A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of SAGE-718 in Parkinson's Disease Cognitive Impairment
Phase: PHASE2
Conditions: Parkinson Disease, Cognitive Dysfunction
Sponsor: Supernus Pharmaceuticals, Inc.

Offi ci al Titl e:             
A R a n d o mi z e d, D o u bl e- bli n d, Pl a c e b o- c o ntr oll e d St u d y t o E v al u at e t h e Eff e ct s of 
N C T I D: 
S A G E- 7 1 8 i n P ar ki n s o n’ s Di s e a s e C o g niti v e I m p air m e nt 
  N C T 0 5 3 1 8 9 3 7
Pr ot o c ol V er si o n 3. 0: 2 1  S e pt e m b er  2 0 2 2
D o c u m e nt D a te:  

S T U D Y TI T L E  
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 Effects of S A G E -7 1 8 i n P ar ki ns o n’s Dise ase 
C o g niti ve I m p air me nt  
S H O R T TI T L E  
A  St u d y t o E v al u ate t he Effects of S A G E -7 1 8 i n P artici p a nts w it h P ar ki ns o n's 
Dise ase C o g niti ve I m p air me nt  
P R O T O C O L N U M B E R: 7 1 8 -C N P -2 0 2  
I N D NU M B E R : 1 3 4 2 1 7  
I n vesti g ati o n al Pr o d uct 
S A G E -7 1 8  
Cli nic al P h ase  
2  
S p o ns or  
Sa ge T h era pe utics , I n c. 
2 1 5 First Street  
Ca m bri d ge, M A 0 2 1 4 2  
S p o ns or C o nt act  a n d Me dic al 
M o nit or  
, M D 
 
Ca m bri d ge, M A 0 2 1 4 2  
P h o ne: 
 
D ate of Ori gi n al Pr ot oc ol  (Versi o n  1)  
D ate of A me n d me nt 1  ( Versi o n 2) 
D ate of A me n d me nt  2  ( Versi o n 3) 
2 2  N o ve m ber  2 0 2 1  
1 0  Fe br uar y 2 0 2 2  
0 9  A u g ust  2 0 2 2  
C o nfi de nti alit y St ate me nt  
T he c o nfi de ntial i nf or mati o n i n t his d oc u me nt is pr o vi de d t o y o u as a n i n vesti gat or or c o ns ulta nt 
f or re vie w b y y o u, y o ur staff, a n d t he a p plica ble I nstit uti o nal Re vie w B oar d/I n de p e n de nt Et hics 
C o m mittee . Y o ur acce pta nce of t his d oc u m e nt c o nstit utes a gree me nt t hat y o u will n ot discl ose 
t he i nf or mati o n c o ntai ne d herei n t o ot hers wit h o ut writte n a ut h orizati o n fr o m Sa ge T h era p e utics , 
I n c. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2  
 
S P O N S O R A P P R O V A L  
 
Pr ot oc ol N u m ber:  
7 1 8 -C N P -2 0 2  
St u d y Title : 
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 Effects of 
S A G E -7 1 8 i n Par ki ns o n’s Disease C o g niti ve 
I m pair me nt 
Pr ot oc ol V ersi o n a n d D ate:  
Versi o n  0 3,  0 9  A u g ust  2 0 2 2   
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Date ( D D M M M Y Y Y Y)  
 
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e}  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
, M D 
Date ( D D M M M Y Y Y Y)  
 
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
, P h D  
Date ( D D M M M Y Y Y Y)  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3  
 
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
, M S 
Date ( D D M M M Y Y Y Y)  
 
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
 
 
Date ( D D M M M Y Y Y Y)  
 
 
 
 
 
 
{ S e e a p p e n d e d el e ctr o ni c si g n at ur e p a g e} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
, M D, P h D 
Date ( D D M M M Y Y Y Y)  
 
 
 
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4  
I N V E S TI G A T O R’ S A G R E E M E N T 
 
I h a ve rea d t he 7 1 8 -C N P -2 0 2  pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d . I a gree t o 
mai ntai n t he c o nfi de ntialit y of all i nf or mati o n r ecei ve d or de v el o pe d i n c o n necti o n wit h t his 
pr ot oc ol.  
 
 
 
 
 
 
 
 
Pri nte d Na me of I n v esti gat or  
 
 
 
 
 
 
 
Si g nat ure of I n vesti gat or  
 
 
 
 
 
 
 
Date ( D D/ M M M/ Y Y Y Y)  
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5  
C O N T A C T IN F O R M A TI O N  
 
T a ble 1 : 
C o nt act Inf or m a ti o n 
Sa ge  St u d y P h ysicia n  a n d 2 4 -h o ur  
e mer ge nc y c o ntact  
, M D 
2 1 5 First Street  
Ca m bri d ge, M A 0 2 1 4 2  
P h o ne: 
 
Seri o us A d verse E ve nt ( S A E ) 
Re p orti n g  C o ntact  
I Q VI A Lifec ycle Safet y 
4 8 2 0 E m per or B o ule var d  
D ur ha m, N C 2 7 7 0 3  
e-mail:  Sa ge. Safet y @i q via.c o m  
Fa x: 1 -8 5 5 -6 3 8 -1 6 7 4  
S A E H otli ne: 1 -8 5 5 -5 6 4 -2 2 2 9   
, M D 
 
 
 
 
, P h D  
 
 
, M D 
Pr o d uct C o m plai nts  
Sa ge T hera pe utics  
e-mail: 
pr o d uctc o m plai nts @sa ger x.c o m  
P h o ne: 1 -8 3 3 -5 5 4 -7 2 4 3  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6  
1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Sa ge T hera pe utics, I nc. ( hereafter referre d t o as Sa ge T hera pe utics, or Sa ge)  
N a me of I n vesti g ati o n al Pr o d uct:  
S A G E -7 1 8 oral s oft gel li pi d ca ps ule 
N a me of Acti ve I n gre die nt:  
S A G E -7 1 8  
Pr ot oc ol N u m ber:  7 1 8 -C N P -2 0 2  
I N D N u m ber: 1 3 4 2 1 7  
E u dra C T N u m ber:  n ot assi g ne d  
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 Effects of S A G E -7 1 8 i n 
Par ki ns o n’s Disease C o g niti ve I m pair me nt  
S h ort Title:  A St u d y t o E val uate t he Effects of S A G E -7 1 8 i n Partici pa nts w it h Par ki ns o n's Disease 
C o g niti ve I m pair me nt  
N u m ber of Sites a n d St u d y L oc ati o n: A p pr o xi matel y 3 0 sites i n t he U nite d States  
P h ase of De vel o p me nt: 2  
Pl a n ne d D ur ati o n f or e ac h St u d y P artici p a nt:  
T he d urati o n of partici pati o n (fr o m Scree ni n g t hr o u g h t he fi nal F oll o w -u p visit) f or eac h partici pa nt is 
esti mate d t o be u p t o 1 4 wee ks, i ncl u di n g 3 -wee k Scree ni n g Peri o d, 1 -wee k Baseli ne Peri o d, 6 -wee k 
Treat me nt Peri o d , a n d 4-wee k F oll o w -u p Peri o d.  
O bjecti ves a n d E n d p oi nts : 
 
O bjecti ves  
E n d p oi nts  
Pri mar y  
•  
T o e val uate t he effect of SA G E -7 1 8 o n 
c o g niti ve perf or ma nce i n partici pa nts 
wit h Par ki ns o n’s Disease  ( P D)– Mil d 
C o g niti ve I m pair me nt ( M CI).  
•  
C ha n ge fr o m Baseli ne t o Da y 4 2 i n t he 
Wec hsler A d ult I ntelli ge nce Scale -I V (W AI S -
I V) C o di n g test . 
Sec o n dar y  
•  
T o e val uate t he safet y a n d t olera bilit y of 
S A G E -7 1 8 i n partici pa nts wit h P D -
M CI . 
•  
Pr o p orti o n of partici pa nts e x perie nci n g 
treat me nt -e mer ge nt a d verse e ve nts ( T E A Es ) 
a n d se verit y of T E A Es.  
•  
N u m ber of partici pa nts w h o wit h dra w d ue t o 
a d verse e ve nts  ( A Es). 
  
•  
T o e val uate t he safet y a n d t olera bilit y of 
S A G E -7 1 8 o n ot her safet y para meters.  
•  
C ha n ge fr o m Baseli ne  i n vital si g ns, cli nical 
la b orat or y para meters, electr ocar di o gra ms 
( E C Gs), a n d 
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7  
St u d y Descri pti o n:  
T his is a ra n d o mize d, place b o-c o ntr olle d, d o u ble -bli n d st u d y t o e val uate t he effects of S A G E -7 1 8 i n 
P D c o g niti ve i m pair me nt.  
Eli gi ble partici pa nts wit h a c o nfir me d dia g n osis of i di o pat hic P D b y 2 0 1 5 M o ve me nt Dis or der 
S ociet y ( M D S) criteria at Scree ni n g a n d w h o meet M D S Tas k F orce Criteria f or M CI i n P D 
(e xcl u di n g re q uire me nt f or U nite d Ki n g d o m ( U K) P D Brai n Ba n k dia g n ostic criteria) will recei ve a 
1. 2  m g d ose of S A G E -7 1 8 or place b o dail y f or 6 wee ks.  
Assess me n ts will be perf or me d as o utli ne d i n t he Sc he d ule of Assess me nts (T a ble  2 ) a n d t he 
Sc he d ule of 
, Bi oc he mical a n d Ge netic Sa m pli n g (T a ble  3 ). T he scales are t o be 
a d mi nistere d after t he dail y d ose of i n vesti gati o nal pr o d uct (I P) d uri n g t he Treat me nt Peri o d, a n d at 
a p pr o xi matel y t he sa me ti me of da y ( ± 2 h o urs) t hr o u g h o ut t he st u d y. F or partici pa nts recei vi n g 
me dicati o n f or P D s y m pt o ms, assess me nts are t o be a d mi nistere d i n t he “ o n” state ( defi ne d as t he 
peri o d i n w hic h m ot or s y m pt o ms are miti gate d d ue t o t he effects of P D me dicati o n).  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8  
 
A b bre viati o ns: C o g niti o n = C o g niti ve assess me nts (i ncl u des Wec hsler A d ult I ntelli ge nce Scale -I V [ W AI S-I V] 
C o di n g  test; 
 
 
, a n d M o ntreal C o g niti ve Assess me nt [ M o C A]. 
 
 
; P D-M CI  =  P ar ki ns o n’s Disease Mil d C o g niti ve I m pair me nt; 
; P O = 
orall y.  
See T a ble  2  f or s pecific sc he d ule of eac h test.  
 
Scree ni n g Peri o d  
T he Scree ni n g Peri o d be gi ns wit h t he i nf or me d c o nse nt pr ocess f or pr os pecti ve partici pa nts, 
i ncl u di n g o pti o nal care gi ver s. S u bse q ue nt scree ni n g assess me nts will be perf or me d bet wee n Da y -2 8 
a n d Da y -8 t o deter mi ne eli gi bilit y, i ncl u di n g assess me nts of c o g niti ve a n d m ot or f u ncti o n. A n a d ult 
care gi ver  is o pti o nal b ut hi g hl y rec o m me n de d f or eac h partici pa nt t o s u p p ort c o m pleti o n of st u d y 
acti vi ties a n d t o a ns wer q uesti o ns a b o ut t he partici pa nt’s c o n diti o n.  
Baseli ne Peri o d  
T he Baseli ne Peri o d will occ ur fr o m Da y -7 t hr o u g h Da y -1. O n Da y -7, partici pa nts will visit t he 
cli nic f or c o nfir mati o n of c o nti n ue d eli gi bilit y a n d c ollecti o n of baseli ne c o g niti ve a n d safet y data. 
Partici pa nts a n d care gi ver s will recei ve trai ni n g o n t he st u d y pr oce d ures a n d de vices. Partici pa nts will 
c o nti n ue t o c o m plete dail y assess me nts of c o g niti ve s y m pt o ms usi n g t he m o bile de vice  d uri n g t he 
Baseli ne Peri o d.  
Treat me nt P eri o d 
Eli gi ble partici pa nts will be ra n d o mize d 1: 1 t o recei ve 1. 2  m g of S A G E -7 1 8, or matc hi n g place b o f or 
4 2 da ys.  Be gi n ni n g o n Da y  1 a n d c o nti n ui n g t hr o u g h Da y 4 2, partici pa nts will self -a d mi nister bli n de d 
i n vesti gati o nal pr o d uct (I P) o nce per da y i n t he m or ni n g. N o d osi n g will be  per mitte d be y o n d Da y 4 2 . 
At sc he d ule d cli nic visits d uri n g t he Treat me nt Peri o d, safet y, efficac y, a n d 
 will be 
perf or me d, a n d st u d y staff will dis p e nse a s ufficie nt a m o u nt of  I P f or dail y a d mi nistrati o n u ntil t he 
ne xt sc he d ule d st u d y visit. A d here nce t o t he d osi n g re gi me n will be assesse d at eac h i n -cli nic visit b y 
e xa mi nati o n of t he use d pac ka gi n g a n d  c o u nti n g a n y ret ur ne d ca ps ules. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
9  
D uri n g t he T reatme nt P eri o d, partici pa nts will be a ble t o recei ve I P if t here are n o d ose li miti n g 
safet y/t olera bilit y c o ncer ns. Partici pa nts w h o disc o nti n ue I P earl y s h o ul d c o m plete t he re mai ni n g 
st u d y visits as sc he d ule d u nless t he partici pa nt wit h dra ws c o nse nt or l oses  t he ca pacit y t o gra nt 
c o nse nt. If a partici pa nt wit h dra ws fr o m t he st u d y/st o ps st u d y partici pati o n earl y, a n earl y ter mi nati o n 
visit s h o ul d be c o n d ucte d. Treat me nt wit h S A G E -7 1 8 ca n be e n de d wit h o ut d o w n titrati o n.  
F oll o w -u p Peri o d  
After c o m pleti n g t he t reat me nt peri o d, partici pa nts will ret ur n t o t he cli nic f or f oll o w-u p visits o n 
Da y  7 0 t o c ollect c o nti n ue d safet y, efficac y, a n d  
.  
N u m ber of P artici p a nts ( pl a n ne d): U p t o 7 6 partici pa nts will be d ose d t o o btai n u p t o 3 0  e val ua ble  
partici pa nts per treat me nt ar m.  
Eli gi bilit y Criteri a  
I ncl usi o n Criteri a: 
Eac h eli gi ble partici pa nt m ust:  
1.  be  ca pa ble of pr o vi di n g i nf or me d c o nse nt;  
2.  ha ve si g ne d a n i nf or me d c o nse nt f or m (I C F) pri or t o a n y st u d y -s pecific pr oce d ures bei n g 
perf or me d;  
3.  be  will i n g a n d, i n t he o pi ni o n of t he i n vesti gat or, a ble t o c o m pl y wit h st u d y pr oce d ures; 
4.  be bet wee n t he a ges of 5 0 a n d 7 5 years, i ncl usi ve, at Scree ni n g;  
5.  meet t he f oll o wi n g criteria f or P D -M CI:  
a. h a ve a c o nfir me d dia g n osis of i di o pat hic P D acc or di n g t o 2 0 1 5 M D S cli nical 
dia g n ostic criteria , a n d 
b.  m eet M D S Tas k F orce Criteria f or M CI i n P D (e xcl u di n g re q uire me nt f or U K P D 
Brai n Ba n k dia g n ostic criteria).  
6.  m eet t he f oll o wi n g criteria f or M o C A:  
a. f or partici pa nts meeti n g Le vel 1 P D-M CI criteria, ha ve a M o C A sc ore of 2 0 t o 2 5 
(i ncl usi ve) at Scree ni n g; 
b.  f or partici pa nts meeti n g Le vel 2 P D-M CI criteria ( wit hi n t he past year), ha ve a 
M o C A sc ore of 1 8 t o 2 5 (i ncl usi ve) at Scree ni n g;  
7.  be a ble t o c o m plete t he C ol or Trails T est 1  (i ncl u di n g t he a bilit y t o f oll o w rater re directi o n 
a n d c orrect err ors ), a n d, base d o n partici pa nt ’s perf or ma nce a n d i n vesti gat or's o pi ni o n , is 
e x pecte d t o  be ca pa ble of e n ga gi n g i n pr ol o n ge d c o g niti ve testi n g  f or t he d urati o n of t he 
st u d y. 
8.  meet criteria f or m o difie d H oe h n a n d Ya hr Sta ge I t o III ( mil d t o m o derate m ot or se verit y) at 
Scree ni n g;  
9.  ha ve sta ble m ot or s y m pt o ms f or at least 4 wee ks pri or t o Scree ni n g, i n t he o pi ni o n of t he 
i n vesti gat or; 
1 0.  ha ve sta ble c o nc o mita nt me dicati o n d ose a n d fre q ue nc y f or at least 4 wee ks pri or t o t he first 
I P a d mi nistrati o n, an d w hic h is e x pecte d t o re mai n sta ble f or t he d urati o n of t he st u d y;  
1 1.  a gree, if fe male, t o use a n acce pta ble hi g hl y effecti ve met h o d of c o ntrace pti o n d uri n g 
partici pati o n i n t he st u d y a n d f or 3 0 da ys f oll o wi n g t he last d ose of I P  (refer t o Secti o n  8. 2. 4  
f or acce pta ble f or ms of c o ntrace pti o n), u nless t he y are p ost me n o pa usal ( defi ne d as n o me nses 
f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use a n d c o nfir me d b y f ollicle sti m ulati n g 

