m pact t he patie nt’s a bilit y t o s afel y p artici pate i n 
t he st u d y.
[ 2 0]
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  co ntrai n dicate d metal (ferr o ma g net ic) i m pla nts/car diac pace ma ker .
[2 1] P ati e nts wit h a hist or y  of h e pat itis B s h o ul d ha ve H Bs A g testi n g at scree ni n g 
a n d are e xcl u de d if H Bs A g is p osit i ve.
[2 2] P ati e nts wh o are h e patitis C vir us ( H C V) a nti b o d y p osi tive s h o uld ha ve 
f oll ow - u p H C V R N A P C R testi n g at scree ni n g a n d are excl u de d if H C V R N A 
P C R i s p ositive.
[ 2 3] Calc ulate d creati ni ne cleara nce <3 0 m L/ mi n ( C oc kcr oft – Ga ul t for m ula; 
C oc kcr oft a n d Ga ul t 1 9 7 6) at scree ni n g.
[2 4] Ala ni ne a mi n otra nsferase ( A L T) ≥2 t he u p per li mit of n or mal ( U L N) of t he 
perf or mi n g la b orat or y , as partate a mi n otra nsferase (A S T) ≥2 U L N, t otal 
bilir u bi n le vel ( T B L) ≥1. 5 U L N, or al kali ne p h os p hatase (A L P) ≥1. 5 U L N 
at scree ni n g.
N O T E:  Patie nts wit h T B L ≥1. 5 U L N are n ot e xcl u de d if t he y meet all o f t he 
f oll owi n g criteria f or Gil bert s y n dr o me:
a.
Bilir u bi n is pre d o mi na ntl y i n direct ( u nc o nj u gate d) at scree ni n g 
( direct bilir u bi n withi n n or mal li mits).
b.
A bse nce of li ver disease .
c.
A L T, A S T, a n d A L P ≤1 U L N at scree ni n g
d.
H e m o gl o bi n is n ot si g nifica nt l y decrease d at scree ni n g.
Pri or/ C o nc o mit a nt T her a p y
[ 2 5] If ta ki n g a n acetylc h o li nesterase i n hi bit or ( A C h EI) a n d/ or me ma nti ne, ha ve 
recei ve d treat me nt wit h a sta ble d ose of a n A C h EI a n d/ or me ma nti ne f or less 
t ha n 2 m o nt hs bef ore ra n d o mizat i on . [If a patie nt has rece nt l y st o p pe d a n 
A C h EI a n d/ or me ma nt i ne, he or s he m ust ha ve disc o nti n ue d treat me nt at least 
2 m o nt hs bef ore ra n d o mizat i on.]

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 8
L Y 3 3 0 3 5 6 0
[ 2 6] C ha n ges i n c o nc omit a nt me d icati on s t hat c o uld p ote nti all y affect c o g nitio n 
a n d t heir d osi n g s h o ul d be sta ble f or at l east 1 m o nt h bef ore scree ni n g, a n d 
bet wee n scree ni n g a n d ra n d o mizati on ( d oes n ot a p pl y t o me dicati ons 
di sc o nti n ue d d ue t o e xcl usi o ns or wit h li mite d d urati o n of use, s uc h as 
a nt i bi otics).
[ 2 7]
Ha ve recei ve d act i ve i m m u nizati o n a ge nts f or t he treat me nt of Alz hei mer’s 
di sease.
[2 8]
H a ve k n o w n aller gi es t o L Y 3 3 0 3 5 6 0 , relate d c o m p o u n ds, or a n y c o mp o ne nts
of  t he f or mulat i on; or hist or y  of si g nifica nt at o p y.
[2 9]
H a ve aller gies t o eit her m o n ocl o nal a nt i b o dies, di p he n h y dra mi ne,
e pi ne p hri ne, or m et h yl pre d nis o l one .
[3 0]
A r e recei vi n g I g G t hera p y (als o k n o w n as ga m ma gl o b uli n or i ntra ve n o us 
i m m u n o glo b uli n [I VI G])
Pr oce d ur al
[ 3 1] Se nsit i vity t o fl orta ucipir F 1 8 .
[3 2] I nt e n d t o use dr u gs k n o w n t o sig nifica nt l y pr ol o ng t he Q T i nter val wit hi n 
1 4 d a y s or 5 half -li ves, w hic he ver is l o n ger, of a n y sc he d ule d fl ort au cipir F 1 8 
P E T sca n, or ha ve a me dical hist or y of a ris k fact or of T orsa des de P oi ntes .
[ 3 3] P o or ve n o us access.
[3 4 ] Co ntrai n dicat i on t o P E T .
[ 3 5] Prese nt or pla n ne d e x p os ure t o i o nizi n g ra diat i on t hat, i n c o m bi nati o n wit h t he 
pl a 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 o m me n de d e x p os ure li mit s.
N ote: See A p pe n di x 5 f or a d ditio nal  florta uci pir F 1 8 Ta u P E T i ma gi n g 
i ncl usi on/e xcl usi o n  crit eria.
Pri or/ C o nc urre nt Cli nic al Tri al E x perie nce
[ 3 6]
Ar e 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 in v o l vi n g a n 
i n vesti gati onal pr o d uct or a n y  ot her t ype 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 .
[3 7]
H a ve part ici pate d wit hi n t he last 3 0 da ys i n a cli nical trial i n v o l vi n g a n
i n vesti gati on al pr o d uct.  If t he pre vi o us i n vesti gati o nal pr o d uct is 
scie ntificall y or me dicall y i nc om p ati ble wit h t his st u d y  a n d has a l o n g 
half -life, 3 m o nt hs or 5 half-li ves ( w hic he ver is l o n ger) s h o ul d ha ve passe d
pri or t o scree ni n g . ( Partici pati on i n o bser vati o nal st u dies ma y be per mitte d 
u p o n re vie w o f 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.)
[ 3 8]
Ha ve pre vi o usl y disc o nt i n ue d L Y 3 3 0 3 5 6 0 treat me nt d ue t o treat me nt -r elate d 
A E.   Pri or treat m e nt wit h L Y 3 3 0 3 5 6 0 i n P hase 1 st u dies ( L M D D) is all o we d 
aft er 3 mo nt hs of was h o ut pri or t o scree ni n g.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 4 9
L Y 3 3 0 3 5 6 0
Ot her E xcl usi o ns
[ 3 9]
Are i n vesti 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 m me diate fa mil y is defi ne d as a s p o use, pare nt, chil d, or 
si bli n g, w het her bi ol ogi c al or le gall y a d o pte d.
[4 0]
A re Lill y  e m plo y ees or are e mpl o y ees of t hir d-part y  or ga nizatio ns ( T P Os) 
i n v ol ve d i n st u d y w h o re q uire e xcl usi on of t heir e m pl o yees, or ha ve st u d y 
part ner s w h o are Lill y e m pl o yees or are e m pl o yees of T P Os i n v o l ve d i n a 
st u d y t hat re q uires e xcl usio n of  t heir e mpl o y ees.
6. 2. 1.
R ati o n al e f or E x cl u si o n of C ert ai n St u d y C a n di d at e s
T he use of L Y 3 3 0 3 5 6 0 i n ol der pati e nts is a nt ici pate d, t h us t his st u d y will s pecificall y e xa mi ne 
t he efficac y a n d safety i n a n el derl y p o p ulati on.  Cri t erio n [ 1 ] defi nes t he p o p ulati on a ge ra n ge 
f or t he p ur p oses of t his st u d y.  T heref ore, patie nts n ot meeti n g t he a ge crit erio n are e xcl u de d.
6. 3.
Lif e st yl e R e stri cti o n s
P ati e nts s h o uld r ef rai n fr o m d o nati ng bl o o d or bl o o d pr o d ucts fr o m t he ti me of t heir scree ni n g 
visit u ntil 6 m o nt hs f oll owi n g t he last d ose of st u d y  dr u g.
6. 4.
S cr e e n F ail ur e s
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y not be 
rescree ne d if t he scree n fail ure is d ue t o n o neli gi ble i ma gi n g res ults.  If t he scree n fail ure is d ue 
t o n ot meet i n g c o g niti ve criteria o n t he M M S E , t he n 1 rescree n will be all o we d after 8 wee ks.  
Rescree ns f or o t her reas o ns ma y be c o nsi dere d, b ut will re q uire s p o ns or a p pr o val .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 5 0
L Y 3 3 0 3 5 6 0
7.
Tr e at m e nt s
7. 1.
Tr e at m e nt s A d mi ni st er e d
T his st u d y  in v o l ves a c o m paris o n of L Y 3 3 0 3 5 6 0 a d mi nistere d as a n I V i nf usi o n of 
a p pr o xi matel y 2 5 0 m L o ver at least 9 0 mi n utes c o m pare d wit h place b o.  I n t he d o u ble -bli n d 
p eri o d, t he treat m e nt gr o u ps will be gi ve n eit her a n I V i nf usi on of L Y 3 3 0 3 5 6 0 or p lace b o f or 
1 0 0 wee ks.  Patie nts assi g ne d t o L Y 3 3 0 3 5 6 0 will recei ve eit her 1 4 0 0 m g or 5 6 0 0 m g, 
a d mi nistere d as a n I V i nf usi o n Q 4 W . Pati e nts will be ra n d o mize d 1: 1: 1 t o recei ve eit her place b o 
or 1 of  t he 2 d ose le vels o f L Y 3 3 0 3 5 6 0.
Ta ble L M D C . 7. 1 s h o ws t he treat me nt re gi me ns d uri n g t he d o u ble-bli n d peri o d.
T he st u d y  als o i ncl u des t he use of t he i n vesti gati on al  dia g n osti c pr o d uct, fl ort a u cipi r F 1 8, f or 
t he deter mi nat i on of a g gre gate d ta u de p osit i on .  I nf or mat i on re gar di n g t he use of fl ort a u cipi r 
F 1 8 i n t he st u d y is pr o vi de d i n A p pe n di x 5 .
T a bl e L M D C . 7. 1.
Tr e at m e nt R e gi m e n s, D o u bl e -Bli n d Tr e at m e nt P eri o d
Re gi me n
D ose
Visit 2 ( Wee k 0) t hr o u g h Visit 2 7 ( Wee k 1 0 0)
1 4 0 0 m g L Y 3 3 0 3 5 6 0
L Y 3 3 0 3 5 6 0: 1 4 0 0 m g I V i nf usi o n Q 4 W f or 1 0 0 wee ks ( Visit 2 [ Wee k 0] –
Visit 2 7 [ Wee k 1 0 0 ]).
5 6 0 0 m g L Y 3 3 0 3 5 6 0
L Y 3 3 0 3 5 6 0: 5 6 0 0 m g I V i nf usi o n Q 4 W f or 1 0 0 wee ks ( Visit 2 [ Wee k 0] –
Visit 2 7 [ Wee k 1 0 0 ]).
Pl ace b o
I V place b o i nf usi o n Q 4 W f or 1 0 0 wee ks ( Visit 2 [ Wee k 0] – Visit 2 7
[ Wee k 1 0 0 ]).
A b bre viati o ns:  I V = i ntra ve n o us; Q 4 W = o nce e ver y 4 wee ks.
I n vesti gati onal pr o d uct will be pre pare d at t he site b y u n bli n de d p har macists or ot her trai ne d
pers o n nel. I n vesti gati onal pr o d uct will be a d mi nistere d at t he site b y  bli n de d n urses or ot her
trai ne d i nf usi on pers o n nel.
T he i n vest i gat or or his/ her desi g nee is res p o nsi ble f or t he f oll owi n g:

e x plai ni n g t he c orrect use of t he i n vesti gati o nal a ge nt(s) t o t he s u bject a n d/ or 
le gal re prese ntati ve

verif yi n g t hat i nstr ucti o ns are f o ll owe d pr o perl y

mai ntai ni n g acc urate rec or ds of i n vesti gati o nal pr o d uct dis pe nsi n g a n d c o llecti on

at t he e n d of t he st u d y, ret ur ni n g all u n use d me dicati o n t o Lill y, or i ts desig nee ,
u nless t he s p o ns or a n d sites ha ve a gree d t hat all u n use d me dicat i on is t o be 
destr o y e d b y t he site, as allo w e d b y lo c al  la w.
7. 1. 1.
P a c k a gi n g a n d L a b e li n g
Cli nical st u d y 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.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 5 1
L Y 3 3 0 3 5 6 0
T he dr u g pr o d u ct  ( L Y3 3 0 3 5 6 0) is s u p plie d f or cli nical trial use as l y o p hilize d p o w der 
f or mulat i on i n vials .  T he vial is rec o nst itut e d/ dil ute d wit h sterile rec o nstituti o n s ol ut i on .  
T he l y o p hilize d dr u g pr o d uct L Y 3 3 0 3 5 6 0 is c om p ose d of L Y 3 3 0 3 5 6 0 a n d t he e xci pie nts 
 
.  T he vial is ma n ufact ure d t o deli ver 
6 0 0 m g o f L Y 3 3 0 3 5 6 0 per vial .  Rec o nstituti n g/ d il uti n g t he vial c o nte nts wit h 2 0 m L of sterile
rec o nstit uti o n s ol uti on gi ves a cl ear/li g ht l y o palesce nt s ol uti on c o ntai ni n g 3 0 m g/ m L o f 
L Y 3 3 0 3 5 6 0 at a p H of 6. 0.  F or cli nical a d mi nistratio n, t he rec o nst itut i on v o l ume f or t he vial 
ma y be a dj uste d t o facilit ate deli ver y of d oses re q uiri n g a hi g her dr u g pr o d uct c o nce ntrati o n. 
F urt her dil ut i on ma y als o be ma de usi n g sterile sali ne.   S u bst itut i on f or 0. 9 % n or mal sali ne ma y 
be per mitte d if all o we d i n t he p har mac y  ma n ual. 
Pl ace b o is t o be a d mi nistere d wit h 2 5 0 m L of 0. 9 % n or m al sali ne.
7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
P ati e nts w h o me et all crit eria for e nr oll me nt will be assi g ne d a st u d y  ( patie nt) n u m ber at Visit 1 
a n d ra n d o mize d t o d o u ble-bli n d treat me nt at Visit 2. Patie nts will be ra n d o mize d t o L Y 3 3 0 3 5 6 0 
or Pl ace b o i n a 1: 1: 1 rati o. Assi g n me nt t o treat me nt gr o u ps will be deter m i ne d b y a c om p uter -
ge nerate d ra n d o m se q ue nce usi n g a n i nteracti ve we b res p o nse s yste m (I W R S). F or t he first ,
a p pr o xi matel y, 3 0 pati e nts, t he I W R S will be pr o gra m me d t o g uara ntee bala nce bet wee n t he 
ar ms for t he fi rst i nteri m a nal ysis f or safety; t his is r eferre d t o as t he b ur n-i n peri o d. After t he 
b ur n -i n peri o d, patie nt ra n d o mizati on will t he n f o ll o w t he d y na mic all ocati on ( mi ni mizat i on) 
met h o d of P oc oc k a n d Si m o n ( 1 9 7 5) t o bala nce t he treat me nt ar ms usi n g i n vest i gati ve site as a 
fact or. T his is t o e ns ur e bala nce d pat ient  assi g n me nt bet wee n treat me nt ar ms wit hi n eac h site at 
t he e n d of t he st u d y.
T he I W R S will be use d t o assi g n a d osi n g re gi me n t o eac h patie nt.
Si te pers o n nel will c o nfir m 
t hat t he y ha ve locate d t he c orrect pac ka ges b y  e nteri n g a c o nfir mat i on n u m ber f o u n d o n t he la bel 
i nto t he I W R S, pri or t o d osi n g t he patie nt.
T he I W R S will be use d t o assi g n a d osi n g re gi me n t o eac h patie nt.  Site pers o n nel will c o nfir m 
t hat t he y ha ve locate d t he c orrect pac ka ge s b y e nteri n g a c o nfir mat i on n u m ber f ou n d o n t he l a bel 
i nto t he I W R S , prior t o d osi n g t he patie nt .
7. 2. 1.
S el e cti o n a n d Ti mi n g of D o s e s
Assess me nt of L Y 3 3 0 3 5 6 0 safety a n d t olera bilit y is a ce ntral o bject i ve; t heref ore, m o nit ori n g 
a p pr o xi matel y 2 3 2 pat ient s o n L Y 3 3 0 3 5 6 0 (1 1 6 per 1 4 0 0 -m g a n d 5 6 0 0 -m g d ose gr o u ps, 
res pecti vel y) o ver 1 0 4 wee ks i n parallel with a p pr o xi matel y 1 1 6 pat ient s o n place b o o ver 
1 0 4 wee ks pr o vi des data t o assess safet y f or furt her cli nical de vel o p me nt.
T he act ual  ti me of L Y 3 3 0 3 5 6 0 d ose a d mi nistrati o ns o n t he da y  of st u d y visits will  be rec or de d i n 
t he s u bject’s case re p ort f or m ( C R F).
N ote t hat at  visits at w hic h c o g nitive assess me nts are 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 V st u d y me dicat i on ( L Y 3 3 0 3 5 6 0 or I V place b o) is a d mi nistere d.
C CI

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 5 2
L Y 3 3 0 3 5 6 0
I ntra ve n o us st u d y me dicatio n ( t hat is, I V pl ace b o or L Y 3 3 0 3 5 6 0 ) is t o be a d mi nistere d Q 4 W .  
Base d o n t he per mitte d visit wi n d o w (see Secti o n 2 ), alt h o u g h I V st u d y me dicatio n c o ul d 
t he oreticall y be a d mi nistere d at a 2-wee k i nter val , I V st u d y me dicat i on m ust n ot be gi ve n at a 
d osi n g i nter val o f less t ha n 2 1 da ys at a n y time d uri n g t he st u d y .  I ntra ve n o us st u d y me dicat i on 
gi ve n at a d osi n g i nter val of less t ha n 2 1 da y s at a n y time d uri n g t he st u d y  will be c o nsi dere d a 
pr ot oc ol  de viat i on . T he d ose of L Y 3 3 0 3 5 6 0 was c h ose n base d o n n o ncli nical a n d cli nical 
P K/ P D a n d safet y fr om S t u d y L M D A ( See Sectio n 5. 5 ).
I nf usi ons s h o uld occ ur o ver t he c o urse of at least 9 0 mi n utes.  If a patie nt de m o nstrates a n 
i nf usi on reacti o n t o L Y 3 3 0 3 5 6 0 , me d icati ons t o ma na ge t he i nf usi o n reacti on ma y be 
a d mi nistere d at t he discret i on of t he i n vest i gat or (see Secti o n 7. 7 ). I n t he e ve nt of i nf usi o n 
reactio ns, r efer t o t he o perati o ns ma n ual. Patie nts s h o uld be o bser ve d f or a mi ni m u m o f 2 h o urs
f oll owi n g eac h i nf usi on of L Y 3 3 0 3 5 6 0 f or t he first 3 i nf usi ons. After t he first 3 d oses, a 
mi ni mal p ost -i nf usi on o bser vat i on ti me of at least 6 0 mi n utes will be re q uire d f or all s u bse q ue nt 
i nf usi ons.
S ites must ha ve res uscitat i on e q ui p me nt a vaila ble.
7. 3.
Bli n di n g
T his is a pati e nt, i n vest i gat or a n d s p o ns or bli n de d st u d y, wit h desi g n t o mai ntai n bli n di n g t o 
L Y 3 3 0 3 5 6 0 treat me nt .  T o preser ve t he bli n di n g of t he st u d y, a mi ni mal n u m ber of Lill y 
pers o n nel , a n d pers o n nel e xter nal t o t he st u d y tea m, will  ha ve access t o t he ra n d o mizat i on ta ble 
a n d treat me nt assi g n me nts bef ore t he st u d y is c o m plet e.  O nl y a st u d y site p har macist or ot her 
trai ne d pers o n will be u n bli n de d at t he site f or i n vesti gati onal pr o d uct pre par at i on. T he 
i n de pe n de nt e xter nal D M C will be u n bli n de d f or a n y safety or efficac y assess me nts. 
E mer ge nc y  u n bli n di n g f or A Es ma y be perf or me d t hr o u g h t he I W R S.  T his o pti o n ma y be use d 
O N L Y if t he s u bject’s well-bei n g re q uires k n o wle d ge of t he s u bject’s tr eat me nt assi g n me nt.  All 
u n bli n di n g e ve nt s are rec or de d a n d re p orte d b y t he I W R S.
If a n i n vesti gat or, site pers o n nel perf or mi n g assess me nts, or s u bject is u n bli n de d, t he s u bject 
m ust be disc o nt i n ue d fr om t he st u d y.  I n cases w here t here are et hical reas o ns t o ha ve t he s u bject 
r e mai n i n t he st u d y, t he i n vesti gat or m ust o btai n s pecific a p pr o val fr om a Lill y cli nical researc h 
p h ysicia n ( C R P) f or t he s u bject t o c o nti n ue i n t he st u d y .
I n case of a n e mer ge nc y, t he i n vesti gat or has t he s ole res p o nsi bility f or deter mi ni n g if u n bli n di n g 
of  a patie nt’s treat me nt assi g n me nt is warra nte d f or me dical ma na ge me nt of t he e ve nt.  T he 
p atie nt ’s safety m u st alwa ys be t he first c o nsi derati o n i n ma ki n g s uc h a deter mi nat i on.  If a 
pati e nt’s treat me nt assi g n me nt is u n bli n de d, Lill y m ust be n otifie d i m me diatel y.  If t he 
i n vesti gat or deci des t hat u n bli n di n g is warra nte d, it is t he res p o nsi bility of  t he i n vestigat or t o 
pr o m ptl y d oc u m e nt t he decisi o n a n d rati o nale a n d n otif y Lill y as s o o n as p ossi ble.
A list of all t h ose w h o are u n bli nde d t o st u d y  treat me nt as t he st u d y pr o gresses will be 
mai ntai ne d a n d st ore d wit h t he fi nal d oc u me ntati o n of t he st u d y .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 5 3
L Y 3 3 0 3 5 6 0
7. 4.
D o s a g e M o difi c ati o n
D osa ge m o dificat i ons will n ot be ma de b y i n vest i gat ors.
7. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
T he i n vest i gat or or hi s/ her desi g nee is res p o nsi ble f or t he f oll owi n g:

c o nfir mi n g a p pr o priate te m perat ure c o n dit i ons ha ve bee n mai ntai ne d d uri n g 
tra nsit for all st u d y  treat me nt 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 st u d y tr e at me nt.

e nsuri n g t hat o nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y treat me nt 
a n d o nl y a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y treat me nt.  All st u d y 
treat me nts must 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 mo ni t or e d 
( ma n ual or aut o m ate d) area in acc or da nce wit h t he la bele d st ora ge c o n dit i ons 
wi t h access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff.

t he i n vest i gat or, i nstitut i on, 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 st u d y treat me nt acc o u nta bilit y,  rec o nciliati on, a n d 
rec or d mai nte na nce (s uc h as recei pt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds).
7. 6.
Tr e at m e nt C o m pli a n c e
T he a d mi nistrati o n of all st u d y  me dicat i on s h o ul d be rec or de d i n t he a p pr o priate secti o ns of t he 
ele ctr o nic case re p ort f or m (e C R F).
Beca use d osi n g occ urs at st u d y  visits, patie nts w h o atte n d all visits a n d s uccessf ull y recei ve 
L Y 3 3 0 3 5 6 0 or pl ace b o i nf usi ons are a ut o m aticall y c o mplia nt wi t h t his treat me nt.  A n y i nf usi o n 
at w hic h 7 5 % (a p pr o xi matel y 1 9 0 m L) or m ore of t he i nf us i on s o l uti on is gi ven will  be 
c o nsi dere d a c o m plete i nf usi o n.
If a patie nt atte n ds a visit b ut d oes n ot recei ve a c o m plete i nf usi o n (f or e xa m ple, 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 wit hi n 2 4 h o urs if p ossi ble.  
If less t ha n 75 % 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 om 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.
7. 7.
C o n c o mit a nt T h er a p y
All c o nc o mit a nt me dicat i ons ta ke n d uri n g t he st u d y must be rec or de d o n t he C o nc o mita nt 
Me dicat i on C R F.  Patie nts 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 vest i 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 nitiati on 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 t he d ose of a n y c urre nt c o nc o mita nt me dicat i ons or 
s u p ple me nts.
T o e ns ure sta n dar d of care f or A D, use of a p pr o ve d a n d/ or sta n dar d -of -care treat me nts f or A D is 
per mitte d i n t his st u d y , a n d n o me dicat i ons are e x plicit l y e x clu d e d f r o m use.  T he secti 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 mita nt me dicati o n use.

