Clinical trial NCT04408755
Conditions: Agitation in Patients With Dementia of the Alzheimer's Type
Keywords: Agitation Dementia of the Alzheimer's type Alzheimer's disease AVP-786 Deudextromethorphan hydrobromide Quinidine sulfate
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2020-07-13; Completion date: 2024-06-27
Enrollment: 184 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was conducted to evaluate the efficacy, safety, and tolerability of AVP-786 (deudextromethorphan hydrobromide \[d6-DM\]/quinidine sulfate \[Q\]) compared to placebo for the treatment of agitation in participants with dementia of the Alzheimer's type.

Detailed description:
Eligible participants for this study had a diagnosis of probable Alzheimer's disease (AD) and had clinically significant, moderate/severe agitation secondary to AD.

This was a multicenter, randomized, double-blind, placebo-controlled study, consisting of 12 weeks of treatment. Screening occurred within 4 weeks prior to randomization. Following screening procedures for assessment of inclusion and exclusion criteria, eligible participants were randomized into the study.

184 participants were enrolled into the study.

Study medication was administered orally twice daily from Day 1 through Day 85.

Arms: arm 1: Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786 matching placebo capsules, twice a day, for 11 weeks in Period B. arm 2: Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786-18 (d6-DM 18 milligrams (mg)/Q 4.9 mg) capsules, twice a day, for 11 weeks in Period B. arm 3: Participants who were enrolled in 1-week double-blind placebo lead-in Period A, were then randomized to receive AVP-786-42.63 (d6-DM 42.63 mg/Q 4.9 mg) capsules, twice a day, for 11 weeks in Period B.
Interventions: intervention 1: AVP-786 intervention 2: Placebo
Intervention descriptions: intervention 1: oral capsules intervention 2: oral capsules

Protocol documents:
Prot_000.pdf: 
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  
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 
 
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  
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 
 
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  
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 
 
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  
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 
 
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  
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 
 
 
 
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  
 
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 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  
 
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 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  
 
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 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).  


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 7 
 
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. 


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 8 
 
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  


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 9 
 
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 


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 0 
 
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. 


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 1 
 
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 


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 2 
 
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. 


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 3 
 
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  
 
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 4 
 
( 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 


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 0 
 
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. 


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 1 
 
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 


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 2 
 
•  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. 


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 3 
 
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 


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 4 
 
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. 


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 5 
 
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  
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 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  
 
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 7 
 
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  
 
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 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.  
J o h ns M W. A n e w m et h o d f or m e as uri n g d ayti m e sl e e pi n ess: t h e E p w ort h sl e e pi n ess sc al e. Sl e e p . 
1 9 9 1; 1 4( 6): 5 4 0 -5.  
5 3.  
S h e e h a n D V, Gi d d e ns J M, S h e e h a n I S. St at us U p d at e o n t h e S h e e h a n -S uici d alit y Tr ac ki n g Sc al e ( S -S T S) 
2 0 1 4. I n n ov Cli n N e ur osci. 2 0 1 4; 1 1( 9-1 0): 9 3 -1 4 0.  
5 4.  
P o dsi a dl o D, Ric h ar ds o n S. T h e ti m e d “ U p & G o”: a t est of b asic f u ncti o n al m o bilit y f or fr ail el d erl y 
p ers o ns. J A m G eri atr S oc. 1 9 9 1; 3 9( 2): 1 4 2-8.  
5 5.  
S h u m w ay -C o ok a, B al d wi n M, P oliss ar NL, Gr u b er W. Pr e dicti n g t h e pr o b a bilit y f or f alls i n c o m m u nit y -
d w elli n g ol d er a d ults. P hys T h er . 1 9 9 7; 7 7( 8): 8 1 2-9.  
5 6.  
R os e n W G, T err y R D, F ul d P A, K atz m a n R, P ec k A. P at h ol o gic al v erific ati o n of isc h e mic sc or e i n 
diff er e nti ati o n of d e m e nti as. A n n N e ur ol . 1 9 8 0; 7( 5): 4 8 6-8.  
5 7.  
I N T E R N A TI O N AL C F H. htt ps:// w w w.ic h. or g/ p a g e/ effic acy-g ui d eli n es. N ov e m b er 2 0 1 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  
 
 
 
 
7 1 
 
1 7.  
S U M M A R Y O F C H A N G E S  
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  
 
 
 
7 2 
 
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  
 
 
 
 
7 3 
 
1 8.  
A P P E N DI C E S  
A p pe n di x 1  
Pr o hi bite d C o nc o mita nt Me dicati 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  
 
 
 
7 4 
 
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  
 
 
 
7 5 
 
C CI

SAP_001.pdf: 
Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1










Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
6


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
7


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
8




Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
11


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
12






Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
15


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
16


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
17




Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
19


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
20


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
22


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
23


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
24


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
25


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
27


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
28










Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
33


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
34




Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
36


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
37


Abbreviated Clinical Study Report 20-AVP-786-306
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
38


CCI


CCI


CCI


CCI


CCI