Cli nical Pr ot oc ol  
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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 0  
h or m o ne [ F S H] > 4 0 mI U/ m L), s ur gicall y sterile ( h ysterect o m y or bilateral o o p h orect o m y or 
bilateral sal pi n gect o m y), or d oes n ot e n ga ge i n se x ual relati o ns w hic h carr y a ris k of 
pre g na nc y  (d oes n ot i ncl u de a bsti ne nce ); 
1 2.  a gree, if male, t o use a n acce pta ble met h o d of hi g hl y effecti ve c o ntrace pti o n d uri n g t he 
Treat me nt Peri o d a n d f or 3 0 da ys after recei vi n g t he last d ose of I P,  u nless t he partici pa nt 
d oes n ot e n ga ge i n se x ual relati o ns t hat carr y a ris k of pre g na nc y  (refer t o Secti o n 8. 2. 4  f or 
acce pta ble f or ms of c o ntrace pti o n ); 
1 3.  a gree, if male, t o a bstai n fr o m s per m d o nati o n d uri n g t he Treat me nt Peri o d a n d f or 3 0  da ys 
after recei vi n g t he last d ose of I P a n d 
1 4.  a gree t o refra i n fr o m dr u gs of a b use f or t he d urati o n of t he st u d y a n d fr o m alc o h ol d uri n g t he 
4 8 h o urs prece di n g eac h st u d y visit . 
E xcl usi o n Criteri a  
Eac h eli gi ble partici pa nt m ust n ot:  
1.  ha ve partici pate d i n a pre vi o us cli nical st u d y of S A G E -7 1 8, ha ve partici pate d i n a pre vi o us 
ge ne t hera p y st u d y, or ha ve recei ve d st u d y treat me nt i n a n y ot her dr u g, bi ol o gic, or de vice 
trial wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver is l o n ger), u nless t he p artici pa nt  partici pate d 
s olel y i n t he place b o ar m of t he st u d y. 
2.  ha ve cli nicall y si g nifica nt c o m or bi d me dical c o n diti o ns, a c hr o nic c o n diti o n t hat is u nsta ble, 
or are ta ki n g c o nc o mita nt me dicati o ns t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y ma ke t he 
part ici pa nt u ns uita ble f or i ncl usi o n or ha ve t he p ote ntial t o c o m pr o mise safet y a n d/ or 
c o m plia nce wit h st u d y re q uire me nts;  
3.  ha ve a dia g n osis of de me ntia of a n y eti ol o g y, i ncl u di n g b ut n ot li mite d t o: De me ntia wit h 
Le w y B o dies, Alz hei mer’s De me ntia, a n d Vasc ula r De me ntia; 
4.  ha ve a n y par ki ns o nis m ot her t ha n P D, i ncl u di n g sec o n dar y par ki ns o nis m or at y pical 
par ki ns o nis m;  
5.  be e x perie nci n g m o t or s y m pt o ms or fl uct uati o ns i n m ot or s y m pt o ms ass ociate d wit h P D t hat 
will i nterfere wit h c o m pleti n g st u d y pr oce d ures, i ncl u di n g assess me nts a d mi nistere d b y 
t o uc h-scree n de vices, i n t he o pi ni o n of t he i n vesti gat or; 
6.  ha ve a n o n g oi n g ce ntral ner v o us s yste m c o n diti o n ot her t ha n P D t hat i n t he o pi ni o n of t he 
i n vesti gat or c o ul d i nfl ue nce t he o utc o me of t he st u d y (i ncl u di n g acti ve ne ur ol o gic a n d/ or 
n o nre mitte d ps yc hiatric dis or ders);  
7.  ha ve e x perie nce d si g nifica nt ps yc h otic s y m pt o ms, i ncl u di n g hall uci nati o ns or del usi o ns, 
wit hi n t he past 3 m o nt hs, i n t he o pi ni o n of t he i n vesti gat or;  
8.  ha ve a hist or y of brai n s ur ger y, dee p brai n sti m ulati o n, or a n y hist or y of h os pitalizati o n d ue 
t o a brai n i nj ur y; 
9.  ha ve a hist or y, prese nce, a n d/ or c urre nt e vi de nce of  cli nicall y rele va nt i ntracra nial 
a b n or malit y (e g,  str o ke, he m orr ha ge, s pace-occ u p yi n g lesi o n);  
1 0.  be recei vi n g a n y of t he f oll o wi n g pr o hi bite d me dicati o ns:  
a. m e dicati o ns wit h p ote nt effects at t he N -met h yl -D -as partate ( N M D A) rece pt or, i ncl u di n g 
me ma nti ne a, a ma nta di ne, keta mi ne, or relate d c o m p o u n ds. 
b.  m e dicati o ns t hat i n hi bit c h olester ol a bs or pti o n (e g, ezeti mi be).  
c. b ile aci d se q uestra nts (e g, c olese vela m, c h olest yra mi ne). 
d.  o t her me dicati o ns gi ve n at d oses, fre q ue ncies, or i n c o m bi nati o ns t hat are li kel y, i n t he 
o pi ni o n of t he i n vesti gat or, t o ha ve a deleteri o us effect o n c o g niti ve perf or ma nce.  

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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 1  
e. ca n na bis or ot her tetra h y dr oca n na bi n ol ( T H C) -c o ntai ni n g s u bsta nces ( a n y r o ute of 
a d mi nistrati o n), re gar dless of w het her or n ot t he y are prescri be d.  
aMe ma nti ne is pr o hi bite d wit hi n 3 0 da ys of scree ni n g a n d d uri n g t he e ntire c o urse of t he 
st u d y.  
1 1.  ha ve a n alc o h ol or dr u g use dis or der wit hi n t he past 1 2 m o nt hs as per Dia g n ostic a n d 
Statistical Ma n ual of Me ntal Dis or ders ( D S M -5) criteria;  
1 2.  ha ve a hist or y of seiz ures or e pile ps y, wit h t he e xce pti o n of a si n gle e pis o de of fe brile 
seiz ures i n c hil d h o o d; 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.  ha ve a n y of t he f oll o wi n g cli nicall y si g nifica nt me dical c o n diti o ns:  
a. an y cli nicall y si g nifica nt fi n di n g o n 1 2 -lea d E C G d uri n g Scree ni n g or Baseli ne 
b.  a n y cli nicall y si g nifica nt s u pi ne vital si g ns ( heart rate, s yst olic a n d diast olic bl o o d 
press ure)  d uri n g Scree ni n g or Baseli ne (n ote: vital si g n meas ure me nts ma y be re peate d 
o nce ).  
1 5.  ha ve si g nifica nt he patic, re nal, car di o vasc ular, p ul m o nar y, gastr oi ntesti nal, he mat ol o gical, 
i m m u n ol o gic, o p ht hal m ol o gic, meta b olic, or o nc ol o gical disease;  
1 6.  ha ve a hist or y, prese nce, a n d/ or c urre nt e vi de nce of ser ol o gic p ositi ve res ults f or h u ma n 
i m m u n o deficie nc y vir us ( HI V)-1  or HI V -2 , a n d/ or has detecta ble he patitis B s urface a nti ge n, 
a nti -he patitis C vir us ( H C V) or  p ositi ve H C V viral l oa d at Scree ni n g; 
1 7.  ha ve a p ositi ve pre g na nc y test, be pre g na nt, be lactati n g, or i nte n d t o breastfee d d uri n g t he 
st u d y;  
1 8.  be i n vesti gati ve site pers o n nel, s p o ns or pers o n nel, or a n i m me diate me m ber of t heir fa mil y 
(s p o use, pare nt, c hil d, or si bli n g w het her bi ol o gical or le gall y a d o pte d) ; or 
1 9.  is k n o w n t o be aller gic t o a n y S A G E-7 1 8 e xci pie nts, i ncl u di n g s o y lecit hi n . 
I n vesti g ati o n al Pr o d uct D os a ge a n d M o de of A d mi nistr ati o n:  
S A G E -7 1 8 1. 2  m g or matc hi n g place b o will be self -a d mi nistere d as oral s oft gel li pi d ca ps ule(s) o nce 
dail y i n t he m or ni n g.  
D ur ati o n of Tre at me nt: I P will be a d mi nistere d o nce dail y f or 4 2 da ys ( 6 wee ks).  
St atistic al Met h o ds:  
A se parate statistical a nal ysis pla n ( S A P) will pr o vi de a detaile d descri pti o n of t he a nal yses t o be 
perf or me d i n t he st u d y. T he S A P will be fi nalize d a n d a p pr o ve d pri or t o data base l oc k.  
Ge ner al C o nsi der ati o ns  
U nless ot her wise s pecifie d, Baseli ne is defi ne d as t he last meas ure me nt pri or t o t he first d ose of I P.  
C o nti n u o us e n d p oi nts will be s u m marize d wit h n, mea n, sta n dar d de viati o n, me dia n, mi ni m u m a n d 
ma xi m u m, Q 1, a n d Q 3. I n a d diti o n, c ha n ge fr o m baseli ne val ues will be calc ulate d at eac h ti me p oi nt 
a n d will be s u m marize d usi n g t he sa me s u m mar y statistics. O ut of ra n ge safet y e n d p oi nts ma y be 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 2  
cate g orize d as l o w or hi g h, w here a p plica ble. F or all cate g orical e n d p oi nts, s u m maries will i ncl u de 
c o u nts a n d perce nta ges.  
A n al ysis Sets  
T he All Ra n d o mize d Set will i ncl u de all partici pa nts w h o ha ve bee n ra n d o mize d a n d wil l be use d t o 
descri be partici pa nt dis p ositi o n.  
T he Safet y Set will i ncl u de all partici pa nts w h o were a d mi nistere d at least o ne d ose of t he I P a n d will 
be use d t o descri be t he safet y data.  
T he F ull A nal ysis Set will i ncl u de all partici pa nts i n t he Safet y Se t w h o ha ve baseli ne a n d at least 
1  p ost baseli ne efficac y e val uati o n.  
 
 
S af et y A n al ysis  
A Es will be c o de d usi n g t he Me dical D icti o nar y f or Re g ulat or y Acti vities ( Me d D R A) versi o n 2 2. 0 or 
hi g her. A T E A E is defi ne d as a n A E wit h o nset after t he first d ose of I P. T he pr o p orti o n of 
partici pa nts e x perie nci n g T E A Es will be dis pla ye d b y treat me nt gr o u p a n d b y s yste m or ga n class a n d 
pref erre d ter m. I n a d diti o n, s u m maries will be pr o vi de d b y i nte nsit y ( mil d, m o derate, se vere) a n d b y 
ca usalit y (relate d, n ot relate d) t o I P. A n y T E A Es lea di n g t o disc o nti n uati o n or i nterr u pti o n of 
treat me nt or wit h dra wal fr o m t he st u d y a n d a n y treat me nt-e mer ge nt S A Es will be s u m marize d.  All 
A Es a n d S A Es (i ncl u di n g t h ose wit h o nset or w orse ni n g bef ore t he start of I P) t hr o u g h t he e n d of t he 
st u d y will be liste d. Vital si g ns, la b orat or y para meters, E C Gs, 
 data will be s u m marize d 
b y treat me nt gr o u p. A d di ti o nal a nal yses will be detaile d i n t he S A P. 
Effic ac y A n al ysis  
T he e n d p oi nts f or eac h c o g niti ve test, i ncl u di n g i n di vi d ual sc ores f or t he W AI S -IV C o di n g test 
 
 
 Descri pti ve statistics of sc ores a n d c ha n ge fr o m baseli ne 
sc ores will be s u m marize d base d o n t he F ull A nal ysis Set. T hese e n d p oi nts will als o be a nal yze d 
usi n g a mi xe d effects m o del f or re pea te d meas ures. T he m o del will i ncl u de c ha n ge fr o m baseli ne 
sc ores as de pe n de nt varia ble; treat me nt, visit, a n d visit b y treat me nt i nteracti o n as fi xe d effects; 
partici pa nts as ra n d o m effects; a n d baseli ne c o g niti ve test sc ores as a c o variate; M o del -base d p o i nt 
esti mates (ie,  least s q uare mea ns, t heir 9 5 % c o nfi de nce i nter vals, a n d ass ociate d p val ues) at eac h 
ti me p oi nt ( visit) will be re p orte d w here a p plica ble. Li ne pl ots of c ha n ge fr o m baseli ne sc ores will be 
pl otte d wit h sta n dar d err or bars. 
 
 will be a nal yze d usi n g si milar met h o ds.  
  
 
 
S a m ple Size C alc ul ati o n  
Ass u mi n g a place b o -a dj uste d treat me nt effect size of  0. 7 5 (B ur dic k 2 0 1 4 ) i n t he W AI S -I V C o di n g 
test, a t otal sa m ple size of 6 0 e val ua ble partici pa nts ( 3 0 per ar m) will pr o vi de 8 0 % p o wer at a t w o -
si de d si g nifica nce le vel α = 0. 0 5. 
A dj usti n g f or a n a ntici pate d 2 0 % dr o p o ut rate, a p pr o xi matel y 7 6 partici pa nts will be ra n d o ml y 
assi g ne d i n a 1: 1 rati o t o eit her S A G E -7 1 8 or place b o.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 3  
T a ble  2 : 
Sc he d ule of Assess me nts   
Assess me nts a  
Scree ni n g 
Peri o d  
B aseli ne  
Tre at me nt Peri o d  
F oll o w -U p 
Peri o d  
D a ys -2 8 t o -8  
D a y  -7  
(± 2  d a ys)  
D a y 1 b  
D a y 1 4  
 ( ± 2 d a ys) 
D a y 2 8 c 
 ( ± 2 d a ys)  
P h o ne C all  
D a y 4 2 d  
 (-2 d a y s)  
D a y 7 0 ( ± 4 d a ys)  
 or E T  
I nf or me d c o nse nt e 
X  
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
X  
 
 
 
 
Ra n d o mizati o n  
 
 
X  
 
 
 
 
M e dical hist or y a n d de m o gra p hics f 
X  
 
 
 
 
 
 
P artici pa nt trai ni n gg  
X  
X  
 
 
 
 
 
B o d y wei g ht  
X  
 
X  
 
 
X  
X  
B o d y hei g ht  
X  
 
 
 
 
 
 
Vital si g ns (i ncl u di n g ort h ostatics) h  
X  
 
X  
X  
 
X  
X  
P h ysical e xa mi nati o n i 
X  
 
X  
X  
 
X  
X  
F S H test j 
X  
 
 
 
 
 
 
Ser ol o g y test k  
X  
 
 
 
 
 
 
1 2 -lea d E C Gl 
X  
 
 
X  
 
X  
X  
Cli nical la b orat or y assess me nts m  
X  
 
X  
X  
 
X  
X  
Uri ne dr u g test  
X  
 
X  
X  
 
X  
X  
Alc o h ol breat h test 
X  
 
X  
X  
 
X  
X  
Pre g na nc y test n  
X  
 
X  
 
 
 
X  
O pti o nal bi oc he mical researc h sa m ple o  
X  
 
 
X  
 
X  
 
O pti o nal ge netic researc h sa m ple o  
X  
 
 
 
 
 
 

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Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 4  
Assess me nts a  
Scree ni n g 
Peri o d  
B aseli ne  
Tre at me nt Peri o d  
F oll o w -U p 
Peri o d  
D a ys -2 8 t o -8  
D a y  -7  
(± 2  d a ys)  
D a y 1 b  
D a y 1 4  
 ( ± 2 d a ys) 
D a y 2 8 c 
 ( ± 2 d a ys)  
P h o ne C all  
D a y 4 2 d  
 (-2 d a y s)  
D a y 7 0 ( ± 4 d a ys)  
 or E T  
M o difie d H oe h n a n d Ya hr sta ge scale  
X  
 
 
 
 
 
 
W AI S -I V C o di n g T est  
 
X  
X  
X  
 
X  
X  
 
 a n d 
P D A Q -1 5  K n o wle d gea ble I nf or ma nt )r 
 
X  
 
 
 
X  
X  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 5  
Assess me nts a  
Scree ni n g 
Peri o d  
B aseli ne  
Tre at me nt Peri o d  
F oll o w -U p 
Peri o d  
D a ys -2 8 t o -8  
D a y  -7  
(± 2  d a ys)  
D a y 1 b  
D a y 1 4  
 ( ± 2 d a ys) 
D a y 2 8 c 
 ( ± 2 d a ys)  
P h o ne C all  
D a y 4 2 d  
 (-2 d a y s)  
D a y 7 0 ( ± 4 d a ys)  
 or E T  
Dail y m o bile assess me nt t ( D S S T, P V T, 
slee p diar y) 
 
X  
 
I P self-a d mi nistrati o n u  
 
 
X ( o nce dail y i n t he m or ni n g)  
 
I P dis pe nsati o nv  
 
 
X  
X  
 
 
 
I P acc o u nta bilit y/ret ur nw  
 
 
X  
X  
 
X  
 
A Es/ S A Es x   
X  
X  
X  
X  
X  
X  
X  
Pri or a n d c o nc o mita nt me dicati o ns y  
X  
A b bre viati o ns: A E = a d verse e ve nt,  
 C O VI D-1 9 = c or o na vir us disease 2 0 1 9; 
 
 
 D S S T = Di git S y m b ol S u bstit uti o n T est; E C G  =  electr ocar di o gra m; E T  =  earl y ter mi nati o n; F S H  =  f ollicle-
sti m ulati n g h or m o ne; HI V = h u ma n i m m u n o deficie nc y vir us;  I C F =  i nf or me d c o nse nt f or m; I P = i n vesti gati o nal pr o d uct; 
 
P D  =  P ar ki ns o n’s Disease; 
 
; P D A Q-1 5 KI = P e n n P ar ki ns o n’s Disease Acti vities Q uesti o n naire -1 5 K n o wle d gea ble I nf or ma nt; 
 
 P R O  =  patie nt -re p orte d o utc o me; P V T = Ps yc h o m ot or Vi gila nce 
T as k ; S A E = seri o us a d verse e ve nt; 
 W AI S-I V = W ec hsler A d ult I ntelli ge nce S cale-I V. 
 
a T he scales are t o be a d mi nistere d after t he dail y d ose of I P d uri n g t he Treat me nt P eri o d, a n d at a p pr o xi matel y t he sa me ti me of da y ( ± 2 h o urs) t hr o u g h o ut t he 
st u d y. F or partici pa nts recei vi n g me dicati o n f or P D s y m pt o ms, t he scales are t o b e a d mi nistere d i n t he “ o n” state ( defi ne d as t he peri o d i n w hic h m ot or 
s y m pt o ms are miti gate d d ue t o t he effects of P D me dicati o n). F or cli nicia n a d mi nistere d s cales, t he sa me i n di vi d ual s h o ul d a d mi nister t he scale w he ne ver 
p ossi ble.  
b All tests o n Da y 1 will be c o n d ucte d pre d ose.  
c P h o ne c hec k -i n o nl y f or A Es/ S A Es a n d c ha n ges t o me dical hist or y or me dicati o ns. 
d D osi n g e n ds o n Da y 4 2 . 
e B ot h partici pa nts a n d care gi ve rs (if a p plica ble) will  be c o nse nte d d uri n g t he Scree ni n g P eri o d . 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 6  
f I n a d diti o n t o f ull me dical hist or y, i ncl u di n g fa mil y hist or y of P D, all me dicati o ns a n d s u p ple me nts ta ke n wit hi n 6 0 da ys  pri or t o Scree ni n g, all me dicati o ns 
use d t o treat P D re gar dless of ti mi n g, a n d all n o n p har mac ol o gical met h o ds (e g, ps yc h os ocial, ps yc h ot hera pe utic) use d t o treat or pre ve nt 
 
