A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type
Phase: PHASE3
Conditions: Agitation in Patients With Dementia of the Alzheimer's Type
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 
 
P R O T O C O L TI T L E:  
A P h ase 3, m ultice nter, r a n d o mize d, d o u ble -bli n d, pl ace b o -c o ntr olle d st u d y t o assess t he 
effic ac y, s afet y, a n d t oler a bilit y of A V P- 7 8 6 ( de u de xtr o met h or p h a n h y dr o br o mi de 
[ d 6-D M]/ q ui ni di ne s ulf ate [ Q]) f or t he tre at me nt of a git ati o n i n p atie nts wit h de me nti a of 
t he Alz hei mer’s t y pe 
 
Pr ot oc ol:  
2 0 -A V P -7 8 6 -3 0 6 A me n d me nt 2  
E U C T N o.:  2 0 2 3 -5 0 4 9 9 0 -1 9 -0 0  
S p o ns or:  
Ots u ka P har mace utical De vel o p me nt & 
C o m mercializati o n, I nc.  
E u dr a C T N o.: 2 0 2 0 -0 0 0 7 9 8 -2 6  
I N D:1 2 4 0 9 9  
Dr u g:  
A V P -7 8 6 (de u de xtr o met h or p ha n  h y dr o br o mi de 
[ d 6-D M] / q ui ni di ne s ulfate [ Q]) 
D ate:  1 5  Ma y  2 0 2 3  
Versi o n : 3 . 0 
S u perse des Versi o n : 2. 0 
 
I m me di atel y Re p ort a ble E ve nt 
S y ne os  He alt h  
 
F a x: 
  
 
E m ail:  
 
 
 
 
Ots u k a P h ar m ace utic al De vel o p me nt & C o m merci aliz ati o n , I nc. 
2 4 4 0 Researc h Bl v d  
R oc k ville, M D 2 0 8 5 0, U nite d States  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T his d oc u me nt c o nt ai ns c o nfi de nti al a n d pr o priet ar y i nf or m ati o n of Ots u k a 
P h ar m ace utic al De vel o p me nt & C o m merci aliz ati o n, I nc. ( O P D C) , a n d it is f or t he s ole 
i nf or m ati o n a n d use of t he I n vesti g at or’s rese arc h te a m a n d t he a p p oi nte d I nstit uti o n al 
Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee.  
C CI
C CI

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 
 
P R O T O C O L A G R E E M E N T  
Pr ot oc ol Title:  
A P hase  3, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d st u d y t o assess t he 
efficac y, safet y, a n d t olera bilit y of A V P - 7 8 6 ( de u de xtr o met h or p ha n h y dr o br o mi de 
[ d 6-D M]/ q ui ni di ne s ulfate [ Q]) f or t he treat me nt of a gitati o n i n patie nts wit h de me ntia of t he 
Alz hei mer’s t y pe.  
Pr ot oc ol N u m ber:  2 0-A V P - 7 8 6- 3 0 6 (A me n d me nt 2 – 1 5 Ma y  2 0 2 3) 
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of Ots u ka P har mace utical De vel o p me nt & 
C o m mercializati o n, I nc . ( O P D C). T he reci pie nt a grees t hat n o u n p u blis he d i nf or mati o n 
c o ntai ne d wit hi n t his d oc u me nt or pr ot oc ol will be discl ose d or p u blis he d wit h o ut pri or c o nse nt 
a n d writte n a p pr o val fr o m O P D C . A n e xce pti o n t o t his a gree me nt ma y be ma de f or t he p ur p oses 
of et hical or re g ulat or y re vie w, i n w hic h case t his  d oc u me nt ma y be discl ose d t o a n Et hics 
Re vie w B oar d or a n y a ut h orize d re prese ntati ve of a nati o nal a ut h orit y as re q uire d b y re g ulati o n. 
T he si g nat ures of t he P ri nci pal I n vesti gat or a n d re prese ntati ve of t he S p o ns or bel o w c o nstit ute  
t heir a p pr o val of t his pr ot oc ol a n d f urt her pr o vi de t he necessar y ass ura nces t hat: 
1.  T his st u d y will be c o n d ucte d acc or di n g t o G o o d Cli nical Practice ( G C P) a n d t o all 
sti p ulati o ns, as s pecifie d i n b ot h cli nical a n d a d mi nistrati ve secti o ns of t he pr ot oc ol 
i ncl u di n g t he Declarati o n of Helsi n ki. 
2.  T he c o n d uct a n d res ults of t his st u d y will be ke pt c o nfi de ntial, a n d t he electr o nic case 
re p ort f or ms (e C R Fs) a n d ot her perti ne nt data will bec o me t he pr o pert y of O P D C . 
3.  T he pr ot oc ol c o ntai ns all necessar y i nf or mati o n re q uire d t o c o n d uct t he st u d y, as o utli ne d 
i n t he pr ot oc ol, a n d t hat t he st u d y will n ot be i nitiate d wit h o ut t he a p pr o val of a n 
a p pr o priate I nstit uti o nal Re vie w B oar d/ I n de pe n de nt Et hics C o m mittee (I R B/ I E C/ E C). 
4.  All partici pa nts i n t his st u d y will pr o vi de writte n i nf or me d c o nse nt i n acc or da nce wit h  
t he re q uire me nts s pecifie d i n t he C o de of Fe deral Re g ulati o ns ( 2 1 C F R Parts  5 0, 5 6, 3 1 2) 
a n d/ or t he Declarati o n of Helsi n ki. All partici pa nts will als o be i nf or me d t hat t heir  
me dical rec or ds will be ke pt c o nfi de ntial e xce pt f or re vie w b y O P D C or its  
re prese ntati ves, t he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A), a n d ot her re g ulat or y 
a ge ncies. 
 
Pri nci pal I n vesti gat or Si g nat ure  
 Date  
Pri nci pal I n vesti gat or Na me:  
 
 
 
 
O P D C Re prese ntati ve Si g nat ure 
 Date  
O P D C Re prese ntati ve : 
, M D 
  
P P D

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 
 
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y: Ots u k a P h ar m ace utic al De vel o p me nt & C o m merci aliz ati o n, I nc . 
N a me of I n vesti g ati o n al Pr o d uct:  
A V P -7 8 6 ( de u de xtr o met h or p ha n h y dr o br o mi de [ d 6 -D M]/ q ui ni di ne s ulfate [ Q])  
N a me of Acti ve I n gre die nt(s):  
de u de xtr o met h or p ha n h y dr o br o mi de [ d 6 -D M] a n d q ui ni di ne s ulfate [ Q]  
Pr ot oc ol N u m ber:  
2 0 -A V P -7 8 6 -3 0 6  
P h ase : 3  
C o u ntr y: U nite d States ( U S), 
E ur o pe , ot her gl o bal sites 
Title of St u d y:  
A P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y, 
safet y, a n d t olera bilit y of A V P-7 8 6 ( de u de xtr o met h or p ha n h y dr o br o mi de [ d 6 -D M]/ q ui ni di ne s ulfate 
[ Q]) f or t he treat me nt of a gitati o n i n patie nts wit h de me ntia of t he Alz hei mer’s t y pe  
St u d y Ce nter(s): A p pr o xi matel y 1 1 0  gl o bal ce nters, i ncl u di n g t he U S a n d E ur o pe  
St u die d P eri o d ( ye ars):  
Esti mate d date first patie nt e nr olle d: J u n 2 0 2 0  
Esti mate d date last patie nt c o m plete d: Oct  2 0 2 4 
P h ase of de vel o p me nt:  
3 
O bjecti ves:  
T he pri mar y o bjecti ve is t o:  
•  
E val uate t he efficac y, safet y, a n d t olera bilit y of A V P -7 8 6 c o m pare d t o place b o f or t he 
treat me nt of a gitati o n i n patie nts wit h de me ntia of t he Alz hei mer’s t y pe 
T he sec o n dar y o bjecti ves are t o:  
•  
E val uate t he effects of A V P -7 8 6 c o m pare d t o place b o o n gl o bal assess me nts of se verit y a n d 
i m pr o ve me nt of a gitati o n 
•  
E val uate t he effects of A V P -7 8 6 c o m pare d t o place b o o n ne ur o ps yc hiatric s y m pt o ms  
•  
E val uate t he effects of A V P -7 8 6 c o m pare d t o place b o o n meas ures of q ualit y of life a n d 
res o urce utilizati o n 
St u d y Desi g n : P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d  st u d y 
Met h o d ol o g y:  
Scree ni n g Peri o d  ( D ays -2 8 t o -1) : A pr ot oc ol eli gi bilit y f or m will be c o m plete d f or eac h patie nt  a n d 
re vie we d b y a Me dical M o nit or f or a p pr o val pri or t o partici pati o n i n t he st u d y . 
1 2 -week D o u ble -bli n d Tre at me nt Peri o d  ( D ays 1-8 5) : All eli gi ble patie nts will be ra n d o ml y assi g ne d 
t o recei ve eit her A V P -7 8 6  or place b o (i de ntical i n a p peara nce t o A V P-7 8 6).  
3 0 -d ay F oll o w -u p Peri o d:  All e nr olle d patie nts, w het her t he y c o m plete t he st u d y or ter mi nate fr o m 
t he st u d y earl y f or a n y reas o n, will ha ve a F oll o w-u p visit 3 0  da ys after t he last d ose of st u d y dr u g  f or 
select efficac y a n d safet y assess me nts. 
Assess me nts a n d Visits : Patie nts will atte n d cli nic visits at Scree ni n g, Baseli ne ( Da y  1), 
Visit  2 ( Da y 8), Visit  3 ( Da y 1 5), Visit  4 ( Da y 2 9), Visit  5 ( Da y 4 3), Visit  6 ( Da y 5 7), 
Visit  7 ( Da y 7 1), Visit  8/ Earl y Ter mi nati o n ( E T) ( Da y 8 5), a n d F oll o w -u p ( 3 0  da ys after t he last 
d ose).   
St u d y pr oce d ures perf or me d at eac h visit are o utli ne d i n t he Sc he d ule of Assess me nts ( Ta ble  1). 

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 
 
N u m ber of P atie nts ( pl a n ne d ): A p pr o xi matel y 7 5 0  patie nts   
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n: Patie nts wit h a gitati o n sec o n dar y t o Alz hei mer’s 
de me ntia; t he dia g n osis of pr o ba ble Alz hei mer’s disease will be base d o n t he ‘ 2 0 1 1 Dia g n ostic 
G ui deli nes f or Alz hei mer’s Disease’ iss u e d b y t he Nati o nal I nstit ute o n A gi n g ( NI A) -Alz hei mer’s 
Ass ociati o n ( A A) w or k gr o u ps. Dia g n osis of a gitati o n will be base d o n t he pr o visi o nal c o nse ns us 
defi niti o n of a gitati o n i n patie nts wit h c o g niti ve dis or ders de vel o pe d b y t he I nter nati o nal 
Ps yc h o geriatric Ass ociati o n (I P A) A gitati o n  Defi niti o n W or k Gr o u p.  
Ke y I ncl usi o n Criteri a:  P atie nts 5 0 t o 9 0  years of a ge (i ncl usi ve) wit h cli nicall y si g nifica nt, 
m o derate -t o-se vere a gitati o n f or at least 2 wee ks pri or t o Scree ni n g  t hat i nterferes wit h dail y r o uti ne 
per t he I n vesti gat or’s j u d g me nt, a n d w h o re q uire p har mac ot hera p y f or t he treat me nt of a gitati o n per 
t he I n vesti gat or’s j u d g me nt after a n e val uati o n of re versi ble fact ors a n d a c o urse of 
n o n p har mac ol o gical i nter ve nti o ns. A Ne ur o ps yc hiatric I n ve nt or y A gitati o n/ A g gressi o n ( N PI -A A)  
sc ore of ≥ 4 a n d Mi ni Me ntal State E xa mi nati o n ( M M S E) sc ore of 8 t o 2 4 (i ncl usi ve) at S cree ni n g 
a n d B aseli ne are re q uire d f or st u d y partici pati o n. Patie nts m ust meet a n a d diti o nal pre deter mi ne d 
bli n de d eli gi bilit y criteri o n, w hic h will re mai n bli n de d t o t he cli nical st u d y site I n vesti gat ors a n d staff. 
Eli gi ble patie nts m ust ha ve a relia ble care gi ver w h o is a ble a n d willi n g t o c o m pl y wit h all st u d y 
pr oce d ures, i ncl u di n g a d here nce t o a d mi nisteri n g st u d y dr u g  a n d n ot a d mi nisteri n g a n y pr o hi bite d 
me dicati o ns d uri n g t he c o u rse of t he st u d y, a n d w h o s pe n ds a mi ni m u m of 2 h o urs per da y f or 4 da ys 
per wee k wit h t he patie nt.  
Ke y E xcl usi o n Criteri a:  Patie nts wit h de me ntia pre d o mi na ntl y of t he n o n -Alz hei mer’s t y pe (e g, 
vasc ular de me ntia, fr o nt ote m p oral de me ntia, Par ki ns o n’s disease, s u bsta nce -i n d uce d de me ntia) a n d 
patie nts wit h s y m pt o ms of a gitati o n t hat are n ot sec o n dar y t o Alz hei mer’s de me ntia  (e g, sec o n dar y t o 
pai n, ot her ps yc hiatric dis or der , or deliri u m) are n ot eli gi ble.  
I n vesti g ati o n al P r o d uct, D os a ge a n d M o de of A d mi nistr ati o n:  
A V P -7 8 6 ca ps ule will be a d mi nistere d orall y BI D at a d ose of A V P -7 8 6 -1 8  (d 6 -D M 1 8  m g/ Q 
4. 9  m g)  or A V P -7 8 6 -4 2. 6 3 ( d 6 -D M 4 2. 6 3 m g/ Q 4. 9 m g) . 
D ur ati o n of T re at me nt: P atie nts will be e nr olle d i n t he st u d y f or a p pr o xi matel y 2 0 wee ks , w hic h 
i ncl u des: 
•  
U p t o a 2 8 -da y Scree ni n g P eri o d 
•  
1 2 -wee k D o u ble -bli n d T reat me nt P eri o d 
•  
3 0 -da y F oll o w -u p P eri o d 
Refere nce T her a p y,  Dos a ge a n d M o de of A d mi nistr ati o n:  
Matc hi n g place b o ca ps ule (i de ntical a p peara nce t o A V P -7 8 6 ca ps ule) will be a d mi nistere d orall y 
BI D. 
Criteri a f or E v al u ati o n:  
Effic ac y: 
Pri m ar y Effic ac y Me as ure : C o he n -Ma nsfiel d A gitati o n I n ve nt or y ( C M AI)  
Ke y S ec o n d ar y  Effic ac y Me as ure : Cli nical Gl o bal I m pressi o n of Se verit y of Ill ness f or A gitati o n 
( C GI S-A gitati o n)  
Ot her  Effic a c y Me as ures : Ot her efficac y meas ures i ncl u de, Cli nical Gl o bal I m pressi o n of C ha n ge 
( C GI C-A gitati o n), N PI -A A, N PI t otal, E ur o Q ol  5- Di me nsi o n 5- Le vel ( E Q-5 D -5 L), a n d  Res o urce 
Utilizati o n i n De me ntia -Lite ( R U D -Lite ).  

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 
 
P h ar m ac o ki netics:  Plas ma c o nce ntrati o ns of d 6 -D M, its meta b olites d 3 -de xtr or p ha n ( d 3 -D X) a n d 
d 3 - 3-met h o x y m or p hi na n ( d 3 - 3-M M), a n d Q will be meas ure d.  Uri ne c o nce ntrati o ns of d 6 -D M a n d its 
meta b olite d 3 -D X  will be meas ure d.  
S afet y: Sa fet y a n d t olera bilit y of A V P-7 8 6 will be assesse d b y re p orte d a d verse e ve nts ( A Es), 
p h ysical a n d  ne ur ol o gical e xa mi nati o ns, vital si g ns, cli nical la b orat or y assess me nts, resti n g 1 2 -lea d 
electr ocar di o gra ms  ( E C Gs), M M S E, t he E p w ort h Slee pi ness Scale ( E S S), a n d t he S hee ha n 
S uici dalit y Trac ki n g Scale ( S -S T S) . 
St atistic al M et h o ds:  C o m plete details of t he pla n ne d statistical a nal ysis will be prese nte d i n t he 
Statistical A n al ysis Pla n ( S A P).  
Effic ac y A n al yses : T he pri mar y efficac y e n d p oi nt is t he c ha n ge fr o m B aseli ne t o t he e n d of t he 
efficac y peri o d  i n t he C M AI t otal sc ore. 
All efficac y a nal yses will be base d o n t he i nte nt -t o-treat a nal ysis set, defi ne d as all patie nts i n t he 
ra n d o mize d p o p ulati o n w h o ta ke at least 1 d ose of st u d y dr u g  ( A V P-7 8 6 or place b o), ha ve a B aseli ne, 
a n d at least 1  p ost - Baseli ne e val uati o n f or t he C M AI t otal sc ore. Descri pti ve statistics will be 
pr o vi de d f or all efficac y varia bles i n ge neral. C o nti n u o us varia bles will be s u m marize d b y ta b ulati o ns 
of mea n, me dia n, ra n ge, a n d sta n dar d de viati o n  ( S D). Ta b ulati o ns of fre q ue nc y distri b uti o ns will be 
pr o vi de d  f or cate g orical varia bles. T he pri mar y e n d p oi nt will be a nal yze d usi n g mi xe d-effect m o del 
re peat meas ures ( M M R M). T he pri mar y statistical c o m paris o n of i nterest is A V P-7 8 6 vers us place b o. 
T he n ull h y p ot hesis of t his c o m paris o n is t hat t here is n o differe nce bet wee n t he A V P -7 8 6  treat me nt 
gr o u p a n d place b o i n c ha n ge fr o m B aseli ne t o t he e n d of t he efficac y peri o d i n t he C M AI t otal sc ore. 
T his c o m paris o n will be teste d f or statistical si g nifica nce at a 0. 0 5  ( 2-si de d) si g nifica nce le vel. Details 
of se nsiti vit y  a nal yses u n der t he ass u m pti o n of missi n g n ot at ra n d o m will be pr o vi de d i n t he S A P.  
P h ar m ac o ki netic A n al yses : Plas ma  c o nce ntrati o ns of d 6 -D M, its meta b olites d 3 -D X a n d d 3 - 3-M M, 
a n d Q will be s u m marize d descri pti vel y . Uri ne c o nce ntrati o ns of d 6 -D M a n d its meta b olite d 3 -D X 
will be s u m marize d descri pti vel y . 
S afet y A n al yses : Safet y a nal yses will be base d o n safet y p o p ulati o n defi ne d as all patie nts w h o are 
ra n d o mize d a n d ta ke at least o ne d ose of st u d y dr u g. It will c o nsist of data s u m maries f or bi ol o gical 
para meters a n d A Es. Descri pti ve statistics will be pr o vi de d f or all safet y varia bles i n ge neral. 
C o nti n u o us varia bles will be s u m marize d b y ta b ulati o ns of mea n, me dia n, ra n ge, a n d S D . Ta b ulati o ns 
of fre q ue nc y distri b uti o ns will be pr o vi de d f or cate g orical varia bles. Safet y a nal yses will be ta b ulate d 
b y treat m e nt. A Es  will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). 
S u m mar y statistics of a bs ol ute val ues a n d perce nta ge c ha n ge fr o m baseli ne f or bl o o d press ure 
(s yst olic a n d diast olic), heart rate, res pirat or y rate, a n d E C G para meters will be pr o vi de d. All val ues 
o utsi de a pre defi ne d n or mal ra n ge will be hi g hli g hte d i n t he i n di vi d ual patie nt data listi n gs. 
La b orat or y para meters will be s u m marize d via descri pti ve statistics a n d via s hifts i n res ults wit h 
res pect t o n or mal ra n ges bet wee n Baseli ne a n d e n d of treat me nt as i ncrease d, decrease d, or n o 
c ha n ge. T he S -S T S, M M S E,  a n d E S S will be s u m marize d via descri pti ve statistics . 
S a m ple Size : A p pr o xi matel y 7 5 0  patie nts. Statistical  ass u m pti o ns a n d a d diti o nal details are pr o vi de d 
i n t he S A P. 
I nteri m A n al ysis: A n i nteri m a nal ysis ma y be perf or me d a n d will be pres pecifie d i n t he I nteri m 
A nal ysis Pla n (I A P).  
 

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0 
 
 
 
8 
 
f At Scree ni n g, 3 E C Gs will be perf or me d (e g, o ne after t he ot her) . 
g E C G will  be perf or me d pre d ose a n d 1 t o 1. 5 h o urs p ost d ose at Baseli ne ( Da y 1) a n d Visit  2 ( Da y  8). 
h E C G will be perf or me d at a n y ti me at Visit  5 ( Da y  4 3) a n d Visit  8 ( Da y  8 5/ E T). 
i T h yr oi d f u ncti o n tests ( T S H, a n d refle x T 3 a n d T 4 if T S H is a b n or mal) will  be perf or me d at Scree ni n g. Gl yc os ylate d he m o gl o bi n ( H b A 1c) test will  be perf or me d at  Scree ni n g 
a n d Visit  8 ( Da y  8 5/ E T). 
j Uri ne pre g na nc y test will  be perf or me d f or w o me n  of c hil d -beari n g p ote ntial o nl y.  
k E S S will  be rate d o nl y b y patie nts w h o ha ve  a M M S E sc ore of ≥ 1 0 at B aseli ne. 
l At Visit  2 ( Da y  8), t he P K bl o o d sa m ple will be c ollecte d 1 t o 4 h o urs p ost d ose. At Visit  5 ( Da y  4 3), t he P K bl o o d sa m ple will be c ollecte d pre d ose. At Visit  7 ( Da y  7 1), t he P K 
bl o o d sa m ple will be c ollecte d at a n y ti me. T he ti me of t he last 2 d oses of st u d y dr u g pri or t o c ollecti o n of t he P K bl o o d sa m ple will be rec or de d i n t he cli nical data base.  
 m At Visit  2 ( Da y  8), t he P K uri ne sa m ple will be c ollecte d 1 t o 4 h o urs p ost d ose. 
 
 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
9 
 
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  
T A B L E O F C O N T E N T S  
P R O T O C O L A G R E E M E N T  ........................................................................................................... 2 
S Y N O P SI S  3 
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  .................................... 9 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ................................................ 1 4 
1.  
I N T R O D U C TI O N ...................................................................................................... 1 7 
1. 1.  
Rati o nale f or I n vesti gati n g A V P -7 8 6 f or Treat me nt of A gitati o n i n De me ntia  ......... 1 7 
1. 2.  
Rati o nale f or t he St u d y Desi g n ................................................................................... 1 8  
1. 3.  
Rati o nale f or A V P - 7 8 6 D ose ...................................................................................... 1 8 
1. 4.  
Rati o nale f or t he D urati o n of A V P - 7 8 6 D osi n g ......................................................... 1 8 
2.  
T RI A L O BJ E C TI V E S A N D P U R P O S E  .................................................................... 1 9 
2. 1.  
Pri mar y O bjecti ve  ....................................................................................................... 1 9 
2. 2.  
Sec o n dar y O bjecti ves  ................................................................................................. 1 9 
3.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 2 0 
3. 1.  
O verall St u d y Desi g n  .................................................................................................. 2 0 
3. 2.  
St u d y Assess me nts a n d Pr oce d ures  ............................................................................ 2 1 
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  .............................................. 2 2 
4. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................ 2 3 
4. 2.  
Patie nt E xcl usi o n Criteria  ........................................................................................... 2 4 
4. 3.  
Patie nt Wit h dra wal Criteria  ........................................................................................ 2 5 
4. 4.  
C T S data base a n d S u bject Data base A ut h orizati o n  ..................................................... 2 6 
5.  
T R E A T M E N T O F P A TI E N T S  .................................................................................. 2 7 
5. 1.  
Descri pti o n of St u d y Dr u g .......................................................................................... 2 7  
5. 2.  
C o nc o mita nt Me dicati o ns a n d N o n dr u g T hera pies .................................................... 2 7  
5. 2. 1.  
Restricte d a n d Pr o hi bite d C o nc o mita nt Me dicati o ns ................................................. 2 7  
5. 3.  
Treat me nt C o m plia nce  ................................................................................................ 2 9 
5. 4.  
Ra n d o mizati o n a n d Bli n di n g ...................................................................................... 2 9  
6.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  ........................................... 3 1 
6. 1.  
St u d y Dr u g C o m p ositi o n ............................................................................................ 3 1  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 0 
 
6. 2.  
St u d y Dr u g Pac ka gi n g a n d La beli n g .......................................................................... 3 1  
6. 3.  
St u d y Dr u g St ora ge ..................................................................................................... 3 1  
6. 4.  
St u d y Dr u g A d mi nistrati o n ......................................................................................... 3 1  
6. 5.  
St u d y Dr u g Acc o u nta bilit y ......................................................................................... 3 2  
6. 5. 1.  
Recei pt of Dr u g S u p plies ............................................................................................ 3 2  
6. 5. 2.  
Rec or d of Dis pe nsi n g ................................................................................................. 3 2  
6. 6.  
St u d y Dr u g Ha n dli n g a n d Dis p osal ............................................................................ 3 2  
7.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................ 3 3 
7. 1.  
C o he n- Ma nsfiel d A gitati o n I n ve nt or y ( C M AI)  .......................................................... 3 3 
7. 2.  
Cli nical Gl o bal I m pressi o n of Se verit y of Ill ness -A gitati o n ( C GI S - A gitati o n) ......... 3 3 
7. 3.  
Cli nical Gl o bal I m pressi o n of C ha n ge- A gitati o n ( C GI C -A gitati o n)  ......................... 3 4 
7. 4.  
Ne ur o ps yc hiatric I n ve nt or y ( N PI) .............................................................................. 3 4  
7. 5.  
E ur o Q ol 5- Di me nsi o n 5 -Le vel ( E Q - 5 D-5 L)  .............................................................. 3 4 
7. 6.  
Res o urce Utilizati o n i n De me ntia ( R U D) Lite  ........................................................... 3 5 
8.  
A S S E S S M E N T O F S A F E T Y  ..................................................................................... 3 6 
8. 1.  
Safet y Para meters  ....................................................................................................... 3 6 
8. 1. 1.  
A d verse a n d Seri o us A d verse E ve nts  ......................................................................... 3 6 
8. 1. 1. 1.  
Defi niti o n of A d verse E ve nts ..................................................................................... 3 6  
8. 1. 1. 2.  
Seri o us A d verse E ve nt  ................................................................................................ 3 7 
8. 1. 1. 3.  
Re p orti n g A d verse E ve nts .......................................................................................... 3 8  
8. 1. 2.  
P h ysical a n d Ne ur ol o gical E xa mi nati o ns ................................................................... 3 8  
8. 1. 3.  
Vital Si g ns  .................................................................................................................. 3 9 
8. 1. 4.  
Wei g ht a n d Hei g ht  ...................................................................................................... 3 9 
8. 1. 5.  
Electr ocar di o gra m ( E C G)  ........................................................................................... 3 9 
8. 1. 6.  
Cli nical La b orat or y Assess me nts  ............................................................................... 4 0 
8. 1. 7.  
Pre g na nc y Tests  .......................................................................................................... 4 0 
8. 1. 8.  
Mi ni Me ntal State E xa mi nati o n ( M M S E)  .................................................................. 4 1 
8. 1. 9.  
E p w ort h Slee pi ness Scale ( E S S)  ................................................................................ 4 1 
8. 1. 1 0.  
S hee ha n S uici dalit y Trac ki n g Scale ( S- S T S)  ............................................................. 4 1 
8. 1. 1 1.  
Assess me nt of Ris k of Falls f or Eli gi bilit y  ................................................................. 4 2 
8. 1. 1 1. 1.  
Ti me d U p a n d G o ( T U G) Test .................................................................................... 4 2  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 1 
 
