A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of CTP-692 as an Adjunctive Treatment in Adult Patients With Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: Concert Pharmaceuticals



 
 
 
                                                                                       
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C T P - 6 9 2 
C P 6 9 2. 2 0 0 1 
 
A R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D  S T U D Y T O  
E V A L U A T E T H E S A F E T Y A N D E F FI C A C Y O F C T P -6 9 2 A S A N A D J U N C TI V E 
T R E A T M E N T I N A D U L T P A TI E N T S W I T H S C HI Z O P H R E NI A  
 
I N V E S TI G A TI O N A L P R O D U C T (I P): 
C T P -6 9 2  
   P R O T O C O L N U M B E R:  
C P 6 9 2. 2 0 0 1 , A me n d me nt # 3 
O RI GI N A L P R O T O C O L : 
A M E N D M E N T # 1:  
A M E N D M E N T # 2:  
A M E N D M E N T # 3:  
2 9 A u g ust 2 0 1 9 
1 6 Oct o ber 2 0 1 9 
1 1 Fe br u ar y 2 0 2 0 
1 4  A pril 2 0 2 0  
E u dr a C T N U M B E R:  
N/ A  
I N D N U M B E R: 
1 3 8, 9 1 2 
S P O N S O R N A M E / A D D R E S S:  
C o ncert P har mace uticals, I n c.  
6 5 Ha y de n A v e n ue, S uite 3 0 0 0 N 
Le xi n gt o n, M A  0 2 4 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O N FI D E N TI A L  
T his pr ot o c ol is pr o vi d e d t o y o u as a n I nvesti g at or, p ote nti al I nvesti g at or, or c o ns ult a nt f or 
revie w b y y o u, y o ur st aff, a n d et hics c o m mittee/i nstit uti o n al revie w b o ar d.  T he i nf or m ati o n 
c o nt ai ne d i n t his d o c u m e nt is re g ar d e d as c o nfi d e nti al a n d, e x ce pt t o t he e xte nt necess ary t o 
o bt ai n i nf or m e d c o nse nt, m a y n ot b e discl ose d t o a n ot her p arty u nless s uc h discl os ure is 
re q uire d b y l a w or re g ul ati o ns.  Pers o ns t o w h o m t he i nf or m ati o n is discl ose d m ust b e 
i nf or m e d t h at t he i nf or m ati o n is c o nfi d e nti al a n d m a y n ot b e f urt her discl ose d b y t he m. 
 

 
 
 
                                                                                       
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 / E M E R G E N C Y C O N T A C T I N F O R M A TI O N  
 
 
C o nt act I nf or m ati o n 
N a me  
Dr.
A d dress  
 
P h o ne  
F acsi mile  
E m ail  
 
 
S P O N S O R  C O N T A C T I N F O R M A TI O N  
 
C o nt act I nf or m ati o n 
N a me  
P h o ne / E m ail 
/
N a me  
P h o ne / E m ail 
/
 
 
 
 
 
 
 
 
 
 
 

 
 
 
                                                                                       
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SI T E P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E P A G E  
 
P R O T O C O L TI T L E: A 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  E v al uate the 
Safet y a n d Efficac y of C T P - 6 9 2 as a n A dj u ncti ve Treat me nt in A d ult Patie nts w it h 
Sc hiz o p hre nia 
 
Pr ot oc ol N u m ber:  C P 6 9 2. 2 0 0 1  
 
 
 
 
 
Si g n at ure of Site Pri nci p al I n vesti g at or 
 
d d m m m y y y y 
 
 
Pri nt e d N a me of Site Pri nci p al I n vesti g at or  
I nstit uti o n N a me:  
B y m y si g n at ure, I a gree t o pers o nall y s u p er vise t he c o n d uct of t his st u d y at m y st u d y 
site a n d t o e ns ure its c o n d uct is i n c o m plia nce wit h t he pr ot oc ol, i nf or me d c o nse nt, 
I nstit uti o nal Re vie w B oar ds (I R Bs) pr oce d ures, i nstr ucti o ns fr o m C o ncert 
re pres e ntati ves, t he D ecl arati o n of H elsi n ki, I nter nati o nal C o u ncil f or Har m o nizati o n  
(I C H) G o o d Cli nical Practices G ui deli nes, a n d l o cal re g ulati o ns g o ver ni n g t he c o n d uct 
of cli nical st u dies.  
 

 
 
 
                                                                                       
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1.  
S Y N O P SI S  
 
N a me of S p o ns or/ C o m p a n y:  C o ncert P har mace uticals, I n c.  
N a me of I n vesti g ati o n al Pr o d uct:  C T P - 6 9 2 
Title of St u d y:  A 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 E val uate t he Safet y  a n d 
Efficac y  of C T P -6 9 2 as a n A dj u ncti ve Treat me nt i n A d ult Patie nts wit h Sc hiz o p hre nia  
St u d y Ce nter(s): A p pr o xi matel y 2 2 cli nical sites i n t he U S  
St u d y D ur ati o n ( ye ars): A p pr o xi matel y 1 year 
P h ase of De vel o p me nt:  2 
O bjecti ves: T h e o bjecti v e of t his st u d y is t o assess t he safet y a n d efficac y of 3 differe nt d oses of C T P-
6 9 2 a d mi nistere d o nce d ail y f or 1 2 wee ks t o a d ult patie nts wit h sc hiz o p hre nia o n sta ble d o pa mi ner gic 
a nti ps yc h otic me di cati o n . 
St u d y Desi g n a n d Met h o d ol o g y:  T his is a ra n d o mize d, d o u ble- bli n d, parallel gr o u p, pl ace b o -
c o ntr olle d, m ultice nter st u d y .  At Scr ee ni n g , p ote ntial st u d y p artici pa nts m ust ha ve a Dia g n ostic a n d 
Statistical Ma n ual -V ( D S M - V) dia g n osis of sc hiz o p hre nia f or at least 2 year s a n d c o nfir me d b y 
ps yc hiatric e v al uati o n a n d MI NI I nter nati o nal Ne ur o ps yc hiatric I nt er vie w ( MI NI ).  T h e st u d y will 
i n v ol ve patie nt partici pati o n f or u p t o 2 0 wee ks a n d will c o nsist of a 5- wee k Scree ni n g / Q ualificati o n 
Peri o d  (t his peri o d ma y b e e xte n de d u p t o 2 wee ks if re peat la b orat or y test res ults f or c o nfir mati o n of 
eli gi bilit y are pe n di n g) a n d a 1 2- wee k Treat me nt Peri o d .  A safet y f oll o w- u p visit will occ ur 
a p pr o xi matel y 1 wee k  aft er t he last d ose of St u d y Me dicati o n .  A p pr o xi matel y 3 0 0 p atie nts, 1 8- 5 5 years 
ol d, will be ra n d o mize d t o recei v e 1 of 3 d oses of C T P- 6 9 2 or P lace b o.  T h ere will be 2 
Scree ni n g/ Q ualificati o n Visits:  At t he first Scree ni n g Visit ( Wee k - 5) p atie nts will pr o vi de i nf or me d 
c o nse nt a n d will be assesse d f or eli gi bilit y bas e d o n st u d y i ncl usi o n a n d e x cl usi o n criteria, i ncl u di n g a 
t otal sc ore of 7 0- 1 1 0 o n t he P ositi ve a n d Ne gati ve S y n dr o me Scale ( P A N S S) .  Patie nts meeti n g 
eli gi bilit y r e q uire me nts at t he first Scree ni n g Visit  will u n der g o a n a d diti o nal i n-cli nic Q ualificati o n Visit 
a p pr o xi matel y 2 wee ks after t he Scr ee ni n g Visit  (at Wee k - 3).  Patie nts w h o c o nti n ue t o meet eli gi bilit y 
criteria b ase d o n assess m e nts t hr o u g h t he Scree ni n g/ Q ualificati o n Visits a n d at Da y 1  will be ra n d o mize d 
i n a 1: 1: 1: 1 rati o t o 1 of t he 4 treat me nt gr o u ps s h o w n bel o w: 
 

 
 
 
                                                                                       
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Patie nts will recei ve t heir first d ose of St u d y Me di cati o n  i n t he cli nic o n Da y 1.  Patie nts will be 
i nstr ucte d t o ta ke St u d y Me dicati o n  at h o me o nce- dail y  ( Q D) i n t he m or ni n g f or t he ne xt 1 2 wee ks.  
Patie nts will ret ur n t o t he cli nic at Wee ks 2, 4,  6, 8, 1 0, a n d 1 2 f or safet y a n d efficac y ass ess me nts  a n d t o 
pic k u p S t u d y M e dicati o n.  D ue t o t he C O VI D- 1 9 pa n de mic a n d t he p ossi bilit y f or site cl os ures a n d/ or 
tra vel restri cti o ns, cli nical la b orat or y bl o o d dra ws ma y b e perf or me d b y a H o me Healt h Care ser vi ce 
pr o vi der or b y a l ocal la b orat or y; ot her safet y a n d efficac y ass ess me nts ma y be p erf or me d re m otel y via 
p h o ne/a u di o or vi de o c o nfere n ci n g platf or ms ( wit h t he e x ce pti o n of Face b o o k).  P h o ne c o ntact will be 
ma de wit h t he patie nt o n Wee ks 1, 3, 5, 7, 9 a n d 1 1 .  T he pri mar y o utc o me meas ure will be assesse d at 
Wee k 1 2.  Patie nts will be re q uir e d t o ret ur n t o t he cli nic a p pr o xi matel y 1 w ee k aft er t he last d ose of 
St u d y M e dicati o n f or s af et y assess me nts i ncl u di n g p h ysical e x a mi nati o n, vital si g ns, a d vers e- e v e nts an d 
c o nc o mita nt me dicati o ns.   D ue t o t he C O VI D-1 9 pa n de mic , t he Safet y F oll o w- u p visit ma y be 
c o n d ucte d r e m otel y vi a p h o ne/a u di o or vi de o c o nfere nci n g platf or ms ( wit h t he e x ce pti o n of Face b o o k) 
per I n vesti gat or discreti o n. 
A n y  p atie nt ma y wit h dra w fr o m partici pati o n i n t he st u d y at a n y ti me.  T h e I n vesti gat or ma y wit h dra w a 
patie nt at a n y ti me if t he y belie v e t he safet y of t h e patie nt or t he i nte grit y of t he data are at ris k.  
Di a g n osis a n d Eli gi bilit y Criteri a:  
I ncl usi o n Criteri a: 
1.  Patie nt s h o ul d be a ble t o rea d, u n dersta n d a n d v ol u ntaril y si g n a n i nf or me d c o nse nt d oc u me nt 
pri or t o a n y st u d y relate d assess me nts a n d pr oce d ures bei n g c o n d u cte d.  Patie nts s h o ul d be 
willi n g t o c o m pl y wit h t h e st u d y visits a n d re q uire me nts of t he st u d y pr ot o c ol.  
2.  Patie nt s h o ul d be bet wee n 1 8 a n d 5 5  years of a ge, i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt d oc u me nt. 
3.  P h ysicia n c o nfir me d D S M - V dia g n osis of sc hiz o p hre nia f or t h e past 2 years base d o n patie nt’s  
hist or y a n d c o nfir me d b y ps yc hiatric e v al uati o n a n d MI NI I nter nati o nal N e ur o ps yc hiatric 
I nter vie w f or Ps yc h otic Dis or ders, versi o n 7. 0. 2 ( MI NI, Versi o n 7. 0. 2). 
4.  T he patie nt  is a n o ut patie nt wit h n o h os pitalizati o n f or w orse ni n g of sc hiz o p hre nia wit hi n 3 
m o nt hs of t he first Scree ni n g Visit ( Wee k - 5). 
5.  Patie nts c urre ntl y treate d wit h o ne a nti ps yc h otic ( A P) me dicati o n w hic h has bee n u nc ha n ge d 
( me dicati o n a n d d ose) f or at least 7 wee ks pri or t o t he first Scree ni n g Visit ( Wee k - 5), a n d 
e x pecte d t o re mai n u nc h a n ge d d uri n g t he Scree ni n g a n d Treat me nt peri o d.  All o we d orall y d ose d 
A Ps are:  
a. Ari pi praz ole 
b.  Ase na pi ne 
c. Bre xi pi praz ole 
d.  Cari prazi ne  
e. L ur asi d o ne 
f. Ola nza pi ne 
g.  Pali peri d o ne 
h.  Q uetia pi ne 
i. Ris peri d o ne 

 
 
 
                                                                                       
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N ote: If t he p atie nt is bei n g tre ate d wit h de p ot or l o n g -acti n g a nti psyc h otics, t hey s h o ul d be o n 
t he tre at me nt f or at le ast 2 dr u g a d mi nistr ati o n cycles pri or t o t he first Scree ni n g Visit ( Week -5).  
6.  Patie nts wit h c o nfir me d bl o o d le vels of t heir c urre nt A P me dicati o n i n sa m ples dra w n at t he 
Q ualificati o n Visit ( Wee k - 3). 
7.  T he patie nt has a relia ble i nf or ma nt w h o is a ble t o pr o vi de i nf or mati o n re gar di n g t h e patie nt a n d 
s u p p ort st u d y partici p ati o n. 
8.  Patie nts wit h cli nicall y sta ble sc hiz o p hre nia wit h resi d ual s y m pt o ms defi ne d as P A N S S t otal 
sc ore of 7 0- 1 1 0 per e val u ati o n at t he first Scree ni n g Visit (Wee k - 5), t he Q u alificati o n Visit 
(Wee k - 3) a n d Da y 1 . 
N ote: At Week - 3 a n d D a y 1 , t he P A N S S t ot al sc ore m ay v ar y by 1 0 p oi nts as c o m p are d t o a 
previ o us visit , as l o n g as t ot al sc ore re m ai ns bet wee n 7 0- 1 1 0 at e a c h of t he t hree visits f or t he 
p atie nt t o be i ncl u de d i n t he st u dy. 
Patie nts m ust als o meet t hese a d diti o nal P A N S S criteria:  
a. P A N S S sc ore of ≤ 4 o n p ositi ve scale ite ms of c o n ce pt ual dis or ga nizati o n a n d h ostilit y 
b.  P A N S S sc ore ≥ 4 o n at le ast t w o  of t he f oll o wi n g ite ms:  
i. Del usi o ns 
ii. Hall uci nati o ns  
iii. S us pici o us ness/ Persec uti o n 
i v. U n us ual t h o u g ht c o nte nt 
c. P A N S S Ne gati ve S y m pt o m Fact or Sc ore ( N S F S) ≥ 1 2 
9.  If of re pr o d ucti ve a ge  a n d n ot i nfertile ( defi n e d bel o w), willi n g a n d a bl e t o use a me dicall y hi g hl y 
effecti ve f or m of birt h c o ntr ol d uri n g t he st u d y a n d f or 4 wee ks f oll o wi n g l ast d ose of St u d y 
Me dicati o n .  E x a m ples of me dicall y hi g hl y effecti ve f or ms of birt h co ntr ol are:  
a. S ur gical sterilit y ( via v as ect o m y, h ysterect o m y or bilateral li gati o n) or p ost - me n o pa usal 
fe males ( h a ve ha d s p o nt a ne o us a me n orr hea f or at l east t he last 1 year a n d at least 1 year 
after t he o ns et of a me n orr hea w hile n ot recei vi n g h or m o ne re place me nt t hera p y a n d ha v e 
a F ollicle-Sti m ulati n g H or m o ne ( F S H) le vel greater t ha n 4 0 mI U/ m L)  
b.  Se x ual part ner is sterile, or of t he sa me s e x  
c. I m pla nts of le v o n or gestr el i n fe males 
d.  Oral c o ntr ace pti ve (c o m bi ne d or pr o gester o ne o nl y) i n fe males 
e. D o u ble- barrier met h o d ( a n y c o m bi nati o n of p h ysical a n d c he mical met h o ds) 
f. I ntr a uteri ne d e vice i n f e males, or ot her met h o d wit h p u blis he d data s h o wi n g t hat t he 
l o west e x pecte d fail ure r ate is less t ha n 1 % per ye ar  
1 0.  Healt h y, as deter mi ne d b y t he I n v esti gat or, bas e d o n a me dical e v al uati o n i ncl u di n g hist or y, 
p h ysical e x a mi nati o n, vital si g ns, electr ocar di o gra m ( E C Gs ) a n d cli nical la b orat or y assess me nts 
at Wee k - 5. 
N ote: A p atie nt wit h a n o n-cli nic ally si g nific a nt a b n or m ality or l a b or at ory p ar a meters o utsi de t he 
refere nce r a n ge m a y be i ncl u de d o nly if t he I nvesti g at or c o nsi ders t h at t he fi n di n g will n ot 

 
 
 
                                                                                       
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c o m pr o mise t he p atie nt’s s afety a n d will n ot i nterfere wit h t he st u dy pr oce d ures or d at a 
i nter pret ati o n. 
1 1.  B o d y mass i n de x ( B MI ) wit hi n t he ra n ge of 1 8 t o 4 0 k g/ m 2, i ncl usi ve, at t he first Scree ni n g Visit 
(Wee k - 5). 
 
E xcl usi o n Criteri a:  
1.  Patie nts wit h D S M -V criteria at t he first Scree ni n g Visit (Wee k - 5) f or dis or ders ot her t h a n 
sc hiz o p hre nia t hat i n t he o pi ni o n of t he I n v esti gat or ma y i nterfere wit h st u d y c o n d u ct a n d 
i nter pretati o n of r es ults. 
2.  Patie nts w h o, i n t he o pi ni o n of t he I n vesti gat or, h a ve a hist or y of a nti ps yc h otic treat me nt 
resista nce. 
3.  Patie nts  c urre ntl y ta ki n g cl oza pi ne.  
4.  Patie nts w h o ha ve bee n pre vi o usl y treate d wit h or are recei vi n g electr o c o n v ulsi ve t hera p y ( E C T).  
5.  Patie nts w h o ha ve i nitiate d or c ha n ge d d ose of a nti de pressa nts or ot her m o o ds sta bilizers wit hi n 7 
wee ks pri or t o t he first Scree ni n g Visit (Wee k - 5). 
6.  Patie nts c urre ntl y ta ki n g lit hi u m.  
7.  Patie nts ta ki n g a n A P ( e. g.  Ser o q u el) as a slee p ai d.  
N ote: P atie nts will be all o we d t o s witc h t o a n o n- A P slee p ai d d uri n g t he Scree ni n g peri o d . 
8.  Patie nts  w h o use prescri pti o n me dicati o ns (sti m ula nts) t o treat atte nti o n defi cit h y peracti vit y 
dis or der or atte nti o n deficit dis or der.  
9.  Scree ni n g la b or at or y meas ure me nts o utsi de t he n or mal ra n ge ass ociate d wit h p ote ntial ris k f or 
t he treat me nt u n der i n vesti gati o n at t he first Scree ni n g Visit (Wee k - 5).  T his will i ncl u de b ut n ot 
li mite d t o: 
a. As partate tr a nsa mi nase ( A S T), ala ni ne tra ns a mi nase ( A L T), ga m ma -gl uta m yl tra nsferas e 
( G G T), or t otal bilir u bi n > 2 x u p per li mit of n or mal ( U L N) 
b.  Esti mate d gl o mer ular filtrati o n rate (e G F R) < 6 0 m L/ mi n ute/ 1. 7 3 m 2 
c. Ser u m creati ni ne  a n d/ or bl o o d urea nitro ge n ( B U N ) > U L N  
d.  Uri nal ysis p ositi ve f or pr otei n or uri ne micr oal b u mi n/creati ni ne rati o ( U A C R) > 3 0 m g/ g  
N ote: T hese l a b or at ory tests m ay be re p e ate d o nce, if t hey are a b n or m al o n first scree ni n g, a n d 
if t here is a me dic al/ a n alytic al re as o n t o believe t he res ults m ay be i n acc ur ate.  If t he re pe at test 
is wit hi n t he refere nce r a n ge, t he p atie nt m ay be i ncl u de d o nly if t he I nvesti g at or c o nsi ders t h at 
t he previ o us fi n di n g will n ot c o m pr o mise t he p atie nt’s s afety a n d will n ot i nterfere wit h t he 
i nter pret ati o n of s afety d at a. 
1 0.  Patie nts wit h s uici dal be ha vi or occ urri n g wit hi n t he past year or w h o  p ose a c urre nt s uici de ris k as 
deter mi ne d b y t he PI or as c o nfir me d at t he first Scree ni n g Visit (Wee k - 5), t he Q ualificati o n Visit 
(Wee k - 3) or Da y 1  b y  affir mati ve a ns wer o n ite ms 4 or 5 o n t he C ol u m bia- S uici de Se verit y 
Rati n g Scale ( C -S S R S) . 

 
 
 
                                                                                       
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1 1.  Treat me nt wit h a n i n vesti gati o nal dr u g wit hi n 7  w ee ks or 5 half -lives (if k n o w n), w hic he v er is 
l o n ger, pri or t o t he first S cree ni n g Visit (Wee k - 5). 
1 2.  D o nati o n of bl o o d wit hi n 4 wee ks of D a y 1. 
1 3.  Hist or y of pr ol o n ge d Q T s y n dr o me or a Scree ni n g Q Tc i nter val wit h Fri deri cia’s c orrecti o n 
( Q Tc F) > 4 5 0 msec f or males or Q Tc F > 4 7 0 ms ec f or fe males.  
1 4.  Fe males w h o ar e n ursi n g, pre g na nt, or pla n ni n g t o bec o me pre g na nt w hile i n t he st u d y a n d f or 4 
wee ks after t he last d ose of S t u d y M e dicati o n. 
1 5.  Hist or y of m eeti n g D S M -5 criteria f or m o derate t o se vere  alc o h ol or s u bst a nce use dis or der 
( ot her t ha n nic oti ne or caffei ne) wit hi n t he 6 m o nt hs bef ore t he first Scree ni n g Visit (Wee k - 5). 
1 6.  P ositi ve alc o h ol breat h test.  
N ote: A re pe at alc o h ol bre at h test w ill be all o we d wit hi n 4 8 h o urs of t he first test o nly at t he first 
Scree ni n g Visit ( Week - 5).  T he r e pe at test m ust b e ne g ative f or i ncl usi o n i n t he st u dy. 
1 7.  P ositi ve uri ne test f or dr u gs of a b use at t he Scree ni n g/ Q ualificati o n Visit s (Wee k - 5, - 3; see 
A P P E N DI X B ). 
N ote:  P atie nts wit h a p ositive uri ne dr u g scree n f or be nz o di aze pi nes m ay b e all o we d i n t he st u dy 
pr ovi de d  t he dr u g w as prescri be d by a p h ysici a n as a n a nxi olytic or slee p ai d. 
N ote:  Use of T H C/c a n n a bi n oi d pr o d ucts is all o we d i n t he st u dy 
1 8.  Patie nts wit h p ositi ve bl o o d scree n f or h u ma n i m m u n o deficie nc y vir us ( HI V a nti b o d y) a n d/ or 
he patitis B vir us s urface a nti ge n. 
N ote: P atie nts wit h asy m pt o m atic he p atitis C are all o we d as l o n g as t he cli nic al l a b or at ory 
me nti o ne d a b ove r e q uire me nts are met. 
1 9.  Patie nts wit h hist or y of r e nal disease or t h ose ta ki n g me dicati o ns t o treat re nal disease.  
2 0.  A n y ot her cli nicall y si g nifica nt me dical c o n diti o n (e. g. fe v er, acti ve i nfecti o n, u nc o ntr olle d 
dia betes, car di o vasc ular c o n diti o ns i ncl u di n g Class III or I V heart fail ure, p ul m o nar y e m b olis m, 
dee p vei n t hr o m b osis, acti ve maj or a ut oi m m u ne disease, ne ur ol o gical disease, ca ncer n ot i n 
re missi o n f or last 3 years e x ce pt basal cell a n d s q u a m o us cell carci n o ma), or pr oce d ure as 
deter mi ne d b y t he I n v esti gat or, t h at ma y u nfa v o ra bl y alter t h e ris k- be n efit of st u d y partici pati o n, 
a d versel y aff ect st u d y c o m plia nce, or c o nf o u n d i nter pretati o n of st u d y res ults.  
 
 

 
 
 
                                                                                       
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Criteri a f or E v al u ati o n  
Pri m ary Effic acy E n d p oi nt:  
•  T he pri mar y efficac y e n d p oi nt will be t he c ha n ge i n P A N S S t otal sc ore at Wee k 1 2 fr o m 
Baseli ne  
Sec o n d ary Effic acy E n d p oi nts : 
•  C ha n ge i n Cli nical Gl o bal I m pr essi o n -Se verit y  ( C GI- S) sc ore at Wee k 1 2 fr o m Baseli ne 
•  C ha n ge i n Pers o nal a n d S ocial Perf or ma nce ( P S P) Scale sc ore at Wee k 1 2 fr o m Bas eli ne 
E x pl or at ory E n d p oi nts : 
•  C ha n ge i n P A N S S t otal sc ore at Wee ks 2, 4, 8, a n d 1 0 fr o m Baseli ne 
•  C ha n ge i n P A N S S P ositi ve S y m pt o ms Fact or Sc ore ( P S F S) at Wee ks 2, 4, 8, 1 0, a n d 1 2 fr o m 
Baseli ne  
•  C ha n ge i n P A N S S Ne gati ve S y m pt o ms Fact or Sc ore ( N S F S)  at Wee ks 2, 4, 8, 1 0, a n d 1 2 fr o m 
Baseli ne  
•  C ha n ge i n C GI- S sc ore at Wee ks 2, 4, 6, 8, a n d 1 0 fr o m Bas eli ne 
•  C ha n ge i n P S P sc ore at Wee k 6 fr o m Baseli ne  
•  C ha n ge i n Sc hiz o p hre nia Q ualit y of Life ( S Q L S)  at Wee k 1 2 fr o m Baseli n e 
 S afety Me as ures :  
•  V ital si g ns, p h ysical e x a mi nati o ns, E C Gs, cli nical la b orat or y para meters i ncl u di n g B U N , ser u m 
creati ni ne a n d c o m plete uri nal ysis 
•  A d verse e ve nts  
•  E xtra p yra mi dal s y m pt o ms ( E P Ss) will be e val uate d usi n g t he Si m ps o n- A n g us Scale ( S A S) 
A b n or mal I n v ol u ntar y M o ve me nt Scale ( AI M S) a n d t he Bar nes A k at hisia Rati n g Scale 
( B A R S) 
•  Assess me nt of s uici dalit y will be perf or me d usi n g t he C -S S R S.  
St atistic al met h o ds:  
S a m ple size: A p pr o xi matel y 7 5 p atie nts will be ra n d o mize d t o eac h treat m e nt ar m t o ac hie v e a sa m ple 
size of a p pr o xi matel y 6 0 patie nts per ar m w h o c o m plete t he st u d y .  A s a m ple size of 6 0 per ar m 
pr o vi des at least 8 0 % p o wer f or t he c ha n ge at Wee k 1 2 fr o m Baseli ne i n P A N S S t otal sc ore, ass u mi n g 
a treat me nt diff ere n ce fr o m place b o of 5. 2 a n d st a n dar d de viati o n of 1 0, o n a t w o-si de d t-test at 0. 0 5 
si g nifica n ce. 
A n alysis P o p ul ati o ns: T he Safet y P o p ulati o n will i ncl u de all ra n d o mize d patie nts w h o recei ve at least 
o ne d o se of St u d y M e dicati o n.  T he Efficac y P o p ulati o n will i ncl u de all patie nts w h o recei v e St u d y 
Me dicati o n  a n d ha v e at l east o ne  p ost-bas eli ne P A N S S assess me nt d uri n g t he Treat me nt Peri o d.   T he 
Per Pr ot oc ol a nal ysis p o p ulati o n will i ncl u de all patie nts i n t he  Efficac y P o p ulati o n w h o were d os e d 
acc or di n g t o pr ot o c ol wit h n o maj or pr ot oc ol de vi ati o ns. 
 

 
 
 
                                                                                       
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Effic acy A n alyses: All statistical tests will be 2 -si de d wit h a si g nifi ca nce v al ue of 0. 0 5.  T here will be 
n o a dj ust me nts f or m ulti ple c o m paris o ns t o place b o i n t his P hase 2 st u d y.  A mi x e d effects re p eate d 
meas ures m o del will be  use d t o assess treat me nt gr o u p differe n ces f or c h a n ge fr o m Baseli ne .  T h e 
m o del will i ncl u de treat me nt, a nal ysis visit, treat me nt-b y -visit i nteracti o n, t he baseli ne val ue as a 
c o variate, a n d patie nt  as a ra n d o m effect.  T he c o m paris o n of eac h C T P - 6 9 2 d ose gr o u p vers us place b o 
will be  assesse d b y f or mi n g t he least s q uares m ea ns esti mate of eac h t he C T P - 6 9 2 d ose gr o u p a n d 
c o m pari n g it t o t he place b o gr o u p at eac h p ost bas eli ne a nal ysis visit.  A n u nstr uct ure d c o v aria n ce 
str uct ure was us e d t o m o del t he wit hi n-patie nt  err ors. 
A d diti o nal details will be s u m marize d i n t he Statistical A nal ysis Pla n.  
S afe ty A n alyses: All safet y s u m maries will be des cri pti ve wit h n o statistical h y p ot hesis testi n g a n d 
will be base d o n t he Saf et y P o p ulati o n.  A d verse e ve nts, vital si g n meas ure me nts, p h ysical 
e x a mi nati o n fi n di n gs, E C G, cli nical la b orat or y i nf or mati o n, c o nc o mit a nt me dicati o ns , E P Ss a n d  
C- S S R S  will be ta b ulate d a n d s u m marize d descri pti vel y.  Patie nts will be s u m marize d acc or di n g t o t he 
S t u d y M e dicati o n r ecei v e d (i.e., as tr eate d), s h o ul d it differ fr o m t he ra n d o mize d treat me nt ar m.   
A d verse e ve nts will be c o de d b y s yste m or ga n class a n d preferre d ter m wit h t he Me dical Dicti o nar y 
f or Re g ulat or y A cti vities ( Me dD R A).  C o nc o mita nt a n d pri or me dicati o ns will be s u m marize d b y 
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y A n at o mical -T hera pe utic -C he mical classificati o n a n d 
preferre d t er m.  
 

 
                                                                                                      
 
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2.  
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  
1.  
S Y N O P SI S  ................................................................................................................... 5 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ............... 1 2 
3.  
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 8 
4.  
I N T R O D U C TI O N ...................................................................................................... 2 2 
4. 1.  
S u m mar y of D -Seri ne Cli nical Data i n Patie nts wit h Sc hiz o p hre nia  .......................... 2 2 
4. 2.  
S u m mar y of C T P- 6 9 2 Cli nical Data  ........................................................................... 2 4 
4. 2. 1.  
St u d y C P 6 9 2. 1 0 0 2 ...................................................................................................... 2 4  
4. 2. 2.  
St u d y C P 6 9 2. 1 0 0 3 ...................................................................................................... 2 6  
5.  
E T HI C S  ...................................................................................................................... 2 8 
5. 1.  
I nstit uti o nal Re view B oar d (I R B) ............................................................................... 2 8  
5. 2.  
Writte n I nf or m e d C o nse nt .......................................................................................... 2 9  
6.  
S T U D Y O BJ E C TI V E S  .............................................................................................. 3 0 
7.  
I N V E S TI G A TIO N A L P L A N  ..................................................................................... 3 1 
7. 1.  
O verall St u d y Desi g n  .................................................................................................. 3 1 
7. 2.  
Rati o nale f or C T P - 6 9 2 D ose Selecti o n ....................................................................... 3 2 
7. 3.  
N u m ber of Patie nts ..................................................................................................... 3 2  
7. 4.  
Criteria f or St u d y Ter mi nati o n  ................................................................................... 3 2 
8.  
S T U D Y P R O C E D U R E S  ............................................................................................ 3 4 
8. 1.  
Sc he d ule of Assess me nts  ............................................................................................ 3 4 
8. 2.  
St u d y Pr o ce d ur es  ........................................................................................................ 3 7 
8. 2. 1  
 Scree ni n g Peri o d Pr oce d ures ( Wee k - 5 a n d Wee k - 3) .............................................. 3 7 
8. 2. 2  
 Treat me nt Peri o d Pr oce d ures ( D a y 1 t o Wee k 1 2) .................................................... 3 8 
8. 2. 2. 1  
P h o ne Call C hec k -I n ( Wee ks 1, 3, 5, 7, 9 a n d 1 1) ..................................................... 4 1 
8. 2. 3  
 Safet y F oll o w - U p Pr o ce d ures ( Wee k 1 3) .................................................................. 4 1 
9.  
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  .............................................. 4 2 
9. 1.  
I n cl usi o n Criteria ........................................................................................................ 4 2 
9. 2.  
E x cl usi o n Criteria  ....................................................................................................... 4 4 
9. 3.  
Patie nt Wit h dra wal Criteria  ........................................................................................ 4 6 

 
                                                                                                      
 
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9. 3. 1.  
Patie nt Wit h dra wal Pr oce d ures  ................................................................................... 4 6 
1 0.  
D E S C RI P TI O N O F S T U D Y  M E DI C A TI O N S  ......................................................... 4 8 
1 0. 1.  
Descri pti o n of St u d y M e dicati o n ................................................................................ 4 8  
1 0. 2.  
Treat me nt C o m plia nce  ................................................................................................ 4 8 
1 0. 3.  
St u d y M e dicati o n Materials a n d Ma na ge me nt  ........................................................... 4 8 
1 0. 3. 1.  
P h ysical D escri pti o n of St u d y Me dicati o n  ................................................................. 4 8 
1 0. 3. 2.  
St u d y M e dicati o n Pac k a gi n g, La b elli n g a n d St ora ge ................................................. 4 9  
1 0. 3. 3.  
St u d y M e dicati o n Pre p ar ati o n a n d A d mi nistrati o n  .................................................... 4 9 
1 0. 3. 4.  
St u d y M e dicati o n Ret ur n a n d Dis p osal ...................................................................... 5 0  
1 0. 3. 5.  
St u d y M e dicati o n Acc o u nta bilit y  ............................................................................... 5 0 
1 0. 4.  
C o nc o mita nt Me dicati o ns a n d Pr oce d ures ................................................................. 5 0  
1 1.  
S T U D Y A S S E S S M E N T S  .......................................................................................... 5 1 
1 1. 1.  
De m o gra p hic C haract eristics a n d Me dical Hist or y  .................................................... 5 1 
1 1. 2.  
P h ysical E x a mi nati o n  ................................................................................................. 5 1 
1 1. 3.  
Vital Si g ns  .................................................................................................................. 5 1 
1 1. 4.  
Electr ocar di o gra m ( E C G)  ........................................................................................... 5 1 
1 1. 5.  
Cli nical La b or at or y Assess me nts  ............................................................................... 5 2 
1 1. 6.  
Assess me nt of Efficac y  ............................................................................................... 5 2 
1 1. 6. 1.  
P ositi ve a n d Ne gati ve S y m pt o m Scale ( P A N S S)  ....................................................... 5 2 
1 1. 6. 2.  
Cli nical Gl o bal I m pr essi o n -Se verit y ( C GI -S) Sc ore  .................................................. 5 2 
1 1. 6. 3.  
Pers o nal a n d S ocial Perf or ma nce Sc ale ( P S P) ........................................................... 5 3 
1 1. 6. 4.  
Sc hiz o p hre nia Q ualit y of Life Scale ( S Q L S)  ............................................................. 5 3 
1 1. 7.  
E xtra p yra mi dal S y m pt o ms  ......................................................................................... 5 3 
1 1. 7. 1.  
Si m ps o n- A n g us Scale ( S A S)  ...................................................................................... 5 3 
1 1. 7. 2.  
A b n or mal I n v ol u ntar y M o ve me nt Scale ( AI M S) ....................................................... 5 3  
1 1. 7. 3.  
Bar n es A kat hisia Rati n g Scale ( B A R S)  ..................................................................... 5 3 
1 1. 8.  
C ol u m bia- S uici de Se verit y Rati n g Scale ( C -S S R S)  ................................................... 5 4 
1 1. 9.  
A nti ps yc h otic ( A P) Me di cati o n Bl o o d Le v el ............................................................. 5 4  
1 1. 1 0.  
C T P - 6 9 2 Bl o o d Le vel ................................................................................................. 5 4 
1 1. 1 1.  
Ge netic Testi n g  ........................................................................................................... 5 4 
1 1. 1 2.  
U nsc he d ule d Visit ....................................................................................................... 5 4  
1 2.  
A D V E R S E E V E N T S .................................................................................................. 5 5 