, a n d c o g niti ve ma nifestati o ns of P D are t o be rec or de d. I nf or mati o n re gar di n g di a g n osis, is olati o n, a n d/ or h os pitalizati o n d u e t o C O VI D -1 9 will b e 
d oc u me nte d as part of me dical hist or y, A E c ollecti o n, a n d pri or/c o nc o mita nt me dicati o n/ pr oce d ure c ollecti o n at Scree ni n g a n d t hr o u g h o ut t he st u d y . 
g P artici pa nts a n d care gi ve rs (if a p plica ble) will be trai ne d b y st u d y staff o n t he use of s oft ware a p plicati o ns a n d de vices necessar y f or t he c o n d uct o f t he st u d y. 
h Vital si g ns i ncl u de  b o d y te m p erat ure, res pirat o r y rate, heart rate, a n d bl o o d press ure. Vital si g ns will be meas ure d pri or t o d osi n g o n da ys  w he n I P is 
a d mi nistere d . B l o o d press ure a n d heart rate will be meas ure d after t he partici pa nt has bee n i n t he s u pi ne p ositi o n f or at l east 5 mi n utes a nd t he n re p e at e d 
a p pr o xi matel y 1 a n d 3  mi n utes after sta n di n g , at all sc he d ul e d ti me p oi nts.  
i A f ull p h ysical e xa mi nati o n will be c o n d ucte d d uri n g Scree ni n g a n d at Da y 4 2 ( E n d of Treat me nt). At ot her visits , a n a b bre viate d p h ysical e xa mi nati o n will 
i ncl u de a brief assess me nt of ge neral a p peara nce, car di o vas c ular, res pirat or y, gastr oi ntesti nal, a n d ne ur ol o gical s yste ms,  f oll o we d b y a tar gete d p h ysic al 
assess me nt as nee de d. A s y m pt o m directe d e xa mi nati o n ma y be c o n d ucte d at a n y ti me at t he discreti o n of t he i n vesti gat or.  
j S er u m F S H test will be c o n d ucte d at Scree ni n g f or t he fe male partici pa nt s w h o are n ot s ur gicall y sterile t o c o nfir m w het her fe mal e partici pa nts  wit h 
≥1 2  m o nt hs of s p o nta ne o us a me n orr hea meet t he pr ot oc ol -defi ne d criteria f or bei n g p ost me n o pa usal.  
k T o i ncl u de he p atitis B a n d C s cree ni n g tests, HI V -1 a n d -2 a nti b o d y . 
l A si n gle E C G will be meas ure d after t he partici pa nt has bee n i n t he s u pi ne p ositi o n f or at l east 5 mi n utes . 
m  Cli nical la b orat or y assess me nts will i ncl u de bl o o d sa m ples f or he mat ol o g y, bi oc he mistr y, c oa g ulati o n, a n d uri ne sa m ples f or uri nal ysis. Sa m ples w ill be 
c ollecte d pri or t o d osi n g o n da ys  w he n I P is a d mi nistere d . O n n o n d osi n g da ys, c ollecti o n ma y occ ur at a n y ti me. 
n Ser u m pre g na nc y tests will be c o n d ucte d f or all fe male parti ci pa nts at Scree ni n g; uri ne pre g na nc y tests will be c o n d ucte d at ot her sc he d ule d ti me p oi nts f or 
fe male partici pa nts w h o  are n ot p ost me n o pa usal o r s ur gicall y sterile. 
o Refer t o T a ble  3  f or details. 
 
 
 
 
 
 
 
r P D A Q -1 5 K n o wle d gea ble I nf or ma nt  is pr o vi de d b y care gi ver. 
 
 
t Dail y re mi n ders will be se nt t o partici pa nts via a m o bile de vice t o c o m plete assess me nts o n re m ote de vice. Dail y assess me nts i ncl u de t he  
 D S S T , 
P V T , a n d t he Nati o nal Slee p F o u n dati o n Slee p Diar y. It is rec o m me n de d t hat assess me nts are co m plete d at a p pr o xi matel y t he sa me ti me eac h da y, wit hi n 1 
h o ur f oll o wi n g I P a d mi nistrati o n. Dail y m o bile assess me nts s h o ul d be c o m plete d i n a q uiet area of partici pa nt’s h o me. O n d osi n g da ys t he re m ote assess me nt 
will b e c o m plete d i n t he cli nic f oll o wi n g d osi n g u n der o bser vati o n b y t he st u d y staff.  
u O n Da ys 1, 1 4, a n d 4 2, t he partici pa nts will self -a d mi nister I P i n t he cli nic u n der t he s u per visi o n of st u d y staff. All sc he d ule d safet y assess me nts  will b e 
c o n d ucte d pri or t o d osi n g a n d all sc he d ule d c o g niti ve tests will be a d mi nistere d p ost d osi n g . 
v St u d y staff will dis pe nse e n o u g h I P f or t he partici pa nt t o ta ke dail y at h o me u ntil t he ne xt sc he d ule d visit . 
w  P artici pa nts will bri n g all use d pac ka gi n g a n d u n use d I P t o t he cli nic at eac h visit f or st u d y staff t o re vie w a n d d oc u me nt . 
x A Es/ S A Es c ollecte d fr o m ti me of I C F t hr o u g h o ut t he d urati o n of partici pati o n . 
y At Scree ni n g, t o i ncl u de all me dicati o ns a n d s u p ple me nts ta ke n wit hi n 6 0 da ys a n d all me dicati o ns use d t o treat P D re gar dless of ti mi n g. At s u bse q ue nt visits, 
all c ha n ges t o a n y me dicati o n s h o ul d be ca pt ure d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 7  
 
T a ble  3 : 
Sc he d ule of 
, Bi oc he mi c al , a n d Ge neti c S a m pli n g   
Assess me nts  
Scree ni n g  
B aseli ne  
Tre at me nt  
F oll o w -U p  
D a ys -2 8 t o -8  
D a y  -7  
( ± 2 d a ys) 
D a y 1  
D a y 1 4  
( ± 2 d a ys) 
D a y 4 2  
(-2 d a y s) 
D a y 7 0 ( ± 4  d a ys)  
 or E T  
Pre d ose  
 
 
 
X  
X  
X  
O pti o n al bl o o d c ollecti o n: bi oc he mic al rese arc h b  
 
X  
 
 
X  
X  
 
O pti o n al bl o o d c ollecti o n: ge netic rese arc h  
 
X  
 
 
 
 
 
A b bre viati o ns:  E T = earl y ter mi nati o n;  I P = i n vesti gati o nal pr o d uct;
 
 
 
 
b  Bi oc he mical sa m ples will be c ollecte d at a n y ti me d uri n g S cree ni n g. O n Da ys 1 4 a n d 4 2, t h e sa m ples will be c ollecte d at ti mes c orres p o n di n g wit h t he  
 
bl o o d dra w.  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 8  
2.  
T A B L E O F C O N T E N T S  
C O N T A C T I N F O R M A TI O N  ..........................................................................................................5  
1.  
S Y N O P SI S  ...................................................................................................................6  
2.  
T A B L E O F C O N T E N T S  ...........................................................................................1 8  
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 .............................2 4  
4.  
I N T R O D U C TI O N ......................................................................................................2 7  
4. 1.  
D ose J ustificati o n  ........................................................................................................2 7  
5.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ..............................................................2 8  
6.  
I N V E S TI G A TI O N A L P L A N .....................................................................................2 9  
6. 1.  
O verall St u d y Desi g n  ..................................................................................................2 9  
6. 1. 1.  
Scree ni n g Peri o d  .........................................................................................................2 9  
6. 1. 2.  
Baseli ne Peri o d  ...........................................................................................................2 9  
6. 1. 3.  
Treat me nt Peri o d  ........................................................................................................2 9  
6. 1. 4.  
F oll o w -u p Peri o d  ........................................................................................................3 0  
6. 2.  
N u m ber of Partici pa nts  ...............................................................................................3 2  
6. 3.  
Treat me nt Assi g n me nt  ................................................................................................3 2  
6. 4.  
D ose A dj ust me nt Criteria  ...........................................................................................3 2  
6. 4. 1.  
St o p pi n g Criteria  .........................................................................................................3 2  
6. 4. 2.  
D ose E val uati o n C o m mittee  .......................................................................................3 2  
6. 4. 3.  
Criteria f or St u d y Ter mi nati o n  ...................................................................................3 2  
6. 5.  
E n d of St u d y Defi niti o n  ..............................................................................................3 3  
7.  
S E L E C TI O N A N D WI T H D R A W A L O F P A R TI CI P A N T S .....................................3 4  
7. 1.  
I n cl usi o n Criteria ........................................................................................................3 4  
7. 2.  
E x cl usi o n Criteria  .......................................................................................................3 5  
7. 3.  
Scree n Fail ures  ............................................................................................................3 6  
7. 4.  
I n v esti gati o nal Pr o d uct Disc o nti n uati o n a n d Earl y Ter mi nati o n fr o m t he 
St u d y  ...........................................................................................................................3 6  
7. 4. 1.  
I n v esti gati o nal Pr o d uct Disc o nti n uati o n .....................................................................3 7  
7. 4. 2.  
Earl y Ter mi nati o n f r o m t he St u d y ..............................................................................3 7  
7. 4. 3.  
L ost t o F oll o w -u p  .......................................................................................................3 7  
7. 4. 4.  
Re place me nt of Partici pa nts  .......................................................................................3 7  
8.  
T R E A T M E N T O F P A R TI CI P A N T S  .........................................................................3 8  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 9  
8. 1.  
Descri pti o n of I n v esti gati o nal Pr o d uct  .......................................................................3 8  
8. 2.  
Pri or Me dicati o ns, C o nc o mita nt Me dicati o ns, Restricti o ns, a n d 
C o ntrace pti o n Re q uire m e nts  ......................................................................................3 8  
8. 2. 1.  
Pri or a n d  C o nc o mita nt Me dicati o ns a n d/ or S u p ple me nts  ..........................................3 8  
8. 2. 2.  
Pr o hi bite d Me dicati o ns  ...............................................................................................3 8  
8. 2. 3.  
Ot her Restricti o ns  .......................................................................................................3 9  
8. 2. 4.  
Acce pt a ble F or ms of C o ntrace pti o n  ...........................................................................3 9  
8. 3.  
I nter ve nti o n aft er t he E n d of t he St u d y .......................................................................4 0  
8. 4.  
Treat me nt A d h ere n ce  ..................................................................................................4 0  
8. 5.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................4 0  
8. 5. 1.  
E mer ge nc y U n bli n di n g  ...............................................................................................4 0  
9.  
I N V E S TI G A TI O N A L P R O DU C T M A T E RI A L S A N D M A N A G E M E N T  .............4 1  
9. 1.  
I n v esti gati o nal Pr o d uct ...............................................................................................4 1  
9. 2.  
I n v esti gati o nal Pr o d uct Pac ka gi n g a n d La beli n g .......................................................4 1  
9. 3.  
I n v esti gati o nal Pr o d uct St ora ge ..................................................................................4 1  
9. 4.  
I n v esti gati o nal Pr o d uct Pre parati o n ............................................................................4 2  
9. 5.  
I n v esti gati o nal Pr o d uct A d mi nistrati o n ......................................................................4 2  
9. 6.  
I n v esti gati o nal Pr o d uct Acc o u nta bilit y, Ha n dli n g, a n d Dis p osal ...............................4 2  
9. 6. 1.  
I n v esti gati o nal Pr o d uct Acc o u nta bilit y, Ha n dli n g, a n d Dis p osal ...............................4 2  
9. 6. 2.  
Pr o d uct C o m plai nts  ....................................................................................................4 3  
1 0.  
S C R E E NI N G, E F FI C A C Y A N D C LI NI C A L P H A R M A C O L O G Y 
A S S E S S M E N T S .........................................................................................................4 4  
1 0. 1.  
Scree ni n g Assess me nts  ...............................................................................................4 4  
1 0. 1. 1.  
M o ntreal C o g niti ve Assess me nt  .................................................................................4 4  
 
4 4  
 
4 4  
1 0. 2. 2.  
Wec hsler A d ult I ntelli ge nce Scale -I V C o di n g Test ...................................................4 5  
 
4 5  
 
 
4 5  
 
4 5  
 
4 5  
 
4 6  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 0  
 
4 6  
 
4 6  
 
4 6  
 
4 6  
 
4 6  
 
4 7  
 
4 7  
 
4 7  
1 0. 3.  
Dail y ( M o bile P h o ne -Base d) Assess me nts  .................................................................4 7  
1 0. 3. 1.  
Ps yc h o m ot or Vi gila nce Tas k  ......................................................................................4 7  
1 0. 3. 2.  
Di git S y m b ol S u bstit uti o n Test  ..................................................................................4 7  
1 0. 3. 3.  
Nati o nal Slee p F o u n d ati o n Slee p Diar y  .....................................................................4 7  
 
4 8  
 
 
4 8  
1 0. 4. 2.  
M o difie d H oe h n  a n d Y a hr Sta gi n g Scale  ...................................................................4 8  
 
4 8  
 
4 8  
 
4 8  
 
4 8  
 
4 9  
 
4 9  
 
4 9  
 
4 9  
1 0. 6. 2.  
Pe n n Par ki ns o n’s Dail y Acti vities Q uesti o n naire -1 5 K n o wle d gea bl e 
I nf or ma nt ( P D A Q-1 5 KI)  ...........................................................................................4 9  
 
5 0  
1 0. 7.  
Cli nical P har mac ol o g y Assess me nts  ..........................................................................5 0  
 
5 0  
 
5 0  
 
5 0  
1 0 . 7. 2. 
P har mac o d y na mic Ass ess me nts  .................................................................................5 0  
1 0. 7. 3.  
O pti o nal Bi oc he mical Researc h  .................................................................................5 1  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 1  
1 0. 7. 4.  
O pti o nal Ge netic Researc h  .........................................................................................5 1  
1 1.  
S A F E T Y A S S E S S M E N T S  ........................................................................................5 2  
1 1. 1.  
Safet y Para met ers  .......................................................................................................5 2  
1 1. 1. 1.  
De m o gra p h y a n d Me dical Hist or y  ..............................................................................5 2  
1 1. 1. 2.  
Wei g ht a n d Hei g ht  ......................................................................................................5 2  
1 1. 1. 3.  
P h ysical E x a mi nati o n  .................................................................................................5 2  
1 1. 1. 4.  
C O VI D -1 9 Q u esti o ns  .................................................................................................5 2  
1 1. 1. 5.  
Vital Si g ns  ..................................................................................................................5 2  
1 1. 1. 6.  
Electr ocar di o gra m ( E C G)  ...........................................................................................5 3  
1 1. 1. 7.  
La b orat or y Ass ess me nts  .............................................................................................5 3  
1 1. 1. 7. 1.  
Dr u gs of A b use, Alc o h ol  ............................................................................................5 3  
1 1. 1. 7. 2.  
Pre g n a nc y T esti n g  ......................................................................................................5 4  
 
5 4  
1 1. 1. 9.  
C O VI D -1 9 Q u esti o ns  .................................................................................................5 4  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts  .........................................................................5 4  
1 1. 2. 1.  
A d verse E v e nt Defi niti o n  ...........................................................................................5 4  
1 1. 2. 2.  
Seri o us A d verse E v e nt ( S A E) Defi niti o n  ...................................................................5 5  
1 1. 2. 3.  
Defi niti o n of Ur ge nt Safet y Meas ure ( U S M) a n d U na ntici pate d Pr o ble m 
( U P) .............................................................................................................................5 6  
1 1. 2. 4.  
Relati o ns hi p t o I n vesti gati o nal Pr o d uct  ......................................................................5 6  
1 1. 2. 5.  
Rec or di n g A d verse E ve nts  .........................................................................................5 7  
1 1. 2. 6.  
Re p orti n g Seri o us A d v erse E ve nts  .............................................................................5 7  
1 1. 3.  
Pre g n a nc y  ...................................................................................................................5 8  
1 1. 4.  
O ver d ose  .....................................................................................................................5 8  
1 2.  
S T A TI S TI C S  ..............................................................................................................5 9  
1 2. 1.  
Data A nal ysis Sets  ......................................................................................................5 9  
1 2. 2.  
Ha n dli n g of Missi n g Dat a  ...........................................................................................5 9  
1 2. 3.  
Ge neral C o nsi derati o ns  ...............................................................................................5 9  
1 2. 4.  
De m o gra p hics a n d Baseli ne C haract eristics  ...............................................................5 9  
1 2. 5.  
Efficac y A nal ysis  ........................................................................................................6 0  
1 2. 5 . 1. 
M ulti plicit y A dj ust me nt ..............................................................................................6 0  
1 2. 5. 2.  
Se nsiti vit y A nal ys es  ....................................................................................................6 0  
1 2. 6.  
Safet y A nal yses  ..........................................................................................................6 0  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 2  
1 2. 6. 1.  
A d verse E v e nts  ...........................................................................................................6 0  
1 2. 6. 2 . 
Cli nical La b orat or y E val uati o ns  .................................................................................6 1  
1 2. 6. 3.  
P h ysical E x a mi nati o ns  ................................................................................................6 1  
1 2. 6. 4.  
Vital Si g ns  ..................................................................................................................6 1  
1 2. 6. 5.  
1 2 -Lea d Electr ocar di o gra m  ........................................................................................6 1  
1 2. 6. 6.  
Pri or a n d C o nc o mita nt Me dicati o ns  ...........................................................................6 1  
 
6 2  
1 2. 6. 8.  
Ot her Safet y A n al ysis  .................................................................................................6 2  
1 2. 7.  
Cli nical P har mac ol o g y A nal yses  ................................................................................6 2  
1 2. 8.  
Sa m ple Siz e a n d P o wer  ..............................................................................................6 2  
1 2. 8. 1.  
I nteri m a n d Dat a M o nit ori n g C o m mittee A nal ysis ....................................................6 2  
1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S .........................................6 3  
1 3. 1.  
St u d y M o nit ori n g  ........................................................................................................6 3  
1 3. 2.  
A u dits a n d I ns p ecti o ns  ................................................................................................6 3  
1 3. 3.  
I nstit uti o nal Re vie w B oar d or I n de p e n de nt Et hics C o m mittee ..................................6 4  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................6 5  
1 5.  
E T HI C S  ......................................................................................................................6 6  
1 5. 1.  
Et hics Re vie w  .............................................................................................................6 6  
1 5. 2.  
Et hical C o n d uct of t he St u d y  ......................................................................................6 6  
1 5. 3.  
Writte n I nf or m e d C o nse nt  ..........................................................................................6 6  
1 5. 4.  
Data Pr otecti o n  ...........................................................................................................6 7  
1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .......................................................6 8  
1 6. 1.  
I ns p ecti o n of Rec or ds .................................................................................................6 8  
1 6. 2.  
Rete nti o n of Rec or ds  ..................................................................................................6 8  
1 7.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................6 9  
1 8.  
LI S T O F R E F E R E N C E S  ............................................................................................7 0  
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 3  
LI S T O F T A B L E S  
Ta ble 1:  
C o ntact I nf or mati o n  ......................................................................................................5  
Ta ble  2:  
Sc he d ule of Assess me nts  ............................................................................................1 3  
Ta ble  3:  
Sc he d ule of 
, Bi oc he mical a n d Ge netic Sa m pli n g ...........................1 7  
Ta ble  4:  
I n v esti gati o nal Pr o d uct ...............................................................................................4 1  
Ta ble  5:  
S u m mar y of Cli nical La b orat or y A nal ytes  .................................................................5 3  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 4  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E F I 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 : 
A b bre vi ati o n  
Defi niti o n  
2 4 S H C  
2 4 (S )-h y dr o x yc h olest er ol  
A E  
a d verse e ve nt  
B MI  
b o d y mass i n de x  
 