8. 1. 1 2.  
Hac hi ns ki Isc he mic Scale ( R ose n M o dificati o n)  ....................................................... 4 2 
9.  
S C H E D U L E O F E V A U A TI O N S A N D P R O C E D U R E S  .......................................... 4 3 
9. 1.  
Descri pti o n of St u d y Pr oce d ures ................................................................................ 4 3  
9. 1. 1.  
Scree ni n g Visit ( Da ys  - 2 8 t o - 1) ................................................................................. 4 3 
9. 1. 2.  
Baseli ne Visit ( Da y  1) ................................................................................................ 4 4 
9. 1. 3.  
Visit  2 ( Da y  8 ± 3- da y wi n d o w) ................................................................................. 4 5 
9. 1. 4.  
Visit  3 ( Da y  1 5 ± 3-da y wi n d o w)  ............................................................................... 4 7 
9. 1. 5.  
Visit  4 ( Da y  2 9 ± 3-da y wi n d o w)  ............................................................................... 4 8 
9. 1. 6.  
Visit  5 ( Da y  4 3 ± 3-da y wi n d o w)  ............................................................................... 4 9 
9. 1. 7.  
Visit  6 ( Da y  5 7 ± 3-da y wi n d o w)  ............................................................................... 5 0 
9. 1. 8.  
Visit  7 ( Da y  7 1 ± 3-da y wi n d o w)  ............................................................................... 5 1 
9. 1. 9.  
Visit  8 ( Da y  8 5 ± 3-da y wi n d o w) / Earl y Ter mi nati o n  .............................................. 5 2 
9. 1. 1 0.  
F oll o w- u p Visit ( 3 0  da ys p ost last d ose; + 7- da y wi n d o w) ........................................ 5 3 
9. 2.  
E n d of Trial ................................................................................................................. 5 3  
1 0.  
S T A TI S TI C S  .............................................................................................................. 5 4 
1 0. 1.  
Sa m ple Size Calc ulati o ns  ........................................................................................... 5 4 
1 0. 2.  
A nal ysis P o p ulati o ns .................................................................................................. 5 4  
1 0. 3.  
Ha n dli n g of Missi n g Data ........................................................................................... 5 4  
1 0. 4.  
Efficac y A nal ysis  ........................................................................................................ 5 4 
1 0. 4. 1.  
Pri mar y Efficac y E n d p oi nt A nal ysis .......................................................................... 5 4  
1 0. 4. 2.  
Ke y Sec o n dar y A nal ysis ............................................................................................. 5 5  
1 0. 4. 3.  
Ot her Efficac y E n d p oi nt A nal ysis .............................................................................. 5 5  
1 0. 4. 4.  
C o ntr ol of E x peri me nt- wise T y pe 1 Err or .................................................................. 5 6  
1 0. 4. 5.  
Ot her Efficac y E n d p oi nt A nal yses ............................................................................. 5 6  
1 0. 5.  
I nteri m A nal ysis .......................................................................................................... 5 6 
1 0. 6.  
A nal ysis of De m o gra p hic a n d Baseli ne C haracteristics  ............................................. 5 6 
1 0. 7.  
Safet y A nal ysis  ........................................................................................................... 5 6 
1 0. 7. 1.  
A d verse E ve nts ........................................................................................................... 5 6  
1 0. 7. 2.  
Cli nical La b orat or y Data  ............................................................................................ 5 7 
1 0. 7. 3.  
P h ysical a n d Ne ur ol o gical E xa mi nati o n a n d Vital Si g n Data .................................... 5 7  
1 0. 7. 4.  
Electr ocar di o gra m Data  .............................................................................................. 5 7 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 2 
 
1 0. 7. 5.  
Ot her Safet y Data  ....................................................................................................... 5 7 
1 0. 7. 6.  
Data a n d Safet y M o nit ori n g B oar d ............................................................................. 5 7  
1 0. 8.  
Ot her A nal yses  ............................................................................................................ 5 8 
1 0. 8. 1.  
P har mac o ki netic A nal ysis  .......................................................................................... 5 8 
1 0. 8. 2.  
P har mac o d y na mic A nal ysis ........................................................................................ 5 8  
1 0. 8. 3.  
P har mac o ki netic/ P har mac o d y na mic A nal ysis  ............................................................ 5 8 
1 0. 8. 4.  
P har mac o ge n o mic A nal ysis ........................................................................................ 5 8  
1 0. 8. 5.  
E x pl orat or y E n d p oi nt A nal ysis  ................................................................................... 5 8 
1 1.  
E T HI C S  ...................................................................................................................... 5 9 
1 1. 1.  
Et hical C o n d uct of t he St u d y ...................................................................................... 5 9  
1 1. 2.  
I nstit uti o nal Re vie w B oar d - Et hics Re vie w  .............................................................. 5 9 
1 1. 3.  
Writte n I nf or me d C o nse nt  .......................................................................................... 5 9 
1 2.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ......................................... 6 1 
1 2. 1.  
D oc u me ntati o n ............................................................................................................ 6 1  
1 2. 2.  
St u d y M o nit ori n g ........................................................................................................ 6 1  
1 2. 3.  
Direct Access t o S o urce Data/ D oc u me nts f or A u dits a n d I ns pecti o ns  ....................... 6 1 
1 3.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ....................................................... 6 3 
1 3. 1.  
Data Ma na ge me nt a n d C ollecti o n  .............................................................................. 6 3 
1 3. 2.  
S o urce Data  ................................................................................................................. 6 4 
1 3. 3.  
Rete nti o n of Rec or ds .................................................................................................. 6 4  
1 3. 4.  
C o nfi de ntialit y of St u d y D oc u me nts a n d Patie nt Rec or ds  ......................................... 6 4 
1 3. 5.  
Re p orts ........................................................................................................................ 6 5  
1 4.  
C RI T E RI A F O R S T U D Y T E R MI N A TI O N  .............................................................. 6 6 
1 5.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 6 7 
1 6.  
LI S T O F R E F E R E N C E S  ............................................................................................ 6 8 
1 7.  
S U M M A R Y O F C H A N G E S  ...................................................................................... 7 1 
1 7. 1.  
Pr ot oc ol A me n d me nt 2 ( Versi o n 3. 0) 1 5 Ma y  2 0 2 3 .................................................. 7 1 
1 7. 2.  
Pr ot oc ol A me n d me nt 1 ( Versi o n  2. 0) 2 4 Ja n uar y 2 0 2 2 ............................................. 7 1 
1 8.  
A P P E N DI C E S  ............................................................................................................ 7 3 
A P P E N DI X  1. P R O HI BI T E D C O N C O MI T A N T M E DI C A TI O N S  ......................................... 7 4 
 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 3 
 
LI S T O F T A B L E S  
Ta ble  1: 
Sc he d ule of Assess me nts a n d Visits  ............................................................................. 6 
Ta ble 2:  
A b bre viati o ns a n d S pecialist Ter ms  ........................................................................... 1 4 
Ta ble  3: 
Restricte d a n d Pr o hi bite d C o nc o mita nt Me dicati o ns ................................................. 2 8  
 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 4 
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre viati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 2: 
A b bre vi ati o ns a n d S peci alist T er ms 
A b bre vi ati o n  
Def i niti o n 
A D W G  
A gitati o n Defi niti o n W or ki n g Gr o u p  
A N C O V A  
a nal ysis of c o varia nce  
A V P -7 8 6 -1 8  
A V P -7 8 6 c o ntai ni n g d 6 -D M 1 8  m g/ Q 4. 9 m g  
A V P -7 8 6 -4 2. 6 3  
A V P -7 8 6 c o ntai ni n g d 6 -D M 4 2. 6 3  m g/ Q 4. 9  m g  
B P 
bl o o d press ure  
C F R 
U S C o de of Fe deral Re g ulati o ns  
C GI C- A gitati o n  
Cli nical Gl o bal I m pressi o n of C ha n ge  
C GI S 
Cli nical Gl o bal I m pressi o n of Se verit y  
C GI S- A gitati o n  
Cli nical Gl o bal I m pressi o n of Se verit y of Ill ness scale f or 
A gitati o n  
C M AI  
C o he n -Ma nsfiel d A gitati o n I n ve nt or y  
C M H 
C oc hra n -Ma ntel -Hae nszel  
C N S  
ce ntral ner v o us s yste m  
C Y P  
c yt oc hr o me P 4 5 0  
d 6 -D M  
d e u de xtr o met h or p ha n h y dr o br o mi de  ( or de u de xtr o met h or p ha n) 
D E M Q O L  
De me ntia Q u alit y of Life  
D M P  
data ma na ge me nt pla n  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
D S M - V-T R  
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, 5 t h 
E diti o n, Te xt Re visi o n  
E C G 
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure  
E P  
E ur o pea n P har mac o p oeia  
E Q -5 D -5 L  
E ur o Q ol 5 -Di me nsi o n 5 -Le vel  
E S S  
E p w ort h Slee pi ness Scale  
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  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 5 
 
A b bre vi ati o n  
Def i niti o n 
G M P  
G o o d Ma n ufact uri n g Practice  
H b A 1c  
gl yc os ylate d he m o gl o bi n  
H R  
heart rate  
I A P 
i nteri m a nal ysis pla n 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C/ E C 
I n de pe n de nt Et hics C o m mittee 
I T T 
i nte nt-t o-treat 
I R B 
I nstit uti o nal Re vie w B oar d 
I W R S 
i nteracti ve we b-res p o nse s yste m 
L O C F  
last o bser vati o n carrie d f or war d 
m A D C S -C GI C -A gitati o n  
M o difie d Alz hei mer’s Disease C o o perati ve St u d y -Cli nical 
Gl o bal I m pressi o n of C ha n ge scale f or A gitati o n  
M A OI  
m o n oa mi ne o xi dase i n hi bit or  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mI T T  
m o difie d i nte nt -t o-treat 
M M R M  
mi xe d -effect m o del f or re peate d meas ures 
M M S E  
Mi ni Me ntal State E xa mi n ati o n  
M N A R  
missi n g data bei n g missi n g n ot at ra n d o m  
NI A -A A  
Nati o nal I nstit ute o n A gi n g - Alz hei mer’s Ass ociati o n  
N PI  
Ne ur o ps yc hiatric I n ve nt or y  
N PI -A A  
Ne ur o ps yc hiatric I n ve nt or y  A gitati o n/ A g gressi o n  
N PI -N H  
Ne ur o ps yc hiatric I n ve nt or y  – Nursi n g H o me  
O C  
o bser ve d case  
O P D C  
Ots u ka P har mace utical De vel o p me nt & C o m mercializati o n, I nc.  
O T C  
o ver -t he-c o u nter 
P K  
p har mac o ki netic  
P V C  
pre mat ure ve ntric ular c o ntracti o ns  
Q 
q ui ni di ne s ulfate  ( or q ui ni di ne) 
Q O L  
q ualit y of life  
Q Tc F  
Q Tc b y Fri dericia’s f or m ula  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 6 
 
A b bre vi ati o n  
Def i niti o n 
R U D -Lite  
Res o urce Utilizati o n i n De me ntia -Lite  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical anal ysis p la n  
S O C  
s yste m or ga n class  
S N RI  
ser ot o ni n-n ore pi ne p hri ne re u pta ke i n hi bit or  
S S RI  
selecti ve ser ot o ni n re u pta ke i n hi bit ors 
S- S T S  
S hee ha n S uici dalit y Trac ki n g Scale  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T S H  
t h yr oi d-sti m ulati n g h or m o ne  
T U G  
Ti me d U p a n d G o  
U N  
u nstr uct ure d varia nce c o varia nce str uct ure  
U S  
U nite d States  
U S P  
U nite d States P har mac o p oeia  
 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 7 
 
1.  
I N T R O D U C TI O N 
Alz hei mer’s disease, t he m ost c o m m o n f or m of de me ntia, is a pr o gressi ve ne ur o de ge nerati ve 
disease t hat e ve nt uall y lea ds t o deat h. T here are a n esti mate d 5. 8 milli o n pe o ple i n t he U nite d 
States ( U S) wit h Alz hei mer’s de me ntia a n d t his n u m ber is e x pecte d t o reac h 1 4 milli o n b y t he 
year 2 0 5 0 1. Nati o nal esti mates of t he pre vale nce of all de me ntias fr o m p o p ulati o n-base d st u dies 
i ncl u di n g t he A gi n g, De m o gra p hics, a n d Me m or y St u d y ( A D A M S), a nati o nall y re prese ntati ve 
sa m ple of ol der a d ults, s h o w t hat 1 4 perce nt of pe o ple a ge 7 1 a n d ol der i n t he U S ha ve de me ntia  
2 ,3. 
A gitati o n is wi del y rec o g nize d b y cli nicia ns as a c o m m o n a n d i m p orta nt cli nical feat ure of 
Alz hei mer’s disease a n d ot her f or ms of de me ntia  4 ,5 ,6 ,7 ,8. A gitati o n , a g gressi o n , de pressi o n, 
hall uci nati o ns, a n d del usi o ns are esti mate d t o affect u p t o a p pr o xi matel y 9 0 % of patie nts wit h 
Alz hei mer’s disease  wit h a n i ncrease i n pre vale nce as t he disease pr o gresses  4 ,9. I n a meta 
a nal yses of data fr o m 5 5  st u dies, o verall pre vale nce of a gitati o n ra n ge d fr o m 5 % t o 8 8 % acr oss 
all st u dies, wit h 2 3 st u dies re p orti n g t he pre vale nce of at least o ne ne ur o ps yc hiatric s y n dr o me 
wit h a ra n ge of 4 0 % t o 1 0 0 %. A gitati o n i n patie nts wit h de me ntia is ass ociate d wit h i ncrease d 
f u ncti o nal disa bilit y, w orse q ualit y of life 1 0 ,1 1 ,1 2, earlier i nstit uti o nalizati o n  1 3, i ncrease d 
care gi ver b ur de n  1 4 ,5 ,1 5 ,1 6 ,1 7 ,1 8, i ncrease d healt hcare c osts 1 9 ,2 0 ,1 3 ,2 1, s h orter ti me t o se vere de me ntia 
2 2 ,2 3, a n d accelerate d m ortalit y  2 3 ,2 4. C urre ntl y, t here is n o a p pr o ve d treat me nt i n t he U S t o 
ma na ge a gitati o n i n patie nts wit h Alz hei mer’s disease  2 5. P har mac ol o gic treat me nts f or patie nts 
wit h a gitati o n i n Alz hei mer’s disease i ncl u de off-la bel use of at y pical a nti ps yc h otics, selecti ve 
ser ot o ni n re u pta ke i n hi bit ors, be nz o diaze pi nes, a n d a ntic o n v ulsa nts 2 6 ,2 7 ,2 8; h o we ver, t hese 
treat me nts pr o vi de o nl y m o dest efficac y t hat is offset b y relati vel y p o or a d here nce, safet y, a n d 
t olera bilit y 2 9 ,3 0. It is wi del y rec o g nize d t hat a safe a n d effecti ve treat me nt f or patie nts wit h 
a gitati o n i n Alz hei mer’s disease  re prese nts a si g nifica nt u n met nee d 3 1. S uc h a treat me nt c o ul d 
pr of o u n dl y i m pact patie nt care, p ote ntiall y re d uce care gi ver b ur de n, a n d i m pr o ve o verall disease 
pr o g n osis. 
1. 1.  
R ati o n al e f or I n vesti g ati n g A V P-7 8 6 f or Tre at me nt of A git ati o n i n 
De me nti a  
A V P - 7 8 6 is a c o m bi nati o n pr o d uct of de u de xtr o met h or p ha n h y dr o br o mi de ( d 6-D M), a ce ntral  
ner v o us s yste m ( C N S)- acti ve a ge nt, a n d q ui ni di ne s ulfate ( Q), use d as a n i n hi bit or of d 6- D M 
meta b olis m via t he c yt oc hr o me P 4 5 0 ( C Y P) li ver is oe nz y me 2 D 6 ( C Y P 2 D 6). A V P - 7 8 6 is bei n g 
de vel o pe d b y Ots u ka P har mace utical De vel o p me nt & C o m mercializati o n, I nc ( O P D C, or 
S p o ns or ) f or t he treat me nt of ne ur o ps yc hiatric c o n diti o ns. 
T he de m o nstrate d rece pt or p har mac ol o g y of d 6- D M s u p p orts a p ote ntial cli nical be nefit f or 
a gitati o n i n patie nts wit h de me ntia of t he Alz hei mer’s t y pe. d 6 -D M bi n ds t o rece pt ors 
res p o nsi ble f or m o d ulati o n of gl uta mate a n d m o n oa mi nes, a n d als o bi n ds t o t he si g ma- 1 
rece pt or; t hese i nteracti o ns ma y be ke y t o C N S t hera pe utics. P har mac ol o g y st u dies c o n d ucte d b y 
t he S p o ns or wit h d 6- D M ha ve de m o nstrate d t hat de uterati o n d oes n ot alter t he basic 
p har mac ol o g y of D M. P har mac o ki netic ( P K) a n d dr u g meta b olis m st u dies i n d icate t hat d 6-D M 
is meta b olize d b y t he sa me meta b olic pat h wa ys as D M, b ut t hat de uterati o n res ults i n a 
decrease d rate of meta b olis m b y C Y P 2 D 6.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 8 
 
St u dies c o n d ucte d b y t he S p o ns or ha ve s h o w n t hat d 6- de uteri u m m o dificati o n of 
de xtr o met h or p ha n re d uces t he rate of C Y P 2 D 6 meta b olis m s uc h t hat a l o w d ose of q ui ni di ne is 
s ufficie nt t o ac hie ve p har mac ol o gicall y rele va nt plas ma c o nce ntrati o ns of d 6 - D M. T he l o w 
le vels of Q i n A V P -7 8 6 ma y mi ni mize t he ris k of i nteracti o ns wit h ot her C Y P 2 D 6 s u bstrates, 
li mit Q le vels e ve n i n t he prese nce of C Y P 3 A 4 i n hi bit ors a n d mi ni mize t he ris k of effects o n 
car diac  re p olarizati o n a n d Q Tc i nter val. 
Base d o n t he a b o ve, f urt her cli nical i n vesti gati o n is warra nte d t o e x pl ore t he p ote ntial efficac y  
a n d safet y of A V P- 7 8 6. 
T he c urre nt st u d y ( St u d y 2 0-A V P - 7 8 6- 3 0 6) is desi g ne d t o e val uate t he efficac y, safet y, a n d 
t olera bilit y of A V P-7 8 6 f or t he treat me nt of a gitati o n i n patie nts wit h de me ntia of t he  
Alz hei mer’s t y pe.  
1. 2.  
R ati o n al e f or t he St u d y Desi g n 
T he ra n d o mize d, place b o-c o ntr olle d, d o u ble- bli n d desi g n re d uces s o urces of bias t hat are  
i n here nt i n less well-c o ntr olle d desi g ns. T he safet y assess me nts use d are sta n dar d i n cli nical  
researc h a n d are ge nerall y rec o g nize d as relia ble, acc urate, a n d rele va nt. T he rati n g scales use d 
t o assess efficac y are well-esta blis he d i nstr u me nts t hat are wi del y use d i n cli nical st u dies of 
a gitati o n i n A lz hei mer’s disease. 
1. 3.  
R ati o n ale f or A V P -7 8 6 D os e 
T he pla n ne d d oses of A V P - 7 8 6 f or t his st u d y are d 6-D M 1 8 m g/ Q  4. 9 m g, hereafter referre d t o 
as A V P- 7 8 6- 1 8, a n d d 6- D M 4 2. 6 3 m g/ Q  4. 9 m g, hereafter referre d t o as A V P - 7 8 6- 4 2. 6 3. 
I n t he c o m plete d St u d y 1 5-A V P - 7 8 6- 3 0 1, A V P- 7 8 6-1 8 de m o nstrate d c o nsiste nt be nefits  
( p ≤ 0. 0 5) o n se veral meas ure s of a gitati o n  a n d ne ur o ps yc hiatric s y m pt o ms, i ncl u di n g t he 
pri mar y efficac y meas ure, t he C M AI T otal sc ore, a n d t he ke y sec o n dar y efficac y meas ure, t he 
m A D C S -C GI C - A gitati o n sc ore. A V P - 7 8 6- 1 8 was safe a n d ge nerall y well  t olerate d. Base d o n 
t he res ults of St u d y 1 5-A V P - 7 8 6- 3 0 1, the o verall be nefit -ris k pr ofile f or A V P- 7 8 6- 1 8 a p peare d 
fa v ora ble. 
I n St u d y 1 5-A V P - 7 8 6- 3 0 1, A V P - 7 8 6- 1 8 de m o nstrate d a str o n g si g nal f or efficac y. Si milarl y, i n 
St u d y 1 5- A V P - 7 8 6- 3 0 2, t here was a tre n d t o war ds efficac y i n s u p p ort of t he A V P - 7 8 6- 4 2. 6 3 
d ose. I n or der t o ass ure a f ull assess me nt of d ose res p o nse , b ot h d oses of A V P- 7 8 6 will be 
e val uate d i n t his st u d y. 
1. 4.  
R ati o n ale f or t he D ur ati o n of A V P -7 8 6 D osi n g  
A dr u g bei n g de vel o pe d f or treat me nt of a c hr o nic c o n diti o n nee ds t o s h o w s o me e vi de nce of 
persiste nce of ac ute effects. A 1 2 - wee k treat me nt d urati o n is ge nerall y c o nsi dere d b y e x perts a n d  
re g ulat ors as a reas o na ble ti me fra me t o assess efficac y a n d safet y of a c o m p o u n d f or c hr o nic 
use.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
1 9 
 
2.  
T RI A L O B J E C TI V E S A N D P U R P O S E  
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o e val uate t he efficac y, safet y, a n d t olera bilit y of A V P - 7 8 6 c o m pare d 
t o place b o f or t he treat me nt of a gitati o n i n patie nts wit h de me ntia of t he Alz hei mer’s t y pe. 
2. 2.  
Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves are t o: 
•  E val uate t he effects of A V P - 7 8 6 c o m pare d t o place b o o n gl o bal assess me nts of 
se verit y a n d i m pr o ve me nt of a gitati o n 
•  E val uate t he effects of A V P - 7 8 6 c o m pare d t o place b o o n ne ur o ps yc hiatric s y m pt o ms 
•  E val uate t he effects of A V P - 7 8 6 c o m pare d t o place b o o n meas ures of q ualit y of life 
a n d res o urce utilizati o n 
 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 0 
 
3.  
I N V E S TI G A TI O N A L PL A N  
3. 1.  
O ver all St u d y Desi g n  
T his is a P hase  3, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d st u d y wit h a 
1 2- wee k treat me nt d urati o n.  T he st u d y c o nsists of a 4- wee k Scree ni n g peri o d, a 1 2- wee k 
d o u ble- bli n d treat me nt peri o d, a n d a 3 0 - da y F oll o w- u p peri o d. A p pr o xi matel y 7 5 0 patie nts wit h 
a gitati o n of t he Alz hei mer’s t y pe will be e nr olle d at a p pr o xi matel y 1 1 0 ce nters i ncl u di n g t he 
U nite d States [ U S] a n d E ur o pe. 
Scree ni n g Peri o d ( D ay  - 2 8 t o D ay -1)  
Patie nt eli gi bilit y will be deter mi ne d d uri n g t he Scree ni n g visit , w hic h will occ ur wit hi n 4 wee ks  
of t he Baseli ne visit . A pr ot oc ol eli gi bilit y f or m will be c o m plete d f or eac h patie nt a n d re vie we d 
b y a Me dical M o nit or f or a p pr o val pri or t o partici pati o n i n t he st u d y.  
D o u ble- bli n d , Tre at me nt Peri o d ( 1 2 Wee ks)  
D uri n g t he d o u ble- bli n d treat me nt peri o d, all eli gi ble patie nts will be ra n d o ml y assi g ne d t o 
recei ve eit her A V P- 7 8 6 or matc hi n g place b o . Ra n d o mizati o n will be stratifie d b y site a n d 
baseli ne  c o nc o mita nt a nti ps yc h otic use ( yes/ n o). St u d y dr u g will be a d mi nistere d t wice dail y 
( BI D; m orni n g a n d e ve ni n g) starti n g fr o m t he Baseli ne visit (Da y  1) t hr o u g h Visit 8 ( Da y  8 5). 
F oll o w- u p Peri o d  
All e nr olle d patie nts, w het her t he y c o m plete t he st u d y or ter mi nate fr o m t he st u d y earl y f or a n y 
reas o n, will ha ve a F oll o w- u p visit 3 0 da ys after t he last d ose of st u d y dr u g  f or select efficac y 
a n d safet y assess me nts.  
Assess me nts a n d Visits:  
Patie nts will atte n d cli nic visits at Scree ni n g  ( Da y - 2 8 t o -1) , Baseli ne  (Da y  1), Visit  2 (Da y  8), 
Visit  3 (Da y  1 5), Visit  4 ( Da y 2 9), Visit  5 (Da y  4 3), Visit  6 (Da y  5 7), Visit  7 (Da y  7 1), Visit  8 
(Da y  8 5; or Earl y Ter mi nati o n [ E T] Visit) , a n d 3 0  da ys after t he last d ose of st u d y dr u g  
( F oll o w- u p visit). 
St u d y assess me nts a n d pr oce d ures will be perf or me d at eac h visit as o utli ne d i n t he Sc he d ule of 
Assess me nts a n d Visits (Ta ble  1). T he pri mar y efficac y meas ure i s t he C o he n -Ma nsfiel d 
A gitati o n I n ve nt or y ( C M AI ). Sec o n dar y efficac y meas ures i ncl u de Cli nical Gl o bal I m pressi o n of 
Se verit y of Ill ness f or A gitati o n ( C GI S -A gitati o n), Cli nical Gl o bal I m pressi o n of C ha n ge f or 
A gitati o n ( C GI C- A gitati o n), Ne ur o ps yc hiatric I n ve nt or y A gitati o n/ A g gressi o n ( N PI-A A), N PI 
t otal, E ur o Q ol 5- Di me nsi o n 5-Le vel ( E Q - 5 D- 5 L), a n d Res o urce Utilizati o n i n De me ntia-Lite 
( R U D-Lite).  
P har mac o ki netic ( P K) meas ure me nts of plas ma  c o nce ntrati o ns of d 6-D M,  its meta b olites d 3-D X 
a n d d 3- 3- M M, a n d Q will be meas ure d fr o m bl o o d sa m ples c ollecte d at Visit 2 ( Da y 8), Visit 5 
(Da y  4 3), a n d Visit 7 ( Da y 7 1). P K meas ure me nts of uri ne c o nce ntrati o ns of d 6 -D M a n d its 
meta b olite d 3 -D X will be meas ure d fr o m a uri ne sa m ple  c ollecte d at Visit  2 ( Da y 8). 
T he safet y a n d t olera bilit y of A V P- 7 8 6 will be assesse d b y re p orte d A Es, p h ysical a n d 
ne ur ol o gical e xa mi nati o n,  vital si g ns, cli nical la b orat or y meas ures, resti n g 1 2- lea d 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 1 
 
electr ocar di o gra ms ( E C G), a n d t he f oll o wi n g  safet y scales: Mi ni- Me ntal State E xa mi nati o n 
(M M S E ), E p w ort h Slee pi ness Scale (E S S ), a n d S h ee ha n S uici dalit y Trac ki n g Scale ( S- S T S ). 
3. 2.  
St u d y Assess me nts a n d Pr oce d ures  
A ta b ular s u m mar y of t he sc he d ule of s t u d y assess me nts a n d pr oce d ures b y visit is pr o vi de d i n 
t he Sc he d ule of Assess me nts  a n d Visits ( S yn o psis Ta ble  1). A m ore detaile d descri pti o n of t he 
assess me nts at eac h visit is pr o vi de d i n Secti o n  9 , Sc he d ule of E val uati o ns a n d Pr oce d ures. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 2 
 