 
                                                                                                      
 
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1 2. 1.  
Defi niti o n of A d vers e E v e nts ..................................................................................... 5 5  
1 2. 2.  
E val uati o n of A d vers e E ve nts .................................................................................... 5 5  
1 2. 2. 1.  
Seri o us A d verse E v e nt ( S A E) .................................................................................... 5 5  
1 2. 2. 2.  
Se verit y/I nt e nsit y  ........................................................................................................ 5 7 
1 2. 3.  
Relati o ns hi p t o St u d y M e dicati o n  .............................................................................. 5 7 
1 2. 3. 1.  
D urati o n ...................................................................................................................... 5 8  
1 2. 3. 2.  
Acti o n Ta ke n  .............................................................................................................. 5 8 
1 2. 3. 3.  
O utc o me ...................................................................................................................... 5 8  
1 2. 3. 4.  
F oll o w- U p  ................................................................................................................... 5 8 
1 2. 3. 5.  
Pre g n a nc y ................................................................................................................... 5 9  
1 2. 3. 6.  
Rec or di n g A d verse E ve nts ......................................................................................... 5 9  
1 2. 3. 7.  
Re p orti n g A d v erse E v e nts .......................................................................................... 5 9  
1 2. 3. 8.  
Re p orti n g Seri o us A d v erse E ve nts ............................................................................. 5 9  
1 2. 3. 9.  
Re p orti n g Ur ge nt Safet y Iss u es  .................................................................................. 6 0 
1 3.  
S T A TI S TI C A L M E T H O D S  ....................................................................................... 6 1 
1 3. 1.  
Sa m ple Size Rati o nale  ................................................................................................ 6 1 
1 3. 2.  
E n d p oi nts .................................................................................................................... 6 1  
1 3. 2. 1.  
Efficac y  ....................................................................................................................... 6 1 
1 3. 2. 2  
 Safet y  ......................................................................................................................... 6 1 
1 3. 3.  
A nal ysis P o p ulati o ns .................................................................................................. 6 2  
1 3. 4.  
A nal ys es  ...................................................................................................................... 6 2 
1 3. 4. 1.  
Dis p ositi o n a n d Baseli ne C haracteris tics .................................................................... 6 2 
1 3. 4. 2.  
Efficac y  ....................................................................................................................... 6 2 
1 3. 4. 3.  
St u d y M e dicati o n C o m plia nce ................................................................................... 6 3  
1 3. 4. 4.  
Safet y  .......................................................................................................................... 6 3 
1 3. 4. 5.  
A d verse E v e nts  ........................................................................................................... 6 3 
1 3. 4. 6.  
C ol u m bia S uici de Se verit y Rati n g Scale  .................................................................... 6 4 
1 3. 4. 7.  
Cli nical La b or at or y  ..................................................................................................... 6 5 
1 3. 4. 8.  
Vital Si g ns  .................................................................................................................. 6 5 
1 3. 4. 9.  
Electr ocar di o gra m  ....................................................................................................... 6 5 
1 4.  
R E G U L A T O R Y C O N SI D E R A TI O N S ...................................................................... 6 6 
1 4. 1.  
G o o d Cli nical Practice  ................................................................................................ 6 6 

 
                                                                                                      
 
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1 4. 2.  
S p o ns or’s Res p o nsi bilities .......................................................................................... 6 6  
1 4. 3.  
I n v esti gat or’s Res p o nsi bilities .................................................................................... 6 7 
1 4. 4.  
Pr ot oc ol A me n d me nts ................................................................................................ 6 8  
1 4. 5.  
A u dits a n d I ns p ecti o ns ................................................................................................ 6 9  
1 4. 6.  
Q ualit y C o ntr ol a n d Q u alit y Ass ura n ce ...................................................................... 6 9  
1 5.  
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  ....................................................... 7 0 
1 5. 1.  
C o nfi de ntialit y  ............................................................................................................ 7 0 
1 5. 2.  
Patie nt Data Pr otecti o n  ............................................................................................... 7 0 
1 5. 3.  
Data C ollecti o n  ........................................................................................................... 7 0 
1 5. 4.  
Case Re p ort F or m C o m pleti o n  ................................................................................... 7 1 
1 5. 5.  
Data base M a na ge me nt, Data Clarificati o n, a n d Q ualit y Ass ura nce  ........................... 7 1 
1 5. 6.  
I ns p ecti o n of Rec or ds ................................................................................................. 7 1 
1 5. 7.  
Rete nti o n of Rec or ds .................................................................................................. 7 2  
1 6.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 7 3 
1 7.  
LI S T O F R E F E R E N C E S  ............................................................................................ 7 4 
1 8.  
A P P E N D I C E S ............................................................................................................ 7 7 
A P P E N DI X A: C O N C O MI T A N T M E DI C A TI O N S  .................................................................... 7 8 
A P P E N DI X B: C LI NI C A L  L A B O R A T O R Y A S S E S S M E N T S  .................................................. 7 9 
A P P E N DI X C:  P O SI TI V E A N D N E G A TI V E S Y M P T O N S C A L E ( P A N S S)  .......................... 8 0 
A P P E N DI X D: C LI NI C A L  G L O B A L I M P R E S SI O N ( C GI -S) S C O R E  ..................................... 8 1 
A P P E N DI X E: P E R S O N A L  A N D S O CI A L P E R F O R M A N C E S C A L E ( P S P)  .......................... 8 2 
A P P E N DI X F: S C HI Z O P H R E NI A Q U A LI T Y O F LI F E S C A L E ( S Q L S)  ................................. 8 4 
A P P E N DI X G: SI M P S O N -A N G U S S C A L E ( S A S)  ..................................................................... 8 5 
A P P E N DI X H: A B N O R M A L  I N V O L U T A R Y M O V E M E N T S C A L E ( AI M S)  ........................ 8 6 
A P P E N DI X I: B A R N E S A K A T HI SI A R A TI N G S C A L E ( B A R S)  ............................................. 8 7 
A P P E N DI X J: C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E ( C -S S R S) 
B A S E LI N E/ S C R E E NI N G V E R SI O N  ....................................................................... 8 8 
A P P E N DI X K: C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E ( C -S S R S) 
SI N C E L A S T VI SI T  ................................................................................................... 9 1 
A P P E N DI X L: MI NI I N T E R N A TI O N A L N E U R O P S Y C HI A T RI C I N T E R VI E W  ................... 9 4 
 
 

 
                                                                                                      
 
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LI S T O F T A B L E S  
Ta ble  1: 
A b bre viati o ns a n d S peci alist Ter ms ........................................................................... 1 8  
Ta ble  2: 
C P 6 9 2. 1 0 0 2 S u m mar y of Plas ma P har mac o ki netic Para meters ................................ 2 5  
Ta ble  3: 
C P 6 9 2. 1 0 0 2 A d verse E v e nts ...................................................................................... 2 6  
Ta ble  4: 
C P 6 9 2. 1 0 0 3 S u m mar y of Plas ma P har mac o ki netic Para meters ................................ 2 7  
Ta ble  5: 
C P 6 9 2. 1 0 0 3 A d verse E v e nts ...................................................................................... 2 8  
Ta ble  6: 
Sc he d ule of Assess me nts  ............................................................................................ 3 5 
Ta ble  7: 
I n v esti gati o nal Pr o d uct ............................................................................................... 4 9 
 

 
                                                                                                      
 
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LI S T O F FI G U R E S  
Fi g ure  1: 
C P 6 9 2. 2 0 0 1 St u d y Desi g n .......................................................................................... 3 1  
 
  

 
                                                                                                      
 
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3.  
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 vi ati 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 1: 
A b bre vi ati o ns a n d S peci alist T er ms  
A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n 
A D D  
Atte nti o n Deficit Dis or der  
A D H D  
Atte nti o n Deficit H y peracti vit y Dis or der  
A E  
A d verse E ve nt  
AI M S  
A b n or mal I n v ol u ntar y M o ve me nt Scale 
A L B  
Al b u mi n 
A L K - P 
Al kali ne P h os p hatase  
A L T  
Ala ni ne A mi n otra nsferase  
A N O V A  
A nal ysis of varia nce  
A P  
A nti ps yc h o tic 
a P T T 
Partial Pr ot hr o m bi n Ti me Test  
A S T  
As partate A mi n otra nsferase 
A U C  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
B A R S  
Bar nes A kat hisia Rati n g Scale  
B MI  
B o d y Mass I n de x  
B U N  
Bl o o d Urea Nitr o ge n 
Ca  
Calci u m  
C B C  
C o m plete Bl o o d C o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C GI - S 
Cli nical Gl o bal I m pressi o n-Se verit y Sc ore  
C K  
Creati ne Ki nase  
Cl  
C hl ori de 
C L/ F  
A p pare nt oral cleara nce  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntrati o n 
C O 2 
Car b o n Di o xi de 
C o g Scree n ®  
C o m p uterize d ne ur oc o g niti ve assess me nt  
C P T  
C o nti n u o us Perf or ma nce Test  
C R A  
Cli nical Researc h Ass ociate  
C R F  
Case Re p ort F or m  

 
                                                                                                      
 
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A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n 
C R O  
C o ntract Researc h Or ga nizati o n  
C R U  
Cli nical Researc h U nit  
C S F  
Cere br os pi nal fl ui d  
C- S S R S  
C ol u m bia- S uici de Se verit y Rati n g Scale  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts 
C V %  
C oefficie nt of Variati o n (i n perce nta ge)  
D M P  
Data Ma na ge me nt Pla n  
D S M  
Dia g n ostic a n d Statistical Ma n ual   
E C G  
Electr ocar di o gra m  
E C T  
Electr oc o n v ulsi ve t hera p y  
e C R F 
Electr o nic Case Re p ort F or m  
e G F R 
Esti mate d Gl o mer ular Filtrati o n R ate 
E P S  
E xtra p yra mi dal s y m pt o ms 
E T  
Earl y T er mi nati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
F S H  
F ollicle - Sti m ulati n g H or m o ne 
g 
Gra ms  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -Gl uta m yl Tra nsferase  
GI  
Gastr oi ntesti nal  
H Bs A g  
He patitis B s urface A nti ge n  
h C G  
H u ma n C h ori o nic G o na d otr o pi n 
H C V -A b  
He patitis C Vir us A nti b o d y 
HI V  
H u ma n I m m u n o deficie nc y Vir us 
HI V -A b  
H u ma n I m m u n o deficie nc y Vir us A nti b o d y  
I B 
I n vesti gat or’s Br oc h ure  
I C F 
I nf or me d C o nse nt F or m  
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I P 
I n vesti gati o nal Pr o d uct 
I N R 
I nter nati o nal N or malize d Rati o  
I R B 
I nstit uti o nal Re vie w B oar d 

 
                                                                                                      
 
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A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n 
K 
P otassi u m 
k g 
Kil o gra m  
L 
Liter  
L D H  
Lactic De h y dr o ge nase  
L O C F  
Last O bser vati o n Carrie d F or war d  
ma x  
Ma xi m u m  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  
MI NI  
MI NI I nter nati o nal Ne ur o ps yc hiatric I nter vie w  
mI U  
Milli -I nter nati o nal U nits 
m L  
Milliliter  
msec  
Millisec o n d  
Na  
S o di u m 
N M D A  
N- met h yl - D-as partate 
N M D A R  
N- met h yl - D-as partate Rece pt or 
N S F S  
Ne gati ve S y m pt o ms Fact or Sc ore  
P A N S S  
P ositi ve a n d Ne gati ve S y m pt o m Scale  
PI  
Pri nci pal I n vesti gat or  
P K  
P har mac o ki netics  
P R  
P ulse Rate  
P S F S  
P ositi ve S y m pt o ms Fact or Sc ore  
P S P  
Pers o nal a n d S ocial Perf or ma nce  
P T  
Pr ot hr o m bi n Ti me Test  
Q D  
T a ke n Dail y  
Q T c F  
Fri dericia’s  C orrecte d Q T i nter val  
R R  
Res pirat or y Rate  
S A E  
Seri o us A d verse E ve nt  
S A S  
Si m ps o n- A n g us Scale  
S A N S  
Scale f or Assess me nt of Ne gati ve S y m pt o ms  
S G O T  
Ser u m Gl uta mic O xal oacetic Tra nsa mi nase  
S G P T  
Ser u m Gl uta mic P yr u vic Tra nsa mi nase  

 
                                                                                                      
 
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A b bre vi ati o n or 
s peci al ter m 
E x pl a n ati o n 
S Q L S  
Sc hiz o p hre nia Q ualit y of Life  
S U S A Rs  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns  
t1/ 2 
Eli mi nati o n half -life 
T ma x  
Ti me t o o bser ve d ma xi m u m plas ma c o nce ntrati o n  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
U A C R  
Uri ne Micr oal b u mi n/ Creati ni ne Rati o  
U L N  
U p per Li mit of N or mal  
U S  
U nite d States  
μ g  
Micr o gra m  
W B C  
W hite Bl o o d Cell  
 

 
                                                                                                      
 
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4.  
I N T R O D U C TI O N 
Sc hiz o p hre nia is a c hr o ni c, c o m ple x a n d de bilitati n g me ntal dis or d er ass oci ate d wit h hi g h 
m or bi dit y a n d m ortalit y.  T y pical o nset of sc hiz o p hre nia is d uri n g late a d ol esce nce a n d e arl y 
a d ult h o o d.  T he disease is c haracterize d b y p ositi ve s y m pt o ms ( hall uci nati o ns, del usi o ns, a n d 
dis or ga nize d t h o u g hts), n e gati ve s y m pt o ms (flat affect, a n h e d o nia, a m bi val e nce, a n d 
a m oti vati o n), a n d c o g niti ve deficits (ass o ciate d wit h me m or y, j u d ge me nt, a n d e x ec uti ve 
pla n ni n g).  I n di vi d uals li vi n g wit h sc hiz o p hre nia re p ort w orse h ealt h-relate d q ualit y of life a n d 
ha ve si g nifica ntl y re d u ce d life e x pecta nc y.  
Des pite i nte nse o n g oi n g researc h, t he o utc o m es fr o m best practice treat me nt are ofte n 
s u b o pti mal.  T he me dia n pr o p orti o n of pe o ple wit h sc hiz o p hre nia w h o meet cli nical a n d s ocial 
rec o ver y criteria is o nl y 1 3. 5 % (C harls o n, 2 0 1 8 ).  A nti ps yc h otic dr u gs t hat act b y bl oc ki n g 
d o pa mi ne D 2 rece pt ors (t y pical a nti ps yc h otics) or b ot h t he D 2 a n d ser ot o ni n ( 5- H T 2) rece pt ors 
(at y pi cal a nti ps yc h otics) ha ve bee n t he mai nsta y of treat me nt f or ps yc h osis a n d p ositi ve 
s y m pt o ms f or ma n y years; h o we ver, a s u bsta ntial pr o p orti o n of patie nts re mai n s y m pt o matic 
(La ne,  2 0 1 3; B u gars ki, 2 0 1 6 ) d ue t o lac k of effi cac y a n d/ or p o or t olera bilit y. 
N -met h yl -D -as partate r ece pt or ( N M D A R) h y p of u ncti o n is belie ve d t o ha ve a n i m p orta nt r ole i n 
t he pat h o p h ysi ol o g y of s c hiz o p hre nia (Bal u, 2 0 1 5 ).  I n patie nts wit h sc hiz o p hre nia, D -s eri ne, a n 
e n d o ge n o us c o- a g o nist f or t he N M D A rece pt or, c o nce ntrati o ns i n t he bl o o d, cere br os pi nal fl ui d 
( C S F), a n d i n p ost m orte m brai n tiss ue ha ve bee n re p orte d t o be l o w er t ha n n or mal c o ntr ols 
(Has hi m ot o, 2 0 0 3 ; Has hi m ot o, 2 0 0 5 ; C h o, 2 0 1 6 ; Be n di k o v, 2 0 0 7 ).  P ote ntiati o n of t he 
N M D A R - me diate d n e ur otra ns missi o n b y gl yci ne site m o d ulat ors, i ncl u di n g D -s eri ne, is 
c o nsi dere d a n o vel treat me nt a p pr oac h t o h el p i m pr o ve s y m pt o ms of s c hiz o p hre nia a n d a n u m ber 
of cli nical st u dies ha ve s h o w n be nefit t o patie nts wit h sc hiz o p hre nia f oll o wi n g treat me nt wit h D -
seri ne (Tsai, 1 9 9 8 ; H eres c o - Le v y, 2 0 0 5; La n e, 2 0 0 5 ; La n e, 2 0 1 0 ; Ka ntr o witz, 2 0 1 0 ; Er mil o v , 
2 0 1 3 ; Ka ntr o witz, 2 0 1 8 ).  A p ote ntial li mitati o n t o t he de vel o p me nt of D -seri ne as a t hera pe utic 
is t hat it has bee n s h o w n i n precli nical testi n g t o ca use ne p hr ot o xicit y i n rats (Ga n ote, 1 9 7 4 ).  
T he ca us e of ne p hr ot o xicit y is belie ve d t o res ult fr o m t he pr o d ucti o n of h y dr o ge n per o xi de i n t he 
ki d ne y b y D -a mi n o aci d o xi dase ( M ot het, 2 0 0 0 ; Verrall, 2 0 1 0 ). 
C T P - 6 9 2 is a de uterate d a nal o g of D -s eri ne a n d i n n o ncli nical st u dies has bee n s h o w n t o ha v e 
nearl y i de ntical bi n di n g a n d f u ncti o nal pr o perties as D -seri n e at t he N M D A rece pt or.  I n rats, 
C T P - 6 9 2 was f o u n d t o ha ve greater brai n e x p os ure w he n c o m p are d t o D -seri ne.  I m p orta ntl y, i n 
ot her pr ecli nical i n vesti gati o ns i n t he rat,  t he re n al t o xicit y of D -s eri ne w as de m o nstrate d b y d ose 
relate d i ncreas es i n ser u m B U N a n d creati ni ne b ut o ver t he sa me d ose ra n ge C T P- 6 9 2 w as f o u n d 
t o ha ve n o si g nifi ca nt i ncrease i n t hes e para meters, s u g gesti n g t he p ote ntial f or a n i m pr o ve d 
re nal saf et y pr ofile f or t h e c o m p o u n d. 
T he C T P - 6 9 2 I n vesti gat or’s Br oc h ur e (I B; C T P -6 9 2 I n v esti gat or’s Br oc h ure , C o ncert 
P har mace uticals I nc., 2 0 1 9. ) s h o ul d be c o ns ulte d f or detaile d tec h nical i nf or mati o n a n d 
disc ussi o n of pre vi o us cli nical a n d n o n- cli nical e v al uati o ns.  
4. 1.  
S u m m ar y of D -Seri ne Cli nic al D at a  i n P atie nts wit h Sc hiz o p hre ni a 
O ne of t he first st u dies t o de m o nstrate t hat D -s eri n e pr o vi de d si g nifica nt be neficial effects o n 
p ositi ve, ne gati ve a n d c o g niti ve sc hiz o p hre nia s y m pt o ms w he n a d mi nistere d as a n a dj u n cti ve 

 
                                                                                                      
 
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t hera p y t o sta ble a nti ps yc h otic ( A P) re gi me ns w as a 6- wee k d o u ble- bli n d, place b o-c o ntr olle d 
trial c o n d ucte d b y Tsai et al (Tsai , 1 9 9 8).  At t he e n d of t he 6-wee k trial, D -seri ne ( 3 0 
m g/ k g/ da y) r es ulte d i n a 1 7 % re d ucti o n i n t he p ositi ve s y m pt o ms ( P ositi ve a n d Ne gati ve 
S y n dr o me Scale [ P A N S S] - p ositi ve s u bscale, p = 0. 0 0 4) a n d a 2 1 % re d u cti o n of t he ne gati ve 
s y m pt o ms ( Scale f or Ass ess me nt of Ne gati ve S y m pt o ms [ S A N S], p = 0. 0 0 0 4); t he place b o gr o u p 
s h o we d a 3 % i ncrease i n P A N S S- p ositi ve s u bscale sc ore a n d 0. 7 % re d ucti o n i n t he S A N S sc ore.  
Sc ores of t he P A N S S -c o g niti ve s u bscal e als o i n dicate d a si g nifica nt 1 2 % i m pr o ve me nt i n t he D -
seri ne gr o u p ( p = 0. 0 0 4) c o m pare d t o 0. 8 % i n t he place b o gr o u p.  I n a n ot her st u d y wit h a si milar 
desi g n a n d d ose of D -seri ne ( 2 g/ da y; La n e H Y, 2 0 1 0 ), t he re d u cti o n i n t he P A N S S t otal sc ore i n 
t he D -seri ne gr o u p ( 1 3 %, p = 0. 0 0 2 4) was s u p eri or t o t hat o bser ve d i n t he pl ace b o gr o u p ( 4 %).  
Hi g her d oses of D -seri n e ( 6 0 m g/ k g a n d 1 2 0 m g/ k g) h a ve als o b ee n e x pl ore d a n d ha ve s h o w n 
d ose- de pe n d e nt i m pr o ve me nts i n P A N S S t otal a n d s u bscale sc ores (K a ntr o witz , 2 0 1 0; 
Ka ntr o witz , 2 0 1 8).  A st u d y t o assess t he effi cac y of D -seri n e as a n a d d- o n p har mac ot hera p y t o 
ris peri d o ne a n d ola nza pi ne (Heresc o - Le v y, 2 0 0 5) res ulte d i n si g nifica nt i m pr o ve me nts i n 
ne gati ve, p ositi ve, c o g niti ve a n d de pr essi o n s y m pt o ms as meas ure d b y t he P A N S S scale. 
T he maj orit y of st u dies wit h D -seri ne i n patie nts ha ve use d a d ose of 3 0 mg/ k g/ da y, a fe w h a ve 
a d mi nistere d 6 0 m g/ k g/ d a y a n d i n o ne st u d y t he hi g hest d ose w as 1 2 0 m g/ k g/ da y.  T h e d oses of 
D -seri ne i n t hes e st u dies a p pr o xi mate d t o 2. 1 g/ da y, 4. 2 g/ da y a n d 8. 4 g/ da y, res pecti vel y, f or a 
b o d y w ei g ht of a b o ut 7 0 k g.  T he d urati o n of treat me nt wit h D -seri ne ra n ge d fr o m 1 da y (si n gle 
d ose) t o 4 wee ks of dail y treat me nt wit h t he 1 2 0 m g/ k g/ da y d ose ( Ka ntr o witz, 2 0 1 0 ) a n d 1 6 
wee ks of d ail y tr eat me nt wit h 6 0 m g/ k g/ d a y ( Ka ntr o witz, 2 0 1 5).  D -seri ne was well t olerat e d i n 
al m ost all s u bjects acr oss all d oses.  Ka ntr o witz ( 2 0 1 0 ) d ose d 3 0 m g/ k g/ da y, 6 0 m g/ k g/ da y a n d 
1 2 0 m g/ k g/ da y as 2 di vi d e d dail y d os es of D -s eri n e f or 4 w ee ks wit h n o safet y iss ues at d oses < 
1 2 0 m g/ k g.  At t he 1 2 0 m g/ k g d ose, 1 of 1 6 p atie nts s h o we d 2 + pr otei n uri a wit h o ut gl yc os uri a 
d uri n g t he fi nal wee k of treat me nt wit h n o si g nifi ca nt c ha n ge i n creati ni ne.  T he pr otei n uria 
res ol ve d f oll o wi n g D -seri ne disc o nti n uati o n, t w o patie nts disc o nti n ue d f or as y m pt o matic 
tra nsa mi nitis w hic h als o res ol ve d, a n d t w o a d diti o nal patie nts wit h dre w c o nse nt f or si de effects 
(i ns o m nia after o n e d ose a n d GI distress).  I n t he Ka ntr o witz ( 2 0 1 5)  st u d y that d ose d 6 0 
m g/ k g/ da y f or 1 6 wee ks, t w o patie nts i n t he D -seri ne gr o u p wit h dre w fr o m t he st u d y d ue t o o ut 
of ra n ge re nal v al ues t hat were p ossi bl y rel ate d t o st u d y treat me nt vers us n o ne i n t he place b o 
gr o u p.  Trace or greater pr otei n uria was o bs er ve d i n 1 7 of 4 5 i n di vi d uals i n p ost- scree ni n g 
uri nal ysis.  Of t h ese 1 7 i n di vi d uals, 1 1 were ra n d o ml y assi g ne d t o D -s eri n e a n d 6 were ra n d o ml y 
assi g ne d t o place b o.  All a b n or malities res ol ve d d uri n g c o nti n ue d treat me nt.  F or ot her a d vers e 
e ve nts, 1 of 2 0 patie nts i n t he D -seri ne gr o u p e x presse d s uici dal t h o u g hts at Wee k 1 1 a n d was 
h os pitalize d b ut re mai ne d i n t he st u d y.  T w o patie nts of 2 4 i n t he place b o gr o u p were wit h dra w n 
fr o m t he st u d y d u e t o c o n versi o n t o ps yc h osis vers us n o ne i n t he D -seri ne gr o u p.  H o we v er, o ne 
patie nt i n t he D -seri ne gr o u p s h o we d ps yc h osis s y m pt o ms at t he fi nal st u d y visit. 
T he res ults descri be d a b o ve s u g gest cli nical be n efit of D -seri ne i n p atie nts wit h sc hiz o p hre nia, 
h o we ver, its f ull cli nical p ote ntial ma y b e li mi te d d ue t o precli nical n e p hr ot o xic fi n di n gs at 
hi g her, a n d p ote ntiall y m ore cli nicall y-rele va nt, d oses.  Gi ve n t he i m pr o ve d precli nical pr ofile, 
C T P - 6 9 2 has t he p ote ntial t o be a n a dj u ncti ve treat me nt of sc hiz o p hre nia wit h less re nal t o xicit y 
ris k c o m pare d t o D -seri n e. 
 

 
                                                                                                      
 
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4. 2.  
S u m m ar y of C T P -6 9 2 Cli nic al D at a  
T he P hase 1 pr o gr a m was desi g ne d t o assess t he s afet y, t olera bilit y a n d p h ar mac o ki netic pr ofile 
of C T P - 6 9 2 i n healt h y v ol u nteers.  T he P hase 1 pr o gra m i ncl u de d t hree st u dies: a cr oss o ver 
c o m paris o n of C T P- 6 9 2 vers us D -seri ne ( C P 6 9 2. 1 0 0 1), a si n gl e-as ce n di n g d ose st u d y t hat als o 
assesse d t he effect of f o o d o n t he p har mac o ki n etics of C T P- 6 9 2 ( C P 6 9 2. 1 0 0 2), a n d a m ulti ple-
asce n di n g d ose trial assessi n g C T P - 6 9 2 d ose d orall y o ver s e ve n da ys ( C P 6 9 2. 1 0 0 3).   T he t otal  
n u m ber of healt h y s u bjects e x p ose d t o o ne or m ore d oses of C T P- 6 9 2 i n t he t hree P has e 1 
st u dies c o n d ucte d t o date is 6 7.  T he g o als of t he earl y cli nical de v el o p me nt pr o gra m f or  
C T P - 6 9 2 were  ( 1) t o c haracterize t he si n gle- a n d m ulti ple- d ose plas ma p har mac o ki netic ( P K ) 
pr ofiles of t he dr u g, ( 2) t o e val uate safet y a n d t olera bilit y of t he dr u g f oll o wi n g si n gle- a n d 
m ulti ple - d ose a d mi nistrati o n a n d ( 3) t o pr o vi de g ui da nce f or d ose selecti o n i n s u bse q ue nt 
efficac y st u dies i n patie nts wit h sc hiz o p hre nia.  T he C T P -6 9 2 I B  (C T P -6 9 2 I n v esti gat or’s 
Br oc h ure , C o ncert P har mace uticals I n c., 2 0 1 9.) s h o ul d be c o ns ulte d f or i nf or mati o n o n 
C P 6 9 2. 1 0 0 1.  T he si n gle- ascen di n g d os e st u d y ( C P 6 9 2. 1 0 0 2) a n d m ulti ple-asce n di n g d os e st u d y 
( C P 6 9 2. 1 0 0 3) are disc usse d bel o w. 
4. 2. 1.  
St u d y C P 6 9 2. 1 0 0 2 
St u d y C P 6 9 2. 1 0 0 2 was a  ra n d o mize d, d o u ble- bli n d, place b o c o ntr olle d, P h ase 1 st u d y i n h ealt h y 
v ol u nteers t o c har acterize t he saf et y, t olera bilit y a n d plas ma P K pr ofile of si n gle as ce n di n g oral 
d oses of C T P- 6 9 2.  T her e wer e 4 c o h orts ( C o h ort 1: 0. 5 g C T P- 6 9 2, C o h ort 3: 2 g C T P- 6 9 2, 
C o h ort 4: 3 g C T P- 6 9 2 a n d C o h ort 5: 4 g C T P- 6 9 2) of 8 s u bjects eac h a n d 1 c o h ort ( C o h ort 2: 1 g 
of C T P - 6 9 2) of 1 0 s u bjects.  S u bjects were ra n d o mize d 3: 1 ( C T P- 6 9 2: place b o) i n C o h orts 1, 3, 
4 a n d 5 a n d 4: 1 ( C T P- 6 9 2: place b o) i n C o h ort 2.  A t otal of 4 2 healt h y v ol u nteers were e nr olle d 
i n t his st u d y ( 3 2 recei ve d C T P- 6 9 2; 1 0 recei ve d pl ace b o).  
T his st u d y i n v ol ve d t w o Peri o ds: I n Peri o d 1, t he safet y a n d plas ma P K pr ofile of si n gle d os es of 
C T P - 6 9 2 were e v al uate d u n der faste d c o n diti o ns.  I n Peri o d 2, t he s u bjects w h o recei ve d 1 g of 
C T P - 6 9 2 i n Peri o d 1 u n der we nt a 4- da y w as h o ut ( 9 6 h o urs fr o m Peri o d 1 d ose a d mi nistrati o n) 
a n d eac h s u bject r ecei ve d t he sa me treat me nt t he y recei v e d i n Peri o d 1 ( 1 g C T P - 6 9 2 or place b o) 
u n der fe d c o n diti o ns.  T he cal oric c o nte nt of t he m eal was  i n acc or d a nce wit h t he F D A g ui da n ce 
f or f o o d-eff ect st u dies  (F D A, 2 0 0 2 ).  I n b ot h peri o ds, C T P-6 9 2 was a d mi nistere d orall y as a 
s ol uti o n f or m ulati o n. 
 
 
 
 
 
 
 
 
 

 
                                                                                                      
 
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P las ma p har mac o ki netic para meters f or C T P-6 9 2 are  s h o w n i n T a ble 2  bel o w. 
T a ble 2:  
C P 6 9 2. 1 0 0 2 S u m m a r y of Pl as m a P h a r m ac o ki netic P ar a meters  
Tre at me nt  
 
M e di a n  
(r a n ge) 
Arit h metic M e a n  
( C V %) 
T m a x  
( hr) 
C m a x  
(µ g/ m L)  
t1/ 2 
( hr) 
A U C 0-tl ast 
/ A U C0- 4 8 hr 
( hr *µ g/ m L)  
A U C i nf 
(µ g * hr / m L) 
C L/ F  
( L/ hr) 
Vz/ F  
( L) 
0. 5 g C T P -6 9 2  
( Faste d, n = 6) 
1. 0  
( 0. 5 – 1. 5)  
1 1. 0  
( 2 6 %) 
1 5. 9  
( 9 %) 
7 5. 1  
( 1 3 %) 
8 2. 2  
( 1 3 %) 
6. 1 7  
( 1 3 %) 
1 4 1  
( 1 2 %) 
1 g C T P -6 9 2  
( Faste d, n = 8) 
1. 0  
( 0. 5 – 1. 5)  
2 2. 3  
( 2 1 %) 
1 9. 2  
( 2 2 %) 
1 4 4  
( 1 6 %) 
1 6 4  
( 1 8 %) 
6. 2 8  
( 1 7 %) 
1 7 1  
( 1 8 %) 
1 g C T P -6 9 2  
( Fe d, n = 8) 
2. 0  
( 1. 0 – 4. 0)  
1 5. 3  
( 3 0 %) 
1 7. 9  
( 1 7 %) 
1 5 3  
( 1 8 %) 
1 7 3  
( 2 1 %) 
5. 9 9  
( 1 9 %) 
1 5 2  
( 1 5 %) 
2 g C T P -6 9 2  
( Faste d, n = 6) 
1. 0  
( 0. 5 – 1. 5)  
4 6. 3  
( 2 0 %) 
2 0. 2  
( 2 2 %) 
2 7 4  
( 2 1 %) 
3 1 5  
( 2 1 %) 
6. 5 6  
( 1 9 %) 
1 9 1  
( 2 5 %) 
3 g C T P -6 9 2  
( Faste d, n = 6) 
1. 0  
( 0. 5 – 2. 0)  
6 9. 1  
( 4 1 %) 
2 0. 6  
( 9 %) 
4 2 5  
( 2 7 %) 
4 8 9  
( 2 7 %) 
6. 6 8  
( 3 1 %) 
1 9 6  
( 3 3 %) 
4 g C T P -6 9 2  
( Faste d, n = 6)  
1. 0  
( 0. 5 – 1. 0)  
9 6. 5  
( 1 9 %) 
1 8. 4  
( 1 5 %) 
5 5 6  
( 2 2 %) 
6 1 8  
( 2 1 %) 
6. 6 9  
( 2 0 %) 
1 7 9  
( 2 7 %) 
 
After si n gle or al a d mi nistrati o n of C T P - 6 9 2 at d ose le vels ra n gi n g fr o m 0. 5 t o 4 g i n t he fast e d 
state, t he me dia n Tma x  was 1 h o ur (ra n ge of 0. 5 t o 2 h o urs) a n d t he mea n t1/ 2 was a p pr o xi matel y 
1 9 h o urs acr oss all 5 d ose gr o u ps.  I ncreas es i n t he d ose le vel of C T P- 6 9 2 lea d t o  
d ose- pr o p orti o nal i ncr eas es i n e x p os ure. 
After si n gle or al d ose a d mi nistrati o n of t he 1  g C T P - 6 9 2 i n t he fe d state t h e Tma x  of  
C T P - 6 9 2 was dela ye d wit h a me dia n val ue of 2 h o urs c o m pare d t o a me dia n Tma x  of 1 h o ur i n t he 
faste d state.  T h e mea n t 1/ 2 was si milar ( 1 8 t o 1 9 h o urs) i n t he fe d a n d faste d states.  C o m paris o n 
of t he C T P- 6 9 2 e x p os ure para meters bet wee n t he faste d a n d t he fe d states i n dicates t hat f o o d 
decreases t he C ma x  of C T P - 6 9 2 b y a b o ut o n e t hir d, wit h o ut a n y effect o n A U C. 
O verall, C T P -6 9 2 was w ell t olerate d i n all s u bjects i n t his st u d y.  T he re nal f u ncti o n la b orat or y 
para meters i n bl o o d (ser u m creati ni ne a n d B U N) a n d uri ne (c o m plete uri nal ysi s) re mai ne d 
wit hi n t he n or mal ra n ge at all ti me p oi nts ( 8, 2 4 a n d 4 8 h o urs) p ost- d ose i n all s u bjects i n t he  
0. 5 g, 1 g, 3 g a n d 4 g d ose gr o u ps.  I n t he 2 g d os e gr o u p o nl y, t he ser u m creati ni ne le vels 
i ncreas e d t o a b o ve t he n or mal ra n ge at 8 h o urs p ost- d ose i n 5 o ut of 6 s u bjects w h o recei ve d 
C T P - 6 9 2 a n d i m p orta ntl y, i n t he 2 s u bjects w h o recei ve d pl ace b o.  T h e creati ni ne le vels ret ur n e d 
t o t he n or mal ra n ge b y  2 4 h o urs p ost- d ose.  O n f urt her i n vesti gati o n, it was deter mi ne d t hat t his 
fi n di n g was att ri b ute d t o a n artifact d ue t o t he meals eate n pri or t o bl o o d dra w  w hic h i ncl u de d c o o ke d 
meat .  T he literat ure s u p p orts t he fi n di n g of i ncreases i n ser u m creati ni ne f oll o wi n g a diet t hat i ncl u des 
c o o ke d meat (Ma yers o h n, 1 9 8 3 ; Nair, 2 0 1 4 ; Pi me nta, 2 0 1 6 ).  Meal c o nte nt a n d ti mi n g was c o ntr olle d 
f or t he 3 a n d 4 g d ose c o h orts a n d n o s uc h i ncrease i n creati ni ne was o bser ve d, s u p p orti n g t he belief 

 
                                                                                                      
 
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t hat t he 2 g c o h ort fi n di n gs were artefact ual.  C T P - 6 9 2- a n d Place b o -relat e d a d verse e v e nts were 
mil d - m o derate i n se verit y a n d wer e re p orte d i n a t otal of 6 a n d 2 s u bjects, res pecti vel y (see 
Ta ble  3 bel o w). 
T a ble 3:  
C P 6 9 2. 1 0 0 2 A d verse E ve nts 
A d verse E ve nt  
N u m ber of E ve nts  
Place b o  
0. 5 g  
C T P -6 9 2  
1 g  
C T P -6 9 2  
2 g  
C T P -6 9 2  
3 g  
C T P -6 9 2  
4 g  
C T P -6 9 2  
N u m ber of S u bj ects: A E/ T otal  
2/ 1 0  
1/ 6  
3/ 8  
1/ 6  
1/ 6  
0/ 6  
Hea dac he  
1 
1 
2 
1 
1 
0 
Ni g ht mares  
0 
0 
1 
0 
0 
0 
F o g gi ness, metallic taste, irrita bilit y  
0 
0 
0 
1 
0 
0 
A b d o mi nal pai n, na usea, v o miti n g  
0 
0 
0 
0 
1 
0 
Tire d ness  
1 
0 
0 
0 
0 
0 
M e ntal f o g gi ness  
1 
0 
0 
0 
0 
0 
All a d verse e ve nts res ol v e d/rec o v ere d b y t h e e n d of t he st u d y.  T h ere were ot her n o ot her 
cli nicall y si g nifica nt  s afet y-r elate d fi n di n gs i ncl u di n g cli nical la b orat or y tests , vital si g ns, a n d 
E C G assess me nts.  
E x pl orat or y assess me nts i ncl u de d a n assess me nt of ne ur oc o g niti ve effects usi n g c o m p uterize d 
testi n g ( C o g Scree n® ).  T he C o g Scr ee n test batter y i ncl u de d t ests of di git s y m b ol s u bstit uti o n 
( pr ocessi n g s pee d), pr e vi o us n u m ber recall ( w or ki n g me m or y), ver b al w or ki n g me m or y, 
e x ec uti ve f u ncti o ni n g, reacti o n ti me, a n d vi gila n ce.  Res ults s h o we d n o e vi de nce of a d verse 
effects o n ne ur o c o g niti ve f u ncti o ni n g at a n y of t he 5 d oses. 
4. 2. 2.  
St u d y C P 6 9 2. 1 0 0 3 
St u d y C P 6 9 2. 1 0 0 3 was a 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 i n healt h y 
v ol u nteers t o c har acterize t he saf et y, t olera bilit y a n d plas ma P K pr ofile of 3 asce n di n g d ose 
le vels of C T P- 6 9 2 f oll o wi n g o nce- dail y oral a d mi nistrati o n f or 7 c o nsec uti ve da ys.  T here w ere 
3 c o h orts ( C o h ort 1: 1 g C T P- 6 9 2, C o h ort 2: 2 g C T P- 6 9 2, C o h ort 3: 4 g C T P- 6 9 2) of u p t o 1 0 
s u bjects ( 8 acti ve a n d 2 place b o) i n eac h c o h ort.  A t otal of 3 0 healt h y v ol u nteers were e nr olle d 
i n t his st u d y ( 2 4 recei ve d C T P- 6 9 2; 6 recei ve d place b o).  Base d o n t he res ults of t he f o o d effect 
o bser ve d (re d uce d C ma x  a n d t he si milar A U C) i n  t he si n gle d os e st u d y ( C P 6 9 2. 1 0 0 2), C T P - 6 9 2 
was  a d mi nistere d or all y as a s ol uti o n f or m ulati o n  wit hi n a p pr o xi matel y 1 h o ur of c o ns u m pti o n 
of f o o d i n t his st u d y. 
Preli mi nar y p las ma p h ar mac o ki netic para meters f or C T P- 6 9 2 are s h o w n i n Ta ble  4 bel o w.  

