Clinical trial NCT04158687
Conditions: Schizophrenia
Sponsor: Concert Pharmaceuticals
Start date: 2019-11-26; Completion date: 2020-12-22
Enrollment: 326 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to assess the safety and efficacy of 3 different doses of CTP-692 administered once daily (QD) for 12 weeks to adult participants with schizophrenia on stable dopaminergic antipsychotic medication.

Detailed description:

Arms: arm 1: Participants received CTP-692 matched-placebo powder for oral solution, once daily (QD) for up to 12 weeks. arm 2: Participants received CTP-692 1 gram powder for oral solution, QD for up to 12 weeks. arm 3: Participants received CTP-692 2 grams powder for oral solution, QD for up to 12 weeks. arm 4: Participants received CTP-692 4 grams powder for oral solution, QD for up to 12 weeks.
Interventions: intervention 1: CTP-692 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as powder for oral solution. intervention 2: Administered as powder for oral solution.

Protocol documents:
Prot_000.pdf: 


 
 
 
                                                                                       
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1 
 
 
  
 
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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7 7 
 
 
  
 
 
1 8.  
A P P E N DI C E S  


 
                                                                                                      
 
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7 8 
 
 
  
 
 
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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7 9 
 
 
  
 
 
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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8 0 
 
 
  
 
 
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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8 4 
 
 
  
 
 
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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8 5 
 
 
  
 
 
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  


 
                                                                                                      
 
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 6 
 
 
  
 
 
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   
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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) 


 
                                                                                                      
 
1 4 A pril 2 0 2 0   
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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 
 


 
                                                                                                      
 
1 4 A pril 2 0 2 0   
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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   
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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.  
 

SAP_001.pdf: 


Concert Pharmaceuticals, Inc. 
 PROTOCOL CP692.2001 
STATISTICAL ANALYSIS PLAN 
PROTOCOL: CP692.2001 
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
SPONSOR: 
Concert Pharmaceuticals, Inc. 
65 Hayden Avenue, Suite 3000N 
Lexington, MA 02421 
PRODUCT : 
CTP-692 
AUTHORS: 
 Ph.D. 
 MS 
 
 Ph.D. 
DATE: 
2 December 2020 
STATUS: 
Final Version 1.0 




Concert Pharmaceuticals, Inc. 
PROTOCOL CP692.2001 
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
Page | 3 
TABLE OF CONTENTS 
AMEMDMENT HISTORY ..................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................. 6 
1 INTRODUCTION ............................................................................................. 9 
2 Study Objectives............................................................................................ 9 
2.1 Primary Efficacy Endpoint ................................................................................... 9 
2.2 Secondary Efficacy Endpoints............................................................................. 9 
2.3 Exploratory Endpoints ......................................................................................... 9 
2.4 Safety Measures ................................................................................................. 10 
3 Study Design ................................................................................................ 10 
3.1 Duration of Study ................................................................................................ 10 
3.2 Number of Participants (Study Population) ...................................................... 10 
3.3 Design ................................................................................................................. 10 
3.3.1 
Schedule of Assessments ................................................................................................. 12 
3.4 Treatment ............................................................................................................ 15 
3.5 Randomization and Blinding .............................................................................. 15 
3.6 COVID-19 Considerations .................................................................................. 15 
3.6.1 
Screening Period Procedures............................................................................................ 15 
3.6.2 
Laboratory Blood Draws, Safety, and Efficacy Assessments ........................................... 15 
3.6.3 
ECG Assessments ............................................................................................................ 15 
3.6.4 
Safety Follow-Up Visit ....................................................................................................... 16 
4 OUTCOME VARIABLE DEFINITIONS ......................................................... 16 
4.1 Demographic Characteristics ............................................................................ 16 
4.2 Screening, Qualification, and Baseline Characteristics ................................... 16 
4.3 Efficacy Assessments ........................................................................................ 16 
4.3.1 
Positive and Negative Syndrome Scale (PANSS)............................................................. 16 
4.3.2 
Clinical Global Impression-Severity (CGI-S) Score ........................................................... 17 
4.3.3 
Personal and Social Performance Scale (PSP) ................................................................ 17 
4.3.4 
Schizophrenia Quality of Life Scale (SQLS) ...................................................................... 17 
4.4 Efficacy Endpoints.............................................................................................. 17 
4.4.1 
Primary Endpoints ............................................................................................................. 17 
4.4.2 
Secondary Endpoints ........................................................................................................ 17 
4.4.3 
Exploratory Endpoints ....................................................................................................... 17 
4.5 Safety and Tolerability Assessments ................................................................ 18 
4.5.1 
Adverse Events ................................................................................................................. 18 
4.5.2 
Columbia Suicide Severity Rating Scale ........................................................................... 19 
4.5.3 
Laboratory Safety Assessments ........................................................................................ 19 
4.5.4 
Vital Signs .......................................................................................................................... 20 
4.5.5 
Electrocardiogram ............................................................................................................. 20 
4.5.6 
Physical Examination ........................................................................................................ 20 
4.6 Extrapyramidal Symptoms ................................................................................. 20 
4.6.1 
Simpson-Angus Scale (SAS) ............................................................................................. 20 
4.6.2 
Abnormal Involuntary Movement Scale (AIMS) ................................................................ 20 
4.6.3 
Barnes Akathisia Rating Scale (BARS) ............................................................................. 21 
4.7 Antipsychotic (AP) Medication Blood Level ..................................................... 21 
4.8 CTP-692 Blood Level .......................................................................................... 21 
4.9 Concomitant Medications .................................................................................. 21 
4.10 Prior Medications ................................................................................................ 21 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 4 
5 STATISTICAL ANALYSES ........................................................................... 21 
5.1 Statistical Methodology ...................................................................................... 22 
5.1.1 
Sample Size Determination ............................................................................................... 22 
5.1.2 
Populations for Statistical Analysis .................................................................................... 22 
5.1.3 
Statistical Analyses – General Considerations .................................................................. 23 
5.1.4 
Procedures for Handling Missing Data .............................................................................. 23 
5.1.5 
Study Day and Visit Window Definitions ........................................................................... 23 
5.2 Screening and Baseline Characteristics ........................................................... 25 
5.3 Patient Disposition ............................................................................................. 25 
5.4 Efficacy Analyses ............................................................................................... 25 
5.4.1 
Primary Analysis ................................................................................................................ 25 
5.4.2 
Secondary Analyses .......................................................................................................... 26 
5.4.3 
Exploratory Analyses ......................................................................................................... 26 
5.5 Safety Analyses .................................................................................................. 27 
5.5.1 
Adverse Events ................................................................................................................. 27 
5.5.2 
Columbia Suicide Severity Rating Scale ........................................................................... 28 
5.5.3 
Clinical Laboratory Evaluations ......................................................................................... 29 
5.5.4 
Physical Examination ........................................................................................................ 29 
5.5.5 
Vital Signs .......................................................................................................................... 29 
5.5.6 
12-Lead Electrocardiogram ............................................................................................... 29 
5.5.7 
Extrapyramidal Symptoms ................................................................................................. 30 
5.5.8 
Antipsychotic Medication Blood Level ............................................................................... 30 
5.5.9 
CTP-692 Blood Level ........................................................................................................ 30 
5.5.10 
Concomitant Medications ................................................................................................ 30 
5.6 Study Medication Exposure ............................................................................... 30 
5.7 Interim Analyses ................................................................................................. 30 
6 REFERENCES .............................................................................................. 31 
7 TABLES, LISTINGS AND FIGURES ............................................................ 32 
 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 5 
AMEMDMENT HISTORY 
Not applicable 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 6 
LIST OF ABBREVIATIONS 
 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
AIMS 
Abnormal Involuntary Movement Scale 
ALB 
Albumin 
ALK-P 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
AP 
Antipsychotic 
aPTT 
Partial Prothrombin Time Test 
AST 
Aspartate Aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count  
CFR 
Code of Federal Regulations  
CGI-S 
Clinical Global Impression-Severity Score 
CK 
Creatine Kinase 
Cl 
Chloride 
CO2 
Carbon Dioxide 
COVID 
Coronavirus disease 
CRO 
Contract Research Organization  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSM 
Diagnostic and Statistical Manual  
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EPS 
Extrapyramidal symptoms 
ET 
Early Termination 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 7 
Abbreviation or 
special term 
Explanation 
FSH 
Follicle-Stimulating Hormone 
G 
Grams 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HCV-Ab 
Hepatitis C Virus Antibody 
HIV 
Human Immunodeficiency Virus 
HIV-Ab 
Human Immunodeficiency Virus Antibody  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio  
K 
Potassium 
kg 
Kilogram 
L 
Liter 
LDH 
Lactic Dehydrogenase 
LOCF 
Last Observation Carried Forward 
Max 
Maximum  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MINI 
MINI International Neuropsychiatric Interview 
mIU 
Milli-International Units 
mL 
Milliliter 
msec 
Millisecond 
Na 
Sodium 
NSFS 
Negative Symptoms Factor Score 
PANSS 
Positive and Negative Syndrome Scale 
PR 
Pulse Rate 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 8 
Abbreviation or 
special term 
Explanation 
PSFS 
Positive Symptoms Factor Score 
PSP 
Personal and Social Performance 
PT 
Prothrombin Time Test 
QD 
Taken Daily 
QTcF 
Fridericia’s Corrected QT interval 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAS 
Simpson-Angus Scale 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SQLS 
Schizophrenia Quality of Life 
TEAE 
Treatment-Emergent Adverse Event 
UACR 
Urine Microalbumin/Creatinine Ratio 
ULN 
Upper Limit of Normal 
US 
United States 
ug 
Microgram 
WBC 
White Blood Cell  