 
 
  
 
 
 
 
 
 
 
 
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C ma x  
ma xi m u m c o nce ntrati o n  
C S  
cli nicall y si g nifica nt  
 
 
 
 
D S S T  
Di git S y m b ol S u bstit uti o n Test  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
F S H  
f ollicle sti m ulati n g h or m o ne  
G C P  
G o o d Cli nical Practice  
 
 
G M P  
G o o d Ma n ufact uri n g Practice  
I A D L 
i nstr u me ntal acti vities of dail y li vi n g  
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 of Tec h ni cal Re q uire me nts f or 
P har mace uticals f or H u m a n Use  
I D 
i de ntificati o n  
I E C 
i n de pe n de nt et hics c o m mittee 
I P 
i n vesti gati o nal pr o d u ct 
I R B 
i nstit uti o nal re vie w b oar d 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 5  
A b bre vi ati o n  
Defi niti o n  
I R T 
i nteracti ve res p o nse tec h n ol o g y 
KI  
k n o wle d gea ble i nf or ma nt  
L C -M S/ M S  
li q ui d c hr o mat o gra p h y wit h ta n de m mass s pectr o metr y  
M CI  
mil d c o g niti ve i m pair me nt  
Me d D R A  
Me dical Dicti o nar y of Re g ul at or y Acti vities  
M D S  
M o ve me nt Dis or der S oci et y  
 
 
M o C A  
M o ntreal C o g niti ve Assess me nt  
N C S  
n ot cli nicall y si g nifica nt  
 
  
N M D A  
N -met h yl -D -as p artate  
 
  
P A M  
p ositi ve all osteric m o d ulat or  
P D  
Par ki ns o n’s Disease  
 
  
P D A Q -1 5 KI  
Pe n n Par ki ns o n’s Dail y Acti vities Q uesti o n naire -1 5 K n o wle d gea bl e 
I nf or ma nt  
 
 
 
 
P K  
p har mac o ki netic  
P V T  
Ps yc h o m ot or Vi gila nce Test  
Q Tc F  
Q T c orrecte d acc or di n g t o Fri deri cia’s f or m ula  
S A E  
seri o us a d vers e e v e nt 
S A P  
statistical a nal ysis pla n 
 
 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T H C  
tetra h y dr oca n na bi n ol 
U P  
u na ntici pate d pr o ble m  
U S  
U nite d States  
U S M  
ur ge nt safet y me as ure  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 6  
A b bre vi ati o n  
Defi niti o n  
W AI S -I V 
Wec hsler A d ult I ntelli ge nce Scale -I V  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 7  
4.  
I N T R O D U C TI O N 
T he esti mate d pre v ale nce f or Par ki ns o n’s Disease  ( P D) i n t he U nite d States ( U S) is nearl y 
1  milli o n , wit h a pr ojecte d i ncreas e t o 1. 2 milli o n b y 2 0 3 0  (Par ki ns o n ’s F o u n dati o n 2 0 2 1 ; Marras  
2 0 1 8 ). Mil d c o g niti ve i m pair me nt ( M CI) is c o m m o n i n patie nts w h o ha ve P D wit h dia g n osis 
rates a p pr oac hi n g 6 0 %  (C h olert o n 2 0 1 3 ). Par ki ns o n’s Disease Mil d C o g niti ve I m pair me nt  
(P D -M CI ) is ass ociate d wit h decrease d q ualit y of life a n d i m paire d f u ncti o n i n g. M ore o v er, 
patie nts wit h P D -M CI are at a hi g h ris k f or de vel o pi n g  de me ntia  (Lit va n 2 0 1 1 ). Des pite t he hi g h 
fre q ue n c y of occ urre nce a n d de bilitati n g i m pact of P D -M CI , t h ere is a l ac k of t hera p e utic 
o pti o ns f or miti gati o n or dela y of c o g niti ve i m pair me nt i n P D  (Marti nez -H orta  2 0 1 9 ).  
Precli nical data i n dicate t hat patie nts w h o ha ve P D  ha ve re d u ce d plas m a le vels of a s pecific  
o x yster ol, 2 4 (S )-h y dr o x yc h olester ol ( 2 4 S H C;  Di  Natale 2 0 1 8 ). T his m olec ule acts as a n 
e n d o ge n o us p ositi ve all osteric m o d ulat or ( P A M) of t he N -met h yl -D -as partate (N M D A ) rece pt or 
(Pa ul 2 0 1 3 ) a n d has b ee n c orrel ate d wit h perf or ma nce o n c o g niti ve tas ks.  N M D A rece pt ors are a 
s u bt y pe of gl uta m ate rece pt ors wit h a f u n da me nt al a n d well-d oc u me nte d r ole i n re g ulati n g 
s y na ptic str e n gt h, healt h, a n d plasticit y. 
S A G E -7 1 8  is a n o vel o x yster ol-b ase d N M D A rece pt or P A M  t hat acts at t h e 2 4 S H C bi n di n g site 
a n d m o d ulates t he res p o nse of t he rece pt or t o e n d o ge n o us gl uta mat e . S A G E -7 1 8  o nl y affects 
rece pt or f u ncti o n i n t he prese nce of e n d o ge n o us gl uta mate –  it d oes n ot directl y acti vate t he 
rece pt or a n d is n ot e x pecte d t o ca use N M D A rece pt or-ass ociate d gl uta m ater gic e x cit ot o xicit y.  
P ositi ve m o d ulati o n of N M D A rece pt ors is h y p ot hesize d t o pr o d uce be n eficial effects  i n 
c o n diti o ns ass ociate d wit h  re d uce d N M D A rece pt or f u ncti o n, acti vit y, or e x pressi o n . Precli nical 
st u dies ha ve s h o w n pr o mise f or i m pr o vi n g c o g niti ve deficits i n co n diti o ns wit h  decrease d plas ma 
le vels of t he e n d o ge n o us N M D A  rece pt or P A M 2 4 S H C  (C olli n gri d ge 2 0 1 3 ). 
4. 1.  
D ose J ustific ati o n  
S A G E -7 1 8  has bee n well  t olerate d i n healt h y partici pa nts, a s mall c o h ort of Hu nti n g t o n’s diseas e 
partici pa nts , a n d i n o n g oi n g cli nic al st u dies  i n partici pa nts wit h Par ki ns o n’s a n d Alz hei mer’s 
Disease . H o we ver, base d o n n o ncli nical fi n di n gs, t he U S F o o d a n d Dr u g A d mi nistrati o n  
i m p ose d a me dia n ma xi m u m c o nce ntrati o n  (C ma x ) ca p of 4 5  n g / m L. T o d ate, cli nical  st u dies 
ha ve use d d oses t h at res ulte d i n e x p os ures wit hi n  t his ca p; neit her S A Es n or A Es lea di n g t o 
disc o nti n uati o n  ha ve bee n re p orte d . F or a d diti o nal i nf or mati o n o n e x p os ure ca ps, see t h e S A G E -
7 1 8 I n v esti gat or’s Br oc h ure.   
A dail y d os e of 1. 2 m g of S A G E -7 1 8 i n a li pi d base d, s oft gel f or m ulati o n, or c orres p o n di n g 
bli n de d place b o, will be gi ve n t o partici pa nts i n t he trial eac h m or ni n g. T he d ose is selecte d t o 
pr o vi de p har mac o ki netic ( P K ) e x p os ures t hat are si milar t o t h ose ac hie ve d i n pri or st u dies t hat 
ha ve s h o w n e vi d e nce of tar get e n ga ge me nt (c o nsiste nt wit h t he N M D A h y p ot hesis f or 
pr o -c o g niti ve effects). 
 
 
 
Effect of S A G E -7 1 8 o n c o g niti ve f u ncti o n i n partici pa nts wit h P D  will be e val uate d i n t his 
ra n d o mize d, place b o-c o ntr olle d, d o u ble -bli n d st u d y. A d diti o nal data o n t h e eff ects of S A G E -7 1 8 
i n partici pa nts wit h P D will be c ollecte d t hr o u g h o ut, i ncl u di n g assess me nts of 
 
.  

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5.  
S T U D Y  O B J E C TI V E S A N D E N D P OI N T S  
O bjecti ves  
E n d p oi nts  
Pri mar y  
•  
T o e val uate t he effect of S A G E -7 1 8 o n 
c o g niti ve perf or ma nce i n partici pa nts 
wit h  P D -M CI.  
•  
C ha n ge fr o m Baseli ne t o Da y 4 2 i n t he Wec hsler 
A d ult I ntelli ge nce Scale -I V ( W AI S-I V) C o di n g 
test. 
Sec o n dar y  
•  
T o e val uate t he safet y a n d t olera bilit y 
of S A G E -7 1 8 oral ca ps ule i n 
partici pa nts wit h P D -M CI.  
•  
Pr o p orti o n of partici pa nts e x perie nci n g 
treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ) a n d 
se verit y of T E A Es. 
•  
N u m ber of partici pa nts w h o wit h dra w d ue t o 
a d verse e ve nts ( A Es).  
  
•  
T o e val uate t he safet y a n d t olera bilit y 
of S A G E -7 1 8 oral ca ps ule o n ot her 
safet y para meters. 
•  
C ha n ge fr o m Baseli ne  i n vital si g ns, cli nical 
la b orat or y para meters, electr ocar di o gra ms 
( E C Gs), a n d 
 
. 

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6.  
I N V E S TI G A TI O N A L P L A N  
6. 1.  
O ver all St u d y Desi g n  
T his i s a ra n d o mize d, place b o-c o ntr olle d, d o u ble -bli n d st u d y t o e val uate t h e effects of 
S A G E -7 1 8 i n P D mil d c o g niti ve i m pair me nt.  
Eli gi ble partici pa nts wit h a c o nfir me d di a g n osis of i di o pat hic P D b y 2 0 1 5 M o ve me nt Dis or der 
S ociet y ( M D S) criteria at Scree ni n g a n d w h o meet M D S Tas k F orce Criteri a f or M CI i n P D 
(e x cl u di n g re q uir e me nt f or U nite d Ki n g d o m ( U K) P D Brai n Ba n k dia g n ostic criteria) will 
recei v e a 1. 2 m g d ose of S A G E -7 1 8 or place b o dail y f or 6 wee ks  ( 4 2 da ys).  
Assess me nts will be perf or me d as o utli ne d i n t he Sc he d ule of Assess me nts (Ta ble  2 ) a n d t he 
Sc he d ule of 
 a n d Bi o c he mical a n d Ge netic  Sa m pli n g ( Ta ble  3 ). T he st u d y 
sc he matic is dis pla ye d i n Fi g ure  1 .  
F or partici pa nts recei vi n g me dicati o n f or P D s y m pt o ms, t he scales are t o be a d mi nistere d i n t he 
“ o n” state ( defi ne d as t he peri o d i n w hic h m ot or s y m pt o ms are miti gate d d ue t o t he effects of P D 
me dicati o n). F or cli nicia n a d mi nistere d scales, t h e sa me i n di vi d ual s h o ul d a d mi nister t he scale 
w he ne ver p ossi ble.  
6. 1. 1.  
Scree ni n g Peri o d  
T he Scree ni n g Peri o d be gi ns wit h t he i nf or me d c o nse nt pr ocess f or pr os pecti ve partici pa nts, 
i ncl u di n g o pti o nal care gi ver s. S u bse q ue nt scree ni n g ass ess me nts will be perf or me d b et wee n 
Da y  -2 8 a n d Da y  -8 t o deter mi ne eli gi bilit y, i n cl u di n g assess me nts of c o g n iti ve a n d m ot or 
f u ncti o n. 
A n a d ult care gi ver is o pti o nal b ut hi g hl y rec o m me n de d f or eac h p artici pa nt t o s u p p ort 
c o m pleti o n of st u d y acti vities a n d t o a ns wer q uesti o ns a b o ut t he partici pa nt’s c o n diti o n . 
6. 1. 2.  
B aseli ne Peri o d  
T he Baseli ne Peri o d will occ ur fr o m Da y -7 t hr o u g h Da y -1. O n Da y -7, partici pa nts will visit 
t he cli nic f or c o nfir mati o n of c o nti n ue d eli gi bilit y a n d c ollecti o n of bas eli ne c o g niti ve a n d safet y 
data. Partici pa nts a n d care gi v er s will recei ve trai ni n g o n t he st u d y pr oce d ures a n d de vices. 
Partici pa nts will c o nti n ue t o c o m plete dail y assess me nts of c o g niti ve perf or ma nce  usi n g t he 
m o bile de vice d uri n g t he Baseli ne Peri o d . 
6. 1. 3.  
Tre at me nt Peri o d  
Eli gi ble partici pa nts will be ra n d o mize d 1: 1 t o recei ve 1. 2  m g of S A G E -7 1 8 or place b o f or 
4 2  da ys.  Be gi n ni n g o n D a y  1 a n d c o nti n ui n g t hr o u g h Da y 4 2, partici pa nts will self -a d mi nister 
bli n de d i n vesti gati o nal pr o d uct (I P) o nce per da y i n t he m or ni n g. N o d osi n g  will be  per mitte d 
be y o n d Da y  4 2.  
At sc he d ule d cli nic visits d uri n g t he  Treat me nt Peri o d,  safet y, efficac y, a n d 
 will 
be perf or me d, a n d st u d y staff will dis pe nse a s ufficie nt a m o u nt of bli n de d I P  f or dail y 
a d mi nistrati o n u ntil t he ne xt sc he d ule d st u d y visit. A d here n ce t o t he d osi n g re gi me n will be 
assesse d at e ac h i n -cli nic visit b y e x a mi nati o n of t he use d pac k a gi n g a n d  c o u nti n g a n y ret ur ne d 
ca ps ules. 

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T he scales are t o b e a d mi nistere d after t he da il y d ose of bli n de d I P  d uri n g t he Treat me nt Peri o d, 
a n d at a p pr o xi matel y t he sa me ti me of da y ( ± 2 h o urs) t hr o u g h o ut t he st u d y.  
D uri n g t h e treat me nt p eri o d, partici pa nts will be a ble t o recei v e I P as l o n g as t here are n o d os e  
li miti n g safet y/t olera bilit y co n cer ns . Partici pa nts w h o disc o nti n ue I P earl y s h o ul d c o m plete t he 
re mai ni n g st u d y visits as sc he d ule d u nless t he partici pa nt wit h dra ws c o nse nt or l oses t he 
ca pacit y t o gra nt c o nse nt. If a partici pa nt wit h dra ws fr o m t he st u d y/st o ps st u d y partici pati o n 
earl y, a n earl y ter mi nati o n visit s h o ul d be c o n d ucte d. Treat me nt wit h I P ca n be e n de d wit h o ut 
d o w n titrati o n.  
6. 1. 4.  
F oll o w -u p Peri o d  
After c o m pleti n g t he treat me nt peri o d, partici pa nts will ret ur n t o t he cli nic f or a f oll o w-u p visit 
o n Da y 7 0 t o c ollect c o nti n ue d sa fet y, efficac y, a n d  
. 
 

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Fi g ure  1 : 
St u d y Sc he m atic  
A b bre viati o ns: C o g niti o n = C o g niti ve assess me nts (i ncl u des Wec hsler A d ult I ntelli ge nce Scale -I V [ W AI S-I V] C o di n g t est; 
 
 
, a n d M o ntreal C o g niti ve Assess me nt [ M o C A]. 
 
 P D-M CI = P ar ki ns o n’s Disease Mil d C o g niti ve I m pair me nt;  
 
; P O = orall y . 
See T a ble  2  f or s pecific sc he d ule of eac h test. 
 

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6. 2.  
N u m ber of P artici p a nt s 
U p t o 7 6 partici pa nts will be d ose d t o o btai n u p t o 3 0  e val ua ble p artici pa nts per  treat me nt ar m. 
A d diti o nal partici pa nts ma y b e ra n d o mize d if t he earl y dis c o nti n uati o n rate is hi g her t ha n 
e x pecte d. 
6. 3.  
Tre at me nt Assi g n me nt  
S A G E -7 1 8 1. 2 m g or place b o  will be self -a d mi nistere d as oral s oft gel li pi d ca ps ule(s) o n ce d ail y 
i n t he m or ni n g 
6. 4.  
D ose A dj ust me nt Criteri a  
6. 4. 1.  
St o p pi n g Criteri a  
If cli nical e v e nts s us pici o us f or seiz ure occ ur aft er Scree ni n g, I P s h o ul d be disc o nti n ue d 
i m me diatel y wit h a p pr o priate cli nical f oll o w-u p, i ncl u di n g el ectr oe n ce p h al o gra m , ser u m 
c he mistr y, uri nal ysis, a n d dr u g/al c o h ol tests.  
6. 4. 2.  
D ose E v al u ati o n C o m mittee  
A D ose E val uati o n C o m mittee ( D E C) will be c o n ve ne d as nee de d 
 
 
 
 
 
 
. T he i nitial D E C meeti n g 
will be c o n ve ne d at a reas o na ble ti me after t h e first 5 n o n place b o  partici p a nts ha ve  c o m plete d 
t he acti ve d osi n g p orti o n of t he st u d y 
 
 
 
 
 
A se parate D E C c h arter will detail t he data t o be re vie we d a n d will be a gree d u p o n a n d si g ne d 
pri or t o a d mi nistrati o n of t he first d ose of I P. 
6. 4. 3.  
Criteri a f or St u d y Ter mi n ati o n  
Sa ge T h era pe utics ma y t er mi nate t his st u d y or a n y p orti o n of t he st u d y at a n y ti me f or safet y 
reas o ns, i ncl u di n g t he occ urre n ce of A Es or ot her fi n di n gs s u g gesti n g u nacce pta ble ris k t o 
partici pa nts, or f or a d mi nistrati ve reas o ns. I n t h e e ve nt of st u d y ter mi nati o n, Sa ge T h era pe utics 
will pr o vi de writte n n otificati o n t o t he i n vesti gat or. I n v esti gati o nal sites m ust pr o m ptl y n otif y 
t heir i nstit uti o nal re vie w b oar d (I R B)/i n de pe n d e nt et hics c o m mittee (I E C), w here re q uire d, a n d 
i nitiate wit h dra wal pr oce d ures f or p artici pa nts. 

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6. 5.  
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y is d efi ne d as t he d ate of  t he l ast visit of t he last participa nt i n t he st u d y . A 
partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if he/s h e has c o m plete d all p hases of t he 
st u d y i ncl u di n g t h e last visit.  