 
                                                                                                      
 
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T a ble 4:  
C P 6 9 2. 1 0 0 3 S u m m a r y of Pl as m a P h a r m ac o ki netic P ar a meters  
Tre at me nt  
D a y  
T m a x  
( hr) 
C m a x  
( µg/ m L)  
t1/ 2 
( hr) 
A U C t a u 
/ A U C0- 2 4 hr 
(µ g * hr / m L) 
A U C i nf 
(µ g * hr / m L) 
1 g C T P -6 9 2  
( n = 8) 
 
1 
1. 5  
( 1. 0 – 3. 0)  
2 2. 2  
 ( 1 4 %) 
N ot 
re p orte d 
1 3 6. 4 
( 1 4 %) 
1 6 2. 6  
( 1 2 %) 
7 
1. 5  
( 0. 5 – 3. 0)  
2 5. 3  
 ( 1 2 %) 
2 1. 1  
( 1 8 %) 
1 7 5. 3 
 ( 2 3 %) 
2 6 3. 2  
 ( 3 0 %) 
2 g C T P -6 9 2  
( n = 8) 
1 
1. 0  
( 1. 0 – 2. 0)  
4 7. 9  
 ( 2 3 %) 
N ot 
re p orte d 
2 5 8. 6  
 ( 1 3 %) 
3 3 0. 7 
 ( 2 3 %) 
7 
1. 0  
( 0. 2 5 – 2. 0)  
5 2. 0  
( 2 3 %) 
2 1. 3  
( 2 3 %) 
3 3 2. 6  
( 1 1 %) 
5 2 2. 0  
 ( 1 9 %) 
4 g C T P -6 9 2  
( n = 8)  
1 
1. 5  
( 1. 0 – 2. 0)  
6 8. 9  
( 3 0 %) 
N ot 
re p orte d 
3 9 3. 5 
 ( 1 1 %) 
5 6 6. 1 
( 2 4 %) 
7 
2. 0  
( 1. 0 – 4. 0)  
7 0. 8  
 ( 2 6 %) 
2 4. 4  
( 2 9 %) 
5 3 9. 1  
 ( 1 4 %) 
9 1 1. 4  
 ( 1 9 %) 
 
After or al a d mi nistrati o n of C T P - 6 9 2 at d ose le vels of 1, 2 a n d 4 g f or 7 c o nsec uti ve da ys, t he 
me dia n T ma x  o n Da y 7 r a n ge d fr o m 1 t o 2 h o urs a n d t he mea n t1/ 2 o n Da y 7 ra n ge d fr o m  
2 1 – 2 4 h o urs acr oss t he 3 d oses.  C T P- 6 9 2 plas ma c o nce ntrati o ns reac he d st ea d y -state b y 
a p pr o xi matel y Da y 5.  O n Da y 7, i ncreases i n t he d ose of C T P- 6 9 2 lea d t o d ose- pr o p orti o nal 
i ncreas es i n Cma x  a n d A U Cta u f or t he 2 g d ose relati ve t o t he 1 g d ose; h o w e ver, t he i ncrease f or 
t he 4 g d os e was less-t h a n d ose pr o p orti o nal.  T he i ncreas e i n A U Ci nf was a p pr o xi matel y  
d ose- pr o p orti o nal acr oss t he 3 d oses o n Da y 7.  T h e C ma x  acc u m ulati o n o n Da y 7 was 
a p pr o xi matel y 1 4 %, 9 % a n d 3 % f or t h e 1, 2 a n d 4 g d oses, res pecti vel y.  T he A U C ta u 
acc u m ulati o n o n Da y 7 was a p pr o xi matel y 2 8 % f or t he 1 a n d 2 g d os es, a n d 3 7 % f or t he 4 g 
d ose. 
C T P -6 9 2 was well t olerate d i n all s u bjects i n t his st u d y.  T he re nal f u n cti o n la b orat or y 
para meters i n bl o o d (ser u m creati ni ne a n d B U N) a n d uri ne (c o m plete uri nal ysis) re mai ne d 
wit hi n t he n or mal ra n ge at all ti me p oi nts ( 2 4 h o urs p ost- d ose a d mi nistrati o n o n eac h d a y) i n all 
s u bjects i n all 3 d ose gr o u ps. 
C T P - 6 9 2- a n d Place b o -relate d a d vers e e v e nts were mil d-m o derate i n se v erit y a n d w ere re p orte d 
i n a t otal of 7 s u bjects a n d 1 s u bject, res pecti vel y (see Ta bl e  5 bel o w). 
 
 
 
 
 

 
                                                                                                      
 
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T a ble 5:  
C P 6 9 2. 1 0 0 3 A d verse E ve nts  
A d verse E ve nt  
N u m ber of E ve nts  
Place b o  
1 g  
C T P -6 9 2  
2 g  
C T P -6 9 2  
4 g  
C T P -6 9 2  
N u m ber of S u bj ects: A E/ T otal  
1/ 6  
5/ 8  
2/ 8  
0/ 8  
Hea dac he  
0 
3 
2 
0 
Er uctati o n, gastric u pset  
0 
1 
0 
0 
Dr y m o ut h  
0 
1 
0 
0 
Slee pi ness/ dr o wsi ness  
0 
1 
1 
0 
L o ose st o ol  
1 
0 
0 
0 
All a d verse e ve nts res ol v e d/rec o v ere d b y t h e e n d of t he st u d y.  T h ere were n o a d verse e ve nts 
re p orte d i n t he 4 g c o h ort.  T here w ere n o ot h er cli nicall y si g nifica nt safet y-relate d fi n di n gs 
i ncl u di n g cli nical la b orat or y tests , vital si g ns, a n d E C G assess me nts.  
5.  
E T HI C S 
T he pr oce d ures set o ut i n t his st u d y pr ot oc ol, pertai ni n g t o t he c o n d uct, e val uati o n a n d 
d oc u me ntati o n of t his st u d y, are desi g n e d t o e ns ure t hat t he S p o ns or a n d t h e I n vesti gat or a bi d e 
b y G o o d Cli nical Practice ( G C P ), i ncl u di n g b ut n ot li mite d t o Title 2 1 C o de of Fe deral 
Re g ulati o ns ( C F R ) Parts 5 0, 5 6, a n d 3 1 2, a n d t he I nter nati o nal C o u ncil f or Har m o nizati o n  (I C H) 
g ui deli nes a n d directi ves.  C o m plia nce wit h t hese re g ulati o ns als o c o nstit utes c o m plia nce wit h 
t he et hical pri nci ples des cri be d i n t he c urre nt re visi o n of t he Declarati o n of Helsi n ki a n d 
a p plica ble l ocal re g ulat or y r e q uire me nts a n d l a w.  
T he I n vesti gat or is r es p o nsi ble f or pr otecti n g t he ri g hts, safet y, a n d welfare of patie nts u n der 
his/ her car e, a n d f or t he c o ntr ol of t he me dicati o ns u n der i n vesti gati o n.  All et hical, re g ulat or y, 
a n d le gal re q uire me nts m ust be met bef ore t h e first patie nt is e nr olle d i n t he st u d y.  
5. 1.  
I nstit uti o n al Re vie w B o ar d (I R B)  
T he I nstit uti o nal Re vie w B oar d (I R B) will meet all F D A re q uire me nts g o ver ni n g I R Bs acc or di n g 
t o C F R, Title 2 1, Part 5 6.  T he I n vesti gat or ( or desi g nee) m ust s u b mit t his st u d y pr ot oc ol a n d a n y 
a me n d me nts, t he S p o ns or’s a p pr o v e d i nf or me d c o nse nt f or m(s) (I C F), p atie nt i nf or mati o n 
s heets, patie nt recr uit me nt materials, a n d ot her a p pr o priate d oc u m e nts t o t he I R B f or re vi e w a n d 
a p pr o val.  F oll o wi n g r e vi e w of t he s u b mitte d materials a c o p y of t he writte n a n d date d 
a p pr o val/fa v ora ble o pi ni o n will be f or war de d t o t he S p o ns or ( or desi g nee). 
A n y a d vertise me nts use d t o recr uit patie nts f or t h e st u d y will be re vi e we d b y t he S p o ns or a n d t h e 
I R B pri or t o use. 

 
                                                                                                      
 
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5. 2.  
Writte n I nf or me d C o nse nt  
Pri or t o perf or mi n g a n y st u d y -r elate d acti vities u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d 
assess me nts, writte n i nf or me d c o nse nt wit h t he a p pr o ve d I C F m ust be o btai ne d fr o m t he patie nt. 
T he I C F, as s pecifie d b y t he cli nical site’s I R B, m ust f oll o w t he Pr otecti o n of H u ma n S u bjects 
re g ulati o ns liste d i n t he C o de of Fe d er al Re g ul ati o ns, Title 2 1, Part 5 0.  T he bac k gr o u n d of t he 
pr o p ose d st u d y, t h e pr oce d ures, t he b e nefits a n d ris ks of t he st u d y, a n d t hat st u d y partici p ati o n is 
v ol u ntar y m ust be e x plai ne d t o t he patie nt.  T he p atie nt m ust be gi ve n s uffi cie nt ti me t o c o nsi der 
w het her t o partici pate i n t he st u d y.  
A c o p y of t he I C F, si g n e d a n d date d b y t he p atie nt, m ust be gi ve n t o t he patie nt.  C o nfir mati o n of 
a patie nt’s i nf or me d c o ns e nt m ust als o be d oc u me nte d i n t he patie nt’s s o urce d oc u me nt ati o n 
pri or t o a n y testi n g u n d er t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts.  T he ori gi n al 
si g ne d c o nse nt f or m will be retai ne d wit h t he st u d y rec or ds. 
All I C Fs us e d i n t his st u d y m ust be a p pr o ve d b y t h e a p pr o pri ate I R B a n d b y t he S p o ns or.  T he 
I C F m ust n ot be altere d wit h o ut t he pri or a gree me nt of t he a n d t he S p o ns or a n d rel e va nt I R B. 
 

 
                                                                                                      
 
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6.  
S T U D Y  O B J E C TI V E S  
T he o bjecti ves of t his st u d y are t o e v al uate t he effi cac y a n d safet y of C T P - 6 9 2 as a n a dj u ncti ve 
treat me nt i n a d ult patie nts wit h sc hiz o p hre nia.  T he effi cac y a n d safet y meas ures are: 
Pri m ary Effic acy E n d p oi nts:   
•  T he pri mar y efficac y e n d p oi nt will be t he c ha n ge i n P A N S S t otal sc ore at Wee k 1 2 fr o m 
Baseli ne  
Sec o n d ary Effic acy E n d p oi nts : 
•  C ha n ge i n Cli nical Gl o bal I m pr essi o n -Se verit y  ( C GI- S) sc ore at Wee k 1 2 fr o m Baseli ne 
•  C ha n ge i n Pers o nal a n d S ocial Perf or ma nce ( P S P) Scale sc ore at Wee k 1 2 fr o m Bas eli ne 
E x pl or at ory E n d p oi nts : 
•  C ha n ge i n P A N S S t otal sc ore at Wee ks 2, 4, 8, a n d 1 0 fr o m Baseli ne 
•  C ha n ge i n P A N S S P ositi ve S y m pt o ms Fact or Sc ore ( P S F S) at Wee ks 2, 4, 8, 1 0, a n d 1 2 
fr o m Bas eli ne 
•  C ha n ge i n P A N S S Ne gati ve S y m pt o ms Fact or Sc ore ( N S F S)  at Wee ks 2, 4, 8, 1 0, a n d 1 2 
fr o m Bas eli ne 
•  C ha n ge i n C GI- S sc ore at Wee ks 2, 4, 6, 8, a n d 1 0 fr o m Bas eli ne 
•  C ha n ge i n P S P sc ore at Wee k 6 fr o m Baseli ne  
•  C ha n ge i n Sc hiz o p hre nia Q ualit y of Life ( S Q L S)  at Wee k 1 2 fr o m Baseli n e 
 S afety Me as ures :  
•  V ital si g ns, p h ysical e x a mi nati o ns, electr ocar di o gra ms ( E C Gs), cli nical la b orat or y 
para meters i ncl u di n g bl o o d urea nitr o ge n ( B U N), ser u m creati ni ne a n d c o m plete 
uri nal ysis  
•  A d verse e ve nts  
•  E xtra p yra mi dal s y m pt o ms ( E P Ss) will be e val uate d usi n g t he Si m ps o n -A n g us Scale 
( S A S) A b n or mal I n v ol u ntar y M o v e me nt Scale ( AI M S) a n d t he Bar nes A k at hisia Rati n g 
Scale ( B A R S)   
•  Assess me nt of s uici dalit y will be perf or me d usi n g t he C ol u m bia- S uici de Se verit y R ati n g 
Scale ( C- S S R S ) 
 
 

 
                                                                                                      
 
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7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n  
T his is a ra n d o mize d, d o u ble- bli n d, parallel gr o u p, place b o -c o ntr olle d, m ultice nter st u d y .  At 
scree ni n g, p ote ntial st u d y partici pa nts m ust ha ve a D S M- V dia g n osis of sc hiz o p hre nia f or at 
least 2 year s a n d c o nfir m e d b y ps yc hiatric e val uati o n a n d MI NI.  T he st u d y will i n v ol ve patie nt 
partici pati o n f or u p t o 2 0 wee ks a n d will c o nsist of a 5- w ee k Scree ni n g / Q u alificati o n Peri o d , a 
1 2- wee k Treat me nt Per i o d a n d a Safet y F oll o w -U p Visit  a p pr o xi matel y 1 wee k  after t he l ast 
d ose of St u d y Me di cati o n .  T he Q ualificati o n peri o d ma y b e e xte n de d u p t o 2 wee ks (after   
Wee k - 3, pri or t o Ra n d o mizati o n) if re peat la b orat or y test res ults f or c o nfir mati o n of eli gi bilit y 
are pe n di n g.  A p pr o xi matel y 3 0 0 patie nts, 1 8- 5 5 years ol d, will be ra n d o mi ze d t o recei ve 1 g, 2 g 
or 4 g of C T P - 6 9 2 or Place b o o nce-dail y ( Q D) .  At t he first Scree ni n g Visit ( Wee k - 5), patie nts 
will pr o vi de i nf or me d c o nse nt a n d will be assesse d f or eli gi bilit y base d o n st u d y i ncl usi o n a n d 
e x cl usi o n criteria, i ncl u di n g a t otal sc ore of 7 0 - 1 1 0 o n t he P ositi ve a n d Ne gati ve S y n dr o me Scale 
( P A N S S).  Patie nts meeti n g eli gi bilit y re q uire me nts at t h e first Scree ni n g Visit will u n der g o a n 
a d diti o nal i n -cli nic Q ualificati o n Visit ( at Wee k - 3).  Patie nts w h o c o nti n ue t o meet eli gi bilit y 
criteria b ase d o n assess m e nts at t he Scree ni n g a n d Q ualificati o n visits  a n d Da y 1 will be 
ra n d o mize d i n a 1: 1: 1: 1 rati o t o 1 of t he 4 treat me nt gr o u ps s h o w n b el o w i n Fi g ure  1: 
Fi g ure  1:  
C P 6 9 2. 2 0 0 1 St u d y Desi g n 
 
Patie nts will recei ve t heir first d ose of St u d y Me di cati o n  i n t he cli nic o n Da y 1.  T he d ose of 
C T P- 6 9 2 or Place b o s h o ul d be a d mi nistere d wit h  f o o d.  Patie nts will be i nstr ucte d t o ta ke St u d y 
Me dicati o n  o nce d ail y at h o me wit h  f o o d i n t he m or ni n g f or t he ne xt 1 2 wee ks.  Patie nts will 
ret ur n t o t he cli nic at Wee ks 2, 4, 6, 8, 1 0, a n d 1 2 f or safet y a n d efficac y assess me nts  a n d t o pic k 
u p St u d y M e dicati o n as s h o w n i n Ta ble  6.  D ue t o t he C O VI D- 1 9 p a n de mic a n d t he p ossi bilit y 
f or site cl os ures a n d/ or tr a vel restricti o ns, cli nical la b orat or y bl o o d dra ws ma y b e perf or me d b y a 
H o me Healt h Car e ser vi ce pr o vi der or b y a l ocal l a b orat or y; ot her s afet y a n d efficac y 
assess me nts ma y be perf or me d re m otel y via p h o n e/a u di o or vi de o c o nfere nci n g platf or ms ( wit h 
t he e x ce pti o n of Face b o o k).  St u d y pers o n n el s h o ul d stri ve t o perf or m assess me nts wit hi n t he 
visit wi n d o w as s h o w n i n Ta ble 6  wit h t he u n derst a n di n g t hat n ot all ass ess me nts ma y be a ble t o 

 
                                                                                                      
 
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be perf or me d .  Misse d assess me nts will  be rec or d e d i n t he e C R F  wit h n otati o n t hat t he misse d 
assess me nt was d ue t o t h e C O VI D - 1 9 p a n de mic.  
P h o ne c o ntact will be ma de wit h t he patie nt o n Wee ks 1, 3, 5, 7, 9 a n d 1 1.  Patie nts ma y be 
re q ueste d t o ma k e U nsc h e d ule d Visits t o t he cli nic if t he I n vesti gat or ( or desi g nee) t hi n ks 
necessar y.    
T he pri mar y o utc o me m eas ure will be t he c ha n ge i n P A N S S t otal sc ore  at Wee k 1 2 fr o m 
Baseli ne .  Patie nts will b e re q uir e d t o ret ur n t o t he cli nic a p pr o xi matel y 1 w ee k aft er t he last d ose 
of St u d y Me dicati o n  f or safet y assess me nts i ncl u di n g p h ysical e x a mi nati o n, a d verse -e ve nts a n d 
c o nc o mita nt me dicati o ns  as s ho w n i n Ta ble  6.  D u e t o t he C O VI D -1 9 p a n d e mic t he Safet y 
F oll o w- u p visit ma y b e c o n d ucte d re m otel y via p h o ne/a u di o or vi de o c o nfere nci n g platf or ms 
( wit h t he e x ce pti o n of Face b o o k) per I n vesti gat or discreti o n.  If a n y of t he safet y para meters 
i ncl u di n g cli nical la b orat or y p ara m eters at t he e n d of t he Treat me nt Peri o d are re p orte d t o be 
a bn or mal, u nsc he d ul e d assess me nts ma y b e perf or me d at t he Safet y F oll o w -U p Visit a n d 
a d diti o nal f oll o w- u p ma y be re q uir e d as t he I n v esti gat ors d ee m necessar y.  Patie nts w h o 
e x perie nce i nt olera bl e s y m pt o ms d uri n g t he T reat me nt Peri o d ma y disc o nti n ue t he st u d y at t he 
discreti o n of t he I n v esti gat or. 
7. 2.  
R ati o n ale f or C T P -6 9 2 D ose Selecti o n  
T he cli nical be n efit of D -seri ne i n patie nts wit h sc hiz o p hre nia has bee n d escri be d i n t he literat ure 
usi n g a d ose ra n ge of a p pr o xi matel y 2 g t o 8 g per da y (ass u mi n g 7 0 k g s u bjects).  Gi ve n its 
precli nical pr ofile, C T P - 6 9 2 has t he p ote ntial t o ha ve a n i m pr o ve d re n al safet y pr ofile a n d h a ve 
s u bsta ntiall y better brai n e x p os ure c o m pare d t o D -seri ne.  C o nse q ue ntl y, t h e t o p d ose of  
C T P - 6 9 2 c h ose n f or t he P hase 1 si n gle- a n d m ulti ple-asce n di n g d os e st u dies was 4 g  (see 
Secti o n  4. 2 ).  T he d oses f or t his P hase 2 st u d y were selecte d b ase d o n t he s afet y, t olera bilit y a n d 
p har mac o ki netic pr ofile of C T P- 6 9 2 i n t he P hase 1 st u dies.  T he 1 g, 2 g a n d 4 g d oses of  
C T P - 6 9 2 fr o m t he P hase 1 st u dies were c h ose n as t he y w ere well t olerate d i n healt h y v ol u nteers 
wit h n o re nal la b or at or y para meter  a b n or m alities a n d n o ot her cli nicall y si g nifica nt safet y-relat e d 
fi n di n gs.  I n t he si n gle- d ose st u dies ( C P 6 9 2. 1 0 0 1 a n d C P 6 9 2. 1 0 0 2), there were o nl y a fe w  
C T P - 6 9 2-relate d mil d-m o derate a d vers e e ve nts re p orte d of w hic h h ea dac h e was t he m ost 
c o m m o n.  T he m ulti ple - d ose st u d y ( C P 6 9 2. 1 0 03) als o re p orte d fe w treat me nt -relate d mil d-
m o derate a d v erse e ve nts wit h hea dac h e bei n g m ost c o m m o n.  T he p har mac o ki netic pr ofile of 
C T P - 6 9 2 s u p p orts o nce- dail y d osi n g wit h m o dest A U C acc u m ulati o n f oll o wi n g 7 c o ns ec uti ve 
da ys of a d mi nistrati o n of all t hree  d oses. 
7. 3.  
N u m ber of P atie nts  
A p pr o xi matel y 7 5 p atie nts will be ra n d o mize d t o eac h treat me nt ar m t o ac hie ve a sa m ple size of 
a p pr o xi matel y 6 0 patie nts per ar m w h o c o m plete t he st u d y.  A t otal of a p pr o xi matel y 3 0 0 
patie nts will be e nr olle d i n t his st u d y.  
7. 4.  
Criteri a f or St u d y Ter mi n ati o n  
T here are n o pr os pecti ve st o p pi n g criteri a f or t his st u d y. T he S p o ns or reser ves t he ri g ht t o 
disc o nti n ue t he st u d y at a n y ti me f or cli nical or a d mi nistrati ve reas o ns.  

 
                                                                                                      
 
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A n y ter mi nati o n re q uire d b y t he S p o ns or m ust be i m ple me nte d b y t h e I n vesti gat or, if i nstr uct e d 
t o d o s o, i n a ti me fra me t hat is c o m pati ble wit h t he patie nt’s well-b ei n g.  

 
                                                                                                                               
 
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8.  
S T U D Y P R O C E D U R E S  
8. 1.  
Sc he d ule of Assess me nts  
T he sc he d ule of st u d y pr oce d ures is pr o vi d e d i n Ta ble  6. 
 
 
 

 
                                                                                                      
 
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8. 2.  
St u d y Pr oce d ures  
8. 2. 1   
Scree ni n g Peri o d Pr oce d ures ( Wee k - 5 a n d Wee k - 3) 
Pri or t o perf or mi n g a n y st u d y -r elate d acti vities or e val uati o ns, t he patie nt m ust be t h or o u g hl y 
i nf or me d a b o ut all as pects of t he st u d y, i ncl u di n g sc he d ule d visits a n d acti vities.  Patie nts will 
si g n t he st u d y-s pecific c o nse nt f or m(s) pri or t o a n y scree ni n g pr oce d ure.  P atie nts will be 
i nstr ucte d t o re p ort all A Es t hat occ ur d uri n g t he st u d y fr o m t he ti me of i nf or me d c o nse nt 
f or war d. 
D ue t o t he C O VI D- 1 9 pa n de mic a n d t he p ossi bilit y f or site cl os ures a n d/ or tra vel restri cti o ns, 
s o me Scree ni n g Peri o d pr oce d ur es ( wit h t he e x ce pti o n of P A N SS) s uc h as t he MI NI, me dical 
hist or y, r e vie w of c o nc o mita nt me dicati o ns) ma y be c o n d ucte d re m otel y p er I n vesti gat or 
d iscreti o n.  T he c o ns e nt pr ocess m ust be c o n d u cte d i n t he cli nic a n d patie nts m ust si g n t he I C F i n 
pers o n i n t he cli nic. 
Patie nts s h o ul d c o nti n ue t o ta ke t heir pres cri be d A P me dicati o n t hr o u g h o ut t he Scree ni n g a n d 
Treat me nt Peri o d s. 
T he f oll o wi n g pr oce d ures will be perf or me d at W ee k - 5: 
•  Assess me nt of eli gi bilit y acc or di n g t o i ncl usi o n/e x cl usi o n criteria  
•  C o n d uct ps yc hiatri c e val uati o n  a n d a d mi nister MI NI I nter n ati o nal Ne ur o ps yc hi atric 
I nter vie w Ps yc h otic Dis or ders, versi o n 7. 0. 2 ( MI NI, Versi o n 7. 0. 2; see     
A P P E N DI X L )  
•  De m o gra p hics, m e di cal hist or y, i ncl u di n g q uer y f or baseli ne si g ns/s y m pt o ms (ie, a n 
A E  wit h o nset pri or t o d osi n g is t o be rec or de d as a pretreat me nt A E )  
•  Re vie w of c o n c o mita nt me dicati o ns i ncl u di n g sta ble bac k gr o u n d A P t hera p y  
•  F ull  p h ysical e x a mi nati o n pl us hei g ht a n d w ei g ht   
•  V ital si g ns i ncl u di n g bl o o d press ure, p ulse rate, res pirat or y rate, a n d te m perat ure 
•  Sta n dar d 1 2- lea d E C G  
•  Uri ne p re g n a nc y tests f or w o me n of c hil d beari n g p ote ntial 
•  Alc o h ol breat h test 
− A re pe at alc o h ol bre at h test will be all o we d wit hi n 4 8 h o urs of t he first test.  If t he 
re pe at test is p ositive, t he p atie nt m ust be excl u de d fr o m t he st u dy 
•  P A N S S  
•  Assess me nt of s uici dal i deati o n usi n g C- S S R S  ( Baseli ne/ Scree ni n g versi o n)  
•  Ser ol o g y, F S H, ser u m c h e mistr y, he m at ol o g y, a n d c oa g ulati o n para meter e val uati o ns 
•  Ser u m re nal para meters a n d u ri nal ysis 

 
                                                                                                      
 
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•  Uri ne dr u g test  
-  P atie nts wit h a p ositive uri ne dr u g scree n  f or be nz o di aze pi nes m ay be 
all o we d i n t he st u dy pr ovi de d  t he dr u g w as prescri be d by a p hysici a n as a n 
a nxi olytic or slee p ai d 
-  Use of T H C/c a n n a bi n oi d pr o d ucts is all o we d i n t he st u dy  
T he f oll o wi n g pr oce d ures will be perf or me d at W ee k - 3: 
•  C o nti n ue t o assess eli gi bilit y a n d re vi e w a d v erse e ve nts a n d c o nc o mita nt m e dicati o ns 
i ncl u di n g sta ble bac k gr o u n d A P t hera p y  
•  Uri ne dr u g test  
-  P atie nts wit h a p ositive uri ne dr u g scree n  f or be nz o di aze pi nes m ay be 
all o we d i n t he st u dy pr ovi de d  t he dr u g w as prescri be d by a p hysici a n as a n 
a nxi olytic or slee p ai d 
-  Use of T H C/c a n n a bi n oi d pr o d ucts is all o we d i n t he st u dy  
•  Alc o h ol breat h test 
-  Alc o h ol bre at h test m ust be ne g ative f or t he p atie nt t o c o nti n ue i n t he st u dy 
•  P A N S S  
•  C- S S R S  ( Si nce Last Visit versi o n)  
•  Bl o o d sa m ple f or assess me nt of prescri be d A P le vels 
-  S p o ns or or desi g nee will pr ovi de c o nfir m ati o n of eli gi bility b ase d o n A P 
bl o o d level 
•  T he Q ualificati o n peri o d ma y b e e xte n de d u p t o 2 wee ks  if re peat la b orat or y test 
res ults f or c o nfir mati o n of eli gi bilit y are p e n di n g   
8. 2. 2   
Tre at me nt Peri o d Pr oce d ures ( D a y 1  t o Wee k 1 2 ) 
T he f oll o wi n g pr oce d ures will be perf or me d at D a y 1:  
•  C o nti n ue t o assess eli gi bilit y  
•  F oll o wi n g c o nfir mati o n of eli gi bilit y, c o nse nti n g patie nts will be ra n d o mize d t o 1 of 
t he 4 St u d y Me dicati o n  gr o u ps.  T he f oll o wi n g pr oce d ures m ust be p erf or me d pri or t o 
a d mi nistrati o n of St u d y Me dicati o n : 
-  Re vie w of a d v erse e ve nts a n d c o nc o mita nt me dicati o ns i ncl u di n g sta ble 
bac k gr o u n d A P t her a p y 
-  F ull  p h ysical e x a mi nati o n pl us a n d wei g ht   
-  Vital si g ns i ncl u di n g bl o o d press ure, p ulse rate, res pirat or y rate, a n d 
te m perat ur e 
-  Sta n dar d 1 2- lea d E C G 

 
                                                                                                      
 
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-  Uri ne pre g n a nc y tests f or w o me n of c hil d beari n g p ote ntial 
-  Alc o h ol breat h test 
o  Alc o h ol bre at h test m ust be ne g ative f or t he p atie nt t o be r a n d o mize d 
t o receive St u d y Me dic ati o n 
-  Ser u m c he mistr y,  h e mat ol o g y, a n d c oa g ulati o n p ara meter e v al uati o ns  
-  Ser u m re nal para meters a n d u ri nal ysis 
-  P A N S S , P S P , C GI - S, S Q L S  
-  C- S S R S  ( Si nce Last Visit versi o n) 
-  S A S, AI M S, B A R S  
-  Bl o o d sa m ple f or ge netic testi n g (if c o ns e nt has bee n gi v e n)  
•  A d mi nistrati o n of first d ose of St u d y Me di cati o n  i n t he cli nic wit h f o o d 
•  Dis pe nsati o n of St u d y M e dicati o n  t o ta ke h o me 
-  A 2 -week s u p ply of t he St u dy Me dic ati o n will be pr ovi de d  
 
T he f oll o wi n g pr oce d ures will be perf or me d at W ee k 2  t hr o u g h Wee k 1 2 : 
•  D ue t o t he C O VI D- 1 9 pa n de mic a n d t he p ossi bilit y f or site cl os ures a n d/ or tra vel 
restricti o ns, cli nical la b or at or y bl o o d dra ws ma y b e perf or me d b y a H o me Healt h 
Care ser vi ce pr o vi der or b y a l o cal la b orat or y; ot her safet y a n d efficac y ass ess me nts 
ma y b e pe rf or me d r e m otel y via p h o n e/a u di o or vi de o c o nfere n ci n g pl atf or ms ( wit h 
t he e x ce pti o n of Face b o o k).  St u d y pers o n n el s h o ul d stri ve t o perf or m assess me nts 
wit hi n t he visit wi n d o w as s h o w n i n Ta ble 6  wit h t he u n dersta n di n g t hat n ot all 
assess me nts ma y be a ble  t o be perf or m e d.  Misse d assess me nts will  be rec or de d i n 
t he e C R F wit h n otati o n t hat t he misse d assess me nt was d ue t o t he C O VI D - 1 9 
pa n de mic. 
•  T he f oll o wi n g pr oce d ures m ust be perf or me d pri or t o a d mi nistrati o n of St u d y 
Me dicati o n : 
-  Re vie w of a d v erse e ve nts a n d c o nc o mita nt me dicati o ns i ncl u di n g sta ble 
bac k gr o u n d A P t her a p y 
-  Brief p h ysi cal e x a mi nati o n pl us wei g ht; v ital si g ns i ncl u di n g bl o o d press ure, 
p ulse rate, r es pirat or y rat e, a n d te m perat ure  ( Wee ks 2, 4, 6, 8, 1 0) 
-  F ull p h ysical e x a mi nati o n pl us wei g ht   
-  V ital si g ns i ncl u di n g bl o o d press ure, p ulse rate, res pirat or y rate, a n d 
te m perat ur e ( Wee k 1 2) 
 