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 9 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for 
the Phase 2 study entitled “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” (Protocol Amendment #3: 14 
April 2020). Mock shells will be produced as a separate working document to 
facilitate programming of Tables, Figures, and Listings (TFLs) according to the 
SAP. The SAP is to be interpreted in conjunction with the protocol, and 
supersedes the statistical considerations identified in the protocol. If the final 
clinical study report contains changes to any planned statistical analyses, the 
justification for any such differences will be fully documented in the clinical study 
report (CSR). 
2 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the efficacy and safety of CTP-692 as 
an adjunctive treatment in adult patients with schizophrenia. The efficacy and 
safety measures are: 
2.1 Primary Efficacy Endpoint 
• The primary efficacy endpoint will be the change in PANSS total score at 
Week 12 from Baseline   
2.2 Secondary Efficacy Endpoints 
• Change in Clinical Global Impression-Severity (CGI-S) score at Week 12 
from Baseline 
• Change in Personal and Social Performance (PSP) Scale score at Week 
12 from Baseline 
2.3 Exploratory Endpoints 
• Change in PANSS total score at Weeks 2, 4, 8 and 10 from Baseline 
• Change in PANSS Positive Symptoms Factor Score (PSFS; items P1-P7) 
at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in PANSS Negative Symptoms Factor Score (NSFS; items N1-
N7) at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in General Psychopathology Symptoms Factor Score (items G1-
G16) at Weeks 2, 4, 8, 10 and 12 from baseline 
• Change in PANSS Cognitive Symptoms (items P2, N5, G5, G10, G11) at 
Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in Marder Negative Symptoms Factor Score (Marder NSFS; items 
N1, N2, N3, N4, N6, G7, G16) at Weeks 2, 4, 8, 10, and 12 from Baseline 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 10 
• Change in PANSS total score at Week 12 from the average of the 
Screening, Qualification, and Day 1 pre-dose assessments 
• Change in CGI-S score at Weeks 2, 4, 6, 8, and 10 from Baseline 
• Change in PSP score at Week 6 from Baseline 
• Change in Schizophrenia Quality of Life (SQLS) at Week 12 from Baseline 
2.4  Safety Measures 
• Vital signs, physical examinations, electrocardiograms (ECGs), clinical 
laboratory parameters including blood urea nitrogen (BUN), serum 
creatinine and complete urinalysis 
• Adverse events  
• Extrapyramidal symptoms (EPSs) will be evaluated using the Simpson-
Angus Scale (SAS) Abnormal Involuntary Movement Scale (AIMS) and 
the Barnes Akathisia Rating Scale (BARS)   
• Assessment of suicidality will be performed using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) 
3 
STUDY DESIGN 
3.1 Duration of Study 
The study will involve patient participation for up to 20 weeks and will consist of a 
5-week Screening/Qualification Period (this period may be extended up to 2 
weeks if repeat laboratory test results for confirmation of eligibility are pending), a 
12-week Treatment Period and a Safety Follow-Up Visit approximately 1 week 
after the last dose of Study Medication.  
3.2 Number of Participants (Study Population) 
An estimated 300 patients will be enrolled at approximately 22 study sites in the 
United States. 
3.3 Design 
This is a randomized, double-blind, parallel group, placebo-controlled, 
multicenter study. At screening, potential study participants must have a DSM-V 
diagnosis of schizophrenia for at least 2 years and confirmed by psychiatric 
evaluation and MINI (MINI International Neuropsychiatric Interview). Adult 
patients, 18-55 years old, will be randomized to receive 1 g, 2 g or 4 g of  
CTP-692 or Placebo once-daily (QD). At the first Screening Visit (Week -5, Day -
35), patients will provide informed consent and will be assessed for eligibility 
based on study inclusion and exclusion criteria, including a total score of 70-110 
on the Positive and Negative Syndrome Scale (PANSS). Patients meeting 
eligibility requirements at the first Screening Visit will undergo an additional in-
clinic Qualification Visit approximately 2 weeks after the Screening Visit (Week -
3).  Patients who continue to meet eligibility criteria based on assessments at the 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 11 
Screening and Qualification visits and Day 1 (Baseline) will be randomized in a 
1:1:1:1 ratio to 1 of the 4 treatment groups shown below in Figure 1. 
 