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All o w e d Me dic ati o ns.   Use of a p pr o ve d a n d/or s ta n dar d-of -care treat me nts for A D is per mitte d 
d uri n g t h e st u d y, pr o vide d t hat s uc h m e dicat i ons d ose has bee n u nc ha n ge d f or 2 m o nt hs bef ore 
Vi sit 2.  D oses of t hese me dicatio ns s h o ul d r e m ai n c o nsta nt t hr o u g h o ut t he d o u bl e- bli n d peri o d 
( Visit 2 t o V isit 2 8).
If a patient  has rece ntl y st o p pe d A C h EIs a n d/ or me ma nt i ne, he or s he m ust ha ve disc o nti n ue d 
treat me nt at least 2 m o nt hs bef ore Visit 2.
Ot her vita mi ns , me dical fo o d, or n utrace uticals gi ve n f or t heir p ossi ble effects o n A D ma y be 
c o nti n ue d o n sta ble d oses be gi n ni n g 2 m o nt hs bef ore Visit 2.
Pri or t o V 2 8 , bef ore a p atie nt st arts, st o ps, or c h a n ges d oses of A C h EIs a n d/ or me m a nti ne or 
ot her tre at me nts f or t heir A D, t he S p o ns or or desi g nee m ust be c o nt acte d t o deter mi ne 
w het her or n ot t he p atie nt s h o ul d c o nti n ue i n t he st u dy a n d w het her or n ot cli nic al o utc o m e 
me as ures s h o ul d be perf or me d.  F ail ure t o n otify Lilly or its desi g nee re g ar di n g st arti n g, 
st o p pi n g, or c h a n gi n g d oses of A C h EIs a n d/ or me m a nti ne or ot her tre at me nts f or t heir A D
pri or t o V 2 8 will be c o nsi dere d a pr ot oc ol vi ol ati o n .
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.   C ha n ges i n t hera pies t hat ma y 
p ote nti all y affect t he patie nts ’ A D s h o ul d be e nc o ura ge d t o be sta ble ; c ha n ges will be allo we d 
a n d s h o ul d be ca pt ure d i n patie nts ’ n otes at t he site.
Use of be nz o diaze pi nes f or treat me nt o n a n as -nee de d basis f or i ns o m nia or dail y d osi n g as 
a n xi o l ytics is per mitte d.  Use of se dat i ves or h y p n otics s h o ul d be a v oi de d f or 8 h o urs bef ore t he 
c o g nitive a n d f u nct i onal tests are c o n d ucte d u nless t he y are gi ve n c hr o nicall y.
If a n i nf usi o n react i on occ urs, me dicat i ons t o ma na ge reactio ns s uc h as, b ut n ot li mite d t o,
di p he n h y dra mi ne, e pi ne p hri ne, a n d/ or met h yl pre d nis o l one ma y be a d mi nistere d at t he di scretio n
of  t he i n vesti gat or (see Secti o n 9. 4. 7. 1 a n d t he cli nical trial Ma n ual o f O perati o ns f or a d ditio n al  
i nf or mat i on). A d mi nistrati o n of me d icati ons pri or t o a n i nf usi on t o pre ve nt a reacti o n d oes n ot 
ca use a disc o nt i n uatio n of  t he patie nt fr o m t he st u d y. If t he nee d f or c o nc o mita nt me dicati on
arises, i ncl usi on or c o nti n uat i on of t he patie nt ma y be at t he discreti o n o f t he i n vest i gat or after
c o ns ultati o n wit h a Lill y C R P .  C o nc o mita nt t hera p y  a d mi nistere d t o treat a n i nf usi o n reacti on or 
as pre me dicat i on f or i nf usi ons s h o uld be d oc u m e nte d.
If it bec omes necessar y f or a patie nt t o start ta ki n g a me dicat i on k n o w n t o pr ol o n g Q T i nter val 
pri or t o perf or ma nce of a n y p ost baseli ne fl orta uci pir F 1 8 sca n, d o n ot perf or m t he sca n or wait 
u nt il t he Q T -pr ol o n gi n g me dicat i on has bee n st o p pe d f or t he l o n ger of 1 4 da ys or 5 half -li ves.  
T he patie nt ma y , h o we ver, re mai n i n t he st u d y.  N o n perf or ma nce of p ost baseli ne fl orta uci pir F 
1 8 P E T sca ns i n pat ient s ta ki n g a me dicati o n k n o w n t o pr ol o n g Q T i nter val will n ot be 
c o nsi dere d a pr ot oc ol vi o lati on.
E xcl u de d Me dic ati o ns
C o nc o mit a nt t her a pies t h at are pr o hi bite d d uri n g tre at me nt wit h L Y 3 3 0 3 5 6 0 :  I g G t hera p y 
( als o k n o w n as ga m ma gl ob uli n or i ntra ve n o us 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.

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7. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
7. 8. 1.
Tr e at m e nt aft er St u d y C o m pl eti o n
P ati e nts w h o c o m plete t hi s st u d y t hr o u g h Visit 2 8 ma y be eli gi ble t o partici pate i n a n act i ve 
treat me nt e xte nsi o n , if a vaila ble.

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8. Di s c o nti n u ati o n Crit eri a
8. 1.
Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
P ossi ble reas o ns lea di n g t o per ma ne nt disc o nti n uati o n of st u d y  treat me nt:

S u bject Decisi o n
o
t he s u bject or t he s u bject’s desi g nee, for e xa m ple t he le gal g uar dia n, re q uests t o 
di sc o nti n ue t he i n vesti gati onal pr o d uct.

Di sc o nti n uatio n d ue t o a he pati c e ve nt or li ver test a b n or malit y
S u bjects w h o are disc o nti n ue d fr o m t he i n vesti gati o nal pr o d uct d ue t o a he patic e ve nt or 
li ver test a b n or mality s h o uld ha v e a d ditio n al he patic safet y data c ollecte d via 
C R F/electr o nic data e ntr y .
Di sc o nti n uatio n of  t he i n vesti gati onal pr o d uct 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 vesti gat or w he n a s u bject meets o ne of t he f o ll owi n g c o n di tio ns after 
c o ns ultatio n wi t h t he Lill y desi g nate d m e dical mo ni t or:
o
ala ni ne a mi n otra nsferase ( A L T ) or as partate a mi n o tra nsferase (A S T ) > 8 X 
u p per li mit of n or mal ( U L N )
o
A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks
o
A L T or A S T > 3 X U L N a n d t otal bilir u bi n le vel (T B L ) > 2 X U L N or 
i nter nat i onal n or m alize d ratio (I N R) > 1. 5
o
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, 
rig 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 %)
o
alkali ne p h os p hatase ( A L P ) > 3 X U L N
o
A L P > 2. 5 X U L N a n d T B L > 2 X U L N
o
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 %) .
I n a d ditio n, s u bjects will be disc o nti n ue d fr om t he i n vesti gat i onal pr o d uct i n t he f o ll owi n g 
circ u msta nces:
o
Se vere ac ute i nf usi on react i on ( f or e xa m ple, n ot res p o nsi ve t o me dicati on 
s uc h as a nti hista mi nes, n o nster oi dal a nti-i nfla m mat or y dr u gs, a n d/ or 
narc oti cs a n d/ or brief int err u ptio n of  inf usi o n ).
o
A n A E i ncl u di n g s y m pt o ms or cli nicall y si g nifica nt la b orat or y v alue, E C G 
resul t, p h ysical e xa mi nat i 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 SR S res ult, or vi t al 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 patie nt .
o
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 safety c o ncer n, i n t he 
j u d g me nt of t he i n vesti gat or.

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o
T he patie nt, f or 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 a n d te m p orar y disc o nti n uatio n cri teria ca n n ot be met  (see Sectio n 8. 1. 1 ).
S u bjects disc o nt i n ui n g fr om t he st u d y treat me nts pre mat urel y f or a n y reas o n s h o ul d c o m plete 
A E a n d ot her f o ll ow- u p pr oce d ures per Secti o n 2 ( Sc he d ule of Acti vities), Secti o n 9. 2 ( A d verse 
E ve nts) , a n d Secti o n 9. 4 ( Safety)  of t his pr ot oc ol.
8. 1. 1.
T e m p or ar y Di s c o nti n u at i o n fr o m St u d y Tr e at m e nt
T e m p orar y  disc o nti n uati on fr om L Y 3 3 0 3 5 6 0 treat me nt is all o we d if a s h ort-t er m treat me nt wi t h
a n e xcl u de d me dicat i on is necessar y, sec o n dar y t o h os pitalizati o n, pers o nal circ u msta nces, or t o 
e val uate t he st u d y dr u g i m pact o n a n u ncertai n A E. St u d y  dr u g ma y be restarte d at t he 
i n vesti gat or’s discreti on. If te m p orar y disc o nti n uati o n 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 C R P . Te m p orar y  tr e at me nt disc o nti n uati o n a n d restarti n g s h o ul d be d oc u me nte d. 
Restarti n g treat m e 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 uld be 
di sc usse d bet wee n t he i n vesti gat or a n d Lill y C R P .
8. 1. 2.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d S u bj e ct s
If t he s p o ns or or i n vesti gat or i de ntifies a s u bject 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, t he n t he s u bject s h o ul d be c o nsid er e d f or disc o nt i n uat i on fr om st u d y 
treat me nt.  If t he i n vest i gat or a n d t he s p o ns or C R P/clinical researc h scie ntist (C R S ) a gree t hat it 
is me dicall y a p pr o priate t o c o nti n ue, t he i n vest i gat or m ust o btai n d oc u me nte d a p pr o val fr om t he 
s p o ns or C R P/ C R S t o all o w t he i na d verte ntl y e nr olle d s u bject t o c o nti n ue i n t he st u d y.
S af et y f oll ow- u p i s as o utli ne d i n Sect i on 2 ( Sc he d ule of Acti vities), Secti o n 9. 2 ( A d verse 
E ve nts) , a n d Secti o n 9. 4 ( Safety)  of t his pr ot oc ol.
8. 2.
Di s c o nti n u ati o n fr o m t h e St u d y
P ati e nts w h o d o n ot meet e ntr y criteria or w h o are e xcl u de d b y e xcl usio n  crit eria fr o m Visit 1 
tests a n d pr oce d ures s h o ul d be disc o nti n ue d fr om t he st u d y before ra n d o mizati o n as a n e ntr y  
fail ure.
S u bjects will als o be disc o nt i n ue d fr om t he st u d y i n t he f oll owi n g circ u msta nces:

e nr o ll me nt 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 pr o d uct or 
e nr o ll me nt i n a n y ot her t y pe of me d ical researc h j u d ge d b y s p o ns or n ot t o be 
scie ntificall y or me dicall y c om pati ble wit h t his st u d y .

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 ulat i ons, a n d g o o d cli nical  
practi ce ( G C P) .

i n vesti gat or decisi on
o
t he i n vest i gat or deci des t hat t he s u bject s h o ul d be di sc o nti n ue d fr om t he 
st u d y.

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o
if t he s u bject, for a n y  reas o n, re q uires treat me nt wit h a n ot her 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 
i n dicati 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 .

s u bject decisi on
o
t he s u bject or t he s u bject’s le gal re prese ntati ve re q uests t o be wit h dra w n fr om 
t he st u d y.

s u bject re q uires a ferr o ma g netic 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.
S u bject s disc o nti n ui n g fr om t he st u d y pre mat urel y f or a n y reas o n m ust c o mplete A E a n d ot her 
safety f oll ow- u p per Secti o n 2 ( Sc he d ule of Acti vities), Secti o n 9. 2 ( A d verse E ve nts), a n d 
Secti o n 9. 4 ( Safety)  of t his pr ot oc ol . I n a d diti on, s u bjects disc o nti n ui n g fr o m t he st u d y 
pr e m at urel y s h o uld be e nc o ura ge d t o ret ur n t o t he site 1 3 wee ks after t heir earl y disc o nti n uati on 
(E D ) visit f or a f oll ow - u p visit ( V 8 0 1).
8. 3.
L o st t o F oll o w -U p
A s u bject 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 
visit s a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.  Site pers o n nel are e x pecte d t o ma ke 
dil i ge nt atte m pts t o c o ntact s u bjects w h o fail t o ret ur n f or a sc he d ule d visit or w h o were 
ot her wi se u na ble t o be f oll owe d u p b y t he site .
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 s u bject 
wi t hi n le gal a n d et hical b o u n daries f or all s u bjects ra n d o mize d, i ncl u di n g t h ose w h o di d n ot get 
i n vesti gati onal pr o d uct.  P u blic s o urces ma y  be searc he d f or vit al stat us i nf or mat i on.  If vital 
stat us is deter mi ne d, t his will be d oc u me nte d a n d t he s u bject will n ot be c o nsi dere d l ost t o 
f oll ow- u p.
Lill y pers o n nel will n ot be i n v o l ve d i n a n y atte m pts t o c ollect vital stat us i nf or mati on.

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9. St u d y  As s e s s m e nt s a n d Pr o c e d ur e s
Secti o n 2 lists t he Sc he d ule of Acti vities, wit h t he st u d y pr oce d ures a n d t heir ti mi n g (i ncl u di n g 
t olera nce li mit s for ti mi n g).
A p pe n di x 2 lists t he cli nical la b orat or y tests t hat will be perf or me d f or t his st u d y.
U nless ot her wise state d i n t he s u bsect i ons bel o w, all sa m ples c ollecte d f or s pecifie d la b orat or y 
tests will be destr o ye d wit hi n 6 0 da ys of receipt of  c o nfir me d test res ults.  Certai n sa m ples ma y 
be retai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h a p plica ble la ws, re g ulat i ons, or 
la b orat or y certificatio n sta n dar ds.
9. 1.
Effi c a c y A s s e s s m e nt s
Scree ni n g meas ures use d f or dia g n osis a n d e sta blis h me nt of st u d y eli gi bility are descri be d 
else w here ( Secti o n 5. 1. 1. 1 ).
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 b let.  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 patie 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 nistrati o n of t he c o g nit i ve a n d f u ncti onal testi n g f or 
ce ntral mo ni t orin g of rater scale a d mi nis tr atio n ( Secti o n 2 ).  C o g nit i ve a n d f u ncti onal testi n g f or 
eac h patie nt s h o ul d be perf or me d at a p pr o xi matel y t he sa me ti me o n eac h da y  t hat testi n g occ urs 
t o re d uce p ote ntial varia bility.   N ote t hat t he A D A S -C o g a n d M M S E s h o uld 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 .  T hese 2 r aters s h o ul d c o nti n ue d o i n g t he sa me 
scale wit h t he sa me patient  t hr o u g h o ut t he st u d y.  If p ossi ble, eac h assess me nt s h o ul d be 
perf or m e d o n a gi ve n patie nt b y t he sa me rater at eac h visit.  T he pri nci pal i n vesti gat or ( PI) has 
t he res p o nsi bilit y of  selecti n g w h o will a d mi nister t he i nstr u me nts at t he site, as l o n g as all 
trai ni n g re q uire me nts ha ve bee n met b y t h ose raters (A p pe n di x 3 , 3. 1. 5 ).
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 first, bef ore me dical 
pr oce d ures t hat c o ul d be stressf ul f or t he patie nt (f or e xa m ple, blo o d dra ws).  N ote t hat s o m e 
pr oce d ures ( M RI a n d fl orta ucipir F 1 8 P E T ta u i ma gi n g ) ca n be c o n d ucte d o n ot her d a y s wi t hi n 
t he visit wi n d o w.
9. 1. 1.
Pri m ar y Effi c a c y A s s e s s m e nt s
I nte gr ate d Alz hei mer’s Dise ase R ati n g Sc ale (iA D R S; Wessels et al. 2 0 1 5 ).  T he i A D R S 
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 nct i on) 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 nati o n o f scales t hr o u g h a nal ysis of data fro m  t he Alz hei mer’s Disease 
Ne ur oi ma gi n g I nit iati ve a n d t he L Y 2 0 6 2 4 3 0 E X P E DI TI O N a n d E X P E DI TI O N 2 st u dies).  T he 
i A D R S is a si m ple li near c o m bi nati 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 i n A D, t he Alz hei mer’ s Disease Assess me nt Scale—
C o g ni tive s u bscale ( A D A S -C o g 1 3) a n d t he Alz hei mer’s Disease C o o perati ve St u d y —
instr u m e nt al Acti vit ies of Dail y Li vi n g I n ve nt ory (A D C S -i A D L), me as uri n g t he c ore d o mai ns o f 
A D .  All it e ms of t hese 2 scales are i ncl u de d with o ut a d dit i 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 m p o ne nts.

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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 a n d will be t he 
pri mar y  efficac y meas ure.  T he A D A S -C o g 1 3 a nd t he A D C S -A D L will be t he act ual scales 
a d mi nistere d t o patie nts.
9. 1. 2.
S e c o n d ar y Effi c a c y A s s e s s m e nt s
I mme diatel y f o ll o wi n g a d mi nistrati o n of t he A D A S -C o g 1 3 a n d A D C S -A D L, a d di tio nal cli nical 
o utc o m e meas ures s h o ul d be a d mi nistere d i n t he sa me or der at e ver y  visit.  T o mi ni mize missi n g 
data, t he rater s h o ul d ver balize t he q uesti o ns f or eac h meas ure wit h t he patie nt or st u d y part ner
(as desi g nate d i n i nstr ucti o ns), rec or di n g res p o nses a p pr o priatel y.
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 ple me nt 
F or m a n d c o g ni tive a n d f u ncti o nal scales are a d mi nistere d.  If a patie nt has a sec o n d st u d y
part ner, i t is preferre d t hat 1 st u d y part ner be pri maril y res p o nsi ble f or t he C D R a n d A D C S-A D L 
assess me nts.
9. 1. 2. 1.
Al z h ei m er’ s Di s e a s e A s s e s s m e nt S c al e — C o g niti v e s u b s c al e 
( 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  
t he d ysf 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 wit h A D
( R ose n et al. 1 9 8 4).  T he A D A S -C o g 1 3 s h o uld be a d mi nistere d b y t he sa me rater fr o m visit t o 
visit t o re d uce p ote ntial varia bilit y .  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 nit i ve f unct i on m o st t ypicall y i m pai re 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 nce lat i on , a n d maze-
c o mplet i on me as ures ( M o hs et al. 1 9 9 7).  T he A D A S -C o g 1 3 all o ws f or better discri mi nat i on of 
differe nces a m o n g mil d patie nts t ha n t he A D A S -C o g 1 1 .  T he A D A S -C o g 1 3 scale ra n ges fr om 0 
t o 8 5 , wit h hi g her sc ores i n dicati n g greater disease se verity.
9. 1. 2. 2.
Al z h ei m er’ s Di s e a s e C o o p er ati v e St u d y — A cti viti e s of D ail y Li vi n g 
I n v e nt ory ( 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 h at is t o 
be a ns were d b y t he patie nt’s st u d y part ner (Galas k o et al. 1 9 9 7, 2 0 0 4).  T he A D C S -A D L s h o ul d
be a d mi nistere d b y  t he sa me rater fr o m visit t o visit t o re d uce p ote ntial varia bility.   T he A D C S -
A D L s u bset of ite ms ( It e ms 6a , 7 t o 2 3) f or i nstr u me ntal act i vities of dail y li vi n g ( A D C S-i A D L) 
will be use d as a sec o n dar y efficac y meas ure.  T he f oc us i n t he earl y s y m pt o mat ic A D 
p o p ul at i on is o n t he i nstr u me ntal acti vities of dail y li vi n g (i A D Ls) rat her t ha n t he basic act i vities 
of  dail y li vi n g ( b A D Ls), w hic h are t h o u g ht t o be affecte d i n m ore se vere sta ges of t he disease.  
T he ra n ge f or t he i A D L sc ore is 0 t o 5 9 , wit h lo wer sc ores i n dicat i n g greater disease se verity.   
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 patient  atte mpte d t h e A D L 
d uri n g t he past 4 wee ks.  If t he patie 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 
pati e nt’s 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 hi g her sc ores i n dicati n g greater le vel of i m pair me nt.  Se parate sc ores f or t he b A D Ls ( 0 t o 
1 9 ) will als o be c o m p ute d.