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7.  
S E L E C TI O N A N D WI T H D R A W A L O F P A R TI CI P A N T S  
7. 1.  
I ncl usi o n Criteri a 
Eac h eli gi ble partici p a nt m ust:  
1.  be  ca p a ble of pr o vi di n g i nf or me d c o ns e nt;  
2.  ha ve si g n e d a n i nf or me d c o nse nt f or m (I C F) pri or t o a n y st u d y -s p ecific pr oce d ures b ei n g 
perf or me d;  
3.  be  willi n g a n d, i n t he o pi ni o n of t he i n vesti gat or, a ble t o c o m pl y wit h st u d y pr oce d ures;  
4.  be bet wee n t he a ges of 5 0 a n d 7 5 years, i n cl usi ve, at Scree ni n g;  
5.  meet t he f oll o wi n g criteri a f or P D -M CI:  
a. ha ve a c o nfir me d dia g n osis of i di o pat hic P D acc or di n g t o 2 0 1 5 M D S cli nical 
dia g n ostic criteria, a n d  
b.  meet M D S Tas k F orce Criteria f or M CI i n P D (e x cl u di n g re q uire me nt f or U K P D 
B rai n Ba n k dia g n ostic criteria). 
6.  meet t he f oll o wi n g criteri a f or M o C A:  
a. f or partici pa nts meeti n g Le v el 1 P D-M CI criteria, ha ve a M o C A sc ore of 2 0 t o 2 5 
(i ncl usi ve) at Scree ni n g; 
b.  f or partici pa nts meeti n g Le v el 2 P D-M CI criteria ( wit hi n t he past year), ha ve a 
M o C A sc ore of 1 8 t o 2 5 (i ncl usi ve) at Scree ni n g;  
7.  be a ble t o c o m plete t he C ol or Trails Test 1 (i ncl u di n g t he a bilit y t o f oll o w rater 
re directi o n a n d c orrect err ors), a n d, b ase d o n partici pa nt’s  perf or ma nce a n d i n vesti gat or's 
o pi ni o n, is e x pecte d t o be ca p a b le of e n ga gi n g i n pr ol o n ge d c o g niti ve testi n g f or t he 
d urati o n of t he st u d y.    
8.  meet criteria f or m o difie d H oe h n a n d Ya hr Sta ge I t o III ( mil d t o m o derat e m ot or 
se verit y) at Scree ni n g; 
9.  ha ve sta ble m ot or s y m pt o ms f or at least 4 wee ks pri or t o Scree ni n g, i n t he o pi ni o n of t he 
i n vesti gat or; 
1 0.  ha ve sta ble c o n c o mita nt me dicati o n d ose a n d fre q ue nc y f or at least 4 wee ks pri or t o t he 
first I P a d mi nistrati o n, a n d w hic h is e x pecte d t o re mai n sta ble f or t he d urati o n of t he 
st u d y;  
1 1.  a gree, if fe mal e, t o use a n acce pta ble hi g hl y effecti ve met h o d of c o ntrace pti o n d uri n g 
partici pati o n i n t he st u d y a n d f or 3 0 da ys f oll o wi n g t he last d ose of I P  (refer t o 
Secti o n  8. 2. 4  f or acce pta ble f or ms of c o ntr ace pti o n),  u nless t he y are p ost me n o pa usal 
( defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use a n d c o nfir me d 
b y f ollicle sti m ulati n g h or m o ne [ F S H] > 4 0 mI U/ m L), s ur gi call y sterile ( h ysterect o m y or 
bilateral o o p h orec t o m y or bilateral sal pi n gect o m y), or d oes n ot e n ga ge i n s e x ual relati o ns 
w hic h carr y a ris k of pre g na n c y ( d oes n ot i ncl u d e a bsti ne nce ); 
1 2.  a gree, if male, t o use a n acce pta bl e met h o d of hi g hl y effecti ve c o ntrace pti o n d uri n g t he 
Treat me nt Peri o d a n d f or 3 0 da y s after recei vi n g t he last d ose of I P, u nless t he partici pa nt 
d oes n ot e n ga ge i n se x ual relati o ns t hat carr y a ris k of pre g na n c y  (refer t o Secti o n 8. 2. 4  
f or acce pta bl e f or ms of c o ntrace pti o n); 

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1 3.  a gree, if male, t o a bstai n fr o m s per m d o nati o n d uri n g t he Treat me nt Peri o d a n d f or 
3 0  da ys after recei vi n g t he last d ose of I P ; a n d  
1 4.  a gree t o refrai n fr o m dr u gs of a b use f or t he d urati o n of t he st u d y a n d fr o m alc o h ol  d uri n g 
t he 4 8 h o urs prece di n g eac h st u d y visit. 
7. 2.  
E xcl usi o n Criteri a  
Eac h eli gi ble partici p a nt m ust n ot:  
1.  ha ve partici p ate d i n a pre vi o us cli nical st u d y of S A G E -7 1 8, ha v e partici pate d i n a 
pre vi o us ge ne t hera p y st u d y, or ha ve recei ve d st u d y treat me nt i n a n y ot her dr u g, bi ol o gic, 
or de vice tri al wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver is l o n ger), u nless t he partici pa nt 
partici pate d s olel y i n t he place b o ar m of t he st u d y.  
2.  ha ve cli nicall y si g nifica nt c o m or bi d me dical c o n diti o ns, a c hr o nic c o n diti o n t hat is 
u ns ta ble, or are ta ki n g c o nc o mita nt me dicati o ns t hat, i n t he o pi ni o n of t he i n vesti gat or, 
ma y ma k e t he partici pa nt u ns uita ble f or i ncl usi o n or ha ve t he p ote ntial t o c o m pr o mise 
safet y a n d/ or c o m plia nce wit h st u d y re q uir e me nts;  
3.  ha ve a dia g n osis of d e me ntia of a n y eti ol o g y, i n cl u di n g b ut n ot li mite d t o: De me ntia wit h 
Le w y B o di es, Alz hei mer’s De me ntia, a n d Vasc ul ar De me ntia;  
4.  ha ve a n y p ar ki ns o nis m ot her t ha n P D, i ncl u di n g s ec o n dar y p ar ki ns o nis m or at y pi cal 
par ki ns o nis m;  
5.  be e x perie nci n g m ot or s y m pt o ms or fl uct uati o ns i n m ot or s y m pt o ms ass oci ate d wit h P D 
t hat will i nterfere wit h c o m pleti n g st u d y pr oce d ures, i ncl u di n g assess me nts a d mi nistere d 
b y t o uc h -s cree n de vic es, i n t he o pi ni o n of t he i n vesti gat or; 
6.  ha ve a n o n g oi n g ce ntral ner v o us s yst e m c o n diti o n ot her t ha n P D t hat i n t he o pi ni o n of t he 
i n vesti gat or c o ul d i nfl ue nce t he o utc o me of t he st u d y (i ncl u di n g acti ve ne ur ol o gic a n d/ or 
n o nre mitte d ps yc hiatric dis or ders);  
7.  ha ve e x perie nce d si g nifica nt ps yc h otic s y m pt o ms, i ncl u di n g hall uci nati o ns or del usi o ns, 
wit hi n t he past  3 m o nt hs, i n t he o pi ni o n of t he i n vesti gat or;  
8.  ha ve a hist or y of brai n s ur ger y, dee p brai n sti m ulati o n, or a n y hist or y of h os pitalizati o n 
d ue t o a brai n i nj ur y;  
9.  ha ve a hist or y, prese nce, a n d/ or c urre nt e vi de n ce of cli nicall y rele va nt i ntracra nial 
a b n or mali t y (e g, str o ke, he m orr ha ge, s pace-occ u p yi n g lesi o n);  
1 0.  be recei vi n g a n y of t he f oll o wi n g pr o hi bite d me di cati o ns:  
a. me dicati o ns wit h p ote nt effects at t he N -m et h yl -D -as partate ( N M D A) rece pt or, 
i ncl u di n g me ma nti nea, a ma nta di ne, keta mi ne, or relate d c o m p o u n ds. 
b.  me dicati o ns t hat i n hi bit c h olester ol a bs or pti o n (e g, ezeti mi be).  
c. bile aci d se q uestr a nts (e g, c olese vela m, c h olest yra mi ne).  
d.  ot her me dicati o ns gi ve n at d oses, fre q u e ncies, or i n c o m bi nati o ns t hat are li kel y, i n 
t he o pi ni o n of t he i n vesti gat or, t o h a ve a d eleteri o us effect o n c o g niti ve perf or ma nce. 
e. ca n na bis or ot her tetra h y dr oca n na bi n ol ( T H C) -c o ntai ni n g s u bsta nces (a n y r o ute of 
a d mi nistrati o n), re gar dl ess of w het her or n ot t he y are prescri b e d.  
aMe ma nti ne is pr o hi bite d wit hi n 3 0 da ys of s cree ni n g a n d d uri n g t he e ntire c o urse of 
t he st u d y.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 6  
1 1.  ha ve a n alc o h ol or dr u g use dis or der wit hi n t he past 1 2 m o nt hs as per Dia g n ostic a n d 
Statistical Ma n ual of Me ntal Dis or ders ( D S M -5) criteria;  
1 2.  ha ve a hist or y of s eiz ures or e pile ps y, wit h t he e x ce pti o n of a si n gl e e pis o de of fe br ile 
seiz ures i n c hil d h o o d; 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.  ha ve a n y of t h e f oll o wi n g cli nicall y si g nifica nt m e dical c o n diti o ns:  
a. a n y cli nicall y si g nif ic a nt fi n di n g o n 1 2-lea d E C G d uri n g Scree ni n g or Bas eli ne 
b.  a n y cli nicall y si g nifica nt s u pi ne vital si g ns ( heart rate, s yst olic a n d diast olic bl o o d 
press ure) d uri n g Scree ni n g or Bas eli ne ( n ote: vital si g n meas ure me nts ma y be 
re peat e d o nce).  
1 5.  ha ve si g nifica nt  he p atic, re nal, car di o vasc ul ar, p ul m o nar y, gastr oi ntesti nal, 
he mat ol o gic al, i m m u n ol o gic, o p ht hal m ol o gic, meta b olic, or o nc ol o gical disease;  
1 6.  ha ve a hist or y, prese nce, a n d/ or c urre nt e vi de n ce of ser ol o gic p ositi ve res ults f or h u ma n 
i m m u n o deficie nc y vir us ( HI V)-1 or HI V -2, a n d/ or has detecta bl e he patitis B s urface 
a nti ge n, a nti -he patitis C vir us ( H C V) or p ositi ve H C V viral l oa d at Scree ni n g;  
1 7.  ha ve a p ositi ve pre g na nc y test, be pre g na nt, b e lactati n g, or i nte n d t o br eastfee d d uri n g 
t he st u d y;  
1 8.  be i n vesti gati ve s ite p ers o n nel, s p o ns or pers o n nel, or a n i m me diate me m ber of t heir 
fa mil y (s p o us e, pare nt, c hil d, or si bli n g w het her bi ol o gical or le gall y a d o pt e d); or 
1 9.  is k n o w n t o be aller gic t o a n y of S A G E-7 1 8 e x ci pie nts, i ncl u di n g s o y lecit hi n ). 
7. 3.  
Scree n F ail ures  
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y assi g ne d t o st u d y i nter ve nti o n  or are n ot e ntere d i n t he st u d y. A mi ni mal set of 
scree n fail ure i nf or mati o n will be c ollecte d, i ncl u di n g  de m o gra p h y, scree n fail ure det ails, 
eli gi bilit y criteria, a n d a n y A Es or  seri o us a d v erse e ve nts (S A E s). 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y  b e 
rescree ne d o n ce, wit h t he a p pr o val of  t he m e dical m o nit or.  
7. 4.  
I n vesti g ati o n al Pr o d uct Disc o nti n u ati o n a n d E arl y Ter mi n ati o n fr o m 
t he St u d y  
A partici pa nt ma y wit h dr a w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest f or a n y reas o n . 
T he i n vesti gat or ma y dis c o nti n ue a partici p a nt fr o m t he st u d y a n d/ or fr o m  I P f or safety, 
be ha vi oral, c o m plia n ce, or a d mi nistrati ve reas o ns.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 7  
7. 4. 1.  
In vesti g ati o n al Pr o d uct Disc o nti n u ati o n  
W he n a partici pa nt is disc o nti n ue d fr o m I P, t he partici pa nt s h o ul d c o nti n ue, if willi n g, t o 
partici pate i n t he re mai n der of t he st u d y b y atte n di n g all sc he d ul e d v isits per t he S O A. 
T he reas o n f or I P disc o nti n uati o n a n d/ or t he reas o n f or earl y t er mi nati o n fr o m t he st u d y m ust be 
d oc u me nte d i n t he partici pa nt’s s o urce d o c u me ntati o n a n d rec or de d i n t he p artici pa nt’s 
electr o nic case re p ort f or m (e C R F).  
T he i n vesti gat or m ust n otif y t he s p o ns or a n d/ or t he me dical m o nit or w he n a partici pa nt 
disc o nti n ues I P a n d/ or st o ps partici pati o n i n t he st u d y f or a n y reas o n.  
7. 4. 2.  
E arl y Ter mi n ati o n fr o m t he St u d y  
At t he ti me of st u d y wit h dra wal/st o p pi n g st u d y partici pati o n, if p ossi ble, a n earl y ter mi nati o n 
visit s h o ul d be c o n d ucte d. T he partici pa nt will be per ma ne ntl y disc o nti n ue d b ot h fr o m t he I P a n d 
fr o m t he st u d y at t hat ti me. 
If t he partici p a nt wit h dra ws c o nse nt f or discl os ur e of f ut ure i nf or mati o n, t he sp o ns or will retai n 
a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s uc h a wit h dra wal of c o nse nt. 
If a partici pa nt wit h dra ws fr o m t he st u d y, h e/s he ma y re q uest destr u cti o n of a n y sa m ples ta ke n 
a n d n ot teste d, a n d t he in vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.  
7. 4. 3.  
L os t t o F oll o w-u p  
A partici pa nt will be dee me d l ost t o f oll o w -u p after 3 atte m pts b y differe nt m o des (e g, p h o ne, 
e mail, letter) at c o nt acti n g t he p artici pa nt ha v e bee n ma de a n d it has b ee n at least 1 m o nt h si nce 
t he last partici pa nt c o nta ct. All atte m pts at c o ntact a n d the reas o n f or disc o nti n uati o n will be 
d oc u me nte d. If t h e i n vesti gat or b ec o mes a ware of a c ha n ge i n t he partici pa nt’s stat us or recei ves 
m ore i nf or mati o n a b o ut a partici pa nt’s dis p ositi o n, t his i nf or mati o n will be d oc u me nte d.  
7. 4. 4.  
Re pl ace me nt of P artici p a nts  
Pa rtici pa nts w h o disc o nti n ue or wit h dra w fr o m t he st u d y will n ot be re place d. H o we ver, 
a d diti o nal partici pa nts ma y b e d ose d if t he earl y disc o nti n uati o n rate is hi g her t ha n e x pecte d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 8  
8.  
T R E A T M E N T O F P A R TI CI P A N T S  
8. 1.  
Descri pti o n of I n vesti g ati o n al Pr o d uct 
S A G E -7 1 8 soft gel li pi d ca ps ules are o p a q ue, w hite t o off -w hite, o val ca ps ules c o ntai ni n g eit her 
0. 3, 0. 6, 0. 9, or 1. 2  m g of S A G E -7 1 8 d r u g su bsta n ce.  Place b o is matc hi n g i n a p peara nce.   
8. 2.  
Pri or Me dic ati o ns, C o nc o mit a nt Me dic ati o ns, Restricti o ns, a n d 
C o ntr ace pti o n Re q uire me nts  
8. 2. 1.  
Pri o r a n d C o nc o mit a nt Me dic ati o ns  a n d/ or S u p ple me nts  
A ll me dicati o ns a n d s u p ple me nts ta ke n wit hi n 6 0 da ys  pri or t o Scree ni n g, all me dicati o ns use d 
t o treat P D re gar dless of ti mi n g, a n d all n o n p har m ac ol o gical met h o ds (e g, ps yc h os o cial, 
ps yc h ot h era p e utic) use d t o treat or pre ve nt 
, a n d c o g niti ve 
ma nifestati o ns of P D are t o be rec or de d . I nf or mati o n re gar di n g dia g n osis, is olati o n, a n d/ or 
h os pitaliz ati o n d ue t o c or o na vir us disease 2 0 1 9  (C O VI D -1 9 ) will be d oc u m e nte d as part of 
me dical hist or y, A E c ollecti o n, a n d pri or/c o nc o mit a nt me dicati o n/ pr oce d ure c ollecti o n at 
scree ni n g a n d t hr o u g h o ut t he st u d y 
At visits s u bse q ue nt t o Scree ni n g, all c h a n ges t o a n y me dicati o n s h o ul d be ca pt ure d. All 
me dicati o ns a n d/ or s u p ple me nts ta ke n fr o m t he first d ose of I P t hr o u g h t h e fi nal st u d y visit 
(i ncl u di n g start a n d e n d d ates, r o ute, d ose/ u nits, fre q ue nc y, a n d i n dicati o n) will be rec or de d o n 
t he case re p ort for m  (eC R F) . A n y c o n c o mita nt me dicati o n deter mi ne d n ecessar y f or t he welf are 
of t he partici pa nt ma y b e gi ve n at t he discreti o n of t he I n v esti gat or at a n y ti me d uri n g t he st u d y.  
Beca use t his st u d y ai ms t o meas ure effects o n c o g niti ve perf or ma n ce, it is i m p or ta nt t o e val uate 
si n gle or c o m bi ne d c o nc o mita nt me dicati o ns a n d t heir d oses f or t heir p ot e ntial effects o n 
c o g niti o n. I n vesti gat ors will caref ull y re vie w c o n c o mita nt me dicati o ns f or p ossi ble c o g niti ve 
effects at Scree ni n g t o deter mi ne partici pa nt eli gi bili t y a n d t hr o u g h o ut t he st u d y. 
8. 2. 2.  
Pr o hi bite d Me dic ati o ns  
P artici pati o n i n a pre vi o us S A G E -7 1 8  st u d y or  ge ne t hera p y st u d y  is pr o hi bite d.  Treat me nt wit h 
a n i n vesti gati o nal dr u g or de vice is pr o hi bite d wit hi n t he 3 0 da ys ( or 5 half -li ves of t he I P, 
w hic he ver is l o n ger) pri or t o Scree ni n g a n d u ntil t he fi nal F oll o w-u p Visit.  
D uri n g t h e c o urs e of t he st u d y, a dj ust me nt of me dicati o n or a d diti o n of me dicati o ns t hat are 
k n o w n t o affect c o g niti ve perf or ma nce (e g, sti m ula nts, be nz o diaze pi nes, a nti ps yc h otics, 
a ntic h oli ner gics) is t o be a v oi de d as m uc h as p ossi ble. A n y m e dicati o n deter mi ne d necess ar y f or 
t he welfare of t he p artici pa nt ma y b e gi ve n at t he discreti o n of t he i n vesti gat or at a n y ti me d uri n g 
t he st u d y, h o w e ver, t he use of a n y pr o hi bite d me di cati o ns will be ca pture d as a pr ot oc ol 
de viati o n.  
Use of t he f oll o wi n g me dicati o ns is pr o hi bite d d uri n g t he e ntire c o urse of t he st u d y:  
•  Me dicati o ns t hat i n hi bit c h olester ol a bs or pti o n ( e g, ezeti mi be) , 
•  Bile aci d s e q uestra nts ( e g, c ol ese vela m, c olesti p ol, c h olest yra mi ne) , 

Cli nical Pr ot oc ol  
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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 9  
•  A n y p s yc h otr o pic me dic ati o ns, i ncl u di n g a nti de pressa nts a n d a n xi ol yti cs, u nless t he d ose 
a n d fre q u e nc y h a ve bee n sta ble f or at least 4  wee ks pri or t o t he first I P a d mi nistrati o n a n d 
are e x pecte d t o re mai n st a ble f or t he d urati o n of t he st u d y , 
•  Me dicati o ns wit h p ote nt effec ts at t he N M D A rece pt or, i ncl u di n g me m a nti nea, 
a ma nta di ne, c ycl os eri ne, keta mi ne, or relate d c o m p o u n ds , 
•  Ot her me dicati o ns gi ve n at d oses, fre q u e ncies, or i n c o m bi nati o ns t hat are li kel y, i n t he 
o pi ni o n of t he i n vesti gat or, t o ha ve a d eleteri o us effect o n c o g niti ve perf or ma nce , 
•  Ca n na bis or ot her T H C -c o ntai ni n g s u bsta nces (a n y r o ute of a d mi nistrati o n), re gar dless of 
w het her or n ot t he y are prescri be d . 
aMe ma nti ne is pr o hi bite d wit hi n 3 0 da ys of s cree ni n g a n d d uri n g t he e ntire c o urse of t he 
st u d y. 
 