Figure 1: 
CP692.2001 Study Design 
 
 
Patients will receive their first dose of Study Medication in the clinic on Day 1.  
The dose of CTP-692 or Placebo should be administered with food. Patients will 
be instructed to take Study Medication once daily at home with food in the 
morning for the next 12 weeks. Patients will return to the clinic at Weeks 2, 4, 6, 
8, 10, and 12 for safety and efficacy assessments and to pick up Study 
Medication as shown in Table 1. Phone contact will be made with the patient on 
Weeks 1, 3, 5, 7, 9 and 11. Patients may be requested to make Unscheduled 
Visits to the clinic if the Investigator (or designee) thinks necessary.   
The primary outcome measure will be the change in PANSS total score at Week 
12 from Baseline. Patients will be required to return to the clinic approximately 1 
week after the last dose of Study Medication for safety assessments including 
physical examination, vital signs, adverse-events and concomitant medications 
as shown in Table 1. If any of the safety parameters including clinical laboratory 
parameters at the end of the Treatment Period are reported to be abnormal, 
unscheduled assessments may be performed at the Safety Follow-Up Visit and 
additional follow-up may be required as the Investigators deems necessary.  
Patients who experience intolerable symptoms during the Treatment Period may 
discontinue the study at the discretion of the Investigator.   
 
 








 
 
Concert Pharmaceuticals, Inc. 
 
 
 PROTOCOL CP692.2001 
 
 
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 15 
3.4 Treatment 
Evaluation of three (3) doses of 1 g, 2 g, and 4 g CTP-692 are planned, in 
addition to placebo.  
3.5 Randomization and Blinding 
The allocation to treatment sequence will be based on a randomization schedule 
generated by an independent statistician. The randomization schedule will be 
kept strictly confidential, accessible only to authorized personnel until the time of 
unblinding.  
The active and placebo treatments are identical in appearance within each group 
and matched placebo will be administered as necessary to maintain the blind. 
3.6 COVID-19 Considerations 
Due to the COVID-19 pandemic, some assessments may be conducted 
remotely. These will be treated the same as on-site assessments and will be 
aggregated with data from the on-site assessments for analysis. 
 
In case of two consecutive missed safety assessments due to the COVID-19 
pandemic, continued patient participation in the study must be discussed by the 
Investigator and the Medical Monitor. 
 
A patient who prematurely discontinues Study Medication/study participation 
should have all Week 12 assessments performed as an Early Termination Visit, 
and if possible, return for the Safety Follow-up Visit. The Safety Follow-Up Visit 
may be waived by the Sponsor in instances where patients have discontinued 
dosing prior to the Early Termination Visit on a case-by-case basis. 
3.6.1 Screening Period Procedures 
Due to the COVID-19 pandemic and the possibility for site closures and/or travel 
restrictions, some Screening Period procedures (with the exception of PANSS) 
such as the MINI, medical history, review of concomitant medications) may be 
conducted remotely per Investigator discretion. The consent process must be 
conducted in the clinic and patients must sign the ICF in person in the clinic. 
3.6.2 Laboratory Blood Draws, Safety, and Efficacy Assessments 
Due to the COVID-19 pandemic and the possibility for site closures and/or travel 
restrictions, clinical laboratory blood draws may be performed by a Home Health 
Care service provider or by a local laboratory; other safety and efficacy 
assessments may be performed remotely via phone/audio or video conferencing 
platforms (with the exception of Facebook). 
3.6.3 ECG Assessments 
Due to the COVID-19 pandemic and the possibility for site closures and/or travel 
restrictions, if Week 6 is a remote visit, ECG assessment may be performed at 
Week 8 or Week 10. 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 16 
3.6.4 Safety Follow-Up Visit 
Due to the COVID-19 pandemic and the possibility for site closures and/or travel 
restrictions, the Safety Follow-up visit may be conducted remotely via 
phone/audio or video conferencing platforms (with the exception of Facebook) 
per Investigator discretion. 
4 
OUTCOME VARIABLE DEFINITIONS 
4.1 Demographic Characteristics 
Demographic characteristics (i.e., sex, ethnic origin, date of birth, and calculated 
body mass index) will be collected. 
4.2 Screening, Qualification, and Baseline Characteristics 
Screening: 
Inclusion/exclusion criteria, demographic characteristics of age, sex, race, 
ethnicity, height, weight, body mass index (BMI), medical history, prior and 
concomitant medications, physical examination, vital signs, adverse events, 
pregnancy test, 12-lead electrocardiogram (ECG), clinical laboratory results, 
urine drug screen, alcohol screen, Positive and Negative Syndrome Scale 
(PANSS), and Columbia-Suicide Severity Rating Scale (C-SSRS) will be 
collected at screening. 
Qualification: 
Patients meeting eligibility requirements at the first Screening Visit will undergo 
an additional in-clinic Qualification Visit during which the following will be 
collected: eligibility, urine drug screen, alcohol screen, PANSS, C-SSRS, 
antipsychotic (AP) blood sample, adverse events, and concomitant medications.   
Baseline (Day 1 Pre-Dose): 
Eligibility, medical history, physical examination, weight, vital signs, 12-lead ECG, 
pregnancy test, clinical laboratory results, alcohol screen, PANSS, Personal and 
Social Performance (PSP), Clinical Global Impression-Severity (CGI-S), 
Schizophrenia Quality of Life Scale (SQLS), C-SSRS, Simpson-Angus Scale 
(SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia 
Rating Scale (BARS) will be collected prior to dose administration. 
4.3 Efficacy Assessments 
The effect of study drug will be evaluated using several validated instruments as 
described below. 
4.3.1 Positive and Negative Syndrome Scale (PANSS) 
The PANSS (Kay et al., 1987) is a psychiatric rating scale designed to measure 
symptom severity among patients with schizophrenia over the preceding 7 days.  
The PANSS items are divided into positive, negative and general 