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9. 1. 2. 3.
Cli ni c al D e m e nti a R ati n g S c al e — S u m of B o x e s ( C D R-S B)
T he C D R is a se mi -str uct ure d i nter vie w perf or me d wit h t he patie nt a n d st u d y part ner (i nf or ma nt) 
t hat pr o vi des a n i n de x of gl o bal f u nct i oni n g ( Ber g e al. 1 9 9 2).  T he C D R s h o ul d be a d mi nistere d 
b y t he sa me rater fr o m visit t o visit t o re d uce p ote ntial varia b ility.   T he i nf or ma nt is q uerie d 
a b o ut t he patie nt’s me m or y, orie nt atio n, j u d g me nt a n d pr o ble m s o l vi n g, c o m m u nity affairs, 
h o me a n d h o b bies, a n d pers o nal care.  T he patie nt’s me m or y, orie ntati o n, j u d g me nt, a n d 
pr o bl e m-s ol vi n g a bility are assesse d.  Hi g her sc ores i n dicate greater disease se verit y.   B y  
assi g ni n g a se verit y sc ore f or eac h of t he 6 d o mai ns, a t otal sc ore k n o w n as s u m of b o xes is 
o btai ne d — he nce t he a b bre viat i on, C D R -S B.
9. 1. 2. 4.
Mi ni -M e nt al St at e E x a mi n ati o n ( 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 el derl y patient s (F olstei n et 
al. 1 9 7 5).  T he M M S E s h o ul d be a d mi nistere d b y  t he sa me rater fr o m visit t o visit t o re d uce 
p ote nti al v aria bilit y.  T he i nstr u me nt is di vi de d i nt o 2 secti o ns.  T he first secti o n meas ures 
ori e nt atio n, me m or y , a n d atte ntio n.  T he ma xi m u m sc ore f or t he first secti o n is 2 1.  T he sec o n d 
secti on tests t he a bilit y of  t he patie nt t o na me o bjects, f oll o w ver bal a n d writte n c o m ma n ds, write 
a se nte nce, a n d c o p y fi g ures.  T he ma xi m u m sc ore f or t he sec o n d secti on is 9.  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 lo wer sc ores i n dicat i n g greater level o f i m pair me nt.
9. 1. 2. 5.
Bi o m ar k er Effi c a c y M e a s ur e s
9. 1. 2. 5. 1.
Fl ort a u ci pir F 1 8 P E T S c a n
C ha n ge i n a g gre gate d ta u de p osit i on (as assesse d b y flort a u ci pi r F 1 8 P E T sig n al ) will be 
c o mpare d i n L Y 3 3 0 3 5 6 0 - a n d place b o -treate d patie nts f or t h ose patie nts w h o u n der g o 
flort a u ci pir F 1 8 P E T sca ns as descri be d i n t he Sc he d ul e of Act i vities (Secti o n 2 ).
9. 1. 2. 5. 2.
V ol u m etri c M RI
Ma g net ic res o na nce i ma gi n g of t he brai n will be perf or me d acc or di n g t o t he Sc he d ule o f 
Act i vities (Secti o n 2 ). L Y 3 3 0 3 5 6 0 - a n d place b o -treat me nt effects o n v o l umetric M RI will be 
assesse d a n d c o m pare d t o e val uate brai n atr o p h y.
9. 1. 3.
E x pl or at or y Effi c a c y M e a s ur e s
9. 1. 3. 1.
C o g St at e Bri ef B att er y ( C B B)
T he C B B is a brief ( 1 5 - t o 1 8-mi n ute), c o m p uter -base d c o g nit i ve test batter y desi g ne d t o 
meas ure ps yc h o m ot or f u nct i on, atte nti o n, w or ki n g me m or y , a n d me mor y  ( Mar uff et al. 2 0 0 9, 
2 0 1 3; Fre dric ks o n et al. 2 0 1 0; Dar b y  et al. 2 0 1 2).  T he C B B has bee n s h o w n t o be se nsiti ve t o 
A D -relate d c o gnit i ve decli ne i n health y o l der a d ults a n d i n a d ults with a m nest ic M CI ( Dar b y et 
al. 2 0 0 2, 2 0 1 2; Li m et al. 2 0 1 3a, b) as well as t o i m pr o ve me nt i n c o g niti on ari si n g fr om treat me nt 
wi t h c o g nitive e n ha nci n g dr u gs ( Da vis o n et al . 2 0 1 1; Jae ger et al. 2 0 1 1; Nat ha n et al. 2 0 1 3).  T he 
C B B will be a d mi nistere d as descri be d i n t he Sc he d ul e of Act i vities ( Sectio n 2 ).
9. 1. 3. 2.
Di git al Cl o c k Dr a wi n g T e st ( D C T Cl o c k)
T he cloc k dra wi n g test i n ma n ual f or m has bee n use d f or m ore t ha n 5 0 y ears as a brief ( 3- t o 
5- mi n ute) scree ni n g t o ol t o differe ntiate n or mal i n di vi d uals fr o m t hose wi t h c o g nitive 

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i m pair me nt.  T he D C T Cl oc k test uses a n o vel di gitizi n g ball p o i nt pe n t hat f u nctio ns i n t he 
s u bjects’ ha n d as a n or di nar y ball p oi nt pe n, b ut di gitall y rec or ds its p ositi on o n t he pa per. T he 
D C T Cl oc k will  be a d mi nistere d t o s u bjects at Visit 2 pri or t o t hei r first d ose a n d si milarl y at 
eac h s u bse q ue nt d osi n g visit t o assess t heir perf or ma nce i n relat i on t o t he ot her efficac y  
meas ures a n d bi o mar kers.  T hese data ca n t he n be use d al o n g wit h t he fi nal res ult t o assess t he 
s u bjects c o g niti ve stat us ( S o uillar d-Ma n dar et al. 2 0 1 6).
9. 1. 3. 3.
Pl a s m a T a u , P h o s p h o 1 8 1 T a u , a n d N e ur ofil a m e nt Li g ht
S a m ples f or t he m eas ure me nt of plas ma ta u , p h os p h o 1 8 1 t a u, a n d Nf L will be c o llecte d at t he 
ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Secti o n 2 ) t o e val uate t he ti me-de pe n de nt effects of 
L Y 3 3 0 3 5 6 0 c o m pare d wit h pl ace b o o ver 1 0 4 wee ks i n pati e nts wi t h earl y s ym pt o m at ic A D.
9. 1. 4.
A p pr o pri at e n e s s of Effi c a c y A s s e s s m e nt s
T he i A D R S, t he pri mar y  efficac y meas ure, is a si m ple li near c o m bi nati on of sc ores fr o m 2 well -
esta blis he d, t hera pe uticall y se nsit i ve, widel y  acce pte d meas ures i n 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 of A D .  It 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 o t h c o g nitio n a n d f u nct i on) 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 nati o n o f scales t hr o u g h a nal ysis of 
data fr o m  t he Alz hei mer’s Disease Ne ur oi ma gi n g I nitiati ve a n d t he L Y 2 0 6 2 4 3 0 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).  C o m p osite e n d p o i nts ha ve bee n i ncreasi n gl y 
use d as pri mar y  e n d p oi nts i n cli nical trials (Free ma nt le et al. 2 0 0 3). Li u- Seifert et  al. ( 2 0 1 7) 
d e m o nstrate d t hat t he treat me nt effect size of t he i A D R S c o mp osi t e is greater t ha n t he mi ni m u m 
treat me nt effect size of its c o mp o ne nts a n d t hat a b o ve certai n t hres h o l ds of c orrelat i ons of 
c o mp o ne nts a n d rati os of c o m p o ne nt effect sizes t he c o m p osite ma y  o ut p erfor m  its c o mp o ne nts.
T he sec o n dar y  efficac y meas ures descri be d i n Secti o n 9. 1. 2 are esta blis he d meas ures of 
c o g nitive a n d f u nct i onal o utc o mes, as well as be ha vi oral s y m pt o ms ass ociate d wit h A D 
d e m e nt ia, a n d c o nsidere d a p pr o pri ate assess me nts f or t he earl y s y m pt o mat ic A D p o p ul at i on.
I n a d diti on, t he pri mar y tar get e n ga ge me nt o utc o me is t he re d ucti o n of cere bral a g gre gate d ta u
de p osi ts as meas ure d b y q ua nt itati ve t a u P E T i ma gi n g ( fl orta ucipir F 1 8 P E T sta n dar dize d 
u pta ke val ue rati o [S U Vr ]) assesse d as s pecifie d i n t he Sc he d ule of Act i vities ( Secti o n 2 ).
9. 2.
A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of pat ient s w h o ha ve e ntere d t his st u d y  
a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he pati e nt.
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s d uri n g t he st u d y.
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.
T he i n vest i gator re mai ns res p o nsi ble f or f o ll owi n g u p , t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us or ot her wi se me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he patie nt [ patie nt/s u bject] t o disc ont i n ue t he i n vest i gati onal 
pr o d uct bef ore c o m pleti n g t he st u d y .  T he patie nt s h oul d be f ol l owe d u nt il t he e ve nt res ol ves, 

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sta bilizes wit h a p pr o priate dia g n ostic e val uat i on, or i s reas o na bl y e x plai ne d.  T he fre q ue nc y of 
f oll ow- u p e val uat i ons of t he A E is le ft t o t he discreti o n of t he i n vesti gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.
After t he i nf or me d c o nse nt f or m (I C F) is si g ne d, st u d y  site pers o n nel will rec or d via 
C R F/electr o nic data e ntr y  t he occ urre nce a n d nat ure of eac h patient ’s pree xisti n g c o n diti ons, 
i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of t he disease u n der treat me nt i n t he st u d y.  
I n a d diti on, si te pers o n nel will rec or d a n y c ha n ge i n t he c on dit i on(s) a n d a n y ne w c o n dit i ons as 
A Es. I n vesti gat ors s h o ul d rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o 
pr ot oc ol  pr oce d ure, i n vesti gati onal pr o d uct, via C R F/electr o nic data e ntr y .
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bility 
of  bei n g relate d t o st u d y treat me nt, i ncl u di n g P E T tracers, or a st u d y  pr oce d ure, ta ki n g i nt o 
acc o u nt t he disease, c o nc o mita nt treat me nt , or pat h o l ogi es.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use -a n d-effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice, a n d/ or st u d y pr oce d ure a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nt i ons s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n dit i on has w orse ne d d uri n g t he c o urse of t he st u d y .
If a patie nt’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via C R F/electr o ni c data e ntr y, clarif yi n g if p ossi ble t he 
circ u msta nces lea di n g t o a n y d osa ge mo dificat i ons, or di sc o nti n uatio ns of  treat me nt.
9. 2. 1.
S eri o u s A d v er s e E v e nt s
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g o utc o m es:

deat h

i nitial or pr ol o n ge d i n patie nt h os pitalizatio n

a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g)

persiste nt or si g nifica nt disa bilit y/ i nca pacity

c o n ge nital a n o ma l y/ birt h defect

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 pitalizat i on b ut m a y je o par dize t he patie nt or ma y re q uire i nter ve nti on 
t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti on a b o ve.  E xa m ples of 
s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me, bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patient  h os pitalizati on, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a b use.

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All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he C R F/electr o nic data e ntr y  a n d 
assesse d f or seri o us criteria.  T he S A E re p orti n g t o t he s p o ns or be gi ns after t he patie nt has 
sig ne d t he I C F a n d has recei ve d a n i n vesti gati o nal pr o d uct, i ncl u di n g P E T tracers.  H o we ver, if 
a n S A E occ urs after si g ni n g t he I C F, b ut pri or t o recei vi n g t he i n vesti gati onal pr o d uct, t he S A E 
sh o ul d be re p orte d t o t he s p o ns or as per S A E re p orti n g re q uire me nts a n d ti meli nes (see 
Secti o n 9. 2 ) if it is c o nsi dere d reas o na bl y p ossi bl y r elate d t o st u d y pr oce d ure.
St u d y  site pers o n nel must al ert Lill y or its desig nee of  a n y S A E wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness o f t he e ve nt via a s p o ns or -a p pr o ve d met h o d.  If alerts are iss ue d via tele p h o ne, t he y 
are t o be i m me diatel y f o ll owe d u p wi t h official n otificati on o n st u d y -s pecific S A E f or ms.  T his 
2 4- h o ur n otificat i on re q uire me nt refers t o t he i nit ial S A E i nf or mati o n a n d all f oll ow -u p S A E 
i nf or mat i on. Patie nts wit h a seri o us he pat ic A E s h o ul d ha ve a d diti onal data c ollecte d usi n g t he 
C R F/electr o nic data e ntr y .
Pre g na nc y ( d uri n g mater nal or pater nal e x p os ure t o i n vest i gati onal pr o d uct) d oes n ot meet t he 
defi nit i on o f a n A E.  H o we ver, t o f ulfill re g ulat or y re q uire me nts , a n y pre g na nc y s h o ul d be 
re p orte d f oll owi n g t he S A E pr ocess t o c ollect data o n t he o utc o me f or b ot h m ot her a n d fet us.
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 i n s u bjects o nce t he y ha ve 
di sc o nti n ue d a n d/ or c o m plete d t he st u d y (t he pati e nt dis p osit i on C R F has bee n c o m plete d).   
H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i nclu di n g a deat h, at a n y  ti me after a s u bject 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 reas o na bl y p ossi bl y relate d t o t he 
st u d y tr e at me nt or st u d y p artici pat i on, t he i n vest i gat or must pr o m ptl y n otif y Lill y .
9. 2. 1. 1.
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
S us pecte d u ne x pecte d seri o us a d verse react i ons ( S U S A Rs) are seri o us e ve nts t hat are n ot liste d 
i n t he I B a n d t hat t he i n vesti gat or i de ntifies as relate d t o i n vesti gati o nal pr o d uct or pr oce d ure.  
U nite d States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Trial Direct i ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d detaile d g ui da nces or nati o nal re g ulat or y  re q uire me nts i n partici pat i n g c o u ntries 
re q uire t he re p orti n g of S U S A Rs.  Lill y has pr oce d ures t hat will be f oll o we d f or t he 
i dent ificati on, rec or di n g, a n d e x pe dite d re p orti n g of S U S A Rs t hat are c o nsiste nt wit h gl o bal 
re g ulat i ons a n d t he ass ociate d detaile d g ui da nces.
9. 2. 2.
C o m pl ai nt H a n dli n g
Lill y c o llects pr o d uct c o m plai nts o n i n vesti gati onal pr o d ucts a n d dr u g deli ver y s yste ms 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 me nts.
P ati e nts will be i nstr ucte d t o c o ntact t he i n vesti 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 w ith t he i n vest i gati onal pr o d uct s o t hat t he sit uati o n ca n be assesse d.
9. 3.
Tr e at m e nt of O v er d o s e
T here i s n o k n o w n a nti d ote t o L Y 3 3 0 3 5 6 0.  I n case of o ver d ose, use a p pr o priate m o nit ori n g a n d 
s u p p orti ve t hera p y.

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9. 4.
S af et y
9. 4. 1.
P h y si c al a n d N e ur ol o gi c al E x a mi n ati o n s
A s i n dicate d i n t he Sc he d ule of Act i vities ( Secti o n 2 ), co m plete p h ysical  e xa mi nati ons will be 
perf or m e d at t he be gi n ni n g a n d e n d of t he d o u ble -bli n d peri o d or at E D; a n d brief p h ysical 
e xa mi nat i ons will be perf or me d at 3 - t o 6-m o nt h i nter vals..  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 m e n ( b o wel s o u n ds, li ver a n d s plee n pal pati on) ; bac k (c ost o verte bral a n gle 
te n der ness); a n d m usc ul os keletal, car dio 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 i ncl u de assess me nts of t he s ki n, l u n gs, car di o vasc ular s yste m, a n d a b d o me n .
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 Sc he d ule of Acti vit ies 
( Sectio n 2 ).  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 gait, 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 trai ni n g of t he 
pri nci pal i n vesti gat or, a ne u r olo gist will be c o ns ult e d i n t he e ve nt of si g nifica nt ne w fi n di n gs.
If a cli nicall y mea ni n gf ul c ha n ge i n a n M RI is n ote d d uri n g t he st u d y, a n a d diti onal f ull 
ne ur o l ogi cal e xa mi nati o n will  be perf or me d as s o o n as p ossi ble, al o n g wit h a n y ot her me dical 
f oll ow- u p dee m e d necessar y b y t he i n vest i gat or.
9. 4. 2.
El e ctr o c ar di o gr a m s
F or eac h patie nt, 1 2 -lea d di gital E C Gs will be c ollecte d as tri plicates d uri n g t he d o u ble -bli n d 
p eri o d acc or di n g t o t he Sc he d ule of Act i vities ( Sectio n 2 ).  Patie nts m ust 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 o n a n d re mai n s u pi ne b ut a wa ke d urin g E C G 
c ollect i on.
C o nsec ut i ve re plicate E C Gs will be o btai ne d at a p pr o xi matel y 1-mi n ute i nter vals.  
Electr ocar d i ogr a m s ma y be o btai ne d at a d ditio nal ti mes, w he n dee me d cli nicall y necessar y .  
C ollect i on of m ore E C Gs ( m ore re plicates) t ha n e x pecte d at a p artic ular 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 uali t y rec or ds.
Electr ocar di o gra ms will i nitiall 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 ollecti o n as p ossi ble, a n d i deall y  
w hile t he patie nt is st ill prese nt, t o deter mi ne w het her t he s u bject meets e ntr y  crit eria at t he
r ele va nt visit(s) a n d f or i m me diate pati e 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/c orrecte d Q T ( Q Tc) i nter val fr om 
baseli ne or ot her cli nicall y  sig nifica nt q ua nt itative or q ualitat i ve c ha n ge fr om baseli ne is 
i de ntifie d, t he pati e nt will be assesse d b y  t he i n vestigat or f or s y m pt o ms ( f or e xa m ple, 
p al pi t atio ns, near s y nc o pe, s y nc o pe) a n d t o deter mi ne w het her t he pati e nt ca n c o nti 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 
pati e nt ma na ge me nt is nee de d .  T he i n vesti 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 uati on fr om at least 1 of t he re plicate E C Gs fr om 
eac h ti me p oi nt.

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All di gital E C Gs will be electr o nicall y tra ns mitt e d t o a desi g nate d ce ntral E C G lab 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 o n 1 of t he re plicates 
(incl u di n g all i nter vals).  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.  F or eac h set of re plicates, t he car di ol o gist will deter mi ne t he R R a n d Q T 
i nter vals, Q R S d urati o n, a n d heart rate o n t h e E C Gs t hat were n ot f ull y o verrea d .  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.  H o we ver, a n y cli nicall y si g nifica nt fi n di n g 
t hat was n ot prese nt o n t he f ull y o verrea d E C G will be re p orte d t o t he i n vesti gat or a n d t o Lill y.  
All d at a f r o m t he o verrea ds will be place d i n t he Lill y data base f or a nal ytical a nd 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 pretatio 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 use d f or st u d y  e ntr y a n d i m me diate patie 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 vestigat or (or q ualifie d desi g nee ) m ust d oc u me nt his/ her re vie w of  o ne of  t he re plicate 
E C Gs pri nte d at t he ti me of c o llecti 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.
9. 4. 3.
Vit al Si g n s
Vi t al si g ns, i ncl u di n g b o d y t e mperat ure, will be meas ure d at all visit s.
9. 4. 3. 1.
Bl o o d Pr e s s ur e
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 i n t he s u pi ne a n d 
stan di n g p osi tio ns at desig nate d visits, as detaile d i n t he Sc he d ule of Act i vities (Secti o n 2 ).
Ort h ost atic Bl o o d Press ure M o nit ori n g:  F or ort h ostatic bl o o d press ure m o nit ori n g, s u bjects 
s h o uld be s u pi ne f or at l east 5 mi n utes a n d sta n d f or at least 3 mi n utes pri or t o ta ki n g t he 
res pecti 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 vit al si g ns meas ure me nt t hat res ult i n a dia g n osis a n d 
t hat occ ur after t he patie nt recei ves t he first d ose of st u d y treat me nt 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 nic data e ntr y.
9. 4. 3. 2.
H ei g ht, W ei g ht, a n d B o d y T e m p er at ur e
H ei g ht a n d b o d y  wei g ht will be meas ure d, wit h s h oes re mo ve d at least for t he hei g ht 
meas ure me nt at t he scree ni n g visit .  The sa me scale s h o ul d be use d f or all meas ure me nts.  B o d y 
mass i n de x ( B MI ) will be calc ulate d fr o m t he hei g ht a n d b o d y wei g ht.  Te mperat 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 met er.

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B o d y  wei g ht will be c ollecte d o n t he la b orat or y re q uisitio n  for creati ni ne cleara nce calc ulat i ons.  
A n y b o d y  w eig ht data e ntere d i nt o t he e C R F will be use d f or t he o verall data a nal ysis.
9. 4. 4.
L a b or at or y T e st s
F or eac h patie nt, lab orat or y  tests detaile d i n A p pe n di x 2 sh o ul d be c o n d ucte d acc or di n g t o t he 
Sc he d ule of Act i vities ( Secti o n 2 ).
Wit h t he e xce pti o n o f lab orat or y  test res ults t hat ma y u n bli n d t he st u d y, Lill y or its desig nee will  
pr o vi de t he i n vest i gat or wit 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 ntral ve n d or is use d f or t he cli nical trial.
A n y cli nicall y  sig ni fica nt fi n di n gs fr om la b orat or y tests t hat res ult i n a dia g n osis a n d t hat occ ur 
after t he patie nt recei ves t he first d ose of i n vest i gati onal pr o d uct 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 nic data e ntr y .
9. 4. 5.
I m m u n o g e ni cit y A s s e s s m ent s
A t t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Acti vities ( Sectio n 2 ), ve n o us bl o o d sa mples 
will be c o llecte d t o deter mi ne a nti b o d y pr o d uctio n a gai nst L Y 3 3 0 3 5 6 0 .  T o i nter pret t he res ults 
of  im m u n o ge nicit y,  a ve n o us bl o o d sa 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 ntratio ns of L Y 3 3 0 3 5 6 0 .  All sa m ples f or i m m u n o ge nicity 
s h o uld be ta ke n pre d ose w he n a p plica 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  L Y 3 3 0 3 5 6 0 at a la b orat or y a p pr o ve d b y t he s p o ns or.  A nti b o dies ma y be furt her c haracteri ze d 
a n d/ or e val uate d f or t heir a bilit y t o ne utralize t he acti vit y of  L Y 3 3 0 3 5 6 0 .
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 patie nt visit, or f or a s h orter 
p eri o d if l ocal  re g ulati 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 uratio 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 L Y 3 3 0 3 5 6 0 .  A n y sa m ples 
r e mai ni n g after 1 5 years will be destr o ye d.
9. 4. 6.
Ot h er T e st s
9. 4. 6. 1.
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 o nsiste nt w ith F o o d a n d Dr u g A d mi nistrati o n ( F D A ) re g ulat or y g uida nce ( F D A 2 0 1 2), a n y  
occ urre nce of s uici de -relate d t h o u g hts a n d be ha vi ors will be assesse d as i n dicate d i n t he 
Sc he d ule of Act i vities ( Sectio n 2 ).  T he C- S S R S is a scale t hat ca pt ures t he occ urre nce, se verit y,  
a n d fre q ue nc y of s uici de-r elate d t h o u g hts a n d be ha vi ors d uri n g t he c orres p o n di n g assess me nt  
p eri o d.  T he scal e i ncl u des s u g geste d q uesti o ns t o elicit t he t ype of i nf or mat i on nee de d t o 
deter mi ne if a s uici de -r elate d t h o u g ht or be ha vi or occ urre d.
T he first ti me t he scale is a d mi nistere d i n t his st u d y , t he C-S S R S “ Baseli ne” versi o n will be 
use d, a n d t he fi n di n gs will c o nst itute t he baseli ne asses s me nt.  T he C-S S R S “ Si nce Last Visit” 
scale will be use d f or all s u bse q ue nt assess me nts.