8. 2. 3.  
Ot her Rest ricti o ns  
Partici pa nts m ust a gree t o refrai n fr o m dr u gs of a b use f or t he d urati o n of t he st u d y a n d fr o m 
alc o h ol d uri n g t h e 4 8 h o urs prece di n g eac h st u d y visit.  
8. 2. 4.  
Acce pt a ble F o r ms of C o ntr ace pti o n  
Acce pt a ble f or ms of hi g hl y effecti ve c o ntrace pti o n f or partici pa nts of c hil d beari n g p ote ntial or 
f or part ners of male p arti ci pa nts w h o are of c hil d b eari n g p ote ntial i ncl u de: 
•  co m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) oral, i ntra va gi nal, or tra ns der mal 
h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n o f o v ulati o n; 
•  o ral, i njecta ble, or i m pla nta ble pr o gest o ge n-o nl y h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n;  
•  intra uteri ne de vic e;  
•  intra uteri ne h or m o ne -rel easi n g s yst e m; 
•  b ilateral t u bal ligati o n or bilateral t u bal occl usi o n ( perf or me d at least 3 m o nt hs pri or 
t o Scree ni n g); 
•  vasect o miz e d part ner ( perf or me d at least 3 m o nt hs pri or t o Scree ni n g).   (N ote: 
vasect o miz e d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat part ner 
is t he s ole se x ual part ner of t he partici pa nts of c hil dbeari n g p ote ntial a n d t h at t he 
vasect o miz e d part ner has recei v e d me dical assess me nt of t he s ur gical s uc cess ) 
Acce pt a ble f or ms of c o ntrace pti o n f or male partici pa nts i ncl u de:  
•  Hist or y of s u ccessf ul vas ect o m y ( perf or me d at least 3 m o nt hs pri or t o Scree ni n g);  
•  C o n d o m wit h s per mici de  use d t o get her wit h hi g hl y effecti ve fe m ale c o ntr ace pti ve 
met h o ds if t he fe male p art ner(s) is of c hil d beari n g p ote ntial (see a b o v e f or list of 
acce pta ble fe male c o ntr ace pti ve met h o ds).  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 0  
8. 3.  
I nter ve nti o n after t he E n d of t he St u d y 
N ot a p plicable . 
8. 4.  
Tre at me nt A d here nce  
Be gi n ni n g o n Da y  1 a n d c o nti n ui n g t hr o u g h Da y 4 2 , partici pa nts will self-a d mi nister bli n de d I P 
o nce per da y i n t he m or ni n g. At cli nic visits, partici pa nts will self-a d mi nister t he I P u n der staff 
s u per visi o n, f oll o we d b y assess me nts of c o g niti ve f u ncti o n, 
 
. St u d y staff will dis pe nse s ufficie nt I P f or dail y 
a d mi nistrati o n u ntil t he ne xt sc he d ule d st u d y visit. A d here n ce t o t he d osi n g re gi me n will be 
assesse d at e ac h i n -cli nic visit b y e x a mi nati o n of t he use d pac k a gi n g, a n d c o u nti n g a n y ret ur ne d 
ca ps ules. T his i nf or mati o n will be d oc u me nte d i n t he s o urce files a n d i nteracti ve res p o nse 
tec h n ol o g y (I R T), al o n g wit h a n y d e viati o ns fr o m t he prescri b e d d osa ge re gi me n. Details a b o ut 
I P acc o u nta bilit y are i ncl u de d i n Secti o n 9. 6. 1 . 
8. 5.  
R a n d o miz ati o n a n d Bli n di n g  
T his is a ra n d o mize d, place b o -c o ntr olle d, d o u ble -bli n d  st u dy. Eli gi ble partici pa nts will be 
ra n d o mize d 1: 1 t o recei v e S A G E-7 1 8 or place b o f or 4 2  da ys.  
Partici pa nts, cli nicia ns, a n d t he st u d y tea m will be bli n de d t o treat me nt all ocati o n. 
Ra n d o mizati o n will be perf or me d ce ntr all y via a n I R T s yste m. Ra n d o mizati on sc he d ules will be 
ge n erat e d b y a n i n de p e n de nt statisticia n. T he all ocati o n t o treat me nt gr o u p will be base d o n t he 
ra n d o mizati o n sc he d ule. T he ra n d o mizati o n sc he d ules will be ke pt strictl y c o nfi de ntial, 
accessi ble o nl y t o a ut h ori ze d pers o n nel u ntil t he t i me of u n bli n di n g. T he bli n di n g of t he st u d y 
will be br o ke n aft er t he d ata base h as bee n l o c ke d.  
8. 5. 1.  
E mer ge nc y U n bli n di n g  
D uri n g t h e st u d y, t he bli n d ca n be br o ke n b y t he i n vesti gat or vi a t he I R T s yste m o nl y w he n t he 
safet y of a p artici pa nt is at ris k a n d t he treat me nt pla n is de pe n de nt o n t he st u d y treat me nt 
recei v e d. U nless a p artici pa nt is at i m me diate ris k, t he i n vesti gator s h o ul d ma ke atte m pts t o 
c o ntact Sa ge pri or t o u n bli n di n g t he I P a d mi nistere d t o a partici pa nt. T h e res p o nsi bilit y t o br ea k 
t he treat me nt c o d e i n e m er ge nc y sit uati o ns resi des s olel y wit h t he i n vesti gat or. If t he u n bli n di n g 
occ urs wit h o ut Sa ge’s k n o wle d ge , t he i n vesti gat or m ust n otif y Sa ge wit hi n 2 4 h o urs of brea ki n g 
t he bli n d. All circ u mstances s urr o u n di n g a pre mat ure u n bli n di n g m ust be cl earl y d oc u me nt e d i n 
t he s o urce rec or ds. T he E arl y T er mi nati o n V isit s h o ul d be c o m plete d aft er a partici pa nt’s 
treat me nt assi g n me nt has bee n u n bli n de d. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 1  
9.  
I N V E S TI G A TI O N A L P R O DU C T M A T E RI A L S A N D 
M A N A G E M E N T  
9. 1.  
I n vesti g ati o n al Pr o d uct 
S A G E -7 1 8 s oft gel li pi d ca ps ules are o p a q ue, w hite t o off -w hite, o val ca ps ules c o ntai ni n g 0. 3, 
0. 6, 0. 9, or 1. 2 m g of S A G E -7 1 8 d r u g su bsta nce. T he ca ps ules are c o m p ose d of S A G E -7 1 8 dr u g 
s u bsta nce a n d b ut ylate d h y dr o x ya nis ole, gelati n, gl yceri n, gl ycer yl m o n o ca pr yl ate, gl ycer yl 
m o n oli n oleate, lecit hi n, me di u m c hai n tri gl yceri d es, p urifie d water, s or bit ol, tita ni u m di o xi de, 
a n d vita mi n E p ol yet h yle ne gl yc ol s ucci nate as e x ci pie nts.  
T a ble  4 : 
I n vesti g ati o n al Pr o d uct  
Pr o d uct N a me:  
S A G E -7 1 8 
0. 3  m g a 
S A G E -7 1 8 
0. 6  m g  
S A G E -7 1 8 
0. 9  m g  
S A G E -7 1 8 
1. 2  m g b  
Place b o  
D os a ge F or m:  
S oft gel li pi d ca ps ule  
U nit D ose  
0. 3 m g  
0. 6 m g  
0. 9 m g  
1. 2 m g  
Matc hi n g 
Place b o  
R o ute of 
A d mi nistr ati o n  
Oral  
P h ysic al 
Descri pti o n  
O pa q ue, w hite t o off -w hite, o val, s oft gel li pi d ca ps ule  
M a n uf act urer  
Catale nt P har ma S ol uti o ns,  
St. Peters b ur g, F L  
a U S o nl y  
b S A G E -7 1 8 1. 2  m g d ose will be a d mi nistere d i n t his st u d y.  
9. 2.  
I n vesti g ati o n al Pr o d uct P ac k a gi n g a n d L a beli n g  
S A G E -7 1 8 a n d matc hi n g place b o o ral s oft gel li pi d ca ps ules are pac ka ge d i n blisters usi n g 
A C L A R ®  ri gi d barri er fil m a n d heat seal a ble f oil li d di n g wit h a n a d diti o nal c hil d resista nt li d 
(refer t o t he p har mac y m a n ual f or f urt her details).  
T he c o m p ositi o n a n d p har mace utical q ualit y of t h e oral  s oft gel li pi d ca ps ul e will be mai ntai ne d 
acc or di n g t o c urre nt G o o d Ma n ufact uri n g Practice ( G M P). La bels wit h all re q uire d i nf or mati o n 
a n d c o nf or mi n g t o all a p plica ble C o de of Fe deral Re g ulati o ns a n d G M P/ G o o d Cli nical Practice 
( G C P) g ui deli nes a n d all ot her a p plica ble re g ulati o ns will be pre pare d b y Sa ge T h era pe utics.  
9. 3.  
I n vesti g ati o n al Pr o d uct St or a ge  
U p o n recei pt of t he I P, t he I n vesti gat or, or t h e res p o nsi ble p har macist or desi g nee, will i ns pect 
t he pr o d uct a n d ac k n o wl e d ge recei pt i n acc or da n ce wit h t he st u d y-s p ecific P har mac y Ma n u al .  
T he I P m ust be caref ull y st ore d at t he te m perat ure s pecifie d i n t he i n vesti gat or’s br oc h ure  a n d 
( w here a p plica bl e) i n t he p har mac y ma n ual, sec urel y a n d se paratel y fr o m ot her dr u gs. T he I P 
ma y n ot be us e d f or a n y p ur p ose ot her t ha n t he pres e nt st u d y. After t he st u d y is c o m plete d, all 

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4 2  
u n use d I P m ust be ret ur n e d per t he sp o ns or’s i nstr ucti o ns or destr o ye d l ocall y per t he site’s 
pr oce d ure(s)  i n a cc or da n ce wit h st u d y-s pecifi c P har mac y M a n ual.  
T he I n vesti gat or or d esi g nee will be res p o nsi ble f or  e ns uri n g a p pr o priate st ora ge, c o m p o u n di n g 
(if a p plica ble), dis pe nsi n g, i n ve nt or y, a n d acc o u nt a bilit y of t he I P. A n acc urate, ti mel y rec or d of 
t he dis p ositi o n of t he I P m ust be mai ntai ne d.  
9. 4.  
I n vesti g ati o n al Pr o d uct Pre p ar ati o n 
S A G E -7 1 8 1. 2 m g or place b o wil l be pr o vi de d as a n oral ca ps ule f or s elf -a d mi nistrati o n o nce 
dail y i n t he m or ni n g t hr o u g h D a y 4 2 visit . 
9. 5.  
I n vesti g ati o n al Pr o d uct A d mi nistr ati o n  
Eac h 1. 2 -m g d ose of I P will be self -a d mi nistere d o nce dail y i n t he m or ni n g.  
Partici pa nts are t o s w all o w t he ca ps ules w h ol e wit h a p pr o xi matel y 2 4 0 m L ( 8 fl ui d o u nces) of 
water. F or d oses ta k e n i n t he cli nic, site staff will watc h t he partici pa nt self -a d mi nister t he I P.  
9. 6.  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y , H a n dli n g, a n d Dis p os al 
9. 6. 1.  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y, H a n dli n g, a n d Dis p os al  
U p o n recei pt of I P, t he I n vesti gat or(s), or t he res p o nsi ble p har macist or desi g nee, will i ns pect t he 
I P a n d c o m plete a n d f oll o w t he i nstr ucti o ns re gar di n g recei pt a n d st ora ge i n t he i n vesti gat or’s 
br oc h ure a n d t he st ud y -s pecific Phar m ac y M a n u al. A c o p y of t he s hi p pi n g d oc u me ntati o n will be 
ke pt i n t he st u d y files.  
T he desi g nate d site staff will dis pe nse t he s u p plie d partici pa nt -s pecific kits t o partici pa nts at t he 
pla n ne d dis pe nsati o n visit i nter vals o utli ne d i n Ta ble  2 .  
Site staff will access t he I R T at t he Scree ni n g Visit t o o btai n a partici pa nt i de ntificati o n (I D) 
n u m ber f or eac h p artici p a nt t hat has si g n e d a n I C F. O n Da y 1, site staff will access t he I R T a n d 
pr o vi de t he necessar y p artici pa nt -i de ntif yi n g i nf or mati o n, i ncl u di n g t he partici pa nt I D n u m b er 
assi g ne d at Scree ni n g, t o ra n d o mize t he eli gi ble p artici pa nt i nt o t he st u d y a n d o btai n t he 
me dicati o n I D n u m ber f or t he I P t o b e dis pe nse d t o t hat partici pa nt. T he m e dicati o n I D n u m ber 
a n d t he n u m ber of ca ps ul es dis pe nse d m ust be rec or de d.  
At t he s u bse q ue nt I P -dis pe nsi n g visit, t he i n vesti gat or or desi g nee will access t he I R T, pr o vi di n g 
t he sa me partici pa nt I D n u m ber assi g ne d at Scree ni n g, t o o btai n t he me dicati o n I D n u m b er f or 
t he I P t o be dis pe ns e d at t hat visit. T he me dicati o n I D n u m ber, t he n u m ber of ca ps ules 
dis pe nse d, a n d t he n u m b er of ca ps ules ret ur ne d b y t he partici pa nt at t his visit m ust be rec or de d.  
If dis pe nsin g err ors or discre pa n cies are disc o vere d b y site staff or S p o ns or’s desi g n ee, t he 
S p o ns or m ust be n otifie d i m me diatel y.  
Sa ge T h era pe utics will be per mitte d access t o t he st u d y s u p plies at a n y ti me wit h a p pr o priat e 
n otice d uri n g a n d/or after c o m pleti o n of t he st u d y.  
T he I n vesti gat or, p h ar macist, or q ualifie d desi g nee is res p o nsi ble f or dr u g acc o u nta bilit y, 
rec o nciliati o n, a n d rec or d mai nte na nce (ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 

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At t he e n d of t he st u d y, a n y u n use d I P will be ret u r ne d t o Sa ge f or destr ucti o n or destr o ye d 
l ocall y p er t he site’s pr o ce d ures i n a cc or da nce wit h st u d y-s pecific P har mac y Ma n u al; dis p ositi o n 
of I P will be d o c u me nte d.  
M ore detaile d i nf or mati o n ca n be f o u n d i n t he S A G E -7 1 8 i n vesti gat or’s br oc h ure a n d st u d y-
s pecific Phar mac y M a n u al.  
9. 6. 2.  
Pr o d uct C o m pl ai nts  
A pr o d uct c o m plai nt is a n y writte n, electr o ni c, or ver bal e x pressi o n of diss atisfacti o n re gar di n g 
t he i de ntit y, q ualit y, relia bilit y, safet y, p urit y, p ote nc y, effecti ve n ess or perf or ma nce (a p plica ble 
f or ap pr o ve d mar k ete d pr o d ucts) of a dr u g pr o d uct after it is release d f or distri b uti o n.  
I n t he c o urse of c o n d u ct of t he st u d y, st u d y pers o n nel ma y b ec o me a ware of a pr o d uct c o m plai nt 
ass ociate d wit h t he use of a Sa ge pr o d u ct. Pers o n nel s hall n otif y Sa ge wit hi n 2 4 h o urs b y 
f or war di n g t h e pr o d uct c o m plai nt i nf or mati o n via t he c o ntact i nf or m ati o n liste d i n Ta ble 1 . 
W here p ossi ble, pers o n n el s h o ul d se gre gate a n d  retai n a n y pr o d uct, mat eri als, or pac k a gi n g 
ass ociate d wit h t he pr o d u ct c o m plai nt u ntil f urt her i nstr ucti o n is pr o vi de d b y Sa ge or its 
desi g nat e d re prese nt ati ve(s).  