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
Patie nts e nr olle d i n t his st u d y m ust ha ve a dia g n osis of pr o ba ble A lz hei mer’s disease a n d m ust 
prese nt wit h cli nicall y si g nifica nt, m o derate-t o-se vere a gitati o n sec o n dar y t o Alz hei mer’s 
disease . T he dia g n osis of pr o ba ble Alz hei mer’s disease will be base d o n t he ‘ 2 0 1 1 Dia g n ostic 
G ui deli nes f or Alz hei mer’s  Disease’ iss ue d b y t he Nati o nal I nstit ute o n A gi n g ( NI A) -
Alz hei mer’s Ass ociati o n ( A A)  w or k gr o u ps 3 2. Neit her Alz hei mer’s disease  n or a gitati o n s h o ul d 
be e x plai na ble b y deliri u m, s u bsta nce use a n d/ or maj or ps yc hiatric dis or ders.  
T he pr o visi o nal c o nse ns us defi niti o n of a gitati o n i n patie nts wit h c o g niti ve dis or ders de vel o pe d 
b y t he A gitati o n Defi niti o n W or k Gr o u p ( A D W G) fr o m t he I nter nati o nal Ps yc h o geriatric 
Ass ociati o n (I P A )3 3  will be use d t o select st u d y patie nts. T his pr o p ose d defi niti o n is li mite d t o 
patie nts wit h c o g niti ve i m pair me nt a n d re q uires: (a) e vi de nce of e m oti o nal distress; ( b) 1 of 
3 o bser va ble t y pes of be ha vi ors : e xcessi ve m ot or acti vit y, ver bal a g gressi o n, or p h ysical 
a g gressi o n; (c) t hat t he be ha vi or ca uses e xcess disa bilit y; a n d ( d) t hat t he be ha vi ors ca n n ot be  
s olel y attri b uta ble t o a s u b o pti mal care e n vir o n me nt or ot her dis or der s uc h as a ps yc hiatric 
ill ness, a me dical ill ness, or effects of a s u bsta nce. 
Eli gi ble patie nts m ust ha ve cli nicall y si g nifica nt, m o derate -t o-se vere a gitati o n f or at least 
2 wee ks  pri or t o Scree ni n g t hat i nterferes wit h dail y r o uti ne per t he I n vesti gat or’s j u d g me nt, a n d 
w h o re q uire p har mac ot hera p y f or t he treat me nt of a gitati o n per t he I n vesti gat or’s j u d g me nt after 
a n e val uati o n of re versi ble fact ors a n d a c o urse of n o n p har mac ol o gical i nter ve nti o ns. 
A n N PI -A A  sc ore of ≥ 4 a n d M M S E sc ore of 8 t o 2 4 (i ncl usi ve) at Scree ni n g a n d Baseli ne are 
re q uire d f or st u d y partici pati o n. Patie nts m ust meet a n a d diti o nal pre deter mi ne d bli n de d 
eli gi bilit y criteri o n, w hic h will re mai n bli n de d t o t he cli nical st u d y site I n vesti ga t ors a n d staff. 
Eli gi ble patie nts are t o ha ve ot her wise acce pta ble a n d sta ble ge neral healt h as re q uire d b y t he  
st u d y pr ot oc ol a n d d oc u me nte d b y me dical hist or y, p h ysical a n d ne ur ol o gical e xa mi nati o n, E C G, 
a n d cli nical la b orat or y e xa mi nati o ns.  
Eli gi ble patie nts m ust ha ve a care gi ver w h o is a ble a n d willi n g t o c o m pl y wit h all re q uire d st u d y 
pr oce d ures, e ns uri n g t hat t he patie nt atte n ds all st u d y visits a n d ta kes t he st u d y dr u g as 
i nstr ucte d, i ncl u di n g a d here nce t o n ot a d mi nisteri n g a n y pr o hi bite d me dicati o ns d uri n g t he 
c o urse of t he st u d y. Care gi vers will als o be i nstr ucte d t o rec or d t he dail y n u m ber of ca ps ules 
ta ke n a n d t he ti me of a d mi nistrati o n i n t he patie nt Diar y Car d. I n a d diti o n, care gi vers are 
res p o nsi ble f or re p orti n g a n y c ha n ges i n patie nt’s stat us, i ncl u di n g a d verse e ve nts a n d sta n dar d 
of care setti n g (e g, bec o mi n g a resi de nt i n a n assiste d li vi n g facilit y), as well as pr o vi di n g t heir 
i m pressi o n a n d assess me nt re gar di n g t he i n vesti gati o nal treat me nt  t o t he st u d y tea m at t he 
I n vesti gat or’s site. A C M AI care gi ver d iar y will be pr o vi de d t o be use d b y t he care gi ver t o 
s u p p ort re p orti n g of be ha vi ors d uri n g t he C M AI i nter vie w pr ocess.  I n or der t o q ualif y as a 
relia ble i nf or ma nt (ie, care gi ver) ca pa ble of assessi n g c ha n ges i n t he patie nt’s c o n diti o n d uri n g 
t his st u d y, t he i n di vi d ual m ust s pe n d a mi ni m u m of 2  h o urs wit h t he patie nt per da y f or 4 da ys 
per wee k . I n a d diti o n, t his i n di vi d ual s h o ul d re mai n as t he patie nt’s care gi ver t hr o u g h o ut t he 
st u d y. 
T he c o m plete list of i ncl usi o n a n d e xcl usi o n criteria f or t his st u d y are pr o vi de d i n t he f oll o wi n g 
secti o ns. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 3 
 
4. 1.  
P atie nt  I ncl usi o n Criteri a 
1.  Males a n d fe males 5 0 t o 9 0 years of a ge  (i ncl usi ve) at t he ti me of i nf or me d c o nse nt. 
2.  Dia g n osis of pr o ba ble Alz hei mer’s disease acc or di n g t o t he 2 0 1 1 NI A- A A w or ki n g 
gr o u ps criteria. Eit her o ut patie nts or resi de nts of a n assiste d li vi n g facilit y, a s kille d 
n ursi n g h o me, a de me ntia u nit, or a n y ot her t y pe of facilit y pr o vi di n g l o n g- ter m care. 
3.  M M S E sc ore bet wee n 8 a n d 2 4 (i ncl usi ve) at Scree ni n g a n d Baseli ne . 
4.  P atie nt has cli nicall y si g nifica nt, m o derate -t o-se vere a gitati o n f or at least 2 wee ks pri or t o 
S cree ni n g t hat i nterferes wit h dail y r o uti ne  per t he I n vesti gat or’s j u d g me nt. 
5.  Patie nts w h o re q uire p har mac ot hera p y f or t he treat me nt of a gitati o n per t he I n vesti gat or’s 
j u d g me nt, after: 
•  A n e val uati o n of re versi ble fact ors (e g, pai n, i nfecti o n, or p ol y p har mac y), a n d 
•  A c o urse of n o n p har mac ol o gical i nter ve nti o ns (e g, re directi n g be ha vi or, gr o u p 
acti vities, m usic t hera p y).  
6.  D ia g n osis of a gitati o n m ust meet t he I nter nati o nal Ps yc h o geriatric Ass ociati o n (I P A) 
pr o visi o nal defi niti o n of a gitati o n.  
7.  N PI - A A t otal sc ore (fre q ue nc y × se verit y) m ust be ≥ 4 at Scree ni n g a n d Baseli ne . 
8.  P atie nt m ust meet a n a d diti o nal pre deter mi ne d bli n de d eli gi bilit y criteri o n .  
9.  Patie nt has sta ble car diac, p ul m o nar y, he patic, a n d re nal f u ncti o n per t he I n vesti gat or’s 
j u d g me nt.  
1 0.  N o cli nicall y si g nifica nt fi n di n gs o n t he Scree ni n g E C Gs base d o n ce ntral re vie w a n d o n 
t he Baseli ne  pre d ose E C G base d o n t he mac hi ne rea d a n d I n vesti gat or’s e val uati o n. 
1 1.  W o me n  w h o are of c hil d beari n g p ote ntial a n d are se x uall y acti ve m ust use a n effecti ve 
met h o d of birt h c o ntr ol f or at least 1  m o nt h pri or t o t he Baseli ne , d uri n g partici pati o n i n 
t he st u d y, a n d f or at least 3 0 da ys after t he last d ose of st u d y dr u g . T he f oll o wi n g 
re q uire me nts m ust be met:  
•  W o me n  w h o are of c hil d beari n g p ote ntial m ust use 2 of t he f oll o wi n g preca uti o ns i n 
or der t o mi ni mize t he ris k of fail ure of 1 met h o d of birt h c o ntr ol: vasect o m y, t u bal 
li gati o n, va gi nal dia p hra g m, i ntra uteri ne de vice, birt h c o ntr ol pills, birt h c o ntr ol de p ot 
i njecti o n, birt h c o ntr ol i m pla nt, or c o n d o m wit h s per mici de or s p o n ge wit h 
s per mici de. Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost- o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he d urati o n of e x p os ure t o 
st u d y dr u g, or wit h drawal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
•  W o me n  w h o are sterile (ie, ha d a n o o p h orect o m y a n d/ or h ysterect o m y), 
p ost me n o pa usal ( defi ne d as 1 2 c o nsec uti ve m o nt hs wit h n o me nses wit h o ut a n 
alter nati ve me dical ca use) , or practice tr ue a bsti ne nce ( w he n t his met h o d is i n li ne 
wit h t he preferre d a n d us ual lifest yle of t he patie nt) are e xe m pt fr o m t his re q uire me nt.  

C O N FI D E N TI A L  
 
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 4 
 
•  W o me n  w h o are lactati n g, pre g na nt, or pla n t o bec o me pre g na nt are n ot eli gi ble f or 
partici pati o n i n t he st u d y.  
1 2.  F or restricte d a n d pr o hi bite d c o nc o mita nt me dicati o ns, patie nts willi n g a n d a ble t o meet 
all pr ot oc ol re q uire me nts f or d urati o n of sta bilit y or was h o ut pri or t o st u d y e ntr y a n d 
d uri n g t he st u d y (see Ta ble  3 Restricte d a n d Pr o hi bite d C o nc o mita nt Me dicati o ns a n d 
A p pe n di x 1  Pr o hi bite d C o nc o mita nt Me dicati o ns).  
1 3.  Care gi ver m ust be willi n g a n d a ble t o c o m pl y wit h all st u d y pr oce d ures, i ncl u di n g 
a d here nce t o a d mi nisteri n g st u d y dr u g  a n d n ot a d mi nisteri n g a n y pr o hi bite d me dicati o ns 
d uri n g t he st u d y. T he care gi ver m ust s pe n d a mi ni m u m of 2 h o urs wit h t he patie nt per 
da y f or at least 4  da ys per wee k t o q ualif y as care gi ver.  
1 4.  Patie nt/care gi ver m ust be willi n g t o si g n a n d recei ve a c o p y of patie nt/care gi ver i nf or me d 
c o nse nt f or m (I C F) after t he nat ure a n d ris ks of st u d y partici pati o n ha ve bee n f ull y 
e x plai ne d. Patie nts w h o are n ot ca pa ble of si g ni n g t he I C F b ut are a ble t o pr o vi de asse nt, 
or t he patie nt’s a ut h orize d re prese ntati ve a grees t o partici pati o n (f or patie nts u na ble t o 
pr o vi de asse nt) are all o we d. 
4. 2.  
P atie nt  E xcl usi o n Criteri a  
1.  Care gi ver is u n willi n g or u na ble, i n t he o pi ni o n of t he I n vesti gat or, t o c o m pl y wit h st u d y 
i nstr ucti o ns. 
2.  Patie nt has de me ntia pre d o mi na ntl y of n o n- Alz hei mer’s t y pe (e g , vasc ular de me ntia, 
fr o nt ote m p oral de me ntia, Par ki ns o n’s disease, s u bsta nce-i n d uce d de me ntia). 
3.  Patie nts wit h s y m pt o ms of a gitati o n t hat are n ot sec o n dar y t o Alz hei mer’s de me ntia (e g, 
sec o n dar y t o pai n, ot her ps yc hiatric dis or der, or deliri u m). 
4.  Patie nt s w h o ha ve bee n dia g n ose d wit h a n A xis 1 dis or der (Dia g n ostic a n d Statistical 
Ma n ual of Me ntal Dis or ders, 5t h E diti o n, Te xt Re visi o n [ D S M - 5] criteria) i ncl u di n g, b ut 
n ot li mite d t o:  
•  Sc hiz o p hre nia, sc hiz oaffecti ve dis or der, or ot her ps yc h otic dis or ders n ot relate d t o 
de me ntia  
•  Bi p olar I or II dis or der, bi p olar dis or der n ot ot her wise s pecifie d 
•  C urre nt Maj or De pressi ve E pis o de: Pat ie nts wit h a hist or y of maj or de pressi ve 
dis or der, t hat is c urre ntl y n ot s y m pt o matic, are eli gi ble. Patie nts c urre ntl y o n a sta ble 
d ose(s) of all o we d a nti de pressa nt me dicati o n(s) f or at least 3 m o nt hs pri or t o t he 
Scree ni n g visit are eli gi ble.  
5.  Patie nts wit h m yast he nia gra vis (c o ntrai n dicati o n f or q ui ni di ne).  
6.  Patie nts wit h a n y pers o nal hist or y of c o m plete heart bl oc k, Q Tc pr ol o n gati o n, or 
t ors a des de p oi ntes . 
a. Scree ni n g a n d Baseli ne  pre d ose Q T i nter val c orrecte d f or heart rate usi n g t he 
Fri dericia’s f or m ula ( Q Tc F) of >  4 5 0 msec f or males a n d >  4 7 0 msec f or fe males 
u nless d ue t o ve ntric ular paci n g ( See Secti o n  8. 1. 5 ). 

C O N FI D E N TI A L  
 
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 5 
 
Scree ni n g E C Gs will be base d o n ce ntral re vie w. Baseli ne  pre d ose E C G will be base d 
o n t he mac hi ne rea d a n d I n vesti gat or’s e val uati o n; if t he Q Tc F  res ult fr o m t he 
mac hi ne rea d is e xcl usi o nar y, d o n ot a d mi nister st u d y dr u g a n d please c o ntact a 
Me dical M o nit or.  
b.  Prese nce of pre mat ure ve ntric ular c o ntracti o ns ( P V Cs) as e val uate d b y a ce ntral 
rea der a n d dee me d cli nicall y si g nifica nt b y t he In vesti gat or . 
7.  Patie nts wit h a n y fa mil y hist or y of c o n ge nital Q T i nter val pr ol o n gati o n s y n dr o me. 
8.  Patie nts wit h k n o w n h y perse nsiti vit y t o D M, Q, o piate dr u gs (c o dei ne, etc), or a n y ot her 
i n gre die nt of t he st u d y dr u g . 
9.  Patie nts w h o ha ve e ver recei ve d D M  c o-a d mi nistere d wit h Q or d 6 -D M c o -a d mi nistere d 
wit h Q.  
1 0.  Patie nts w h o w o ul d be li kel y t o re q uire a pr o hi bite d c o nc o mita nt me dicati o n d uri n g t he 
st u d y (see Ta ble  3, Restricte d a n d Pr o hi bite d C o nc o mita nt Me dicati o ns a n d A p pe n di x 1  
Pr o hi bite d C o nc o mita nt Me dicati o ns).  
1 1.  Patie nts wit h c o -e xiste nt cli nicall y si g nifica nt or u nsta ble s yste mic diseases t hat c o ul d 
c o nf o u n d t he i nter pretati o n of t he safet y res ults of t he st u d y (e g, mali g na nc y [e xce pt s ki n 
basal -cell carci n o ma], p o orl y c o ntr olle d dia betes, p o orl y c o ntr olle d h y perte nsi o n, 
u nsta ble p ul m o nar y, re nal or he patic diseas e, u nsta ble isc he mic car diac disease, dilate d 
car di o m y o pat h y, or u nsta ble val v ular heart disease). Certai n ot her n o n metastatic ca ncer 
ma y be all o we d. Eac h case is t o be e val uate d i n di vi d uall y wit h a M e dical M o nit or. 
1 2.  Patie nts w h o are c urre ntl y partici pati n g i n or w h o ha ve partici pate d i n ot her 
i nter ve nti o nal ( dr u g or de vice) cli nical st u d y, or f o u n d t o be a “ Virt uall y Certai n” matc h 
i n Cli nical Trial S u bject Data base ( C T S data base) wit h a patie nt w h o has partici pate d i n 
a n ot her i nter ve nti o nal dr u g or de vice st u d y wit hi n 3 0 da ys of Baseli ne . 
1 3.  Patie nts wit h hist or y of p ost ural s y nc o pe  or a n y hist or y of u ne x plai ne d s y nc o pe 
(e val uate d o n a case- b y-case basis) wit hi n 1 2  m o nt hs of Baseli ne . 
1 4.  Patie nts wit h a hist or y of s u bsta nce a n d/ or alc o h ol a b use wit hi n 1 2 m o nt hs of Baseli ne . 
1 5.  Patie nts deter mi ne d t o ha ve a hi g h i m mi ne nt ris k of falls d uri n g t he st u d y base d o n a 
cli nical e val uati o n b y t he I n vesti gat or. 
1 6.  Patie nts wit h e vi de nce of seri o us ris k of s uici de at Scree ni n g a n d Baseli ne  base d o n t he 
S hee ha n S uici dalit y Trac ki n g Scale ( S- S T S), ie, a sc ore of 3 or 4 o n a n y o ne q uesti o n 2 
t hr o u g h 6 or 1 1, or a sc ore of 2 or hi g her o n a n y o ne q uesti o n 1a, 7 t hr o u g h 1 0, or 1 2, or 
w h o i n t he o pi ni o n of t he I n vesti gat or prese nt a seri o us ris k of s uici de.  
1 7.  Patie nts w h o, i n t he o pi ni o n of t he I n vesti gat or, M e dical M o nit or , or S p o ns or, s h o ul d n ot 
partici pate i n t he st u d y.  
4. 3.  
P atie nt  Wit h dr a w al Criteri a  
Patie nts a n d care gi vers will be a d vise d ver ball y a n d i n t he writte n I C F t hat t he y ha ve t he ri g ht t o 
wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice or l oss of be nefits t o w hic h t he y are 

C O N FI D E N TI A L  
 
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Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
2 6 
 
ot her wise e ntitle d. T he In vesti gat or or S p o ns or ma y disc o nti n ue a patie nt fr o m t he st u d y i n t he 
e ve nt of a n i nterc urre nt ill ness, a d verse e ve nt, ot her reas o ns c o ncer ni n g t he healt h or well - bei n g 
of t he patie nt, or i n t he case of lac k of c o o perati o n, n o nc o m plia nce, pr ot oc ol vi olati o n, or ot her 
a d mi nistrati ve reas o ns. If a patie nt d oes n ot ret ur n f or a sc he d ule d visit, e ver y eff ort s h o ul d be 
ma de t o c o ntact t he patie nt. Re gar dless of t he circ u msta nce, e ver y eff ort s h o ul d be ma de t o 
d oc u me nt patie nt o utc o me, if p ossi ble. T he I n vesti gat or s h o ul d i n q uire a b o ut t he reas o n f or 
wit h dra wal, re q uest t he care gi ver ret ur n all u n use d st u d y dr u g, a n d f oll o w- u p wit h t he patie nt 
re gar di n g a n y u nres ol ve d a d verse e ve nts. 
I n a d diti o n, patie nts w h o prese nt at a n y ti me after t he Baseli ne v isit ( Da y 1) wit h a persiste nt 
Q Tc i nter val ( Q Tc F) >  5 0 0 msec ( u nless d ue  t o ve ntric ular paci n g) or a persiste nt Q Tc F i nter val 
c ha n ge fr o m t he pre d ose Baseli ne  E C G of  > 6 0 msec, t hat is c o nfir me d b y t he ce ntral E C G 
rea der, will be wit h dra w n fr o m t he st u d y after c o ns ultati o n wit h a Me dical M o nit or . T he Q Tc F 
val ues will be assesse d f or cli nical si g nifica nce a n d rec or de d.  
Patie nts w h o ter mi nate earl y  fr o m t he st u d y will ha ve a n E T  visit t o c o m plete t he 
Visit  8 (Da y  8 5/ E T) assess me nts a n d a F oll o w-u p visit  3 0 da ys after t he last d ose of st u d y dr u g 
f or select efficac y a n d  safet y assess me nts. If a patie nt ter mi nates earl y fr o m t he st u d y, t he 
I n vesti gat or a n d site pers o n nel s h o ul d ma ke e ver y eff ort t o ha ve t he patie nt a n d care gi ver ret ur n 
t o t he cli nic f or t he E T  visit  a n d t he F oll o w- u p visit. 
If t he patie nt wit h dra ws fr o m t he st u d y, a n d c o nse nt is wit h dra w n b y t he care gi ver a n d/ or 
patie nt’s re prese ntati ve f or discl os ure of f ut ure i nf or mati o n, n o f urt her e val uati o ns s h o ul d be 
perf or me d, a n d n o a d diti o nal data s h o ul d be c ollecte d. T he S p o ns or ma y retai n a n d c o nti n ue t o 
use a n y data c ollecte d bef ore s uc h wit h dra wal of c o nse nt. Patie nts w h o wit h dra w fr o m t he st u d y 
will n ot be re place d.  
4. 4.  
C T S d at a b ase a n d S u bject D at a b ase A ut h oriz ati o n  
Cli nical trial re gistries, s uc h as C T S data base, see k t o re d uce d u plicate e nr oll me nt b y i de ntif yi n g 
d u plicates bef ore ra n d o mizati o n. At t he ti me of pr o vi di n g t he I nf or me d C o nse nt f or t he st u d y, 
t he I n vesti gat or or desi g nee will e x plai n t he I R B/I E C/ E C-a p pr o ve d S u bject Data base 
A ut h orizati o n t o t he patie nt a n d wit ness t he si g nat ure.  
D uri n g Scree ni n g, site staff w h o ha ve recei ve d trai ni n g a n d l o gi n i nf or mati o n access t o 
w w w.cts data base.c o m  will e nter t he patie nt st u d y I D a n d a ut h orize d patie nt i de ntifiers. A n 
i m me diate re p ort detaili n g matc hes is ge nerate d a n d s h o ul d be pri nte d f or s o urce d oc u me ntati o n. 
T he re p ort will s pecif y eit her ( 1) n o matc hes f o u n d, ( 2) a matc h was f o u n d wit h a s u bject 
partici pati n g i n a n ot her st u d y wit hi n 3 0 da ys, or ( 3) t he s u bject matc hes wit h a s u bject w h o has 
prescree ne d at a n ot her site.  
At t he last patie nt c o ntact, site staff will access C T S data base, e nter t he patie nt St u d y I D a n d 
nat ure of t he last c o ntact (ie, earl y ter mi nati o n, c o m plete d st u d y).  

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Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
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5.  
T R E A T M E N T O F P A TI E N T S  
5. 1.  
Descri pti o n of St u d y Dr u g  
St u d y dr u g will be pr o vi de d as o pa q ue har d gelati n ca ps ules wit h a p ur ple ca p a n d w hite b o d y. 
Eac h ca ps ule c o ntai ns o ne of t he f oll o wi n g: 
•  A V P - 7 8 6-1 8  c a ps ules:  1 8 m g of d 6- D M a n d 4. 9 m g of Q ( U S P; E P) 
•  A V P - 7 8 6- 4 2. 6 3 c a ps ules: 4 2. 6 3 m g of d 6- D M a n d 4. 9  m g of Q ( U S P; E P)  
•  Pl ace b o c a ps ules: matc hi n g A V P - 7 8 6 i n a p peara nce 
Dr u g s u p plies will be pr o vi de d t o t he site i n d o u ble- bli n d, i n di vi d ual, prela bele d blister car ds. 
5. 2.  
C o nc o mit a nt Me dic ati o ns  a n d N o n dr u g T her a pies  
At eac h visit,  care gi vers will be q uerie d as t o w het her or n ot t he patie nt has ta ke n a n y 
c o nc o mita nt me dicati o ns a n d, if s o, t he I n vesti gat or will rec or d t he me dicati o ns ta ke n a n d t he 
reas o ns f or t heir use. 
A V P - 7 8 6 c o ntai ns q ui ni di ne w hic h is a P- gl yc o pr otei n i n hi bit or. C o nc o mita nt a d mi nistrati o n of 
q ui ni di ne wit h di g o xi n, a P- gl yc o pr otei n s u bstrate, res ults i n ser u m di g o xi n le vels t hat ma y be as 
m uc h as d o u ble d. Plas ma di g o xi n c o nce ntrati o ns s h o ul d be cl osel y m o nit ore d i n patie nts ta ki n g 
di g o xi n c o nc o mita ntl y a n d d ose re d uce d, as necessar y. 
I n cases of pr o dr u gs w h ose acti o ns are me diate d b y t he C Y P 2 D 6- pr o d uce d meta b olites (f or 
e xa m ple, c o dei ne a n d h y dr oc o d o ne, w h ose a nal gesic a n d a ntit ussi ve effects a p pear t o be 
me diate d b y m or p hi ne a n d h y dr o m or p h o ne, res pecti vel y), it ma y n ot be p ossi ble t o ac hie ve t he 
desire d cli nical be nefits i n t he prese nce of A V P - 7 8 6 d ue t o q ui ni di ne- me diate d i n hi biti o n of 
C Y P 2 D 6. Alter nati ve treat me nt s h o ul d be c o nsi dere d. 
F or patie nts w h o ter mi nate earl y, t he c o n diti o ns of use f or all o we d c o nc o mita nt me dicati o ns a n d  
n o n dr u g t hera pies or pr o hi bite d me dicati o ns d o n ot a p pl y bet wee n t he E T visit a n d t he 
F oll o w- u p visit. A n y use of me dicati o ns d uri n g t his peri o d will be at t he discreti o n of t he 
I n vesti gat or. Patie nts s h o ul d all o w at least 1 4  da ys after st o p pi n g st u d y dr u g bef ore starti n g a 
m o n oa mi ne o xi dase i n hi bit or (M A OI ). 
5. 2. 1.  
Restricte d a n d Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
Ps yc h otr o pic c o nc o mita nt me dicati o ns t hat are eit her all o we d wit h certai n restricti o ns or 
pr o hi bite d are liste d i n Ta ble  3. A detaile d list of pr o hi bite d c o nc o mita nt me dicati o ns  t hat ma y 
res ult i n si g nifica nt dr u g-dr u g i nteracti o ns  is pr o vi de d i n A p pe n di x 1 . 
D ue t o differe nces i n t he c o m mercial a vaila bilit y of all o we d c o nc o mita nt me dicati o ns i n t he  
s pecific c o u ntr y, please c o ntact a Me dical M o nit or t o disc uss a n y alter nati ve me dicati o ns n ot 
liste d bel o w. 