 
                                                                                                      
 
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-  Sta n dar d 1 2- lea d E C G (Wee k s 6 a n d 1 2 o nl y; if Wee k 6 visit is a re m ote visit, 
E C G assess me nt ma y be perf or me d at Wee k 8 or 1 0 ) 
-  Uri ne pre g n a nc y tests f or w o me n of c hil d beari n g p ote ntial  
-  Alc o h ol breat h test 
o  P atie nt m ay be disc o nti n ue d if t hey test p ositive at a ny t w o visits 
d uri n g t he tre at me nt peri o d 
-  Ser u m c he mistr y,  h e mat ol o g y, a n d c oa g ulati o n p ara meter e v al uati o ns  (Wee k s 
6 a n d 1 2 o nl y) 
-  Ser u m re nal para meters a n d u ri nal ysis 
-  Bl o o d sa m ple f or assess me nt of C T P- 6 9 2 le vels ( pre- d ose if d os e of St u d y 
Me dicati o n is a d mi nistere d i n t he cli nic at Wee k s 2, 4, 6, 8, a n d 1 0) 
o  If p ossi ble, ti me of l ast d ose t ake n s h o ul d als o be rec or de d 
•  Dis pe nsati o n of St u d y M e dicati o n  t o ta ke h o me 
-  A 2 -week s u p ply of t he St u dy Me dic ati o n will be pr ovi de d at e ac h visit  exce pt 
Week 1 2  
-  W h e n st u dy assess me nts are n ot c o n d ucte d i n t he cli nic d ue t o t he C O VI D- 1 9 
p a n de mic, t he St u dy Me dic ati o n m ay be se nt directly  t o t he p atie nt  
•  P A N S S  ( Wee ks 2, 4, 8, 1 0, a n d 1 2) 
•  C GI - S ( Wee ks 2, 4, 6, 8, 1 0, a n d 1 2) 
•  C- S S R S  ( Si nce Last Visit versi o n) 
•  P S P ( Wee k s 6 a n d Wee k 1 2  o nl y) 
•  S Q L S ( Wee k 1 2  o nl y) 
•  S A S, AI M S a n d B A R S ( Wee k s 6 a n d Wee k 1 2  o nl y)  
•  Bl o o d sa m ple f or assess me nt of C T P- 6 9 2 le vels ( p ost- d ose; Wee k 1 2  o nl y) 
-  Bl o o d s a m ple s h o ul d be t ake n at t he e n d of t he visit 
-  Ti me of C T P - 6 9 2 d ose a n d bl o o d dr a w s h o ul d be rec or de d 
•  A d mi nistrati o n of d ose of St u d y Me dicati o n  i n t he cli nic wit h f o o d at t he Week 1 2 
visit 
-  P ost D ose bl o o d sa m ple f or assess me nt of C T P- 6 9 2 le ve ls (Wee k 1 2 o nl y)  
o  Bl o o d s a m ple s h o ul d be t ake n at t he e n d of t he visit 
o  Ti me of C T P - 6 9 2 d ose a n d bl o o d dr a w s h o ul d be rec or de d 
 

 
                                                                                                      
 
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8. 2. 2. 1  P h o ne C all C hec k -I n ( Wee ks 1, 3, 5, 7, 9 a n d 1 1 ) 
•  P atie nts will recei ve a p h o ne call 7 ± 2 da ys  after eac h i n -cli nic visit (e x ce pt after 
Wee k 1 2 ) t o disc uss a n y p ossi ble a d verse e ve nts or ot her me dical c ha n ges t hat ma y 
ha ve occ urr e d si nce t he ir last visit 
•  Patie nt s will als o be as ke d a b o ut c o m plia nce t o A P a n d St u d y M e dicati o n  sc he d ule 
8. 2. 3   
S afet y  F oll o w -U p Pr oce d ures ( Wee k 1 3 ) 
•  D ue t o t he C O VI D- 1 9 pa n de mic a n d t he p ossi bilit y f or site cl os ures a n d/ or tra vel 
restricti o ns, t he Safet y F oll o w- u p visit ma y be c o n d ucte d re m otel y via p h o ne/a u di o or 
vi de o c o nfere nci n g platf or ms ( wit h t he e x ce pti o n of Face b o o k) p er I n v esti gat or 
discreti o n.  
-  Re vie w of a d v erse e ve nts a n d c o nc o mita nt me dicati o ns i ncl u di n g sta ble 
bac k gr o u n d A P t her a p y 
-  Brief p h ysi cal e x a mi nati o n  (if i n-cli nic visit) 
 
 

 
                                                                                                      
 
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9.  
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  
9. 1.  
I ncl usi o n Criteri a 
1.  Patie nt s h o ul d be a ble t o rea d, u n dersta n d a n d v ol u ntaril y si g n a n i nf or me d c o nse nt 
d oc u me nt pri or t o a n y st u d y r elate d ass ess me nts a n d pr oce d ures bei n g c o n d ucte d.  
Patie nts s h o ul d be wi lli n g t o c o m pl y wit h t he st u d y visits a n d re q uire me nts of t he st u d y 
pr ot oc ol. 
2.  Patie nt s h o ul d be bet wee n 1 8 a n d 5 5  years of a ge, i ncl usi ve, at t he ti me of si g ni n g t he 
i nf or me d c o nse nt d oc u m e nt. 
3.  P h ysicia n c o nfir me d D S M - V dia g n osis of sc hiz o p hre nia f or t h e past 2 years base d o n 
patie nt’s  hist or y a n d c o nfir me d b y ps yc hiatric e v al uati o n a n d MI NI I nt er nati o nal 
Ne ur o ps yc hiatric I nter vi e w Ps yc h otic Dis or ders, versi o n 7. 0. 2 ( MI NI, Versi o n 7. 0. 2 ; see 
A P P E N DI X L ). 
4.  T he patie nt  is a n o ut patie nt wit h n o h os pitalizati o n f or w orse ni n g of sc hiz o p hre nia wit hi n 
3 m o nt hs of t he first Scree ni n g Visit ( Wee k -5) . 
5.  Patie nts c urre ntl y treate d wit h o ne a nti ps yc h otic ( A P) me dicati o n w hic h has bee n 
u nc ha n ge d ( m e dicati o n a n d d ose) f or at least 7 wee ks pri or t o t he first Scree ni n g Visit 
( Wee k - 5), a n d e x pecte d t o re mai n u nc ha n ge d d uri n g t he Scree ni n g a n d Treat me nt 
peri o d.  All o we d or all y d ose d A Ps are: 
a. Ari pi praz ole 
b.  Ase na pi ne 
c. Bre xi pi praz ole 
d.  Cari prazi ne  
e. L ur asi d o ne 
f. Ola nza pi ne 
g.  Pali peri d o ne 
h.  Q uetia pi ne 
i. Ris peri d o ne 
N ote: If t he p atie nt is bei n g tre ate d wit h de p ot or l o n g- acti n g a nti psyc h otics, t hey s h o ul d 
be o n t he tre at me nt f or at le ast 2 dr u g a d mi nistr ati o n cycles pri or t o t he first Scree ni n g 
Visit ( Week -5).  
6.  Patie nts wit h c o nfir me d bl o o d le vels of t heir c urre nt A P me dicati o n i n sa m ples dra w n at 
t he Q ualificati o n Visit ( Wee k -3).  
7.  T he patie nt has a relia ble i nf or ma nt w h o is a ble t o pr o vi de i nf or mati o n re gar di n g t h e 
patie nt  a n d s u p p ort st u d y partici pati o n. 
 
 
 

 
                                                                                                      
 
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8.  Patie nts wit h cli nicall y st a ble sc hiz o p hre nia wit h resi d ual s y m pt o ms defi ne d as P A N S S 
t otal sc ore of 7 0- 1 1 0 p er e val uati o n at t he first Scree ni n g Visit ( Wee k - 5), t he 
Q ualificati o n Visit ( Wee k - 3) a n d D a y 1 . 
N ote: At Week - 3 a n d D a y 1 , t he P A N S S t ot al sc ore m ay v ar y by 1 0 p oi nts as c o m p are d t o 
a previ o us visit, as l o n g as t ot al sc ore re m ai ns bet wee n 7 0- 1 1 0 at e ac h of t he t hree visits 
f or t he p atie nt t o be i ncl u de d i n t he st u dy. 
Patie nts m ust als o meet t hese a d diti o nal P A N S S criteria:  
a. P A N S S sc ore of ≤ 4 o n p ositi ve scale ite ms of c o n ce pt ual dis or ga nizati o n a n d 
h ostilit y  
b.  P A N S S sc ore ≥ 4 o n at le ast t w o  of t he f oll o wi n g ite ms:  
a. Del usi o ns 
b.  Hall uci nati o ns  
c. S us pici o us ness/ Persec uti o n 
d.  U n us ual t h o u g ht c o nte nt 
c. P A N S S Ne gati ve S y m pt o m Fact or Sc ore ( N S F S) ≥ 1 2 
9.  If of r e pr o d ucti ve a ge a n d n ot i nfertile ( defi n e d bel o w), willi n g a n d a bl e t o use a 
me dicall y hi g hl y effecti ve f or m of birt h c o ntr ol d uri n g t he st u d y a n d f or 4 wee ks  
f oll o wi n g last d ose of St u d y Me di cati o n.  E x a m ples of me dicall y hi g hl y effecti ve f or ms 
of birt h c o ntr ol ar e: 
a. S ur gical sterilit y ( via v as ect o m y, h ysterect o m y or bilateral li gati o n) or 
p ost- me n o pa usal fe m ales  ( ha ve ha d s p o nt a ne o us a me n orr hea f or at least t he last 1 
year a n d at least 1 year after t he o nset of a m e n orr h ea w hile n ot recei vi n g h or m o ne 
re place me nt t hera p y a n d ha ve a F ollicle-Sti m ulati n g H or m o ne ( F S H) le vel greater 
t ha n 4 0 mI U/ m L) 
b.  Se x ual part ner is sterile, or of t he sa me s e x  
c. I m pla nts of le v o n or gestr el i n fe males 
d.  Oral c o ntr ace pti ve (c o m bi ne d or pr o gester o ne o nl y) i n fe males 
e. D o u ble- barrier met h o d ( a n y c o m bi nati o n of p h ysical a n d c he mical met h o ds) 
f. I ntr a uteri ne d e vice i n f e males, or ot her met h o d wit h p u blis he d data s h o wi n g t hat t he 
l o west e x pecte d fail ure r ate is less t ha n 1 % per ye ar 
1 0.  Healt h y, as deter mi ne d b y t he I n v esti gat or, bas e d o n a me dical e v al uati o n i ncl u di n g 
hist or y, p h ysical e x a mi nati o n, vital si g ns, electr o car di o gra m ( E C Gs ) a n d cli nical 
la b orat or y ass ess me nts at Wee k - 5. 
N ote: A p atie nt wit h a n o n-cli nic ally si g nific a nt a b n or m ality or l a b or at ory p ar a meters 
o utsi de t he refere nce r a n ge m ay be i n cl u de d o nly if t he I nvesti g at or c o nsi ders t h at t he 
fi n di n g will n ot c o m pr o mise t he p atie nt’s s afety a n d will n ot i nterfere wit h t he st u dy 
pr oce d ures or d at a i nter pret ati o n. 
 
 

 
                                                                                                      
 
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1 1.  B o d y mass i n de x ( B MI ) wit hi n t he ra n ge of 1 8 t o 4 0 k g/ m 2, i ncl usi ve, at t he first 
Scree ni n g Visit ( Wee k -5) . 
9. 2.  
E xcl usi o n Criteri a  
1.  Patie nts wit h D S M -V criteria at t he first Scree ni n g Visit ( Wee k -5)  f or dis or ders ot her 
t ha n sc hiz o p hre nia t hat i n t he o pi ni o n of t he I n vesti gat or ma y i nterfere wit h st u d y 
c o n d uct a n d i nter pretati o n of res ults.  
2.  Patie nts w h o, i n t he o pi ni o n of t he I n vesti gat or, h a ve a hist or y of a nti ps yc h otic 
treat me nt resista n ce. 
3.  Patie nts c urre ntl y ta ki n g cl oza pi ne.  
4.  Patie nts w h o ha ve bee n pre vi o usl y treate d wit h or are recei vi n g electr o c o n v ulsi ve 
t hera p y ( E C T). 
5.  Patie nts w h o ha ve i nitiate d or c ha n ge d d ose of a nti de pressa nts or ot her m o o ds 
sta bilizers wit hi n 7 wee ks pri or t o t he first Scree ni n g Visit ( Wee k -5).  
6.  Patie nts c urre ntl y ta ki n g lit hi u m.  
7.  Patie nts ta ki n g a n A P ( e. g. Ser o q u el) as a slee p ai d.  
N ote: P atie nts will be all o we d t o s witc h t o a n o n- A P slee p ai d d uri n g t he Scree ni n g 
peri o d . 
8.  Patie nts w h o use prescri pti o n me dicati o ns (sti m ula nts) t o treat atte nti o n defi cit 
h y peracti vit y dis or der or atte nti o n deficit dis or der.  
9.  Scree ni n g la b or at or y meas ure me nts o utsi de t he n or mal ra n ge ass ociate d wit h 
p ote ntial ris k f or t he treat me nt u n der i n vesti gati o n at t he first Scree ni n g Visit  
( Wee k -5).  T his will i ncl u de b ut n ot li mite d t o:  
a. As partate tr a nsa mi nase ( A S T), ala ni ne tra ns a mi nase ( A L T), ga m ma -
gl uta m yl tra ns f eras e ( G G T), or t otal bilir u bi n > 2 x u p per li mit of n or mal 
( U L N) 
b.  Esti mate d gl o mer ular filtrati o n rate (e G F R) < 6 0 m L/ mi n ute/ 1. 7 3 m 2 
c. Ser u m creati ni ne  a n d/ or bl o o d urea nitr o ge n (B U N ) > U L N  
d.  Uri nal ysis p ositi ve f or pr otei n or uri ne micr oal b u mi n/creati ni ne rati o 
( U A C R) > 3 0 m g/ g 
N ote: T hese l a b or at ory tests m ay be re p e ate d o nce, if t hey are a b n or m al o n first 
scree ni n g, a n d if t here is a me dic al/ a n alytic al re as o n t o believe t he res ults m ay be 
i n acc ur ate.  If t he re p e at test is wit hi n t he refere nce r a n ge, t he p atie nt m ay be i ncl u de d 
o nly if t he I nvesti g at or c o nsi ders t h at t he previ o us fi n di n g will n ot c o m pr o mise t he 
p atie nt’s s afety a n d will n ot i nterfere wit h t he i nter pret ati o n of s afety d at a.  
 
 
 

 
                                                                                                      
 
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1 0.  Patie nts wit h s uici dal be ha vi or occ urri n g wit hi n t he past year or w h o  p ose a c urre nt 
s uici de ris k as deter mi ne d b y t he PI or as c o nfir me d at t he first Scree ni n g Visit  
( Wee k -5), t he Q u alificati o n Visit ( Wee k - 3) or D a y - 1 b y  affir mati ve a ns wer o n 
ite ms 4 or 5 o n t he C ol u m bia-S uici de Se verit y Rati n g Scal e ( C -S S R S) . 
1 1.  Tre at me nt wit h a n i n vesti gati o nal dr u g wit hi n 7 w ee ks or 5 half-li ves (if k n o w n), 
w hic he ver is l o n ger, pri or t o t he first Scree ni n g Visit ( Wee k -5).  
1 2.  D o nati o n of bl o o d wit hi n 4 wee ks of D a y 1. 
1 3.  Hist or y of pr ol o n ge d Q T s y n dr o me or a Scree ni n g Q Tc i nter val wit h Fri deri cia’s 
c orrecti o n ( Q Tc F) >  4 5 0 msec f or males or Q Tc F >  4 7 0 msec f or fe mal es.  
1 4.  Fe males w h o ar e n ursi n g, pre g na nt, or pla n ni n g t o bec o me pre g na nt w hile i n t he 
st u d y a n d f or 4 wee ks aft er t he last d ose of st u d y me dicati o n. 
1 5.  Hist or y of m eeti n g D S M -5 crite ria f or m o derate t o se vere alc o h ol or s u bst a nce use 
dis or der ( ot her t ha n nic oti ne or caffei ne) wit hi n t he 6 m o nt hs bef ore t he first 
Scree ni n g Visit ( Wee k -5) . 
1 6.  P ositi ve alc o h ol breat h test.  
N ote: A re pe at alc o h ol bre at h test will be all o we d wit hi n 4 8 h o urs of t he first test  o nly at 
t he first Scree ni n g Visit (Week - 5).  T he re p e at test m ust be ne g ative f or i ncl usi o n i n t he 
st u dy. 
1 7.  P ositi ve uri ne test f or dr u gs of a b use at t he Scree ni n g/ Q ualificati o n Visit ( Wee k - 5,  
- 3; see A P P E N DI X B ). 
N ote:  Patie nts wit h a p ositive uri ne dr u g scree n  f or be nz o di aze pi nes m ay b e all o we d i n 
t he st u dy pr ovi de d t he dr u g w as prescri be d by a p hysici a n as a n a nxi olytic or slee p ai d  
N ote: Use of T H C/c a n n a bi n oi d pr o d ucts is all o we d i n t he st u dy  
1 8.  Patie nts wit h p ositi ve bl o o d scree n f or h u ma n i m m u n o deficie nc y vir us ( HI V 
a nti b o d y) a n d/ or he p atitis B vir us s urface a nti ge n.  
N ote: P atie nts wit h asy m pt o m atic he p atitis C are all o we d as l o n g as t he cli nic al 
l a b or at ory me nti o ne d a b ove re q uire m e nts are met. 
1 9.  Patie nts wit h hist or y of r e nal disease or t h ose ta ki n g me dicati o ns t o treat re nal 
disease.  
2 0.  A n y ot her cli nicall y si g nifica nt me dical c o n diti o n (e. g. fe v er, acti ve i nfecti o n, 
u nc o ntr olle d dia betes, car di o vasc ular c o n diti o ns i ncl u di n g Class III or I V heart 
fail ure, p ul m o nar y e m b olis m, dee p vei n t hr o m b osis, acti ve maj or a ut oi m m u ne 
disease, ne ur ol o gical disease, ca ncer n ot i n re missi o n f or last 3 years e x ce pt basal cell 
a n d s q ua m o us cell carci n o ma), or pr oce d ure as det er mi ne d b y t he I n v esti gat or, t hat 
ma y u nf a v or a bl y alter t h e ris k - be nefit of st u d y partici pati o n, a d versel y affect st u d y 
c o m plia nce, or c o nf o u n d i nter pretati o n of st u d y res ults. 
 
 

 
                                                                                                      
 
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9. 3.  
P atie nt  Wit h dr a w al Criteri a  
P atie nts ma y wit h dra w fr o m partici pati o n i n t he st u d y at a n y ti me.  T he I n v esti gat or m a y 
wit h dra w a patie nt at a n y ti me if t he y belie v e t he s afet y of t he p atie nt or t he i nte grit y of t he d ata 
are at ris k .  I n a d diti o n, patie nts s h o ul d be wit h dra w n if t he y: 
•  E x perie nce a seri o us or i nt olera ble A E  
•  De vel o p a cli nicall y si g nifica nt la b orat or y or E C G a b n or malit y  
•  De vel o p pr otei n uri a of 1- 2 + or U A C R  > 3 0 m g/ g as c o nfir me d b y a re p eat la b test  
•  De vel o p e G F R le vels < 6 0 m L/ mi n ute/ 1. 7 3 m 2 as c o nfir me d b y a re peat la b test  
•  De vel o p sy m pt o m atic A L T or A S T ele vati o n ≥ 2x t he U L N o n t w o re p eat la b tests  or 
de vel o p asy m pt o m atic  A L T or A S T ele vati o n ≥ 3x t he U L N as c o nfir me d b y a re peat 
la b test 
•  De vel o p t otal bilir u bi n ≥ 2 x t he U L N as c o nfir me d b y a re peat la b test  
•  E x hi bit s uici dal be ha vi or as deter mi ne d b y  a n affir mati ve a ns wer o n ite ms 4 or 5 o n 
t he C-S S R S  
•  D o n ot f oll o w g ui deli nes s pecifie d i n t he pr ot oc ol ( i.e., is n o nc o m plia nt wit h pr ot oc ol 
pr oce d ur es or St u d y M e dicati o n  a d mi nistrati o n) or s pecific i nstr ucti o ns b y t he st u d y 
staff 
•  A n y me di call y a p pr o priate reas o n or si g nifica nt pr ot oc ol vi olati o n, i n t he o pi ni o n of 
t he I n v esti gat or 
•  Are l ost t o f oll o w  u p 
I n case of t w o c o nsec uti ve misse d safet y ass ess me nts d ue t o t he C O VI D - 1 9 pa n d e mic, c o nti n ue d 
patie nt partici pati o n i n t he st u d y m ust be disc usse d b y t he I n vesti gat or a n d t he Me dical M o nit or. 
9. 3. 1.  
P ati e nt Wit h dr a w al Pr oce d ures  
A patie nt w h o pre mat urel y disc o nti n ues St u d y M e dicati o n /st u d y partici pati o n s h o ul d ha ve all 
Wee k 1 2 assess me nts perf or me d as a n Earl y T er mi nati o n Visit , a n d if p ossi ble, ret ur n f or t he 
Safet y F oll o w - u p Visit.  I n li g ht of t he C O VI D - 1 9 pa n de mic, st u d y p ers on n el s h o ul d stri ve t o 
perf or m ass ess me nts per Ta ble 6  wit h t he u n dersta n di n g t hat n ot all assess me nts ma y be a ble t o 
be perf or me d.   All misse d assess me nts  will  be d oc u me nte d i n t he e C R F wit h n otati o n t hat t he 
misse d assess me nt was d ue t o t he C O VI D - 1 9 p a n demic .  T he Safet y F oll o w -U p Visit ma y b e 
wai ve d b y t he S p o ns or i n i nsta nces w here patie nts ha ve disc o nti n ue d d osi n g pri or t o t he Earl y 
Ter mi nati o n Visit o n a case -b y -case basis.  
If a patie nt ter mi nates earl y fr o m t he st u d y, t he I n v esti gat or will rec or d t h e reas o n(s) f or earl y 
ter mi nati o n o n t he rele va nt electr o nic case re p ort f or m ( e C R F).  T h e s pecifi c reas o n f or t he 
wit h dra wal s h o ul d be car ef ull y d o c u me nte d o n t he e C R F. 

 
                                                                                                      
 
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A d verse e ve nts res ulti n g i n patie nt earl y ter mi nati o n will be f oll o we d t o t he satisfact o r y 
res ol uti o n a n d deter mi nati o n of o utc o me, as ascert ai ne d b y t he I n vesti gat or (a n d/ or S p o ns or, or 
its desi g nee); (See Secti o n  1 2 ).  T he data will be rec or de d o n t h e a p pr o priate e C R F. 
 
 
 

 
                                                                                                      
 
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1 0.  
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N S 
1 0. 1.  
Descri pti o n of St u d y Me dic ati o n  
Patie nts meeti n g eli gi bilit y criteria will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o o ne of t he f oll o wi n g 4 
treat me nt ar ms: 
•  D o u ble- bli n de d C T P- 6 9 2, 1 g Q D f or 1 2 w ee ks 
•  D o u ble- bli n de d C T P- 6 9 2, 2 g Q D f or 1 2 w ee ks 
•  D o u ble- bli n de d C T P- 6 9 2, 4 g Q D f or 1 2 w ee ks 
•  D o u ble- bli n de d Place b o, Q D f or 1 2 w ee ks 
Patie nts will ta ke t he first d ose of  St u d y Me di cati o n  i n t he cli nic o n Da y 1 of t he Treat me nt 
Peri o d, after t he Baseli ne assess me nts ha ve b ee n p erf or me d a n d wit h  f o o d.  Patie nts will be 
i nstr ucte d t o c o nti n ue ta ki n g t heir St u d y M e dicati o n  o nce dail y  wit h  f o o d, f or a t otal of 1 2 
wee ks.  O n cli nic visit da ys, w h e n p atie nts ta ke t h eir d ose of St u d y Me dicati o n  i n t he cli nic, t he 
d ose s h o ul d be a d mi nistere d aft er t he cli nical la b orat or y bl o o d dra ws a n d uri ne c ollecti o n are 
c o m plete d.   If cli nical la b orat or y bl o o d dra ws a n d uri ne c ollecti o n are perf or me d b y a H o m e 
Healt h Care s er vice pr o vi der or b y a l ocal la b orat or y , p atie nts s h o ul d tr y t o ta ke t heir St u d y 
Me dicati o n per t heir n or mal sc he d ule. 
1 0. 2.  
Tre at me nt C o m pli a nce  
At eac h sc h e d ule d st u d y visit after ra n d o mizati o n, t he I n v esti gat or or d esi g nee wi ll i nter vie w t he 
patie nt re gar di n g tr eat me nt c o m plia nce a n d c o m pare t he n u m ber of dis pe nse d vers us ret ur ne d 
St u d y M e dicati o n  p o uc h es.  W he n st u d y assess m e nts  are n ot c o n d u cte d i n t he cli nic d ue t o t he 
C O VI D - 1 9 pa n d e mic, treat me nt c o m plia nce ma y be assesse d via p h o n e/a u di o or vi de o 
c o nfer e nci n g platf or ms or b y t he H o me H ealt h C are ser vice pr o vi der.  T he use d a n d u n use d 
St u d y M e dicati o n p o uc h es ma y b e se nt bac k t o t he site or t he patie nt ma y  s a ve t he use d a n d 
u n use d p o uc hes a n d bri n g bac k t o t he ne xt i n- cli nic visit.  Patie nts s h o ul d stri ve f or 1 0 0 % 
c o m plia nce wit h t he dail y d osi n g sc he d ul e.  Retrai ni n g o n treat me nt c o m plia nce s h o ul d occ ur f or 
patie nts wit h less t ha n 8 0 % c o m plia nce at a n y visit a n d t he S p o ns or s h o ul d be n otifie d .  
1 0. 3.  
St u d y Me dic ati o n  M ateri als a n d M a n a ge me nt  
A c o m plete descri pti o n of t he St u d y Me dicati o n  a n d re q uire me nts f or st ora ge, h a n dli n g, 
dis pe nsi n g, acc o u nta bilit y, r et ur ns a n d d estr ucti o n ca n be f o u n d i n t he P har mac y Ma n ual. 
1 0. 3. 1.  
P h ysic al Des cri pti o n of St u d y Me dic ati o n  
St u d y M e dicati o n  will be C T P - 6 9 2 or matc hi n g Pl ace b o.  D etails re gar di n g f or m ulati o n a n d 
d osa ge ar e s h o w n i n Ta bl e  7.  
 
 
 

 
                                                                                                      
 
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T a ble 7:  
I n vesti g ati o n al Pr o d uct 
 
 
1 0. 3. 2.  
St u d y Me dic ati o n  P ac k a gi n g, L a belli n g a n d St or a ge 
C T P - 6 9 2 a n d Place b o will be pac ka ge d i n f oil p o uc hes a n d la b ele d b y a n a p pr o priatel y q ualifie d 
ve n d or.  Starti n g at Da y 1  a n d at eac h sc he d ul e d i n-cli nic visit, eac h patie nt will recei ve 2 kits 
c o ntai ni n g d oses f or 2 w ee ks.  W he n st u d y assess me nts are  n ot c o n d u cte d i n t he cli nic d ue t o t he 
C O VI D - 1 9 pa n d e mic, t h e St u d y Me dicati o n will  be se nt  directl y t o t he patie nt.   
Details of t he pac ka gi n g, la beli n g a n d dis pe nsi n g i nstr ucti o ns ca n be f o u n d i n t he P har mac y 
Ma n ual.  
St u d y M e dicati o n  s h o ul d be st ore d at t he cli nic i n t he ori gi nal p ac ka ge bet wee n 1 5° C t o 2 5° C 
( 5 9° F t o 7 7° F), as state d o n t he pr o d uct la bel, i n a sec ure, t e m perat ure- m o nit ore d, l oc ke d area, 
u n der t he r es p o nsi bilit y of t he I n vesti gat or or ot h er a ut h orize d i n di vi d ual u ntil dis pe nse d t o t he 
patie nts.  
Patie nts s h o ul d be a d vise d t o st ore t heir St u d y Me dicati o n i n t he ori gi nal p ac ka ge at r o o m 
te m perat ur e as state d o n t he pac k a ge la b el.  N o s pecial ha n dli n g pr oce d ures are re q uire d. 
1 0. 3. 3.  
St u d y Me dic ati o n  Pre p ar ati o n a n d A d mi nistr ati o n 
St u d y M e dicati o n  will be s u p plie d t o patie nts as p o w der i n a f oil p o uc h.  P atie nts will o pe n t he 
p o uc h b y h a n d usi n g a f ol d- o ver tear n otc h or b y usi n g sciss ors t o c ut acr oss t he t o p of t he 
p o uc h.  T he d ose s ol uti o n s h o ul d be pre pare d dail y b y diss ol vi n g t he e ntire c o nte nts of a si n gle 
p o uc h i n a p pr o xi matel y a half -glass or h alf -c u p of water a n d mi xi n g wit h a s p o o n f or 
a p pr o xi matel y 3 0 sec o n ds u ntil diss ol ve d.  U p o n c o m pleti o n of pre parati o n, t he d ose s ol uti o n is 
c ol orless a n d sli g htl y haz y i n a p p ear a nce.  T he d os e s ol uti o n s h o ul d be c o ns u me d i m me diatel y. 
Patie nts will ta ke t he first d ose of St u d y Me di cati o n  i n t he cli nic o n Da y 1 a n d will be i nstr ucte d 
t o c onti n ue ta ki n g St u d y Me dicati o n  o nce d ail y  wit h f o o d, f or a t otal of 1 2 wee ks.  Patie nts 
s h o ul d be i nstr ucte d t o ta ke St u d y Me dicati o n  at a p pr o xi matel y t he s a me ti me eac h d a y.  If a 
d ose is misse d, t he patie nt s h o ul d res u me d osi n g as s o o n as p ossi ble.  T he patie nt s h o ul d n ot ta ke 
 
I n vesti g ati o n al Pr o d uct 
Pr o d uct N a me:  
C T P - 6 9 2 or Matc hi n g Pl ace b o 
D os a ge F or m:  
P o w der f or oral s ol uti o n 
U nit D ose  
1 g, 2 g or 4 g C T P- 6 9 2 or Place b o 
R o ute of A d mi nistr ati o n  
Oral  
P h ysic al Des cri pti o n  
W hite t o off- w hite p o w der i n a f oil p o uc h 
M a n uf act urer  
S har p Cli nical Ser vices, I nc.  

 
                                                                                                      
 
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t w o d oses at t he sa me ti me.  De viati o ns fr o m prescri be d d osi n g s h o ul d be disc usse d at eac h visit 
f or assess me nt of c o m plia nce a n d retr ai ni n g w he n necessar y. 
1 0. 3. 4.  
St u d y Me dic ati o n  Ret ur n a n d Dis p os al  
T he S p o ns or or desi g nee will re vie w wit h t he I n vesti gat or a n d rele v a nt site pers o n nel t he pr o cess 
f or St u d y Me di cati o n  ret ur n, dis p osal, a n d/ or destr ucti o n, i ncl u di n g res p o nsi bilities f or t he site 
vers us t he S p o ns or ( or d esi g nee).  S pecific re q uire me nts f or destr ucti o n or ret ur n ca n b e f o u n d i n 
t he P har mac y Ma n u al. 
1 0. 3. 5.  
St u d y Me dic ati o n  Acc o u nt a bilit y  
T o satisf y re g ulat or y r e q uire me nts re gar di n g dr u g acc o u nta bilit y, all St u d y Me dicati o n  will be 
rec o ncile d i n f ull.  T he I n vesti gat or or desi g nee m ust mai ntai n acc urate rec or ds of t he recei pt of 
St u d y M e dicati o n , i ncl u di n g date recei ve d, l ot n u m ber, a m o u nt recei ve d, c o n diti o n of t he 
pac ka ge, a n d t he dis p ositi o n of St u d y Me dicati o n . 
C urre nt dis pe nsi n g rec or ds will als o be mai ntai ne d, i ncl u di n g t he dat e a n d a m o u nt of m e dicati o n 
dis pe nse d t o eac h i n di vi d ual patie nt.  Ret ur ne d St u d y Me dicati o n  rec or ds will be mai ntai ne d a n d 
fi nal St u d y Me dicati o n rec o nciliati o n will als o be rec or d e d f or eac h patie nt. 
1 0. 4.  
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
All patie nts will be i nstr ucte d t o ta ke t heir sta n d ar d A P me dicati o n t hr o u g h o ut t he st u d y.  All 
me dicati o ns, i ncl u di n g t h e sta n dar d A P me dicati o n a n d o ver- t h e-c o u nter t h era pies (e . g., 
vita mi ns, her bal, a n d n utriti o nal s u p ple me nts), ta ke n at t he ti me of t he Scree ni n g Visit  ( Wee k - 5 
Visit ) t hr o u g h t he F oll o w-U p Visit  will be rec or d e d i n t he patie n t’s s o urce d oc u me ntati o n a n d 
d oc u me nte d i n t he e C R F. 
A n y c o nc o mita nt me dicati o n dee me d necessar y f or t he well bei n g of t he p atie nt ma y b e gi ve n at 
t he discreti o n of t he I n v esti gat or.  Us e of me dicati o ns t hat are pr o hi bite d per pr ot oc ol ma y lea d 
t o patie nt wit h dra wal fr o m t he st u d y.  
A list of all o we d a n d pr o hi bite d c o nc o mita nt me dicati o ns is s h o w n i n A P P E N DI X  A. 
 