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1 0.  
S C R E E NI N G, E F FI C A C Y A N D C LI NI C A L P H A R M A C O L O G Y 
A S S E S S M E N T S  
A variet y of meas ures will be e m pl o ye d i n t his st u d y t o e val uate c o g niti ve f u ncti o n, 
. All assess me nts are t o be 
c o m plete d acc or di n g t o t he Sc he d ule of Assess me nts ( Ta ble  2 ) a n d t h e Sc h e d ule of 
, Bi oc he mical a n d Ge n etic  Sa m pli n g ( T a ble  3 ).  
D uri n g t h e Scree ni n g a n d Baseli ne Peri o d, partici pa nts will be trai ne d b y st u d y staff o n t he use 
of all s oft ware a p plicati o ns a n d  de vices n ecess ar y f or t he c o n d u ct of t he st u d y.  
T hese asses s me nts are t o be a d mi nistere d after t he dail y d ose of I P d uri n g t he Treat me nt Peri o d, 
a n d at a p pr o xi matel y t he sa me ti me of da y ( ± 2 h o urs) t hr o u g h o ut t he st u d y. F or partici pa n ts 
recei vi n g me dicati o n f or P D s y m pt o ms, assess me nts are t o be a d mi nistere d i n t he “ o n” state 
( defi ne d as t he peri o d i n w hic h m ot or s y m pt o ms are miti gate d d ue t o t he effects of P D 
me dicati o n) . F or cli nicia n a d mi nistere d scales, t h e sa me i n di vi d ual s h o ul d a d mi nister t he scale 
w he ne ver p ossi ble.  
I n-cli nic visits will e ntail c o g niti ve assess me nt a d mi nistere d b y c o m p uter -base d a n d pa p er/ pe n  
f or ms, self-re p ort q uesti o nnaires, a n d i nter vi e w m eas ures . 
Partici pa nts will c o m plete dail y assess me nts eac h m or ni n g d uri n g t he Treat me nt Peri o d. 
Partici pa nts will als o be iss ue d a m o bile de vice t h at will be use d t o c o m plete dail y assess me nts . 
At sc he d ule d cli nic visits, t he tas k will be perf or me d i n t he cli nic u n der o bser vati o n b y st u d y 
staff, ot her wis e t he partici pa nt will perf or m t his tas k re m otel y (at h o me).  
A n a d ult care gi ver is o pti o nal b ut hi g hl y rec o m me n de d f or eac h p artici pa nt t o s u p p ort 
c o m pleti o n of st u d y acti vities a n d t o a ns wer q uesti o ns a b o ut t he partici p a nt’s c o n diti o n . 
1 0. 1.  
Scree ni n g Assess me nts  
1 0. 1. 1.  
M o ntre al C o g niti ve Ass ess me nt  
T he M o ntreal C o g niti ve Assess me nt (M o C A ) is a cli nicia n-a d mi nistere d m eas ure d esi g n e d 
s pecificall y t o detect M CI a n d is wi del y use d i n cli nical setti n gs. T his assess me nt is e x pecte d t o 
ta ke a p pr o xi matel y 1 0 mi n utes t o c o m plete. T he test is sc ore d fr o m zer o t o 3 0, wit h sc ores 2 6 or 
hi g her i n dicati n g n or mal c o g niti o n ( N as re d di ne 2 0 0 5 ). 
N ote: I n a d diti o n t o Scree ni n g , 
 as o utli ne d i n 
Ta ble  2 . 
 
 
 
 
 
 
 
 
 
 

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1 0. 2. 2.  
Wec hsler A d ult I ntelli ge nce Sc ale -I V C o di n g T est  
T he  W ec hsler A d ult I ntelli ge nce Scale -I V (W AI S -I V) C o di n g t est  is a vali d a n d se nsiti ve 
meas ure of c o g niti ve d ysf u ncti o n i m pacte d b y ma n y d o mai ns t hat c orrelat es wit h real -w orl d 
f u ncti o nal o utc o mes (e g, t he a bilit y t o acc o m plis h e ver y da y t as ks) a n d rec o ver y fr o m f u n cti o nal 
disa bilit y. In -cli nic a d mi nistrati o n of t he W AI S -I V C o di n g test will use t he tra diti o nal  pa per -
a n d-pe n f or mat, i n w hic h t he partici pa nt is re q uir ed  t o i de ntif y t he s y m b ols matc he d t o n u m bers 
usi n g  a k e y a n d  write i n t he s y m b ol be n eat h t he ass ociate d n u m ber . T h e sc ore is base d o n t he 
t otal n u m ber of c o des c orrectl y c o m plete d o ver a 1 2 0  sec o n d ti me li mit. 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 0. 3.  
D ail y  (M o bile  P h o ne -B ase d) A ssess me nt s  
1 0. 3. 1.  
Ps yc h o m ot or Vi gil a nce T as k  
T he Ps yc h o m ot or Vi gila nce Tas k ( P V T) has partici pa nts press a b utt o n i n res p o nse t o a si m ple 
vis ual sti m ul us pr o vi de d at ra n d o m i nter vals. T h e pri mar y meas ure is t he n u m ber of misse d 
res p o nses, w hic h d escri b es t he partici pa nt’s s ustai ne d atte nti o n. T his test will be a d mi nistere d 
eac h m or ni n g d uri n g t he Treat me nt Peri o d usi n g a m o bile de vice. At sc he d ule d cli nic visits, t he 
tas k will be perf or m e d i n t he cli nic u n der o bser vati o n b y st u d y staff, ot her wise  t he partici pa nt 
will perf or m t his tas k re m otel y (at h o me).  
1 0. 3. 2.  
Di git S y m b ol S u bstit uti o n Test  
Di git S y m b ol S u bstit uti o n Test ( D S S T) is wi del y use d t o m o nit or c ha n ges i n c o g niti ve f u n cti o n 
o ver ti me a n d f or earl y d etecti o n of c o g niti ve d ysf u ncti o n. T he tas k re q uir es partici pa nts t o use a 
refere nce ke y t o pair s pecific n u m bers wit h ge o m etric fi gures. T h e n u m ber of c orrect pairi n gs 
ac hie ve d wit hi n 9 0  sec o n ds is s u m me d t o ge nerate a t otal sc ore. T his test will be a d mi nistere d 
eac h m or ni n g d uri n g t he Treat me nt Peri o d usi n g a t o uc h scree n m o bile de vice. At sc he d ule d 
cli nic visits, t he tas k will be perf or me d i n t he cli ni c u n der o bser vati o n b y st u d y staff, ot her wis e 
t he partici pa nt will perf or m t his tas k re m otel y (at h o me). 
1 0. 3. 3.  
N ati o n al Slee p F o u n d ati o n Slee p Di ar y  
O nce dail y i n t he m or ni n g, partici pa nts will briefl y a ns wer 5 q uesti o ns a b o ut slee p le n gt h, slee p 
late nc y, ni g ht a wa k e ni n gs, a n d slee p q ualit y. T hes e q uesti o ns ha ve bee n m o difie d fr o m versi o n 6 
of t he Nati o nal Slee p F o u n dati o n Slee p Diar y ( S u ni 2 0 2 1 ). T his diary will be c o m plete d eac h 
m or ni n g d uri n g t he Treat me nt Peri o d usi n g a m o bile de vice. At sc h e d ule d cli nic visits, t he tas k 

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will be perf or me d i n t he cli nic u n der o bser va ti o n b y st u d y staff, ot h er wise t he partici pa nt will 
perf or m t his tas k re m otel y (at h o me).  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1 0. 4. 2.  
M o difie d H oe h n a n d Y a hr St a gi n g Sc ale   
M o difie d H oe h n a n d Y a hr Sta gi n g Scale ( G oetz 2 0 0 4 ) is a scale us e d b y cli nicia ns t o cate g orize 
t he de gree of pr o gressi o n of P D i n a n i n di vi d ual. 
 
  
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 

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1 0. 6. 2.  
Pe n n P ar ki ns o n’s D ail y Act i vities Q uesti o n n aire-1 5 K n o wle d ge a ble I nf or m a nt 
( P D A Q-1 5 KI)  
T he Pe n n Par ki ns o n’s Dail y Acti vities Q uesti o n naire -1 5 K n o wle d gea ble I nf or ma nt  ( KI) (P D A Q -
1 5  KI ) is a care gi v er -re p orte d o utc o me t hat meas ure s t he c o g niti ve I A D L i n P D. T he i nstr u me nt 
is c o m plete d b y a pers o n k n o wle d gea ble of  t he partici pa nt, t he KI . T he P D A Q -1 5 KI  was create d 
as a n a b bre viate d v ersi o n of t he P D A Q -5 0 c o nsisti n g of 1 5 of t he ori gi nal 5 0 ite ms a n d 
de m o nstrates str o n g ps yc h o metric pr o perties acr oss t he s pectr u m of c o g niti ve i m pair me nt. T he 
ite ms are sc ore d f or diffi c ult y i n perf or mi n g eac h I A D L o n a ‘ n o ne’ ( 4), ‘a little’ ( 3), ‘s o me w hat’ 

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( 2), ‘a l ot’ ( 1) a n d ‘ca n n ot d o’ ( 0) wit h t he t otal sc ore ra n gi n g fr o m 0  t o 6 0 ( hi g her sc ores 
i n dicati n g better I A D L f u ncti o n). 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 0. 7. 2.  
P h ar m a c o d y n a mi c Ass ess me nts  
Bl o o d sa m ples will be c ollecte d, st ore d, a n d a nal yze d t o i de ntif y bi oc he mical a n d/ or ge netic 
mar kers ass o ciate d wit h S A G E -7 1 8  p har mac o d y n a mic c haracteristics.  T he sa m ples a n d t he 
res ults of t he a nal yses m a y b e use d t o hel p desi g n f ut ure cli nical st u dies, de vel o p c o m p o u n ds, or 

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de vel o p assa ys a n d dia g n ostic or ot her tests. T he s p o ns or will st ore t he de -i de ntifie d sa m ples i n a 
sec ure st or a ge s pace wit h a de q uate m eas ures t o pr otect partici pa nt c o nfi de ntialit y. O nl y t h e 
s p o ns or a n d t h ose pers o ns or e ntities w or ki n g wit h t he s p o ns or will ha ve access t o t he sa m ples 
a n d ass ociate d d ata.  
1 0. 7. 3.  
O pti o n al Bi oc he mic al R ese arc h  
W he n partici pa nt c o nse nt is pr o vi de d, plas ma sa m ples f or e x pl orat or y bi oc he mical a nal ysis will 
be c ollecte d at t he ti me p oi nts i n dicate d i n Ta ble  2  a n d Ta ble  3 , a n d m a y be st ore d f or f ut ure 
researc h. T h e p ur p ose of t his researc h is t o i de ntif y bi oc he mical pat h wa ys relate d t o diseas e 
s usce pti bilit y a n d t o assess fact ors i n v ol ve d i n t he meta b olis m or res p o nse t o S A G E -7 1 8 . 
A d diti o nal bi oc he mical a nal yses m a y be c o n d u cte d if it is h y p ot h esiz e d t hat  t he a nal ys es ma y 
hel p a d va nce u n derst a n di n g of t he cli nical data.  
1 0. 7. 4.  
O pti o n al Ge netic Rese a rc h  
W he n partici pa nt c o nse nt is pr o vi de d, a w h ole bl o o d sa m ple f or ge n etic testi n g will be c ollecte d 
at t he ti me p oi nts i n dicate d i n Ta ble  2  a n d T a ble  3 . The o bjecti ve of t his ge netic testi n g is t o 
c ollect a n d st ore bl o o d sa m ples f or p ossi ble D N A e xtracti o n a n d e x pl orat or y researc h i nt o h o w 
ge n es or s pecific ge n etic variati o ns ma y i nfl ue nce a n i n di vi d ual’s res p o nse (ie, distri b uti o n, 
safet y, t olera bilit y, a n d efficac y) t o S A G E -7 1 8 . S pecific ge n etic vari ati o ns of i nterest i ncl u de b ut 
are n ot li mite d t o: classes of ge nes e n c o di n g e nz y mes i n v ol ve d i n t he meta b olis m of S A G E -7 1 8 , 
ge n es ass ociat e d wit h t he e x pressi o n a n d f u ncti o n of N M D A rece pt ors, a n d ge n es ass ociat e d 
wit h t he pr o d ucti o n a n d de gra dati o n of gl yci n e a n d gl uta mat e.  
F ut ure researc h ma y s u g gest ot her ge nes or ge ne cate g ories as p ote ntial ca n di dates f or 
i nfl ue nci n g n ot o nl y res p o nse t o S A G E -7 1 8 , b ut als o s usce pti bilit y t o dis or ders f or w hi c h 
S A G E -7 1 8  is bei n g d e vel o pe d. T h us, t his ge netic researc h ma y i n v ol ve t he st ud y of a d diti o nal 
u n na me d ge nes or ge ne cate g ories, b ut o nl y as relate d t o disease s usce pti bilit y a n d dr u g acti o n.  

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1 1.  
S A F E T Y A S S E S S M E N T S  
1 1. 1.  
S afet y P ar a meters  
All assess me nts will be c o n d ucte d acc or di n g t o t he Sc he d ule of Assess me nts ( Ta ble  2 ) a n d 
Sc he d ules of 
, Bi oc h e mical , a n d Ge netic  Sa m pli n g ( Ta ble  3 ). 
A b n or malities i n p h ysical e x a mi nati o ns, vital si g ns, E C Gs, a n d o ut of ra n ge val ues i n la b orat or y 
test res ults will be i nter prete d b y a n i n vesti gat or as cli nicall y si g nifica nt ( C S) or n ot cli nicall y 
si g nifica nt ( N C S) i n the s o urce d oc u m e nts.  
1 1. 1. 1.  
De m o gr a p h y a n d Me dic al Hist or y  
De m o gra p hic c haracteristics (a ge, race, s e x, et h nicit y, years of e d ucati o n, e m pl o y me nt hist or y, 
a n d c urre nt e m pl o y m e nt stat us) a n d a f ull me dical hist or y will be d oc u me nt e d.  
1 1. 1. 2.  
Wei g ht a n d Hei g ht  
Hei g ht a n d wei g ht will be meas ur e d a n d d oc u m e nte d. B o d y mass i n de x ( B MI) will be calc ul ate d 
a n d d oc u me nte d.  
1 1. 1. 3.  
P h ysic al E x a mi n ati o n  
W he ne ver p ossi ble, t he s a me i n di vi d ual s h o ul d perf or m all p h ysical e xa mi nati o ns.  
A f ull p h ysic al e x a mi nati o n will be c o n d ucte d d uri n g Scree ni n g a n d at Da y 4 2 ( E n d of 
Treat me nt). At ot her visits ( Ta ble  2 ), a n a b bre viate d p h ysical e x a mi nati o n will i ncl u de a brief 
assess me nt of ge n eral a p pear a n ce, car di o v asc ular, res pirat or y, gastr oi ntesti nal, a n d ne ur ol o gical 
s yste ms, f oll o we d b y a tar gete d p h ysical assess me nt as deter mi ne d b y t he i n vesti gat or. 
U nsc he d ule d,  s y m pt o m directe d e x a mi nati o ns ma y be c o n d ucte d at a n y ti me at t he discreti o n of 
t he i nvesti gat or.  
A n y a b n or malit y i n p h ysical e x a mi nati o ns will be i nter prete d b y a n in vesti gat or as a b n or m al, 
N C S , or a b n or mal , C S , i n s o urce d oc u m e nts. 
1 1. 1. 4.  
C O VI D -1 9 Q uesti o ns  
Detaile d i nf or mati o n re gar di n g di a g n osis, is olati o n, a n d/ or h os pitalizati o n d ue t o C O VI D -1 9 a n d 
C O VI D -1 9 vacci ne hist or y will be d oc u me nte d as part of me dical hist or y. I n a d diti o n, 
i nf or mati o n f oc use d o n C O VI D-1 9 (e g, A E c ollecti o n, a n d pri or/c o nc o mit a nt 
me dicati o n/ pr oce d ures) will be c ollecte d at Scree ni n g a n d t hr o u g h o ut t he st u d y.  
1 1. 1. 5.  
Vit al Si g ns  
Vital si g ns c o m prise h eart rate, res pir at or y rate, te m perat ure, a n d bl o o d press ure. S yst olic a n d 
diast olic bl o o d press ure are t o be meas ure d after t h e partici pa nt has b ee n s u pi ne f or at least 
5  mi n utes pri or t o t he meas ure me nt. Ort h ostatic bl o o d press ur e a n d heart rate will be meas ure d 
after t he p artici pa nt has b ee n i n t he s u pi ne p ositi o n f or at least 5 mi n utes a n d t he n re peate d 
a p pr o xi matel y 1 a n d 3 mi n utes after sta n di n g.  
A n y a b n or malit y i n vital si g ns will be i nter prete d b y a n i n v esti gat or as a b n or ma l, N C S; or 
a b n or mal, C S i n s o urce d oc u me nts.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 3  
1 1. 1. 6.  
Electr oc a r di o gr a m ( E C G)  
A si n gle 1 2 -l ea d E C G will be perf or me d at t he ti me p oi nts descri be d i n Ta ble  2 . T he sta n dar d 
i nter vals ( heart rate, P R, Q R S, Q T, a n d Q T c orrecte d acc or di n g t o Fri derici a’s f or m ula [ Q Tc F ]) 
as well as a n y r h yt h m a b n or malities will be rec or de d.  
Electr ocar di o gra ms will be perf or me d after t he p artici pa nt has bee n resti n g i n a s u pi ne p ositi o n 
f or at least 5 mi n utes. W he n E C G meas ure me nts c oi nci de wit h safet y assess me nts, vital si g ns 
assess me nt or bl o o d dra ws, pr oce d ures s h o ul d be carri e d o ut i n sai d or der  as defi ne d i n S O A.  
A ll a b n or mal E C Gs will be i nter pret e d b y a n i n vesti gat or as C S or N C S i n s o urce d oc u m e nts. 
1 1. 1. 7.  
L a b or at or y Assess me nts  
Bl o o d a n d uri ne s a m ples f or cli nical la b orat or y ass ess me nts will be c ollecte d. A nal yt es t o be 
e val uate d are s u m mariz e d i n  Ta ble  5 . 
T a ble  5 : 
S u m m ar y of Cli nic al L a b or at or y A n al ytes  
Bi oc he mistr y  
Re n al P a nel : gl uc ose, calci u m, p h os p h or us, bl o o d urea nitr o ge n, creati ni ne, 
s o di u m, p otassi u m, c hl ori de, bicar b o nate 
He p atic P a nel : al b u mi n, ala ni ne a mi n otra nsferase, al kali ne p h os p hatase, as partate 
a mi n otra nsferase, t otal bilir u bi n, direct bilir u bi n, i n direct bilir u bi n, t otal pr otei n, 
lactate de h y dr o ge nase, ga m ma gl uta m yl tra nsferase  
Ot her : tri gl yceri des, t otal c h olester ol, l o w de nsit y li p o pr otei n [ L D L], hi g h de nsit y 
li p o pr otei n [ H D L], creati ne p h os p h o ki nase, t h yr oi d sti m ulati n g h or m o ne [T S H ] 
a n d refle x t o free trii o d ot h yr o ni ne ( T 3)/t h yr o xi ne ( T 4) if T S H is a b n or mal. 
He m at ol o g y  
Re d bl o o d cell ( R B C) c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell c o u nt wit h 
differe ntial, platelet c o u nt, R B C i n dices ( mea n c or p usc ular v ol u me [ M C V], mea n 
c or p usc ular he m o gl o bi n [ M C H], a n d mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
[ M C H C]).  
Uri n al ysis  
Pr otei n, gl uc ose, p H, bl o o d, le u k oc yte esterase, ur o bili n o ge n, bilir u bi n, ket o nes, 
nitrite s 
C o a g ul ati o n  
Acti vate d partial t hr o m b o plasti n ti me, pr ot hr o m bi n ti me, a n d i nter nati o nal 
n or malize d rati o  
Ser ol o g y 
(scree ni n g o nl y) 
He patitis B a n d C scree ni n g tests, h u ma n i m m u n o deficie nc y vir us ( HI V )-1 a n d -2 
a nti b o d y 
All cli nical la b orat or y test res ults 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 C S; or a b n or mal, C S i n s o urce d oc u m e nts. 
S er u m FS H test will be c o n d ucte d at Scree ni n g f or t he fe mal e partici pa nts  w h o are n ot s ur gi call y 
sterile t o c o nfir m w het h er a fe m ale partici p a nt  wit h ≥1 2 m o nt hs of s p o nta ne o us a me n orr hea 
meets t he pr ot oc ol -defi ne d criteria f or bei n g p ost me n o pa usal.  
1 1. 1. 7. 1.  Dr u gs of A b use , Alc o h ol 
Se parate uri ne sa m ples f or assess me nt of dr u gs of a b use (a m p h eta mi nes, b ar bit urates, 
be nz o diaze pi nes, ca n na bi n oi ds / T H C, c ocai ne, a n d o piates) will be c ollecte d. A breat h test f or 
alc o h ol will be perf or me d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 4  
1 1. 1. 7. 2.  Pre g n a nc y Testi n g  
A ser u m pre g n a nc y test  will be c o n d ucte d f or all fe male partici pa nts at Scree ni n g; a uri ne 
pre g na nc y t est will be c o n d ucte d at ot her sc he d ule d ti me p oi nts f or fe male partici pa nts t hat are 
n ot p ost me n o pa usal or s ur gic all y st erile.  
 