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T a ble  3: 
Restricte d a n d Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
Me dic ati o n  
Pri or t o St u d y E ntr y  
D uri n g D o u ble -Bli n d 
Tre at me nt Peri o d  
1.  
Me dicati o ns t o treat 
Alz hei mer’s disease ( e g, 
c h oli nesterase i n hi bit ors, 
me ma nti ne, or ot her 
c o g niti ve e n ha ncers a p pr o ve d 
i n t he res pecti ve c o u ntr y) 
All o we d pr o vi de d t hat t he d ose has 
bee n sta ble f or at least 3  m o nt hs pri or 
t o t he Scree ni n g visit, A N D t here is n o 
c ha n ge i n d ose or disc o nti n uati o n 
wit hi n t he sa me ti me peri o d  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y, e xce pt w he n me dicall y 
i n dicate d d ue t o a c ha n ge i n t he 
u n derl yi n g me dical c o n diti o n  
2.  
At y pical A nti ps yc h otics  
•  e xce pt cl oza pi ne  
•  e xce pt bre x pi praz ole  
All o we d pr o vi de d t hat t he d ose has 
bee n sta ble f or at least 1 m o nt h pri or t o 
t he Scree ni n g visit, A N D t here is n o 
c ha n ge i n d ose or disc o nti n uati o n 
wit hi n t he sa me ti me peri o d  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
Cl oza pi ne  
N ot all o we d wit hi n 1 m o nt h pri or t o t he 
Scree ni n g visit  
Pr o hi bite d  
T y pical A nti ps yc h otics   
N ot all o we d wit hi n 1 m o nt h pri or t o t he 
Scree ni n g visit  
Pr o hi bite d  
Bre x pi praz ole  
N ot all o we d wit hi n 1 m o nt h pri or t o t he 
Scree ni n g visit  
Pr o hi bite d  
3.  
A nti de pressa nts   
•  select a nti de pressa nts liste d 
bel o w are  restricte d or 
pr o hi bite d  
All o we d pr o vi de d t hat t he d ose has 
bee n sta ble f or at least 3  m o nt hs pri or 
t o t he Scree ni n g visit a n d is wit hi n t he 
ra n ge s pecifie d i n t he prescri bi n g 
i nf or mati o n f or t hat me dicati o n, A N D 
t here is n o c ha n ge i n d ose or 
disc o nti n uati o n wit hi n t he sa me ti me 
peri o d  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
Par o xeti ne  
All o we d wit h a ma xi m u m d ose of 
1 0  m g/ da y  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
Traz o d o ne  
All o we d wit h a ma xi m u m d ose of 
5 0  m g/ da y  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
Nefaz o d o ne  
N ot all o we d wit hi n 3  m o nt hs pri or t o 
t he Scree ni n g visit 
Pr o hi bite d  
Tric yclic A nti de pressa nts   
N ot all o we d wit hi n 3  m o nt hs pri or t o 
t he Scree ni n g visit 
Pr o hi bite d  
M o n oa mi ne O xi dase 
I n hi bit ors ( M A OI) 
N ot all o we d wit hi n 3  m o nt hs pri or t o 
t he Scree ni n g visit 
Pr o hi bite d  
Patie nts s h o ul d all o w at least 
1 4  da ys after st o p pi n g st u d y 
dr u g bef ore starti n g a n M A OI  
4.  
Be nz o diaze pi nes  
N ot all o we d wit hi n 1 m o nt h pri or t o t he 
Scree ni n g visit  
Pr o hi bite d  

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Me dic ati o n  
Pri or t o St u d y E ntr y  
D uri n g D o u ble -Bli n d 
Tre at me nt Peri o d  
5.  
H y p n otic Slee p A ge nts  
(e g, z ol pi de m, zale pl o n, 
z o picl o ne, esz o picl o ne, or 
ot her slee p a ge nt a p pr o ve d i n 
t he res pecti ve c o u ntr y) 
All o we d if t he d ose of t he slee p a ge nt 
f or i ns o m nia was ta ke n o n a re g ular 
basis f or at least 1 m o nt h pri or t o t he 
Scree ni n g visit , A N D t here is n o 
c ha n ge i n d ose or fre q ue nc y, or 
disc o nti n uati o n i n t he sa me ti me peri o d  
S h o ul d re mai n o n t he sa me d ose 
a n d at t he sa me fre q ue nc y 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
6.  
Ot her all o we d ps yc h otr o pic 
me dicati o ns t hat ma y i m pact 
a gitati o n (e g, m o o d 
sta bilizers, a ntie pile ptics) 
•  select me dicati o ns liste d 
bel o w are pr o hi bite d  
All o we d pr o vi de d t hat t he d ose has 
bee n sta ble f or at least 1 m o nt h pri or t o 
t he Scree ni n g visit, A N D t here is n o 
c ha n ge i n d ose or disc o nti n uati o n 
wit hi n t he sa me ti me peri o d  
S h o ul d re mai n o n t he sa me d ose 
t hr o u g h o ut t he d urati o n of t he 
st u d y 
At o m o xeti ne, c ar ba maze pi ne, 
f os p he n yt oi n, pe nt o bar bital, 
p he n o bar bital, p he n yt oi n, 
pri mi d o ne  
N ot all o we d wit hi n 1 m o nt h pri or t o t he 
Scree ni n g visit  
Pr o hi bite d  
7.  
Ot her p r o hi bite d c o nc o mita nt 
m e dicati o ns (see A p pe n di x  1) 
N ot all o we d wit hi n 2 wee ks or 
5 half -li ves ( w hic he ver is l o n ger) pri or 
t o t he Baseli ne visit 
Pr o hi bite d  
 
5. 3.  
Tre at me nt C o m pli a nce  
Patie nts a n d care gi vers will be i nstr ucte d t o ret ur n all dis pe nse d st u d y dr u g, i ncl u di n g u n use d 
a n d use d e m pt y blister car ds , t o t he cli nic o n Visits  2 t hr o u g h 8 (Da ys  8, 1 5, 2 9, 4 3, 5 7, 7 1, a n d 
8 5 / E T). F or t his st u d y, c o m plia nce will be defi ne d as w he n a patie nt ta kes at least 8 0 % of t heir 
sc he d ule d d oses (c o m plia nce ra n ge 8 0% t o 1 2 0 %). Care gi vers will be pr o vi de d wit h diar y car ds 
a n d will be i nstr ucte d  t o rec or d dail y t he n u m ber of ca ps ules ta ke n a n d t he ti me of 
a d mi nistrati o n. Diar y car ds will be  re vie wed f or c o m plia nce a n d c ollecte d o n Visits  2 t hr o u g h 8, 
or at t he ti me of  earl y st u d y disc o nti n uati o n. Patie nts s h o ul d bri n g t heir Diar y Car d t o eac h of 
t hese visits f or c o m plia nce re vie w; t he Diar y Car d will be ret ur ne d t o t he patie nt a n d c ollecte d at 
t he ne xt visit, if a p plica ble.  
5. 4.  
R a n d o miz ati o n a n d Bli n di n g  
Eli gi ble patie nts will be ra n d o mize d t o eit her treat me nt wit h A V P - 7 8 6 or place b o acc or di n g t o a 
ra n d o mizati o n sc he me de vise d b y t he S p o ns or or its re prese ntati ve a n d ma na ge d wit hi n a n 
i nteracti ve we b res p o nse s yste m (I W R S). T he ra n d o mizati o n will be stratifie d b y site a n d 
baseli ne  c o nc omita nt  a nti ps yc h otic use  ( yes/ n o). 
If i n t he In vesti gat or’s j u d ge me nt, it bec o mes me dicall y necessar y t o i de ntif y w hic h treat me nt a  
patie nt has recei ve d, t he bli n d ca n be br o ke n b y t he I n vesti gat or. If i de ntificati o n of t he st u d y  
treat me nt is re q uire d f or e mer ge nc y t hera pe utic meas ures, t he I n vesti gat or or desi g nee ca n 
i m me diatel y o btai n t he c urre nt treat me nt assi g n me nt electr o nicall y t hr o u g h t he I W R S. I n a n y 
sit uati o n re q uiri n g u n bli n di n g, i deall y t he I n vesti gat or s h o ul d c o ntact t he st u d y Me dical M o nit or 

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t o disc uss t he u n mas ki n g of a patie nt. If t his is n ot p ossi ble, t he st u d y Me dical M o nit or s h o ul d be 
n otifie d as s o o n as p ossi ble. 

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6.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
6. 1.  
St u d y Dr u g  C o m p ositi o n  
Eac h ca ps ule of st u d y dr u g will c o ntai n o ne of t he f oll o wi n g: 
•  A V P - 7 8 6- 1 8/ 4. 9: 1 8 m g of d 6- D M a n d 4. 9 m g of Q (U S P; E P ) 
•  A V P - 7 8 6- 4 2. 6 3/ 4. 9: 4 2. 6 3 m g of d 6- D M a n d 4. 9 m g of Q ( U S P; E P) 
•  Matc hi n g Place b o:  i de ntical i n a p peara nce t o A V P - 7 8 6 ca ps ules; c o ntai ni n g i nacti ve 
i n gre die nts o nl y 
T he i nacti ve i n gre die nts are cr oscar mell ose s o di u m, micr ocr ystalli ne cell ul ose, c oll oi dal silic o ne 
di o xi de, a n d ma g nesi u m stearate. 
St u d y dr u g will be pre pare d, pac ka ge d, a n d la bele d i n acc or da nce wit h G o o d Ma n ufact uri n g 
Practice ( G M P) g ui deli nes, I nter nati o nal C o u ncil o n Har m o nisati o n (I C H), G o o d Cli nical 
Practice ( G C P) g ui deli nes, a n d a p plica ble la ws a n d re g ulati o ns.  
6. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
T he I n vesti gat ors will be s u p plie d wit h prela bele d, i n di vi d uall y pre pac ka ge d blister car ds  
( 1-wee k  a n d 2-wee k blister car ds) . T he pa nel of t he 1- wee k blister car d ( 1  wee k of st u d y dr u g) 
c o nsists of 3 r o ws of 7 ca ps ules; o ne r o w f or t he m or ni n g d ose, o ne r o w f or t he e ve ni n g d ose, 
a n d o ne r o w f or e xtra s u p plies . T he pa nel of t he 2 -wee k blister car d ( 2  wee ks of st u d y dr u g) 
c o nsists of 5 r o ws of 7 ca ps ules; o ne r o w f or t he m or ni n g a n d o ne r o w f or t he e ve ni n g d ose f or 
t he first wee k a n d sec o n d wee k , a n d o ne r o w f or e xtra s u p plies. 
All la bels will c o ntai n t he pr ot oc ol n u m ber, pr o d uct na me, blister car d kit n u m ber ( Me d I D N o.), 
a n i n vesti gati o nal dr u g war ni n g, d osa ge i nstr ucti o ns t o ta ke o ne ca ps ule i n t he m or ni n g ( A M) 
a n d o ne ca ps ule i n t he e ve ni n g ( P M), st ora ge c o n diti o ns, a n d c o m pa n y na me. T he blister car d 
la bel will c o nsist of eit her a 2-pa nel la bel or b o o klet la bel. B ot h will ha ve a detac ha ble pa nel t hat 
will be re m o ve d a n d affi xe d t o t he st u d y dr u g Dis pe nsi n g L o g pa ge at t he ti me of dis pe nsi n g.  
6. 3.  
St u d y Dr u g St or a ge  
Cli nical s u p plies m ust be st ore d i n c o m plia nce wit h la bel re q uire me nts i n a sec ure place a n d ke pt 
at r o o m te m perat ure : 2 5° C ( 7 7° F), wit h e xc ursi o ns per mitte d t o 1 5° C t o 3 0° C ( 5 9° F- 8 6° F).  
6. 4.  
St u d y Dr u g A d mi nistr ati o n  
All patie nts will recei ve st u d y dr u g acc or di n g t o t he blister car d kit n u m bers assi g ne d b y a n 
I W R S ra n d o mizati o n sc he me. Desi g nate d staff at eac h site will dis pe nse st u d y dr u g. St u d y dr u g 
s h o ul d be a d mi nistere d t o t he patie nt b y t he care gi ver, fa mil y me m ber, n ursi n g h o me staff, or 
self-a d mi nistere d wit h s u per visi o n, e xce pt o n a p plica ble cli nic visit da ys w he n patie nts will be 
a d mi nistere d t heir d ose of st u d y dr u g  at t he cli nic i n t he prese nce of site pers o n nel, re gar dless of 
t he ti me of da y; t he m or ni n g d ose of st u d y dr u g will be a d mi nistere d i n t he cli nic at 
Baseli ne  ( Da y 1), Visit  2 ( Da y  8), a n d Visit 5 ( Da y 4 3). F or t he re mai ni n g visits (Visit  3 
[ Da y 1 5], Visit  4 [ Da y 2 9] , Visit  6 [ Da y 5 7], Visit  7 [Da y  7 1] , a n d Visit 8 [ Da y 8 5]/ E T), t he 

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m or ni n g d ose of st u d y dr u g  ca n be a d mi nistere d at h o me pri or t o t he  cli nic visit; t he ti me of t he 
m or ni n g d osi n g s h o ul d be n ote d b y t he patie nt/care gi ver. 
Patie nts a n d care gi vers will be i nstr ucte d t hat t he patie nt s h o ul d ta ke t he st u d y dr u g orall y  wit h 
water a p pr o xi matel y e ver y 1 2  h o urs ± 4 h o urs ( m or ni n g a n d e ve ni n g). T he ti me t he patie nt ta kes 
eac h d ose of me dicati o n s h o ul d be rec or de d i n t he diar y car d. Patie nt’s misse d d oses will  be 
n ote d i n t he electr o nic case re p ort f or m (e C R F).  
All st u d y dr u g will be s u p plie d a n d a d mi nistere d i n a d o u ble- bli n d ma n ner t hr o u g h o ut t he e ntire 
d urati o n of t he st u d y.  
6. 5.  
St u d y Dr u g Acc o u nt a bilit y  
6. 5. 1.  
Recei pt of Dr u g S u p plies  
T he In vesti gat or is res p o nsi ble f or mai ntai ni n g a n i n ve nt or y of eac h s hi p me nt of st u d y dr u g 
recei ve d a n d c o m pari n g it wit h t he acc o m pa n yi n g Dr u g Acc o u nta bilit y Re p ort/ Material S hi p pi n g 
F or m , as well as c o m pleti n g t he recei pt verificati o n i n I W R S. T he In vesti gat or will verif y t he 
acc urac y of t he i nf or mati o n o n t he f or m, si g n a n d date it, a n d ret ur n t he f or m t o t he S p o ns or or 
its re prese ntati ve. All st u d y dr u g s u p plie d is f or use o nl y i n t his st u d y a n d s h o ul d n ot be use d f or 
a n y ot her p ur p ose. All blister car d kit n u m bers will als o be rec or de d a n d trac ke d at t he site usi n g 
t he Dr u g Acc o u nta bilit y L o g. 
6. 5. 2.  
Rec or d of Dis pe nsi n g  
Acc urate rec or di n g of all st u d y dr u g dis pe nsi n g f or i n di vi d ual patie nts will be ma de i n t he 
a p pr o priate secti o n of t he patie nt’s e C R F. T his e C R F will c o ntai n t he f oll o wi n g i nf or mati o n: (i) 
patie nt  n u m ber t o w h o m t he st u d y dr u g was dis pe nse d; (ii) t he date(s) a n d q ua ntit y of t he st u d y 
dr u g dis pe nse d t o t he patie nt; a n d (iii) t he blister car d kit  n u m ber assi g ne d t o t he patie nt via 
I W R S. 
A d diti o nall y, t he detac ha ble pa nel of t he la bel o n eac h blister car d will be re m o ve d a n d affi xe d 
t o t he st u d y dr u g Dis pe nsi n g L o g pa ge at t he ti me of dis pe nsi n g. T he detac ha ble pa nel c o ntai ns 
t he st u d y n u m ber a n d kit n u m ber ( Me d I D N o.). S pace is  pr o vi de d o n t he affi xe d part of t he  la bel 
t o rec or d patie nt n u m ber, t he visit wee k a n d dis pe nse date.  
6. 6.  
St u d y Dr u g H a n dli n g a n d Dis p os al  
At t he e n d of t he st u d y, all u n use d i n vesti gati o nal s u p plies m ust be i n ve nt orie d o n t he Dr u g 
Acc o u nta bilit y L o g a n d ret ur ne d t o t he S p o ns or or its re prese ntati ve, al o n g wit h a c o m plete d a n d  
si g ne d Dr u g Acc o u nta bilit y Re p ort/ Material S hi p pi n g F or m. A n y st u d y dr u g ret ur ns will be 
re p orte d i n I W R S. If a n y st u d y dr u g is l ost or da ma ge d, it s h o ul d be i n dicate d o n t he f or m a n d 
s h o ul d be rep orte d i n I W R S. 

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7.  
A S S E S S M E N T O F E F FI C A C Y  
W he ne ver p ossi ble, eac h patie nt a n d care gi ver s h o ul d ha ve t he rati n g scales  a d mi nistere d b y t he 
sa me raters t hr o u g h o ut t he st u d y, f or c o nsiste nc y of rati n gs. T he f oll o wi n g scales M U S T be 
a d mi nistere d b y t he sa me rater at eac h visit: C M AI, C GI S - A gitati o n, C GI C -A gitati o n,  a n d N PI.  
7. 1.  
C o he n -M a nsfiel d A git ati o n I n ve nt or y ( C M AI)  
T he C M AI will be use d as t he pri mar y efficac y meas ure i n t his st u d y. T he C M AI  (l o n g-f or m 
versi o n) is use d t o assess t he fre q ue nc y of ma nifestati o ns of a gitate d be ha vi ors i n el derl y 
pers o ns. It c o nsists of 2 9 a gitate d be ha vi ors t hat are f urt her cate g orize d i nt o disti nct a gitati o n 
s y n dr o mes, als o k n o w n as C M AI fact ors of a gitati o n  3 4. T hese disti nct a gitati o n s y n dr o mes 
i ncl u de: a g gressi ve be ha vi or, p h ysicall y n o na g gressi ve be ha vi or, a n d ver ball y a gitate d be ha vi or 
3 5. Sc ores  f or t he 3 di me nsi o ns will be deri ve d base d o n t he fact or str uct ure descri be d b y 
Ra bi n o witz, et al,  2 0 0 5 3 6; f urt her details are pr o vi de d i n t he statistical a nal ysis pla n (S A P ). Eac h 
of t he 2 9 ite ms is rate d o n a 7-p oi nt scale of  fre q ue nc y ( 1 = ne ver, 2 = less t ha n o nce a wee k b ut 
still occ urri n g, 3 = o nce or t wice a wee k,  4 = se veral ti mes a wee k, 5 = o nce or t wice a da y, 6 = 
se veral ti mes a da y, 7 = se veral ti mes a n h o ur). T he rati n gs are base d o n t he 2 wee ks prece di n g 
assess me nt of t he C M AI.  
T he C M AI will be assesse d at Scree ni n g ( Da y - 2 8 t o Da y - 1), Baseli ne ( Da y  1), Visit 2  ( Da y 8), 
Visit  3 ( Da y  1 5), Visit 4  (Da y  2 9), Visit  5 (Da y  4 3), Visit  6 (Da y  5 7), Visit 7 ( Da y  7 1) , Visit 8 
(Da y  8 5/ E T), a n d t he F oll o w- u p visit ( 3 0 da ys p ost d ose). T he C M AI m ust be a d mi nistere d b y 
t he sa me rater at eac h visit. 
7. 2.  
Cli nic al Gl o b al I m pressi o n of S ever it y of Ill ness-A git ati o n 
( C GI S-A git ati o n)  
T he C GI S is a n o bser ver- rate d scale t hat meas ures ill ness se verit y a n d is o ne of t he m ost wi del y 
use d brief assess me nt t o ols i n ps yc hiatr y researc h.  
T he Earl y Cli nical Dr u g E val uati o n U nit versi o n of t he C GI S is t he m ost wi del y use d  f or mat of 
t his vali date d t o ol, a n d as ks t hat t he cli nicia n rate t he patie nt relati ve t o t heir past e x perie nce 
wit h ot her patie nts wit h t he sa me dia g n osis, wit h or wit h o ut c ollateral i nf or mati o n.  T he C GI S 
has pr o ve d t o be a r o b ust meas ure of efficac y i n ma n y cli nical dr u g trials 3 7 ,3 8 ,3 9 ,4 0 ,4 1 a n d is eas y 
a n d q uic k t o a d mi nister, pr o vi de d t hat t he cli nicia n k n o ws t he patie nt well 4 2. 
Relia bilit y a n d vali dit y of C GI ha ve bee n teste d i n m ulti ple st u dies, i ncl u di n g patie nts wit h  
de me ntia, sc hiz o p hre nia a n d affecti ve dis or ders. O verall, C GI s h o we d hi g h c orrelati o n (r: ~ 9 0 %) 
wit h ot her assess me nt i nstr u me nts a n d it has als o s h o w n p ositi ve si g nifica nt relati o ns hi ps a n d 
c o nc urre nt vali dit y wit h ot her cli nicia n’s rati n g. I n a d diti o n, t he scale has g o o d se nsiti vit y t o 
c ha n ge o ver ti me  4 3 ,4 4 ,4 5. 
T he C GI S -A gitati o n  is a 7-p oi nt ( 1 -7) scale ( 1 = n or mal, n ot at all ill; 7 = a m o n g t he m ost 
e xtre mel y ill patie nts) a n d assesses se verit y of a gitati o n i n t his st u d y. T he C GI S -A gitati o n will 
be assesse d at  Scree ni n g ( Da y -2 8 t o Da y -1), Baseli ne ( Da y  1), Visit  2 ( Da y  8), 
Visit  3 ( Da y 1 5), Visit 4 ( Da y 2 9), Visit 5 ( Da y  4 3), Visit  6 ( Da y 5 7), Visit 7 ( Da y  7 1), Visit  8 

C O N FI D E N TI A L  
 
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( Da y 8 5/ E T), a n d t he F oll o w- u p visit ( 3 0 da ys p ost d ose). T he  C GI S -A gitati o n m ust be 
a d mi nistere d b y t he sa me rater at eac h visit.  
7. 3.  
Cli nic al Gl o b al I m pressi o n of C h a n ge -A git ati o n  ( C GI C-A git ati o n)  
T he C GI C - A gitati o n is a 7- p oi nt ( 1-7) scale ( 1 = ver y m uc h i m pr o ve d; 7 = ver y m uc h w orse ) 
t hat assesses t he c ha n ge i n t he se verit y of a gitati o n i n t his st u d y 4 2. T he C GI C - A gitati o n 
e val uati o n will be c o n d ucte d at Visit  2 ( Da y 8), Visit  3 ( Da y  1 5), Visit 4 ( Da y 2 9), Visit 5 
( Da y 4 3), Visit 6 ( Da y 5 7), Visit  7 ( Da y 7 1), a n d Visit  8 ( Da y  8 5/ E T). T he C GI C - A gitati o n m ust 
be a d mi nistere d b y t he sa me rater at eac h visit.  
7. 4.  
Ne ur o ps yc hi atric I n ve nt or y ( N PI)  
T he N PI is a vali date d cli nical i nstr u me nt f or e val uati n g ps yc h o pat h ol o g y i n a variet y of disease 
setti n gs, i ncl u di n g de me ntia. T he N PI is a retr os pecti ve care gi ver-i nf or ma nt i nter vie w c o veri n g 
1 2 ne ur o ps yc hiatric s y m pt o m d o mai ns: del usi o ns, hall uci nati o ns, a gitati o n/a g gressi o n, 
de pressi o n/ d ys p h oria, a n xiet y, elati o n/e u p h oria, a pat h y/i n differe nce, disi n hi biti o n, 
irrita bilit y/la bilit y, a berra nt m ot or be ha vi or, slee p a n d ni g htti me be ha vi oral dis or ders, a n d 
a p petite/eati n g dis or ders 4 6. Ne ur o ps yc hiatric ma nifestati o ns wit hi n a d o mai n are c ollecti vel y 
rate d b y t he care gi ver i n ter ms of b ot h fre q ue nc y ( 1 t o 4) a n d se verit y ( 1 t o 3), yiel di n g a 
c o m p osite s y m pt o m d o mai n sc ore (fre q ue nc y x se verit y). Care gi ver distress is rate d  f or eac h 
p ositi ve ne ur o ps yc hiatric s y m pt o m d o mai n o n a scale a nc h ore d b y sc ores of 0 ( n ot distressi n g at 
all) t o 5 (e xtre mel y distressi n g).  
T he N PI will be a d mi nistere d t o t he patie nt’s care gi ver at Baseli ne ( Da y  1), Visit 2 ( Da y  8), 
Visit  5 ( Da y  4 3), Visit 7 ( Da y  7 1), a n d Visit  8 ( Da y  8 5/ E T). O nl y t he A gitati o n/ A g gressi o n 
d o mai n of t he  N PI ( N PI -A A) will be a d mi nistere d t o t he patie nt’s care gi ver at Scree ni n g 
( Da y -2 8 t o Da y -1), Visit  3 ( Da y 1 5), Visit  4 ( Da y 2 9), a n d Visit 6 ( Da y  5 7). T he recall peri o d 
will be 2  wee ks f or all t he visits. T he N PI m ust be  a d mi nistere d b y t he sa me rater at eac h visit. 
T he N PI n ursi n g- h o me versi o n ( N PI -N H) will be  use d f or patie nts fr o m i n -patie nt or assiste d 
li vi n g facilities. 
7. 5.  
E ur o Q ol 5 -Di me nsi o n 5 -Le vel ( E Q -5 D -5 L)  
T he E Q - 5 D- 5 L is a ge neric q uesti o n naire meas uri n g healt h-relate d q ualit y of life a n d c o nsists of 
a descri pti ve s yste m a n d t he E ur o Q ol Vis ual A nal o g ue Scale ( E Q V A S)  4 7. T he descri pti ve 
s yste m c o m prises 5 di me nsi o ns ( m o bilit y, self-care, us ual acti vities, pai n/ disc o mf ort,  a n d 
a n xiet y/ de pressi o n) a n d eac h di me nsi o n has 5 le vels: n o pr o ble ms, sli g ht pr o ble ms, m o derate 
pr o ble ms, se vere pr o ble ms, a n d e xtre me pr o ble ms. T he E Q V A S rec or ds t he res p o n de nt’s self-
rate d healt h o n a vertical, vis ual a nal o g ue scale w here t he e n d p oi nts are la bele d ‘ Best i ma gi na ble 
healt h state’ a n d ‘ W orst i ma gi na ble healt h state’. T his i nf or mati o n ca n be use d  as a q ua ntitati ve 
meas ure of healt h o utc o me as j u d ge d b y t he i n di vi d ual res p o n de nts. T here are 2 versi o ns of t he 
E Q - 5 D- 5 L, a versi o n rate d b y t he patie nt a n d a versi o n ( E Q - 5 D- 5 L- pr o x y) rate d b y care gi ver. 
T he patie nt versi o n will be rate d o nl y b y patie nts wit h a n M M S E sc ore of ≥ 1 0 at t he Baseli ne  
visit.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 5 
 