 
 
 
 
Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 17 
psychopathology factors utilizing a 30-item, 7-point rating scheme. Scoring 
instructions will be provided (to the Rater) with each item accompanied by a 
complete definition as well as detailed anchoring criteria for all 7 rating points, 
which represent increasing levels of psychopathology: 1=absent, 2=minimal, 
3=mild, 4=moderate, 5=moderate severe, 6=severe and 7= extreme. The PANSS 
is scored by summation of ratings across items such that the potential ranges are 
7 to 49 for each of the Positive and Negative Scales and 16 to 112 for the 
General Psychopathology Scale. The PANSS total score is the score of all 30 
PANSS items taken together.  
4.3.2 Clinical Global Impression-Severity (CGI-S) Score 
The CGI-S rating scale (Guy, 1976) is a commonly used measure of symptom 
severity and treatment response. The severity scale (CGI-S) is a 7-point scale 
that requires the clinician to rate the severity of the patient's illness at the time of 
assessment. CGI-S scores of zero (not assessed) will be treated as missing.  
4.3.3 Personal and Social Performance Scale (PSP) 
The PSP (Morosini et al., 2000) is measure of personal and social functioning of 
patients with psychiatric disorders. The scale is a hundred-item scale, divided in 
10 similar intervals. The score is based on the assessment of a patient’s 
performance in four categories: socially useful activities, personal and social 
relationships, self-care, disturbing and aggressive behavior.  
4.3.4 Schizophrenia Quality of Life Scale (SQLS) 
The SQLS (Heinrichs et al., 1984) is a self-report Quality of Life scale developed 
specifically for patients with schizophrenia. It is a 30-item questionnaire 
comprised of three domains (‘psychosocial’, ‘motivation and energy’, and 
‘symptoms and side-effects’).  
4.4 Efficacy Endpoints 
4.4.1 Primary Endpoints 
The primary efficacy endpoint will be the change in PANSS total score at Week 
12 from Baseline (Day 1, prior to dosing). 
4.4.2 Secondary Endpoints 
The secondary endpoints for this study are: 
• Change in CGI-S score at Week 12 from Baseline 
• Change in PSP scale score at Week 12 from Baseline 
4.4.3 Exploratory Endpoints 
Exploratory efficacy endpoints are: 


 
 
 
 
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• Change in PANSS total score at Weeks 2, 4, 8 and 10 from Baseline 
• Change in PANSS Positive Symptoms Factor Score (PSFS; items P1-P7) 
at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in PANSS Negative Symptoms Factor Score (NSFS; items N1-
N7) at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in General Psychopathology Symptoms Factor Score (items G1-
G16) at Weeks 2, 4, 8, 10 and 12 from baseline 
• Change in PANSS Cognitive Symptoms (items P2, N5, G5, G10, G11 at 
Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in Marder Negative Symptoms Factor Score (Marder NSFS; items 
N1, N2, N3, N4, N6, G7, G16) at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in PANSS total score at Week 12 from the average of the 
Screening, Qualification, and Day 1 pre-dose assessments 
• Change in CGI-S score at Weeks 2, 4, 6, 8, and 10 from Baseline 
• Change in PSP score at Week 6 from Baseline 
• Change in Schizophrenia Quality of Life (SQLS) at Week 12 from Baseline 
4.5 Safety and Tolerability Assessments 
Safety of CTP-692 will be assessed by evaluating adverse events, vital signs, 
concomitant medications, clinical laboratory parameters including blood urea 
nitrogen (BUN) and creatinine, urinalysis, ECG results, as well as physical 
examinations. Extrapyramidal symptoms (EPSs) will be evaluated using SAS, 
AIMS, and the BARS. Assessment of suicidality will be performed at every visit 
using the C-SSRS. 
4.5.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence that may appear or 
worsen in a patient during the course of a study. It may be a new intercurrent 
illness, a worsening concomitant illness, an injury, or any concomitant 
impairment of the patient’s health, including laboratory test values, regardless of 
etiology. Any worsening (i.e., any clinically significant adverse change in the 
frequency or intensity of a pre-existing condition) will be considered an adverse 
event.   
A worsening of the condition under study will not be considered as an AE. 
An AE can be any unfavorable and unintended sign (including a new, clinically 
important abnormal laboratory finding), symptom, or disease temporally 
associated with the Study Medication, whether or not it is related to the product. 