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T he C - S S R S will be a d mi nistere d t o t he patie nt wit h t he st u d y part ner/st u d y inf or m a nt prese nt or 
a vaila ble b y tele p h o ne, after t he c o g niti ve a n d f u ncti o nal assess me nts.  Res p o nses fr o m b ot h t he 
st u d y part ner/st u d y inf or m a nt a n d patie nt will be c o nsidere d w he n a d mi nisteri n g t he scale.  If a 
s uicid e -r elate d t h o u g ht or be ha vi or is i de ntifie d at a n y ti me d uri n g t he st u d y, a t h or o u g h 
e val uat i on will be perf or me d b y a st u d y  p h ysicia n, a n d a p pr o priate me dical care will be 
pr o vi de d.
T he Lill y Self -H ar m  S u p ple me nt s h o uld be c o m plete d e ver y  ti me t he C-S S R S is a d mi nistere d.  
If, base d o n a d mi nistrati o n of t he C-S S R S, i t is deter mi ne d that s uici de -relate d be ha vi ors ha ve 
occ urre d, t he n t he Lill y Self -H ar m  Fol l ow- U p f or m will be use d t o c ollect a d ditio n al  inf or m at i on 
t o all o w f or a m ore c o m plete assess me nt of t hese be ha vi ors.
9. 4. 6. 2.
M a g n eti c R e s o n a n c e I m a gi n g
Ma g net ic res o na nce i ma gi n g of t he bra i n will be perf or me d acc or di n g t o t he Sc he d ule o f 
Act i vities ( Secti o n 2 ) an d as cli nic all y in dicate d.  T h ese i ma ges will  be use d t o c hec k f or 
e vi de nce of cli nicall y rele va nt e xcl usi o n crit eria a n d safety fi n di n gs. ( T he M RI data will als o be 
use d t o calc ulate brai n v o l ume tric meas ures, as n ote d i n Secti o n 9. 1. 2. 5 .)
T he M RI sca ns will be re vie we d b y t he i n vest i gat or or q ualifie d desi g nee f or i m me diate patie nt 
ma na ge me nt .  A n y cli nicall y si g nifica nt fi n di n gs n ote d at baseli ne t hat res ult i n a dia g n osis 
s h o uld be rec o r de d as a pree xisti n g c o n diti on or A E.   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.  Fi nal  M RI eli gi bility at scree ni n g will be 
deter mi ne d b y t he ce ntr alize d M RI ve n d or desi g nate d b y Lill y a n d t he M RI res ults wi ll be 
re p orte d t o t he site alo n g wi t h a deter mi nati on as t o w het her t he sca n meets M RI eli gi bilit y 
criteria.  S pecific a nal yses of t he sca ns a n d calc ulati o ns of brai n v o l ume tric meas ures will be 
perf or m e 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 tin g p ur p oses.  Res ults 
of  ce ntrall y rea d M RIs re gar di n g patie nt care/safet y will be re p orte d bac k t o sites.
9. 4. 7.
S af et y M o nit ori n g
Lill y will peri o dicall y  re vie w e v ol vi n g a g gre gate safety data wi t hi n t he st u d y b y a p pr o priate 
met h o ds.
Lill y will re vi e w S A Es wit hi n t i me fra mes (see Secti o n 9. 2. 1 ) ma n date d b y  c o mpa n y pr oce d ures.  
T he Lill y C R P or sci e nt ist will, as a p pr o priate, c o ns ult wit h t he fu n cti o nall y i n de p e nd e nt Gl o bal  
P ati e nt Safet y t hera pe utic area p h ysicia n or cli nical scie nt ist, a n d c o n d uct bli n de d trial le vel 
safety re vie ws, i ncl u di n g assess me nt of t he f oll owi n g :

tre n ds i n safet y d at a

la b orat or y a nal ytes i ncl u di n g blo o d h e m at olo g y , c he mistr y, a n d uri nal ysis

A Es i ncl u di n g m onit ori n g of h y perse nsit i vity a n d i nf usi on reacti o ns, E C G 
fi n di n gs, ne ur ol ogical fi n di n gs, as ide nt ifie d b y i n vesti gat or, a n d s uici de-relate d 
t ho u g hts a n d be ha vi ors.
T his a p pr oac h will all o w f or t he earl y assess me nt of  safety a n d t olera bilit y.

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If safety m o nit ori n g u nc o vers a n iss ue t hat nee ds t o be a d dresse d b y  u n bli n di n g at t he gr o u p 
le vel, o nl y me m bers of t he D M C (a n a d vis or y gr o u p f or t his st u d y for m e d t o pr otect t he i nte grit y 
of  data; refer t o I nteri m A nal yses sect i on [ Sectio n 1 0. 3. 6 ]) ca n c o n d uct a d diti onal a nal yses of t he 
safety data.
9. 4. 7. 1.
I nfu si o n R e a cti o n s
T here i s a ris k of a n i nf usi on reacti o n wit h a n y bi o l ogical a ge nt; t heref ore, all pat ient s s h o ul d be
m o nit ore d cl os el y .  S y m pt o ms a n d si g ns t hat ma y occ ur as part of a n i nf usi on reacti o n i ncl u de,
b ut are n ot li mite d t o, fe ver, c hills, na usea, hea dac he, br o nc h os pas m, h y p ote nsi o n, a n gi oe de ma,
t hr oat irrit atio n, ras h, pr urit us, m yal gia, a n d dizzi ness.  
Ma na ge me nt of t he i nf usi o n react i on s h o ul d pr ocee d acc or di n g t o t he se verit y of  t he reactio n .  
A d dit i onal data s h o ul d als o be c o llecte d via t he C R F/electr o nic data e ntr y; please refer t o t he 
O perati o ns Ma n ua l f or more detail s.
A d dit i onal, u nsc he d ule d st ore d ser u m sa m ples f or p ossi ble i m m u ne safet y la b orat or y testi n g 
(incl u di n g b ut n ot li mite d t o β tr y ptase, t otal  I gE, a n d i m m u ne c o m p le x testi n g) s h o uld als o be 
c ollecte d a p pr o xi matel y 6 0 t o 1 2 0 mi n utes a n d 4 t o 6 wee ks after m o derate or se vere i nf usi on 
reactio ns.   Res ults of t hese sa m ples will re mai n bli n de d t o t he i n vest i gat or u ntil t he e n d of t he 
st u d y.
9. 4. 7. 2.
I m m u n o g e ni cit y
P ati e nts are t o ret ur n t o t he site f or i m m u n o ge nicit y a n d safet y f oll ow- u p visit , wit h Visi t 8 0 1 at 
Wee k 1 1 3 ( or 1 3 wee ks after t heir last d ose of st u d y dr u g) f or c ollecti on of bl o o d sa m ples f or 
A D A (a nti -L Y 3 3 0 3 5 6 0 a nt i b o d y), P K meas ure me nt , assess me nt of A Es, c o nc o mita nt 
me dicat i ons, C -S S R S, a n d vital si g ns.   See t he Sc he d ul e of Act i vities ( Secti o n 2 ) f or t he ti mi n g 
of  e ve nts a n d t he meas ures t o be assesse d. 
Treat me nt -e mer ge nt A D As are defi ne d i n Sect i on 1 0. 3. 4. 5 .  A P K sa m ple ma y be c ollecte d at 
t he f o ll ow- u p i m m u n o ge nicit y assess me nt if warra nte d a n d a gree d u p o n bet wee n b ot h t he 
i n vesti gat or a n d s p o ns or.
I n t he e ve nt of dr u g h y perse nsit i vity react i ons d uri n g t he i nf usi o n or d uri n g m o nit ori n g 
after war ds, a d dit i onal sa m ples will be c ollecte d as close t o t he o nset of t he e ve nt as p ossi ble, at 
t he res olut i on of t he e ve nt, a n d 3 0 da ys f o ll owi n g t he e ve nt .  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.  T he act ual date a n d ti me ( 2 4-h o ur 
cloc k ti me) of eac h sa m pli n g will be rec or de d.
9. 4. 7. 3.
H e p ati c S af et y M o nit ori n g
If a st u d y p atie nt e x perie nces ele vate d A L T ≥3 X U L N , A L P ≥2 X U L N, or el e vate d T B L ≥2 X 
U L N, li ver testi n g ( A p pe n di x 4 ) s h o uld be re peate d wi t hi n 3 t o 5 da ys i ncl u di n g A L T, A S T, 
A L P, T B L, direct bilir u bi n, ga m ma -gl uta m yl  tra nsferase, a n d creati ne ki nase 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 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 s h o uld be i ni tiate d b y t he i n vesti gat or a n d i n 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 0
L Y 3 3 0 3 5 6 0
c o ns ultati o n wit h t he st u d y  me dical m o nit or.  M o ni t ori n g of A L T, A S T, T B L, a n d A L P s h o ul d 
c o nti n ue u ntil le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
He p atic S afet y D at a C ollecti o n
A d dit i onal safety data s h o ul d be c o llecte d via t he C R F/electro ni c data e ntr y if 1 or more of t he 
f oll owi n g c o n dit i ons occ ur: 

ele vat i on of ser u m  AL T t o ≥5 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

ele vate d ser u m T B L t o ≥ 2 X U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome)

ele vat i on of ser u m  AL P t o ≥2 X U L N o n 2 or m o re c o nsec uti ve bl o o d tests

pati e nt disc o nt i n ue d fr om treat me nt d ue t o a he patic e ve nt or a b n or malit y of 
li ver tests