 
 
 
 
 
 
 

 
                                                                                                      
 
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1 1.  
S T U D Y A S S E S S M E N T S  
T he Sc he d ule of Assess me nts  is prese nte d i n Ta ble  6 a n d s h o ul d be refere nce d f or d etails 
re gar di n g t he c ollecti o n of eac h assess me nt at eac h visit i n t he res pecti ve st u d y peri o ds.   
D ue t o t he C O VI D- 1 9 pa n de mic a n d t he p ossi bilit y f or site cl os ures a n d/ or tra vel restri cti o ns, 
cli nical la b orat or y bl o o d dra ws ma y be p erf or me d b y a H o me Healt h Care s er vice pr o vi der or b y 
a l ocal la b or at or y; ot her s afet y a n d efficac y assess me nts ma y be p erf or me d re m otel y vi a 
p h o ne/a u di o or vi de o c o nfere n ci n g platf or ms ( wit h t he e x ce pti o n of Face b o o k).   
St u d y p ers o n nel s h o ul d stri ve t o perf or m assess me nts wit hi n t he visit wi n d o w as s h o w n i n Ta ble 
6 wit h t he u n dersta n di n g t hat n ot all assess me nts ma y b e a ble t o be p erf or me d .  Safet y -relate d 
assess me nts m ust be pri oritize d.  Misse d assess me nts will  be rec or de d i n t h e e C R F  wit h n otati o n 
t hat t he misse d assess me nt was d ue t o t he C O VI D - 1 9 pa n de mic.  I n case of t w o c o nsec uti ve 
misse d safet y assess me nts, c o nti n ue d patie nt parti ci pati o n i n t he st u d y m ust be disc usse d b y t he 
I n v esti gat or a n d t he M e dical M o nit or. 
1 1. 1.  
De m o gr a p hic C h ar acteristics a n d Me dic al Hist or y  
De m o gra p hic c har acteristics (i .e., se x, et h nic ori gi n, date of birt h, a n d calc ulate d b o d y m ass 
i n de x) will be c ollecte d a n d detaile d o n t he e C R F. 
At Wee k - 5, t he patie nts m ust ha ve a c o nfir m e d D S M- V dia g n osis of s c hiz o p hre nia f or t h e past 
2 years bas e d o n patie nt’s  hist or y a n d als o c o nfir me d b y ps yc hiatric e v al u ati o n a n d MI NI 
I nter nati o nal N e ur o ps yc hiatric I nter vie w Ps yc h otic Dis or ders, v ersi o n 7. 0. 2 ( MI NI, V ersi o n 
7. 0. 2 ; see A P P E N DI X L ). 
1 1. 2.  
P h ysic al E x a mi n ati o n  
A f ull p h ysical e x a mi nati o n will i ncl u de  a n e x a mi nati o n of all maj or or ga n s yste ms.  Brief 
p h ysical  e x a mi nati o ns will be s y m pt o m -direct e d.  
1 1. 3.  
Vit al Si g ns  
Vital si g ns will be meas ure d aft er t he patie nt h as b ee n i n a s u pi ne or s e mi -s u pi ne p ositi o n f or at 
least 5 mi n utes a n d will i ncl u de bl o o d press ure, p ulse rate, res pirat or y rate, a n d te m perat ure . 
Wei g ht a n d hei g ht will be meas ur e d  a n d use d t o calc ulat e t he patie nt’s B MI Wei g ht a n d hei g ht 
will be c o n verte d as nee d e d t o kil o gra ms a n d ce nti meters, res p ecti vel y, pri or t o statistical 
a nal ys es.  
1 1. 4.  
Electr oc ar di o gr a m ( E C G)  
T wel ve -lea d electr ocar di o gr a ms will be perf or me d after t he p atie nt  has reste d i n a s u pi ne or 
se mi-s u pi ne p ositi o n f or at least 5 mi n utes.  I n di vi d ual para met ers i ncl u di n g P R, Q T, Q Tc F, 
Q R S, a n d R R i nter vals will be c ollecte d.  Re peat electr ocar di o gra ms (if d ee me d necess ar y) 
s h o ul d be perf or m e d at least 5 mi n utes a part.  T he I n v esti gat or s h o ul d in dicate re vie w of t he 
electr ocar di o gr a m re p orts t hr o u g h o ut t he st u d y b y si g ni n g a n d dati n g eac h re p ort. 

 
                                                                                                      
 
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1 1. 5.  
Cli nic al L a b or at or y Assess me nts  
Cli nical l a b orat or y assess me nts will i ncl u de ser ol o g y, he m at ol o g y, c oa g ulati o n la b orat or y 
para meters,  ser u m c h e mistr y, ser u m re n al la b orat or y p ara m eters, c o m plet e uri nal ysis, uri ne 
pre g na nc y t est, uri ne dr u g scree n a n d alc o h ol breat h test.  T he list of s pecific tests is s h o w n i n 
A P P E N DI X B .  Sa m ples f or la b orat or y assess me nts s h o ul d be c ollecte d at t he be gi n ni n g of t he 
St u d y Visit a n d pri or t o t he d ose. 
T he res ults of t he la b orat or y tests c o n d ucte d at W ee k - 5 m ust be ass esse d b y t he I n vesti gat or t o 
deter mi ne eac h  patie nt’s eli gi bilit y f or partici pati o n i n t he st u d y.  T he I n v esti gat or s h o ul d 
i n dicate re vie w of t he la b orat or y re p orts t hr o u g h o ut t he st u d y b y si g ni n g a n d dati n g eac h re p ort. 
W here a p plica ble, l a b orat or y r es ults t hat fall o utsi de t he refere nce ra n ge will be i nter prete d b y 
t he I n v esti gat or as A b n or mal, n ot cli nicall y si g nifica nt, or A b n or m al, cli nicall y si g nifica nt. 
La b orat or y res ults dee me d A b n or mal, cli nicall y si g nifica nt will be rec or de d as a n a d verse e v e nt 
i n t he e C R F a n d s h o ul d b e f ull y i n vesti gat e d a n d re peate d f or verificati o n.  Cli nicall y si g nifica nt 
la b orat or y a b n or malities re q uiri n g i nter ve nti o n s h o ul d be disc usse d wit h t he Me dical M o nit or.  
A d diti o nal tests a n d e val uati o ns re q uire d t o esta blis h t he si g nifica n ce or eti ol o g y of a cli nicall y 
si g nifica nt a b n or mal r es ult or t o m o nit or t he c o urse of a n a d v erse e ve nt s h o ul d be o btai ne d w he n 
cli nicall y i n dicat e d.  W he ne ver p ossi ble, t he eti ol o g y of t h e cli nicall y si g nifica nt a b n or m al 
fi n di n gs will be d oc u me nte d o n t he e C R F. 
A n y si g nifica nt la b orat or y a b n or malities t hat are eit her seri o us or u ne x pect e d will be pr o m ptl y 
re p orte d t o t he S p o ns or.  A n y a d diti o nal rele va nt l a b orat or y res ults o btai ne d b y t he I n vesti gat or 
d uri n g t he c o urse of t his st u d y will be re p orte d t o t he S p o ns or or desi g n e e.  
1 1. 6.  
Assess me nt of Effic ac y  
1 1. 6. 1.  
P ositi ve a n d Ne g ati v e S y m pt o m Sc ale ( P A N S S) 
T he P A N S S is a ps yc hiatric rati n g scal e desi g ne d t o meas ure s y m pt o m se verit y a m o n g patie nts  
wit h sc hiz o p hre nia o ver t he prece di n g 7 da ys.  T h e P A N S S ite ms are di vi de d i nt o p ositi ve, 
ne gati ve a n d ge ner al ps yc h o pat h ol o g y fact ors utilizi n g a 3 0- ite m, 7-p oi nt rati n g sc h e me .  
Sc ori n g i nstr ucti o ns will be pr o vi de d (t o t he Rater)  wit h e ac h ite m acc o m p a nie d b y a c o m plet e 
defi niti o n as well as detaile d a nc h ori n g criteria f or all 7 rati n g p oi nts, w hic h re pres e nt i ncreasi n g 
le vels of ps yc h o pat h ol o g y: 1 =a bse nt, 2 = mi ni mal, 3 = mil d, 4 = m o derate, 5 = m o derate se v ere, 
6 =se ver e a n d 7 = e xtre me.  T he P A N S S is sc ore d b y s u m mati o n of rati n gs acr oss ite ms s uc h t hat 
t he p ote ntial ra n ges are 7 t o 4 9 f or eac h of t he P ositi ve a n d Ne gati ve Scales a n d 1 6 t o 1 1 2 f or t he 
Ge ner al  Ps yc h o p at h ol o g y Scal e.  T he P A N S S t otal sc ore is t he sc ore of all 3 0 P A N S S ite ms 
ta ke n t o get her. (see A P P E N DI X C ) 
1 1. 6. 2.  
Cli nic al Gl o b al I m pressi o n -Se verit y ( C GI -S) Sc ore  
T he C GI -S rati n g scale is a c o m m o nl y use d m eas ure of s y m pt o m se verit y a n d treat me nt 
res p o nse.  T he s e verit y s cale ( C GI -S) is a 7 -p oi nt scale t hat re q u ires t he cli nicia n t o rate t he 
se verit y of t he patie nt's ill ness at t he ti me of assess me nt. (see A P P E N DI X  D) 

 
                                                                                                      
 
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1 1. 6. 3.  
Pers o n al a n d S oci al Perf or m a nce Sc al e ( P S P) 
T he P S P is meas ure of p ers o nal a n d s o cial f u ncti o ni n g of p atie nts wit h ps yc hi atric dis or ders.  
T he scale  is a h u n dre d-it e m scale, di vi de d i n 1 0 si milar i nter vals.  T he sc ore is base d o n t he 
assess me nt of a p atie nt’s perf or ma n ce i n f o ur cat e g ories : s o ciall y us ef ul acti vities, pers o nal a n d 
s ocial relati o ns hi ps, self- care, dist ur bi n g a n d a g gressi ve be ha vi or. (see A P P E N DI X E ) 
1 1. 6. 4.  
Sc hiz o p hre ni a Q u alit y of Life Sc ale ( S Q L S)  
T he S Q L S is a self -r e p ort Q ualit y of Life scal e de vel o pe d s pecifi call y f or p atie nts wit h 
sc hiz o p hre nia.  It is a 3 0-ite m q uesti o n naire c o m prise d of t hree d o mai ns (‘ ps yc h os o cial’, 
‘ m oti vati o n a n d e ner g y’, a n d ‘s y m pt o ms a n d si de-effects’). (s ee A P P E N DI X F ) 
1 1. 7.  
E xtr a p yr a mi d al S y m pt o ms  
1 1. 7. 1.  
Si m ps o n -A n g us Sc ale ( S A S)  
T he S A S c o nsists of a list of 1 0 s y m pt o ms of par ki ns o nis m ( gait, ar m dr o p pi n g, s h o ul der 
s ha ki n g, el b o w ri gi dit y, wrist ri gi dit y, h ea d r otati o n, gla b ella ta p, tre m or, s ali vati o n, a n d 
a kat hisia).  Eac h ite m is rate d o n a 5 - p oi nt scale, wit h a sc ore of o n e re prese nti n g a bse n ce of 
s y m pt o ms, a n d a sc ore of 5 re pres e nti n g a se vere c o n diti o n.  T he S A S total sc ore is t he s u m of 
t he sc ores f or all 1 0 ite ms. (see A P P E N DI X G ) 
1 1. 7. 2.  
A b n or m al I n v ol u nt ar y M o ve me nt Sc al e ( AI M S) 
T he A b n or mal I n v ol u ntar y M o v e me nt Scale ( AI M S) is a 1 0-ite m cli nicia n-rate d scale t o assess 
se verit y of d ys ki nesias (s pecificall y, or ofaci al m o ve me nts a n d e xtre mit y a n d tr u ncal m o ve me nts) 
i n patie nts ta ki n g ne ur ole ptic me dicati o ns.  B o d y areas of i nterest i ncl u de Facia l a n d Oral, 
E xtre mities a n d L o wer, a n d Tr u n k.  Eac h ite m is s c ore d o n a n or di nal scal e t hat ra n ges fr o m 0 t o 
4: n o ne, mi ni mal, mil d, m o derate, or s e vere.  A d diti o nal gl o bal ite ms assess t he o verall se verit y, 
tar di ve d ys ki nesia-ass oci ate d f u ncti o nal i m pair m e nt, a n d t he patie nt ’s le vel of a ware ness of t he 
m o ve me nts a n d distress ass ociate d wit h t he m.  (see A P P E N DI X H ) 
1 1. 7. 3.  
B ar nes A k at hisi a R ati n g Sc ale ( B A R S) 
T he Bar nes A k at hisia Rati n g Scale (B A R S ) c o nsists of 4 ite ms relate d t o a kat hisia: o bjecti ve 
o bser vati o n of a k at hisia b y t he I n vesti gat or, s u bjecti ve feeli n gs of restless n ess b y t he p atie nt , 
distress d ue t o a kat hisia, a n d gl o b al e val uati o n of a kat hisia.  T he first 3 ite ms are rat e d o n a 4 -
p oi nt scale, wit h a sc or e of 0 re pr ese nti n g a bse n ce of s y m pt o ms a n d a s c ore of 3 re prese nti n g a 
se vere c o n diti o n.  T he gl o bal cli nical e val uati o n is ma de o n a 6 - p oi nt scal e, wit h 0 re pres e nti n g 
a bse nce of s y m pt o ms a n d a sc ore of 5 re prese nti n g se v ere a kat hisia.  T o c o m plete t his scale, 
patie nt s are obser ve d w hile t he y wer e seat e d a n d t he n sta n di n g f or a mi ni m u m of 2 mi n utes i n 
eac h p ositi o n.  S y m pt o ms o bser ve d i n ot her sit uati o ns (e. g., w hile e n ga ge d i n ne utral 
c o n versati o n or e n ga ge d i n acti vit y o n t he w ar d) are als o rat e d.  S u bjecti ve p he n o me na are t o be 
elicite d b y dir ect q uesti o ni n g . (see A P P E N DI X I) 

 
                                                                                                      
 
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1 1. 8.  
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C-S S R S)  
T he C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) is a s uici dal i deati o n rati n g s cale.  T h e 
scale i de ntifies be h a vi ors a n d t h o u g hts t hat are ass ociate d wit h a n i ncreas e d ris k of s uici dal 
acti o ns i n t he f ut ure. T h ere ar e 2 versi o ns of t h e scale bei n g use d i n t his pr ot oc ol. (see 
A P P E N DI X J) 
1 1. 9.  
A nti ps yc h otic ( A P) Me dic a ti o n Bl o o d Le vel  
Bl o o d sa m ples will be ta ke n t o assess bl o o d le vels of t he A P me dicati o n b ei n g ta k e n b y t he 
patie nt.  T he c o nfir m ati o n of le vels of o ne of t he A P me dicati o ns liste d i n A P P E N DI X A will be 
re q uire d t o be eli gi ble f or ra n d o mizati o n t o t he Trea t me nt Peri o d .  T he details o n c ollecti o n, 
pr ocessi n g, st ora ge a n d s hi p pi n g of bl o o d sa m ples f or A P assess me nt ca n b e f o u n d i n t he st u d y 
La b orat or y M a n ual.  
1 1. 1 0.  
C T P -6 9 2 Bl o o d Le vel  
C T P - 6 9 2 bl o o d le vels will be meas ure d f oll o wi n g st u d y c o m pleti o n .  T he d etails o n c ollecti o n, 
pr ocessi n g, st ora ge a n d s hi p pi n g of bl o o d sa m ples f or C T P- 6 9 2 assess me nt ca n be f o u n d i n t he 
st u d y La b orat or y Ma n u al. 
1 1. 1 1.  
Ge netic Testi n g   
A b l o o d sa m ple f or ge n etic testi n g is o pti o nal.  O nl y o ne bl o o d sa m ple is re q uire d f or ge n etic 
testi n g.  T he ge netic mar kers a nal yze d ma y b e rel ate d t o cli nical s y m pt o ms , a n d/ or ot her fact ors  
as deter mi ne d b y t he S p o ns or.  T he details o n c oll ecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g of 
bl o o d sa m ples f or ge neti c testi n g ca n be f o u n d i n t he st u d y La b orat or y Ma n ual. 
1 1. 1 2.  
U nsc he d ule d Visit  
I n a d diti o n t o re g ularl y s c he d ule d pr ot oc ol visits, a n U nsc he d ul e d Visit ma y be c o n d ucte d t o 
e ns ure a p pr o priate s afet y m o nit ori n g or f oll o w- u p of t he patie nt, at t he discreti o n of t he 
I n v esti gat or.  F or e x a m ple, a n U nsc h e d ule d Visit ma y b e sc he d ule d t o m o nit or p ote ntial or act ual 
cli nicall y mea ni n gf ul saf et y la b orat or y res ults  or f or ot her cli nical si g ns, s y m pt o ms, or 
c o nsi derati o ns t hat warra nt a d diti o nal safet y f oll o w- u p.  A n U nsc h e d ule d Visit ma y als o be 
c o n d ucte d t o acc o m m o date re peat testi n g of n o n- s afet y relate d la b orat or y assess me nts.  O nl y 
t h ose criteria re q uiri n g a d diti o nal m o nit ori n g s h o ul d be perf or m e d at t he U nsc he d ule d Visit.  A n 
U nsc he d ule d Visit will n ot re place re g ularl y s c he d ule d pr ot oc ol visits. 
 
 

 
                                                                                                      
 
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1 2.  
A D V E R S E E V E N T S  
1 2. 1.  
Defi niti o n of A d verse E ve nts  
A n a d vers e e ve nt ( A E) is a n y u nt o w ar d me dical o cc urre nce t hat ma y a p pear or w orse n i n a 
patie nt d uri n g t he c o urse of a st u d y.  It ma y be a n e w i nterc urre nt ill ness, a w orse ni n g 
c o nc o mita nt ill ness, a n i nj ur y, or a n y c o n c o mita nt i m pair me nt of t he patie nt’s healt h, i ncl u di n g 
la b orat or y test val ues, re gar dless of eti ol o g y.  A n y w orse ni n g (i.e., a n y cli nicall y si g nifica nt 
a d verse c ha n ge i n t he fr e q ue nc y or i nte nsit y of a pre-e xisti n g c o n diti o n) s h o ul d be c o nsi dere d a n 
a d verse e ve nt.  A dia g n osis or s y n dr o me s h o ul d b e rec or de d o n t he a d vers e e ve nt pa ge of t he 
e C R F rat her t ha n t he i n di vi d ual si g ns or s y m pt o ms of t he dia g n osis or s y n dr o me.  A w ors e ni n g 
of t he c o n diti o n u n der st u d y will n ot be re p orte d as a n a d verse e v e nt.  
All patie nts will be m o nit ore d f or a d vers e e ve nts d uri n g t he st u d y.  Assess me nts ma y i ncl u de 
m o nit ori n g of t he f oll o wi n g para mete rs: t he patie nt’s cli nical s y m pt o ms, la b orat or y, p h ysical 
e x a mi nati o n fi n di n gs, or fi n di n gs fr o m ot her tests a n d/ or pr oce d ures. 
A n a d vers e e ve nt re p orte d after i nf or me d c o nse nt, b ut bef ore t he first d ose of St u d y Me dicati o n  
(i.e., Da y 1), will be c o nsi dered a pretreat me nt a d v erse e v e nt  a n d will be ca pt ure d o n t he e C R F.  
A d verse e ve n ts will be c o nsi dere d treat me nt-e mer ge nt if t he o nset is after t he first d ose of St u d y 
Me dicati o n . 
A n a b n or mal la b or at or y val ue is c o nsi dere d t o b e a n a d vers e e v e nt if t he a b n or m alit y:  
•  res ults i n disc o nti n uati o n fr o m t he st u d y; 
•  is j u d ge d b y t he I n v esti gat or t o be of si g nifica nt cli nical i m p orta nce re q uiri n g 
treat me nt, m o dificati o n/i nterr u pti o n of i n vesti gati o nal pr o d uct d ose, or a n y ot her 
t hera pe utic i nter v e nti o n. 
Re gar dless of se v erit y gr a de, o nl y la b orat or y a b n or malities t hat f ulfill a seri o us ness criteri o n 
nee d t o be d oc u m e nte d as a seri o us a d verse e v e nt. 
If a la b or at or y a b n or malit y is o ne c o m p o ne nt of a dia g n osis or s y n dr o m e, t he n o nl y t he di a g n osis 
or s y n dr o me s h o ul d be r ec or de d o n t he a d vers e e v e nt e C R F.  If t he a b n or m alit y was n ot a p art of 
a dia g n osis or s y n dr o me, t he n t he la b orat or y a b n or malit y s h o ul d be rec or d e d as t he a d v erse 
e ve nt.  If p ossi ble, t he la b orat or y a b n or malit y s h o ul d be rec or de d as a me dical ter m a n d n ot 
si m pl y as a n a b n or mal la b orat or y res ult (e. g., rec or d t hr o m b oc yt o p e nia rat her t ha n decrease d 
platelets).  
1 2. 2.  
E v al u ati o n of A d verse E ve nt s 
A q ualifie d I n vesti gat or will e val uate all a d verse e ve nts as t o seri o us ness, se verit y/i nte nsit y, a n d 
relati o ns hi p t o St u d y M e d icati o n, d urati o n, acti o n ta ke n, a n d o utc o me. 
1 2. 2. 1.  
Seri o us A d verse E ve nt ( S A E)  
A seri o us a d verse e v e nt is a n a d vers e e ve nt, as per Title 2 1 C F R 3 1 2. 3 2 a n d I C H E 2 A.II. B  t hat 
f ulfills t he f oll o wi n g crit eria: 

 
                                                                                                      
 
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•  Is fatal (r es ults i n deat h); 
•  Is life-t hreate ni n g ( N ote: t he ter m "life-t hreate ni n g" refers t o a n e ve nt i n w hic h t he 
patie nt was at ris k of d eat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat 
c o ul d h y p ot heticall y h a v e ca use d d eat h ha d it bee n m ore se vere);  
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
( h os pitalizati o n is defi ne d as a n i n patie nt a d missi o n, re gar dl ess of le n gt h of sta y); 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y (a s u bsta ntial disr u pti o n of t he 
patie nt 's a bilit y t o c o n d u ct n or mal life f u ncti o ns); 
•  Is a c o n ge nital a n o mal y/ birt h defect; or 
•  C o nstit utes a n i m p orta nt me dical e ve nt t hat ma y j e o par dize t he patie nt or ma y 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 ot her o utc o mes liste d a b o ve. 
I m p ort a nt me dical e v e nts are defi ne d as t h ose o cc urre nces t hat ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h, h os pitalizati o n, or disa bilit y, b ut ma y je o par dize t he patie nt or 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d a b o ve.  
E x a m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n 
a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitalizati o n.  
E ve nts n ot c o nsi dere d  t o be seri o us a d v erse e ve nts are h os pitalizati o ns f or: 
•  A pr oce d ure f or pr ot oc ol/ disease-relate d i n vesti gati o ns (e. g., s a m pli n g f or l a b orat or y 
tests).  H o we ver, h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n of 
s uc h pr oce d ures r e mai ns a re p ort a ble seri o us a d v erse e ve nt. 
•  H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n f or tec h nical, practical, or s ocial 
reas o ns, i n a bse n ce of a n a d verse e ve nt. 
•  A pr oce d ure t hat is pla n n e d (i.e., pla n ne d pri or t o t he starti n g of treat me nt o n st u d y); 
m ust be d oc u me nte d i n t he s o urce d o c u me nt a n d t he e C R F.  H os pitalizati o n or 
pr ol o n ge d h os pitalizati o n f or a c o m plicati o n re mai ns a re p orta bl e seri o us a d verse 
e ve nt.  
•  A n electi ve tr eat me nt of or a n electi ve pr oce d ure f or a pre -e xisti n g me dical c o n diti o n 
t hat d oes n ot w orse n. 
•  E mer ge nc y o ut p atie nt treat me nt or o bser vati o n t hat d oes n ot res ult i n a d missi o n, 
u nless f ulfilli n g ot her seri o us ness criteria a b o v e. 
If a n a d v erse e ve nt is c o nsi dere d seri o us, t he a d verse e ve nt e C R F m ust be c o m plete d. 
F or eac h seri o us a d verse e ve nt, t he I n vesti gat or will  pr o vi de i nf or mati o n o n se verit y, start a n d 
st o p dates, relati o ns hi p t o i n vesti gati o nal pr o d u ct, acti o n ta ke n re gar di n g i n vesti gati o nal pr o d u ct, 
a n d o utc o me. 
 

 
                                                                                                      
 
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Q ueries pertai ni n g t o s eri o us a d verse e ve nts will be ha n dle d t hr o u g h t he electr o nic data ca pt ure 
s yste m or ot her a p pr o priate mea ns.  Ur ge nt q ueri es (e. g., missi n g ca usalit y ass ess me nt) ma y be 
ha n dle d b y tele p h o ne. 
1 2. 2. 2.  
Se verit y/I nte nsit y  
F or b ot h a d v erse e ve nts a n d seri o us a d vers e e v e nts, t he I n v esti gat or m ust assess t he 
se verit y/i nte nsit y of t he e ve nt. 
T h e Nati o nal C a ncer Instit ute - C o m m o n Ter mi n ol o g y Criteria f or A d v erse E ve nts (C T C A E ) 
Versi o n  5. 0 s h o ul d be us e d t o gr a de t he s e verit y/i nte nsit y of all e v e nts.  T h ese criteria will be  
pr o vi de d i n a st u d y m a n u al .  If a C T C A E criteri o n d oes n ot e xist, t he In v es ti gat or s h o ul d gra de 
t he se verit y acc or di n g t o t he f oll o wi n g criteria: 
•  Gra de 1 ( mil d): d oes n ot i nterfere wit h t he patie nt’s us ual f u ncti o n 
•  Gra de 2 ( m o derat e): i nterferes t o s o me e xte nt wit h patie nt's us ual f u n cti o n  
•  Gra de 3 (se vere): i nterfer es si g nifica nt l y wit h pati e nt's us ual f u ncti o n 
•  Gra de 4 (life -t hr eate ni n g): res ults i n a t hreat t o life or i n a n i nca p acitati n g disa bilit y 
•  Gra de 5 ( deat h): res ults i n deat h  
T he ter m “se v er e” is ofte n use d t o descri be t he i nt e nsit y of a s pecifi c e ve nt (as i n mil d, m o derate 
or se ver e m y o car dial i nfarcti o n); t he e ve nt itself, h o we ver, ma y be of relati vel y mi n or me dical 
si g nifica n ce (s u c h as se v ere hea dac he).  T his criteri o n is n ot t he sa me as “s eri o us” w hic h is 
base d o n patie nt/e ve nt o utc o me or acti o n criteria ass ociate d wit h e ve nts t hat p ose a t hreat t o a 
patie nt’s life or f u n cti o ni n g.  
Seri o us ness, n ot se verit y, ser ves as a g ui de f or d efi ni n g re g ul at or y o bli gati o ns. 
1 2. 3.  
Rel ati o ns hi p t o St u d y Me dic ati o n  
Relati o ns hi p s h o ul d be assesse d a n d pr o vi de d f or e ver y a d v erse e ve nt/seri o us a d verse e ve nt 
base d o n c urre ntl y a vaila ble i nf or mati o n.  Relati o ns hi p is t o be reassesse d a n d pr o vi de d as 
a d diti o nal i nf or mati o n bec o mes a vaila ble.  A d vers e e ve nts will be classifi e d b y t he I n vesti gat or 
as f oll o ws: 
Defi nitel y Rel ate d : T her e is clear e vi de nce t o s u g gest a ca us al relati o ns hi p, a n d ot her p ossi ble 
c o ntri b uti n g f act ors ca n be r ule d o ut.  T he cli nical e ve nt, i ncl u di n g a n a b n or mal la b orat or y test 
res ult, occ urs i n a pl a usi ble ti me relati o ns hi p t o dr u g a d mi nistrati o n a n d ca n n ot be e x plai ne d b y 
c o nc urr e nt disease or ot her dr u gs or c he micals.  T he e ve nt res ol ves or i m pr o ves u p o n wit h dra wal 
of dr u g ( de -c halle n ge).  T he e ve nt w o ul d be c o nsi dere d as d efi nitel y relate d t o t he St u d y 
Me dicati o n  u p o n res ults of a p ositi ve re-c halle n ge pr oce d ure.  
Pr o b a bl y Rel at e d : T her e is e vi de nce t o s u g gest a ca usal relati o ns hi p (e. g., t he e ve nt occ urre d 
wit hi n a reas o na bl e ti me after a d mi nistrati o n of t he trial me dicati o n).  H o w e ver, t he i nfl u e nce of 
ot her fact ors t hat ma y ha ve c o ntri b ute d t o t he e v e nt (e. g., t h e patie nt’s cli nical c o n diti o n, ot her  
 

 
                                                                                                      
 
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c o nc urr e nt disease, c o nc o mita nt me dicati o ns or e ve nts) is u nli kel y, a n d t h e e ve nt f oll o ws a 
cli nicall y r eas o na ble res p o nse u p o n wit h dra wal of dr u g ( de- c halle n ge).  
P ossi bl y Rel ate d: T h ere is e vi de nce t o s u g gest a ca usal relati o ns hi p (e. g., t he e ve nt occ urre d 
wit hi n a reas o na bl e ti me after a d mi nistrati o n of t he St u d y Me dicati o n ).  H o we ver, t he i nfl ue nce 
of ot her fact ors ma y ha v e c o ntri b ute d t o t he e ve nt (e. g., t he patie nt’s cli nical c o n diti o n, ot her 
c o nc urr e nt disease, c o nc o mita nt me dicati o ns or e ve nts). 
U nli kel y Rel ate d : A cli nical e ve nt, i ncl u di n g a n a b n or mal la b orat or y test res ult, w h ose te m p oral 
relati o ns hi p t o dr u g a d mi nistrati o n ma kes a ca us al relati o ns hi p i m pr o ba ble (e. g., t he e v e nt di d 
n ot occ ur wit hi n a r eas o n a ble ti me after a d mi nistrati o n of t he trial me dicati o n) a n d i n w hic h 
ot her dr u gs or c o n c urr e nt or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns (e. g., t he patie nt’s 
cli nical c o n diti o n, ot her c o nc o mita nt treat me nts).  
N ot  rel at e d : T he a d verse e ve nt is c o m pletel y i n de pe n de nt of St u d y M e dicati o n  a d mi nistrati o n, 
a n d/ or e vi de nce e xists t hat t he e ve nt is defi nitel y relate d t o a n ot her eti ol o g y.  T here m ust be a n 
alter nati ve, defi niti ve eti ol o g y d oc u me nt e d b y t he cli nicia n.  
1 2. 3. 1.  
D ur at i o n 
F or all a d v erse e ve nts w h et her or n ot c o nsi dere d s eri o us, t he I n vesti gat or will pr o vi de a rec or d of 
t he start a n d st o p dates of t he e ve nt.  E ver y eff ort s h o ul d be ma de t o res ol ve all a d verse e ve nts 
wit h c o nti n ue d f oll o w- u p wit h t he patie nt u ntil a p pr o p riate res ol uti o n ca n be ac hie v e d.  If a n 
e ve nt is u nres ol ve d at t he e n d of t he st u d y it will be rec or de d as o n g oi n g. 
1 2. 3. 2.  
Acti o n T a ke n  
T he I n vesti gat or will rec or d t he acti o n ta ke n wit h i n vesti gati o nal pr o d u ct as a res ult of a n 
a d verse e ve nt or s eri o us a d verse e ve nt o n t he e C R F, as a p plica ble (e. g., disc o nti n uati o n, or 
i nterr u pti o n of i n vesti gati o nal pr o d uct, as a p pr o pri ate) a n d rec or d if c o n c o mita nt a n d/ or 
a d diti o nal treat me nts wer e gi v e n f or t he e ve nt.  
1 2. 3. 3.  
O utc o me  
T he I n vesti gat or will rec or d t he o utc o me of a d verse e ve nts o n t he e C R F, as a p plica ble (e. g., 
rec o vere d, r ec o v ere d wit h se q uelae, n ot rec o v ere d, or deat h ( d u e t o t he a d v erse e v e nt). 
1 2. 3. 4.  
F oll o w- U p  
A d verse e ve nts assess e d as n ot relate d t o St u d y M e dicati o n, i ncl u di n g cli nicall y si g nifica nt 
la b orat or y tests, E C Gs , or p h ysical e x a mi nati o n fi n di n gs, m ust be f oll o we d u ntil t he e ve nt 
res ol ves, t he c o n diti o n sta bilizes, t he e ve nt is ot her wise e x plai ne d, or t he fi nal st u d y visit occ urs, 
w hic he ver c o mes first.  
A d verse e ve nts assess e d as relate d t o St u d y Me dicati o n  a n d seri o us a d verse e ve nts will be 
f oll o we d f or as l o n g as n ecessar y t o a de q u atel y e v al uate t he patie nt’s s afet y, or u ntil t he e ve nt 
sta bilizes, is ot her wise e x plai ne d, deat h occ urs, or t he patie nt  is l ost t o f oll o w u p.  If res ol ve d, a 
res ol uti o n date s h o ul d be pr o vi de d.  T he I n v esti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w- u p 
i ncl u des a n y s u p ple me nt al i n vesti gati o ns i n dicate d t o el uci date t he nat ure a n d/ or ca us alit y of t he 

 
                                                                                                      
 
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a d verse e ve nt.  T his ma y i ncl u de a d diti o nal cli nical la b orat or y testi n g or i n v esti gati o ns, 
e x a mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals as is practical. 
1 2. 3. 5.  
Pre g n a nc y  
T he S p o ns or m ust be i nf or me d wit hi n 2 4 h o urs u p o n lear ni n g t hat a patie n t, or male patie n t’s 
part ner, h as bec o m e pre g na nt a n y ti me after t he first d ose of St u d y Me dicati o n u ntil 4 wee ks  
after t he l ast d ose of St u d y Me dicati o n .  Patie nt pre g n a ncies ( or pre g na nc y of a male patie n t’s 
part ner) m ust be f oll o we d u ntil ter mi nati o n of pre g na n c y or t he birt h of t h e c hil d. 
If a f e male part ner of a m ale patie nt ta ki n g i n vesti gati o nal pr o d u ct bec o m es pre g na nt, t he male 
patie n t ta ki n g t he i n vesti gati o nal pr o d u ct s h o ul d n otif y t he I n v esti gat or, a n d t he pre g na nt fe male 
part ner s h o ul d be a d vise d t o call her healt hcare pr o vi der i m me diatel y. 
1 2. 3. 6.  
Rec or di n g A d verse E ve nts  
All a d verse e ve nts (r e gar dless of seri o us ness or relati o ns hi p t o St u d y Me di cati o n ) i ncl u di n g 
t h ose fr o m t he ti me i nf or me d c o nse nt is o btai ne d t hr o u g h t o t he fi nal st u d y visit are t o be 
rec or d e d i n t he e C R F.  E ac h i n di vi d ual a d vers e e v e nt is t o be liste d as a se p arate e ntr y.  T he 
I n v esti gat or will pr o vi de i nf or mati o n a b o ut dates of o nset a n d res ol uti o n, seri o us ness, se verit y, 
acti o n(s) ta ke n, o ut c o me, a n d relati o ns hi p t o t he St u d y Me dicati o n .  All a d verse e v e nts s h o ul d be 
d oc u me nte d i n t he patie nt’s s o urce d o c u m e nts. 
1 2. 3. 7.  
Re p orti n g A d verse E ve nts  
T he I n vesti gat or m ust re p ort t o S p o ns or or its desi g nee all a d verse e v e nts t hat occ ur d uri n g t h e 
st u d y fr o m t he ti me writte n i nf or me d c o ns e nt is gi ve n u ntil t he fi nal st u d y visit or earl y 
ter mi nati o n, re gar dl ess of t heir relati o ns hi p t o t he St u d y M e dicati o n .  Seri o us a d verse e ve nts a n d 
pre g na nci es will be re p orte d fr o m t he ti me writte n i nf or me d c o nse nt is gi ve n t hr o u g h 4 w ee ks  
be y o n d t h e last d ose of St u d y Me dicati o n . 
1 2. 3. 8.  
Re p orti n g Seri o us A d verse E ve nts  
T he I n vesti gat or is r e quir e d t o n otif y t he S p o ns or, a n d t he S p o ns or’s desi g n ate d Dr u g Safet y 
U nit wit hi n 2 4 h o urs after bec o mi n g a w are of t he occ urre nce of a  s eri o us a d verse e v e nt.  All 
seri o us a d vers e e v e nts will be re p orte d t hr o u g h c o m pleti o n of t he a d verse e ve nt e C R F.  T he 
I nv esti gat or  will be res p o nsi ble f or re p orti n g seri o us a d verse e ve nts t o t he I R B. 
E mer ge nc y C o nt act I nf or m ati o n: 
Dr.
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
e-mail
  
  
  
  
  
  
Fa x: 
P h o ne:
e- mail:
 
 

 
                                                                                                      
 
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If a n I n v esti gat or bec o m es a ware of a seri o us a d v erse e v e nt wit hi n 4 wee ks after t he last d ose of 
St u d y M e dicati o n  a n d it is c o nsi dere d b y hi m/ her t o be ca use d b y t h e St u d y Me dicati o n  wit h a 
reas o na bl e p ossi bilit y, t h e e ve nt m ust be d oc u me nte d a n d re p orte d t hr o u g h c o m pleti o n of t he 
a d verse e ve nt  e C R F. 
1 2. 3. 9.  
Re p orti n g Ur ge nt S af et y Iss ues  
If t he st u d y site staff bec o mes a war e of a n act ual or p ote ntial ur ge nt safet y iss ue, t he n t he 
S p o ns or a n d S p o ns or’s desi g nee ( Me di cal M o nit or) m ust be i m me diatel y c o ntacte d s o t hat 
a p pr o priate ur ge nt saf et y meas ures ca n be a gree d u p o n.  A n ur ge nt safet y iss ue is defi ne d as: 
•  A n i m me diate hazar d t o t he healt h or s afet y of p atie nts partici pati n g i n a cli nical 
st u d y 
•  A seri o us ris k t o h u ma n healt h or p ote ntiall y a seri o us ris k t o h u ma n healt h 
A n ur ge nt saf et y iss ue ma y i n cl u de: ( 1) iss ues wit h a n i n vesti gati o nal dr u g or c o m parat ors;  
( 2) st u d y pr oce d ures; ( 3) i nter-c urre nt ill ness (i ncl u di n g pa n d e mic i nfecti o ns); ( 4) c o nc o mita nt 
me dicati o ns; ( 5) c o nc urr e nt me dical c o n diti o ns; or ( 6) a n y ot her iss ues rel ate d t o t he safe 
c o n d uct of t he st u d y or t hat p ose a ris k t o st u d y p atie nts. 
I n e x ce pti o nal circ u msta nces of i m mi ne nt hazar d a n d i n or der t o safe g uar d t he healt h or safet y of 
i n di vi d uals, t he I n vesti gat ors ma y ta k e ur ge nt s afet y meas ures bef ore i nf or mi n g t he S p o ns or, b ut 
t he S p o ns or m ust be i nf or me d i m me diatel y after t he hazar d has res ol ve d. 
 