 
 
 
 
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4.5.2 Columbia Suicide Severity Rating Scale 
The Columbia Suicide Severity Rating Scale (C-SSRS, Oquendo et al., 2003) is 
a suicidal ideation rating scale. The scale identifies behaviors and thoughts that 
are associated with an increased risk of suicidal actions in the future. There are 2 
versions of the scale being used in this protocol (Baseline/Screening and Since 
Last Visit).  
4.5.3 Laboratory Safety Assessments 
Samples for the following laboratory tests will be collected at the time points 
specified in the Schedule of Assessments (Table 1). 
 
Alcohol breathalyzer: 
Assesses ethyl alcohol 
Coagulation: 
Includes prothrombin time test (PT), partial 
prothrombin time test (aPTT), international normalized 
ratio (INR) 
Hematology: 
Consists of complete blood count, platelet count, white 
blood cell count with differential 
Pregnancy: 
Assesses hCG; conducted for females of childbearing 
potential only 
Serum renal 
parameters: 
Includes blood urea nitrogen (BUN), serum creatinine, 
eGFR 
Serology screen: 
Includes human immunodeficiency virus antibody 
(HIV-Ab), hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (HCV-Ab) 
Serum chemistry: 
Includes alanine aminotransaminase (ALT; SGPT), 
albumin (ALB), alkaline phosphatase (ALK-P), 
amylase, aspartate aminotransaminase (AST; SGOT), 
total bilirubin, direct bilirubin, indirect bilirubin, calcium 
(Ca), carbon dioxide (CO2), chloride (Cl), total 
cholesterol, creatine kinase (CK), follicle-stimulating 
hormone (FSH), gamma-glutamyl transferase (GGT), 
glucose, lactic dehydrogenase (LDH), lipase, 
magnesium, total protein, phosphorus, potassium (K), 
sodium (Na), uric acid 
Urinalysis: 
Includes bilirubin, glucose, ketones, nitrates, occult 
blood, protein, specific gravity, urobilinogen, pH, 
leukocytes, microscopy, creatinine, UACR, urine 
volume 


 
 
 
 
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Urine drug screen: 
Includes amphetamines/methamphetamines, 
barbiturates, benzodiazepines*, cocaine metabolites, 
methadone, phencyclidine, opiates 
* Positive test at Week -5 and Week -3 allowed if drug is prescribed by a physician. 
 
4.5.4 Vital Signs 
Resting vital signs, including systolic, diastolic blood pressure, heart rate 
(measured as pulse), respiratory rate and temperature will be measured after the 
patient has been in a supine or semi-supine position for at least 5 minutes at the 
time points specified in the schedule of events (Table 1).  
Weight and height will be measured and used to calculate the patient’s BMI. 
Weight and height will be converted as needed to kilograms and centimeters, 
respectively, prior to statistical analyses. 
4.5.5 Electrocardiogram 
Twelve-lead electrocardiograms (ECGs) will be performed after the patient has 
rested in a supine or semi-supine position for at least 5 minutes. Individual 
parameters including PR, QT, QTcF, QRS, and RR intervals will be collected.  
Repeat electrocardiograms (if deemed necessary) should be performed at least 5 
minutes apart. ECG will be performed at Screening, Baseline, Week 6, and Week 
12; if Week 6 visit is a remote visit, ECG assessment may be performed at Week 
8 or 10). 
4.5.6 Physical Examination 
A full physical examination will be performed at Screening, Baseline, and Week 
12. It will include an examination of all major organ systems. Brief physical 
examinations will be symptom-directed and performed at Weeks 2, 4, 6, 8, 10, 
and 13 (follow-up); the Week 13 brief physical exam will be conducted if the visit 
occurs in-clinic. 
4.6 Extrapyramidal Symptoms 
4.6.1 Simpson-Angus Scale (SAS) 
The SAS consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia). Each item is rated on a 5-point scale, with a score of 
one representing absence of symptoms, and a score of 5 representing a severe 
condition. The SAS total score is the sum of the scores for all 10 items.  
4.6.2 Abnormal Involuntary Movement Scale (AIMS) 
The Abnormal Involuntary Movement Scale (AIMS) is a 10-item clinician-rated 
scale to assess severity of dyskinesias (specifically, orofacial movements and 
extremity and truncal movements) in patients taking neuroleptic medications.  
Body areas of interest include Facial and Oral, Extremities and Lower, and 


 
 
 
 
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Trunk. Each item is scored on an ordinal scale that ranges from 0 to 4: none, 
minimal, mild, moderate, or severe. Additional global items assess the overall 
severity, tardive dyskinesia-associated functional impairment, and the patient’s 
level of awareness of the movements and distress associated with them.  
4.6.3 Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Rating Scale (BARS) consists of 4 items related to 
akathisia: objective observation of akathisia by the Investigator, subjective 
feelings of restlessness by the patient, patient distress due to akathisia, and 
global evaluation of akathisia. The first 3 items are rated on a 4-point scale, with 
a score of 0 representing absence of symptoms and a score of 3 representing a 
severe condition. The global clinical evaluation is made on a 6-point scale, with 0 
representing absence of symptoms and a score of 5 representing severe 
akathisia. To complete this scale, patients are observed while they were seated 
and then standing for a minimum of 2 minutes in each position. Symptoms 
observed in other situations (e.g., while engaged in neutral conversation or 
engaged in activity on the ward) are also rated. Subjective phenomena are to be 
elicited by direct questioning.  
4.7 Antipsychotic (AP) Medication Blood Level 
Blood samples will be taken to assess blood levels of the AP medication being 
taken by the patient. The confirmation of levels of one of the AP medications 
listed in APPENDIX A of the protocol will be required for patients to be eligible for 
randomization to the Treatment Period.  
4.8 CTP-692 Blood Level 
CTP-692 blood levels will be analyzed and reported separately by the 
bioanalytical laboratory. Times of blood draws relative to dosing of Study 
Medication will be provided in a listing. 
4.9 Concomitant Medications 
Concomitant medications will be reviewed and documented each visit during the 
study and are defined as any medications received at or after the first dose of 
study medication, medication that was received before initial dosing and 
continued after initial dosing of study medication, or medication with missing stop 
date. 
4.10 Prior Medications 
Prior medications are any medications that ended before the first dose of study 
medication. 
5 
STATISTICAL ANALYSES 
Statistical analyses will be performed using SAS® software version 9.4. 