he pat ic e ve nt c o nsi dere d t o be an S A E
9. 4. 8.
A p pr o pri at e n e s s of S af et y A s s e s s m e nt s
T he cli nical safet y meas ure me nts ( A E re p orti n g, p h ysical e xa m i nati ons, ne ur ol o gical 
e xa mi nat i ons, vit al si g ns, E C Gs, a n d cli nical safet y la b orat or y t ests [i ncl u di n g i m m u n o ge nicity] ; 
Secti o n 9. 2 a n d Secti o n 9. 4 ) are well-esta blis he d met h o ds i n dr u g de vel o p me nt researc h a n d are 
sta n dar d pr oce d ures f or cli nical trials.
Re g ular M RIs will assess f or a n y  e mer ge nt ra dio gra p hic a b n or malit ies d uri n g treat me nt wit h 
L Y 3 3 0 3 5 6 0.
L Y 3 3 0 3 5 6 0 is a n a nt i b o d y t hera p y.  T heref ore, i m m u n o ge nicity a nal yses are i n dicate d.  B l oo d 
sa m ples f or t he assess me nt of i m m u n o ge nicity will  be ta ke n at re g ular i nter vals t hr o u g h o ut t he 
st u d y.
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Sectio n 2 ), 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 ons of L Y 3 3 0 3 5 6 0 .  I nstr uctio ns f or t he 
c ollect i on 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 .  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 n y sa m ples t hat are t o be 
c ollecte d f oll o wi n g a n i nf usi o n m ust n ot be c ollecte d fr o m t he sa me site t hat was use d t o i nf use 
st u d y dr u g (f or e xa m ple, s a mple s h o ul d be c ollec te d fr o m t he ar m t hat did n ot recei ve t he 
i nf usi on of st u d y  dr u g).
Dr u g c o nce ntrati o n i nf or mat i on t hat m a y u n bli n d t he st u d y will n ot be re p orte d t o i n vesti gati ve 
sites or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d.
A ma xi m u m of 3 bl o o d sa m ples p er patie nt ma y be dra w n at a d ditio nal  time p oi 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 vesti gat or a n d s p o ns or. I nstr uctio ns f or
t he c ollect i on 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.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 1
L Y 3 3 0 3 5 6 0
Bi oa nal yt ical sa m ples c ollecte d t o meas ure L Y 3 3 0 3 5 6 0 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 ma y be use d f or e x pl orat or y p ur p oses s uc h as bi oa nal ytical 
met h o d de vel o p me nt/ vali dati o n w or k.
9. 6.
P h ar m a c o d y n a mi c s
9. 6. 1. C h a n g e i n A g gr e g at e d T a u D e p o siti o n a s E sti m at e d b y 
F l ort a u ci pir F 1 8
T he fl ort a u cipi r F 1 8 P E T pr o vi des a meas ure of  t au de p osit i on i n t he brai n, e x presse d as a n 
S U Vr, a n d ca n ser ve as a P D bi omar ker of c ha n ge i n e xtracell ular s o l uble a g gre gate d ta u
de p osi tio n . Details o f t he a nal ysis met h o ds will be pr o vi de d i n t he P E T I ma gi n g Ma n ual.
C ha n ge fr o m scree ni n g i n flort a u ci pi r F 1 8 si g nal will be c o m pare d i n L Y 3 3 0 3 5 6 0 - a n d place b o -
treate d patie nts f or t h ose patie nts w h o u n der g o fl orta ucipir F 1 8 P E T sca ns as descri be d i n t he 
Sc he d ule of Act i vities (Secti o n 2 ).
9. 7.
P h ar m a c o g e n o mi c s [ O R] G e n eti c s
9. 7. 1.
A p oli p o pr o t ei n E G e n ot y pi n g
A p o li p o pr otei n E ( A P O E) ge n ot y pi n g is a ma n dat or y part of t his st u d y, u nless c o u ntr y-s pecific 
la ws a n d re g ulati o ns pr o hi bit t his ty pe of testi n g.  Bl o o d sa m pli n g f or A P O E ge n ot y pi n g will be 
perf or m e d as s h o w n i n t he Sc he d ule of Act i vities ( Sectio n 2 ).  Neit her patie nts n or i n v estigat ors 
will recei ve t he ge n ot y pe res ul ts u nless t here is a c o u ntr y-s pecific la w or re g ulat i on t hat re q uires 
n otificati o n o f t he res ults.  Failure t o c ollect sa m ples f or A P O E will n ot be c o nsi dere d a pr ot oc ol 
de viat i on if c o u ntr y-s pecific re g ulati ons pr o hi bit t he testi n g of ge net ic material or tra ns p ortati o n 
of  s uc h mat erial o utside of t he c o u ntr y .
9. 7. 2.
W h ol e Bl o o d S a m pl e s f or P h ar m a c o g e n eti c R e s e ar c h
A w h o le bl o o d sa m ple will be c ollecte d f or p har mac o ge netic a nal ysis as s pecifie d i n t he 
Sc he d ule of Act i vities ( Secti o n 2 ) w here lo c al  re g ulati ons all o w.
S a m ples will  not be use d t o c o n d uct u ns pecifie d disease or p o p ulat i on ge net ic researc h eit her 
n o w or i n t he f ut ure.  Sa m ples will be use d t o i n vesti gate varia ble res p o nse t o L Y 3 3 0 3 5 6 0 a n d t o 
i n vesti gate ge netic varia nts t h o u g h t t o pla y a r ole i n A D .  Assess me nt of varia ble res p o nse ma y 
i ncl u de e val uati on of A Es or differe nces i n efficac y.
All sa m ples will be c o de d wi t h t he patie 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 patie nt o nl y b y t he i n vesti gat or site 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 patie nt visit f or t he st u d y, or f or a s h orter peri o d if l ocal re g ulati o ns a n d/ or 
E R Bs/i n vest i gati onal re vie w b oar ds (I R Bs) i m p ose s h orter ti me li mits.  T his rete nti o n peri o d 
e na bles use of ne w tec h n o l ogies, res p o nse t o re g ulat or y  q uesti ons, a n d i n ves tigat i on of varia ble 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 2
L Y 3 3 0 3 5 6 0
res p o nse t hat ma y n ot be o bser ve d u ntil later i n t he de vel o p me nt of L Y 3 3 0 3 5 6 0 or af t er 
L Y 3 3 0 3 5 6 0 bec o me s c o m merciall y a vaila ble.
M olec ular tec h n o l ogi es are e x pecte d t o i m pr o ve d uri n g t he 1 5 -ye ar st ora ge peri o d a n d t heref ore 
ca n n ot be specificall y na me d.  H o we ver, e xist i n g a p pr oac hes i ncl u de w h ole ge n ome or e x o me 
se q ue nci n g, ge n ome -wi de ass oci at i on st u dies, a n d ca n di date ge ne st u dies.  Re gar dless of 
tec h n ol og y  utilize d, ge n ot y pi n g data ge nerate d will be use d o nl y f or t he s pecific researc h sc o pe 
descri be d i n t his sect i on.
9. 8.
Bi o m ar k er s
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 di s p ositio n, tar get 
e n ga ge me nt, P D, mec ha nis m of act i on, varia bilit y of  patie nt res p o nse (i ncl u di n g safet y), a n d 
cli nical o utc o me.  Sa m p le c ollecti on is i nc or p orate d i nt o cli nical st u dies t o e na ble e xa mi nati 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 de o x yrib o n ucleic aci d, R N A, 
pr otei ns, li pi ds, a n d ot her cell ular ele me nts.
S a m ples f or t he m eas ure me nt of plas ma ta u , p h os p h o 1 8 1ta u , Nf L, a n d bi o mar ker st ora ge will be 
c ollecte d at t he ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Secti o n 2 ).
S er u m , plas ma, a n d w h ole bl o o d R N A sa m ples f or bio m ar ker researc h will be c ollecte d at t he 
ti mes s pecifie d i n t he Sc he d ule of Acti vities ( Secti o n 2 ) 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 
L Y 3 3 0 3 5 6 0 , pat h wa ys ass ociat e d wit h A D , mec ha nis m of acti on of L Y 3 3 0 3 5 6 0 , a n d/ or researc h 
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 .
All sa m ples will be c o de d wit h t he patie 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 patie nt o nl y b y t he i n vesti gat or site 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 patie nt visit for t he st u d y , or for a s h orter peri o d if l ocal re g ulati o ns a n d E R Bs 
i m p ose s h orter ti me li mits.  T his rete nti o n 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 m a y not be o bser ve d u nt il later 
i n t he de vel o p me nt of L Y 3 3 0 3 5 6 0 or after L Y 3 3 0 3 5 6 0 bec o me s c o m merciall y a vaila ble.
9. 9.
M e di c al R e s o ur c e Utili z ati o n a n d H e alt h E c o n o mi c s
De pe n de nce, or t he le vel o f assista nce re q uire d b y a p atie nt, has bee n s u g geste d as a c o nstr uct 
f or assessi n g t he effect of A D treat me nt.  T he pr ocess of i ncreasi n g de pe n de nce o n ot hers is 
i nte n de d as a c o mple me ntar y  meas ure t o e xist i n g cli nical meas ures i n or der t o hel p e x plai n t he 
i m pact of A D o n ec o n o mic iss ues s uc h as t he ris k of inst ituti o nalizat i on a n d care gi ver b ur de n 
( Mc La u g hli n et al. 2 0 1 0; S pac k ma n et al. 2 0 1 3).  Rece ntl y, t he A D C S -A D L sc ores were use d t o 
ma p i n di vi d uals i nt o 1 of  6 de pe n de nce le vels ( 0 t o 5):  Le vel 0 – N o i A D L/ b A D L i m pair me nt; 
Le vel 1 – S o m e s u per visi o n nee d e d o n is olate d i A D Ls; Le vel 2 – S u per visi o n o n m ult i ple i A D Ls 
or l oss of at l east 1 h o use h old act i vity; Le vel 3 – S u per visi o n o n all t y pes of  iA D Ls or 
h o me b o u n d; Le vel 4 – S u per visi o n o n s o me b A D Ls; a n d Le vel 5 – I mp ai re d tra nsfer or 
c o mplete i nc o nt i ne nce ( Ka hle-Wr o bles ki et al. 2 0 1 5).
A n a p pr oac h t o tra nsf or mi n g c o nt i n u o us 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 3
L Y 3 3 0 3 5 6 0
f u ncti onal scale sc ores i nt o discrete le vels o f de pe n de nce was e xa mi ne d pre vi o usl y i n a 
l on git u di nal o bser vati o nal st u d y , wit h preli mi nar y r es ults s u g gesti n g acce pta ble vali dity a n d 
pr o gressi o n i n de pe n de nce le vel o ver ti me ( Ka hle - Wr o bles ki et al. 2 0 1 7). At baseli ne, 4 9. 6 % of 
t hose wi t h mil d A D de me ntia ha d de pe n de nce l e vel 2 a n d 4 2. 7 % were at le vels 3 or 4. At 1 8 
m o nt hs, t he pr o p orti o n of patie nts at le vel 2 decli ne d t o 3 1. 2 % w hereas t hose at  le vels 3 a n d 4 
r ose t o 5 8. 8 %. A nal yses will be c o n d ucte d t o e xa mi ne c ha n ges i n de pe n de nce le vels acr oss t he 
trial p o p ulat i on as well as p ote ntial differe nces o n de pe n de nce le vel b y treat me nt gr o u p 
assi g n me nt.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 4
L Y 3 3 0 3 5 6 0
1 0. St ati sti c al C o n si d er ati o n s
1 0. 1. S a m pl e Si z e D et er mi n ati o n
St u d y  L M D C was p o were d us i n g a mi xe d -m o del re peate d m eas ures ( M M R M) a nal ysis. 
A d dit i onal p o wer calc ulat i ons usi n g D P M are descri be d bel o w.
Ori gi nall y, a p pr o xi matel y 2 8 5 s u bjects were pla n ne d t o be e nr olle d a n d ra n d o mize d i n a 1: 1: 1 
r atio t o t he 2 L Y 3 3 0 3 5 6 0 treat me nt ar ms a n d pl ace b o.  Beca use of a n u ne x pecte d i ncrease i n 
pati e nts e nteri n g scree ni n g a n d a dr o p i n t he scree n fail rate at t he e n d of t he e nr oll me nt peri o d, 
a p pr o xi matel y 3 5 0 participa nts will be ra n d o mize d. Ass u mi n g a d r o p o ut rate of 2 0 %, it is 
e x pecte d t hat a p pr o xi matel y 2 8 0 s u bjects will c om plete t he d o u ble - bli n d treat me nt peri o d of t he 
st u d y (a p pr o xi matel y 9 3 per treat me nt ar m) . T his sa m ple size will pr o vi de a p pr o xi matel y 8 7 % 
p o wer t o de m o nstrate t hat at  least 1 of  the acti ve treat me nt ar m s has a ≥0. 6 p osteri or pr o ba bilit y 
of  slo wi n g of  iA D R S pr o gressi o n o ver pl ace b o b y at least 4 p oi nts (t hat is, 2 5 % sl o wi n g r elat i ve 
t o place b o, base d o n a mea n c ha n ge fr o m baseli ne i n t he place b o gr o u p of 1 6 p oi nts a n d mea n 
c ha n ge fr o m  baseli ne o n at least o ne of t he acti ve treat me nt ar ms of at m ost 1 2 p oi nts ) aft er 1 0 4
wee ks (a p pr o xi matel y  2 4 m o n t hs) o n st u d y treat me nt. T he ass u m pt i on f or t he p o wer calc ulati on 
is t hat t he mea n c ha n ge fr om baseli ne i n i A D R S le vels i n place b o a n d L Y 3 3 0 3 5 6 0 ar ms are 
a p pr o xi matel y 1 6, 1 1, a n d 8 p oi nts ( t hat is, 3 3 % sl o wi n g o n 1 4 0 0 m g L Y 3 3 0 3 5 6 0 a n d 5 0 % 
slo wi n g o n 5 6 0 0 m g L Y 3 3 0 3 5 6 0 r elat i ve t o place b o) at a p pr o xi matel y 1 0 4 wee ks , res pecti vel y, 
wi t h a c o m mo n  sta n dar d de viati o n of t he c ha n ge fr o m baseli ne of 2 0 p oi nts. If b ot h acti ve 
treat me nt ar ms are place b o-li ke wit h n o efficac y, t he pr o ba bility of passi n g t he efficac y  crit erio n  
s pecifie d a b ove ( t hat is, false p ositive) is a p pr o xi matel y 8 %.   T he si m ulat i on f or t he p o wer 
calc ulat i on a n d sa m ple size deter mi nati o n was carrie d o ut i n F A C T S Versi o n 5. 5.
Base d o n t he D P M, 3 6 0 e nr olle d pat ient s, a 3 0 % dr o p o ut rate , a n d a 3-m o nt h dela y o f treat me nt 
effect o nset , t his sa m ple size will  pr o vi de m o re t ha n 9 5% p o wer t o d e m o nstrate t hat at least o ne
of  t he acti ve treat me nt ar ms has sl o we d c o g nitive/f u nct i onal decli ne. T his clai m of sl o wi n g 
c o g nitive/f u nct i onal decli ne is base d o n s h o wi n g t hat at least o ne of  t he acti ve treat me nt ar ms 
has a ≥0. 6 p osteri or pr o ba bilit y of  slo wi n g of  iA D R S pr o gressi o n o ver pl ace b o b y at l east 4 
p oi nts (t hat is, 2 5 % sl o wi n g relat i ve t o place b o, base d o n a mea n c ha n ge fr o m baseli ne i n t he 
pl ace b o gr o u p of 1 6 p oi nts a n d mea n c ha n g e fr o m baseli ne o n at least o ne of t he acti ve treat me nt 
ar ms of at most 1 2 p oi nt s) aft er 1 0 4 wee ks (a p pr o xi matel y 2 4 m o n t hs) o n st u d y treat me nt. T h is
p o wer cal c ulat i on c o mes fr o m si m ulati ons usi n g a place b o decli ne of 1 9. 5 6 p oi nts a n d 3 3 % 
slo wi n g o n 1 4 0 0 m g L Y 3 3 0 3 5 6 0 a n d 5 0 % sl o wi n g o n 5 6 0 0 m g L Y 3 3 0 3 5 6 0 relati ve t o place b o
at 1 0 4 wee ks. T he varia nce -c o v aria n c e matri x i n t he si m ulat i ons ha d a varia nce at W ee k 1 0 4 of 
4 3 6. 8 5 (e q ual t o a sta n dar d de viati o n of 2 0. 9) . If b ot h acti ve treat me nt ar ms are place b o li ke 
wi t h n o efficac y, t he pr o ba bilit y of passi n g t he efficac y crit erio n s pecifie d a b o ve ( t hat is, false 
p osi tive) is a p pr o xi matel y 2. 5 %. T o test t he h y p ot hesis of a disease pr o gressi o n be nefit , we 
calc ulate t he p osterior pr o ba bilit y of s u peri ori t y in c o g nitive /f u ncti onal slo wi n g, a n d if it is 
a b o ve a pre-s pecifie d t hres h ol d ( w hic h c o ntr ols t he e x peri me nt-wise t y pe I err or at 2. 5 %) , t he n a 
clai m of c o g nit i ve sl o wi n g will be ma de.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 5
L Y 3 3 0 3 5 6 0
1 0. 2. P o p ul ati o n s f or A n al y s e s
F or p ur p oses of a nal ysis, i n ge neral, t he fol l owi n g p o p ulat i ons are defi ne d u nless ot her wi se 
s pecifie d:
F or pri mar y efficac y a nal ysis, the F ull A nal ysis Set will gr o u p patie nts acc or di n g t o ra n d o mize d 
treat me nt assig n me nt, e ve n if t he pat ient  d oes n ot ta ke t he assi g ne d treat me nt, d oes n ot recei ve 
t he c orrect treat me nt, or ot her wise d oes n ot f o ll ow t he pr ot oc ol . T his i s t he i nte nt-t o-treat (I T T)
p o p ul at i on. W he n c ha n ge fr o m baseli ne is assesse d, patie nts will be i ncl u de d i n t he a nal ysis 
o nl y  if bot h  a baseli ne a n d at least 1 vali d p ost baseli ne meas ure are a vaila ble.
F or safet y a nal ysis (s afet y p o p ul at i on) , all patient s w h o recei ve d at least 1 d ose of st u d y 
treat me nt ( L Y 3 3 0 3 5 6 0 or pl ace b o) will be i ncl u de d i n t he safet y a nal ysis set.  I n safet y data 
prese ntati o ns, err o ne o usl y  treate d patie nts (f or e xa m ple, t h ose ra n d o mize d t o “ Treat me nt A” b ut 
act uall y gi ve n “ Treat me nt  B”) will be acc o u nte d f or i n t heir act ual treat me nt gr o u ps.
1 0. 3. St ati sti c al A n al y s e s
1 0. 3. 1. G e n er al St ati sti c al C o n si d er ati o n s
U nless ot her wise n ote d, all pair wise fre q ue ntist tests of treat me nt effects will be c o n d ucte d at a 
2- side d al p ha le vel o f 0. 0 5; 2 -side d c o nfi de nce i nter vals ( CIs) will be di s pla ye d wit h a 9 5 % 
c o nfi de nce le vel. All tests of i nteracti o ns bet wee n treat me nt a n d ot her fact ors will be c o n d ucte d 
at a n al p ha le vel of 0. 0 5.   Details o n t he gra p hical a p pr oac h a n d testi n g strate g y will be s pecifie d 
i n t he statistical a nal ysis pla n ( S A P).
All efficac y a nal yses will f o ll ow t he I T T pri nci ple u nless ot her wise s pecifie d. A n I T T a nal ysis 
is a n a nal ysis o f data b y  t he gr o u ps t o w hic h s u bjects are assi g ne d b y ra n d o m all ocat i on, e ve n if 
t he s u bject d oes n ot ta ke t he assi g ne d treat me nt, d oes n ot recei ve t he c orrect treat me nt, or 
ot her wi se d oes n ot f oll ow t he pr ot oc ol .
W he n c ha n ge fr o m baseli ne is assesse d, s u bjects 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 p ost baseli ne me as ure are a vaila ble.  U nless ot her wise defi ne d, a baseli ne meas ure 
is t he last n o n missi n g o bser vat i on c ollecte d pri or t o t he first a d mi nistrati o n of  st u d y me dicatio n s.
F or efficac y a nal yses desc ribe d i n t he E fficac y Anal ysis sect i on (1 0. 3. 3 ), o bser vati ons c o llecte d 
at n o nsc he d ule d visit s will n ot be i ncl u de d i n t he a nal yses.
A data base l oc k is e x pecte d t o occ ur after all ra n d o mize d s u bjects ha ve ha d a c ha nce t o c o m plete 
t he d o u ble -bli n d peri o d of t he st u d y . Efficac y a n d safet y a nal yses will be c o n d ucte d base d o n 
data c ollecte d d uri n g d o u ble -bli n d peri o d. Data c ollecte d at t he foll o w -u p visi t will be 
s u m marize d a n d a nal yze d se paratel y.
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 N L Y if it c ha n ges a pri nci pal feat ure of t he pr ot oc ol.  A n y ot her 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 a n d t he j ustificati o n f or ma ki n g t he c ha n ge will be descri be d 
i n t he S A P a n d cli nical st u d y re p ort.  A d ditio nal  e xpl or 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.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 6
L Y 3 3 0 3 5 6 0
D et ails of t he statistical met h o ds are s pecifie d i n t he S A P f or St u d y L M D C.
1 0. 3. 1. 1. H a n dli n g of Mi s si n g It e m s f or S c al e s
If a n y of t he i n di vi d ual ite ms f or A D A S -C o g or A D C S -A D L 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 or ite ms.
F or A D A S -C o g 1 3 , if 3 or fe wer of a t otal of 1 3 ite ms are missi n g, t he t otal sc ore ( ma xi m u m = 8 5)
will be i m p ute d as f o ll ows:  the t otal fr o m t he re mai ni n g ite ms will be m ulti plie d b y a fact or t hat 
i ncl u des t he ma xi m u m sc ore f or t he missi n g ite ms.  F or e xa m ple, if t he first item,  “ W or d-Recall
Tas k,” w hic h ra n ges fr o m a sc ore of 0 t hr o u g h 1 0 ( ma xi m u m = 1 0), is missi n g, a n d t he sec o n d 
ite m “ C o m ma n ds,” w hic h ra n ges fr o m a sc ore of 0 t o 5 ( ma xi m u m = 5), is missi n g, t he n t he 
m ult i plicati o n fact or = 8 5 /(8 5 - [1 0 + 5 ]) = 8 5/ 7 0 = 1. 2 1 . T h us, t he t otal sc ore f or t his e xa m ple 
will be t he s u m o f t he r e mai ni n g 1 1 ite ms mul tiplie d b y  1. 21 .  T he i m p ute d n u m ber will be 
r o u n de d u p t o t he nearest i nte ger.  If m ore t ha n 3 ite ms are missi n g, t he t otal sc ore f or 
A D A S -C o g 1 3 at  t hat visit will be c o nsi dere d missi n g.
F or t he A D C S -i A D L, if < 3 0 % of t he ite ms are missi n g, t he t otal sc ore will be i m p ute d.  T he s u m 
of  t he n o n missi n g ite ms will be pr orate d t o t he s u m of t otal ite ms.  T he i m p ute d n u m ber will be 
r o u n de d u p t o t he nearest i nte ger.  If t he nearest i nte ger is greater t ha n t he ma xi m u m p ossi ble 
sc ore, t he i m p ute d sc ore will be e q ual t o t he ma xi m u m sc ore.  If > 3 0 % of t he ite ms are missi n g, 
t he t otal sc ore f or A D C S -i A D L at t hat visit will be c o nsi dere d missi n g.  T he sa me i m p utati o n 
tec h ni q ue will be a p plie d t o t he A D C S -A D L t otal  sc ore.  N ote t hat, de pe n di n g o n t he s pecific 
ite m res p o nses t hat are missi n g, it is p ossi ble t o ha ve a n i m p ute d t otal sc ore f or b ot h t he A D C S-
i A D L a n d t he A D C S-A D L, a n i m p ute d t otal sc ore f or o ne b ut n ot t he ot her, or b ot h t otal sc ores 
missi n g.
T he sa me i m p utati o n tec h ni q ue will be a p plie d t o t he C D R -S B.  If o nl y 1 b o x ( of 6) of t he C D R 
is missi n g, t he s u m of t he b o xes will be i m p ute d b y pr orati n g t he s u m fr o m t he ot her 5 b o xes.  If 
t he sc ore fr o m m ore t ha n 1 b o x is n ot a va ila ble, t he C D R-S B at t hat visit will be c o nsi dere d 
missi n g.
T he i A D R S sc ore is calc ulate d as f o ll ows : i A D R S sc ore = [−1 (A D A S - C o g 1 3) + 8 5 ] 
+ A D C S -i A D L ( Wessels et al. 2 0 1 5) .  If eit her 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.
F or all ot her scales, if a n y ite m is missi n g, a n y  t otal or s u m in v o l vi n g t hat ite m will be 
c o nsi dere d missi n g.
1 0. 3. 2. Tr e at m e nt Gr o u p C o m p ar a bilit y
1 0. 3. 2. 1. S u bj e ct Di s p o siti o n
All patie nts w h o disc o nt i n ue fr om t he st u d y will b e ide nt ifie d, a n d t he e xte nt of t heir
parti ci pat i on i n t he st u d y will be re p orte d.  If k n o w n, a reas o n f or t heir disc o nti n uati on will be 
gi ve n.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 7
L Y 3 3 0 3 5 6 0
T he reas o ns f or disc o nt i n uati on will be c ollecte d w he n t he patie nt’s part ici pati on i n t he st u d y 
e n ds a n d will be s u m marize d b y tr e at me nt gr o u p f or al l ra n d omize d s u bjects.  T he perce nta ge of 
s u bjects disc o nti n ui n g fr o m eac h tr e at me nt gr o u p will be c o m pare d bet wee n gr o u ps usi n g 
Fis her’s e xact test.  T he c o m paris o ns will be d o ne f or t he o verall perce nta ge of patie nts w h o 
di sc o nti n ue a n d als o f or select specific reas o ns f or disc o nti n uat i on.
1 0. 3. 2. 2. S u bj e ct C h ar a ct eri sti c s
T he patie nt’s a ge, ge n der, race, hei g ht, b o d y  wei g ht, B MI ( wei g ht ( k g)/[ hei g ht ( m)] 2 ), t o bacc o 
use, al c o h o l use, caffei ne use, y ears of e d ucati o n, w or k stat us, ti me si nce o nset of first A D 
s y m pt oms, ta u P E T b ur de n ( vari o us meas ures), ti me si nce dia g n osis, M M S E sc ore at Visit 1, 
A P O E ge n ot y pe ( E 4 carri er vs n o ncarrier), ha vi n g 1 or more fi rst-de gree relati ves wit h A D, a n d 
A C h EI a n d/ or me ma nt i ne use at baseli ne will  be rec or de d.
Baseli ne c haracteristics will be s u m marize d b y tr e at me nt gr o u p a n d o verall.  S u m maries will 
i ncl u de descri pti ve statistics for c o nti n u o us a n d cate g orical meas ures.  Fis her’s e xact test or 
Pears o n’s c hi -s q uare test will be use d f or treat me nt-gr o u p c o m paris o ns o f cat e g orical data.  F or 
c o nti n u o us data, a nal ysis of varia nce, wit h i n de pe n de nt fact ors f or treat me nt a n d i n vest i gat or
(p o ol e d as necessar y), will be use d.
1 0. 3. 2. 3. Pri or a n d C o n c o mit a nt T h er a p y
Pri or me dicat i ons are defi ne d as t h ose t hat st o p bef ore ra n d o mizat i on ( Vis it 2).  C o nc o mita nt 
me dicat i ons are defi ne d as t h ose bei n g ta ke n o n or after ra n d o mizat i on ( Vi sit 2).  A s u m mar y of 
c o nc o mita nt me dicat i ons will be prese nte d as fre q ue ncies a n d perce nta ges f or eac h treat me nt 
gr o u p.  Fi s her’s e xact test will be use d t o test f or treat me nt differe nces bet wee n gr o u ps.
If t he start or st o p dates of t hera pies are missi n g or partial t o t he de gree t hat deter mi nati o n ca n n ot 
be ma de of w het her t he t hera p y  is prior or c o nc o mi ta nt, t he t hera p y will be dee me d c o nc o mita nt.
Pri or a n d c o nc o mita nt m e dicat i ons will be liste d.
S u m mar y  ta bles will als o be pr o vi de d f or c o nc o mita nt a ntic h oli ner gics t hat affect c o g niti ve 
f u ncti on a n d A C h EI/ me ma nt i ne me dicat i ons.
Me dicat i ons will be c o de d usi n g t he W orl d Healt h Or ga nizat i on dr u g dicti o nar y .
1 0. 3. 2. 4. Tr e at m e nt C o m pli a n c e
S u m mar y  statistics f or L Y 3 3 0 3 5 6 0 treat me nt c o m plia nce will be pr o vi de d f or t he total  nu m ber 
of  c o mplete i nf usi o n s recei ve d, d uratio n of  c o mpl et e i nf usi o n , a n d v o l ume of c o m p lete i nf usi on 
b y treat me nt gr o u p.
Fre q ue ncies a n d perce nta ges of reas o ns w h y  inf usi o n was st o p pe d will als o be prese nte d.
1 0. 3. 3. Effi c a c y A n al y s e s
1 0. 3. 3. 1. Pri m ar y A n al y s e s
T he pri mar y  o bjecti ve of t his st u d y is t o test t he h y p ot hesis t hat I V i nf usi on of L Y 3 3 0 3 5 6 0 will 
slo w t he c o g niti ve a n d/ or f unct i onal decli ne of A D as meas ure d b y t he c o m p osite meas ure 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 8
L Y 3 3 0 3 5 6 0
i A D R S c o m pare d wit h place b o i n patie nts wit h earl y s y m pt o matic A D.  T his will be assesse d 
usi n g a d isease p r o gressio n m o d el ( D P M) as t he pri mar y a nal ysis.
T he D P M is as f o ll ows:
   =   +        +   ,  = 1, 2, … ;  = 1, 2, … w here    de n otes t he cli nical o utc o me at V isit j f or partici pa nt i, cli nical o utc o me sc ore at  
baseli ne ( pri or t o treat me nt) is   .  (i= 1, 2, …, k), w hic h re prese nts t he ra n d o m partici pa nt 
effects.   de n ote s t he treat me nt ar m f or partici pa nt i.     is t he disease pr o gressi o n r atio ( D P R ) 
f or treat me nt T a n d    = 1 f or place b o. F urt her mor e,   is t he c ha n ge i n mea n c o g niti ve sc ore 
f or place b o fr om visi t v-1 t o v.    is t he err or ter m. A d diti onal c o variates s uc h as a ge, A P O E 4 
stat us, c o nc o mita nt use of a p pr o ve d prescri pt i on A D me dicat i ons at baseli ne ( y es/ n o) ma y b e 
a d de d t o t he m o del an d s pecifie d i n t he S A P. A DP R l ess t ha n 1 fav ors L Y 3 3 0 3 5 6 0 a n d 
c orres p o n ds t o a slo wi n g of  disease pr o gressio n wit h L Y 3 3 0 3 5 6 0 i n c o m par is o n t o place b o; a 
D P R greater t ha n 1 fav ors place b o . T he D P M will be fitt e d t o t he data a n d Ba yesia n i nfere nces 
will be s u m marize d i ncl u di n g p osteri or distri b ut i on of D P R a n d p osteri or pr o ba bilit ies of vari o us 
D P R t hres h ol ds of i nterest (f or e xa m ple, 0. 7 5 w hi c h tra nslates t o 2 5 % sl o wi n g of disease 
pr o gressi o n wit h L Y 3 3 0 3 5 6 0 gr o u p vers us place b o ). T o test t he h y p ot hesis of a disease 
pr o gressi o n be nefit , we cal c ulate t he p osteri or pr o ba bilit y of  s u periori t y in c o g nit i ve/fu n cti o n al
slo wi n g a n d if i t is a b o ve a pre-s pecifie d t hres h ol d ( w hic h c o ntr ols t he e x peri me nt-wi s e t ype I 
err or at 2. 5 %), t he n a clai m of c o g nit i ve/fu n cti o n al slo wi n g will be ma de. Detail s descri bi n g t he 
pre -s pecifie d t hres h ol d will be i ncl u de d i n t he S A P. T he n ull h y p ot hesis is t hat t he D P R bet wee n 
t he L Y 3 3 0 3 5 6 0 gr o u p vers us place b o e q uals 1.  Ba yesia n i nfere nces f or t he pri mar y a nal yses 
usi n g D P M will use n o n -i nf or mati ve pri or distri b uti o ns a n d will be f urt her detaile d i n t he S A P.
1 0. 3. 3. 2. S e c o n d ar y Effi c a c y A n al y s e s
T he M M R M a nal ysis will als o be assesse d f or t he i A D R S as a se nsit i vity a nal ysis. T he c ha n ge 
fr om baseli ne sc ore o n t he i A D R S at eac h sc he d ule d p ost -baseli ne visit (acc or di n g t o t he S o A i n 
Secti o n 2 ) d uri n g t he treat me nt peri o d will be t he de pe n de nt varia ble.  T he m o del f or t he fi xe d 
effects will i ncl u de t he f o ll owi n g ter m s:  baseli ne sc ore, p o ole d i n vesti gat or, treat me nt, visit, 
treat me nt -b y- visit i nteracti o n, baseli ne - b y-visit i nteracti o n, c o nc o mit a nt A C h EI a n d/ or 
me ma nt i ne use at baseli ne ( yes/ n o), a n d a ge at baseli ne.  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 za g ote ne ma b gr o u p vers us pl ace b o 
at t he last 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 wit 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 owi 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 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 7 9
L Y 3 3 0 3 5 6 0