 
                                                                                                      
 
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1 3.  
S T A TI S TI C A L M E T H O D S  
A d diti o na l details f or statistical met h o ds a n d a nal ysis will be pr o vi de d i n t he Statistical A nal ysis 
Pla n.  
1 3. 1.  
S a m ple Size R ati o n ale  
A p pr o xi matel y 7 5 p atie nts will be ra n d o mize d t o eac h treat me nt ar m t o ac hie ve a sa m ple size of 
a p pr o xi matel y 6 0 patie nts per ar m w h o c o m plete t he st u d y.  A s a m ple size of 6 0 per ar m 
pr o vi des at least 8 0 % p o wer f or a treat me nt differe nce of 5. 2 (sta n dar d de viati o n of 1 0) bet wee n 
Wee k 1 2 a n d Baseli ne  i n P A N S S t otal sc ore, o n a t w o-si de d t-test at 0. 0 5 si g nifica nce l e vel. 
1 3. 2.  
E n d p oi nts  
1 3. 2. 1.  
Effic ac y  
T he pri mar y efficac y e n d p oi nt will be t he cha n ge i n P A N S S t otal sc ore at Wee k 1 2 fr o m 
Baseli ne  
Sec o n dar y efficac y e n d p oi nts i ncl u de: 
•  C ha n ge i n C GI - S sc ore at Wee k 1 2 fr o m Bas eli ne 
•  C ha n ge i n P S P sc ore  at Wee k 1 2 fr o m Baseli ne 
E x pl orat or y efficac y e n d p oi nts i ncl u de:  
•  C ha n ge i n P A N S S t otal sc ore at  Wee ks 2, 4, 8, a n d 1 0 fr o m Baseli ne 
•  C ha n ge i n P A N S S P ositi ve S y m pt o ms Fact or Sc ore ( P S F S) at Wee ks 2, 4, 8, 1 0, a n d 1 2 
fr o m Bas eli ne 
•  C ha n ge i n P A N S S Ne gati ve S y m pt o ms Fact or Sc ore ( N S F S)  at Wee k s 2, 4, 8, 1 0, a n d 1 2 
fr o m Bas eli ne 
•  C ha n ge i n C GI- S sc ore at Wee ks 2, 4, 6, 8, a n d 1 0 fr o m Bas eli ne 
•  C ha n ge i n P S P sc ore at Wee k 6  fr o m Baseli ne 
•  C ha n ge i n  Sc hiz o p hre nia Q ualit y of Life ( S Q L S) at Wee k 1 2  fr o m Baseli n e 
1 3. 2. 2    
S afet y  
Safet y of C T P - 6 9 2 will be assesse d b y e val uati n g a d verse e ve nts, vital si g ns, c o nc o mita nt 
me dicati o ns, cli nical la b orat or y par a meters i ncl u di n g bl o o d urea nitr o ge n ( B U N) a n d creati ni ne, 
uri nal ysis, E C G r es ults, as well as p h ysi cal e x a mi nati o ns.  E xtra p yra m i dal s y m pt o ms ( E P Ss) will 
be e val uat e d usi n g S A S, AI M S , a n d t h e B A R S.  Assess me nt of s uici dalit y will be perf or me d at 
e ver y visit usi n g t he C- S S R S.  
 
 
 

 
                                                                                                      
 
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1 3. 3.  
A n al ysis P o p ul ati o ns  
T he Safet y P o p ulati o n will i ncl u de all ra n d o mize d patie nts w h o recei ve at least o ne d ose of 
St u d y M e dicati o n .  T he Efficac y P o p ulati o n will i ncl u de all patie nts w h o recei ve St u d y 
Me dicati o n  a n d ha v e at l east o ne  p ost- bas eli ne P A N S S assess me nt d uri n g t he Treat me nt Peri o d.   
T he Per Pr ot oc ol a nal ysis p o p ulati o n will i ncl u de all patie nts i n t he Efficac y P o p ulati o n w h o 
were d os e d acc or di n g t o pr ot oc ol wit h n o maj or pr ot oc ol de viati o ns. 
1 3. 4.  
A n al yses  
F or t he Treat me nt Peri o d, data will be s u m marize d b y treat me nt gr o u p  (C T P - 6 9 2 1 g Q D,  
C T P - 6 9 2 2 g Q D, C T P- 6 9 2 4 g Q D, or place b o).  All data f or a n al ysis will be liste d b y patie nt.  
C o nti n u o us meas ures will be s u m marize d descri pti vel y ( mea n, me dia n, sta n dar d de viati o n, 
me dia n, mi ni m u m val ue, a n d ma xi m u m val ue) a n d cate g ori cal meas ures will be prese nte d as 
n u m ber a n d perce nt a ge. 
A d diti o nal details f or statistical met h o ds will be pr o vi de d i n t he Statistical A nal ysis Pla n.  
1 3. 4. 1.  
Dis p ositi o n a n d B aseli ne C h ar acteristics  
Dis p ositi o n will be s u m marize d b y r a n d o mize d treat me nt gr o u p.  T h e n u m ber a n d perce nt a ge of 
patie nts, w h o are ra n d o mize d, treate d, pre mat urel y disc o nti n ue d ( o verall a n d b y reas o n), a n d 
c o m plete t he st u d y will be s u m marize d.  
Baseli ne c har acteristics will be s u m marize d b y treat me nt gr o u p.  
T he n u m ber of p atie nts i n eac h tr eat me nt gr o u p will be s u m marize d f or eac h i n vesti gati ve site 
f or eac h a n al ysis p o p ulati o n.  Me dical hist or y will be c o de d wit h t he Me di cal Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A ) ter mi n ol o g y.  C o nc o mita nt me dicati o ns will be s u m marize d b y 
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y A n at o mical -T hera pe utic -C he mical classificati o n 
a n d pref err e d ter m.   Me dical hist or y a n d c o nc o mit a nt me dicati o ns will be s u m marize d f or t he 
Safet y P o p ulati o n. 
1 3. 4. 2.  
Effic ac y  
All statistical tests wil l be 2-si de d wit h a si g nifica nce val ue of 0. 0 5.  Patie nts will be s u m marize d 
b y r a n d o mize d treat me nt gr o u p.  T h ere will be n o a dj ust me nts f or m ulti ple c o m paris o ns t o 
place b o.  
A mi x e d effects re p eate d meas ures m o del will be  use d t o assess treat me nt gr o u p differe nces f or 
c ha n ge fr o m baseli ne .  T he m o del will i ncl u de treat me nt gr o u p, a nal ysis visit, treat me nt-b y -visit 
i nteracti o n, t he bas eli ne val ue as a c o vari ate, a n d patie nt as a ra n d o m effect.   T he c o m paris o n of 
eac h C T P - 6 9 2 d ose gr o u p vers us place b o will be assesse d b y f or mi n g t he l east s q uares m ea ns 
esti mate of eac h t he C T P - 6 9 2 d ose gr o u p a n d c o m pari n g it t o t he place b o gr o u p at eac h 
p ost baseli ne a nal ysis visit.  A n u nstr uct ure d c o v aria nce str uct ure will be  us e d t o m o del t he 
wit hi n -patie nt  err ors.  
 

 
                                                                                                      
 
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As a s e nsiti vit y a nal ysis, t he last o bser vati o n carri e d f or w ar d ( L O C F) met h o d will be use d t o 
i m p ute missi n g val ues for patie nt s w h o wit h dra w fr o m t he st u d y pri or t o t he c o m pleti o n of t he 
1 2- wee k Treat me nt Peri o d.  
A d diti o nal details will be s u m marize d i n t he Statistical A nal ysis Pla n.  
1 3. 4. 3.  
St u d y Me dic ati o n  C o m pli a nce 
St u d y M e dicati o n  c o m pli a nce will be s u m marize d f or eac h treat me nt gr o u p.  T he n u m ber of 
da ys of  St u d y Me di cati o n  a d mi nistrati o n will be s u m marize d f or eac h treat me nt gr o u p. 
St u d y M e dicati o n  c o m pli a nce will be meas ure d b y t he perce nta ge of sc he d ule d d oses t hat were 
ta ke n.  Descri pti ve statistics will be use d t o s u m marize t he d osi n g c o m plia nce perce nta ge wit hi n 
eac h tr eat me nt gr o u p.  
1 3. 4. 4.  
S af et y  
All safet y s u m maries will be descri pti ve wit h n o statistical h y p ot hesis testi n g a n d b ase d o n t he 
Safet y P o p ulati o n.  Patie nts will be s u m marize d acc or di n g t o t he st u d y me dicati o n recei ve d (i.e., 
as treate d), s h o ul d it differ fr o m t he ra n d o mize d treat me nt a r m.  All safet y e n d p oi nts will be 
liste d i n b y-patie nt data listi n gs.  
A d verse e ve nts will be c o de d usi n g Me d D R A  a n d s u m marize d b y s yste m or ga n class a n d 
preferre d t er m.  Cli nicall y si g nifica nt d eteri orati o ns i n p h ysical e x a mi nati o n fi n di n gs will be 
re p orted a n d s u m marize d as a d vers e e ve nts.   A b n or mal, cli nicall y si g nifica nt la b orat or y val ues 
will be re p orte d a n d s u m marize d as a d vers e e v e nts.  
1 3. 4. 5.  
A d verse E ve nts  
A n a d vers e e ve nt re p orte d after i nf or me d c o nse nt, b ut bef ore t he first d ose of St u d y Me dicati o n  
(i.e., Da y  1), will be c o nsi dere d a pre-treat me nt a d verse e v e nt.  Treat me nt-e mer ge nt a d verse 
e ve nts ( T E A Es) will be defi ne d as a n y a d verse e v e nt t hat occ urs aft er a d mi nistrati o n of t he first 
d ose of St u d y Me di cati o n or A Es n ote d pri or t o t he first St u d y Me dicati o n a d mi nistrati o n t hat 
w orse n after Baseli ne.  T he n u m ber a n d p erce nta ge of patie nts w h o re p ort T E A Es will be 
s u m marize d b y s yste m or ga n class a n d preferre d t er m.  Treat me nt e mer ge nt a d verse e ve nts will 
als o be s u m marize d b y i nte nsit y as w ell as relati o ns h i p t o St u d y Me dicati o n .  F or s u m maries b y 
relati o ns hi p, relati o ns hi p will be dic h ot o mize d as relate d ( p ossi bl y, pr o ba bl y, a n d d efi nitel y 
relate d) or n ot relate d. 
Patie nts w h o re p ort t he s a me preferre d ter m o n m ulti ple occasi o ns will be c o u nte d o nce f or t he 
preferre d t er m: u n der t he hi g hest se v erit y w he n s u m marize d b y se v erit y a n d u n der t he cl osest 
relati o ns hi p t o St u d y M e dicati o n  w he n s u m marize d b y relati o ns hi p.  If a p atie nt re p orts m ulti ple 
preferre d t er ms f or a s yst e m or ga n class, t he p atie nt will be c o u nte d o nl y o nce f or t h at s yste m 
or ga n class.  
Pr o p orti o ns f or a d vers e e ve nts t hat are ge n der-s pecific (e. g., d ys me n orr hea) will be base d o n t he 
n u m ber of patie nts fr o m t hat ge n der. 
 

 
                                                                                                      
 
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T he n u m ber a n d p erce nta ge of patie nts w h o e x peri e nce T E A Es will be s u m marize d b y treat me nt 
gr o u p f or t he f oll o wi n g: 
•  B y s yste m or ga n class a n d preferre d t er m  
•  B y se verit y/i nte nsit y, s yste m or ga n class, a n d preferre d t er m  
•  B y rel ati o ns hi p t o St u d y Me dicati o n  (rel ate d, n ot relate d), s yste m or ga n class, a n d 
preferre d t er m  
•  Seri o us a d vers e e ve nts b y s yste m or ga n class a n d preferre d t er m  
•  Seri o us a d verse e ve nts b y r elati o ns hi p t o St u d y M e dicati o n , s yst e m or ga n class, a n d 
preferre d t er m  
•  A d verse e ve nts res ulti n g i n disc o nti n uati o n of St u d y Me dicati o n  b y s yste m or ga n 
class a n d preferre d ter m  
•  A d verse e ve nts t hat res ult i n St u d y Me dicati o n  d ose i nterr u pti o n b y s yste m or ga n 
class a n d preferre d ter m  
B y - patie nt listi n gs will b e pr o vi de d f or a n y deat hs, seri o us a d vers e e v e nts, a n d a d vers e e v e nts 
lea di n g t o disc o nti n uati o n of treat me nt.  Treat me nt -e mer ge nt a d vers e e ve nts t hat res ult i n d ose 
i nterr u pti o n will als o be i de ntifie d. 
1 3. 4. 6.  
C ol u m bi a S uici de  Se verit y R ati n g Sc ale 
T he C -S S R S data will be s u m marize d descri pti vel y.  O nl y t he f oll o wi n g s p ecific s uici dal 
i deati o n a n d be ha vi or cat e g or y q uesti o ns wit h a n y “ Yes” res p o nses will be s u m marize d i n a 
fre q ue n c y distri b uti o n ta ble at eac h p ost-ra n d o mi zati o n visit: 
•  A n y S uici dal I d eati o n Cate g or y:  
o  Wis h t o be Dea d  
o  N o n - S pecific A cti ve S uici dal T h o u g hts 
o  Acti ve S uici dal I deati o n wit h A n y Met h o ds ( N ot Pla n) wit h o ut I nte n t t o A ct 
o  Acti ve S uici dal I deati o n wit h S o me I nte nt t o Act, wit h o ut S pecific Pla n  
o  Acti ve S uici dal I deati o n wit h S pecific Pla n a n d I nte nt  
•  A n y S uici dal Be ha vi or Cate g or y:  
o  C o m plete d S uici de 
o  N o n -Fatal S uici de Atte m pt  
o  I nterr u pte d Atte m pt 
o  A b orte d Atte m pt 
o  Pre parat or y Acts or Be h a vi or  
 

 
                                                                                                      
 
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o  A n y S uici dal I d eati o n or Be ha vi or Cate g or y 
1 3. 4. 7.  
Cli nic al L a b or at or y 
Patie nts  wit h cli nicall y si g nifica nt  a b n or mal la b orat or y v al ues will be i de ntifie d.  Cli nicall y 
si g nifica nt, tr eat me nt-e m er ge nt la b or at or y val ues (i.e., baseli ne < Gra d e 3 a n d p ost -baseli ne 
meets ≥ Gra de 3,  acc or di n g t o C T C A E, versi o n 5. 0) will be s u m marize d b y treat me nt gr o u p.   
La b orat or y v al ues will be s u m marize d at eac h ti m e p oi nt f or eac h treat me nt gr o u p, usi n g 
descri pti ve statistics . 
1 3. 4. 8.  
Vit al Si g ns  
Vital si g ns will be s u m marize d at eac h ti me p oi nt f or eac h treat me nt gr o u p, usi n g descri pti ve 
statistics.  C ha n ge fr o m baseli ne i n vital si g ns val u es will als o be s u m marize d.  
Baseli ne will be defi ne d as t he last vital si g n val u e o btai ne d bef ore t he first d ose of St u d y 
Me dicati o n  o n Da y 1. 
1 3. 4. 9.  
Electr oc a r di o gr a m  
T he c ha n ge fr o m bas eli ne i n E C G i nter vals ( P R, Q T, Q Tc F, Q R S, a n d R R) t o eac h s c he d ule d 
assess me nt will be s u m marize d descri pti vel y b y treat me nt gr o u p.  
Fre q u e nc y distri b uti o ns of t he Q Tc F i nter val will be dis pla ye d b y treat me nt gr o u p f or 
a b n or mall y hi g h v al ues t hat are great er t ha n t heir baseli ne val ue at a n y p ost - baseli ne visit a n d t he 
f oll o wi n g data c uts: 
> 4 5 0 msec a n d > Baseli n e val ue  
> 4 7 0 msec a n d > Baseli n e val ue  
> 5 0 0 msec a n d > Baseli n e val ue  
A d diti o nall y, t he c h a n ge fr o m baseli ne fre q ue n c y distri b uti o ns of t he Q Tc F i nter val will 
dis pla ye d b y tr eat me nt gr o u p f or t he f oll o wi n g dat a c uts: 
> 3 0 msec i ncr ease  
> 6 0 msec i ncr ease  
 
 
 
 
 
 
 

 
                                                                                                      
 
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1 4.  
R E G U L A T O R Y C O N SI D E R A TI O N S 
It is t he r es p o nsi bilit y of t he cli nical site an d staff t o n otif y t he S p o ns or a n d S p o ns or’s desi g n ee 
i m me diatel y u p o n bec o mi n g a w are of a seri o us breac h of G C P  or of t he st u d y pr ot oc ol.  It is t he 
res p o nsi bilit y of t he S p o ns or or its desi g n ee t o n otif y a p pr o priate re g ulat or y a ut h orities  of a n y 
seri o us breac h w hic h is li kel y t o effect, t o a si g nifica nt de gree, t he s afet y or me ntal i nte grit y of 
t he patie nts of t he st u d y or t he scie ntific val u e of t he st u d y. 
1 4. 1.  
G o o d Cli nic al  Pr actice  
T he pr oce d ures set o ut i n t his st u d y pr ot oc ol pertai ni n g t o t he c o n d u ct, e val uati o n, a n d 
d oc u me ntati o n of t his st u d y are desi g n e d t o e ns ure t hat t he S p o ns or, its a ut h orize d 
re pres e ntati ve, a n d I n vesti gat or a bi d e b y G C P, as descri be d i n I C H G ui d eli ne E 6 a n d i n 
acc or d a nce wit h t he ge neral et hical pri nci ples o utli ne d i n t he Declarati o n of Helsi n ki.  T he st u d y 
will recei ve a p pr o val fr o m t he I R B pri or t o c o m m e nce me nt.  T h e I n vesti gat or will c o n d uct all 
as pects of t his st u d y i n acc or da n ce wit h a p plica bl e nati o nal, state, a n d l ocal la ws of t he perti ne nt 
re g ulat or y a ut h orities. 
1 4. 2.  
S p o ns or’s Res p o nsi bilities  
T he S p o ns or or its desi g n ee is res p o nsi ble f or t he f oll o wi n g: 
•  Selecti n g q u alifie d I n vesti gat ors  
•  Pr o vi di n g I n vesti gat ors wit h t he i nf or mati o n t he y nee d t o pr o perl y c o n d uct  
a n i n vesti gati o n  
•  E ns uri n g pr o p er m o nit ori n g of t he i n v esti gati o n 
•  E ns uri n g t hat t he a p plica ble re g ulat or y a ut h orities, a n d all partici pati n g I n v esti gat ors 
are pr o p erl y i nf or me d of s i g nifica nt n e w i nf or mati o n re gar di n g a d vers e e ve nts or 
ris ks ass ociate d wit h t he me dicati o n bei n g st u die d 
Bef ore a n i n v esti gati o nal site ca n e nter a patie nt i nt o t he st u d y, a re pres e ntati ve of t he S p o ns or 
will visit t he i n vesti gati o nal st u d y site t o:  
•  Deter mi ne t he a de q uac y of t he facilities  
•  Disc uss wit h t he I n v esti gat or(s) a n d ot h er pers o n n el t heir res p o nsi bilities wit h re gar d t o 
pr ot oc ol a d her e nce, a n d t he res p o nsi bilities of t he S p o ns or or its re prese nt ati ves.  T his 
will be d oc u me nte d i n a Cli nical St u d y A gree m e nt bet wee n t he S p o ns or a n d t he 
I n v esti gat or. 
D uri n g t h e st u d y, a m o nit or fr o m C o ncert P har m ace uticals or its re prese nt ati ve will ha ve re g ular 
c o ntacts wit h t he i n vesti gati o nal site, f or t he f oll o wi n g:  
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he I n v esti gat or (s) 
•  C o nfir m t hat facilities re mai n acce pta ble  
 

 
                                                                                                      
 
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•  C o nfir m t hat t he i n vesti gati o nal tea m is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc ur atel y r ec or d e d i n t he case re p ort f or ms, a n d t hat i n vesti gati o nal pr o d u ct 
acc o u nta bilit y c hec ks ar e bei n g p erf or m e d 
•  Perf or m s o urce data v erificati o n.  T his i ncl u des a c o m paris o n of t he data i n t he case 
re p ort f or ms wit h t he pati e nt’s me dical rec or ds at t he h os pital or practice, a n d ot her 
rec or ds rele v a nt t o t he st u d y.  T his will re q uire direct access t o all ori ginal r ec or ds f or 
eac h p atie nt (e. g.,  cli nic c harts).   D u e t o t he C O VI D - 1 9 pa n d e mic a n d t he p ossi bilit y f or 
site cl os ures a n d/ or tr a vel restricti o ns, s o urce d ata verificati o n ma y b e perf or me d 
re m otel y. 
•  Rec or d a n d r e p ort a n y pr ot oc ol de viati o ns. 
•  C o nfir m a d verse e v e nts a n d seri o us a d vers e e v e nts ha ve bee n pr o perl y d o c u me nte d o n 
e C R Fs a n d c o nfir m a n y s eri o us a d vers e e v e nts ha ve bee n f or war de d t o t he S p o ns or a n d 
t h ose seri o us a d verse e v e nts t hat met criteria f or re p orti n g ha v e bee n f or w ar de d t o t he 
I R B. 
T he m o nit or wi ll be a vaila ble bet wee n visits if t he I n v esti gat or(s) or ot her st aff nee ds 
i nf or mati o n or a d vice. 
As t he S p o ns or, C o ncert P har mace uticals has dele gat e d s o me res p o nsi bilities t o a desi g nee, or 
C o ntract Resear c h Or ga nizati o n.  
1 4. 3.  
I n vesti g at or’s Res p o nsi bilities 
I n v esti gat or res p o nsi bilities are set o ut i n t he I C H G ui deli ne f or G C P a n d i n t he l ocal 
re g ulati o ns.  Eac h I n vesti gat or p artici pati n g i n t his st u d y is re q uire d t o mai ntai n c o m plete a n d 
acc ur ate st u d y d oc u me nt ati o n i n c o m plia nce wit h c urre nt G C P sta n dar ds a n d all a p plica ble l ocal 
re g ulati o ns relate d t o t he c o n d uct of a cli nical st u d y. 
T he Pri nci pal I n vesti gat or will e ns ure t hat all pers o ns assisti n g wit h t he st u d y are a d e q uatel y 
i nf or me d a b o ut t he pr ot o c ol, a n y a me n d me nts t o t he pr ot oc ol, t he St u d y M e dicati o n, a n d t heir 
st u d y-r elate d d uties a n d f u ncti o ns.  T he Pri nci pal I n vesti gat or will mai ntai n a list of s u b-
I n v esti gat ors a n d ot her a p pr o priatel y q ualifie d p ers o ns t o w h o m he or s he h as dele gate d 
si g nifica nt st u d y-r elate d d uties.  I n di vi d uals i neli gi ble fr o m c o n d ucti n g or w or ki n g o n cli nical 
st u dies, i ncl u di n g t h ose i neli gi ble as a res ult of d e bar me nt u n der t h e Ge n eric Dr u g E nf orce me nt 
Act of 1 9 9 2, will n ot be all o we d t o c o n d uct or w or k o n st u dies s p o ns ore d b y C o ncert 
P har mace uticals.  T he I n vesti gat or is r e q u ire d t o i m me diatel y discl ose t o t he S p o ns or i n writi n g, 
if a n y p ers o n i n v ol ve d i n t he c o n d uct of t he st u d y is de barre d p urs ua nt t o a heari n g b y t he F D A 
u n der t his a nti-fra u d l a w, or if a n y pr ocee di n g f or de bar me nt is pe n di n g, or is (t o t he best of t he 
I n v esti gat or’s k n o wle d ge) t hreate n e d. 
T he I n vesti gat or is r es p o nsi ble f or kee pi n g a rec or d of all patie nts w h o si g n a n i nf or me d c o ns e nt 
d oc u me nt a n d ar e scr ee n e d f or e ntr y i nt o t he st u d y.  Patie nts w h o fail scree ni n g m ust ha ve t h e 
reas o n(s) rec or de d i n t he patie nt’s s o urce d o c u me nts. 
T he I n vesti gat or s h o ul d i nf or m t he I R B of a n y e v e nt li kel y t o affect t he s afet y of p atie nts or t he 
c o nti n ue d c o n d uct of t he st u d y, i n partic ular a n y c ha n ge i n safet y.  A d diti o nall y, all u p dat es t o  

 
                                                                                                      
 
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t he I B will be se nt t o t he I R B.  A pr o gress re p ort will be se nt t o t he I R B a n d t he pr ot oc ol will be 
re vie we d a n n uall y ( e. g., r e-a p pr o v e d) or m ore fre q ue ntl y, as re q uire d b y t h e I R B or l ocal 
re g ulati o ns. 
T he I n vesti gat or will mai ntai n a c o p y of all c orres p o n de nce wit h t he I R B, i ncl u di n g c o pi es of 
a p pr o ve d d oc u me nts.  T he I n vesti gat or will als o m ai ntai n a c o p y of t he I R B me m bers hi p list 
wit h occ u pati o n a n d q ualificati o n ( or a stat e me nt c o nfir mi n g c o m plia n ce wit h G C P re q uire me nts 
f or c o m mittee c o m p ositi o n). 
T he I n vesti gat or will n otif y t he I R B of t he c o ncl usi o n of t he cli nical st u d y wit hi n 1 m o nt h of 
c o m pleti o n or ter mi nati o n of t he st u d y.  T h e fi nal re p ort se nt t o t he I R B will als o be se nt t o t he 
S p o ns or al o n g wit h t he c o m plete d electr o nic case re p ort f or ms (e C R Fs) a n d all necessar y 
re g ulat ory d oc u m e nts, t here b y f ulfilli n g t he I n v esti gat or’s re g ulat or y res p o nsi bilit y.  
T he I n vesti gat or, or a desi g nate d m e m ber of t h e I n vesti gat or’s staff, m ust b e a vaila ble d uri n g 
m o nit ori n g visits t o re vie w data, res ol v e q ueries a n d all o w direct access t o patie nt rec or ds (e. g., 
me dical rec or ds, offi ce c harts, h os pital c harts, a n d st u d y- relate d c h arts) f or s o urce dat a 
verificati o n.  T he I n vesti gat or m ust e ns ure ti mel y a n d acc urate c o m pleti o n of e C R Fs a n d q ueries. 
1 4. 4.  
Pr ot oc ol A me n d me nts  
A n y p er ma ne nt c ha n ge t o t he pr ot oc ol, w het her it is a n o verall c h a n ge or a c ha n ge f or s pecific 
st u d y ce nt er(s), m ust be ha n dle d as a pr ot oc ol a m e n d me nt.  All a me n d me nts t o t he pr ot oc ol will 
be writte n b y t he S p o ns or.  T he I n vesti gat or will n ot ma ke a n y c h a n ges t o t his pr ot oc ol wit h o ut 
pri or writte n c o nse nt fr o m t he S p o ns or a n d s u bse q ue nt a p pr o val b y t he I R B.  E x ce pt f or 
a d mi nistrati ve a me n d me nts, I n vesti gat ors m ust a wait I R B a p pr o val of pr ot oc ol a me n d me nts 
bef ore i m ple me nti n g t he c ha n ge(s).  T he S p o ns or will e ns ure s u b missi o n of a n y pr ot oc ol 
a me n d me nts t o t he a p pr o priate re g ul at or y a ge n cies.  
I n li g ht of t he F D A iss ue d G ui da nce f or I n d ustr y, I n v esti gat ors, a n d I nstit uti o nal Re vie w B o ar ds, 
e ntitle d “ G ui da nce o n C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D- 1 9 
Pa n de mic” trial c o n d u ct ma y b e i m pacte d b y t he C O VI D - 1 9 pa n d e mic.  C hallen ges ma y arise 
(e. g., q uar a nti nes, site cl os ures, tra vel li mitati o ns, i nterr u pti o ns t o t he s u p pl y c h ai n f or t he 
i n vesti gati o nal pr o d u ct, etc) lea di n g t o diffic ulties i n meeti n g pr ot oc ol-s pecifie d pr oce d ures, 
i ncl u di n g a d mi nisteri n g or usi n g t he i n vesti gatio n al pr o d uct or a d h eri n g t o pr ot oc ol- s pecifi e d 
visits a n d la b orat or y/ di a g n ostic testi n g.  T o mi ni mize or eli mi nate i m me diate hazar ds or t o 
pr otect t he life a n d well - bei n g of researc h partici p a nts (e. g., t o li mit e x p os ure t o C O VI D-1 9) 
a me n d me nts t o pr ot oc ol defi ne d criteria ma y b e i m ple me nte d pri or t o  I R B a p pr o val or b ef ore 
fili n g a n a m e n d me nt t o t he I N D.   
A d mi nistrati ve a me n d me nts are defi n e d as ha vi n g n o effect o n t he safet y of t he researc h 
s u bjects, sc o pe of t he i n v esti gati o n, or q u alit y of t he st u d y.  H o we ver, a pr ot oc ol c ha n ge 
i nte n de d t o eli mi nate a n a p pare nt i m me diate h azar d t o patie nts s h o ul d be i m ple me nte d 
i m me diatel y, a n d t he I R B n otifie d wit hi n 5 da ys. 
W he n, i n t he j u d g me nt of t he c hair m a n of t he l ocal I R B, t he I n v esti gat ors, a n d/ or t he S p o ns or, 
t he a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y desi g n a n d/ or i ncreas es t he p ote ntial 
ris k t o t he patie nt, t he c urre ntl y a p pr o ve d writte n I C F will re q uire si milar m o dificati o n.  I n s uc h 

 
                                                                                                      
 
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cases, r e peat i nf or me d c o nse nt will be o btai ne d fr o m patie nts e nr olle d i n t he st u d y bef ore 
c o nti n ue d partici pati o n u n der t he ne w a me n d me nt. 
1 4. 5.  
A u dits a n d I ns pecti o ns  
T he S p o ns or’s Q ualit y Ass ura nce U nit ( or re prese ntati ve) ma y c o n d uct a u dits at t he st u d y site(s) 
or re m otel y .  A u dits will i ncl u de, b ut are n ot li mite d t o: dr u g s u p pl y, prese nce of re q uire d 
d oc u me nts, t he i nf or me d c o nse nt pr ocess, la b orat or y s p eci me n pr o cessi n g, a n d c o m paris o n of 
e C R Fs wit h s o urce d o c u me nts.  T he I n vesti gat or a grees t o c o o perate wit h a u dits c o n d ucte d at a 
reas o na bl e ti me a n d i n a reas o na bl e ma n ner. 
Re g ulat or y a ut h orities w orl d wi de ma y als o a u dit t he I n vesti gat or d uri n g or after t he st u d y.  T h e 
I n v esti gat or s h o ul d c o ntact t he S p o ns or i m me diatel y if t his occ urs, a n d m ust f ull y c o o perate wit h 
t he a u dits c o n d ucte d at a reas o na bl e ti me i n a reas o na ble ma n ner. 
T he I n vesti gat or is r e q uir e d t o ma ke all st u d y d o c u me ntati o n pr o m ptl y a vaila ble f or i ns pecti o n, 
re vie w or a u dit at t he st u d y site u p o n r e q uest b y S p o ns or, its re prese nt ati ves, or a n y a p pr o priate 
re g ulat or y a ge ncies. 
1 4. 6.  
Q u alit y C o ntr ol a n d Q u a lit y A ss ur a nce 
All as pects of t he st u d y will be caref ull y m o nit ore d b y t h e S p o ns or or its a ut h orize d 
re pres e ntati ve f or c o m plia nce wit h a p plica ble g o v er n me nt re g ul ati o ns wit h res pect t o c urre nt 
G C P  a n d sta n dar d o per ati n g pr oce d ur es. 
A q ualit y c o ntr ol a n d q ualit y ass ura n ce pla n a d dressi n g as pects of t he st u d y t hat ma y i m pact data 
i nte grit y or t he pr otecti o n of h u ma n s u bjects ma y be i nstit ute d f or t his st u d y.  All a u dit fi n di n gs 
will be s u m marize d a n d place d o n file wit h a p pr o priate d oc u me ntati o n of res p o nse/res ol uti o n. 
I n li g ht of t he C O VI D- 1 9 pa n de mic, patie nt safet y will be e ns ure d b y mai nt ai ni n g c o m plia n ce 
wit h G o o d C li nical P ractice ( G C P) a n d mi ni mizi n g ris ks t o patie nt safet y a n d data i nte grit y.  
T hese eff orts i ncl u de a d diti o nal ris k miti gati o n strate gie s a n d a p pr o priate d oc u me ntati o n of 
pr ot oc ol de viati o ns occ urri n g pri or t o i m ple me ntati o n of pr ot oc ol a me n d me nts.   
 

 
                                                                                                      
 
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1 5.  
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 5. 1.  
C o nfi de nti alit y  
All i nf or mati o n discl ose d or pr o vi de d b y t he S p o ns or ( or desi g nee), or ge nerate d or pr o d u ce d 
d uri n g t he st u d y i ncl u di n g, b ut n ot li mite d t o, t he pr ot oc ol, t he e C R Fs, t he I n v esti gat or’s 
Br oc h ure, a n d t he res ults o btai ne d d uri n g t h e c o urse of t he st u d y, are c o nfi de ntial.  T he 
I n v esti gat or or a n y p ers o n u n der his/ her a ut h orit y a grees t o k ee p c o nfi de ntial a n d n ot t o discl ose 
t he i nf or mati o n t o a n y t hir d part y wit h o ut t he pri or writte n a p pr o val of t h e S p o ns or. 
S u b missi o n of t his pr ot oc ol a n d a n y ot her n ecessar y d o c u me ntati o n t o t he I R B is e x pressl y 
per mitte d, I R B me m bers ha vi n g t he s a me o bli gati o n of c o nfi de ntialit y.  A ut h orize d re g ul at or y 
officials a n d s p o ns or p ers o n nel ( or desi g nee) will 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.  T h e c o pie d a n d i ns pecte d rec or ds will re mai n at t he site a n d will n ot be tra ns mitte d or 
re m o ve d fr o m t he site.  St u d y Me dicati o n , patie nt 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 a n d res p o nsi ble et hics c o m mittee(s) or re g ulat or y a ut h orities. 
Patie nts ’ na mes ma y, h o we ver, b e ma de k n o w n t o a re g ulat or y a ge n c y or ot her a ut h orize d 
officials i n t he e ve nt of i ns pecti o ns.  D oc u me nts c o ntai ni n g t he f ull na me or ot her pers o n all y 
i de ntifia ble i nf or mati o n of t he patie nt are t o re mai n at t he site.  T his i nf or matio n will n ot be 
tra nsferre d t o t he S p o ns or n or be c o nt ai ne d i n re g ulat or y fili n gs. 
1 5. 2.  
P atie nt D at a Pr otecti o n  
Pri or t o a n y testi n g u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts, ca n di dates 
m ust als o pr o vi de all a ut h orizati o ns re q uire d b y l ocal la w (e. g., pr otecte d healt h i nf or mati o n 
a ut h orizati o n). 
Patie nts will be i de ntifie d o nl y b y u ni q ue patie nt n u m bers i n e C R Fs a n d ot her datas ets ge nerate d 
f or t his st u d y.  T he p atie nt will n ot be i de ntifie d b y na m e i n t he e C R F, i n a n y st u d y sa m ples or 
st u d y re p orts.  All data ge nerat e d i n t his st u d y is f or researc h p ur p oses o nl y.  T he S p o ns or, its 
part ner(s) a n d desi g n ee(s), a n d vari o us g o v er n me nt healt h a ge ncies m a y i ns pect t he rec or ds of 
t his st u d y.  E v er y eff ort will be ma de t o kee p t he patie nt’s pers o nal me di cal data c o nfi de ntial.  
T he S p o ns or will pr otect i n di vi d ual patie nt i nf or mati o n t o t he f ullest e xte nt p ossi ble d uri n g t his 
st u d y.  At n o ti me will a patie nt bec o me i de ntifie d i n a n y p u blicati o n or prese ntati o n.  H o we ver, 
t he patie nt ma y ha ve t o b ec o me i de ntifie d i n t he e ve nt of a re g ulat or y a ut h orit y a u dit or 
i ns pecti o n i n or der t o verif y t he acc urac y of t he data.  Access t o patie nt i nf or mati o n is at t he 
discreti o n of t he S p o ns or a n d ca n n ot occ ur pri or t o data base l oc k or ot her s pecifie d e v e nts as 
deter mi ne d s olel y b y t he discreti o n of t he S p o ns or. 
1 5. 3.  
D at a C ollecti o n  
All data o btai ne d f or a nal ysis i n t he cli nical st u d y descri be d i n t his pr ot oc ol will use a n 
electr o nic d ata ca pt ure s yste m.  Data re p orte d i n t he e C R Fs s h o ul d be c o nsiste nt wit h a n d 
s u bsta ntiate d b y t he p atie nt’s me dical rec or d a n d ori gi nal s o urce d oc u m e nts.  A n y discre pa n cies 
m ust be e x plai ne d. 