 
 
 
 
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5.1 Statistical Methodology 
5.1.1 Sample Size Determination 
Approximately 75 patients will be randomized to each treatment arm to achieve a 
sample size of approximately 60 patients per arm who complete the study. A 
sample size of 60 per arm provides at least 80% power for the change at Week 
12 from Baseline in PANSS total score, assuming a treatment difference from 
placebo of 5.2 and standard deviation of 10, on a two-sided t-test at 0.05 
significance level. 
5.1.2 Populations for Statistical Analysis 
5.1.2.1 
Safety Population 
The Safety Population (SP) includes all patients who receive at least one dose of 
study medication. 
5.1.2.2 
Efficacy Population 
The Efficacy Population (EP) will include all patients who receive Study 
Medication and have at least one post-baseline PANSS assessment during the 
Treatment Period.  
5.1.2.3 
Efficacy Population – COVID Related 
Due to the pandemic during the conduct of the trial, a COVID-related Efficacy 
Population (COVID-EP) will also be identified. COVID-EP will be defined as all 
patients who receive study medication and have at least one post-baseline 
PANSS assessment during the Treatment Period and have not discontinued from 
the study or had a dose interruption due to direct COVID-related events. The 
COVID-related Efficacy Population will be identified prior to database lock and 
will exclude individuals who contracted the virus, had clinic access restricted due 
to COVID conditions, etc.  
5.1.2.4 
Per-Protocol Population 
The Per Protocol analysis population (PP) will include all patients in the Efficacy 
Population who were dosed according to protocol with no major protocol 
deviations with respect to eligibility criteria and efficacy assessments, and will be 
finalized prior to database lock.  
The full set of efficacy analyses will be conducted for the EP and COVID-EP, 
whereas analyses for the PP analysis population will be restricted to the change 
in PANSS Total Score at weeks 2, 4, 8, 10, and 12. 
Individual assignment to each analysis population will be provided in a listing. 
5.1.2.5 
Subjects Enrolled More Than Once 
In the event subjects are found to have enrolled (been randomized and treated) 
more than once within the study, the first enrollment will be designated as the 


 
 
 
 
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primary enrollment.  Only the primary enrollment will be included in efficacy 
analyses.  Safety data from additional enrollments will generally be included in 
analyses, depending on analysis type and treatments received. 
5.1.3 Statistical Analyses – General Considerations 
For the Treatment Period, data will be summarized by treatment group (CTP-692 
1 g QD, CTP-692 2 g QD, CTP-692 4 g QD, or placebo). All data for analysis will 
be listed by patient. 
The same number of decimal places as in the raw data will be presented when 
reporting minimum and maximum, 1 more decimal place than in the raw data will 
be presented when reporting mean and standard deviation. 
Continuous variables will be summarized by treatment using descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum). For categorical 
variables, frequencies and percentages will be presented by treatment. Baseline 
is defined as the last observation prior to initiation of Study Medication.  
Listings for CSR Appendix 16.2 will include all the patient data points being 
collected or derived for analyses. Data listings will be provided for all patients up 
to the point of study completion or withdrawal. 
All statistical tests will be 2-sided with a significance value of 0.05. Patients will 
be summarized by randomized treatment group, except for the Safety 
Population, which will be summarized by actual treatment received. There will be 
no adjustments for multiple comparisons. 
5.1.4 Procedures for Handling Missing Data 
In general, missing data will not be imputed, as the Mixed Model Repeated 
Measures (primary analysis approach) is considered valid under a Missing at 
Random (MAR) missingness mechanism. 
As a sensitivity analysis for the primary endpoint, the last observation carried 
forward (LOCF) method will be used to impute missing values for patients who 
withdraw from the study prior to the completion of the 12-week Treatment Period.   
A listing will be provided indicating patients and visits with missing data or remote 
visits due to COVID-19, as well as early terminations due to COVID-19. 
5.1.5 Study Day and Visit Window Definitions 
The baseline assessment for all efficacy endpoints is defined as last assessment 
prior to the first dose of Study Medication on Day 1. Data obtained during 
unscheduled and at the Week 12/Early Termination early visits will be allocated 
to the scheduled time point corresponding to the visit window in which they fall in 
as specified in Table 2. For patients completing the study, data will be analyzed 
based on the nominal visits and nominal time points. If the data from the nominal 
visit or time point are missing or the patient did not complete the study, data from 


 
 
 
 
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unscheduled visits or the Week 12/Early Termination visit within the time interval 
for the same nominal visit or time point will be used. If multiple visits among 
unscheduled or Early Termination assessments fall in the same visit window or 
time point, the non-missing assessment closest to target time point will be 
selected for analysis. If multiple values are the same number of days away from 
the target study day, then the latter value will be used. In the unlikely event an 
unscheduled or Early Termination visit, associated with a particular visit window, 
falls either prior to the actual previous nominal visit date or after the subsequent 
nominal visit date, it will not be used. This is done simply to ensure the data 
assigned to particular analysis time points will not be out of sequence. 
The first date on which patient received the Study Medication will be used as the 
Study Day 1. Study days for other visits will be calculated as follows: 
• Before Study Day 1 visit: Study Day = date of assessment – date of Study 
Day 1 
• On or after Study Day 1 visit: Study Day = date of assessment – date of 
Study Day 1 + 1 
Last study date is the last visit date of any scheduled, unscheduled, or Early 
Termination visits. Last Study Day is calculated as: 
• Last Study Day = last study date – date of Study Day 1 + 1 
The target study days of Study Center Visits are summarized below.  
Table 2 – Guidelines for Assigning Unscheduled and Early Termination 
Visits for Efficacy Assessments 
Week/Visit 
Time Interval 
(Day) 
Target Time Point 
(Day) 
-5/Screening 
Use nominal 
-35* 
-3/Qualification 
Use nominal 
-24 to -21* 
1 (Baseline/Day 1) 
Last assessment prior to 
dosing 
1 
2 
8 to 21 
14 
4 
22 to 35 
28 
6 
36 to 49  
42 