c o mp o u n d s y m metr y  c o varia nce str uct ure
T he Ke n war 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. T he pri mar y ti me p oi nt f or treat m e nt c o m paris o n will be at Wee k 1 0 4 .  T he treat me nt 
gr o u p c o ntrast i n least -s q uares mea n pr o gressi o n a n d its ass ociate d p-val ue a n d 9 5 % CI will be 
calc ulate d f or t he treat me nt c o m paris o n of za g ote ne ma b vers us place b o usi n g t he M M R M m o del 
s pecifie d a b o ve.
I n a d diti on t o t he D P M a n d M M R M m o dels descri be d a b o ve, t he mea n f or eac h treat me nt gr o u p 
o ver t he e nt ire d o u ble-bli n d d urati o n of t he st u d y  ca n be mo dele d usi n g nat ural  c u bic s pli nes 
(Bates a n d C ha m bers 1 9 9 2). T he n at ur al cu bic spli ne ( N C S) m o d el  pr o vides a t y p e of  s mo ot hi n g 
f u ncti on t o t he data a n d ca n a de q uatel y est i mate l o n git u di nal traject ories u n der a variety of  
s ha pes (f or e xa m ple, li near a n d q ua dratic) f or eac h treat me nt gr o u p. T he de grees of free d o m o f 
t he mo d el  ca n be pres pecifie d to esta blis h t he le vel of s m o ot hi n g of t he data. T he n u m ber a n d 
l ocat i on of t he “ k n ots” is utilize d t o parse o ut differe nt ti me peri o ds w here t he data ma y 
tra nsitio n f r o m o ne s ha pe t o a n ot her t o pr o vi de a n a de q uate fit.
Eac h of t he sec o n dar y  efficac y o utc o mes will be assesse d usi n g D P M (si milar t o t he pri mar y 
a nal yses) , M M R M, a n d N C S a nal yses. T hese sec o n dar y efficac y o utc o mes i ncl u de A D A S -
C o g 1 3, A D C S-i A D L, C D R-S B , a n d M M S E. i A D R S will als o be assesse d usi n g M M R M a n d 
N C S a nal yses. A d dit i onal details are desc ribe d i n t he S A P.
T he c ha n ge fr o m baseli ne t o e n d p oi nt i n ta u S U Vr (as calc ulate d fr o m fl ort a u cipi r F 1 8 P E T 
sca ns) will be a nal yze d usi n g a n a nal ysis of c o varia nce m o del wit h ter ms of baseli ne val ue a n d 
treat me nt. L o n gi t u di nal c ha n ges fr o m baseli ne i n v M RI para meters will be a nal yze d usi n g 
M M R M i ncl u di n g t he f o ll owi n g ter m s i n t he mo del:  baseli ne para meter val ue, treat me nt, visit, 
treat me nt - b y-visit i nteracti o n, a n d baseli ne - b y-visit i nteracti o n .
A n y a d dit i on al  a nal yses of sec o n dar y efficac y o utc o mes a n d bi o mar kers will be s pecifie d i n t he 
S A P.
1 0. 3. 4. S af et y A n al y s e s
All s u bjects w h o recei ve at least 1 d ose of L Y 3 3 0 3 5 6 0 will be e val uate d f or safet y a n d 
t olera bilit y . Safet y para m eters ( A Es, la b orat or y a nal yt es, vit al si g ns, E C Gs, a n d M RIs) will be 
s u m marize d usi n g descri pt i ve statistics for c o nti n u o us vari a bles a n d fre q ue ncies al o n g wit h 
perce nta ges f or cate g orical varia bles d uri n g t he treat me nt peri o d.
1 0. 3. 4. 1. A d v er s e E v e nt s
Treat me nt -e mer ge nt a d verse e ve nts will be defi ne d as e ve nt s t hat first occ urre d or w orse ne d o n
or after ra n d o mizat i on ( Visit 2 ). S h o ul d t here be i ns ufficie nt data f or A E start date a n d st o p date,
t he A E will be c o nsi dere d T E .
Treat me nt -e mer ge nt a d verse e ve nts will be calc ulate d base d o n A E i de ntifier a n d c o de d 
acc or di n g t o esta blis he d Me dical Dict i onar y  for Re g ul at or y Acti vities ( Me d D R A) t er ms a n d 
s u m marize d b y Me d D R A S yste m Or ga n Class a n d Preferre d Ter m.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 0
L Y 3 3 0 3 5 6 0
A n o ver vie w of A Es , i ncl u di n g t he n u m ber a n d perce nta ge of s u bjects w h o die d, ha d S A E s, 
di sc o nti n ue d d ue t o A Es, a n d w h o ha d T E A Es, will be s u m marize d b y tr e at me nt gr o u p .
1 0. 3. 4. 2. Vit al Si g n s a n d W ei g ht
Vi t al si g n meas ure me nts a n d wei 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 T E a b n or malit ies).
S u m mar y  statistics will be prese nte d f or o bser ve d val ues at baseli ne a n d eac h sc he d ule d 
p ost baseli ne visit a n d f or c ha n ge fr o m baseli ne res ults at eac h sc he d ule d p ost baseli ne visit .  
S y st olic a n d diast olic bl o o d press ure a n d p ulse (c ollecte d i n sitti n g p osi tio n), b o d y t e mperat ure, 
a n d wei g ht will be s u m marize d.
T he i nci de nce of T E a b n or mal hi g h or l o w vital si g ns a n d wei g ht will be s u m marize d b y 
treat me nt gr o u ps.  Treat me nt -e mer ge nt vit al si g n e val uati ons are defi ne d f or e val uat i ons 
c ollecte d after t he i nitiati on of st u d y  me dicat i on.  Cri teria f or a b n or mal vit al si g ns a n d wei g ht
will be i de nt ifie d pr os pecti vel y a n d pr o vi de d i n t he S A P.  A n y vital si g n or weig ht o utsi de t he 
crit erio n val ues will be c o nsi dere d a b n or mal.
1 0. 3. 4. 3. L a b or at or y A n al y s e s
La b orat or y  meas ure me nts will be a nal yze d as c o nti n u o us data (c ha n ge fr o m baseli ne) meas ure d 
as I nter nati o nal S yste m U nits ( SI) or as cate g orical data ( pr o p orti o n of T E a b n or malit ies).
If t here are m ulti ple rec or ds of la b orat or y meas ure me nts at baseli ne or p ost baseli ne visits, t he
last rec or d will be use d.
C ha n ge fr o m baseli ne t o p ost baseli ne visit s at w hic h la b orat or y meas ure me nts are ta ke n will be
s u m marize d usi n g descri pti ve statistics.
F or all la b orat or y  a nal yt es, fre q ue ncies of s u bjects wit h n ota ble c ha n ges ( t hat is, i ncreases or
decreases o f a pres pecifie d a m o u nt u ni q ue t o eac h a nal yte) fr o m baseli ne t o eac h p ost baseli ne
visit will als o be s u m marize d f or all s u bjects a n d stratifie d b y lo w, n or m al, or hig h at baseli ne.
1 0. 3. 4. 4. El e ctr o c ar di o gr a m s
T he E C G m eas ure me nts 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 T E a b n or malit ies).
Si nce E C G is meas ure d i n tri plicates d uri n g t he d o u ble -bli n d peri o d, t he a vera ge of tri plicates 
will be use d at baseli ne a n d eac h d o u ble -bli n d peri o d visit.  If t here are m ult i ple rec or ds after 
a vera gi n g E C G tri plicates wit hi n a visit, t he last rec or d of a vera ges will be use d.
T he a nal ysis will be d o ne f or t he f o ll owi 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 yses of Q Tc will be carrie d o ut usi n g t he Fri dericia 
c orrectio 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 visit at w hic h E C G 
meas ures are perf or me d.
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 ure me nts are ta ke n will be 
assesse d usi n g a n A nal ysis o f c o varia nce ( A N C O V A ) m o d el .  T his a nal ysis will be d o ne 
se paratel y for eac h E C G para meter.

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I nci de nce of T E a b n or mal E C Gs will be assesse d b y c o m par is o ns at ( 1) a n ytime a n d ( 2) eac h 
p ost baseli ne visit bet wee n treat me nt gr o u ps wit h Fis her’s e xact test.  F or a nal yses of T E
a b n or mal E C Gs, baseli ne will be c o nsi dere d as all visits bef ore t he i nitiati o n of dr u g d ose.
Cri teria f or a b n or mal E C Gs a n d Q Tc F pr olo n gati o n will be i de ntifie d pr os pecti vel y  a nd pr o vi d e d 
i n t he S A P.
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, a n d Q T a n d 
Q Tc F i nter vals) are t he val ues t hat are lo w or n or mal at all baseli ne visits a n d fall i nt o hi g h 
a b n or mal cate g ories p ost baseli ne.  Si milarl y, T E l o w E CG para meters ( heart rate, P R i nter val, 
a n d Q R S d urati o n) are t he val ues t hat are hi g h or n or mal at all baseli ne visits a n d fall i nt o l o w 
a b n or mal cate g ories.
F or eac h T E hi g h E C G para meter, o nl y s u bjects w h o were l o w or n or mal at baseli ne a n d ha ve at 
least 1 p ost baseli ne val ue will be i ncl u de d i n t he de n o mi nat or w he n c o m p ut i n g t he pr o p orti o n of 
s u bjects wit h T E hi g h val ues.  Si milarl y, o nl y s u bjects w h o were hi g h or n or mal at baseli ne a n d 
ha ve at least 1 p ost baseli ne val ue will be i ncl u de d i n t he de n o mi nat o r w he n c om p ut i n g t he 
pr o p orti o n of  s u bjects wit h T E l ow val ues.
F or pr ol o n ge d Q Tc F i nter val assess me nts, w he n c o m p ut i n g t he pr o p orti o n of s u bjects wit h T E
hi g h a b n or malit ies, o nl y s u bjects w h o were n or mal at baseli ne a n d ha d a n o n missi n g res ult at 
t hat p ost baseli ne visit will be i ncl u de d i n t he de n o mi nat or.  
I n a d diti on, treat m e nt differe nces i n t he pr o p orti o n of s u bjects w h o ha ve n or mal baseli nes wit h a 
c ha n ge t o a b n or mal hi g h or a b n or mal l o w val ues at a n y p ost baseli ne visits will be s u m marize d.   
Treat me nt -e mer ge nt q ualitati ve E C G fi n di n gs will als o be s u m marize d.
1 0. 3. 4. 5. E v al u ati o n of I m m u n o g e ni cit 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 A , A D A at a n y time 
after baseli ne, a n d T E -A D A s t o L Y 3 3 0 3 5 6 0 will be ta b ul ate d.  If n o A D As are detecte d at 
baseli ne, T E -A D A s 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 M R D of 
t he assa y.  F or sa m ples wit h A D A detecte 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 ons) i ncrease i n t iter c o m pare d t o baseli ne.  F or t he T E-A D A s u bjects, t he 
di stri b uti 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 o ns hi p bet wee n t he prese nce of a nt i b o dies t o L Y 3 3 0 3 5 6 0 a n d P K, 
P D, safet y a n d/ or efficac y assess me nt ma y be assesse d.
1 0. 3. 4. 6. S ui ci d al I d e ati o n a n d B e h a vi or
S ui ci de-relate d t h o u g hts a n d be ha vi ors, base d o n t he C-S S R S, will be liste d b y s u bject a n d visit.  
O nl y s u bjects w h o s h o w s uici dal i deati on/ be ha vi or will be dis pla ye d ( t hat is, if a s u bject’s 
a ns wers are all “ n o” f or t he C-S S R S, t he n t hat s u bject will n ot be di s pla ye d). H o we ver, if a 
s u bject re p orte d a n y i deati on or be ha vi or at a n y  time p oi nt, t he n all t heir i deat i on a n d be ha vi or 
will be dis pla ye d, e ve n if n ot p osit i ve.

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1 0. 3. 5. P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
C o m part me nt al mo deli n g of  L Y 3 3 0 3 5 6 0 P K data usi n g n o nli near mi xe d effects m o deli n g or 
ot her a p pr o priate met h o ds ma y be e x pl ore d, a n d p o p ulat i on est i mates f or cleara nce a n d ce ntral 
v o l ume of distri b ut i on ma y be re p or te d. De pe n di n g o n t he m o del selecte d, ot her P K para meters 
ma y als o be re p orte d. E x pl orat or y  gra p hical a nal yses of t he effect of d ose level or de m o gra p hic 
fact ors o n P K para meters ma y be c o n d ucte d. If a p pr o priate, data fr o m ot her st u dies of 
L Y 3 3 0 3 5 6 0 ma y be use d i n t his a nal ysis.
T he P K/ P D relat i ons hi ps bet wee n plas ma L Y 3 3 0 3 5 6 0 c o nce ntrati o n a n d S U Vr, c o g nit i ve 
e n d p o i nts, or ot her mar kers of P D acti vity ma y be e x pl ore d gra p hicall y.  T he rel at i ons hi p 
bet wee n t he prese nce o f a nt i b o dies t o L Y 3 3 0 3 5 6 0 a n d P K, P D, safet y, a n d/ or efficac y ma y be 
assesse d gra p hicall y.  If warra nte d, a d diti onal a nal ysis ma y be e x pl ore d t o e val uate p ote ntial 
i nteract i ons f or A D A, P D, a n d ot her e n d p o i nts ( P E T sca n, safety , etc.).
A d dit i onal m o deli n g ma y  be p erf or m e d base d o n t he res u lts of t he gra p hical a nal yses.
1 0. 3. 6. I nt eri m A n al y s e s
A n e xter nal D M C is a ut h orize d t o e val uate res ults fr o m u n bli n de d i nteri m a nal yses t o

assess safety , 

assess efficac y t o inf or m  fut ure de vel o p m e nt as nee de d , a n d 

rec o m me n d a n y mo difi c ati o ns t o t he st u d y  (s uc h as st o p pi n g t he st u d y or dr o p pi n g a n 
ar m). 
O perati o nal  details a n d t he decisio n  r ules will be pr o vide d i n t he D M C c harter a n d D M C S A P .
St u d y  sites will recei ve i nf or mati on a b o ut i nteri m res ults O N L Y if rele va nt f or the safet y of  t heir 
pati e nts.
U n bli n di n g details will be s pecifie d i n a se parate u n bli n di n g pla n d oc u me nt. 
First D M C Revie w .  A n u n bli n de d D M C re vie w f or safety will be c o n d ucte d o nce a p pr o xi matel y 
3 0 pati e nts ha ve c o m plete d 3 m o nt hs of e x p os ure t o st u d y treat me nt (t hat is, after c o mplet i n g 4 
wee ks f o ll owi n g t he t hir d d ose of st u d y tr e at me nt ).
No pati e nts be yo n d t hi s i nitial gr o u p of  
a p pr o xi matel y 3 0 pat ient s will be d ose d u ntil t he D M C re vie w has bee n c om p lete d a n d t he
rec o m me n dati on is t o c o nt i n ue t he st u d y.  T his i nit ial gr o u p will c o nti n ue treat me nt d uri n g t he 
assess me nt peri o d.
Sec o n d D M C Revie w .  A sec o n d u n bli n de d D M C re vie w will be c o n d ucte d t o e val uate efficac y 
res ults fr o m u n bli n de d i nteri m a nal yses t o i nf or m f ut ure de vel o p me nt, as well as t o e valuate 
safety .  It will be c o n d ucte d aft er a pr o p orti o n of patie nts, f or e xa m ple a p pr o xi matel y 1 0 0% of
pati e nts, ha ve c o m plete d 1 2 m o nt hs of e x p os ure t o st u d y treat me nt (t hat is, 4 wee ks after t he 1 2t h
d ose at Vi sit 1 5 [ Wee k 5 2]) . T he efficac y re vie w will n ot affect t he o perati o n of t he st u d y . 
H o we ver, t o c o ntr ol f or t he re m ote p ossi bilit y t hat t he st u d y will be st o p pe d f or efficac y, a 
Ha y bitt le-Pet o a dj ust me nt ( Ha y bittle 1 9 7 1 ; Pet o et al . 1 9 7 6) will be use d if efficac y is teste d at 
t his re vie w. A si gnifica nce le vel o f α = 0. 0 0 0 2 5, acc o u nti n g f or t he B o nferr o ni a dj ust me nt a n d a 
si milar p ote nti al a nal ysis at t he t hir d D M C re vie w, w o ul d be use d f or c o m paris o ns bet wee n eac h 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 3
L Y 3 3 0 3 5 6 0
L Y 3 3 0 3 5 6 0 treat me nt gr o u p a n d t he place b o gr o u p. Beca use of t he s mall al p ha use d i n t his 
re vie w, the fi nal a nal ysis at t he c o ncl usi o n of t he st u d y  w o ul d n ot a dj ust al p ha as a res ult of t his 
re vie w. E nr oll me nt a n d/ or treat me nt will c o nt i n ue d uri n g t he sec o n d i nteri m a nal ysis.
T hir d D M C Revie w .  A t hird u n bli n de d D M C re vie w will be c o n d ucte d t o e valuate safet y after a 
pr o p orti o n of  patient s, f or e xa m ple, a p pr o xi matel y 1 0 0 % of patie nts, ha ve c o m plete d 1 8 m o nt hs 
of  e x p os ure t o st u d y treat me nt (t hat is, 4 wee ks after t he 1 8 t h d ose at Vi sit 2 1 [ Wee k 7 6 ]).  
A d dit i onal u n bli n de d i nteri ms ma y be re q ueste d b y t he S p o ns or or D M C, a n d if nee de d, w o ul d 
be c o n d ucte d b y  t he D M C. A n y efficac y re vie w w o ul d n ot affect t he o perati o n o f t he st u d y.
T o facilitate P K/ P D i nteri m a nal yses a n d t o i nitiate t he fi nal p o p ulat i on P K/ P D m o del 
de vel o p me nt pr ocesses , a li mite d n u m ber of prei de ntifie d i n di vi d uals ma y als o gai n access t o t he 
u n bli n de d data, as s pecifie d i n t he u n bli n di n g pla n . T hi s will be c o n d ucte d at t he sa me ti me as 
t he sec o n d D M C re vie w. I n pre parati o n f or t he fi nal a nal ysis, access ma y als o be gra nte d after 
all patie nts c o m plete 6 4 wee ks of treat me nt ( t hat is, Visit 1 8). I nf or mati on t hat m a y u n bli n d t he 
st u d y d uri n g t he a nal yses will n ot be re p orte d t o st u d y sites or bli n de d st u d y tea m unt il t he st u d y 
has bee n u n bli n de d.
Q uarterl y , bli n de d trial le vel safet y re vie ws will be carrie d o ut as d oc u me nte d i n t he trial le vel 
safety re vie w pla n.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
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L Y 3 3 0 3 5 6 0
1 1. R ef er e n c e s
Ala ka K, Ca m p bell G, Fleis her A, Ha ke A, Irizarr y  M, Miller B, P o ntec or v o M, Sie mers E, Si ms 
J, Yaari R. T he n os ol o g y of Alz hei mer’s disease a n d a p plicati on of c o nce pts t o a m yl o i d-
tar geti n g treat me nts: a n i nter nal s u m mar y of Lill y t hi n ki n g. W hite Pa per. 2 0 1 5.
Bates D M , C ha m bers J M. N o nli near m o dels . I n: C ha m bers J M, Hastie TJ , e dit ors. St atistic al 
M o dels i n S. Wa ds w ort h & Br o o ks/ C ole ; 1 9 9 2.
Ber g L, Miller J P, Bat y  J, R u bi n E H, M orris J C, Fi giel G. Mil d se nile de me ntia of t he 
Alz hei mer’s t y pe. 4. E val uat i on of i nter ve nti o n. A n n Ne ur ol . 1 9 9 2; 3 1( 3): 2 4 2- 2 4 9.
Braa k H, Braa k E. Ne ur o pat h ol o gical sta gi n g of  Alz hei mer-r elate d c ha n ges. Act a Ne ur o p at h ol . 
1 9 9 1; 8 2( 4): 2 3 9 - 2 5 9.
Bretz F, Ma urer W, Bra n nat h W, P osc h M. A gra p hical a p pr oac h t o se q ue ntiall y reject i ve 
m ult i ple test pr oce d ures. St at Me d . 2 0 0 9; 2 8( 4): 5 8 6- 6 0 4.
B retz F, P osc h M , Gli m m E, Kli n gl m ueller F, Ma urer W, R o h me yer K. Gra p hical a p pr oac hes 
f or mul tipl e c o m paris o n pr oce d ures usi n g wei g hte d B o nferr o ni, Si mes, or para metric tests. 
Bi o m J . 2 0 1 1; 5 3( 6): 8 9 4-9 1 3.
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creat i ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n . 
1 9 7 6; 1 6( 1): 3 1 - 4 1.
Dar b y  D, Mar uff P, C ollie A, Mc Ste p he n M. Mil d c o g niti ve i m pair me nt ca n be detecte d b y 
m ult i ple assess me nts i n a si n gle da y. Ne ur ol o gy . 2 0 0 2; 5 9( 7): 1 0 4 2- 1 0 4 6.
Dar b y  D G, Pietrza k R H, Fre dric ks o n J, W o o d war d M, M o ore L, Fre dric ks o n A, Sac h J, 
Mar uff
P. I ntrai n di vi d ual c o g nit i ve decli ne usi n g a brief c o m p uterize d c o g niti ve scree ni n g test. 
Alz hei mers De me nt . 2 0 1 2; 8( 2): 9 5- 1 0 4.
Da vis o n S L, Bell RJ, Ga vrilesc u M, Searle K, Mar uff P, G o g os A, R ossell S L, A da m s J, E ga n 
G F, Da vis S R. Test oster o ne i m pr o ves ver bal lear ni n g a n d me m or y i n p ost me n o pa usal w o me n: 
res ults fr o m a pilot st u d y . M at urit as . 2 0 1 1; 7 0( 3): 3 0 7- 3 1 1.
D el ac o urte A, Da vid J P, Ser gea nt N, B uée L, Wattez A, Ver mersc h P, G h ozali F, Fallet -Bi a nc o 
C, Pas q uier F, Le bert F, Petit H, Di Me nza C . T he bi oc he mical pat h wa y of ne ur ofi brillar y 
de ge nerati o n i n a gi n g a n d Alz hei mer’s disease. Ne ur ol o gy . 1 9 9 9; 5 2( 6): 1 1 5 8- 1 1 6 5.
D u y c kaerts C, Brio n J -P, Ha u w JJ, Fl a me nt -D ura n d J. Q ua ntitati ve assess me nt of t he de nsit y of  
ne ur ofi brillar y  ta n gles a n d se nile pla q ues i n se nile de me ntia of t he Alz hei mer t ype. 
C o m paris o n of i m m u n oc y t oc he mistr y wit h a s pecific a nti b o d y a n d B o dia n’s pr otar g ol met h o d.
Act a Ne ur o p at h ol ( Berl) . 1 9 8 7; 7 3( 2): 1 6 7-1 7 0 .
[ F D A] U nite d States F o o d a n d Dr ug A d mi nistrati o n. G ui da nce f or I n d ustr y. S uici de i deat i on a n d 
be ha vi or: pr os pecti ve assess me nt of occ urre nce i n cli nical trials [ draft g ui da nce]. A u g ust 2 0 1 2. 
A vaila ble at: htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nces/ U C M 2 2 5 1 3 0. p df. Accesse d 
A u g ust 0 6, 2 0 1 7.
F o lstei n M F, F o lstei n S E, Mc H u g h P R. “ Mi ni-Me ntal  State”. A practical met h o d f or gra di n g t he 
c o g nitive state of patie nts f or t he cli nicia n. J Psyc hi atr Res . 1 9 7 5; 1 2( 3): 1 8 9-1 9 8.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 5
L Y 3 3 0 3 5 6 0
Fre dri c ks o n J, Mar uff P, W o o d war d M, M o ore L, Fre dric ks o n A, Sac h J, Dar b y  D. E val uati on of 
t he usa bilit y of  a brief c om p uterize d c o g nit i ve scree ni n g test i n ol der pe o ple f or 
e pide mi ol o gical st u di es. Ne ur oe pi de mi ol o gy . 2 0 1 0; 3 4( 2): 6 5- 7 5.
Free ma nt le N, Cal vert M, W o o d J, Easta u g h J, Griffi n C. C o m p osite o utc o mes i n ra n d o mize d 
trials. Greater precisi o n b ut wit h greater u ncertai nt y? J A M A . 2 0 0 3; 2 8 9( 1 9): 2 5 5 4- 2 5 5 9.
G al as k o D, Be n nett D, Sa n o M , Er nest o C, T h o mas R, Gr u n d ma n M, Ferris S . A n i n ve nt or y t o 
assess act ivit ies of dail y li vi n g f or cli nical trials i n Alz hei mer’s disease. T he Alz hei mer’s 
Di sease C o o perati ve St u d y . Alz hei mer Dis Ass oc Dis or d. 1 9 9 7 ; 1 1(s u p pl 2):S 3 3 -S 3 9 .
G al as k o D, Kers ha w P R, Sc h nei der L, Z h u Y, Tari ot P N. Gala nta mi ne mai ntai ns a bilit y t o 
perf or m  acti vities of dail y li vi n g i n patient s wit h Alz hei mer’s disease. J A m Geri at S oc. 
2 0 0 4; 5 2( 7): 1 0 7 0 - 1 0 7 6.
Ha y bitt le J L. Re peate d assess me nts of res ults i n cli nical trials of ca ncer treat me nt. B J R a di ol . 
1 9 7 1; 4 4( 5 2 6): 7 9 3 - 7 9 7.
H y ma n B T, P hel ps C H, Beac h T G, Bi gi o E H, Cair ns NJ, Carrill o M C, Dic ks o n D W, 
D u y c kaerts C, Fr osc h M P, Maslia h E, Mirra S S, Nels o n P T, Sc h nei der J A, T hal D R, T hies B, 
Tr oj a n o ws ki J Q, Vi nters H V, M o nti ne TJ. Nati o nal I nstitute o n A gi n g – Alz hei mer ’s 
Ass oci at i on g ui deli nes o n ne ur o pat h ol o gi c assess me nt of Alz hei mer ’s disease. Alz hei mers 
De me nt . 2 0 1 2; 8( 1): 1- 1 3.
Jae ger J, Hår de mar k H-G, Zetter gre n A, Sj ö gre n N, Ha n nes d ottir K. D oes re peate d dail y test i n g 
i m pr o ve meas ure me nt se nsiti vity t o t he c o g nitive effects of d o ne pezil i n mil d -t o-m o derate 
Alz hei mer’s Disease? Alz hei mers De me nt . 2 0 1 1: 7( 4):e 5 9. Pa per prese nte d at t he Alz hei mer’s 
Ass oci at i on I nter nat i onal C o nfere nce, Paris, Fra nce.
Ka hle -Wr o bles ki K, A n dre ws J S, Bel ger M, Ga ut hier S , Ster n Y, Re ntz D M, Galas k o D. Cli nical 
a n d ec o n o mic c haracterist ics of milest o nes al o n g t he c o nt i n u u m of Alz hei mer’s disease: 
tra nsf or mi n g f u ncti o nal sc ores i nt o le vels of de pe n de nce. J Prev Alz hei mers Dis. 
2 0 1 5; 2( 2): 1 1 5 - 1 2 0.
Ka hle -Wr o bles ki K, A n dre ws J S, Bel ger M, Ye W, Ga ut hier S, Re ntz D M, Galas k o D. 
De pe n de nce le vels as i nteri m cli nical milest o nes al o n g t he c o nti n u u m o f Alz hei mer’s disease: 
1 8- m o nt h res ults fr o m t he G E R A S O bser vat i onal St u d y . J Prev Alz hei mers Dis. 
2 0 1 7; 4( 2): 7 2 - 8 0.
Li m Y Y, Ellis K A, A mes D, Dar b y  D, Harri n gt o n K, Marti ns R N, Masters C L, R o we C, Sa va ge 
G, Sz oe ke C, Ville ma g ne V L, Mar uff P; AI B L Researc h Gr o u p. A β a m yl o i d, c o g nitio n, a n d 
A P O E ge n ot y pe i n heal t h y older a d ul ts. Alz hei mers De me nt. 2 0 1 3a; 9 ( 5): 5 3 8- 5 4 5.
Li m Y Y, Ellis K A, Har rin gt o n K, Pietrza k R H, Gale J, A mes D, B us h AI, Dar b y D, Marti ns R N, 
Masters C L, R o we C C, Sa va ge G, Sz oe ke C, Ville ma g ne V L, Mar uff P, f or t he AI B L 
Researc h Gr o u p. C o g niti ve decli ne i n a d ults wit h a m nestic mil d c o g nit i ve i m pair me nt a n d 
hi g h a m yl o i d β a m yl oi d: pr o dr o m al Alz hei mer’s disease? J Alz hei mers Dis.
2 0 1 3 b; 3 3( 4): 1 1 6 7 - 1 1 7 6.
Li u- Seifert H, A n ders o n S, Case M, S par ks J, H ol dri d ge K C, Wessels A M, He n dri x S, Aise n P, 
Si e mers E. Statistical pr o perties of c o nti n u o us c o m p osite scales a n d i m plicati ons f or dr u g 
de vel o p me nt. J Bi o p h ar m St at . 2 0 1 7; 2 7( 6): 1 1 0 4-1 1 1 4 .