T he E Q - 5 D- 5 L- pr o x y (a n d E Q- 5 D- 5 L f or patie nts wit h M M S E ≥ 1 0) will be assesse d at  
Baseli ne ( Da y  1) a n d Visit 8 ( Da y  8 5 / E T). 
7. 6.  
Res o urce Utiliz ati o n i n De me nti a  ( R U D) Lite 
T he R U D is use d t o calc ulate healt hcare c osts ass ociate d wit h de me ntia  4 8. It e val uates de me ntia 
patie nts’ utilizati o n of f or mal a n d i nf or mal healt hcare res o urces, i ncl u di n g  h os pitalizati o ns a n d 
d oct or visits, li vi n g assista nce, a n d ti me s pe nt b y n o n pr ofessi o nal care gi vers. Wit hi n t he c o nte xt 
of cli nical trials, t he R U D is ofte n use d t o deter mi ne t he c ost  effecti ve ness of ne w 
p har mace utical treat me nts  4 9. 
T he R U D is a d mi nistere d as a se mi -str uct ure d i nter vie w wit h t he patie nt’s pri mar y care gi ver, 
a n d c o ntai ns 2 secti o ns; o ne f oc usi n g o n care gi ver i m pact (l oss of w or k a n d leis ure ti me i nc urre d 
b y care gi ver) a n d t he ot her f oc usi n g o n t he patie nt’s use of healt hcare res o urces. T he t otal  
healt hcare c osts ass ociate d wit h t he patie nt’s de me ntia ca n be esti mate d b y m ulti pl yi n g t he  
n u m ber of u nits use d (e g, h o urs of care gi ver ti me, visits t o d oct ors, ni g hts i n acc o m m o dati o n) b y 
t he c orres p o n di n g u nit price vect or. 
T he R U D -Lite  ( R U D 5. 0) is a s h orter versi o n of t he R U D de vel o pe d t o re d uce t he i nter vie w 
b ur de n o n care gi vers. Q uesti o ns relate d t o care gi ver res o urce use (e g, w or k stat us, res pite or 
h os pital care, s ocial ser vices , da y care, or dr u g use), w hic h i n ge neral is l o w f or care gi vers, ha ve 
bee n re m o ve d fr o m t he R U D-Lite 5 0.  
T he R U D -Lite  will be assesse d at Baseli ne ( Da y  1) a n d Visit 8 (Da y  8 5/ E T). 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 6 
 
8.  
A S S E S S M E N T O F S A F E T Y  
8. 1.  
S afet y P ar a meters  
8. 1. 1.  
A d verse a n d Seri o us A d verse E ve nts  
8. 1. 1. 1.  
Defi niti o n of A d verse E ve nts  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce or u ni nte n de d c ha n ge ( e g, p h ysical, 
ps yc h ol o gical, or be ha vi oral), i ncl u di n g i nter- c urre nt ill ness, w het her c o nsi dere d relate d t o st u d y 
dr u g or n ot. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n y 
cli nicall y si g nifica nt a b n or mal la b orat or y  fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a st u d y dr u g, w het her or n ot c o nsi dere d relate d t o t he st u d y dr u g. 
C ha n ges ass ociate d wit h n or mal gr o wt h a n d de vel o p me nt t hat d o n ot var y i n fre q ue nc y or 
ma g nit u de fr o m t hat or di naril y a ntici pate d cli nicall y are n ot A Es (e g, o nset of me nstr uati o n 
occ urri n g at a p h ysi ol o gicall y a p pr o priate ti me).  
Cli nical A Es s h o ul d be descri be d b y dia g n osis a n d n ot b y s y m pt o ms w he n p ossi ble (e g, c ol d or 
seas o nal aller gies, i nstea d of r u n n y n ose). 
A n o ver d ose is a deli berate or i na d verte nt a d mi nistrati o n of a treat me nt at a d ose hi g her t ha n 
s pecifie d i n t he pr ot oc ol a n d hi g her t ha n k n o w n t hera pe utic d oses. It m ust be re p orte d 
irres pecti ve of o utc o me, e ve n if t o xic effects were n ot o bser ve d. 
A Es will be gra de d o n a 3- p oi nt se verit y scale a n d re p orte d i n detail as i n dicate d o n t he e C R F: 
Mil d:   
easil y t olerate d, ca usi n g mi ni mal disc o mf ort a n d n ot i nterferi n g wit h  
n or mal e ver y da y acti vities 
M o derate:   
s ufficientl y disc o mf orti n g t o i nterfere wit h n or mal e ver y da y acti vities  
Se vere:    
i nca pacitati n g a n d/ or pre ve nti n g n or mal e ver y da y acti vities 
T he relati o ns hi p of eac h A E t o st u d y dr u g s h o ul d be deter mi ne d b y t he I n vesti gat or usi n g t he 
f oll o wi n g e x pla nati o ns: 
N ot relate d:  
t he e ve nt is clearl y relate d t o ot her fact ors s uc h as t he patie nt’s cli nical 
state, t hera pe utic i nter ve nti o ns, or c o nc o mita nt me dicati o ns a d mi nistere d 
t o t he patie nt 
U nli kel y relate d :  t he e ve nt is m ost li kel y pr o d uce d b y ot her fact ors s uc h as t he patie nt’s 
cli nical state, t hera pe utic i nter ve nti o ns, or c o nc o mita nt me dicati o ns 
a d mi nistere d t o t he patie nt; a n d d oes n ot f oll o w a k n o w n res p o nse patter n 
t o t he st u d y me dicati o n 
P ossi bl y relate d :  t he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he ti me of st u d y 
dr u g a d mi nistrati o n; a n d/ or f oll o ws a k n o w n res p o nse patter n t o t he st u d y 
dr u g; b ut c o ul d ha ve bee n pr o d uce d b y ot her fact ors s uc h as t he patie nt’s 
cli nical state, t hera pe utic i nter ve nti o ns, or c o nc o mita nt me dicati o ns 
a d mi nistere d t o t he patie nt  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 7 
 
Relate d :  
t he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he ti me of st u d y 
dr u g a d mi nistrati o n; a n d f oll o ws a k n o w n res p o nse patter n t o t he st u d y 
dr u g; a n d ca n n ot be reas o na bl y e x plai ne d b y ot her fact ors s uc h as t he 
patie nt’s cli nical state, t hera pe utic i nter ve nti o ns, or c o nc o mita nt 
me dicati o ns a d mi nistere d t o t he patie nt  
8. 1. 1. 2.  
Seri o u s A d verse E ve nt 
A seri o us ad verse e ve nt ( S A E) is a n y A E occ urri n g at a n y d ose t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes: 
1.  Deat h  
2.  Life -t hreate ni n g e x perie nce ( o ne t hat places t he patie nt, i n t he vie w of t he i nitial re p orter, 
at i m me diate ris k of deat h fr o m t he A E as it occ urre d, ie, it d oes n ot i ncl u de a n A E t hat, 
ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h) 
3.  Persiste nt or si g nifica nt disa bilit y/i nca pacit y ( disa bilit y is a s u bsta ntial disr u pti o n of a 
pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns)  
4.  I n-patie nt h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n  
5.  C o n ge nital a n o mal y/ birt h defect  
I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, or be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y 
ma y je o par dize t he patie nt or re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he  
o utc o mes liste d i n t he defi niti o n. 
T he ter ms “ca ncer” a n d “ o ver d ose” are n ot necessaril y c o nsi dere d S A Es, b ut if a patie nt  
e x perie nces ca ncer or o ver d ose, t he y are still re p orta ble as A Es.  
Pre g na nc y is n ot c o nsi dere d t o be a n A E or a n S A E, b ut all re p orte d pre g na ncies occ urri n g 
d uri n g t he st u d y will be re p orte d o n t he Pre g na nc y a n d Breastfee di n g E x p os ure F or m ( P B E F). 
T he site s h o ul d f oll o w- u p eac h tri mester wit h t he patie nt / part ner u ntil t he fi nal o utc o me is k n o w n 
(ie, n or mal deli ver y, a b n or mal deli ver y, s p o nta ne o us/ v ol u ntar y/t hera pe utic a b orti o n). S h o ul d a 
c o m plicati o n occ ur t hat meets t he re q uire me nts f or a n A E or S A E, it m ust be re p orte d wit hi n 
2 4 h o urs of a ware ness. Patie nts w h o are pre g na nt or li kel y t o bec o me pre g na nt are e xcl u de d 
fr o m t his st u d y. I n t he e ve nt a patie nt bec o mes pre g na nt d uri n g t he st u d y, st u d y dr u g m ust be 
disc o nti n ue d, a pre g na nc y re p ort f or m m ust be c o m plete d t o ca pt ure p ote ntial dr u g e x p os ure 
d uri n g pre g na nc y, a n d t he pre g na nc y m ust be re p orte d wit hi n 2 4 h o urs of a ware ness.  
A pre g na nc y re p ort f or m m ust als o be c o m plete d i n t he e ve nt t hat t he part ner of c hil d - beari n g 
p ote ntial of a male patie nt i n t he st u d y bec o mes pre g na nt wit hi n 3 0 da ys after his last d ose of 
st u d y dr u g or st u d y c o m pleti o n, w hic he ver is greater. 
T he ter m ‘se vere’ is a meas ure of i nte nsit y; t h us, a se vere A E is n ot necessaril y seri o us. F or 
e xa m ple, na usea of se veral h o urs d urati o n ma y be rate d as se vere b ut ma y n ot be cli nicall y 
seri o us. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 8 
 
8. 1. 1. 3.  
Re p ort i n g A d verse E ve nts 
Care gi vers will be q uerie d re gar di n g A Es at eac h cli nic visit after t he Scree ni n g visit ( Baseli ne  
[ Da y 1], Visit s 2- 8 [Da ys  8, 1 5, 2 9, 4 3, 5 7, 7 1, a n d 8 5/ E T], a n d F oll o w- u p visit). O nl y treat me nt 
emer ge nt ad verse eve nts ( T E A E) t hat occ ur after a d mi nistrati o n of t he first d ose of st u d y dr u g 
will be ca pt ure d f or t he p ur p oses of t he st u d y. A n y i nterc urre nt A Es  t hat occ ur after t he si g ni n g 
of t he i nf or me d c o nse nt a n d pri or t o t he patie nt ’s first d ose of st u d y dr u g will be ca pt ure d as 
me dical hist or y. I n t he i nsta nce t hat t he site bec o mes a ware of a n y s uc h i nterc urre nt a d verse 
e ve nts s u bse q ue nt t o c o nfir mati o n a n d a p pr o val of eli gi bilit y f or a n e nr olle d patie nt, t he site 
s h o ul d u p date t he me dical hist or y rec or ds t o reflect t his u p date d i nf or mati o n a n d e ns ure t hat t he 
u p date d i nf or mati o n is pr o vi de d t o t he M e dical M o nit or. A n y A E ne wl y re p orte d after recei vi n g 
t he last d ose of st u d y dr u g  a n d u p u ntil 3 0 da ys after recei vi n g t he last d ose of st u d y dr u g  will be 
f oll o we d. 
T he S p o ns or ma y re q uest a d diti o nal i nf or mati o n o n certai n e ve nts, s uc h as falls. E ve nt t o 
M o nit or data c ollecti o n f or ms a n d c o m pleti o n g ui deli nes will be pr o vi de d f or t he I n vesti gat or t o 
c o m plete f or s uc h e ve nts. T hese f or ms s h o ul d be s u b mitte d t o t he S p o ns or as s pecifie d o n t he 
f or m. 
A deat h occ urri n g d uri n g t he st u d y, or w hic h c o mes t o t he atte nti o n of t he I n vesti gat or wit hi n 
3 0 da ys after st o p pi n g t he st u d y dr u g w het her c o nsi dere d dr u g -relate d or n ot, m ust be re p orte d t o 
t he S p o ns or. 
F or all S A Es t he I n vesti gat or s h o ul d c o ns ult wit h t he S p o ns or’s M e dical M o nit or or desi g nate d 
re prese ntati ve as nee de d a n d re p ort a n y S A E via t he Seri o us A d verse E ve nt Re p orti n g ( S A E R) 
F or m b y fa x/e mail (as detaile d bel o w) n o later t ha n 2 4  h o urs after bec o mi n g a ware of t he e ve nt. 
T he S A E m ust be assesse d f or t he f oll o wi n g details: seri o us ness criteria of t he e ve nt, S A E start 
date, S A E st o p date, se verit y, relati o ns hi p t o st u d y dr u g, acti o n ta ke n re gar di n g st u d y dr u g, a n d 
o utc o me t o date. T he narrati ve secti o n of t he f or m ma y be use d t o detail a n y treat me nt 
i nf or mati o n. 
S A E a n d E ve nts t o M o nit or re p orti n g b y F A X or e -m ail c orres p o n de nce:  
E- m ail:  
 
Preli mi nar y (i nitial) re p orts will be f oll o we d b y detaile d descri pti o ns, w hic h ma y i ncl u de c o pies 
of h os pital rec or ds/ disc har ge s u m maries, a ut o ps y re p orts, deat h certificates, a n d ot her relate d 
d oc u me nts as re q ueste d. 
T he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (I R B/ I E C/E C) will be n otifie d of 
s uc h a n e ve nt i n writi n g as s o o n as is practical i n c o m plia nce wit h fe deral a n d l ocal re g ulati o ns.   
8. 1. 2.  
P h ysic al a n d Ne ur ol o gic al E x a m i n ati o ns 
P h ysical a n d ne ur ol o gical e xa mi nati o ns will be perf or me d at Scree ni n g ( Da y - 2 8 t o Da y - 1) a n d 
Visit  8 ( Da y  8 5/ E T). T he p h ysical e xa mi nati o n will i ncl u de assess me nts of hea d, e yes, ears, 
n ose, t hr oat, l y m p h n o des, s ki n, e xtre mities, res pirat or y, gastr oi ntesti nal, m usc ul os keletal, 
car di o vasc ular, a n d ner v o us s yste ms. T he ne ur ol o gical e xa mi nati o n will i ncl u de assess me nts of 
me ntal stat us, cra nial ner ves, m ot or s yste m, refle xes, c o or di nati o n, gait  a n d stati o n, a n d se ns or y 
C CI

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
3 9 
 
s yste m. T he p h ysical a n d ne ur ol o gical e xa mi nati o ns s h o ul d be perf or me d b y t he sa me pers o n 
eac h ti me, w he ne ver p ossi ble.  
P h ysical a n d ne ur ol o gical e xa mi nati o n a b n or malities deter mi ne d b y t he I n vesti gat or t o be 
cli nicall y si g nifica nt at Scree ni n g s h o ul d be rec or de d as me dical hist or y.  
A n y cli nicall y si g nifica nt c ha n ges i n p h ysical a n d ne ur ol o gical e xa mi nati o n fi n di n gs fr o m t he 
scree ni n g e xa mi nati o n s h o ul d be rec or de d as A Es. 
8. 1. 3.  
Vit al Si g ns  
Ort h ostatic bl o o d press ure ( B P) a n d heart rate ( H R) meas ure me nts will be perf or me d at all cli nic 
visits , e xce pt  t he F oll o w- u p visit. S u pi ne B P a n d H R will be meas ure d after a patie nt has reste d 
f or at least 5 mi n utes i n t he s u pi ne p ositi o n. Eac h meas ure me nt will be ta ke n t wice i n t he sa me 
p ositi o n a n d rec or de d. After t he meas ure me nt of s u pi ne B P a n d H R, t he patie nt will sta n d still 
f or u p t o 3 mi n utes a n d a  si n gle meas ure me nt of sta n di n g B P a n d H R will be rec or de d wit hi n 
1 t o 3 mi n utes of sta n di n g. 
Res pirat or y rate ( breat hs/ mi n ute) a n d b o d y te m perat ure (º F/º C) will be assesse d at all cli nic  
visits.  
8. 1. 4.  
Wei g ht a n d Hei g ht  
Hei g ht a n d wei g ht will be meas ure d at Baseli ne ( Da y 1); o nl y wei g ht will be meas ure d at Visit  8 
( Da y 8 5/ E T). 
8. 1. 5.  
Electr oc ar di o gr a m ( E C G)  
A resti n g 1 2- lea d E C G will be perf or me d at Scree ni n g , Baseli ne, Visit  2 ( Da y  8), Visit  5 
( Da y 4 3), a n d Visit 8 ( Da y  8 5/ E T). At Scree ni n g, 3 E C G s will be perf or me d  (e g, o ne after t he 
ot her) . At Baseli ne ( Da y 1) a n d Visit 2 ( Da y 8), 2 E C Gs will be  perf or me d; o ne pre d ose a n d o ne 
p ost d ose 1 t o 1. 5 h o urs after st u d y dr u g d osi n g. A n E C G will be perf or me d at a n y ti me at Visit  5 
( Da y 4 3) a n d Visit 8 ( Da y  8 5/ E T). 
E C G e q ui p me nt will be pr o vi de d b y t he ce ntral rea der. E C G data will be rec or de d at t he st u d y 
ce nter a n d will  i ncl u de ge neral fi n di n gs, heart rate ( beats/ mi n ute), Q R S c o m ple x , P R a n d Q Tc 
i nter vals ( millisec o n ds). Res ults will be pr o vi de d b y t he ce ntral rea der t o t he I n vesti gat ors wit hi n 
2 4 h o urs. E C G a b n or malities prese nt at Scree ni n g will be rec or de d as me dical hist or y. A n y 
c ha n ges fr o m t he E C G stat us at Scree ni n g v isit t hat are dee me d t o be cli nicall y si g nifica nt b y t he 
I n vesti gat or s h o ul d be ca pt ure d as A Es. A n y cli nicall y si g nifica nt a b n or mal E C G s h o ul d be 
disc usse d  wit h a Me dical M o nit or  a n d, if necessar y , be re peate d wit hi n a 1 - wee k peri o d. 
F or eli gi bilit y t o e nr oll i n t he st u d y, t he Q Tc F assess me nt of t he 3 E C Gs c o n d ucte d at Scree ni n g 
will be base d o n t he ce ntral re vie w. A patie nt will be e xcl u de d if 2 of t he 3 Scree ni n g E C Gs ha ve 
a Q Tc F > 4 5 0 msec i n males  a n d > 4 7 0 msec i n fe males, u nless d ue t o ve ntric ular paci n g. If o nl y 
1 Scree ni n g E C G  has a Q Tc F > 4 5 0 msec i n males a n d > 4 7 0 msec i n fe males , w hic h is n ot 
re pr o d uce d i n eit her of t he ot her 2 Scree ni n g E C Gs, t he n t he patie nt ma y be eli gi ble f or t he 
st u d y. T he assess me nt of E C Gs c o n d ucte d at Baseli ne will be base d o n t he mac hi ne rea d a n d 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 0 
 
I n vesti gat or e val uati o n of t he rea d. If t he Baseli ne pre d ose E C G Q Tc F res ult fr o m t he mac hi ne 
rea d is e xcl usi o nar y, t he patie nt s h o ul d n ot be d ose d a n d a Me dical M o nit or s h o ul d be c o ns ulte d. 
8. 1. 6.  
Cli nic al L a b or at or y Assess me nts  
U nless ot her wise s pecifie d, t he f oll o wi n g cli nical la b orat or y assess me nts are t o be perf or me d at 
Scree ni n g ( Da y -2 8 t o Da y  -1), Visit  5 ( Da y  4 3) , a n d Visit 8 ( Da y  8 5/ E T): 
•  Bl o o d c he mistr y (calci u m, ma g nesi u m, p h os p h or us, gl uc ose, s o di u m, p otassi u m, 
c hl ori de, car b o n di o xi de, bl o o d urea nitr o ge n, ser u m creati ni ne, uric aci d, al b u mi n, 
t otal bilir u bi n, al kali ne p h os p hatase, lactate de h y dr o ge nase, as partate 
a mi n otra nsferase/ser u m gl uta mic o xal oacetic tra nsa mi nase, ala ni ne 
a mi n otra nsferase/ser u m gl uta mic p yr u vic tra nsa mi nase, creati ne ki nase, 
ga m ma -gl uta m yl tra nsferase, tri gl yceri des, t otal pr otei n, a n d t otal c h olester ol)  
•  He mat ol o g y (re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell [ W B C] 
c o u nt, ne utr o p hils, ba n ds, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils, platelet 
c o u nt, a n d m or p h ol o g y)   
•  Uri nal ysis ( p H, s pecific gra vit y, pr otei n, gl uc ose, ket o nes, bl o o d, le uc oc yte esterase, 
nitrates, a n d micr osc o pic a p peara nce)  
•  T h yr oi d f u ncti o n tests ( T S H, a n d refle x T 3 a n d T 4 if T S H is a b n or mal) at Scree ni n g 
visit o nl y  
•  Gl yc os ylate d he m o gl o bi n ( H b A 1c) test at t he Scree ni n g visit a n d Visit 8 ( Da y  8 5) 
o nl y 
•  C Y P 2 D 6 ge n ot y pi n g at Visit 2 ( Da y 8) o nl y 
•  A m yl oi d β bi o mar ker at Visit 2 ( Da y 8) o nl y 
A n y patie nts wit h cli nicall y si g nifica nt a b n or mal la b orat or y test res ults ma y be re q uire d b y a 
Me dical M o nit or  t o ha ve a re peat test 1 wee k  later or earlier, if me dicall y i n dicate d. Cli nicall y 
si g nifica nt la b orat or y a b n or malities ma y be a basis f or e xcl usi o n fr o m st u d y e ntr y.  
8. 1. 7.  
Pre g n a nc y Tests  
Uri ne pre g na nc y tests are t o be perf or me d f or w o me n  of c hil d beari n g p ote ntial at Scree ni n g  
( Da y -2 8 t o Da y -1), Baseli ne ( Da y  1), a n d Visit  8 ( Da y  8 5/ E T). 
All fe male patie nts of c hil d beari n g p ote ntial s h o ul d be i nstr ucte d t o use a p pr o priate birt h c o ntr ol  
met h o ds f or u p t o 4  wee ks f oll o wi n g t he last d ose of st u d y dr u g . 
W o me n of c hil d beari n g p ote ntial w h o are se x uall y acti ve m ust use a n effecti ve met h o d of birt h  
c o ntr ol f or at least 1  m o nt h pri or t o ra n d o mizati o n, d uri n g t he c o urse of t he st u d y, a n d f or at least 
3 0 da ys after t he last d ose of st u d y dr u g. T he f oll o wi n g re q uire me nts m ust be met: 
•  W o me n of c hil d beari n g p ote ntial m ust use 2 of t he f oll o wi n g preca uti o ns i n or der t o  
mi ni mize t he ris k of fail ure of 1 met h o d of birt h c o ntr ol: vasect o m y, t u bal li gati o n,  
va gi nal dia p hra g m, i ntra uteri ne de vice, birt h c o ntr ol pills, birt h c o ntr ol de p ot 
i njecti o n, birt h c o ntr ol i m pla nt, or c o n d o m wit h s per mici de or s p o n ge wit h 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 1 
 
s per mici de. Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he d urati o n of e x p os ure t o 
st u d y dr u g, or wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n. 
•  W o me n w h o are sterile (ie, ha d a n o o p h orect o m y a n d/ or h ysterect o m y), 
p ost me n o pa usal ( defi ne d as 1 2 m o nt hs wit h n o me nses wit h o ut a n alter nati ve me dical  
ca use) , or practice tr ue a bsti ne nce ( w he n t his met h o d is i n li ne wit h t he preferre d a n d  
us ual lifest yle of t he patie nt) are e xe m pt fr o m t his re q uire me nt.  
•  W o me n w h o are lactati n g, pre g na nt, or pla n t o bec o me pre g na nt are n ot eli gi ble f or 
partici pati o n i n t he st u d y.  
8. 1. 8.  
Mi ni Me nt al St ate E x a mi n ati o n ( M M S E)  
T he M M S E is a brief 3 0 -p oi nt q uesti o n naire test t hat is use d t o scree n f or  c o g niti ve i m pair me nt. 
It is c o m m o nl y use d i n me dici ne t o scree n f or de me ntia. It is als o use d t o esti mate t he se verit y of 
c o g niti ve i m pair me nt at a s pecific ti me a n d t o f oll o w t he c o urse of  c o g niti ve c ha n ges i n a n 
i n di vi d ual o ver ti me, t h us ma ki n g it a n effecti ve wa y t o d oc u me nt a n i n di vi d ual’s res p o nse t o 
treat me nt. T he M M S E scale c o m prises 1 1 q uesti o ns or si m ple tas ks c o ncer ni n g orie ntati o n, 
me m or y, atte nti o n, a n d la n g ua ge t o e val u ate t he patie nt’s c o g niti ve  state 5 1. T he M M S E t otal 
sc ore ra n ges fr o m 0 t o 3 0, wit h hi g her sc ores i n dicati n g better c o g niti ve f u ncti o n. It re q uires o nl y 
5 t o 1 0 mi n utes f or a trai ne d rater t o a d mi nister it.  
T he M M S E will be assesse d at Scree ni n g ( Da y - 2 8 t o Da y - 1), Baseli ne ( Da y  1), a n d Visit  8 
(Da y  8 5). 
8. 1. 9.  
E p w ort h Slee pi ness Sc ale ( E S S)  
T he E S S is a n 8 -ite m q uesti o n naire t hat is use d t o meas ure slee pi ness b y rati n g t he pr o ba bilit y of 
falli n g aslee p o n 8 differe nt sit uati o ns t hat m ost pe o ple e n ga ge i n d uri n g t he da y 5 2. T he 
q uesti o ns are rate d o n a 4 - p oi nt scale ( 0 t o 3) w here 0 = w o ul d ne ver d oze, 1 = sli g ht c ha nce of 
d ozi n g, 2 = m o derate c ha nce of d ozi n g, a n d 3 = hi g h c ha nce of d ozi n g. A t otal sc ore of 0 t o 9 is 
c o nsi dere d t o be n or mal. 
T he E S S will be assesse d at Baseli ne ( Da y  1) a n d Visit  8 (Da y  8 5/ E T) f or patie nts wit h a n 
M M S E sc ore of  ≥ 1 0 at t he Baseli ne  visit.  
8. 1. 1 0.  
S hee h a n S uici d alit y Tr ac ki n g Sc ale ( S -S T S)  
T he S -S T S is a pr os pecti ve scale t hat assesses treat me nt -e mer ge nt s uici dal t h o u g hts a n d 
be ha vi ors 5 3. Eac h ite m of t he S -S T S is sc ore d o n a 5 -p oi nt Li kert scale ( 0  = n ot at all; 1 = a 
little; 2 = m o derate; 3 = ver y; a n d 4 = e xtre mel y). T he S- S T S ca n be a nal yze d as i n di vi d ual ite m 
sc ores, s uici dal i deati o n s u bscale sc ore, s uici dal be ha vi or s u bscale sc ore, or t otal sc ore. F or t he 
S cree ni n g visit, t he ti mefra me f or t he ite ms o n t he scale will be ‘i n t he past 6  m o nt hs’ a n d f or all 
ot her visits it will be ‘si nce last visit’.  
T he S -S T S will be assesse d at Scree ni n g ( Da y - 2 8 t o Da y -1), Baseli ne ( Da y  1), a n d Visit 8 
( Da y 8 5/ E T). A n y c ha n ge i n t he S-S T S sc ore i n dicati n g t he prese nce of  s uici dalit y s h o ul d be 
e val uate d b y t he I n vesti gat or a n d re p orte d t o a Me dical M o nit or. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 2 
 
8. 1. 1 1.  
Asse ss me nt of Ris k of F alls f or Eli gi bilit y 
8. 1. 1 1. 1.  Ti me d U p a n d G o ( T U G ) Test 
T he T U G test meas ures t he ti me (i n sec o n ds) ta ke n f or a n i n di vi d ual t o sta n d u p fr o m a sta n dar d 
ar mc hair, wal k 3  meters, t ur n, wal k bac k t o t he c hair a n d sit d o w n. It is a c o m m o nl y use d scale 
f or meas uri n g f u ncti o nal m o bilit y a n d ris k of falls 5 4 ,5 5. T he T U G test will be perf or me d o nl y at 
Scree ni n g ( Da y -2 8 t o Da y - 1) t o assess t he ris k of falls f or t he p ur p ose of eli gi bilit y f or t he 
st u d y. 
8. 1. 1 2.  
H ac hi ns ki Isc he mic Sc ale ( R ose n M o dific ati o n)  
T he R ose n -m o difie d Hac hi ns ki Isc he mic Scale  assesses w het her a patie nt’s  de me ntia is li kel y 
d ue t o vasc ular ca uses b y t he res p o nse t o 8 q uesti o ns:  a br u pt o nset, ste p wise deteri orati o n, 
s o matic c o m plai nts, e m oti o nal i nc o nti ne nce, hist or y of h y perte nsi o n, hist or y of str o ke, f ocal 
ne ur ol o gic si g ns, a n d f ocal ne ur ol o gic s y m pt o ms 5 6. T he  t otal sc ore ra n ges fr o m 0 t o 1 2, wit h 
hi g her sc ores i n dicati n g a greater ris k of vasc ular de me ntia. T he R ose n - m o difie d Hac hi ns ki 
Isc he mic Scale will be c o m plete d at t he Scree ni n g visit  t o assess t he ris k of vasc ular de me ntia 
a n d eli gi bilit y f or t he st u d y b y t he sa me p h ysicia n w h o perf or ms t he ne ur ol o gical e xa mi nati o n. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 3 
 