 
 
 
 
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*5-week Screening/Qualification Period may be extended up to 2 weeks if repeat laboratory test 
results for confirmation of eligibility are pending. 
5.2 Screening and Baseline Characteristics 
Summary tables will be constructed for the following screening or pre-dose data 
and summarized by treatment group: demographic characteristics of age, sex, 
race, ethnicity, weight, height and body mass index (BMI), medical history, prior 
and concomitant medications, laboratory examinations, vital signs, and ECG for 
the safety population.  
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA, version 23.1 September 2020) terminology. Prior and concomitant 
medications will be summarized by World Health Organization Drug Dictionary 
Anatomical-Therapeutic-Chemical classification and preferred term (September 
2020 version). Medical history and prior and concomitant medications will be 
summarized for the Safety Population. 
 
Listings will be provided for eligibility criteria violations, demographics, medical 
history, and prior and concomitant medications. 
5.3 Patient Disposition  
The number and percentage of patients in each treatment group will be 
summarized for each investigative site (and combined) for each analysis 
population. The number and percentage of patients who are randomized, treated, 
prematurely discontinued (overall and by reason), and who complete the study 
will be summarized. The frequency and percentage of patients who withdraw or 
discontinue from the study, along with the reason for withdrawal or 
discontinuation, will be summarized by treatment. Individual patient dispositions 
will be provided by a listing. 
 
All reported major protocol deviations and determined exclusions from any 
analysis population(s) will be provided in a listing. 
5.4 Efficacy Analyses 
5.4.1 Primary Analysis 
The primary efficacy endpoint will be the change in PANSS total score at Week 
12 from Baseline. A mixed model for repeated measures (MMRM) will be used to 
8 
50 to 63  
56 
10 
64 to 77 
70 
12 
78 to 1 day prior to Safety 
Follow-up 
84 
13/Safety Follow-up 
Use nominal 
91 


 
 
 
 
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assess treatment group differences for change from baseline. Fixed effects will 
include treatment group, analysis visit, treatment-by-visit interaction, and a 
baseline-by-visit interaction. Visit will be fit as a repeated effect using the 
repeated statement in SAS. The baseline score will be included as a continuous 
covariate. An unstructured covariance structure and Kenward-Roger degrees of 
freedom will be used. In the event an unstructured covariance structure fails to 
converge, a Toeplitz structure will be used.  
Least squares means will be presented for treatment*visit, with the significance 
level of the treatment-by-visit interaction presented in summary tables. Pair-wise 
comparisons of differences in LS means, two-sided 95% confidence intervals 
(CIs) on differences, and p-values will be provided for each active treatment 
versus placebo for each visit. 
A listing for PANSS individual questions as well as subscale totals will be 
provided. 
5.4.2 Secondary Analyses 
Change in CGI-S score and PSP score at Week 12 from Baseline will be 
evaluated as secondary endpoints. 
MMRM analyses, as described for the primary analysis, will be conducted on the 
change scores for the CGI-S and PSP. Individual patient scores for the CGI-S 
and PSP will be provided in listings. 
5.4.3 Exploratory Analyses 
The following exploratory analyses will be conducted using MMRM as specified 
above: 
• Change in PANSS total score at Weeks 2, 4, 8 and 10 from Baseline 
• Change in PANSS Positive Symptoms Factor Score (PSFS; items P1-P7) 
at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in PANSS Negative Symptoms Factor Score (NSFS; items N1-
N7) at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in General Psychopathology Symptoms Factor Score (items G1-
G16) at Weeks 2, 4, 8, 10 and 12 from baseline 
• Change in PANSS Cognitive Symptoms (items P2, N5, G5, G10, G11) at 
Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in Marder Negative Symptoms Factor Score (Marder NSFS; items 
N1, N2, N3, N4, N6, G7, G16) at Weeks 2, 4, 8, 10, and 12 from Baseline 
• Change in PANSS total score at Week 12 from the average of the 
Screening, Qualification, and Day 1 pre-dose assessments 
• Change in CGI-S score at Weeks 2, 4, 6, 8, and 10 from Baseline 


 
 
 
 
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• Change in PSP score at Week 6 from Baseline 
• Change in Schizophrenia Quality of Life (SQLS) at Week 12 from Baseline 
5.5 Safety Analyses 
All safety summaries will be descriptive with no statistical hypothesis testing and 
based on the Safety Population. Patients will be summarized according to the 
study medication received (i.e., as treated), should it differ from the randomized 
treatment arm. All safety endpoints will be listed in by-patient data listings. 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Affairs (MedDRA version 23.1 coding system and summarized by system organ 
class and preferred term. Clinically significant deteriorations in physical 
examination findings will be reported and summarized as adverse events.  
Abnormal, clinically significant laboratory values will be reported and summarized 
as adverse events. 
5.5.1 Adverse Events 
An adverse event reported after informed consent, but before the first dose of 
Study Medication (i.e., Day 1), will be considered a pre-treatment adverse event. 
These will be listed. Treatment-emergent adverse events (TEAEs) will be defined 
as any adverse event that occurs after administration of the first dose of Study 
Medication or AEs noted prior to the first Study Medication administration that 
worsen after Baseline. Individual patient TEAEs will be provided in a listing. 
The number and percentage of patients who report TEAEs will be summarized 
by system organ class and preferred term. Treatment emergent adverse events 
will also be summarized by severity (mild, moderate, severe) as well as 
relationship to Study Medication (possibly, probably, or definitely related, unlikely 
related, or not related). 
Patients who report the same preferred term on multiple occasions will be 
counted once for the preferred term under the highest severity when summarized 
by severity and under the closest relationship to Study Medication when 
summarized by relationship. If a patient reports multiple preferred terms for a 
system organ class, the patient will be counted only once for that system organ 
class. 
Proportions for adverse events that are gender-specific (e.g., dysmenorrhea) will 
be based on the number of patients from that gender. 
The number and percentage of patients who experience TEAEs will be 
summarized by treatment group for the following: 
• By system organ class and preferred term  
• By severity/intensity, system organ class, and preferred term  