 
                                                                                                      
 
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Pri or t o t he start of t he st u d y, t he Pri nci pal I n vesti gat or will c o m plete a D ele gati o n of A ut h orit y 
f or m ( Site Si g nat ur e a n d Dele gati o n L o g), s h o wi n g t he si g nat ures a n d ha n d writte n i nitials of all 
i n di vi d uals a n d t he dele gati o n of res p o nsi bilities, s uc h as i de ntif yi n g t h os e i n di vi d uals w h o are 
a ut h orize d t o ma ke or c h a n ge e ntries o n e C R Fs. 
1 5. 4.  
C ase Re p ort F or m C o m pleti o n  
Data wit hi n t he e C R F will be m o nit ore d b y a Cli nical Researc h Ass ociat e acc or di n g t o t he 
M o nit ori n g Pla n.  Q ueries will be ge n erat e d base d o n discre pa n cies f o u n d w hile m o nit ori n g.  
Site pers o n nel will re vie w a n d res p o n d t o t hes e q ueries a p pr o priatel y.  A d diti o nall y, t h e 
S p o ns or’s desi g n ee a n d t he S p o ns or ma y p eri o dicall y perf or m a g gre gate d ata re vie ws, w hic h 
c o ul d res ult i n q ueries bei n g ge n erate d f or site pers o n nel res ol uti o n.  T he c o m plete d e C R F f or 
eac h p atie nt m ust be si g n e d a n d date d b y t h e Pri nci pal I n v esti gat or t o si g nif y t hat t he Pri nci pal 
I n v esti gat or has r e vie we d t he e C R F a n d certifies it t o be c o m plete a n d acc urate. I n li g ht of t he 
C O VI D - 1 9 pa n d e mic, st u d y e C R Fs will be m o difie d t o i nc or p orate c ha n ges t o st u d y pr oce d ures 
(e. g., misse d assess me nts, re m ote visits, etc.).    
1 5. 5.  
D at a b ase M a n a ge me nt, D at a Cl arific ati o n, a n d Q u alit y Ass ur a nce  
T he S p o ns or’s desi g nee (i.e., a desi g nate d C o ntract Researc h Or ga nizati o n) will be res p o nsi ble 
f or data ma n a ge me nt.  D ata Ma na ge me nt will de v el o p a Data M a na ge m e nt Pla n (D M P ) 
d oc u me nt, a n d pr o vi de it t o t he S p o ns or f or a p pr o val.  T he D M P d oc u me nt will defi ne all 
acti vities i n t he data c ollecti o n a n d clea ni n g pr o cess.  T he detaile d D M P will be base d o n t he 
pr ot oc ol, w or k sc o p e, c o ntract, a nal ysis pla ns, dat a- fl o ws, e C R Fs, d ata clea ni n g pr o ce d ures, 
ot her s u p p orti n g d o c u me nts, a n d data ma na ge me nt sta n dar ds a n d practices. 
T he pr o gra m me d d ata vali dati o ns will be r u n t o c hec k f or d ata bas e c o m plete ness a n d 
c o nsiste nc y, a n d q ueries will be ge n erat e d u p o n d ata e ntr y or vi a re vie w b y a Cli nical D ata 
Ma na ge r after e ntr y.  T h e sites will res p o n d t o t he data q ueries i n a ti mel y ma n ner. 
Q ualit y c o ntr ol pr oce d ur es will be c o n d ucte d pri or t o data base l o c k acc or di n g t o t he desi g nat e d 
C o ntract Resear c h Or ga nizati o n sta n dar d o perati n g pr o ce d ures.  
W he n t he data base h as b ee n declare d t o b e c o m pl ete a n d acc urate, it will be l oc ke d.  A n y 
c ha n ges t o t he dat a base after t hat ti me will o nl y be ma de b y j oi nt writte n a gree me nt bet w ee n t he 
S p o ns or, Statisticia n, Data Ma na ger, a n d Q u alit y Ass ura nce A u dit or acc or di n g t o desi g nate d 
sta n dar d o per ati n g pr oce d ures of t he C o ntract Researc h Or ga nizati o n. 
1 5. 6.  
I ns pecti o n of Rec or ds 
Acc or di n g t o t he I C H g ui deli nes f or G C P, t he S p o ns or or desi g nee m ust verif y d ata e nt ere d i n 
t he e C R F e ntries a gai nst t he s o urce d o c u me nts.  T he o bjecti ve of s o urce d o c u me nt verificati o n is 
t o c o m pl y wit h G C P a n d i nter nati o nal re g ulat or y re q uire me nts a n d t o re d uce t he ris ks of fra u d.  
S o urce d oc u me nt verificati o n mea ns e ns uri n g t hat s o urce d oc u me nts are a n acc urate a n d 
c o nfir ma ble r eflecti o n of t he patie nt’s e val u at i o ns d uri n g partici pati o n i n t he st u d y a n d t hat all 
rele va nt i nf or m ati o n rec or de d i n t he s o urce d oc u m e nt is acc uratel y e ntere d i nt o t he e C R F.  All 
s o urce d oc u m e nts s h o ul d be c orr ectl y la bele d a n d file d a n d ass ociat e d wit h a si n gle, v erifia ble 
patie nt.  

 
                                                                                                      
 
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All data re q uir e d f or t his st u d y s h o ul d be ca pt ure d i n s o urce n otes.  N o d ata o btai ne d b y t h e 
I n v esti gat or or ot her st u d y pers o n nel s h o ul d be ca pt ure d directl y i n t he e C R F.  All s o urce 
d oc u me nts pertai ni n g t o t his st u d y will be mai ntai ne d b y t h e I n vesti gat or a n d ma de a vaila ble f or 
i ns pecti o n b y a ut h orize d pers o ns.  If electr o nic pr o gress n otes a n d ot her el ectr o nic s o urce 
d oc u me nts are n ot c o m plia nt wit h a p plica ble re g ul at or y g ui d a nce, t h e y are n ot c o nsi dere d a v ali d 
s o urce f or t his st u d y.  All patie nt pr o gress n otes m ust be date d a n d si g ne d at t he ti me of t he visit.  
T he S p o ns or reser ves t he ri g ht t o ter mi nate t he st u d y f or ref usal of t he I n vesti gat or t o s u p pl y 
ori gi nal s o ur ce d oc u m e ntati o n f or t his cli nical st u d y. 
T he I n vesti gat or will n ot e i n a s o urce i n de pe n d e nt fr o m t he e C R F t he f oll o wi n g i nf or m ati o n: 
•  I nf or mati o n t o c o nfir m t hat t he patie nt e xists (e. g., i nitials, date of birt h, a n d se x); 
•  C o nfir mati o n t hat t he patie nt satisfies t he i ncl usi o n/e x cl usi o n criteria;  
•  C o nfir mati o n t hat t he patie nt is ta ki n g part i n t he cli nical st u d y;  
•  C o nfir mati o n of t he i nf or me d c o nse nt pr ocess; 
•  Visit dates a n d d oc u me nt ati o n of pr ot oc ol assess m e nts a n d pr oce d ures; 
•  I nf or mati o n c o ncer ni n g all a d verse e v e nts; 
•  Details of c o nc o mita nt a n d i n vesti gati o nal me dicati o ns.  
S o urce d oc u me nt verificati o n is n ot a s u bstit ute f or cli nical st u d y m o nit ori n g, t he p ur p ose of 
w hic h is t o e ns ure t hat t h e pr ot oc ol has bee n f oll o we d c orrectl y, t he e C R F has bee n f ull y a n d 
acc ur atel y c o m plete d, s o urce d oc u m e nt verificati o n has bee n carri e d o ut, a n d t he st u d y t i meli nes 
a n d e nr oll me nt g oals a n d re q uire me nts ha v e bee n met. I n li g ht of t he C O VI D- 1 9 pa n de mic. 
s o urce d oc u m e nt verificati o n ma y occ ur re m otel y.  A d diti o nal detail o n re m ote s o urce d oc u m e nt 
verificati o n will be d oc u me nte d se par atel y  i n t he Trial M aster Fi le.  
1 5. 7.  
Rete nti o n of Rec or ds  
F or i n vesti gati o nal dr u g st u dies, cli nical I n v esti gat ors m ust retai n st u d y rec or ds f or a p eri o d of 2 
years f oll o wi n g t he dat e a mar keti n g a p plicati o n is a p pr o ve d f or t he dr u g f or t he i n dicati o n f or 
w hic h it is bei n g i n vesti gate d; or, if n o a p plicati o n is t o be file d or if t he a p plicati o n is n ot 
a p pr o ve d f or s uc h i n dicati o n, u ntil t w o years after t he i n vesti gati o n is disc o nti n ue d a n d F D A is 
n otifie d. 
T he I n vesti gat or m ust mai ntai n all st u d y d oc u me ntati o n as c o nfi de ntial, a n d ta ke me as ures t o 
pre ve nt acci de ntal or pre mat ure destr ucti o n of t h ese d oc u me nts. 
T he I n vesti gat or m ust n otif y t he S p o ns or pri or t o destr o yi n g a n y st u d y ess e ntial d oc u me nts. 
If t he I n vesti gat or ca n n o l o n ger e ns ure arc hi vi n g, he/s he s hall i nf or m t he S p o ns or.  T he rel e va nt 
rec or ds s h all be tra nsf err e d t o a m ut uall y a gree d u p o n desi g n ee. 

 
                                                                                                      
 
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1 6.  
P U B LI C A TI O N P O LI C Y 
T he res ults of t his st u d y ma y b e p u blis he d i n a me dical p u blicati o n, j o ur nal, or a n ot her p u blic 
disse mi nati o n, or ma y be prese nte d at a me dical c o nfere n ce or us e d f or t eac hi n g p ur p oses.  
A d diti o nall y, t his st u d y a n d its res ults ma y be s u b mitte d f or i ncl usi o n i n all a p pr o priate h ealt h 
a ut h orit y st u d y re gistries, as well as p u blicati o n o n healt h a ut h orit y st u d y re gistr y we b sites, as 
re q uire d b y l ocal healt h a ut h orit y re g ul ati o ns.  Selecti o n of first a ut h ors hi p will be base d o n 
se veral c o nsi derati o ns, i n cl u di n g, b ut n ot li mite d t o st u d y partici p ati o n, c o ntri b uti o n t o t he 
pr ot oc ol de vel o p me nt, a n d a nal ysis a n d i n p ut i nt o t he ma n uscri pt, relat e d a bstracts, a n d 
prese ntati o ns i n a st u d y. 
 

 
                                                                                                      
 
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1 7.  
LI S T O F R E F E R E N C E S  
1.  C harls o n FJ, Ferr ari AJ, Sa nt o ma ur o D F, Di mi nic S, St oc ki n gs E, Sc ott J G, Mc Grat h JJ, 
Witef or d H A. Gl o b al e pi de mi ol o gy a n d b ur de n of sc hiz o p hre ni a: fi n di n gs fr o m t he 
Gl o b al B ur de n of Dise ase st u dy 2 0 1 6. Sc hiz o p hre nia B ulleti n ( 2 0 1 8): e p u b. 
2.  La n e H Y, Li n C H, Gree n M F, Helle ma n n G, H ua n g C C, C he n P W, T u n R, C ha n g Y C, 
T hai G E. A d d- o n tr eat me nt of Be nz oate f or sc hiz o p hre nia: a ra n d o mize d, d o u ble- bli n d, 
place b o -c o ntr olle d trial of D -a mi n o aci d o xi dase i n hi bit or. J A M A Ps yc hiatr y ( 2 0 1 3),  
7 0 ( 1 2 ): 1 2 6 7- 1 2 7 5. 
3.  B u gars ki -Kir ola D, I w ata N, Sa melja k S, Rei d C, Blaettler T, Millar L, M ar q ues T R, 
Gari bal di G, K a n p ur S. Efficac y a n d safet y of a dj u ncti ve bit o perti n vers us place b o i n 
patie nts wi t h s u b o pti mall y c o ntr olle d s y m pt o ms of sc hiz o p hre nia treate d wit h 
a nti ps yc h otics: r es ults fr o m t hree p hase 3, ra n d o mise d, d o u ble- bli n d, parallel- gr o u p, 
place b o -c o ntr olle d, m ultice nter st u dies i n t he Searc h L yt e cli nical trial pr o gra m me. 
La n cet Ps yc hiatr y  ( 2 0 1 6), 3: 1 1 1 5- 1 1 2 8. 
4.  Bal u D T, C o yle J T. T he N M D A rece pt or “ glyci ne m o d ul at ors site ” i n sc hiz o p hre ni a: D -
seri ne, glyci ne, a n d b ey o n d. C urr O pi n P har mac ol ( 2 0 1 5 ), 2 0: 1 0 9- 1 1 5. 
5.  Has hi m ot o K, F u k us hi ma T, S hi miz u E, K o mats u N, Wata na be H, S hi n o da N, Na kazat o 
M, K u ma kiri C, O ka da S, Hase ga wa H, I m ai K, I y o M.  Evi de nce i n s u p p ort of t he N-
Met hyl -D - As p art ate rece pt or hy p of u ncti o n hy p ot hesis of sc hiz o p hre ni a.  Arc h Ge n 
Ps yc hiatr y  ( 2 0 0 3), 6 0: 5 7 2- 5 7 6. 
6.  Has hi m ot o K, E n g b er g G, S hi miz u E, N or di n C, Li n dstr o m L H, I y o M.   R e d uce d D -
seri ne t o t ot al seri ne r ati o i n t he cere br os pi n al fl ui d of dr u g n aïve sc hiz o p hre nic p atie nts. 
Pr o gr ess i n Ne ur o- Ps yc h o p har mac ol o g y a n d Bi ol o gical Ps yc hiatr y ( 2 0 0 5 ), 2 9: 7 6 7- 7 6 9. 
7.  C h o S E, Na K S, C h o SJ, Ka nt S G.  L o w D -seri ne levels i n sc hiz o p hre ni a: a syste m atic 
revie w a n d met a- a n alysis. Ne ur oscie n ce Lett ers  ( 2 0 1 6), 6 3 4: 4 2- 5 1. 
8.  Be n di k o v I, N a dri C, A m ar S, Pa nizz utti R, De Mira n da J, W ol os ker H, A ga m G.  A C S F 
a n d p ost m orte m br ai n st u dy of D -seri ne m et a b olic p ar a meters i n sc hiz o p hre ni a. 
Sc hiz o p hre nia Resear c h  ( 2 0 0 7), 9 0: 4 1- 5 1. 
9.  Tsai G, Ya n g Pi nc he n, C he n L C, La n ge N, C o yle J T. D -seri ne a d de d t o a nti psyc h otics 
f or t he tre at me nt of sc hiz o p hre ni a. Bi ol Ps yc hi atr y  ( 1 9 9 8): 4 4( 1 1): 1 0 8 1- 1 0 8 9. 
1 0.  Heres c o -Le v y U, J a vitt D C, E bstei n  R, Vass A, Lic hte n b er g P, Bar G, Cati nari S, 
Er mil o v M. D -seri ne effic acy as a d d- o n p h ar m ac ot her a py t o Ris peri d o ne a n d Ol a nz a pi ne 
f or tre at me nt-refr act ory sc hiz o p hre ni a. Bi ol Ps yc hiatr y  ( 2 0 0 5), 5 7( 6): 5 7 7- 5 8 5. 
1 1.  La n e H Y, C ha n g Y C, Li u Y C, C hi u C C, Tsai G E.  S arc osi ne or D -seri ne a d d- o n 
tre at me nt f or ac ute ex a cer b ati o n of sc hiz o p hre ni a: a 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 dy. Arc h G e n Ps yc hi atr y  ( 2 0 0 5), 6(1 1 ): 1 1 9 6- 1 2 0 4. 
1 2.  La n e H Y, Li n C H, J ua na YJ, Lia o C H, C ha n g Y C, T hai G.  A r a n d o mize d, d o u ble- bli n d, 
pl ace b o-c o ntr olle d, c o m p aris o n st u dy of s arc osi ne ( N- met hyl glyci ne) a n d D -seri ne a d d-

 
                                                                                                      
 
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o n tre at me nt f or sc hiz o p hre ni a . I nt er nati o nal J o ur nal of Ne ur o ps yc h o p har mac ol o g y 
( 2 0 1 0), 1 3( 4): 4 5 1- 4 6 0. 
1 3.  Ka ntr o witz J T, Mal h otra A K, C or n blatt B, et al. Hi g h d ose D -seri ne i n t he tre at me nt of 
sc hiz o p hre ni a. Sc hiz o p hre nia Researc h ( 2 0 1 0), 1 2 1( 1-3):  1 2 5- 1 3 0. 
1 4.  Er mil o v E, Gelfi n E, Le vi n R, Lic hte n ber g P, Has hi m ot o K, J a vitt D, Heresc o- Le v y U. A 
pil ot d o u ble- bli n d c o m p aris o n of D -seri ne a n d hi g h- d ose ol a nz a pi ne i n tre at me nt-
resist a nt p atie nts wit h sc hiz o p hre ni a. Sc hiz o p hre nia Researc h  ( 2 0 1 3), 1 5 0: 6 0 4- 6 0 5. 
1 5.  Ka ntr o witz J T, E pstei n M L, Lee M, Le hrfel d N, N ola n K, S h o pe C, Pet k o va E, Sili p o G, 
J a vitt D. I m pr ove me nt i n mis m atc h ne g ativity ge ner ati o n d uri n g D -seri ne tre atme nt i n 
sc hiz o p hre ni a: c orrel ati o n wit h sy m pt o ms. Sc hiz o p hre nia Researc h.  ( 2 0 1 8), 1 9 1: 7 0- 7 9. 
1 6.  Ga n ote C E, Peters o n D R, Car o ne F A. T he n at ure of D -seri ne-i n d uce d ne p hr ot oxicity. 
A merica n J o ur nal of Pat h ol o g y ( 1 9 7 4 ), 7 7: 2 6 9- 2 8 2. 
1 7.  M ot het J P, Pare nt A T, W ol os ker H, Bra d y R O, Li n de n D, Ferris C D, R o ga ws ki M A, 
S n y der S H. D -seri ne is a n e n d o ge n o us li g a n d f or t he glyci ne site of t he N-me htyl  D-
as p art ate rece pt or.  Pr oc Natl Aca d Sci. ( 2 0 0 0), 9 7 ( 9) 4 9 2 6- 4 9 3 1. 
1 8.  Verr all L, B ur n et P WJ, Betts J F, Harris o n PJ. T he ne ur o bi ol o gy of D - a mi n o aci d oxi d ase 
a n d its i nv olve me nt i n sc hiz o p hre ni a.  M olec ular Ps yc hiatr y  ( 2 0 1 0), 1 5( 2): 1 2 2- 1 3 7. 
1 9.  C T P -6 9 2 I n vesti gat or’s Br oc h ure, C o ncert P har mace uticals I n c. , 2 0 1 9.  
2 0.  Ka ntr o witz J T, W o o ds S W, Pet k o va E, C or n blatt B, C orc ora n C M, C he n H, Sili p o G, 
J a vitt D C. D -seri ne f or t he tre at me nt of ne g ative s y m pt o ms i n i n divi d u als at cli nic al hi g h 
risk of sc hiz o p hre ni a: a pil ot, d o u ble- bli n d, pl ace b o-c o ntr olle d, r a n d o mise d p ar allel 
gr o u p mec h a nistic pr o of- of-c o nce pt tri al.  La ncet Ps yc hiatr y  ( 2 0 1 5), 2( 5): 4 0 3- 4 1 2. 
2 1.  Calcia M A, Ma deir a C, Al geria F V, Sil va T C S, Ta n n os F M, V ar gas - L o p es C, 
G ol de nstei n N, Brazil A M, Ferreira S T, Pa nizz utti R. Pl as m a levels of D -seri ne i n 
Br azili a n i n divi d u als wit h sc hiz o p hre ni a.  Sc hiz o p hre nia Researc h  ( 2 0 1 2), 1 4 2( 1): 8 3- 8 7. 
2 2.  Ya ma m ori H, H as hi m ot o R, F ujita Y, N u mata S, F uji m ot o M, O hi K, U me da- Ya n o S, It o 
A, O h m ori T, Has hi m ot o K, Ta ke da M. C h a n g es i n pl as m a D -seri ne, L -s eri ne, a n d 
glyci ne levels i n tre at me nt -resist a nt sc hiz o p hre ni a bef ore a n d after cl oz a pi ne tre at me nt. 
Ne ur os cie n ce Lett ers  ( 2 0 1 4), 5 8 2: 9 3- 9 8. 
2 3.  Leza k M D, H o wies o n D B, L ori n g D W.  Di git Sy m b ol- C o di n g. Ne ur o ps yc h ol o gical 
assess me nt . Ne w Y or k: O xf or d U ni versit y Press  ( 2 0 0 4): 3 6 8 – 3 7 0. 
2 4.  M ore hea d R P, P oe W D, Willia ms J O, Laze n b y M E.  T he I nfl ue n ce of A ge a n d S pecies 
o n t he Ne p hr ot o xic Acti o n of D L- Seri ne.   A meric a n J o ur n al of P at h ol o gy  ( 1 9 4 6), 2 2: 
6 5 8- 6 5 9.  
 
 
 

 
                                                                                                      
 
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2 5.  Nair S, O’ Brie n S V, Ha y de n K, Pa n d ya B, Lis b oa PJ G, Har d y KJ, Wil di n g J P H.  Effec t 
of a C o oke d Me at Me al o n Ser u m Cre ati ni ne a n d Esti m ate d Gl o mer ul ar Filtr ati o n R ate 
i n Di a betes -Rel ate d Ki d n ey Dise ase.   Di a betes C are  ( 2 0 1 4), 3 7: 4 8 3- 4 8 7. 
2 6.  Pi me nta E, J e nse n M, J u n g D, Sc h a u ma n n F, B o x nic k S, Tr ue bel H.  Effect of Diet o n 
Ser u m Creati ni ne  i n Healt h y S u bjects D uri n g a P h ase I St u d y.  J o ur n al of Cli nic al 
Me dici ne R ese arc h  ( 2 0 1 6), 8( 1 1): 8 3 6- 8 3 9. 
 

 
                                                                                                      
 
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1 8.  
A P P E N DI C E S  

 
                                                                                                      
 
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A P P E N DI X A: C O N C O MI T A N T M E DI C A TI O N S  
 
A L L O W E D M E DI C A TI O N S  
P R O HI BI T E D M E DI C A TI O N S  
A nti ps yc h otics  
Ari pi praz ole  
Ase na pi ne  
Bre xi pi praz ole  
Cari prazi ne  
L urasi d o ne  
Ola nza pi ne  
P ali peri d o ne  
Q uetia pi ne  
Ris peri d o ne  
 
C o ntrace pti ves ( oral a n d i m pl a nts)  
 
N o n -a nti ps yc h otic slee p me di cati o ns  
A D D prescri pti o n me dicati o ns  
A D H D prescri pti o n me dicati o ns  
Cl oza pi ne  
Lit hi u m  
 
 
 
 

 
                                                                                                      
 
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A P P E N DI X B: C LI NI C A L L A B O R A T O R Y A S S E S S M E N T S  
 
H E M A T O L O G Y ( bl o o d)  
S E R U M C H E MI S T R Y ( bl o o d)  
S E R U M R E N A L L A B S ( bl o o d) a n d  
U RI N A L Y SI S ( uri ne)  
C o m plete bl o o d c o u nt ( C B C)  
Platelet c o u nt  
W hite bl o o d cell ( W B C)  
c o u nt wit h differe ntial  
Ala ni ne a mi n otra nsa mi nase ( A L T; S G P T)  
Al b u mi n ( A L B)  
Al kali ne  p h os p hatase ( A L K -P)  
A m ylase  
As partate a mi n otra nsa mi nase  ( A S T; S G O T) 
T otal bilir u bi n  
Direct bilir u bi n  
I n direct bilir u bi n 
Calci u m ( Ca)  
Car b o n Di o xi de ( C O 2) 
C hl ori de ( Cl)  
T otal c h olester ol  
Creati ne ki nase ( C K)  
F ollicle -Sti m ulati n g H or m o ne ( F S H)  
Ga m ma -gl uta m yl tra nsferase  ( G G T) 
Gl uc ose  
Lactic de h y dr o ge nase ( L D H)  
Li pase  
Ma g nesi u m  
T otal pr otei n  
P h os p h or us  
P otassi u m ( K)  
S o di u m ( Na)  
Uric aci d  
Ser u m  
Bl o o d urea nitr o ge n ( B U N)  
Ser u m creati ni ne  
e G F R  
Uri ne  
Bilir u bi n  
Gl uc ose  
Ket o nes  
Nitrates  
Occ ult bl o o d  
Pr otei n  
S pecific gra vit y  
Ur o bili n o ge n  
p H  
Le u k oc ytes  
Micr osc o p y  
Creati ni ne  
U A C R  
Uri ne V ol u me  
 
C O A G U L A TI O N ( bl o o d)  
S E R O L O G Y S C R E E N ( bl o o d)  
U RI N E D R U G S C R E E N  
Pr ot hr o m bi n ti me test ( P T)  
P artial pr ot hr o m bi n ti me test 
(a P T T) 
I nter nati o nal n or malize d rati o 
(I N R) 
 
H u ma n i m m u n o deficie nc y vir us a nti b o d y  
( HI V-A b)  
He patitis B s urface a nti ge n   
( H Bs A g) 
He patitis C vir us a nti b o d y  
( H C V-A b)  
A m p heta mi nes/ met ha m p heta mi nes  
B ar bit urates  
B e nz o diaze pi nes *  
C ocai ne meta b olites  
Met ha d o ne  
P he nc ycli di ne  
O piates  
B R E A T H T E S T  
P R E G N A N C Y ( uri ne)  
Et h yl alc o h ol  
h C G  
* P ositi ve test at W ee k - 5 a n d W ee k - 3 all o we d if dr u g is prescri be d b y a p h ysicia n  
 
 

 
                                                                                                      
 
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A P P E N DI X C:   P O SI TI V E A N D N E G A TI V E S Y M P T O N S C A L E  (P A N S S ) 
 
 
 
 
P A N S S  R A T I N  G  F O R
M   
 
 
 
 
 
a bs e nt  
mi ni m al  
mil d  
m o derate  
m o derate 
severe 
s e v er e 
e xtr e m e  
P 1 
P 2 
P 3 
P 4 
P 5 
P 6  
P 7  
D el usi o ns  
C o nce pt ual dis or ga nisati o n 
H all u ci n at or y b e h a vi o ur 
E x cit e me nt  
Gr a n di osit y 
S us pici o us ness/ persec uti o n  
H ostilit y  
1 
1 
1 
1 
1 
2  
2  
2  
2  
2  
3  
3  
3  
3  
3  
4  
4  
4  
4  
4  
5  
5  
5  
5  
5  
6  
6  
6  
6  
6  
7  
7  
7  
7  
7  
1 
1 
2  
2  
3  
3  
4  
4  
5  
5  
6  
6  
7  
7  
N 1 
N 2  
N 3  
Bl u nt e d aff e ct 
E m oti o n al wit h dr a w al 
P o or r a p p ort  
P assi v e/ a p at h eti c s o ci al 
wit h dr a w al  
Diffic ult y i n a bstract thinking 
L a c k of s p o nt a n eit y & 
fl o w of c o n v ers ati o n 
St er e ot y p e d t hi n ki n g  
1 
1 
1 
2  
2  
2  
3  
3  
3  
4  
4  
4  
5  
5  
5  
6  
6  
6  
7  
7  
7  
N 4  
1 
2  
3  
4  
5  
6  
7  
N 5  
1 
2  
3  
4  
5  
6  
7  
N 6  
1 
2  
3  
4  
5  
6  
7  
N 7  
1 
2  
3  
4  
5  
6  
7  
G 1 
G 2 
G 3 
G 4 
G 5 
G 6 
G 7 
G 8 
G 9 
G 1 0 
G 1 1 
G 1 2 
G 1 3 
G 1 4 
G 1 5  
G 1 6  
S o mati c c o n c er n 
A n xi et y  
G uilt f e eli n gs 
T e nsi o n  
M a n n eris ms & p ost uri n g 
D e pr essi o n  
M ot or r et ar d ati o n 
U n c o o p er ati v e n ess 
U n us u al t h o u g ht c o nt e nt 
Dis ori e nt ati o n  
P o or att e nti o n  
Lac k  of  j u d ge me nt &  i nsi g ht 
Dist ur b a n c e of v oliti o n 
P o or i m p uls e c o ntr ol 
Pr e o c c u p ati o n  
A cti v e s o ci al a v oi d a n c e  
1 
1 
1 
1 
2  
2  
2  
2  
3  
3  
3  
3  
4  
4  
4  
4  
5  
5  
5  
5  
6  
6  
6  
6  
7  
7  
7  
7  
1 
1 
1 
2  
2  
2  
3  
3  
3  
4  
4  
4  
5  
5  
5  
6  
6  
6  
7  
7  
7  
1 
1 
1 
2  
2  
2  
3  
3  
3  
4  
4  
4  
5  
5  
5  
6  
6  
6  
7  
7  
7  
1 
1 
1 
2  
2  
2  
3  
3  
3  
4  
4  
4  
5  
5  
5  
6  
6  
6  
7  
7  
7  
1 
1 
1 
2  
2  
2  
3  
3  
3  
4  
4  
4  
5  
5  
5  
6  
6  
6  
7  
7  
7  

 
                                                                                                      
 
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A P P E N DI X D: C LI NI C A L G L O B A L I M P R E S SI O N ( C GI -S) S C O R E 
 
 
 
 
 
 
 
Cli nic al Gl o b al I m pressi o ns -Se verit y ( C GI -S)  
C o nsi deri n g y o ur t otal cli nical e x perie nce wit h t his pa rtic ular p o p ulati o n, h o w  
me ntall y  ill is t he patie nt at t his ti me? 
0 = N ot assesse d  
1 = N or mal, n ot ill at all  
2  = B or derli ne  me ntall y  ill 
3 = Mil dl y ill  
4 = M o deratel y ill  
5 = Mar ke dl y ill  
6 = Se verel y ill  
7 = A m o n g t he m ost e xtre mel y ill patie nts  
 
G uy W, e dit or. 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 gy. 1 9 7 6. R oc kvill e, M D, U. S. 
D e p art m e nt of H e alt h, E d uc ati o n, a n d W elf ar e.  

 
                                                                                                      
 
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A P P E N DI X F: S C HI Z O P H R E NI A Q U A LI T Y O F LI F E S C A L E ( S Q L S)  
 
 
 
S QL S  It e ms 
1. I lac k  t h e e n er g y t o d o t hi n gs  
2. I a m b ot h er e d b y m y s h a ki n g/tr e m bli n g.  
3. I f e el u nst e a d y w al ki n g.  
4. I f e el a n gr y.  
5. I a m tr o u bl e d b y a dr y m o ut h.  
6. I c a n’t b e b ot h er e d t o d o t hi n gs.  
7. I w orr y a b o ut m y f ut ur e. 
8. I f e el l o n el y.  
9. I f e el h o p el ess.  
1 0. M y m uscl es g et stiff.   
1 1. I f e el v er y j u m p y a n d e d g y   
1 2. I a m a bl e t o c arr y o ut m y d a y-t o-d a y acti viti es.   
1 3. I t a k e p art i n e nj o y a bl e acti viti es.  
1 4. I t a k e t hi n gs p e o pl e s a y t h e wr o n g w a y.  
1 5. I li k e t o pl a n a h e a d. 
1 6. I fin d it h ar d t o c o nc e ntr at e . 
1 7. I t e n d t o st a y at h o m e.  
1 8. I fi n d it diffic ult t o mix wit h p e o pl e.  
1 9. I f e el d o w n a n d d e pr ess e d. 
2 0. I fi n d t h at I c a n c o p e.  
2 1. M y visi o n is bl urr e d.  
2 2. I f e el v er y mix e d-u p a n d u ns ur e of m ys elf.   
2 3. M y sl e e p is dist u r b e d.  
2 4. M y f e eli n gs g o u p a n d d o w n.   
2 5. I g et m uscl e t witc h es.  
2 6. I a m c o nc er n e d t h at I w o n’t g et b ett er. 
2 7. I w orr y a b o ut t hi n gs.  
2 8. I f e el t h at p e o pl e t e n d t o a v oi d m e.   
2 9. I g et u ps et t hi n ki n g a b o ut t h e p ast.  
3 0. I g et dizz y s p ells.   

 
                                                                                                      
 
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A P P E N DI X G: SI M P S O N -A N G U S S C A L E  ( S A S) 
 
 
P ati e nt  N a m e:   
 
D at e:    
 
 
SI M P S O N -A N G U S E X T R A P Y R A MI D A L SI D E E F F E C T S S C A L E  
T h e e x a m s h o ul d b e c o n d u ct e d i n a r o o m w h er e t h e s u bj e ct c a n w al k a s uffi ci e nt di st a n c e t o all o w hi m/ h er t o g et i nt o a n at ur a l 
r h yt h m ( e. g. 1 5 p a c e s). E a c h si d e of t h e b o d y s h o ul d b e e x a mi n e d. If o n e si d e s h o w s m or e pr o n o u n c e d p at h ol o g y t h a n t h e 
ot h er, t hi s s c or e s h o ul d b e n ot e d a n d t hi s t a k e n. C o g w h e el ri gi dit y m a y b e p al p at e d w h e n t h e e x a mi n ati o n i s c arri e d o ut f or 
it e m s 3, 4, 5, a n d 6. It i s n ot r at e d s e p ar at el y a n d I s m er el y a n ot h er w a y t o d et e ct ri gi dit y.  It w o ul d i n di c at e t h at a mi nim u m 
s c or e of 1 w o ul d b e  m a n d at or y.  
 