9.  
S C H E D U L E O F E V A U A TI O N S A N D P R O C E D U R E S  
A sc he d ule of e val uati o ns a n d pr oce d ures b y visit is pr o vi de d i n Ta ble  1. 
9. 1.  
Descri pti o n of St u d y Pr oce d ures  
At eac h visit t hr o u g h o ut t he st u d y, site staff will be re q uire d t o e nter i nf or mati o n i nt o t he I W R S 
re gar di n g patie nt data a n d pre defi ne d st u d y assess me nt res ults. F urt her i nstr ucti o ns will be 
pr o vi de d i n t he I W R S Site Ma n ual. 
9. 1. 1.  
Scree ni n g Visit ( D a ys - 2 8 t o -1)  
T he f oll o wi n g pr oce d ures will be perf or me d at Scree ni n g ( wit hi n 2 8 da ys pri or t o Da y 1). T he 
scree ni n g peri o d ma y be e xte n de d after disc ussi o n wit h a n d a p pr o val b y a Me dical M o nit or . I n 
t he e ve nt t hat a patie nt is rescree ne d f or e nr oll me nt, ne w i nf or me d c o nse nt a n d/ or asse nt 
d oc u me nts m ust be si g ne d, ne w patie nt n u m ber assi g ne d, a n d all scree ni n g pr oce d ures re peate d.  
1.  T he In vesti gat or will pr o vi de t he patie nts, a ut h orize d re prese ntati ves , a n d/ or t heir 
care gi vers wit h i nf or me d c o nse nt a n d/ or asse nt d oc u me nts a n d will e x plai n t he rati o nale  
f or t he st u d y, pr o vi di n g a m ple ti me f or partici pa nts, a ut h orize d re prese ntati ves, a n d/ or 
care gi vers t o as k q uesti o ns.  
2.  Re vie w i ncl usi o n/e xcl usi o n criteria ( pr ot oc ol eli gi bilit y f or m  c o m plete d b y site). 
3.  Me dical , ps yc hiatric, a n d ne ur ol o gical hist or y  will be re vie we d a n d rec or de d, i ncl u di n g 
patie nt de m o gra p hics, a n y pri or a n d c o nc o mita nt me dicati o ns (i ncl u di n g o ver- t he-c o u nter 
[O T C ], vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
4.  Ris k assess me nt f or falls will be perf or me d ( w or ks heet a n d T U G test ). 
5.  Vital si g ns will be meas ure d a n d rec or de d. 
6.  P h ysical a n d ne ur ol o gical e xa mi nati o n will be perf or me d . 
7.  T hree resti n g 1 2 -lea d E C Gs will be perf or me d. 
8.  A bl o o d a n d uri ne s peci me n will be c ollecte d f or safet y la b orat or y assess me nts (i ncl u di n g 
t h yr oi d f u ncti o n tests a n d H b A 1c) . 
9.  A uri ne pre g na nc y test will be perf or me d f or w o me n  of c hil d beari n g p ote ntial o nl y  
(Secti o n  8. 1. 7 ). 
1 0.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI- A A s h o ul d be 
a d mi nistere d  bef ore t he C GI S -A gitati o n ): 
•  C M AI  
•  N PI -A A d o mai n; a sc ore of ≥ 4 is re q uire d f or st u d y e ntr y 
•  C GI S -A gitati o n  
•  M M S E; a sc ore bet wee n 8 a n d 2 4 (i ncl usi ve) is re q uire d f or st u d y e ntr y 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 4 
 
•  S- S T S  
1 1.  Re gister t he Scree ni n g v isit i n I W R S. 
F oll o wi n g scree ni n g pr oce d ures f or assess me nt of i ncl usi o n a n d e xcl usi o n criteria, t he site will 
c o m plete a pr ot oc ol eli gi bilit y f or m t o be re vie we d b y a Me dical M o nit or f or a p pr o val pri or t o 
partici pati o n i n t he st u d y. Patie nts dee me d eli gi ble b y t he I n vesti gat or  a n d a Me dical M o nit or 
will pr ocee d t o t he Baseli ne visit of t he  st u d y.  
Patie nts w h o ha ve E C G or la b orat or y test res ults o utsi de of t he refere nce n or mal ra n ge t hat t he 
I n vesti gat or c o nsi ders t o be cli nicall y si g nifica nt a n d ma y p ut t he patie nt at a hi g her ris k f or 
st u d y partici pati o n, will n ot be e nr olle d.  
9. 1. 2.  
B aseli ne Visit ( D a y 1) 
T he Baseli ne visit (Da y  1) s h o ul d occ ur i n t he m or ni n g. T he f oll o wi n g pr oce d ures will be 
perf or me d . 
Bef ore D osi n g:  
1.  Re vie w i ncl usi o n/e xcl usi o n criteria.  
2.  Vital si g ns will be meas ure d a n d rec or de d. 
3.  Wei g ht a n d hei g ht will be meas ure d a n d rec or de d. 
4.  A resti n g 1 2- lea d E C G will be perf or me d (pre d ose ). 
5.  A uri ne pre g na nc y test will be perf or me d f or patie nts of c hil d beari n g p ote ntial o nl y 
(Secti o n  8. 1. 7 ). 
6.  T he care gi ver will be q uerie d re gar di n g A Es , c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
7.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI s h o ul d be a d mi nistere d 
bef ore t he C GI S -A gitati o n ): 
•  C M AI  
•  N PI  
•  C GI S -A gitati o n  
•  E Q - 5 D- 5 L 
•  R U D -Lite  
•  M M S E  
•  E S S  ( o nl y f or patie nts wit h a n M M S E sc ore of ≥ 1 0 at Baseli ne) 
•  S- S T S  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 5 
 
Patie nts will pr ocee d wit h t he Baseli ne visit  o nce it is deter mi ne d t hat t he y satisf y all of t he 
i ncl usi o n a n d n o ne of t he e xcl usi o n criteria ( o n t he basis of t he S cree ni n g a n d B aseli ne 
assess me nts descri be d a b o ve)  a n d will be assi g ne d wit h a blister car d  kit n u m ber via I W R S.  
St u d y Dr u g  D osi ng: 
T he first d ose of st u d y dr u g  will be a d mi nistere d at t he cli nic re gar dless of t he ti me of da y fr o m 
t he A M stri p of t he blister car d ( 1 -wee k blister car d) after pre d ose assess me nts are c o m plete d; 
n ote t he ti me of d osi n g.  
After D osi n g:  
1.  A resti n g 1 2- lea d E C G will be perf or me d ( 1 t o 1. 5  h o urs p ost d ose).  
2.  T he care gi ver will be q uerie d re gar di n g A Es.  
3.  Patie nt Diar y Car d a n d a blister car d ( 1 -wee k  blister car d) will be  dis pe nse d. 
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 7  da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns  
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d  visit 
( Visit 2, Da y 8), care gi vers will be a d vise d t hat t he patie nt’s m or ni n g d ose of st u d y dr u g  will be 
a d mi nistere d  at t he cli nic .  
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d  
of t he m.  
9. 1. 3.  
Visit  2 (D a y  8 ± 3-d a y wi n d o w)  
Visit  2 ( Da y  8) s h o ul d occ ur i n t he m or ni n g pri or t o t he m or ni n g d ose of st u d y dr u g. T he 
f oll o wi n g pr oce d ures will be perf or me d. 
Bef ore D osi n g:  
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  A resti n g 1 2- lea d E C G will be perf or me d ( pre d ose). 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 6 
 
4.  T he f oll o wi n g assess me nts will be c o m plete d ( t he C M AI a n d N PI s h o ul d be a d mi nistere d 
bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
5.  Re gister t he st u d y visit i n  I W R S a n d a blister car d  kit n u m ber will be assi g ne d t o patie nt 
( 1-wee k blister car d) . 
St u d y Dr u g D osi n g:  
T he m or ni n g d ose of st u d y dr u g will be a d mi nistere d at t he cli nic fr o m t he A M stri p of t he ne w 
blister car d ( 1 -wee k blister car d)  after pre d ose assess me nts are c o m plete d;  n ote t he ti me of 
d osi n g. 
After D osi n g:  
1.  A resti n g 1 2- lea d E C G will be perf or me d ( 1 t o 1. 5 h o urs p ost d ose). 
2.  A bl o o d a n d uri ne sa m ple will be c ollecte d f or P K assess me nts ( 1 t o 4 h o urs p ost d ose). 
3.  A bl o o d sa m ple will be c ollecte d f or C Y P 2 D 6  ge n ot y pi n g. 
4.  A bl o o d sa m ple will be c ollecte d f or a m yl oi d β bi o mar ker.  
5.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d  ( 1-wee k  blister car d) . 
6.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 7  da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d t he patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d 
visit ( Visit  3, Da y 1 5), care gi vers will be a d vise d t o a d mi nister t he m or ni n g d ose of st u d y dr u g t o 
t he patie nt pri or t o t he cli nic a p p oi nt me nt a n d n ote t he ti me of d osi n g. 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 7 
 
9. 1. 4.  
Visit  3 ( D a y 1 5 ± 3-d a y wi n d o w)  
Visit  3 ( Da y 1 5) s h o ul d occ ur i n t he m or ni n g. T he m or ni n g d ose of st u d y dr u g ca n be 
a d mi nistere d at h o me a n y ti me pri or t o t he visit; t he ti me of d osi n g s h o ul d be n ote d b y t he 
patie nt/care gi ver.  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 3: 
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI-A A  s h o ul d be 
a d mi nistere d bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI -A A  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
4.  Re gister st u d y visit i n I W R S a n d a blister car d kit n u m ber will be assi g ne d t o patie nt 
( 2-wee k  blister car d).  
5.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d ( 2 -wee k  blister car d) .  
6.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 1 4 da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d t he patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d 
visit ( Visit  4, Da y 2 9), care gi vers will be a d vise d t o a d mi nister t he m or ni n g d ose of st u d y dr u g t o 
t he patie nt pri or t o t he cli nic a p p oi nt me nt a n d n ote t he ti me of d osi n g. 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 8 
 
9. 1. 5.  
Visit  4 ( D a y 2 9 ± 3 -d a y wi n d o w)  
Visit  4 ( Da y  2 9) s h o ul d occ ur i n t he m or ni n g. T he m or ni n g d ose of st u d y dr u g ca n be 
a d mi nistere d at h o me a n y ti me pri or t o t he cli nic visit ; t he ti me of d osi n g s h o ul d be n ote d b y t he 
patie nt/care gi ver.  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit  4: 
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI- A A s h o ul d be 
a d mi nistere d bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI -A A  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
4.  Re gister st u d y visit i n I W R S a n d a blister car d kit n u m ber will be assi g ne d t o patie nt  
( 2-wee k  blister car d).  
5.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d ( 2- wee k  blister car d) .  
6.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 1 4  da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d t he patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d 
visit ( Visit  5, Da y 4 3), care gi vers will be a d vise d t hat t he patie nt’s m or ni n g d ose of st u d y dr u g 
will be a d mi nistere d  at t he cli nic . 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
4 9 
 
9. 1. 6.  
Visit  5 ( D a y 4 3 ± 3 -d a y wi n d o w ) 
Visit  5 ( Da y 4 3) s h o ul d occ ur i n t he m or ni n g pri or t o t he m or ni n g d ose of st u d y dr u g. T he 
f oll o wi n g pr oce d ures will be perf or me d at Visit 5. 
Bef ore D osi n g:  
1.  A bl o o d sa m ple will be c ollecte d f or safet y la b orat or y assess me nts  a n d P K assess me nts.  
T he f oll o wi n g pr oce d ures  m a y be perf or me d at a n y ti me:  
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  A resti n g 1 2- lea d E C G will be perf or me d (at a n y ti me d uri n g t his visit). 
4.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI s h o ul d be a d mi nistere d 
bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
5.  Re gister st u d y visit i n I W R S  a n d a blister car d kit n u m ber will be assi g ne d t o patie nt 
( 2-wee k blister car d) . 
6.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d ( 2 -wee k  blister car d) .  
7.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
St u d y Dr u g D osi n g : 
T he m or ni n g d ose of st u d y dr u g will be a d mi nistere d at t he cli nic fr o m t he A M stri p of t he ne w 
blister car d ( 2 -wee k blister car d) after pre d ose assess me nts are c o m plete d;  n ote t he ti me of 
d osi n g. 
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs 
± 4 h o urs) f or 1 4 da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d t he patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 0 
 
visit ( Visit  6, Da y 5 7), care gi vers will be a d vise d t o a d mi nister t he m or ni n g d ose of st u d y dr u g t o 
t he patie nt pri or t o t he cli nic a p p oi nt me nt a n d n ote t he ti me of d osi n g. 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  
9. 1. 7.  
Visit  6 ( D a y 5 7 ± 3 -d a y wi n d o w ) 
Visit  6 ( Da y  5 7) s h o ul d occ ur i n t he m or ni n g. T he m or ni n g d ose of st u d y dr u g ca n be 
a d mi nistere d at h o me a n y ti me pri or t o t he cli nic visit; t he ti me of d osi n g s h o ul d be n ote d b y t he 
patie nt/care gi ver.  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit  6: 
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI- A A s h o ul d be 
a d mi nistere d bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI -A A  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
4.  Re gister st u d y visit i n I W R S a n d a blister car d kit n u m ber will be assi g ne d t o patie nt 
( 2-wee k blister car d) . 
5.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d ( 2 -wee k  blister car d) . 
6.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 1 4  da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 
a n y u n use d st u d y dr u g a n d t he patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 1 
 
visit ( Visit  7, Da y  7 1), care gi vers will be a d vise d t o a d mi nister t he m or ni n g d ose of st u d y dr u g t o 
t he patie nt pri or t o t he cli nic a p p oi nt me nt a n d n ote t he ti me of d osi n g. 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  
9. 1. 8.  
Visit  7 ( D a y 7 1 ± 3 -d a y wi n d o w ) 
Visit  7 ( Da y  7 1) s h o ul d occ ur i n t he m or ni n g. T he m or ni n g d ose of st u d y dr u g ca n be 
a d mi nistere d at h o me a n y ti me bef ore t he cli nical visit; t he ti me of d osi n g s h o ul d be n ote d b y t he 
patie nt/care gi ver.  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit  7: 
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
3.  A bl o o d s a m ple will be c ollecte d f or P K assess me nts  (at a n y ti me d uri n g t his visit ). 
4.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI s h o ul d be a d mi nistere d 
bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
5.  Re gister st u d y visit i n I W R S a n d a blister car d kit n u m ber will be assi g ne d t o patie nt 
( 2-wee k blister car d) . 
6.  U n use d st u d y dr u g will be acc o u nte d f or c o m plia nce, a n d a ne w blister car d will be 
dis pe nse d ( 2 -wee k  blister car d) .  
7.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce a n d ret ur ne d t o t he patie nt.  
P atie nt/ C are gi ver I nstr ucti o n  
Care gi vers will be i nstr ucte d t o a d mi nister t o t he patie nt t he st u d y dr u g t wice-dail y ( 1  ca ps ule of 
st u d y dr u g fr o m t he t o p r o w [ A M] of blister car d i n t he m or ni n g a n d 1 ca ps ule of st u d y dr u g 
fr o m t he b ott o m r o w [ P M] of t he blister car d i n t he e ve ni n g, a p pr o xi matel y e ver y 1 2 h o urs ± 
4 h o urs) f or 1 4  da ys. 
T he I n vesti gat or a n d/ or st u d y c o or di nat or will gi ve patie nts a n d care gi vers detaile d i nstr ucti o ns 
re gar di n g st u d y pr oce d ures i ncl u di n g h o w t o c o m plete t he patie nt’s Diar y Car d. T he y will als o 
be i nstr ucte d t o c o ns ult wit h t he st u d y site pri or t o ta ki n g a n y n o n- st u d y me dicati o ns. T hese 
re q uire me nts will be re vie we d i n pers o n. Care gi vers will als o be i nstr ucte d t o bri n g t o t he cli nic 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 2 
 
a n y u n use d st u d y dr u g a n d patie nt’s Diar y Car d at eac h st u d y visit. F or t he ne xt sc he d ule d visit 
( Visit 8, Da y 8 5/ E T), care gi vers will be a d vise d t o a d mi nister t he m or ni n g d ose of st u d y dr u g t o 
t he patie nt pri or t o t he cli nic a p p oi nt me nt a n d n ote t he ti me of d osi n g. 
A C M AI care gi ver diar y will be pr o vi de d t o be use d b y t he care gi ver t o s u p p ort re p orti n g of 
be ha vi ors d uri n g t he C M AI i nter vie w pr ocess. 
Care gi vers will be q uerie d at t he e n d of eac h visit t o be certai n t he y u n dersta n d w hat is re q uire d 
of t he m.  
9. 1. 9.  
Visit  8 ( D a y 8 5 ± 3 -d a y wi n d o w ) / E arl y Ter mi n ati o n 
Visit  8 ( Da y  8 5/ E T) s h o ul d occ ur i n t he m or ni n g. T he m or ni n g d ose of st u d y dr u g ca n be 
a d mi nistere d at h o me a n y ti me pri or t o t he cli nic visit; t he ti me of d osi n g s h o ul d be n ote d b y t he 
patie nt/care gi ver.  
Patie nts w h o wit h dra w pri or t o st u d y c o m pleti o n are re q uire d t o c o m plete st u d y pr oce d ures as 
liste d f or Visit 8/ E T wit hi n 4 8 h o urs of t he last d ose of st u d y dr u g. 
T he f oll o wi n g pr oce d ures will be perf or me d at Visit  8 ( or E T): 
1.  Vital si g ns will be meas ure d a n d rec or de d. 
2.  Wei g ht will be meas ure d a n d rec or de d.  
3.  P h ysical a n d ne ur ol o gical e xa mi nati o n will be perf or me d . 
4.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
5.  A resti n g 1 2- lea d E C G will be perf or me d (a n y ti me d uri n g t his visit). 
6.  A bl o o d a n d uri ne s peci me n will be c ollecte d f or safet y la b orat or y assess me nts. 
7.  A uri ne pre g na nc y test will be perf or me d f or w o me n  of c hil d beari n g p ote ntial o nl y 
(Secti o n  8. 1. 7 ). 
8.  T he f oll o wi n g assess me nts will be c o m plete d  (t he C M AI a n d N PI s h o ul d be a d mi nistere d 
bef ore t he C GI S - A gitati o n a n d C GI C-A gitati o n ): 
•  C M AI  
•  N PI  
•  C GI S -A gitati o n  
•  C GI C -A gitati o n  
•  E Q - 5 D- 5 L 
•  R U D -Lite  
•  M M S E  
•  E S S ( o nl y f or patie nts wit h a n M M S E sc ore of ≥ 1 0 at Baseli ne) 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 3 
 
•  S- S T S  
9.  Re gister st u d y visit i n I W R S . 
1 0.  A n y u n use d st u d y dr u g will be ret ur ne d a n d acc o u nte d f or c o m plia nce. 
1 1.  Patie nt’s Diar y Car d will be re vie we d f or c o m plia nce.  
1 2.  A n y pre vi o usl y re p orte d a n d n ot yet res ol ve d A E a n d a n y ne wl y re p orte d A E at t he ti me 
of t his visit  will be f oll o we d - u p f or u p t o 3 0 da ys after t he last d ose of st u d y dr u g. 
1 3.  If E T, site staff will access C T S data base, e nter t he patie nt St u d y I D a n d nat ure of t he last 
c o ntact (ie, earl y ter mi nate d).  
Care gi vers a n d patie nts will be i nstr ucte d  t o ret ur n t o t he cli nic f or a F oll o w-u p visit 3 0  da ys 
after t he last d ose of st u d y dr u g. 
9. 1. 1 0.  
F oll o w- u p Visit ( 3 0  d a ys p ost l ast d ose; +  7- d a y wi n d o w) 
T he F oll o w- u p visit s h o ul d occ ur 3 0 da ys ( + 7- da y wi n d o w) after t he last d ose of st u d y dr u g.  
T he f oll o wi n g pr oce d ures will be perf or me d: 
1.  T he care gi ver will be q uerie d re gar di n g A Es, c o nc o mita nt me dicati o ns (i ncl u di n g O T C, 
vita mi ns, a n d s u p ple me nts), n o n dr u g t hera pies, a n d a n y n o n p har mac ol o gical 
i nter ve nti o ns f or t he treat me nt of a gitati o n. 
2.  T he f oll o wi n g assess me nts will be c o m plete d:  
•  C M AI (c o m plete d first)  
•  C GI S -A gitati o n  
3.  S ite staff will access t he C T S data base  a n d e nter t he patie nt St u d y I D a n d nat ure of t he 
last c o ntact (ie, c o m plete d st u d y). 
9. 2.  
E n d of Tri al  
T he e n d of t he trial is defi ne d as t he “ Last Patie nt Last Visit”, w hic h is t he date o n w hic h t he last  
patie nt has his or her last visit  (ie, t he F oll o w- u p visit) or assess me nt , eit her f or t hera pe utic or 
f oll o w- u p p ur p oses. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 4 
 
1 0.  
S T A TI S TI C S  
1 0. 1.  
S a m ple Size C alc ul ati o ns  
T he pla n ne d sa m ple size f or t his trial is a p pr o xi matel y 7 5 0 ra n d o mize d patie nts. Statistical 
ass u m pti o ns a n d a d diti o nal details are pr o vi de d i n t he S A P.  
1 0. 2.  
A n al ysis P o p ul ati o ns  
T he f oll o wi n g a nal ysis p o p ulati o n are defi ne d f or t his st u d y: 
•  E nr olle d: all patie nts e nr olle d i n t his st u d y  
•  Ra n d o mize d: all patie nts w h o are ra n d o mize d i nt o t his st u d y 
•  Safet y: all patie nts w h o are ra n d o mize d i n t his st u d y a n d ta ke at least o ne d ose of 
st u d y dr u g 
•  Efficac y: all patie nts i n t he ra n d o mize d p o p ulati o n w h o ta ke at least 1 d ose of st u d y 
dr u g, ha ve a baseli ne C M AI t otal sc ore , a n d at least 1 p ost baseli ne e val uati o n f or t he 
C M AI t otal sc ore.  
I n ge neral, baseli ne of a n efficac y e n d p oi nt is defi ne d as t he last o bser vati o n of t he e n d p oi nt 
bef ore t he patie nt is ra n d o mize d.  
T he c ore dataset f or all efficac y a nal yses is base d o n t he I T T p o p ulati o n, w hic h is defi ne d i n t he 
efficac y a nal ysis set a b o ve. As will be descri be d bel o w, i n or der t o ha n dle missi n g data a n d 
restricti o ns i m p ose d b y differe nt t y pes of a nal yses (e g, c ha n ge fr o m baseli ne a nal ysis), datasets 
deri ve d fr o m t he I T T p o p ulati o n will be use d f or t he efficac y a nal yses. 
1 0. 3.  
H a n dli n g of Missi n g D at a  
I n ge neral, missi n g data will be ha n dle d b y a nal ysis of mi xe d-effect m o del re peate d meas ures 
( M M R M) met h o d ol o g y base d o n o bser ve d-case ( O C) data fr o m pr ot oc ol s pecifie d visits i n t he 
I T T p o p ulati o n u n der t he ass u m pti o n of missi n g at ra n d o m. Details of se nsiti vit y a nal yses u n der 
t he ass u m pti o n of missi n g data bei n g missi n g n ot at ra n d o m ( M N A R) will be pr o vi de d i n t he 
S A P as well as a d diti o nal se nsiti vit y a nal yses, as a p plica ble.  
T he O C dataset c o nsists of act ual o bser vati o ns rec or de d at eac h visit d uri n g t he d o u ble- bli n d 
treat me nt peri o d, a n d n o missi n g data will be i m p ute d. 
1 0. 4.  
Effic ac y A n al ysis  
1 0. 4. 1.  
Pri m ar y Effic ac y E n d p oi nt  A n al ysis 
T he pri mar y efficac y e n d p oi nt is t he c ha n ge fr o m baseli ne t o t he e n d of t he efficac y peri o d i n t he 
C M AI t otal sc ore. T he c ha n ge fr o m baseli ne t o t he e n d of t he efficac y peri o d i n t he C M AI t otal 
sc ore will be a nal yze d usi n g a M M R M a nal ysis wit h a n u nstr uct ure d varia nce c o varia nce 
str uct ure ( U N). T he m o del will i ncl u de fi xe d class effect ter ms f or treat me nt, st u d y site, baseli ne 
c o nc o mita nt a nti ps yc h otic use ( yes/ n o), visit wee k, a n d a n i nteracti o n ter m of treat me nt b y visit 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 5 
 
wee k, a n d will i ncl u de t he i nteracti o n ter m of baseli ne val ues of t he C M AI t otal sc ore a n d  
N PI -A A sc ore b y visit wee k as a c o variate. All sc he d ule d visits after baseli ne d uri n g t he 
d o u ble- bli n d treat me nt peri o d will be i ncl u de d i n t he m o del.  
C o m plete details of t he pla n ne d statistical a nal ysis will be prese nte d i n t he S A P. Details of 
se nsiti vit y a nal yses f or M N A R, as well as a d diti o nal se nsiti vit y a nal yses will be pres pecifie d i n 
t he S A P. 
1 0. 4. 2.  
Ke y Sec o n d ar y A n al ysis  
T he ke y sec o n dar y efficac y varia ble is t he c ha n ge fr o m baseli ne t o e n d of efficac y peri o d i n t he 
C GI -S sc ore, as relate d t o a gitati o n. It will be a nal yze d b y t he sa me statistical met h o d ol o g y 
s pecifie d f or t he a nal ysis of t he pri mar y efficac y varia ble. T he pr oce d ure t o c o ntr ol t he o verall 
t y pe I err or rate f or t his ke y sec o n dar y efficac y a nal ysis will be descri be d i n t he S A P . 
1 0. 4. 3.  
Ot her Effic ac y E n d p oi nt A n al ysis 
Ot her efficac y varia bles i ncl u de t he f oll o wi n g:  
•  C ha n ge fr o m baseli ne t o eac h  st u d y visit i n efficac y peri o d i n C M AI T otal sc ore  
•  C ha n ge fr o m baseli ne t o eac h st u d y visit i n efficac y  peri o d i n C GI S- A gitati o n sc ore  
•  C GI C -A gitati o n sc ore at eac h st u d y visit i n t he efficac y peri o d  
•  C ha n ge fr o m baseli ne t o eac h st u d y visit i n  efficac y peri o d i n N PI-A A sc ore  
•  C ha n ge fr o m baseli ne t o eac h st u d y visit  i n efficac y peri o d i n N PI t otal sc ore  
•  C M AI Res p o nse Rate  at eac h st u d y visit i n efficac y peri o d, w here res p o nse is defi ne d 
as ≥ 3 0 % re d ucti o n i n C M AI T otal Sc ore fr o m baseli ne  
•  C M AI Res p o nse Rate  at eac h st u d y visit i n efficac y peri o d, w here res p o nse is defi ne d 
as ≥ 5 0 % re d ucti o n i n C M AI T otal Sc ore fr o m baseli ne  
•  C ha n ge fr o m baseli ne t o eac h st u d y visit i n efficac y peri o d i n t he E Q- 5 D-5 L t otal 
sc ore  
•  C ha n ge fr o m baseli ne t o eac h st u d y visit i n efficac y peri o d i n t he R U D-Lite  
C ha n ge fr o m baseli ne will be e val uate d usi n g t he sa me M M R M m o del descri be d i n t he pri mar y 
a nal ysis. 
C ha n ge fr o m baseli ne f or t he e n d p oi nts wit h o ne p ost baseli ne assess me nt will be e val uate d usi n g 
a nal ysis of c o varia nce ( A N C O V A ) wit h baseli ne val ue, st u d y site a n d baseli ne c o nc o mita nt 
a nti ps yc h otic use ( yes/ n o) as a c o variate a n d treat me nt as mai n fact or.  
T he res p o nse varia bles will be e val uate d b y t he C oc hra n -Ma ntel -Hae nszel ( C M H) Ge neral 
Ass ociati o n Test c o ntr olli n g, i n last- o bser vati o n- carrie d-f or war d ( L O C F) a nal yses, f or st u d y site 
a n d baseli ne c o nc o mita nt a nti ps yc h otic use ( yes/ n o). T he O C a nal ysis will n ot c o ntr ol f or 
stratificati o n fact ors. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 6 
 