 
 
 
 
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• By relationship to Study Medication (related, not related), system organ 
class, and preferred term  
• Serious adverse events by system organ class and preferred term  
• Serious adverse events by relationship to Study Medication, system organ 
class, and preferred term  
• Adverse events resulting in discontinuation of Study Medication by system 
organ class and preferred term  
• Adverse events that result in Study Medication dose interruption by 
system organ class and preferred term  
By-patient listings will be provided for any deaths, serious adverse events, and 
adverse events leading to discontinuation of treatment. 
A summary of adverse events will be provided in a table and will include numbers 
of subjects and percentages for following: 
• Total TEAEs in each treatment group 
• Number of patients with TEAEs 
• Moderate or severe TEAEs (Grade 2 or above) 
• Any related TEAE 
• TEAEs leading to discontinuation 
• Total SAEs 
• Max severity of SAEs 
• Any related SAE 
• SAEs leading to discontinuation 
• SAEs leading to death 
 
Treatment-emergent adverse events that result in dose interruption (with 
subsequent resumption of dose) will also be identified. 
5.5.2 Columbia Suicide Severity Rating Scale 
The C-SSRS data will be summarized descriptively. Individual patient data will be 
provided in a listing. Only the following specific suicidal ideation and behavior 
category questions with any “Yes” responses will be summarized in a frequency 
distribution table at each post-randomization visit: 
• Any Suicidal Ideation Category: 
o Wish to be Dead 
o Non-Specific Active Suicidal Thoughts 


 
 
 
 
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o Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act 
o Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
o Active Suicidal Ideation with Specific Plan and Intent 
• Any Suicidal Behavior Category: 
o Completed Suicide 
o Non-Fatal Suicide Attempt 
o Interrupted Attempt 
o Aborted Attempt 
o Preparatory Acts or Behavior 
o Any Suicidal Ideation or Behavior Category 
5.5.3 Clinical Laboratory Evaluations 
Patients with clinically significant abnormal laboratory values will be identified.  
Clinically significant, treatment-emergent laboratory values (i.e., baseline < 
Grade 3 and post-baseline meets ≥ Grade 3, according to CTCAE, version 5.0) 
will be summarized by treatment group. Laboratory values will be summarized at 
each time point for each treatment group, using descriptive statistics. The tables 
will also include changes from Baseline. Individual patient listings will be 
provided. 
5.5.4 Physical Examination 
A listing of physical examination findings will be provided by patient. Pregnancy, 
alcohol screening, and drug testing results will be provided by patient. 
5.5.5 Vital Signs 
Vital signs will be summarized at each time point for each treatment group, using 
descriptive statistics. Change from baseline in vital signs values will also be 
summarized. Individual patient listings will be provided. 
Baseline will be defined as the last vital sign value obtained before the first dose 
of Study Medication on Day 1.  
5.5.6 12-Lead Electrocardiogram 
The change from baseline in ECG intervals (PR, QT, QTcF, QRS, and RR) to 
each scheduled assessment will be summarized descriptively by treatment 
group. A table presenting frequencies and percentages of ECG findings 
described as “abnormal, clinically significant,” “abnormal, not clinically 
significant,” and “normal” will be provided by treatment group.  


 
 
 
 
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Frequency distributions of the QTcF interval will be displayed in a table by 
treatment group for abnormally high values that are greater than their baseline 
value at any post-baseline visit for the following data cuts: 
>450 msec and > Baseline value 
>470 msec and > Baseline value 
>500 msec and > Baseline value 
Additionally, the change from baseline frequency distributions of the QTcF 
interval will be displayed in a table by treatment group for the following data cuts: 
>30 msec increase 
>60 msec increase 
5.5.7 Extrapyramidal Symptoms 
Scores on the SAS, AIMS, and BARS will be summarized for each corresponding 
visit. Individual patient scores will be listed. 
5.5.8 Antipsychotic Medication Blood Level 
The presence (Yes/No) of antipsychotic medications in the blood at the 
Qualification Visit will be provided per patient as a listing. 
5.5.9 CTP-692 Blood Level 
A listing indicating the time of CTP-692 blood draw relative to time of dose will be 
provided per patient. 
5.5.10 Concomitant Medications 
Concomitant medications will be summarized (n and %) by ATC class and 
preferred term (coded by WHODrug coding dictionary version B3 September 
2020) for each treatment group. This table will also include an overall total 
column. Concomitant medications for individual patients will be provided in a 
listing. A separate table for concomitant antipsychotic medications will also be 
provided. 
5.6 Study Medication Exposure 
The number of days of Study Medication administration will be summarized for 
each treatment group, as well as provided in a listing per patient. 
5.7 Interim Analyses 
No interim analyses are planned for this study. 


 
 
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6 
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Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, 
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Alcohol, Drug Abuse, and Mental Health Administration; 1976. 
Heinrichs DW, Hanlon TE, Carpenter WT. The quality of life scale: an instrument 
for rating the schizophrenic deficit syndrome. Schizophrenia Bull. 1984;10:388-
398. 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale 
(PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
Lindenmayer JP, Bernstein-Hyman RB, Grochowski S. A new five factor model of 
schizophrenia. Psychiatric Quarterly. 1994;299:322. 
Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five 
dimensions of schizophrenia derived by factor analysis: combined results of the 
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Concert Pharmaceuticals, Inc. 
 
 
PROTOCOL CP692.2001 
   
Statistical Analysis Plan: Final Version 1.0, 2 December 2020 
 
 
Page | 32 
7 
TABLES, LISTINGS AND FIGURES 
A separate document containing the list of tables, listings, and figures (TFLs) to 
be included in the post-text Appendix 14 of the CSR will be provided. TFLs may 
be modified with Sponsor’s approval and as deemed necessary without update to 
the SAP.