1.  
G ait : T h e p ati e nt i s e x a mi n e d a s h e w al k s i nt o t h e 
e x a mi ni n g r o o m, hi s g ait, t h e s wi n g of hi s ar m s, hi s g e n er al 
p o st ur e, all f or m t h e b a si s f or a n o v er all s c or e f or t hi s it e m. 
T hi s i s r at e d a s  f oll o w s: 
0  
N or m al  
1  
Di mi n uti o n i n s w i n g w hil e t h e p ati e nt i s w al ki n g  
2  
M ar k e d di mi n uti o n i n s wi n g wit h o b vi o u s ri gi dit y i n t h e 
ar m  
3  
Stiff g ait wit h ar m s h el d ri gi dl y b ef or e t h e  a b d o m e n  
4  
St o o p e d s h uffli n g g ait wit h pr o p ul si o n a n d  r etr o p ul si o n 
 
2.  
Ar m Dr o p pi n g: T h e p ati e nt a n d t h e e x a mi n er b ot h r ai s e 
t h eir ar m s t o s h o ul d er h ei g ht a n d l et t h e m f all t o t h eir si d e s. 
I n a n or m al s u bj e ct, a st o ut sl a p i s h e ar d a s t h e ar m s hit  
t h e si d e s.  I n t h e p ati e nt wit h e xtr e m e P ar ki n s o n’ s 
s y n dr o m e, t h e ar m s f all v er y  sl o wl y:  
0  
N or m al, fr e e f all wit h l o u d sl a p a n d  r e b o u n d 
1  
F all sl o w e d sli g htl y wit h l e s s a u di bl e c o nt a ct a n d littl e 
r e b o u n d 
2  
F all sl o w e d, n o  r e b o u n d 
3  
M ar k e d sl o wi n g, n o sl a p at  all  
4  
Ar m s f all a s t h o u g h a g ai n st r e si st a n c e; a s t h o u g h 
t hr o u g h gl u e  
 
3.  
S h o ul d er S h a ki n g: T h e s u bj e ct’ s ar m s ar e b e nt at a ri g ht 
a n gl e at t h e el b o w a n d ar e t a k e n o n e at a ti m e b y t h e 
e x a mi n er w h o gr a s p s o n e h a n d a n d al s o cl a s p s t h e ot h er 
ar o u n d t h e p ati e nt’ s el b o w. T h e s u bj e ct’ s u p p er ar m i s 
p u s h e d t o a n d fr o a n d t h e h u m er u s i s e xt er n all y r ot at e d. 
T h e d e gr e e of r e si st a n c e fr o m n or m al t o e xtr e m e ri gi dit y i s 
s c or e d a s  f oll o w s: 
0  
N or m al  
1  
Sli g ht stiff n e s s a n d  r e si st a n c e 
2  
M o d er at e stiff n e s s a n d  r e si st a n c e 
3  
M ar k e d ri gi dit y wit h diffi c ult y i n p a s si v e  m o v e m e nt  
4  
E xtr e m e stiff n e s s a n d ri gi dit y wit h al m o st a fr o z e n 
s h o ul d er  
 
4.  
El b o w Ri gi dit y: T h e el b o w j oi nt s ar e s e p ar at el y b e nt at 
ri g ht a n gl e s a n d p a s si v el y e xt e n d e d a n d fl e x e d, wit h t h e 
s u bj e ct’ s bi c e p s o b s er v e d a n d si m ult a n e o u sl y p al p at e d. 
T h e r e si st a n c e t o t hi s pr o c e d ur e i s r at e d. ( T h e pr e s e n c e of 
c o g w h e el ri gi d it y i s n ot e d s e p ar at el y.)  
0  
N or m al  
1  
Sli g ht stiff n e s s a n d  r e si st a n c e 
2  
M o d er at e stiff n e s s a n d  r e si st a n c e 
3  
M ar k e d ri gi dit y wit h diffi c ult y i n p a s si v e  m o v e m e nt  
4  
E xtr e m e stiff n e s s a n d ri gi dit y wit h al m o st a fr o z e n  el b o w  
 
5.  
Wri st Ri gi dit y or Fi x ati o n of P o siti o n: T h e wri st i s h el d i n 
o n e h a n d a n d t h e fi n g er s h el d b y t h e e x a mi n er’ s ot h er h a n d, 
wit h t h e wri st m o v e d t o e xt e n si o n, fl e xi o n a n d ul n ar a n d r a di al 
d e vi ati o n:  
0  
N or m al  
1  
Sli g ht stiff n e s s a n d  r e si st a n c e 
2  
M o d er at e stiff n e s s a n d  r e si st a n c e 
3  
M ar k e d ri gi dit y wit h diffi c ult y i n p a s si v e  m o v e m e nt  
4  
E xtr e m e stiff n e s s a n d ri gi dit y wit h al m o st fr o z e n  wri st  
6.  
L e g P e n d ul o u s n e s s: T h e p ati e nt sit s o n a t a bl e wit h hi s 
l e g s h a n gi n g d o w n a n d s wi n gi n g fr e e. T h e a n kl e i s 
gr a s p e d b y t h e e x a mi n er a n d r ai s e d u ntil t h e k n e e i s 
p arti all y e xt e n d e d. It i s t h e n all o w e d t o f all.  T h e 
r e si st a n c e t o f alli n g a n d t h e l a c k of s wi n gi n g f or m t h e 
b a si s f or t h e s c or e o n t hi s  it e m: 
0  
T h e l e g s s wi n g  fr e el y 
1  
Sli g ht di mi n uti o n i n t h e s wi n g of t h e  l e g s 
2  
M o d er at e r e si st a n c e t o  s wi n g  
3  
M ar k e d r e si st a n c e a n d d a m pi n g of  s wi n g  
4  
C o m pl et e a b s e n c e of  s wi n g  
 
7.  
H e a d Dr o p pi n g: T h e p ati e nt li e s o n a w ell -p a d d e d 
e x a mi ni n g t a bl e a n d hi s h e a d i s r ai s e d b y t h e e x a mi n er’ s 
h a n d.  T h e h a n d i s t h e n wit h dr a w n a n d t h e h e a d all o w e d 
t o dr o p. I n t h e n or m al s u bj e ct t h e h e a d will f all u p o n t h e 
t a bl e.  T h e m o v e m e nt i s d el a y e d i n e xtr a p yr a mi d al  
s y st e m di s or d er, a n d i n e xtr e m e p ar ki n s o ni s m it i s a b s e nt. 
T h e n e c k m u s cl e s ar e ri gi d a n d t h e h e a d d o e s n ot r e a c h 
t h e e x a mi ni n g t a bl e.  S c ori n g i s a s f oll o w s: 
0  
T h e h e a d f all s c o m pl et el y wit h a g o o d t h u m p a s it 
hit s t h e  t a bl e 
1  
Sli g ht sl o wi n g i n f all, m ai nl y n ot e d b y l a c k of sl a p a s 
h e a d m e et s t h e  t a bl e 
2  
M o d er at e sl o wi n g i n t h e f all q uit e n oti c e a bl e t o t h e 
e y e  
3  
H e a d f all s stiffl y a n d  sl o wl y  
4  
H e a d d o e s n ot r e a c h t h e e x a mi ni n g  t a bl e 
 
8.  
Gl a b ell a T a p : S u bj e ct i s t ol d t o o p e n e y e s wi d e a n d n ot 
t o bli n k.  T h e gl a b ell a r e gi o n i s t a p p e d at a st e a d y,  
r a pi d s p e e d. T h e n u m b er of ti m e s p ati e nt bli n k s i n 
s u c c e s si o n i s n ot e d:  
0  
0 -5  bli n k s  
1  
6 -1 0  bli n k s  
2  
1 1 -1 5  bli n k s  
3  
1 6 -2 0  bli n k s  
4  
2 1 a n d m or e  bli n k s  
 
9.  
Tr e m or: P ati e nt i s o b s er v e d w al ki n g i nt o e x a mi ni n g 
r o o m a n d i s t h e n r e e x a mi n e d f or t hi s it e m: 
0  
N or m al  
1  
Mil d fi n g er tr e m or, o b vi o u s t o si g ht a n d  t o u c h 
2  
Tr e m or of h a n d or ar m o c c urri n g  s p a s m o di c all y  
3  
P er si st e nt tr e m or of o n e or m or e  li m b s 
4  
W h ol e b o d y  tr e m or 
 
1 0.  S ali v ati o n: P ati e nt i s o b s er v e d w hil e t al ki n g a n d t h e n 
a s k e d t o o p e n hi s m o ut h a n d el e v at e hi s t o n g u e. T h e 
f oll o wi n g r ati n g s ar e gi v e n:  
0  
N or m al  
1  
E x c e s s s ali v ati o n t o t h e e xt e nt t h at p o oli n g t a k e s 
pl a c e if t h e m o ut h i s o p e n a n d t h e t o n g u e  r ai s e d 
2  
W h e n e x c e s s s ali v ati o n i s  pr e s e nt a n d mi g ht 
o c c a si o n all y r e s ult i n diffi c ult y  s p e a ki n g  
3  
S p e a ki n g wit h diffi c ult y b e c a u s e of e x c e s s  s ali v ati o n  
4  
Fr a n k  dr o oli n g  

 
                                                                                                      
 
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A P P E N DI X H: A B N O R M A L I N V O L U T A R Y  M O V E M E N T S C A L E ( AI M S)  
 
 
A B N O R M A L I N V O L U N T A R Y M O V E M E N T S C A L E ( AI M S)  
 
 
P u blic  H e alt h  Ser vic e  
N A M E:   
 
Alc o h ol, Dr u g A b use, a n d M e ntal  H e alt h  A d mi nistr ati o n  
D A T E:    
 
N ati o nal I nstit ute of  M e ntal  H e alt h  
P r esc ri bi n g  P r a ctiti o ne r:    
 
 
 
 
I N S T R U C TI O N S: 
C O D E:  0 = N o ne  
1 = Mi ni mal, ma y b e e xtr e me n or mal 
2 = Mil d  
C o m plet e E x a mi n ati o n P r o c e d ur e ( att a c h me nt d.) 
bef o r e m a ki n g r ati n gs  
 
3 = M o d er ate  
4 - Se ver e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fi nal: 9/ 2 0 0 0  
M O V E M E N T R A TI N G S: R ate hi g hest se verit y o bser ve d. Rate 
m o ve me nts t hat o c c ur u p o n a cti vati o n o ne less t ha n t h ose o bser ve d 
s p o nta ne o usl y. Cir cle m o ve m e nt as well as c o d e n u m b er t hat 
a p plies.  
R A T E R  
 
D ate  
R A T E R  
 
D ate  
R A T E R  
 
D ate  
R A T E R  
 
D ate  
Fa cial a n d 
Or al 
M o v e me nts  
1.  M uscles of F a ci al  E x pr essi o n  
e. g. m o ve me nts of f or e he a d, e ye br o ws 
p eri or bital ar e a, c he e ks, i ncl u di n g fr o w ni n g 
bli n ki n g, s mili n g, gri ma ci n g  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
2.  Li ps a n d P e ri o r al  A r e a  
e. g., p uc keri n g, p o uti n g, s ma c ki n g  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3  4  
3.  J a w e. g. biti n g, cle nc hi n g,  c he wi n g,  m o ut h  
o p e ni n g, later al  m o ve me nt  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
4.  T o n g ue Rate o nl y i ncr e ases  i n m o ve me nt  
b ot h i n a n d o ut of m o ut h. N O T i na bilit y t o 
s ustai n m o ve me nt. D arti n g i n a n d o ut of 
m o ut h.  
 
0  1  2  3 4  
 
0  1  2  3 4  
 
0  1  2  3  4  
 
O  1  2  3 4  
 
 
E xt r e mit y 
M o ve me nts  
5.  U p pe r ( a r ms, w rists,,  h a n ds,  fi n g e rs) 
I ncl u d e c h or eic m o ve me nts (i. e., r a pi d, 
o bj e cti vel y p ur p oseless, irr e g ular, 
s p o nta ne o us) at het oi d m o ve m e nts (i. e., sl o w, 
irr e g ular, c o m ple x, ser p e nti ne). D O N O T 
I N C L U D E T R E M O R (i. e., r e p etiti ve, 
r e g ular, r h yt h mic) 
 
 
0  1  2  3 4  
 
 
0  1  2  3 4  
 
 
0  1  2  3  4  
 
 
0  1  2  3 4  
6.  L o w e r (le gs, k ne es, a n kles,  t o es) 
e. g., later al k ne e m o ve me nt, f o ot ta p pi n g, 
he el dr o p pi n g, f o ot s q uir mi n g, i n versi o n a n d 
e versi o n of f o ot.  
 
 
0  1  2  3 4  
 
 
0  1  2  3 4  
 
 
0  1  2  3  4  
 
 
0  1  2  3 4  
Tr u n k 
M o ve me nts  
7.  N e c k, s h o ul de rs, hi ps  e. g.,  r o c ki n g, 
t wisti n g, s q uir mi n g, p el vic g yr ati o ns  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
 
Gl o b al 
J u d g me nts  
8.  Se v e rit y of a b n o r m al m o v e me nts  o v e r all  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
9.  I nc a p a cit ati o n d ue t o a b n o r m al  
m o v e me nts  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
0  1  2  3 4  
1 0. P atie nt’s a w a r e ness of a b n o r m al 
m o v e me nts. Rate o nl y p atie nt’s r e p ort 
N o  a war e ness  
0  
A war e,  n o  distr ess  
1  
A war e,  mil d  distr ess  
2  
A war e,  m o d er ate  distr ess  
3  
A war e,  se ver e distr ess  
4  
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
 
D e nt al St at us  
1 1. C ur r e nt pr o ble ms wit h t e et h a n d/ o r 
de nt ur es  
 
N o  
Yes  
 
N o  
Y es  
 
N o  
Y es  
 
N o  
Yes  
 
1 2.  A r e de nt ur es us u all y w or n ?  
N o  
Yes  
N o  
Y es  
N o  
Y es  
N o  
Yes  
 
1 3.  E de nti a ?  
N o  
Yes  
N o  
Y es  
N o  
Y es  
N o  
Yes  
 
 
1 4.  D o m o v e me nts dis a p pe a r i n sle e p ?  
N o  
Yes  
N o  
Y es  
N o  
Y es  
N o  
Yes  
 

 
                                                                                                      
 
1 4 A pril 2 0 2 0   
Pr ot oc ol C P 6 9 2. 2 0 0 1                                                                        C o ncert P har mace uticals, I n c.                          
 
8 7 
 
 
  
 
 
A P P E N DI X I: B A R N E S A K A T HI SI A R A TI N G S C A L E ( B A R S)  
 
 
P ati e nt  n a me:  
D at e of  ass ess me nt:  
 
P ati e nt  I D: 
Ass ess o r:  
 
B A R N E S A K A T HI SI A R A TI N G S C A L E  
 
B ar n es T R ( 1 9 8 9) A r ati n g s cal e f or dr u g -i n d u c e d a k at hisi a. Britis h J o ur n al of Psy c hi atry 1 5 4: 6 7 2 – 6 7 6  
 
1.  O bj e cti v e  
S C O R E:    
 
 
0.  
N or mal, o c c asi o n al fi d g et y m o v e me nts of  li m bs. 
1.  
Pr es e n c e of c h ar a ct eristi c r estl ess m o v e m e nts: s h uffli n g or tr a m pi n g m o v e m e nts of t h e l e gs/f e et 
or s wi n gi n g of o n e l e g  w hil e  sitti n g, a n d/ or r o c ki n g fr o m f o ot t o f o ot or ‘ wal ki n g o n t h e s p ot’ 
w h e n st a n di n g, b ut m o v e m e nts pr es e nt f or l ess t h a n h alf t h e ti me  o bs er v e d.  
2.  
O bs er v e d p h e n o me n a, as d es cri b e d i n ( 1) a b o v e, w hi c h ar e pr es e nt f or at l e ast h alf t h e o bs er v ati o n  
p eri o d.  
3.  
P ati e nt  is  c o nst a ntl y  e n g a g e d  i n  c h ar a ct eristi c  r estl ess  m o v e me nts, a n d/ or h as  t h e  i n a bilit y  t o 
r e mai n s e at e d or st a n di n g wit h o ut wal ki n g or p a ci n g, d uri n g t h e ti m e o bs er v e d.  
 
 
2.  S u bj e cti v e: A w a r e n ess  of  r estl ess n ess  
S C O R E:    
 
 
0.  
A bs e n c e of i n n er  r estl ess n ess. 
1.  
N o n -s p e cifi c s e ns e of i n n er r estl ess n ess. 
2.  
P ati e nt is a war e of a n i n a bilit y t o  k e e p  t h e  l e gs still,  or  a  d esir e  t o  m o v e  t h e  l e gs,     a n d/ or  
c o m pl ai ns of i n n er r estl es s n ess a g gr a v at e d s p e cifi c all y b y b ei n g r e q uir e d t o st a n d still.  
3.  
A war e n ess of a n i nt e ns e c o m p ulsi o n t o m o v e m ost of t h e ti m e a n d/ or r e p orts a str o n g d esir e t o 
wal k or p a c e m ost of t h e  ti m e. 
 
 
3.  S u bj e cti v e: Dist r ess r el at e d  t o r estl ess n ess  
S C O R E:    
 
 
0.  
N o  distr ess.  
1.  
Mil d.  
2.  
M o d er at e.  
3.  
S e v er e.  
 
 
4.  Gl o b al cli ni c al ass ess me nt  of  a k at hisi a  
S C O R E:    
 
 
0.  
A bs e nt.   
N o e vi d e n c e of a war e n ess of r estl ess n ess. O bs er v ati o n of c h ar a ct eristi c m o v e m e nts of 
a k at hisi a i n t h e a bs e n c e of a s u bj e cti v e r e p ort of i n n er r estl ess n ess or c o m p ulsi v e d esir e 
t o m o v e t h e l e gs s h o ul d b e cl assifi e d as ps e u d o a k at hisi a. 
1.  
Q u esti o n a bl e.  
N o n -s p e cifi c i n n er t e nsi o n a n d fi d g et y m o v e me nts. 
2.  
Mil d  a k at hisi a.  
A war e n ess of r estl ess n ess i n t h e l e gs a n d/ or i n n er r estl ess n ess w ors e w h e n r e q uir e d t o 
st a n d still. Fi d g et y m o v e m e nts pr es e nt, b ut c h ar a ct eristi c r estl ess m o v e m e nts of a k at hisi a 
n ot n e c ess aril y o bs er v e d. C o n diti o n c a us es littl e or n o distr ess.  
3.  
M o d er at e  a k at hisi a.  
A war e n ess  of  r estl ess n ess  as  d es cri b e d  f or  mil d  a k at hisi a  a b o v e,  c o m bi n e d  wit h 
c h ar a ct eristi c  r estl ess  m o v e m e nts  s u c h  as  r o c ki n g  fr o m  f o ot  t o  f o ot  w h e n  st a n di n g. 
P ati e nt fi n ds t h e c o n diti o n distr essi n g.  
4.  
M ar k e d  a k at hisi a.  
S u bj e cti v e  e x p eri e n c e  of  r estl ess n ess  i n cl u d es  a  c o m p ulsi v e  d esir e  t o  wa l k  or  p a c e. 
H o we v er, t h e p ati e nt is a bl e t o r e mai n s e at e d f or at l e ast fi v e mi n ut es. T h e c o n diti o n is 
o b vi o usl y distr essi n g.  
5.  
S e v er e  a k at hisi a.  
T h e p ati e nt r e p orts a str o n g c o m p ulsi o n t o p a c e u p a n d d o w n m ost of t h e ti m e. U n a bl e t o 
sit or li e d o w n f or m or e t h a n a f e w  mi n ut es. C o nst a nt r estl ess n ess  w hi c h is ass o ci at e d 
wit h i nt e ns e distr ess a n d i ns o m ni a.  
 
( e n d) 

 
                                                                                                      
 
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8 8 
 
 
  
 
 
A P P E N DI X J: C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E  
( C-S S R S) B A S E LI N E/ S C R E E NI N G V E R SI O N  
 
 
C O L U M BI A -S UI CI D E S E V E RI T Y 
R A TI N G S C A L E  
( C-S S R S)  
Baseli ne/ Scree ni n g Versi o n  
 
Versi o n 1/ 1 4/ 0 9  
 
 
 
P os ner, K.; Bre nt, D.; L uc as, C.; G o ul d, M.; St a nley, B.; Br o w n, G.; Fis her, P.; Zel az ny, J.; B ur ke, 
A.; O q ue n d o, M.; M a n n, J.  
 
Discl ai mer:  
 
T his sc ale is i nte n de d to be use d by i n divi d u als w ho h ave receive d tr ai ni ng i n its a d mi nistr atio n. T he q uestio ns co nt ai ne d i n  t he 
Col u m bi a -S uici de Severity R ati ng Sc ale are s uggeste d pro bes. Ulti m ately, t he deter mi n atio n of t he prese nce of s uici d al i de atio n 
or be h avior de pe n ds o n t he j u dg me nt of t he i n divi d u al a d mi nisteri ng t he sc ale.  
 
 
 
 
Defi nitio ns of be h avior al s uici d al eve nts i n t his sc ale are b ase d o n t hose use d i n T h e C ol u m bi a S ui ci d e Hist or y F or m , 
develo pe d by Jo h n M a n n, M D a n d M ari a O q ue n do, M D, Co nte Ce nter for t he Ne uroscie nce of Me nt al Disor ders ( C C N M D), 
Ne w York St ate Psyc hi atric I nstit ute, 1 0 5 1 Riversi de Drive, Ne w York, N Y, 1 0 0 3 2. ( O q ue n do M. A., H al berst a m B. & M a n n J. 
J., Risk f actors for suici d al be h avior: utility a n d li mit atio ns of rese arc h i nstr u me nts. I n M. B. First [ E d.] Sta n dar diz e d Eval uati o n 
i n Cli nical Practic e, p p. 1 0 3 -1 3 0, 2 0 0 3.)  
 
 
For re pri nts of t he C-S S R S co nt act Kelly Pos ner, P h. D., Ne w York St ate Psyc hi atric I nstit ute, 1 0 5 1 R iversi de Drive, Ne w York, 
Ne w York, 1 0 0 3 2; i n q uiries a n d tr ai ni ng re q uire me nts co nt act pos nerk @ nys pi.col u m bi a.e d u  
 
© 2 0 0 8 T h e R es earc h F o u n dati o n f or M e ntal Hygi e n e, I nc.  

 
                                                                                                      
 
1 4 A pril 2 0 2 0   
Pr ot oc ol C P 6 9 2. 2 0 0 1                                                                        C o ncert P har mace uticals, I n c.                          
 
9 1 
 
 
  
 
 
A P P E N DI X K: C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E  
( C-S S R S) SI N C E L A S T VI SI T  
 
 
 
 
C O L U M BI A -S UI CI D E S E V E RI T Y 
R A TI N G S C A L E  
( C-S S R S)  
Si nce Last Visit  
 
Versi o n 1/ 1 4/ 0 9  
 
 
 
P os ner, K.; Bre nt, D.; L uc as, C.; G o ul d, M.; St a nley, B.; Br o w n, G.; Fis her, P.; Zel az ny, J.; 
B ur ke, A.; O q ue n d o, M.; M a n n, J.  
 
 
 
Discl ai mer:  
 
T his sc ale is i nte n de d to be use d by i n divi d u als w ho h ave receive d tr ai ni ng i n its a d mi nistr atio n. T he q uestio ns co nt ai ne d i n 
t he Col u m bi a-S uici de Severity R ati ng Sc ale are s uggeste d pro bes. Ulti m ately, t he deter mi n atio n of t he prese nce of s uici d al 
i de ation or be h avior de pe n ds o n t he j u dg me nt of t he i n divi d u al a d mi nisteri ng t he sc ale.  
 
 
 
 
Defi nitio ns of be h avior al s uici d al eve nts i n t his sc ale are b ase d o n t hose use d i n T h e C ol u m bi a S ui ci d e Hist or y F or m , 
develo pe d by Jo h n M a n n, M D a n d M ari a O q ue n do, M D, Co n te Ce nter for t he Ne uroscie nce of Me nt al Disor ders ( C C N M D), 
Ne w Yor k St ate Psyc hi atric I nstit ute, 1 0 5 1 Riversi de Drive, Ne w Yor k, N Y, 1 0 0 3 2. ( O q ue n do M. A., H al berst a m B. & M a n n J. 
J., Ris k f actors for s uici d al be h avior: utility a n d li mit atio ns of rese arc h i nstr u me nts. I n M. B. First [ E d.] Sta n dar diz e d Eval uati o n 
i n Cli nical Practic e, p p. 1 0 3 -1 3 0, 2 0 0 3.)  
 
 
For re pri nts of t he C-S S R S co nt act Kelly Pos ner, P h. D., Ne w Yor k St ate Psyc hi atric I nstit ute, 1 0 5 1 Riversi de Drive, Ne w 
Yor k, Ne w Yor k, 1 0 0 3 2; i n q uiries a n d tr ai ni ng re q uire me nts co nt act pos ner k @ nys pi.col u m bi a.e d u  
 
© 2 0 0 8 T h e R es earc h F o u n dati o n f or M e ntal Hygi e n e, I nc.  

 
                                                                                                      
 
1 4 A pril 2 0 2 0   
Pr ot oc ol C P 6 9 2. 2 0 0 1                                                                        C o ncert P har mace uticals, I n c.                          
 
9 4 
 
 
  
 
 
A P P E N DI X L: MI NI I N T E R N A TI O N A L N E U R O P S Y C HI A T RI C 
I N T E R VI E W 
 

 
                                                                                                      
 
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9 5 
 
 
  
 
 
 

 
                                                                                                      
 
1 4 A pril 2 0 2 0   
Pr ot oc ol C P 6 9 2. 2 0 0 1                                                                        C o ncert P har mace uticals, I n c.                          
 
9 6 
 
 
  
 
 
 

 
                                                                                                      
 
1 4 A pril 2 0 2 0   
Pr ot oc ol C P 6 9 2. 2 0 0 1                                                                        C o ncert P har mace uticals, I n c.                          
 
9 7 
 
 
  
 
 
 

C P 6 9 2. 2 0 0 1 A me n d me nt # 1    
  
  
  
  
  
1 6 Oct o ber 2 0 1 9 
C o ncert P h ar m ace utic als, I nc.  
C P 6 9 2. 2 0 0 1  
A 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 E v al u ate t he 
S afet y a n d Effic ac y of C T P -6 9 2 as a n A dj u ncti ve Tre at me nt i n  
A d ult P atie nts wit h Sc hiz o p hre ni a   
Pr ot o c ol A me n d m e nt # 1 , 1 6 Oct o b er 2 0 1 9  
S u m m ar y of C h a n ges  
T his a me n d me nt i ncl u d es t he f oll o wi n g c ha n ges t o t he C P 6 9 2. 2 0 0 1 pr ot oc ol:  
S e cti o n (s) 
C h a n g e  
R e as o n  
S y n o psis  a n d Secti o n 
9. 2, E x cl usi o n 
Criteria # 1 6  
 
C ha n ge d w or di n g fr o m “ P ositi ve 
alc o h ol bre at h test at t h e 
Scre e ni n g/ Q ualific ati o n Visit 
( We e ks -5, -3)” t o “ P ositi ve alc o h ol 
bre at h test .” 
 
C ha n ge d N ote bel o w E xcl usi o n 
Criteria #  1 6 fr o m “ A r e pe at alc o h ol 
bre at h test will be all o w e d wit hi n 4 8 
h o urs of t h e first test ” t o “ A re pe at 
alc o h ol bre at h test will be all o we d 
wit hi n 4 8 h o urs of t h e first test o nl y  
at t he first S cre e ni n g Visit ( We e k -
5) .”  
T o clarif y t hat s u bje cts wit h 
p ositi ve alc o h ol test d uri n g 
Scre e ni n g Peri o d a n d D a y 1 
will be e xcl u de d.  
 
 
T o clarif y t hat a re pe at test 
is all o we d o nl y at t he first 
Scre e ni n g Visit at We e k -5.  
S y n o psis, Criteria 
f or E val uati o n a n d 
Se cti o n 6, St u d y 
O bje cti ves  
C ha n ge d “ Me as ures” t o “ E n d p oi nts” 
a n d a d de d a d diti o nal details t o 
E x pl orat or y E n d p oi nts.  
T o clarif y all e n d p oi nts 
bei n g assesse d i n t he st u d y 
a n d t o ke e p c o nsiste nt wit h 
Se cti o n 1 3. 2.  
Ta ble 6, Sc he d ule of 
Assess me nts  
A d de d F S H assess me nt al o n g wit h 
Ser ol o g y a n d f o ot n ote “ F S H test f or 
p ost -me n o pa usal w o me n o nl y .” 
 
A d de d f o ot n ote “ Patie nts m ust si g n 
t he o pti o nal ge netic bl o o d sa m ple 
ge netic rese arc h c o nse nt f or m .”  
T o clarif y F S H assess me nt 
at first Scre e ni n g Visit o nl y 
a n d re q uire me nts pri or t o 
assess me nts  bei n g 
c o n d ucte d. 
Se cti o n 8 . 2. 2, 
pr oc e d ures 
perf or me d We e k 2 
t h r o u g h We e k 1 2 
Alc o h ol bre at h test: “ P atie nt will  b e 
disc o nti n u e d if t h ey test p ositi ve at 
a n y t w o visits d uri n g t h e tre at me nt 
peri o d ” c ha n ge d t o “ P atie nt m a y  b e 
disc o nti n u e d if t h ey test p ositi ve at 
a n y t w o visits d uri n g t h e tre at me nt 
peri o d ” 
 
T o all o w f or 
I n vesti gat or/ Me dic al 
M o nit or/ S p o ns or disc ussi o n 
a n d discreti o n pri or t o 
disc o nti n ui n g patie nt  

S e cti o n(s)  
C h a n g e  
R e as o n  
Se cti o n 1 2. 3. 8, 
Re p orti n g Seri o us 
A d verse E ve nts  
A d de d a d diti o nal E mer ge nc y C o ntact 
I nf or mati o n 
T o pr o vi de m ore o pti o ns 
f or Re p orti n g of Seri o us 
A d verse E ve nts  
Se cti o n 1 3. 4. 2, 
Effic a c y a nal yses  
Delete d “T h e perce nta ge of 
res p o n ders will be esti mate d at Wee k 
1 2 base d o n perce nt c h a n ge i n t he 
P A N N S t otal sc ore fr o m Baseli ne t o 
Wee k 1 2.  F o ur d efi niti o ns of a 
res p o n der will be s u m marize d: ≥2 0 %, 
≥3 0 %, ≥4 0 %, a n d ≥5 0 % decrease 
fr o m Bas eli ne.  T he differe nce 
bet wee n eac h C T P - 6 9 2 gr o u p a n d t he 
place b o gr o u p will be assesse d wit h 
t he c hi-s q uare test.” 
 
Res p o n der a nal ysis n ot 
pla n ne d a n d t his se cti o n 
was i na d verte ntl y i nsert e d 
i n t he pr ot oc ol. 
Se cti o n 1 3. 4. 3, 
St u d y Me dic ati o n 
C o m plia nc e  
C ha n ge d Se cti o n title fr o m “ St u d y 
Me dic ati o n E x p os ure a n d 
C o m plia nc e ” t o St u d y Me dic ati o n 
C o m plia nc e ”  
T o clarif y t hat t his se cti o n 
refers t o a nal ysis of da ys of 
St u d y Me dic ati o n 
a d mi nistrati o n a n d n ot 
bl o o d le vels of St u d y 
Me dic ati o n  
Se cti o n 1 7, List of 
Refere nces  
A d de d refere nc e f or C T P -6 9 2 
I n vesti gat or’s Br oc h ure. 
C T P -6 9 2 I n vesti gat or’s 
Br oc h ure has be e n referre d 
t o i n t he mai n te xt of t h e 
pr ot oc ol.  
A p pe n di x E  
Re pla c e d P S P W or ks he et  
T o pr o vi de versi o n wit h 
sc ori n g g ui deli nes   
 
A d diti o nal a d mi nistrati ve e dits were als o ma de f or clarit y.  
 
 
 
 

C P 6 9 2. 2 0 0 1 A me n d me nt # 2    
  
  
  
  
  
1 1 Fe br u ary 2 0 2 0 
C o ncert P h ar m ace utic als, I nc.  
C P 6 9 2. 2 0 0 1  
A 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 E v al u ate t he 
S afet y a n d Effic ac y of C T P -6 9 2 as a n A dj u ncti ve Tre at me nt i n  
A d ult P atie nts wit h Sc hiz o p hre ni a   
Pr ot o c ol A me n d m e nt # 2 , 1 1  F e br u a r y 2 0 2 0  
S u m m ar y of C h a n ges  
T his a me n d me nt i ncl u d es t he f oll o wi n g c ha n ges t o t he C P 6 9 2. 2 0 0 1 pr ot oc ol:  
S e cti o n (s) 
C h a n g e  
R e as o n  
S y n o psis , St u d y 
Desi g n  M et h o d ol o g y, 
a n d Secti o n 7. 1, 
O verall St u d y Desi g n   
 
St u d y partici pati o n e xte n de d fr o m 
1 8 we e ks t o u p t o 2 0 we e ks.  
A d de d e xte nsi o n of Q ualific ati o n 
Peri o d f or u p t o 2 we e ks.  
 
A d de d f o ot n ote t o St u d y Desi g n 
sc he matic. 
T o all o w f or re pe at 
la b orat or y testi n g f or 
c o nfir mati o n of eli gi bilit y .   
S y n o psis a n d Secti o n 
9. 1, I n cl usi o n Criteria 
# 9 
P ost -me n o pa usal fe male defi ne d as 
t h ose w h o ha ve ha d a m e n orr he a f or 
at le ast 1-ye ar (f or i ncl usi o n i n t he 
st u d y) a n d F ollicle-Sti m ulati n g 
H or m o ne ( F S H) le vel gre ater t ha n 
4 0 mI U/ m L.  
 
Re m o ve d “ estra di ol le v el less t ha n 
3 0 p g/ m L”.  
Pre vi o us versi o ns of t he 
pr ot oc ol defi ne d p ost -
me n o pa usal fe males as 
t h ose w h o ha d a me n orr he a 
f or at le ast 2 ye ars (f or 
i ncl usi o n i n t he st u d y) 
w hic h is i nc o nsiste nt wit h 
t he I C F w hic h states: 
“ p ost me n o pa usal is defi ne d 
as t he per ma ne nt c essati o n 
of me nstr uati o n f or at le ast 
1 2 m o nt hs ” 
 
Estra di ol le vel re q uire me nt 
re m o ve d as estra di ol le v el 
is n ot bei n g me as ure d at 
Scre e ni n g.  
Se cti o n 8, Ta ble 6, 
Sc he d ule of 
Assess me nts  
Re m o ve d “ X” f or A P bl o o d sa m ple 
c olle cti o n at We e ks 2, 6 a n d 1 2  
Data n ot re q uire d f or st u d y 
e n d-p oi nt a nal ysis  
Secti o n 8. 2. 1, 
Scree ni n g Peri o d 
Pr oce d ures at Wee k - 3 
A d de d e xte nsi o n of Q ualific ati o n 
Peri o d f or u p t o 2 we e ks.  
 
T o all o w f or re pe at 
la b orat or y testi n g f or 
c o nfir mati o n of eli gi bilit y .   

Se cti o n 8. 2. 2, 
pr oc e d ures 
perf or me d We e k 2 
t h r o u g h We e k 1 2 
Re m o ve d  A P bl o o d sa m ple 
c olle cti o n at We e ks 2, 6 a n d 1 2  
Data n ot re q uire d f or st u d y 
e n d-p oi nt a nal ysis  
Se cti o n 9. 3, Patie nt 
Wit h dra wal Criteria  
A d de d patie nt wit h dra w al criteria if 
t he y: 
•  E x hi bit s uici dal be ha vi or as 
deter mi ne d b y  a n affir m ati ve 
a ns wer o n ite ms 4  or 5 o n t he  
C- S S R S  
Re q ueste d b y F D A  
Se cti o n 1 1. 1, 
U nsc he d ule d Visit  
A d de d: A n U nsc he d ule d Visit ma y 
als o be c o n d ucte d t o a c c o m m o date 
re pe at testi n g of n o n-safet y relate d 
la b orat or y assess me nts. 
T o all o w f or re pe at testi n g 
of n o n -safet y relate d 
la b orat or y para meters. 
 
A d diti o nal a d mi nistrati ve e dits were als o ma de f or clarit y.