T he C GI C - A gitati o n sc ore will be e val uate d b y t he C oc hra n –Ma ntel – Hae nszel r o w mea n sc ore 
differ test ( va n Elter n) , c o ntr olli n g f or st u d y site a n d baseli ne c o nc o mita nt a nti ps yc h otic use 
( yes/ n o) i n t he L O C F a nal ysis. T he O C a nal ysis will n ot c o ntr ol f or stratificati o n fact ors.  
F urt her details a n d a nal ysis met h o ds will be descri be d i n t he S A P . 
1 0. 4. 4.  
C o ntr ol of E x peri me nt -wise T y pe 1 Err or  
C o ntr ol of e x peri me nt - wise T y pe 1 err or is descri be d i n t he S A P. 
1 0. 4. 5.  
Ot her Effic ac y E n d p oi nt A n al yses  
A d diti o nal a nal ys es of efficac y e n d p oi nts are descri be d i n t he S A P. 
1 0. 5.  
I nteri m A n al ysis 
O ne i nteri m a nal ysis ma y be perf or me d ; the details of t he i nteri m a nal ysis will be pr o vi de d i n a n 
i nteri m a nal ysis pla n (I A P). 
1 0. 6.  
A n al ysis of De m o gr a p hic a n d B aseli ne C h ar acteristics  
De m o gra p hic c haracteristics a n d disease se verit y at baseli ne will be s u m marize d b y descri pti ve 
statistics, e g, pr o p orti o n, mea n, me dia n, sta n dar d de viati o n, a n d mi ni m u m a n d ma xi m u m val ues. 
1 0. 7.  
S afet y A n al ysis  
Sta n dar d safet y varia bles t o be a nal yze d i ncl u de A Es, cli nical la b orat or y tests, vital si g ns, E C Gs, 
a n d p h ysical a n d ne ur ol o gical e xa mi nati o n. I n a d diti o n, data fr o m t he f oll o wi n g safet y scales 
will be e val uate d: M M S E, E S S, a n d  S-S T S. Safet y a nal ysis will be c o n d ucte d base d o n t he 
Safet y P o p ulati o n. I n ge neral, baseli ne of a safet y varia ble is defi ne d as t he last o bser vati o n of 
t he varia ble bef ore ta ki n g t he first d ose of st u d y dr u g, u nless s pecifie d ot her wise. Pr os pecti vel y 
defi ne d cri teria will be use d t o i de ntif y p ote ntiall y cli nicall y rele va nt a b n or mal val ues f or cli nical 
la b orat or y tests, vital si g ns, E C Gs. Details of safet y a nal yses will be pr o vi de d i n t he S A P. 
1 0. 7. 1.  
A d verse E ve nts  
All A Es will be c o de d b y s yste m or ga n class a n d Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) preferre d ter m. T he i nci de nce of t he f oll o wi n g e ve nts will be s u m marize d b y 
treat me nt gr o u p: 
•  T E A Es  
•  T E A Es b y se verit y  
•  T E A Es p ote ntiall y ca usall y relate d t o t he st u d y dr u g  
•  T E A Es wit h a n o utc o me of deat h 
•  Seri o us T E A Es  
•  T E A Es lea di n g t o disc o nti n uati o n of t he st u d y dr u g 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 7 
 
T he a b o ve s u m maries will als o be pre pare d f or T E A Es p ote ntiall y ca usall y relate d t o t he st u d y 
dr u g. 
1 0. 7. 2.  
Cli nic al L a b or at or y D at a  
S u m mar y statistics f or c ha n ges fr o m baseli ne i n t he r o uti ne cli nical la b orat or y meas ure me nts 
will be pr o vi de d. I n a d diti o n, t he i nci de nce of p ote ntiall y cli nicall y rele va nt val ues i de ntifie d 
usi n g pr os pecti vel y defi ne d criteria f or la b orat or y tests will be  s u m marize d. 
1 0. 7. 3.  
P h ysic al a n d Ne ur ol o gic al E x a mi n ati o n a n d Vit al Si g n D at a  
P h ysical a n d ne ur ol o gical e xa mi nati o n fi n di n gs will be liste d b y patie nt. P ote ntiall y cli nicall y 
rele va nt res ults i n vital si g ns a n d b o d y wei g ht will als o be s u m marize d. S u m mar y statistics f or 
c ha n ge fr o m baseli ne i n vital si g ns will be pr o vi de d. 
1 0. 7. 4.  
Electr oc ar di o gr a m D at a  
Mea n c ha n ge fr o m baseli ne will be s u m marize d b y treat me nt gr o u p a n d b y visit. I nci de nce of 
cli nicall y rele va nt c ha n ges will be calc ulate d f or E C G para meters a n d s u m marize d b y treat me nt 
gr o u p a n d b y visit. 
T he a nal ysis of Q T a n d c orrecte d Q T i nter val ( Q Tc) data fr o m 3 c o nsec uti ve c o m ple xes 
(re prese nti n g 3 c o nsec uti ve heart beats) will be meas ure d t o deter mi ne a vera ge val ues. T he 
f oll o wi n g Q T c orrecti o ns will be use d: 
•  Q Tc F is t he le n gt h of t he Q T i nter val c orrecte d f or heart rate b y t he Fri dericia’s 
f or m ula:  Q Tc F = Q T/( R R) 0. 3 3  
Res ults will be s u m marize d b y visit.  
1 0. 7. 5.  
Ot her S afet y D at a  
C ha n ge fr o m baseli ne i n sc ores f or t he M M S E  a n d E S S will be e val uate d usi n g A N C O V A wit h 
baseli ne val ue as a c o variate a n d treat me nt as mai n fact ors. T he a nal yses will be base d o n t he O C 
a n d L O C F datasets of t he Safet y P o p ulati o n.  
T he s uici dalit y (e g, S- S T S) will be s u m marize d b y treat me nt gr o u p base d o n t he O C dataset of 
t he Safet y P o p ulati o n. Details will be descri be d i n S A P. 
1 0. 7. 6.  
D at a a n d S afet y M o nit ori n g B o ar d 
T he S p o ns or will a p p oi nt a Data a n d Safet y M o nit ori n g B oar d ( D S M B) f or t he peri o dic re vie w 
of a vaila ble st u d y data. 
T he D S M B is a n i n de pe n de nt gr o u p of e x perts t hat a d vises t he S p o ns or a n d t he st u d y 
I n vesti gat ors. T he me m bers of t he D S M B ser ve i n a n i n di vi d ual ca pacit y a n d pr o vi de t heir 
e x pertise a n d rec o m me n dati o ns. T he pri mar y res p o nsi bilities of t he D S M B are t o 
( 1) peri o dicall y re vie w a n d e val uate t he acc u m ulate d st u d y data f or partici pa nt safet y, st u d y 
c o n d uct a n d pr o gress, a n d ( 2)  ma ke rec o m me n dati o ns t o t he S p o ns or c o ncer ni n g t he 
c o nti n uati o n, m o dificati o n, or ter mi nati o n of t he st u d y.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 8 
 
T he D S M B c o nsi ders st u d y -s pecific data as well as rele va nt bac k gr o u n d k n o wle d ge a b o ut t he 
disease, test a ge nt, or patie nt p o p ulati o n u n der st u d y. 
T he D S M B is res p o nsi ble f or defi ni n g its deli berati ve pr ocesses, i ncl u di n g e ve nt tri g gers t hat 
w o ul d call f or a n u nsc he d ule d re vie w, st o p pi n g g ui deli nes, u n mas ki n g, a n d v oti n g pr oce d ures 
pri or t o i nitiati n g a n y data re vie w. T he D S M B is als o res p o nsi ble f or  mai ntai ni n g t he 
c o nfi de ntialit y of its i nter nal disc ussi o ns a n d acti vities as well as t he c o nte nts of re p orts pr o vi de d 
t o it. 
D uri n g t he c o n d uct of t he A V P- 7 8 6 de vel o p me nt pr o gra m, t he e xter nal D S M B c o m prisi n g of 
2 ps yc hiatrists, a geriatricia n, a ne ur ol o gist a n d a bi o metricia n m o nit ors t he u n bli n de d A E pr ofile 
of A V P - 7 8 6 e ver y 3 t o 4 m o nt hs. A d diti o nal details a b o ut t he D S M B ca n be f o u n d i n t he D S M B 
c harter. 
1 0. 8.  
Ot her A n al yses  
1 0. 8. 1.  
P h ar m ac o ki netic A n al ysis  
N o P K a nal ysis is pla n ne d , as o nl y s parse sa m ples will be o btai ne d. Plas ma c o nce ntrati o ns of 
d 6- D M , its meta b olites d 3- D X a n d d 3- 3-M M,  a n d Q will be s u m marize d usi n g descri pti ve 
statistics b y d ose a n d ti me p oi nt. Uri ne  c o nce ntrati o ns of d 6-D M a n d its meta b olite d 3 -D X will 
be s u m marize d usi n g descri pti ve statistics b y d ose a n d ti me p oi nt. 
1 0. 8. 2.  
P h ar m ac o d y n a mic A n al ysis 
N o p har mac o d y na mic ( P D) a nal ysis is pla n ne d.  
1 0. 8. 3.  
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al ysis 
A p o p ulati o n or P K/ P D  m o deli n g ma y be perf or me d usi n g t he data fr o m t his st u d y a n d ot her 
st u dies a n d w o ul d be re p orte d se paratel y. 
1 0. 8. 4.  
P h ar m ac o ge n o mic A n al ysis 
C Y P 2 D 6 ge n ot y pe a n d pre dicte d p he n ot y pe will be liste d f or all patie nts b y treat me nt gr o u p. 
1 0. 8. 5.  
E x pl or at or y E n d p oi nt A n al ysis 
E x pl orat or y e n d p oi nt a nal ysis will be descri be d i n t he S A P. 

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
5 9 
 
1 1.  
E T HI C S  
1 1. 1.  
Et hic al C o n d uct of t he St u d y  
T his st u d y will be c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve t heir ori gi n i n 
t he Declarati o n 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 nce 
( CI O M S); a n d will be c o nsiste nt wit h G C P, I C H G ui deli nes, a n d t he U nite d States ( U S) F o o d 
a n d Dr u g A d mi nistrati o n ( F D A) C F R ( 2 1 C F R Parts 5 0 a n d 5 6) f or t he pr otecti o n of t he ri g hts 
a n d welfare of h u ma n patie nts partici pati n g i n bi o me dical researc h, a n d t he a p pli ca ble re g ulat or y 
re q uire me nts. 
1 1. 2.  
I nstit uti o n al Re vie w B o ar d - Et hics Re vie w  
All I nstit uti o nal Re vie w B oar ds /I n de pe n de nt Et hics  C o m mittee  (I R Bs/I E Cs/ E Cs) m ust meet t he 
re q uire me nts as descri be d i n Part 5 6, Title  2 1 of t he C o de of Fe deral Re g ulati o ns ( C F R) a n d 
c o nf or m t o l ocal la ws a n d c ust o ms w here a p pr o priate. Writte n I R B/I E C/ E C a p pr o val f or t he 
pr ot oc ol a n d t he si g ne d I C F m ust be o btai ne d a n d tra ns mitte d t o t he S p o ns or or its re prese ntati ve 
bef ore t he st u d y ca n be i nitiate d.  
T he pr ot oc ol, t he pr ot oc ol a me n d me nts, a n d t he sa m ple I C F m ust be re vie we d a n d a p pr o ve d b y 
a n I R B/I E C/ E C of t he partici pati n g st u d y ce nter i n acc or da nce wit h t he C F R, t he I nter nati o nal 
C o nfere nce o n Har m o nisati o n (I C H), a n d G o o d Cli nical Practice ( G C P) bef ore i nitiati o n of t he 
st u d y at t heir res pecti ve ce nter. All pr ot oc ol a me n d me nts a n d a n y c ha n ges t o t he IC F t hat 
occ urre d d uri n g t he st u d y m ust be a p pr o ve d b y t he S p o ns or a n d t he I R B/I E C/ E C. 
T he I n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or ma nce wit h l ocal la ws a n d 
acc or di n g t o Nati o nal a n d State la ws of t he U S ( I n vesti gat or Res p o nsi bilities 5 7 a n d t he W orl d 
Me dical Ass ociati o n Declarati o n of Helsi n k i). T he Pri nci pal I n vesti gat or is res p o nsi ble f or 
i nf or mi n g t he I R B/I E C/ E C of a n y a me n d me nt t o t he pr ot oc ol i n acc or da nce wit h l ocal 
re q uire me nts. I n a d diti o n, t he I R B/I E C/ E C m ust a p pr o ve all a d vertisi n g use d t o recr uit patie nts 
f or t he st u d y. T he pr ot oc ol m ust be re-a p pr o ve d b y t he I R B/I E C/ E C u p o n recei pt of a me n d me nts 
a n d a n n uall y, as l ocal re g ulati o ns re q uire. 
T he Pri nci pal I n vesti gat or is als o res p o nsi ble f or pr o vi di n g t he I R B/I E C/ E C wit h re p orts of a n y 
re p orta ble seri o us a d verse dr u g reacti o ns fr o m a n y ot her st u d y c o n d ucte d wit h t he st u d y dr u g. 
T he S p o ns or will pr o vi de t his i nf or mati o n t o t he PI.  
Pr o gress re p orts a n d n otificati o ns of seri o us a d verse dr u g reacti o ns will be pr o vi de d t o t he 
I R B/I E C/ E C acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes. 
1 1. 3.  
Writte n I nf or me d C o nse nt  
T he I C F will f oll o w t he pri nci ples o utli ne d i n t he c urre nt versi o n of t he Declarati o n of Helsi n ki. 
F or eac h patie nt f o u n d t o be eli gi ble f or t he st u d y, i nf or me d c o nse nt will be o btai ne d fr o m t he 
patie nt (if t he patie nt is ca pa ble i n t he j u d g me nt of t he I n vesti gat or  t o pr o vi de i nf or me d c o nse nt) 
or t he a ut h orize d re prese ntati ve as deter mi ne d b y l ocal re g ulati o ns. F or patie nts w h o are n ot 
ca pa ble of pr o vi di n g i nf or me d c o nse nt, b ut are ca pa ble of pr o vi di n g asse nt, t he patie nt will be 
as ke d t o pr o vi de asse nt. If  t he patie nt is n ot ca pa ble of pr o vi di n g asse nt, t he I n vesti gat or will 

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d oc u me nt t he reas o ns w h y a n d mai ntai n t hat d oc u me ntati o n wit h t he ot her i nf or me d c o nse nt 
d oc u me nts. T he patie nt’s care gi ver will als o be as ke d t o pr o vi de i nf or me d c o nse nt as t he y will 
be pr o vi di n g data o n t he msel ves a n d t he patie nt, as well as, bei n g res p o nsi ble f or e ns uri n g 
c o m plia nce fr o m t he patie nt bet wee n st u d y visits.  
T he patie nts a n d/ or patie nt’s a ut h orize d re prese ntati ve a n d t he care gi ver will be pr o perl y 
i nf or me d of t he p ur p ose of t he st u d y. T he patie nts a n d/ or patie nt’s a ut h orize d re prese ntati ve a n d 
t he care gi ver will be alerte d t o a n y a ntici pate d A E t hat ma y be e nco u ntere d wit h t he st u d y dr u g. 
A si g ne d I C F will be o btai ne d fr o m all patie nts a n d/ or patie nt’s a ut h orize d re prese ntati ve a n d t he 
care gi ver pri or t o patie nt e ntr y i nt o t his st u d y. Patie nts a n d/ or patie nt’s a ut h orize d re prese ntati ve 
a n d t he care gi ver will be pr o vi de d wit h a c o p y of t heir si g ne d a n d date d I C F. 
T he I n vesti gat ors or desi g nee will als o e x plai n t he I R B/I E C/ E C-a p pr o ve d S u bject Data base 
A ut h orizati o n t o t he patie nt a n d wit ness t he si g nat ure. All partici pa nts will als o be i nf or me d t hat 
t heir me dical rec or ds will be ke pt c o nfi de ntial e xce pt f or re vie w b y t he S p o ns or or its 
re prese ntati ves, t he U S F D A, or ot her re g ulat or y a ge ncies if a p plica ble. 

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1 2.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Sta n dar ds f or G C P a n d t he et hical re q uire me nts e q ui vale nt t o t he pr o visi o ns of 
Directi ve  2 0 0 1/ 2 0/ E C ( Cli nical Trials Directi ve) m ust be a d here d t o f or all st u d y -base d 
pr oce d ures. 
1 2. 1.  
D oc u me nt ati o n  
F or eac h pr ocess, e val uati o n, or test t hat ge nerates st u d y data b ut is n ot descri be d i n t he pr ot oc ol 
or e C R F, a writte n descri pti o n of t he data ge nerati o n pr oce d ures s hall be retai ne d i n t he q ualit y 
ass ura nce secti o n of t he st u d y files. I n t he case of r o ut i ne cli nical dia g n ostic pr oce d ures, o nl y a 
c o p y of t he rele va nt certificati o n d oc u me nt is re q uire d.  
1 2. 2.  
St u d y M o nit ori n g  
T hr o u g h o ut t he c o urse of t he st u d y, t he st u d y m o nit or will ma ke fre q ue nt c o ntacts wit h t he 
I n vesti gat or. T his will i ncl u de tele p h o ne calls a n d o n-site visits. T he st u d y will be r o uti nel y 
m o nit ore d t o e ns ure c o m plia nce wit h t he st u d y pr ot oc ol a n d t he o verall q ualit y of data c ollecte d. 
As part of t he data a u dit, s o urce d oc u me nts will be ma de a vaila ble f or re v ie w b y t he st u d y 
m o nit or. T he st u d y m o nit or ma y peri o dicall y re q uest re vie w of t he I n vesti gat or st u d y file t o 
ass ure t he c o m plete ness of d oc u me ntati o n i n all res pects of cli nical st u d y c o n d uct.  
T he st u d y m o nit or will verif y t hat eac h patie nt has pr o per c o nse nt d oc u me ntati o n fr o m t he 
patie nt a n d/ or patie nt’s a ut h orize d re prese ntati ve a n d t he care gi ver f or st u d y pr oce d ures a n d f or 
t he release of me dical rec or ds t o t he S p o ns or, F D A, ot her re g ulat or y a ut h orities, a n d t he 
I R B/I E C/ E C. T he st u d y m o nit or will als o verif y t hat asse nt was o btai ne d f or patie nts n ot ca pa ble 
of pr o vi di n g i nf or me d c o nse nt or t hat d oc u me ntati o n is pr o vi de d b y t he I n vesti gat or e x plai ni n g 
w h y t he patie nt was u na ble t o pr o vi de asse nt. T he I n vesti gat or or a p p oi nte d dele gate will recei ve 
t he st u d y m o nit or d uri n g t hese o n-site visits a n d will c o o perate i n pr o vi di n g t he d oc u me nts f or 
i ns pecti o n a n d res p o n d t o i n q uiries. I n a d diti o n, t he I n vesti gat or will per mit i ns pecti o n of t he 
st u d y files b y a ut h orize d re prese ntati ves of t he re g ulat or y a ge ncies. 
O n c o m pleti o n of t he st u d y, t he st u d y m o nit or will arra n ge f or a fi nal re vie w of t he st u d y files 
after w hic h t he files s h o ul d be sec ure d f or t he a p pr o priate ti me peri o d.  
1 2. 3.  
Direct Access t o S o urce D at a/ D oc u me nts f or A u dits a n d I ns pecti o ns  
T he I n vesti gat or s h o ul d u n dersta n d t hat s o urce d oc u me nts f or t his st u d y s h o ul d be ma de 
a vaila ble t o a p pr o priatel y q ualifie d pers o n nel or desi g nee(s) fr o m t he S p o ns or or t o healt h 
a ut h orit y i ns pect ors after a p pr o priate n otificati o n. T he verificati o n of t he data ma y be b y direct 
i ns pecti o n of s o urce d oc u me nts ( w here per mitte d b y la w) or t hr o u g h a n i nter vie w e xc ha n ge. 
T he i ns pect or fr o m t he re g ulat or y a ut h orit y will be es peciall y i ntereste d i n t he f oll o wi n g ite ms:  
•  Visits fr o m t he S p o ns or ’s re prese ntati ves 
•  I R B/I E C/ E C a p pr o val(s) 
•  St u d y dr u g acc o u nta bilit y 

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•  St u d y pr ot oc ol a n d a me n d me nts 
•  I C Fs of t he patie nt (if ca pa ble of pr o vi di n g I C F, acc or di n g t o t he I n vesti gat or) or 
patie nt’s a ut h orize d re prese ntati ves a n d care gi vers  
•  Asse nt of t he patie nts (if ca pa ble of pr o vi di n g asse nt, acc or di n g t o t he I n vesti gat or) 
•  Me dical rec or ds s u p p orti ve of e C R F data 
•  Re p orts t o t he I R B/I E C/ E C a n d t he S p o ns or 
•  Rec or d rete nti o n  
T he S p o ns or will be a vaila ble t o hel p I n vesti gat ors pre pare f or a n i ns pecti o n. 

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1 3.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 3. 1.  
D at a M a n a ge me nt a n d C ollecti o n  
T he S p o ns or or desi g nate d re prese ntati ve (e g, c o ntract researc h or ga nizati o n ) will perf or m t he 
data ma na ge me nt acti vities i n acc or da nce wit h t he data ma na ge me nt pla n ( D M P). T he D M P will 
o utli ne t he s yste ms a n d pr oce d ures t o be use d i n t he st u d y. 
S o urce d oc u me nts a n d s o urce data will be ca pt ure d electr o nicall y ( w here per mitte d b y l ocal 
re g ulati o n) i n t his trial a n d will meet t he sa me f u n da me ntal ele me nts of data q ualit y (e g, 
attri b uta ble, le gi ble, c o nte m p ora ne o us, ori gi nal, a n d acc urate) as pa per rec or ds. T hese data will 
be c ollecte d i nt o a s yste m t hat is f ull y vali date d acc or di n g t o 2 1 C F R Part 1 1. C ha n ges t o t he 
data will be ca pt ure d b y a n a ut o matic a u dit trail. 
I nf or mati o n t o be ori gi nall y ca pt ure d a n d re vie we d electr o nicall y s hall i ncl u de details of t he 
s u bject visit a n d t he pr ot oc ol re q uire d assess me nts perf or me d as a part of t hese visits, me dical 
hist or y, A Es, a n d c o nc o mita nt me dicati o ns. Beca use t his trial is usi n g a n electr o nic s o urce rec or d 
as t he ori gi nal p oi nt of data ca pt ure, t here is n o a d diti o nal data e ntr y ste p f or t he trial site f or data 
c ollecte d directl y i nt o t he a p plicati o n, rat her, t he electr o nic s o urce rec or d directl y p o p ulates t he 
trial data base. 
S o me data ma y be ca pt ure d via pa per a n d t he n e ntere d i nt o t he e S o urce s yste m. T hese a n d a n y 
ot her data treate d i n t his ma n ner will be s o urce data verifie d per t he m o nit ori n g pla n a n d t he 
l ocati o n of t he s o urce data (ie, e S o urce, pa per, or a l ocal electr o nic s yste m) will be d oc u me nte d 
bef ore t he trial start. A n y c ha n ges t o i nf or mati o n i n pa per s o urce d oc u me nts will be i nitiale d a n d 
date d o n t he da y t he c ha n ge is ma de b y a trial site staff me m ber a ut h orize d t o ma ke t he c ha n ge. 
C ha n ges will be ma de b y stri ki n g  a si n gle li ne t hr o u g h err o ne o us data (s o as n ot t o o bliterate t he 
ori gi nal data), a n d clearl y e nteri n g t he c orrect data (e g , wr o n g data ri g ht data). If t he reas o n f or 
t he c ha n ge is n ot a p pare nt, a brief e x pla nati o n f or t he c ha n ge will be writte n i n t he s o urce 
d oc u me ntati o n b y t he I n vesti gat or or t heir desi g nee.  
A n ot her e xce pti o n will be safet y la b orat or y [ or ce ntral E C G data], w here t he official s o urce 
d oc u me ntati o n will be c o nsi dere d t he re p ort iss ue d b y t he a nal yzi n g la b orat or y. 
Desi g nate d trial site staff will n ot be gi ve n access t o t he electr o nic s o urce s yste m u ntil t he y ha ve 
bee n a p pr o priatel y trai ne d. All st u d y -site pers o n nel m ust use a pass w or d- pr otecte d user acc o u nt 
t o e nter, re vie w, or c orrect st u d y data. Electr o nic si g nat ure pr oce d ures s hall c o m pl y wit h t he 
C F R  Title  2 1 Part 1 1. Pass w or ds will be strictl y c o nfi de ntial.  
All e C R F data will be e x p orte d fr o m t he electr o nic data ca pt ure ( E D C) s yste m a n d tra nsferre d t o  
t he S p o ns or or re prese ntati ve. T he S p o ns or or re prese ntati ve will als o recei ve electr o nic tra nsfers  
of n o n- e C R F data s uc h as la b orat or y data fr o m t he ce ntral la b orat or y, E C G data fr o m t he ce ntral  
E C G rea der, as well as ot her data fr o m t hir d - part y ve n d ors as a p pr o priate. T he electr o nic data 
f or mat of all tra nsfers will be a gree d u p o n wit h t he S p o ns or or re prese ntati ve a n d d oc u me nte d i n 
t he D M P or ve n d or data tra nsfer re q uire me nts d oc u me nt as a p pr o priate. 
Re m ote m o nit ori n g of t he ori gi nal electr o nic s o urce rec or ds will ta ke place; h o we ver, o n site 
m o nit ori n g i ns pecti o ns will c o nti n ue t o ta ke place i n or der t o re vie w data e ntr y of s o urce 
d oc u me ntati o n directl y ca pt ure d o n pa per a n d tra nscri be d i nt o t he s yste m, t o e ns ure pr ot oc ol 

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a d here nce, t o assess trial site o perati o nal ca pa bilities a n d t o perf or m ot her m o nit ori n g acti vities 
t hat ca n n ot be perf or me d re m otel y. 
T he cli nical m o nit ori n g staff will perf or m s o urce data verificati o n of t he data rec or de d i n  t he 
E D C s yste m acc or di n g t o t he data  ma na ge me nt pla n a n d cli nical m o nit ori n g pla n. T he data will 
be s u bjecte d t o c o nsiste nc y a n d  vali dati o n c hec ks wit hi n t he E D C s yste m wit h s u p ple me ntal data 
re vie ws perf or me d o utsi de of t he E D C s yste m. 
Me dical hist or y a n d a d verse e ve nts will be c o de d usi n g a c urre nt versi o n of Me d D R A, a n d 
c o nc o mita nt me dicati o ns usi n g a c urre nt versi o n of t he W H O Dr u g Dicti o nar y. T he S p o ns or or 
re prese ntati ve will perf or m a me dical safet y re vie w of t he c o di n g. 
At t he e n d of t he trial, t he I n vesti gat or m ust certif y t hat t he data e ntere d i nt o t he e S o urce 
a p plicati o n are c o m plete a n d acc urate. After data base l oc k, t he I n vesti gat or will recei ve a n 
electr o nic c o p y of t he s u bject data. C o m plete d e C R F i ma ges wit h a date - a n d ti me-sta m pe d 
electr o nic a u dit trail i n dicati n g t he user,  t he data e ntere d, a n d a n y reas o n f or c ha n ge (if 
a p plica ble) will be arc hi ve d at t he I n vesti gat or’s  site a n d at t he S p o ns or ’s site. 
1 3. 2.  
S o urce D at a  
S o urce d oc u me nts are defi ne d as t he res ults of ori gi nal o bser vati o ns a n d acti vities of a cli nical 
i n vesti gati o n. S o urce d oc u me nts will i ncl u de b ut are n ot li mite d t o me dical rec or ds, electr o nic 
data, l o gs, a n d rec or de d data fr o m a ut o mate d i nstr u me nts or a p plicati o ns. 
Data will be defi ne d a n d d oc u me nte d i n t he i n- h o use st u d y master file i ncl u di n g t he perce nta ge 
of eac h of t he s o urce data t o be verifie d a n d t he perce nta ge of patie nts’ data t o be m o nit ore d. 
1 3. 3.  
Rete nti o n of Rec or ds  
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y a ut h orities or t he S p o ns or , t he I n vesti gat or 
a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y of all partici pati n g patie nts (s ufficie nt i nf or mati o n 
t o li n k rec or ds, e g, e C R Fs a n d h os pital rec or ds), all ori gi nal si g ne d I C Fs, c o pies of all e C R Fs, 
S A E f or ms, s o urce d oc u me nts, a n d detaile d rec or ds of treat me nt dis p ositi o n, a n d a de q uate 
d oc u me ntati o n of rele va nt c orres p o n de nce (e g, letters, meeti n g mi n utes, tele p h o ne call re p orts). 
T he rec or ds s h o ul d be retai ne d b y t he I n vesti gat or acc or di n g t o I nter nati o nal C o nfere nce o n 
Har m o nizati o n sta n dar ds, l ocal re g ulati o ns, or as s pecifie d i n t he Cli nical Trial A gree me nt, 
w hic he ver is l o n ger.  
If t he I n vesti gat or bec o mes u na ble f or a n y reas o n t o c o nti n ue t o retai n st u d y rec or ds f or t he 
re q uire d peri o d (e g, retire me nt, rel ocati o n), t he S p o ns or s h o ul d be pr os pecti vel y n otifie d. T he 
st u d y rec or ds m ust be tra nsferre d t o a desi g nee acce pta ble b y t he S p o ns or, s uc h as a n ot her 
I n vesti gat or, a n ot her i nstit uti o n, or t o t he S p o ns or. T he I n vesti gat or m ust o btai n t he S p o ns or’s 
writte n per missi o n bef ore dis p osi n g of a n y rec or ds, e ve n if rete nti o n re q uire me nts ha ve bee n 
met.  
1 3. 4.  
C o nfi de nti alit y of St u d y D oc u me nts a n d P atie nt Rec or ds  
All i nf or mati o n ge nerate d i n t his trial will be c o nsi dere d c o nfi de ntial a n d will n ot be discl ose d t o 
a n y o ne n ot directl y c o ncer ne d wit h t he trial wit h o ut t he S p o ns or ’s pri or writte n per missi o n. 