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 6
L Y 3 3 0 3 5 6 0
Mar uff P, Li m Y Y, Dar b y  D, Ellis K A, Pietrza k R H, S n yder PJ, B us h AI, Sz oe ke C, Sc he m bri 
A, A mes D, Masters C L, AI B L Researc h Gr o u p. Cli nical ut ility of  t he c o gstate brief batt er y in 
i de ntif yi n g c o g niti ve i m pair me nt i n mil d c o g niti ve i m pair me nt a n d Alz hei mer’s disease. B M C 
Psyc h ol . 2 0 1 3; 1( 1): 3 0.
Mar uff P, T h o mas E, C ysi q ue L, Bre w B, C ollie A, S n y der P, Pi etrza k R H. Vali dit y of  t he 
C o g State brief batter y : r el atio ns hi p t o sta n dar dize d tests a n d se nsit i vity t o c o g nit i ve 
i m pair me nt i n mil d tra u matic brai n i nj ur y , sc hiz o p hre nia, a n d AI D S de me ntia c om p le x. Arc h 
Cli n Ne ur o psyc h ol. 2 0 0 9; 2 4( 2) :1 6 5- 1 7 8.
Mc La u g hli n T, Fel d ma n H, Fillit H, Sa n o M, Sc h mitt F, Aise n P, Lei b ma n C, M uc ha L, R ya n 
J M, S ulli va n S D, S pac k ma n D E, Ne u ma n n PJ, C o he n J, Ster n Y. De pe n de nce as a u nif yi n g 
c o nstr uct i n defi ni n g Alz hei mer’s disease se verit y.  Alz hei mers De me nt. 2 0 1 0; 6( 6): 4 8 2- 4 9 3.
M o hs R C, K n o p ma n n D, Peterse n R C, Ferri s S H, Er nest o C , Gr u n d ma n M , Sa n o M , 
Bi elia us kas L , G el d mac her D , Cl ar k C, T hal LJ . De vel o p me nt of c o g niti ve i nstr u me nts f or use 
i n cli nical trials of a nt i de me ntia dr u gs: a d diti ons t o t he Alz hei mer’s Disease As sess me nt Scale 
t hat br oa de n its sc o pe. T he Alz hei mer’s Disease C o o perati ve St u d y . Alz hei mer Dis Ass oc 
Dis or d . 1 9 9 7; 1 1(su p pl  2): S 1 3 -S 2 1.
Nat ha n PJ, B oar dle y R, Sc ott N, Ber ges A, Mar uff P, Si va na nt ha n T, U pt o n N, L o w y  M T, 
Nest or PJ, Lai R. T he safet y,  t oler a bilit y, p har mac o ki net ics a n d c o g niti ve effects of 
G S K 2 3 9 5 1 2, a selecti ve hista mi ne H 3 rece pt or a nta g o nist i n patie nts wit h mil d t o m o derate 
Alz hei mer’s disease: a preli mi nar y i n vest i gati on. C urr Alz hei mer Res . 2 0 1 3; 1 0( 3): 2 4 0- 2 5 1.
Pet o R, Pi ke M C, Ar mita ge P, Bresl o w N E, C o x D R, H o war d V, Ma ntel N, Mc P hers o n K, Pet o 
J, S mith P G . Desig n a n d a nal ysis of ra n d o mize d cli nical trials re q uiri n g pr ol o n ge d o bser vat i on 
of  eac h patie nt. I. I ntr o d uctio n a n d desi g n. Br J C a ncer . 1 9 7 6; 3 4( 6): 5 8 5- 6 1 2.
P oc oc k S. J, Si m o n R. Se q ue nt ial treat me nt assig n me nt wi t h bala nci n g f or pr o g n ostic fact ors i n 
t he c o ntr olle d cli nical trial. Bi o metrics. 1 9 7 5; 3 1 ( 1): 1 0 3– 1 5.
Qi a n J, H y ma n B T, Bete ns k y R A. Ne ur ofi brillar y ta n gle sta ge a n d t he rate of pr o gressi o n of 
Alz h ei mer s y m pt o ms: mo deli n g usi n g a n a ut o ps y  c o h ort a n d a p plicati on t o cli nical trial 
desi g n. J A M A Ne ur ol . 2 0 1 7; 7 4( 5): 5 4 0- 5 4 8.
R ose n W G, M o hs R C, Da vis K L. A ne w rat i n g scale f or Alz hei mer’s disease. A m J Psyc hi atry . 
1 9 8 4; 1 4 1( 1 1): 1 3 5 6 - 1 3 6 4.
S el k oe DJ. T he m ol ec ular pat h olo g y  of Alz hei mer’s disease. Ne ur o n . 1 9 9 1; 6( 4): 4 8 7- 4 9 8.
S o uillar d -Ma n dar
W, Da vis R, R u di n C, A u R, Li b o u DJ, S we ns o n R, Price C C, La mar ό M, 
Pe n ne y D L. Lear ni n g classificat i on m o dels of c o g nit i ve c o n diti ons fr o m  s u btle be ha vi ors i n 
t he di gital Cl oc k Dra wi n g Test. M ac h Le ar n . 2 0 1 6; 1 0 2( 3): 3 9 3- 4 4 1.
S pac k m a n D E, Ka di yala S, Ne u ma n n PJ, Vee nstra D L, S ulli va n S D. T he vali dit y of de pe n de nce 
as a healt h o utc o m e meas ure i n Alz hei mer’s disease. A m J Alz hei mers Dis Ot her De me n. 
2 0 1 3; 2 8( 3): 2 4 5 - 2 5 2.
Wa n g Y , Ma n del k o w E. Ta u i n p h ysi o l og y  a n d pat h olo g y . N at ure Rev Ne ur osci .
2 0 1 6; 1 7 ( 1): 5- 2 1.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 7
L Y 3 3 0 3 5 6 0
Wessels A M, Sie mers E R, Y u P, A n derse n S W, H ol dri d ge K C, Si ms J R, S u n dell K, Ster n Y, 
Re ntz D M, D u b ois B, J o nes R W, C u m mi n gs J, Aise n P S. A C o m bi ne d Meas ure of C o g nit i on 
an d F u ncti o n f or Cli nical Trials: T he I nte grate d Alz hei mer’s Disease Rat i 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.
W o rld Me dical Ass oci at i on. Declarat i on of Helsi n ki – et hical pri nci ples f or me dical researc h 
i n v ol vi n g h u ma n s u bjects. 2 0 1 3. A vaila ble at: htt ps:// w w w. w ma. net/ p olicies -p ost/ w m a-
decl arat i on- of -helsi n ki -et hical-pri nci ples -f or-me dical -researc h-i n v ol vi n g-h u ma n -s u bjects/. 
Accesse d A u g ust 2 7, 2 0 1 7.

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 8
L Y 3 3 0 3 5 6 0
1 2. A p p e n di c e s

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 8 9
L Y 3 3 0 3 5 6 0
A p p e n di x 1.
A b br e vi ati o n s a n d D efi niti o n s
Ter m
Defi niti o n
A β
a m yl oi d beta
A C h EI
acet ylc h oli nesterase i n hi bit or
A D
Alz hei mer’s disease
A D A
anti -dr u g a nti b o dies
A D A S -C o g 1 3
Alz hei mer’s Disease Assess me nt Scale — C o g niti ve s u bscale 1 3
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 -b A D L
Alz hei mer’s Disease C o o perati ve St u d y — basic A cti vities of D ail y L i vi n g
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 n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti ga ti on 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati ons hi p wit h t his treat me nt.  A n a d verse e ve nt 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 dise ase 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A N C O V A
A nal y sis of c o varia nce
A P O E
a p oli p o pr otei n s u bt y pe E
A S T
as partate a mi n otra nsferase
bli n di n g/ m as ki n g
A si n gle -bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or his staff are a ware of t he 
treat me nt b ut t he patie nt is n ot, or vice versa, or w he n t he s p o ns or is a ware of t he 
treat me nt b ut t he i n vesti gat or a n d/ his staff a n d t he patie nts are n ot.
A d o u ble -bli n d st u d y is o ne i n w hic h neit her t he patie nt n or a n y of t he i n vesti gat or or 
s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he s u bjects are 
a ware of t he treat me nt recei ve d.
B MI
b o d y mass i n de x
C B B
C o g State Brief Batter y
C D R -S B
Cli nical De me ntia Rati n g Scale — S u m of B o xes

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 9 0
L Y 3 3 0 3 5 6 0
CI
c o nfi de nce i nter val
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 N S
ce ntral ner v o us s yste m
c o m pl ai nt
A c o m plai nt is a n y wr itte n, electr onic, 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 nce
A d here nce t o all st u d y -relate d, go 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 R F
case re p ort f or m
C R P
cli nical researc h p h ysicia n:  I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y.  
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nica l researc h 
scie ntist, gl o bal safet y p h ysicia n or ot her me dical officer.
C R S
cli nical researc h scie ntist
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
D C T Cl oc k
Di gital Cl oc k Dra wi n g Test
D M C
D ata 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 Cli nical O utc o me Assess me nt
e C R F
electr o nic case re p ort f or m
E D
earl y disc o nti n uati o n
E n d of st u d y
E n d of t he st u d y is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n 
t he Sc he d ule of Acti vities ( Secti o n 2 ) f or t he last patie nt.
e nr oll
T he act of assi g ni n g a patie nt t o a treat me nt.  Patie 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 nter
Patie nts e ntere 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 D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
g o o d cli nical practice
H Bs A g
h e patitis B s urface a nti ge n
H C V
h e patitis C vir us

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
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I A C
i nter nal assess me nt c o m mittee
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 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 nf or me d c o nse nt
A pr ocess b y w hic h a patie 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 patie nt’s decisi o n t o partici pate.  I nf or me d c o nse nt is doc 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 nteri m a n al ysis
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se parate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data base is create d/l oc ke d.
i n vesti g ati o n al 
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 he 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 T T
i ntent t o treat:  T he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be best 
assesse d b y e val uati n g o n t he basis of t he i nte nti o n t o treat a patie nt ( t hat is, t he pla n ne d 
treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n.  It has t he c o nse q ue nce t hat 
patie nts all ocate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, assesse d, a n d a nal yze d as 
me m bers of t hat gr o u p irres pecti ve of t heir c o m plia nce t o t he pla n ne d c o urse of 
treat me nt.
I V
i ntra ve n o us
I VI G
i ntra ve n o us i m m u n o gl o b uli n
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
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M M R M
mi xe d -effect m o del re peate d meas ures
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
N C S
n at ural cu bic spli ne
Nf L
ne ur ofila me nt li g ht
N F T
ne ur ofi brillar y ta n gle

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 9 2
L Y 3 3 0 3 5 6 0
N O A E L
n o -o bser va ble -a d verse-effect s le vel
P C R
p ol y merase c hai n reacti o n
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 D
p har mac o ki netic (s)/ p har mac o d y na mic(s)
P S P
pr o gressi ve s u pra n uclear pals y
Q 4 W
o nce e ver y 4 wee ks
Q T
Q T i nter val o n  t he E C G
Q Tc
c orrecte d Q T i nter val
Q Tc F
Fri dericia’s c orrecte d Q T i nter val
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 C
s u bc uta ne o us
scree 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 H S F
Self -Har m S u p ple me nt f orm
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
S U Vr
sta n dar dize d u pta ke val ue rati o
T B L
t otal bilir u bi n le vel
T E
treat me nt-e mer ge nt
T E A E
treat me nt-e mer ge nt a d verse e ve nt:  A n u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pr etreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.
T P O
t hir d-part y or ga nizati o n
U L N
u p per li mit of n or mal
V
visit
v M RI
v ol u metric ma g netic res o na nce i ma gi n g

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 9 3
L Y 3 3 0 3 5 6 0
W B C
w h ite bl o o d cell

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 9 4
L Y 3 3 0 3 5 6 0
A p p e n di x 2.
Cli ni c al L a b or at or y  T e st s
Cli nic al L a b or at or y Tests
He m at ol o g y a, b
Cli nic al C he mistr y a, b,c
He m o gl o bi n
Ser u m C o nce ntr ati o ns of:
He mat ocrit
S o di u m
Er y t hr oc yte c o u nt ( R B C)
P otassi u m
Mea n cell v ol u me
T otal bilir u bi n
Mea n cell he m o gl o bi n c o nce ntrati o n
Direct bilir u bi n
Le u k oc ytes ( W B C)
Al kali ne p h os p hatase ( A L P)
Ne utr o p hils, se g me nte d
Ala ni ne a mi n otra nsferase ( A L T)
L y m p h oc y t es
As partate a mi n otra nsferase ( A S T)
M o n oc ytes
Bl o o d urea nitr o ge n ( B U N)
E osi n o p hils
Creati ni ne
Bas o p hils
Ur ic aci d
Platelets
Calci u m
Gl uc ose , n o nfasti n g
Uri n al ysis a, b
Al b u mi n
S pecific gra vit y
C h olester ol
p H
Creati ne ki nase ( C K)
Pr otei n
Ot her Tests
Gl uc ose
A P O E ge n ot y pi n g a,c, d
Ket o nes
Hi g h se nsiti vit y C- reacti ve pr otei nc
Bl o o d
Calc ulate d creati ni ne cleara nce ( C oc kcr oft a n d Ga ult 1 9 7 6)
Ur i ne le u k oc yte esterase
H Bs A g e
H C V a nti b o d y
H C V R N A P C R f
I m m u ne S afet y L a bsg
Β tr y ptase
T otal I m m u n o gl o b uli n E
I m m u ne c o m ple x testi n g
A b bre viati o ns:  A P O E = a p oli p o pr otei n s u bt y pe E ; H Bs A g = h e patitis B s urface a nti ge n ; H C V = he patitis C vir us; 
P C R = p ol y merase c hai n reacti o n; R B C = re d bl o o d cells; R N A = ri b o n ucleic aci d; W B C = w hite bl o o d cells.
a
Assa y e d b y Lill y-desi g nate d (ce ntral) la b orat or y.
b
Res ults will be c o nfir me d b y t he Lill y -desi g nate d (ce ntral) la b orat or y at t he ti me of i nitial testi n g.
c
Sa m ples c ollecte d f or s pecifie d la b orat or y tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test 
res ults.  Certai n sa m ples ma y be retai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h a p plica ble la ws, 
r eg ulati o ns, or la b orat or y certificati o n sta n dar ds.
d
Neit her patie nts n or i n vesti gat ors will recei ve t he ge n ot y pe res ults u nless t here is a c o u ntr y -s pecific la w or 
re g ulati o n t hat re q uires n otificati o n of t he res ults.  Fail ure t o c ollect sa m ples f or A P O E ge n ot y pi n g will n ot be 
c o nsi dere d a pr ot oc ol vi olati o n if c o u ntr y-s pecific re g ulati o ns pr o hi bit t he testi n g of ge netic material or 
tra ns p ortati o n of s uc h material o utsi de of t he c o u ntr y.
e
La b orat o r y test t o be perf or me d o nl y f or patie nts wit h a hist or y  of h e patitis B.
f
La b orat o r y test t o be perf or me d o nl y f or patie nts w h o are h e patitis C a nti b o d y p ositi ve .
g
La b orat o r y tests t o be perf or me d o nl y f or patie nts wit h m o derate-t o-se vere i nf usi o n reacti o n (see Secti o n 9. 4. 7. 1
f or ti mi n g of sa m ple c ollecti o n). I n vesti gat ors will re mai n bli n de d t o t he i m m u ne safet y la b res ults u ntil t he e n d 
of st u d y.