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S u bject c o nfi de ntialit y re q uire me nts of t he re gi o n(s) w here t he trial is c o n d ucte d will be met. 
H o we ver, a ut h orize d re g ulat or y officials a n d s p o ns or pers o n nel ( or t heir re prese ntati ves) ma y be 
all o we d f ull access t o i ns pect a n d c o p y t he rec or ds, c o nsiste nt wit h l ocal re q uire me nts. All I M Ps, 
s u bject b o dil y fl ui ds, a n d/ or ot her materials c ollecte d s hall be use d s olel y i n acc or da nce wit h t his 
pr ot oc ol, u nless ot her wise a gree d t o i n writi n g b y t he S p o ns or. 
S u bjects will be i de ntifie d o nl y b y u ni q ue s u bject I D. If f urt her s u bject i de ntificati o n is re q uire d, 
s u bjects’ f ull na mes ma y be ma de k n o w n t o a re g ulat or y a ge nc y or ot her a ut h orize d officials if 
necessar y, s u bject t o l ocal re g ulati o ns.  
T he I n vesti gat or s h o ul d kee p a se parate l o g of patie nt’s c o des, na mes, a n d a d dresses. D oc u me nts 
n ot f or s u b missi o n t o t he S p o ns or, f or e xa m ple, patie nts’ si g ne d I C Fs, s h o ul d be mai ntai ne d b y 
t he I n vesti gat or i n strict c o nfi de nce. 
1 3. 5.  
Re p orts  
At t he c o m pleti o n of t he st u d y, t he I n vesti gat or s hall pr o vi de t he S p o ns or wit h a n a de q uate 
re p ort s h ortl y after c o m pleti o n of t he I n vesti gat or's partici pati o n i n t he st u d y as descri be d i n C F R 
Title  2 1, Part 3 1 2. 6 4. 

C O N FI D E N TI A L  
 
O P D C  
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A V P - 7 8 6 
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6 6 
 
1 4.  
C RI T E RI A F O R S T U D Y T E R MI N A TI O N  
B ot h t he S p o ns or a n d t he Pri nci pal I n vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y at t he site 
at a n y ti me. S h o ul d t his be necessar y, t he pr oce d ures t o effect st u d y ter mi nati o n will be arra n ge d 
after re vie w a n d c o ns ultati o n b y b ot h parties. I n ter mi nati n g t he st u d y, t he S p o ns or a n d t he 
I n vesti gat or will ass ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’s 
i nterests. 

C O N FI D E N TI A L  
 
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A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
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1 5.  
P U B LI C A TI O N P O LI C Y  
It is a ntici pate d t hat a re p ort of t his st u d y will be p u blis he d i n t he scie ntific literat ure b y t he 
S p o ns or. T he I n vesti gat or will n ot see k t o arra n ge f or p u blicati o n of a n y of t he i nf or mati o n or 
res ults fr o m t he st u d y i n a n y scie ntific j o ur nal, or ot her p u blicati o n or b y wa y of lect ure wit h o ut 
t he S p o ns or’s pri or re vie w a n d writte n c o nse nt. 

C O N FI D E N TI A L  
 
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A V P - 7 8 6 
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6 8 
 
1 6.  
LI S T O F R E F E R E N C E S  
Refere nce List  
1.  
htt ps:// w w w. alz. or g/ alz h ei m ers - d e m e nti a/f acts-fi g ur es . 2 0 1 9. 
2.  
Pl ass m a n BL L K Fis h er G G, H e eri n g a S G, W eir D R, Ofst e d al M B, et al. Pr ev al e nc e of d e m e nti a i n t h e U nit e d 
St at es: T h e A gi n g, D e m o gr a p hics, a n d M e m ory St u dy. N e ur o e pi d e mi ol o gy . 2 0 0 7; 2 9( 1-2): 1 2 5 -3 2.  
3.  
Wils o n R S W D L e ur g a ns S E, Ev a ns D A, H e b ert L E, L a n g a K M, et al. S o urc es of v ari a bilit y i n esti m at es of t h e 
pr ev al e nc e of Alz h ei m er’s dis e as e i n t h e U nit e d St at es. Alz h ei m ers D e m e nt . 2 0 1 1; 7( 1): 7 4-9.  
4.  
St ei n b er g M, S h a o H, Z a n di P, et al. P oi nt a n d 5 -y e ar p eri o d pr ev al e nc e of n e ur o psyc hi atric sy m pt o ms i n 
d e m e nti a: t h e C ac h e C o u nty St u dy. I nt J G eri atr Psyc hi atry. 2 0 0 8; 2 3( 2): 1 7 0-7.  
5.  
F a ut h E B, Gi b b o ns A. W hic h b e h a vi or al a n d psyc h ol o gic al sy m pt o ms of d e m e nti a ar e t h e m ost 
pr o bl e m atic ? V ari a bilit y b y pr e v al e nc e, i nt e nsit y, distr ess r ati n gs, a n d ass oci ati o ns wit h c ar e giv er 
d e pr essi v e s y m pt o ms. I nt J G eri atr Psyc hi atry. 2 0 1 4; 2 9( 3): 2 6 3-7 1.  
6.  
B orsj e P, W etz els R B, L uc ass e n PL, P ot A M, K o o p m a ns R T. T h e c o urs e of n e ur o psyc hi atric sy m pt o ms i n 
c o m m u nity-d w elli n g p ati e nts wit h d e m e nti a: a syst e m atic r evi e w. I nt Psyc h o g eri atr. 2 0 1 5; 2 7( 3): 3 8 5-4 0 5.  
7.  
W etz els R B, Z ui d e m a S U, d e J o n g h e J F M, V er h e y F RJ, K o o p m a ns R T C M. C o urs e of n e ur o psyc hi atric 
sy m pt o ms i n r esi d e nts wit h d e m e nti a i n n ursi n g h o m es o v er 2-y e ar p eri o d. A m J G eri atr Psyc hi atry . 
2 0 1 0; 1 8( 1 2): 1 0 5 4 -6 5.  
8.  
G a ut hi er S, L o p ez OL, W al d e m ar G, et al. Eff ects of d o n e p ezil o n activiti es of d aily livi n g: i nt e gr at e d 
a n al ysis of p ati e nt d at a fr o m st u di es i n mil d, m o d er at e a n d s ev er e Alz h ei m er’s dis e as e. I nt Psyc h o g eri atr. 
2 0 1 0; 2 2( 6): 9 7 3 -8 3.  
9.  
A n atc h k o v a M, Br o o ks A, S w ett L, et al. A git ati o n i n p ati e nts wit h d e m e nti a: a syst e m atic r evi e w of 
e pi d e mi ol o g y a n d ass oci ati o n wit h s ev erit y a n d c o urs e. I nt Psyc h o g eri atr. 2 0 1 9; 1 1: 1-1 4.  
1 0.   
C o n d e-S al a JL, T urr o -G arri g a O, Pi n a n -H er n a n d ez S, et al. Eff ects of a n os o g n osi a a n d n e ur o psyc hi atric 
sy m pt o ms o n t h e q u alit y of lif e of p ati e nts wit h Alz h ei m er’s dis e as e: a 2 4 -m o nt h f oll o w -u p st u dy. I nt J 
G eri atr Psyc hi atry . 2 0 1 6; 3 1( 2): 1 0 9-1 9.  
1 1.  
L a y b o ur n e A, Li vi n gst o n G, C o usi ns S, et al. C ar er c o pi n g a n d r esi d e nt a git ati o n as pr e dict ors of q u alit y of 
lif e i n c ar e h o m e r esi d e nts livi n g wit h d e m e nti a: M a n a gi n g A git ati o n a n d R aisi n g Q u alit y of Lif e ( M A R Q U E) 
E n glis h n ati o n al c ar e h o m e pr os p ecti v e c o h ort st u dy. I nt J G eri atr Psyc hi atry. 2 0 1 9; 3 4( 1): 1 0 6-1 1 3.  
1 2.  
Livi n gst o n G, B ar b er J, M arst o n L, et al. Pr ev al e nc e of a n d ass oci ati o ns wit h a git ati o n i n r esi d e nts wit h 
d e m e nti a livi n g i n c ar e h o m es: M A R Q U E cr oss -s ecti o n al st u dy. BJ Psyc h O p e n . 2 0 1 7; 3( 4): 1 7 1-1 7 8.  
1 3.  
K n a p p M, C h u a K -C, Br o a d b e nt M, et al. Pr e dict ors of c ar e h o m e a n d h os pit al a d missi o ns a n d t h eir c osts 
f or ol d er p e o pl e wit h Alz h ei m er’s dis e as e: fi n di n gs fr o m a l ar g e L o n d o n c as e r e gist er. B MJ O p e n . 
2 0 1 6; 6( 1 1): e 0 1 3 5 9 1.  
1 4.  
S e n a n ar o n g V, J a mj u mr as P, H ar m p h a d u n gkit K, et al. A c o u ns eli n g i nt erv e nti o n f or c ar e giv ers: eff ect o n 
n e ur o psyc hi atric s y m pt o ms. I nt J G eri atr Psyc hi atry. 2 0 0 4; 1 9( 8): 7 8 1-8.  
1 5.  
Is m ail M S, D a g er m a n K, T ari ot P N, A b b ott S, K a v a n a g h S, Sc h n ei d er L S. N ati o n al I nstit ut e of M e nt al H e alt h 
Cli nic al A nti psyc h otic Tri als of I nt erv e nti o n Eff ectiv e n ess - Alz h ei m er’s Dis e as e ( C A TI E -A D): b as eli n e 
c h ar act eristics. C urr Alz h ei m er R es . 2 0 0 7; 4( 3): 3 2 5-3 5.  
1 6.  
H uis I n H et V el d J, V er k ai k R, v a n M eij el B, et al. S elf -m a n a g e m e nt by f a mily c ar e giv ers t o m a n a g e c h a n g es 
i n t h e b e h a vi or a n d m o o d of t h eir r el ativ e wit h d e m e nti a: a n o nli n e f oc us gr o u p st u dy. B M C G eri atr . 
2 0 1 6; 1 6: 9 5.  
1 7.  
d e M a ul e o n A, S ot o M, O uss et PJ, N o ur h as h e mi F, L e p a g e B, V ell as B. P ot e nti all y m o difi a bl e f act ors 
ass oci at e d wit h a git ati o n a n d a g gr essi o n i n Alz h ei m er’s dis e as e: r es ults of t h e I C T U S st u d y. I nt 
Psyc h o g eri atr . 2 0 1 9; 3 1( 1 0): 1 5 0 9-1 5 1 6.  
1 8.  
S hi n H -Y, C h u n g E -K, R h e e J -A, Y o o n J -S, Ki m J -M. [ Pr ev al e nc e a n d r el at e d f act ors of d e m e nti a i n a n ur b a n 
el d erl y p o p ul ati o n usi n g a n e w scr e e ni n g m et h o d]. J Pr ev M e d P u blic H e alt h. 2 0 0 5; 3 8( 3): 3 5 1-8.  
1 9.  
C ost a N, W u b k er A, D e M a ul e o n A, et al. C osts of C ar e of A git ati o n Ass oci at e d Wit h D e m e nti a i n 8 
E ur o p e a n C o u ntri es: R es ults Fr o m t h e Ri g ht Ti m e Pl ac e C ar e St u d y. J A m M e d Dir Ass oc. 2 0 1 8; 1 9( 1): 9 5. e 1-
9 5. e 1 0.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
6 9 
 
2 0.  
Y u X, C h e n S, C h e n X, et al. Cli nic al m a n a g e m e nt a n d ass oci at e d c osts f or m o d er at e a n d s ev er e 
Alz h ei m er’s dis e as e i n ur b a n C hi n a: a D el p hi p a n el st u dy. Tr a nsl N e ur o d e g e n er . 2 0 1 5; 4: 1 5. 
2 1.  
V ossi us C, S el b a e k G, S alt yt e B e nt h J, Wi m o A, B er g h S. T h e us e of dir ect c ar e i n n ursi n g h o m e r esi d e nts: A 
l o n git u di n al c o h ort st u d y o v er 3 y e ars. I nt J G eri atr Psyc hi atry. 2 0 1 9; 3 4( 2): 3 3 7-3 5 1.  
2 2.  
Z a h o d n e L B, Or nst ei n K, C os e nti n o S, D ev a n a n d D P, St er n Y. L o n git u di n al r el ati o ns hi ps b et w e e n Alz h ei m er 
dis e as e pr o gr essi o n a n d ps yc h osis, d e pr ess e d m o o d, a n d a git ati o n/ a g gr essi o n. A m J G eri atr Psyc hi atry . 
2 0 1 5; 2 3( 2): 1 3 0 -4 0.  
2 3.  
P et ers M E, Sc h w artz S, H a n D, et al. N e ur o psyc hi atric sy m pt o ms as pr e dict ors of pr o gr essi o n t o s ev er e 
Alz h ei m er’s d e m e nti a a n d d e at h: t h e C ac h e C o u nty D e m e nti a Pr o gr essi o n St u d y. A m J Psyc hi atry . 
2 0 1 5; 1 7 2( 5): 4 6 0 -5.  
2 4.  
S a m ps o n EL, W hit e N, L or d K, et al. P ai n, a git ati o n, a n d b e h a vi o ur al pr o bl e ms i n p e o pl e wit h d e m e nti a 
a d mitt e d t o g e n er al h os pit al w ar ds: a l o n git u di n al c o h ort st u dy. P ai n . 2 0 1 5; 1 5 6( 4): 6 7 5-8 3.  
2 5.  
A h m e d M, M ali k M, T es eli n k J, L a nct ot KL, H err m a n n N. C urr e nt A g e nts i n D ev el o p m e nt f or Tr e ati n g 
B e h a vi or al a n d Ps yc h ol o gic al S y m pt o ms Ass oci at e d wit h D e m e nti a. Dr u gs A gi n g . 2 0 1 9; 3 6( 7): 5 8 9-6 0 5.  
2 6.  
S eitz D P, Gill S S, H err m a n n N, et al. P h ar m ac ol o gic al tr e at m e nts f or n e ur o psyc hi atric sy m pt o ms of 
d e m e nti a i n l o n g -t er m c ar e: a s yst e m atic r evi e w. I nt Psyc h o g eri atr. 2 0 1 3; 2 5( 2): 1 8 5-2 0 3.  
2 7.  
B a n erj e e S. T h e us e of a nti ps yc h otic m e dic ati o n f or p e o pl e wit h d e m e nti a: Ti m e f or acti o n. T h e I nstit ut e 
of Psyc hi atry . 2 0 0 9. 
2 8.  
Mc D er m ott CL, Gr u e n e w al d D A. P h ar m ac ol o gic M a n a g e m e nt of A git ati o n i n P ati e nts wit h D e m e nti a. C urr 
G eri atr R e p . 2 0 1 9; 8( 1): 1-1 1.  
2 9.  
M a h er A R, M a gli o n e M, B a gl e y S, et al. Effic ac y a n d c o m p ar ativ e eff ectiv e n ess of aty pic al a nti psyc h otic 
m e dic ati o ns f or   off-l a b el us es i n a d ults: a syst e m atic r evi e w a n d m et a-a n al ysis. J A M A. 
2 0 1 1; 3 0 6( 1 2): 1 3 5 9 -6 9.  
3 0.  
P a n el A. U p d at e d A G S B e ers Crit eri a ® f or p ot e nti ally i n a p pr o pri at e m e dic ati o n us e i n ol d er a d ults. J A m 
G eri atr S oc . 2 0 1 9; 6 7( 4): 6 7 4-6 9 4.  
3 1.  
G ar a y R P, Citr o m e L, Gr oss b er g G T, C a v er o I, Ll orc a P -M. I n v esti g ati o n al dr u gs f or tr e ati n g a git ati o n i n 
p ers o ns wit h d e m e nti a. Ex p ert O pi n I nv esti g Dr u gs . 2 0 1 6; 2 5( 8): 9 7 3-8 3.  
3 2.  
Mc K h a n n G M, K n o p m a n D S, C h ert k o w H, et al. T h e di a g n osis of d e m e nti a d u e t o Alz h ei m er’s dis e as e: 
r ec o m m e n d ati o ns fr o m t h e N ati o n al I nstit ut e o n A gi n g-Alz h ei m er’s Ass oci ati o n w or k gr o u ps o n di a g n ostic 
g ui d eli n es f or Alz h ei m er’s dis e as e. Alz h ei m ers D e m e nt . 2 0 1 1; 7( 3): 2 6 3-9.  
3 3.  
C u m mi n gs J, Mi ntz er J, Br o d at y H, et al. A git ati o n i n c o g nitiv e dis or d ers: I nt er n ati o n al Psyc h o g eri atric 
Ass oci ati o n pr o visi o n al c o ns e ns us cli nic al a n d r es e arc h d efi niti o n. I nt Psyc h o g eri atr. 2 0 1 5; 2 7( 1): 7-1 7.  
3 4.   
C o h e n-M a nsfi el d J, M arx M S, R os e nt h al A S. A d escri pti o n of a git ati o n i n a n ursi n g h o m e. J G er o nt ol. 
1 9 8 9; 4 4( 3): M 7 7 -8 4.  
3 5.   
C o h e n-M a nsfi el d J. A git at e d b e h a vi ors i n t h e el d erl y. II. Pr eli mi n ary r es ults i n t h e c o g nitiv el y d et eri or at e d. 
J A m G eri atr S oc. 1 9 8 6; 3 4( 1 0): 7 2 2-7.  
3 6.  
R a bi n o witz J, D a vi ds o n M, D e D P P, K atz I, Br o d at y H, C o h e n -M a nsfi el d J. F act or a n alysis of t h e C o h e n -
M a nsfi el d A git ati o n I n v e nt ory i n t hr e e l ar g e s a m pl es of n ursi n g h o m e p ati e nts wit h d e m e nti a a n d 
b e h a vi or al dist ur b a nc e. A m eric a n J o ur n al of G eri atric Psyc hi atry . 2 0 0 5; 1 3( 1 1): 9 9 1-9 9 8.  
3 7.  
T ari ot P N, Er b R, P o d g ors ki C A, et al. Effic acy a n d t ol er a bilit y of c ar b a m az e pi n e f or a git ati o n a n d 
a g gr essi o n i n d e m e nti a. A m J Psyc hi atry . 1 9 9 8; 1 5 5( 1): 5 4-6 1.  
3 8.  
L a ks J, E n g el h ar dt E, M ari n h o V, et al. Effic acy a n d s af et y of ris p eri d o n e or al s ol uti o n i n a git ati o n 
ass oci at e d wit h d e m e nti a i n t h e el d erly. Ar q N e ur o psi q ui atr . 2 0 0 1; 5 9( 4): 8 5 9-6 4.  
3 9.  
R a vi n a B, P utt M, Si d er o wf A, et al. D o n e p ezil f or d e m e nti a i n P ar ki ns o n’s dis e as e: a r a n d o mis e d, d o u bl e 
bli n d, pl ac e b o c o ntr oll e d, cr oss o v er st u d y. J N e ur ol N e ur os ur g Psyc hi atry. 2 0 0 5; 7 6( 7): 9 3 4-9.  
4 0.  
C a kir S, K ul a ksiz o gl u I B. T h e effic acy of mirt az a pi n e i n a git at e d p ati e nts wit h Alz h ei m er’s dis e as e: A 1 2 -
w e e k o p e n -l a b el pil ot st u d y. N e ur o psyc hi atr Dis Tr e at . 2 0 0 8; 4( 5): 9 6 3-6.  
4 1.  
L es e m M D, Tr a n-J o h ns o n T K, Ri es e n b er g R A, et al. R a pi d ac ut e tr e at m e nt of a git ati o n i n i n divi d u als wit h 
sc hiz o p hr e ni a: m ultic e ntr e, r a n d o mis e d, pl ac e b o-c o ntr oll e d st u d y of i n h al e d l ox a pi n e. Br J Psyc hi atry . 
2 0 1 1; 1 9 8( 1): 5 1 -8.  
4 2.  
G u y W. E C D E U Ass ess m e nt M a n u al f or Psyc h o p h ar m ac ol o g y. 1 9 7 6: 7 6 -3 3 8.  

C O N FI D E N TI A L  
 
O P D C  
Pr ot oc ol 2 0- A V P - 7 8 6- 3 0 6 
 
A V P - 7 8 6 
Pr ot oc ol A me n d me nt 2, Versi o n 3 . 0  
 
 
 
 
7 0 
 
4 3.  
D a hl k e F, L o h a us A, G utz m a n n H. R eli a bilit y a n d cli nic al c o nc e pts u n d erlyi n g gl o b al j u d g m e nts i n 
d e m e nti a: i m plic ati o ns f or cli nic al r es e arc h. Psyc h o p h ar m ac ol B ull . 1 9 9 2; 2 8( 4): 4 2 5-3 2.  
4 4.  
L e o n A C, S h e ar M K, Kl er m a n GL, P ort er a L, R os e n b a u m J F, G ol d e n b er g I. A c o m p aris o n of sy m pt o m 
d et er mi n a nts of p ati e nt a n d cli nici a n gl o b al r ati n gs i n p ati e nts wit h p a nic dis or d er a n d d e pr essi o n. J Cli n 
Psyc h o p h ar m ac ol . 1 9 9 3; 1 3( 5): 3 2 7-3 1.  
4 5.  
S p e ari n g M K, P ost R M, L e v eric h G S, Br a n dt D, N ol e n W. M o dific ati o n of t h e Cli nic al Gl o b al I m pr essi o ns 
( C GI) Sc al e f or us e i n bi p ol ar ill n ess ( B P): t h e C GI-B P. Psyc hi atry R es . 1 9 9 7; 7 3( 3): 1 5 9-7 1.  
4 6.  
C u m mi n gs JL, M e g a M, Gr a y K, R os e n b er g -T h o m ps o n S, C ar usi D A, G or n b ei n J. T h e N e ur o psyc hi atric 
I n v e nt or y: c o m pr e h e nsiv e ass ess m e nt of psyc h o p at h ol o gy i n d e m e nti a. N e ur ol o gy . 1 9 9 4; 4 4( 1 2): 2 3 0 8-1 4.  
4 7.   
E ur o Q ol--a n e w f acilit y f or t h e m e as ur e m e nt of h e alt h -r el at e d q u alit y of lif e. H e alt h P olicy . 
1 9 9 0; 1 6( 3): 1 9 9 -2 0 8.  
4 8.  
Wi m o A W A M ast e y V, Wi n bl a d B. E v al u ati o n of t h e r es o urc e utiliz ati o n a n d c ar e giv er ti m e i n a nti -
d e m e nti a dr u g tri als – a q u a ntit ativ e b att ery. H e alt h ec o n o mics of d e m e nti a . 1 9 9 8: 4 6 5-4 9 9.  
4 9.  
G ust a vss o n A, C att eli n F, J o nss o n L. C osts of c ar e i n a mil d -t o-m o d er at e Alz h ei m er cli nic al tri al s a m pl e: k e y 
r es o urc es a n d t h eir d et er mi n a nts. Alz h ei m ers D e m e nt . 2 0 1 1; 7( 4): 4 6 6-7 3.  
5 0.  
Wi m o A, G ust avss o n A, J o nss o n L, Wi n bl a d B, Hs u M -A, G a n n o n B. A p plic ati o n of R es o urc e Utiliz ati o n i n 
D e m e nti a ( R U D) i nstr u m e nt i n a gl o b al s etti n g. Alz h ei m ers D e m e nt . 2 0 1 3; 9( 4): 4 2 9-4 3 5. e 1 7.  
5 1.  
F olst ei n M F, F olst ei n S E, Mc H u g h P R. “ Mi ni-m e nt al st at e”. A pr actic al m et h o d f or gr a di n g t h e c o g nitiv e 
st at e of p ati e nts f or t h e cli nici a n. J Psyc hi atr R es. 1 9 7 5; 1 2( 3): 1 8 9-9 8.  
5 2.  
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