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A p p e n di x 3.
St u d y  G o v er n a n c e C o n si d er ati o n s
A p p e n di x 3. 1 . R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
A p p e n di x 3. 1. 1 .
I nf or m e d C o n s e nt
T he i n vest i gat or is res p o nsi ble f or:

e ns uri n g t hat t he s u bject/s u bject’s le gal re prese ntati ve u n dersta n ds t he nat ure of t he 
st u d y, t he p ote ntial ris ks a n d be nefits of partici pati n g i n t he st u d y , a n d t hat t heir 
parti ci pat i on is v o l unt ar y.

e ns uri n g t hat i nf or me d c o nse nt is gi ve n b y eac h s u bject or le gal re prese ntati ve.  T his 
i ncl u des o btai ni n g t he a p pr o priate si g nat ures a n d dates o n t he i nf or me d c o nse nt f or m 
(I C F) pri or t o t he perf or ma nce of a n y  pr ot oc ol pr oce d ures a n d pri or t o t he a d mi nistrati o n 
of  in vesti gati o nal pr o d uct.

a ns weri n g a n y q uest i ons t he s u bject/s u bject’s le gal re prese ntati ve ma y ha ve t hr o u g h o ut 
t he st u d y a n d s hari n g i n a ti mel y ma n ner a n y  ne w i nfor m at i on t hat m a y be rele va nt t o t he 
s u bject’s/s u bject’s le gal re prese ntati ve’s willi n g ness t o c o nti n ue his or her partici pati o n 
i n t he st u d y.

e ns uri n g t hat a c o p y of t he I C F is pr o vide d t o t he s u bject or t he s u bject’s le gal 
re prese ntati ve a n d is ke pt o n file.

e ns uri n g t hat t he me dical rec or d i ncl u des a state me nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he s u bject was e nr olle 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.
St u d y  part ners will als o si g n t he i nf or me d c o nse nt. If it is n ot k n o w n t hat t he st u d y part ner will 
c ha n ge, t he ne w st u d y part ner w o ul d nee d t o si g n t he I C F w he n he/s he ta kes o ver t he care f or t he 
s u bject a n d st u d y partici pat i on. T he c ha n ge i n st u d y part ner w o ul d als o nee d t o be d oc u me nte d 
o n t he e C R F.
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
s u bjects or t hei r le gal re prese ntati ves a n d b y st u d y part ners.
A p p e n di x 3. 1. 2 .
R e cr uit m e nt
Lill y or i ts desig nee is res p o nsi ble f or t he ce ntral recr uit me nt  strate g y for s u bjects.  I n di vi d ual 
i n vesti gat ors ma y ha ve a d diti onal l ocal re q uire me nts or pr ocesses.
A p p e n di x 3. 1. 3.
Et hi c al R e vi e w
T he i n vesti gat or or a n a p pr o priate l ocal re prese ntati ve m ust gi ve ass ura nce t hat t he et hical 
re vie w b oar d (E R B ) was pr o perl y c o nstit ute d a n d c o n ve ne d as re q uire d b y t he I nter nati onal 
C o u ncil f or Har m o nisat i on ( I C H) g ui deli nes a n d ot her a p plica ble la ws a n d re g ulat i ons.

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D oc u m e nt atio n of  E R B a p pr o val of t he pr ot oc ol a n d t he I C F m ust be pr o vi de d t o Lill y before t he 
st u d y ma y be gi n at t he i n vestigati ve si te(s).  Lill y or its re prese ntati ves m ust a p pr o ve t he I C F, 
i ncl u di n g a n y c ha n ges ma de b y t he E R Bs, bef ore it is use d at t he i n vesti gati ve site(s).  All I C Fs 
m ust be c o m plia nt wit h t he I C H g ui deli ne o n G o o d Cli nical Pract ice ( G C P).
T he st u d y  site’s E R B(s) s h o uld be pr o vi de d wi t h t h e fol l owi n g:

t he pr ot oc ol a n d relate d a me n d me nts a n d a d de n da , c urre nt I n vesti gat or Br oc h ure 
(I B) a n d u p dates d uri n g t he c o urse of t he st u d y

i nf or me d c o nse nt f or m

ot her rele va nt d oc u m e nts ( f or e xa m ple, c urric ula vit a e, a d vertise me nts)
A p p e n di x 3. 1. 4.
R e g ul at or y C o n si d er ati o n s
T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he:

co nse ns us et hics pri nci ples deri ve d fr o m i nter nat i onal et hics g ui deli nes, i ncl u di n g 
t he Declarat i on of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of
Me dical
Scie nces (CI O M S ) I nter natio nal Et hi cal G uideli 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
S o m e of t he o bli gati ons of t he s p o ns or will be assi g ne d t o a t hir d part y .
A p p e n di x 3. 1. 5.
I n v e sti g at or I nf or m ati o n
F or t hi s cli nical trial, t h e fol l owi n g q ualificat i ons are re q uire d f or t he pri nci pal i n vest i gat or ( PI):

P h ysicia n wit h a s pecialt y i n ne ur ol o g y, g eriatrics, or ps yc hiatr y

E x peri e nce i n c o n d uct i n g cli nical trials i n t he treat me nt of A D
If t he PI d oes n ot meet t hese q ualificati o ns, t he n t he site m ust ha ve a s u bi n vesti gat or w h o meets
t hese q ualificat i ons a n d t he PI m ust be a lice nse d cli nicia n wit h e x perie nce i n c o n d ucti n g cli nical 
trials i n t he treat me nt of A D.
C o g ni tive assess me nts m ust be a d mi nistere d b y a n i n di vi d ual trai ne d i n t he use of t hese 
i nstr u me nts.  I n vest i gat ors a n d site pers o n nel w h o will perf or m rati n gs will be trai ne d a n d 
a p pr o ve d b y Lill y or its desig nee pri or t o parti ci pati n g i n t he st u d y.  I n most cases, e val uat i on 
a n d n otificat i on will occ ur via o nli ne trai ni n g sessi o ns.  N ote t hat t he A D A S -C o g a n d M M S E 
s h o uld be a d mi nistere d b y differe nt rater t ha n t he A D C S -A D L a n d C D R.   T he PI has t he 
res p o nsi bility of select i n g w h o will a d mi nister t he i nstr u me nts at t he site, as l o n g as all trai ni n g 
re q uire me nts ha ve bee n met b y t h ose raters. H o we ver, it is a best practice t hat t he meas ure me nts 
be perf or m e d o n a gi ve n patie nt b y t he sa me rater at eac h visit.

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A p p e n di x 3. 1. 6.
Pr ot o c ol Si g n at ur e s
T he s p o ns or’s res p o nsi ble me dical o fficer will a p pr o ve t he pr ot oc ol, c o nfir mi n g t hat, t o t he best 
of  his or her k n o wle d ge, t he pr ot oc ol acc uratel y descri bes t he pla n ne d desi g n a n d c o n d uct of t he
st u d y.
After rea di n g t he pr ot oc ol, eac h PI will si g n t he pr ot oc ol si g nat ure pa ge a n d se n d a c o p y  of t he 
sig ne d pa ge t o a Lill y re prese ntati ve.
A p p e n di x 3. 1. 7.
Fi n al R e p ort Si g n at ur e
T he cli nical st u d y re p ort (C S R ) c o or di nati n g i n vesti gat or will si g n t he fi nal C S R f or t his st u d y, 
i n dicati n g a gree me nt t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he 
c o n d uct a n d res ults of t he st u d y.
T he i n vest i gat or wit h t he m ost q ualifie d s u bjects will ser ve as t he C S R c o or di nat i n g i n vesti gat or.  
If t his i n vesti gat or is u na ble t o f ulfill t his f u ncti on, a n ot her i n vest i gat or will be c h ose n b y Lill y t o 
ser ve as t he C S R c o or dinati n g i n vest i gat or.
T he s p o ns or’s res p o nsi ble me dical o fficer a n d statisticia n will  a p pr o ve t he fi nal C S R f or t his 
st u d y, c onfir mi n g t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he 
c o n d uct a n d res ults of t he st u d y.
A p p e n di x 3. 2.
D at a Q u alit y A s s ur a n c e
T o e ns ure acc urate, c o m plete, a n d relia ble data, Lill y or its re prese ntati ves will d o t he f oll owi n g:

pr o vi de i nstr ucti o nal materi al t o t he st u d y sites, as a p pr o priate

s p o ns or i n vesti gat or st u d y site trai ni n gs t o i nstr uct t he i n vesti gat ors a n d st u d y 
c o or di nat ors.  T his trai ni n g will  gi ve i nstr uctio n o n t he pr ot oc ol, t he c o m plet i on 
of  t he C R Fs, an d st u d y  pr oce d ures.

ma ke peri o dic visit s t o t he st u d y sit e

be a vaila ble f or c o ns ultati o n a n d sta y  in c o ntact wit h t he st u d y site pers o n nel b y 
mail, tel e p h o ne, a n d/ or fa x

re vie w a n d e val uate eC R F data a n d use sta n dar d c o m p uter e dits t o detect err ors i n 
dat a c ollect i on

c o n d uct a q ualit y re vie w of t he data base
I n a d diti on, Lill y or its re prese ntati ves will p eri o dicall y c hec k a sa m ple of t he s u bject 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 dit e d b y Lill y or its 
re prese ntatives, 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.
T he i n vest i gat or will kee p rec or ds of all ori gi nal s o urce data.  T his mi g ht i ncl u de la b orat or y 
tests, me dical rec or ds, a n d cli nical n otes.  If re q uested, t he i n vest i gat or will pr o vi de t he s p o ns or, 
a p plica ble re g ulat or y a ge ncies, a n d a p plica ble E R Bs wit h direct access t o ori gi nal s o urce 
d oc u m e nts.

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A p p e n di x 3. 2. 1.
D at a C a pt ur e S y st e m
A n electr o nic data ca pt ure s y st e m will be use d i n t his st u d y.  T he sit e mai ntai ns a se parate s o urce 
f or t he data e ntere d b y t he site i nt o t he s p o ns or-pr o vi de d electr o nic data ca pt ure s yste m.
Electr o nic Cli nical O utc o m e Assess me nt (e C O A) meas ures ( f or e xa m ple, a rati n g scale, 
i ncl u di n g a u di o v oice rec or di n gs of t he rater’s q uesti ons a n d t he patie nt’s a n d st u d y  part ner’s 
res p o nses) are e ntere d i nt o a n e C O A i nstr u me nt (at t he ti me t hat t he i nf or mati o n is o btai ne d ).  
T he e C O A ta blet has b ot h ke y b oar d e ntr y  a n d a u di o v oice rec or di n g ca pa bilities.  I n t hese 
i nsta nces w here t here is n o pri or writte n or electr o nic s o urce data at t he site, t he e C O A
i nstr u me nt rec or d will ser ve as t he s o urce.
If e C O A rec or ds are st ore d at a t hir d part y site, i n vestigat or si tes will ha ve c o nti n u o us access t o 
t he s o urce d o c u me nts d uri n g t he st u d y a n d will recei ve a n arc hi val c o p y at t he e n d of t he st u d y 
f or rete ntio n.
A n y data f or w hic h t he e C O A i nstr u me nt rec or d will ser ve t o c ollect s o urce data will be 
i de ntifie d a n d d oc u me nte d b y eac h site i n t hat site’s st u d y file.
Case re p ort f or m data will be e nc o de d a n d st ore d i n a cli nical trial data base.  Data ma na ge d b y a 
ce ntral ve n d or, s uc h as a u dio v oi ce rec or di n gs, lab orat or y  test data or E C G data, will be st ore d 
ele ctr o nicall y i n t he ce ntral ve n d or’s data base s yst e m.  Wit h t he e xce pt i on of t he a u di o v o ice 
rec or di n gs, w hic h are o nl y use d f or ce ntral m onit ori n g p ur p oses, d at a 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 Lill y data ware h o use .
A n y data f or w hic h pa per d oc u me ntati o n pr o vi de d b y t he s u bject wil l ser ve as t he s o urce 
d oc u m e nt will be ide ntifie d a n d d oc u me nte d b y  eac h site i n t hat site’s st u d y file.
Data fr o m c o m p lai nt f or ms s u b mitte d t o Lill y 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 mplai nt m a na ge me nt s yst e m.
A p p e n di x 3. 3.
St u d y a n d Sit e Cl o s ur e
A p p e n di x 3. 3. 1.
Di s c o nti n u ati o n of St u d y Sit e s
St u d y  sit e p artici pat i on ma y be disc o nt i n ue d if Lill y  or its desig nee , th e i n vest i gat or, or t he E R B 
of  t he st u d y sit e j u d ges it necessar y f or me dical, safety,  re g ulat or y, or ot her reas o ns c o nsiste nt 
wi t h a p plica ble la ws, re g ulat i ons, a n d G C P.
A p p e n di x 3. 3. 2.
Di s c o nti n u ati o n of t h e St u d y
T he st u d y  will b e di sc o nti n ue d if Lill y or its desi g nee j u d ges it necessar y for m e dical, safet y,  
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 ulatio ns, a n d G C P.
A p p e n di x 3. 4.
P u bli c ati o n P oli c y
T he p u blicat i on p o lic y f or St u d y L M D C is descri be d i n t he Cli nical Trial A gree me nt.

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A p p e n di x 4.
H e p ati c M o nit ori n g T e st s f or 
Tr e at m e nt -E m er g e nt A b n or m alit y
S el ecte d tests ma y be o btai ne d i n t he e ve nt of a treat me nt -e mer ge nt he patic a b n or malit y a n d ma y 
be re q uire d i n f o ll o w-u p wi t h p atie nts i n c o ns ultat i o n wit h t he Lill y, or its desig nee, cli nical 
researc h p h ysicia n.
He p atic M o nit ori n g Tests
He p atic He m at ol o g y a
H a pt o gl o bi n a
He m o gl o bi n
He mat ocrit
He p atic C o a g ul ati o n a
R B C
Pr ot hr o m bi n Ti me
W B C
Pr ot hr o m bi n Ti me, I N R
Ne utr o p hils, se g me nte d
L y m p h oc y t es
He p atic Ser ol o gies a, b
M o n oc ytes
He patitis A a nti b o d y, t otal
E osi n o p hils
He patitis A a nti b o d y, I g M
Bas o p hils
He patitis B s urface a nti ge n
Platelets
He patitis B s urface a nti b o d y
He patitis B C ore a nti b o d y
He p atic C he mistr y a
He patitis C a nti b o d y
T otal bilir u bi n
He patitis E a nti b o d y, I g G
Direct bilir u bi n
He patitis E a nti b o d y, I g M
Al kali ne p h os p hatase
A L T
A nti -n ucle ar a nti b o d y a
A S T
G G T
Al k ali ne P h os p h at ase Is oe nz y mes a
C P K
A nti -s m o ot h m uscle a nti b o d y ( or a nti-acti n 
a nti b o d y) a
A b bre viati o ns:  A L T = ala ni ne a mi n otra nsferase; A S T = as pirate a mi n otra nsferase; C P K = creati ni ne 
p h os p h o ki nase; G G T = ga m ma -gl uta m yl tra nsferase; I g = i m m u n o gl o b uli n; I N R = i nter nati o nal n o r maliz e d 
rati o; R B C = re d bl o o d cells; W B C = w hite bl o o d cells.
a
Assa y e d b y Lill y-desi g nate d or l ocal la b orat or y.
b
Refle x/c o nfir mati o n de pe n de nt o n re g ulat or y re q uire me nts a n d/ or testi n g a vaila bilit y.

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A p p e n di x 5.
Fl ort a u ci pir F 1 8 T a u P E T I m a gi n g
A scree ni n g fl ort a u cipir F 1 8 P E T sca n will be perf or me d as part of t he st u d y eli gi bilit y cri t eria.  
A d di tio n al flort a u ci pi r F 1 8 P E T sca n s will be perf or m e d at Visit 1 5 a n d Visi t 2 8 , a n d at earl y 
di sc o nti n uati on ( E D) if E D occ urs aft er t he patie nt has at least c o m plete d Visit 1 1.  S pecific 
i nstr uctio ns f or t he fl orta ucipir F 1 8 P E T sca n i tself will be pr o vi de d i n t he P E T I m a gi n g 
Ma n ual .
I ncl usi o n Criteri a f or Fl ort a uci pir F 1 8 P E T Sc a ns
A pat ient  must m eet all ot her Visit 1 eli gi bilit y crit eria bef ore ha vi n g a fl ort a u cipir F 1 8 P E T 
sca n wit h t he e xce pti on of t he M RI .
[4 2]
Cri t erio n [ # 4 2] has bee n delete d .
E xcl usi o n Criteri a f or F l ort a uci pir F 1 8 P E T Sc a ns
A pat ient  will be e xcl u de d fr o m partici pati o n i n flort a u ci pi r F 1 8 i ma gi n g if he or s he meets a n y 
of  t he crit eria belo w:
[ 4 3] Has a n y c o n dit i on t hat, i n t he i n vesti gat or’s o pi ni o n, c o ul d i ncrease ris k t o t he 
pati e nt, li mit t he patie nt’s a bilit y t o t olerate t he e x peri me ntal pr oce d ures, or 
i nterfere wit h a nal ysis of t he data (f or e xa m ple, patie nts wit h c hr o nic bac k 
pai n mi g ht n ot b e a ble t o lie st ill d uri n g t he sca n ni n g pr oce d ures).
[4 4] Has a b n or mal fi n di n gs o n p h ysical e xa mi nat i on, la b orat or y  scree ni n g tests, or 
scree ni n g E C Gs t hat s u g gest t he patie nt mi g ht ha ve a c o n dit i on t hat c o ul d, i n 
t he o pini o n of t he i n vest i gat or, affect his or her res p o nse t o t he 
r a dio p har mace ut ical a n d relate d testi n g pr oce d ures.
[ 4 5] Is dee me d li kel y t o be u na ble t o c o m plete t he i ma gi n g pr oce d ure f or a n y  
reas o n.
[4 6 ] Is recei vi n g ot her ra diati on e x p os ure t hat, w he n a d de d t o t he fl ort a u cipir F 1 8
P E T sca n, w o ul d e xcee d l ocal or nati o nal  re g ulat or y li mits for a patie nt.
Si te i n vesti gat ors, patie nts, a n d st u d y part ners will n ot be i nf or me d of t he res ults of P E T sca ns 
o btai ne d f o ll owi n g ra n d o mizati o n, as t he y relate t o t he st u d y .  A n y fi n di n gs t hat ma y be of 
p ote nti al me dical c o ncer n will be pr o vid e d f or a p pr o pri at e foll o w - 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 t he P E T I m a gi n g Ma n ual.  T he sca nni n g tec h n o l ogi sts will be bli n de d t o patie nts’ 
treat me nt assig n me nts.

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P a g e 1 0 1
L Y 3 3 0 3 5 6 0
Sc a n S afet y
T he pri mar y  ris k relate d t o fl ort a u cipi r F 1 8 is ra diatio n 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 
Ta ble A P P. 5. 1 .  I n a d diti o n, t he ta u li ga n d fl orta uci pir F 1 8 c o nti n ues t o be i n cli nical e val uat i on, 
a n d ris ks fr o m t he a ge nt are n ot f ull y k n o w n.  Details o n t he cli nical i nf or mati o n t o date 
re gar di n g fl orta ucipir 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 mati o n 
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 florta uci pir F 1 8 ma y be f ou n d i n t he 
I n vesti gat or’s Br oc h ure.
P ati e nts must 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 1 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 oti o n a n d 
pati e nt disc o mf o rt.
T a bl e A P P. 5 . 1.
Eff e cti v e R a di ati o n D o s e ( m S v)
Effecti ve 
D ose 
( m S v) per 
S c a n a
N u m ber of 
S c a ns i n 
F irst Y e ar b
Effecti ve 
D ose ( m S v) 
f or S c a ns i n 
F irst Ye ar
N u m ber 
of S c a ns 
i n S ec o n d 
Y e ar b
Effecti ve 
D ose ( m S v) 
f or S c a ns i n 
S ec o n d Y e ar
Effecti ve 
D ose ( m S v) 
f or Ye ars 1 
a n d 2
Fl orta uci pir F 1 8 
Sca n ( 1 0 m Ci I V)
9. 1 0
1
9. 1 0
2
1 8. 2 0 
2 7. 3 0
T otals
1
9. 1 0
2
1 8. 2 0 
2 7. 3 0
A b bre viati o ns:  C T = c o m p uterize d t o m o gra p h y; I V = i ntra ve n o us i nf usi o n; P E T = p ositr o n e missi o n t o m o gra p h y.
a
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 als o 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 pr ocess w h e n t he sca n is perf or me d 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.
b
If t h e patie nt is disc o nti n ue d fr o m St u d y L M D C , t he s u bject will be as ke d t o partici pate i n a disc o nti n uati o n visit.  
Patie nts w h o disc o nti n ue fr o m t he st u d y earl y will ha ve a fl orta uci pir sca n perf or me d at t he E D visit o nl y if t he y 
disc o nti n ue t he st u d y after t he y ha ve at least c o m plete d V 1 1 .
Vi sits t hat i ncl u de i ma gi n g s h o ul d be c o m plete d o ver a djace nt da ys. N ote t hat fl orta ucipi r F 1 8
P E T ta u i ma gi n g ca n be perf or me d 1 or 2 da ys after c o g nitive a n d f u nct i onal testi n g .
Wit h res pect t o ot her c o m p o u n d -relate d ris ks, A V -1 4 5 1 was p osit i ve i n t he i n vitr o h u ma n 
et her - à-g o -g o -relate d g e ne (h E R G ) assa y.   Alt h o u g h t he mar gi n o f safety a p pears hi g h, a n d i n 
vi v o car di o vasc ular assess me nts i n d o gs s h o we d n o e vi de nce of Q T pr ol o n gati o n , s u bjects wit h a 
hist or y  of ris k fact ors f or T orsa des de P oi ntes a n d patie nts ta ki n g dr u gs k n o w n t o pr ol o n g t he Q T 
i nter val will b e e x clu d e d f r o m t his st u d y.
If cli nicall y mea ni n gf ul a b n or malities are n ote d o n t he E C G, t he a d visa bilit y of  t he florta uci pir 
sca n s h o uld be c o nsi dere d b y  t he i n vesti gat or i n c o ns ultati on wi t h t he Lill y-desi g nate d m e dical 
m o nit or. 

I 8 G-M C -L M D C( c) Cli ni c al Pr ot o c ol
P a g e 1 0 2
L Y 3 3 0 3 5 6 0
If it bec omes necessar y f or a patie nt t o start ta ki n g a me dicat i on k n o w n t o pr ol o n g Q T i nter val 
pri or t o perf or ma nce of a n y p ost baseli ne fl ort a u cipir F 1 8 sca n, d o n ot perf or m t he sca n or wai t 
u nt il t he Q T -pr ol o n gi n g me dicat i on has bee n st o p pe d f or t he l o n ger of 1 4 da ys or 5 half -li ves.  
T he patie nt ma y , h o we ver, r e mai n i n t he st u d y.  N o n perf or ma nce of p ost baseli ne fl ort a u cipir F 
1 8 P E T sca ns i n pat ient s ta ki n g a me dicati o n k n o w n t o pr ol o n g Q T i nter val will n ot be 
c o nsi dere d a pr ot oc ol vi o lati on.

L e o  D o c u m e n t  I D  =  4 7 9 1 e 5 5 3 - 5 9 7 8 - 4 2 1 8 - 8 c e 2 - 7 a d 9 e c 0 e 8 a d 3
A p p r o v e r :
A p p r o v a l  D a t e  &  T i m e :  2 9 - M a r - 2 0 2 1  1 2 : 3 2 : 5 5  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 :  2 9 - M a r - 2 0 2 1  1 3 : 2 6 : 5 7  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