 
 
 
 
 
 
  
 
 
  
1 1. 1. 9.  
C O VI D -1 9 Q uesti o ns  
Detaile d i nf or mati o n re gar di n g di a g n osis, is olati o n, a n d/ or h os pitalizati o n d ue t o C O VI D -1 9 a n d 
C O VI D -1 9 vacci ne hist or y will  be d oc u me nte d as part of me dical hist or y. I n a d diti o n, 
i nf or mati o n f oc use d o n C O VI D-1 9 (e g, A E c ollecti o n, a n d pri or/c o nc o mit a nt 
me dicati o n/ pr oce d ures) will be c ollecte d at Scree ni n g a n d t hr o u g h o ut t he st u d y.  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts  
1 1. 2. 1.  
A d verse E ve nt Defi niti o n  
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 i n a patie nt or cli nical i n vesti gati o n 
partici pa nt a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y h a ve a ca us al 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m or disease te m p orall y ass o ciate d wit h t he 
use of a me dici n al (i n vesti gati o nal) pr o d u ct w het h er or n ot rel ate d t o t he m e dici nal 
(i n vesti gati o nal) pr o d uct. I n cli nical st u dies, a n A E ca n i ncl u de a n u n desir a ble me dical c o n diti o n 
occ urri n g at a n y ti me, i ncl u di n g bas eli ne or was h o ut peri o ds, e ve n if n o st u d y treat me nt has bee n 
a d mi nistere d.  
A treat me nt-e mer ge nt a d verse e v e nt (T E A E ) is defi ne d as a n A E wit h o nset after t he start of I P, 
or a n y w ors e ni n g of a pre -e xisti n g me dical c o n diti o n/ A E wit h o nset after t he start of I P a n d 
t hr o u g h o ut t he st u d y. T h e ter m I P i ncl u des a n y Sa ge I P, a c o m parat or, or a place b o a d mi nistere d 
i n a cli nical trial.  
La b orat or y a b n or malities a n d c ha n ges fr o m bas eli ne i n vital si g ns, a n d E C Gs are c o nsi dere d A Es 
if t he y res ult i n disc o nti n uati o n or i nterr u pti o n of st u d y treat me nt, re q uir e t hera pe utic m e dical 
i nter ve nti o n, meet pr ot oc ol s pecific criteria (if a p plica ble) or if t he I n vesti gat or c o nsi ders t he m t o 
be C S. A n y a b n or malities t hat meet t he criteri a f or a S A E s h o ul d be re p ort e d i n a n e x pe dite d 
ma n ner. La b orat or y a b n or malities a n d c ha n ges fr o m baseli ne i n vital si g ns a n d E C Gs t hat are 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 5  
clearl y attri b uta ble t o a n ot her A E d o n ot re q uir e discrete re p orti n g (e g,  electr ol yte dist ur ba nces 
i n t he c o nte xt of de h y drati o n, c he mistr y a n d h e mat ol o gic dist ur ba nces i n t he c o nte xt of se psis). 
All A Es t hat occ ur after a n y p artici pa nt has si g ne d t he i nf or me d c o nse nt a n d t hr o u g h o ut t he 
d urati o n of t he st u d y, w h et he r or n ot t he y are relat e d t o t he st u d y, m ust be re p orte d t o Sa ge 
T hera p e utics.  
Partici pa nts w h o disc o nti n ue t he I P d ue t o a n A E, re gar dl ess of I n vesti gat or -deter mi ne d 
ca usalit y, s h o ul d b e f oll o we d u ntil t he e ve nt is res ol ve d, c o nsi dere d sta bl e, or t he I n ve sti gat or 
deter mi nes t he e v e nt is n o l o n ger C S. A n y A Es t h at are u nres ol ve d at t he p artici pa nt’s last A E 
assess me nt i n t he st u d y are f oll o we d u p b y t he I n v esti gat or f or as l o n g as m e dicall y i n dicate d, 
b ut wit h o ut f urt her rec or di n g i n t he e C R F. T h e S p o ns or o r its re pres e ntati ve retai ns t he ri g ht t o 
re q uest a d diti o nal i nf or m ati o n f or a n y partici pa nt wit h o n g oi n g A E(s)/ S A E(s) at t he e n d of t he 
st u d y, if j u d ge d necessar y. 
1 1. 2. 2.  
Seri o us A d verse E ve nt ( S A E) Defi niti o n  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
•  Res ults i n deat h  
•  Places t he partici p a nt  at i m me diate ris k of deat h (a life -t hreat e ni n g e ve nt); h o we ver, 
t his d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve 
ca use d deat h  
•  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  
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y  
•  Res ults i n a c o n ge nital a b n or malit y or birt h defect  
A n S A E ma y als o be a n y ot her me dicall y i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or 
ma y je o p ar d iz e t he partici pa nt or ma y re q uir e me dical i nter ve nti o n t o pre ve nt 1 of t he o utc o mes 
liste d a b o ve (e x a m ples of s uc h e ve nts i ncl u de aller gic br o nc h os p as 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 c o n v ulsi o ns occ urri n g at h o me t hat d o n ot re q uire a n 
i n patie nt h os pitaliz ati o n). 
All S A Es t hat occ ur aft er a n y p artici pa nt has si g ne d t he I C F a n d t hr o u g h o ut t he d urati o n of t he 
st u d y, w het h er or n ot t he y are relate d t o t he st u d y, m ust be rec or de d o n t he S A E re p ort f or m 
pr o vi de d b y Sa ge T hera p e utics. A n y S A E t hat is o n g oi n g w he n t h e partici p a nt c o m pletes t heir 
fi nal st u d y visit, will be f oll o we d b y t he I n vesti gat or u ntil t he e ve nt has res ol ve d, sta bilize d, 
ret ur ne d t o bas eli ne stat us, or u ntil t he partici pa nt dies or is l ost t o f oll o w u p. 
A presc h e d ule d or  electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt will n ot be c o nsi dere d a n 
S A E, e ve n if t he partici pa nt is h os pitalize d. T he site m ust d oc u me nt all of t he f oll o wi n g:  
•  T he presc h e d ule d or electi ve pr oce d ure or r o uti nel y sc h e d ule d treat me nt was 
sc he d ule d ( or o n a w aiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he partici pa nt’s 
c o nse nt t o partici pate i n t he st u d y.  
•  T he c o n diti o n re q uiri n g t he presc h e d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d 
treat me nt was pr ese nt bef ore a n d di d n ot w orse n or pr o gress, i n t he o pi ni o n of a n 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 6  
I n v esti gat or, bet wee n t he partici pa nt’s c o ns e nt t o partici pate i n t he st u d y a n d at t he 
ti me of t he pr oce d ure or treat me nt. 
1 1. 2. 3.  
Defi niti o n of Ur ge nt S af et y Me as ure ( U S M) a n d U n a ntici p ate d Pr o ble m ( U P)  
I n acc or da n ce wit h Articl e 1 0( b) of Directi ve 2 0 0 1/ 2 0/ E C, s o me re p orte d e v e nts ma y res ult i n a n 
ur ge nt safet y me as ure ( U S M), defi ne d as a n acti o n t hat t he s p o ns or a n d i n vesti gat or m a y ta ke i n 
or der t o pr ote ct t he partici pa nts of a st u d y a gai nst a n y i m me diat e hazar d t o t heir healt h or safet y . 
E x a m ples of U S Ms i ncl u de:  
•  S us pe nsi o n of e nr oll me nt d ue t o si g nifica ntl y hi g h er i nci de nce of deat h at o ne site  
•  A d diti o nal cli nical or n o n -cli nical i n vesti gati o ns perf or me d d u e t o i ncreas e d 
fre q ue n c y of A Es 
•  H alti n g a cli nical st u d y f or safet y reas o ns  
I n acc or da n ce wit h F o o d a n d Dr u g A d mi nistrati o n  G ui da nce 2 1 C o de of F e deral R e g ulati o ns  
Part 3 1 2. 6 6, s o me re p ort e d e ve nts ma y q ualif y as a n u na ntici pate d pr o bl e m ( U P), defi ne d as a n y 
i nci de nt, e x perie nce, or o utc o me t hat meets all of t he f oll o wi n g criteria: 
•  U ne x pecte d (i n ter ms of nat ure, se v erit y, or fre q u e nc y) gi ve n (i) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol -rel ate d d oc u me nts, s uc h as t h e 
I R B -a p pr o ve d researc h pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt; a n d (ii) t he 
c haracteristics of t he p o p ulati o n bei n g st u die d; rel ate d or p ossi bl y relate d t o a n 
i n di vi d ual’s partici pati o n i n t he st u d y; a n d 
•  S u g gests t he st u d y ma y place t he partici pa nt or ot h ers at a greater ris k of har m 
(i ncl u di n g p h ysic al, ps yc h ol o gical, ec o n o mic, or s ocial har m) relate d t o t he st u d y 
t ha n was pre vi o usl y k n o w n or rec o g nize d. 
A n y U P m ust be re p orte d wit hi n 2 4 h o urs of a ware ness via e mail t o Sa ge a n d desi g n ee d ue t o t he 
ur ge nt re p orti n g re q uire me nts t o re g ul at ors a n d I R B(s)/ IE Cs(s).  
1 1. 2. 4.  
Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct  
T he I n vesti gat or m ust ma ke t he det er mi nati o n of relati o ns hi p t o t he I P f or eac h A E ( n ot relat e d, 
relate d). T h e f oll o wi n g d efi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es 
a n d S A Es t o t he I P.  
N ot Relate d  
A n A E will be c o nsi dere d “ n ot rela te d” t o t he use of t he I P if t here is n ot a reas o na ble 
p ossi bilit y t hat t he e ve nt has b ee n ca use d b y t he I P. Fact ors p oi nti n g t o war ds t his assess me nt 
i ncl u de b ut are n ot li mite d t o t he lac k of te m p oral relati o ns hi p bet wee n a d mi nistrati o n of t he 
I P a n d t he e ve nt, t he prese nce of bi ol o gicall y i m pla usi ble rel ati o ns hi p bet wee n t he pr o d uct a n d 
t he A E, or t he prese nce of a m ore li kel y alter nati ve e x pla nati o n f or t he A E. 
Relate d  
A n A E will be c o nsi dere d “relate d” t o t he use of t he I P if t here is a reas o na ble p ossi bilit y t hat 
t he e ve nt ma y ha ve bee n ca us e d b y t he pr o d uct u n der i n vesti gati o n. Fact ors t hat p oi nt t o war ds 
t his assess me nt i ncl u de b ut ar e n ot li mite d t o: a p ositi ve rec halle n ge, a reas o na ble te m p oral 
se q ue nce bet wee n a d mi nistrati o n of t he dr u g a n d t he  e ve nt, a k n o w n res p o nse patter n of t he 
s us pecte d dr u g, i m pr o ve me nt f oll o wi n g disc o nti n uati o n or d ose re d ucti o n, a bi ol o gicall y 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 7  
pla usi ble relati o ns hi p bet wee n t he dr u g a n d t he A E, or a lac k of alter nati ve e x pla nati o n f or t he 
A E.  
1 1. 2. 5.  
Rec or di n g A d verse E ve nts  
A E s s p o nta ne o usl y re p orte d b y t he p artici pa nt a n d/ or i n res p o nse t o a n o pe n q uesti o n fr o m t he 
st u d y pers o n n el or re veal e d b y o bs er vati o n will be rec or de d d uri n g t he st u d y at t he 
i n vesti gati o nal site. T he A E ter m s h o ul d be re p orte d i n sta n dar d me dical ter mi nol o g y w he n 
p ossi ble. F or eac h A E, t h e I n vesti gat or will e val u ate a n d re p ort t he o nset ( d ate a n d ti me), 
res ol uti o n ( date a n d ti me), i nte nsit y, ca usalit y, acti o n ta ke n, o utc o me a n d s eri o us ness (if 
a p plica ble), a n d w het her or n ot it ca use d t he partici pa nt t o disc o nti n ue t he I P or wit h dra w earl y 
fr o m t he st u d y. 
I nte nsit y will be ass esse d acc or di n g t o t he f oll o wi n g scale: 
•  Mil d: s y m pt o m(s) barel y n oticea ble t o partici p a nt or d oes n ot ma ke partici pa nt 
u nc o mf orta ble; d oes n ot i nfl ue nce perf or m a nce or f u ncti o ni n g; p rescri pti o n dr u g n ot 
or di naril y n ee d e d f or relief of s y m pt o m(s)  
•  M o derate: s y m pt o m(s) of a s ufficie nt se v erit y t o ma ke partici p a nt u nc o mf orta ble; 
perf or ma n ce of dail y acti vit y is i nfl ue nce d; p artici pa nt is a ble t o c o nti n ue i n st u d y; 
treat me nt f or s y m pt o m(s) ma y b e nee d e d 
•  Se vere: s y m pt o m(s) ca us e se vere disc o mf ort; s y m pt o ms ca use i nca p acitati o n or 
si g nifica nt i m pa ct o n partici pa nt’s dail y life; se v erit y ma y ca use cessati o n of 
treat me nt wit h I P; treat m e nt f or s y m pt o m(s) ma y be gi v e n a n d/ or partici pa nt 
h os pita lize d  
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d s e vere A Es. Se verit y is a meas ure of i nte nsit y 
w hereas seri o us ness is defi ne d b y t h e criteria u n der Secti o n  1 1. 2. 2 . A n A E of se vere i nte nsit y 
ma y n ot ne cessaril y b e c o nsi dere d seri o us.  
1 1. 2. 6.  
Re p orti n g Seri o us A d verse E ve nts  
I n or der t o a d here t o all a p plica ble la ws a n d re g ulati o ns f or re p orti n g a n S A E(s), t he st u d y site 
m ust n otif y Sa ge T hera p e utics a n d desi g nee wit hi n 2 4 h o urs of t he st u d y site staff bec o mi n g 
a ware of t he S A E(s)  (see Ta ble 1  f or c o ntact i nf or mati o n). T he I n vesti gat or m ust c o m plete, si g n 
a n d date t he S A E re p ort f or m, verif y t he acc urac y of t he i nf or mati o n rec or de d o n t he S A E re p ort 
f or m wit h t he c orres p o n di n g s o urce d oc u me nts, a n d se n d a c o p y t o Sa ge T h era pe utics or 
desi g nee.  
A d diti o nal f oll o w -u p i nf or mati o n, if re q uire d or a vaila ble,  s h o ul d all be se nt t o Sa ge 
T hera p e utics a n d desi g nee wit hi n 2 4 h o urs of recei pt o n a f oll o w -u p S A E re p ort f or m a n d place d 
wit h t he ori gi nal S A E i nf or mati o n a n d ke pt wit h t he a p pr o pri ate secti o n of t he e C R F a n d/ or 
st u d y file. 
S A Es occ urri n g after t he desi g nat e d f oll o w u p ti me f or t he st u d y, s h o ul d be re p orte d t o Sa ge 
T hera p e utics a n d desi g nee acc or di n g t o t he ti meli nes n ote d a b o ve o nl y if t h e i n vesti gat or 
c o nsi ders t he S A E relate d t o I P.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 8  
Sa ge T h era pe utics, or d esi g nee, is res p o nsi ble f or n otif yi n g t he rele va nt r e g ulat or y a ut h orities of 
certai n e v e nts. It is t he pri nci pal i n vesti gat or’s res p o nsi bilit y t o n otif y t he I R B/I E C of all S A Es 
t hat occ ur at his or h er site. I n vesti gat ors will als o be n otifie d of all s us pect e d u ne x pecte d seri o us 
a d verse reacti o ns ( S U S A Rs) t hat occ ur d uri n g t he cli nical st u d y. I R Bs/I E Cs will be n otifie d of 
S A Es a n d/ or S U S A Rs as re q uire d b y l ocal la w.  
I n a d diti o n, a p pr o priate p ers o n nel i n Sa ge T hera p e utics Dr u g Safet y a n d P h ar mac o vi gila nce or 
desi g nee will u n bli n d S U S A Rs f or t he p ur p ose of re g ulat or y re p orti n g. Sa ge T hera pe utics or 
desi g nee will s u b mit S U S A Rs (i n bli n de d or u n bli n de d fas hi o n) t o re g ul at or y a ge nci es acc or di n g 
t o l ocal la w. Sa ge, or desi g nee, will s u b mit S U S A R S t o I n v esti gat ors i n a bli n de d fas hi o n. 
1 1. 3.  
Pre g n a nc y  
If a partici pant bec o m es pre g na nt after t he first a d mi nistrati o n of I P, pre g n a nc y i nf or mati o n m ust 
be c ollecte d a n d rec or de d o n t he Pre g na nc y f or m a n d s u b mitte d t o t he s p o ns or wit hi n 2 4  h o urs of 
lear ni n g of t he pre g na n c y. D etails will be c ollecte d f or all pre g n a ncies f or w hic h c o nce pti o n was 
li kel y t o ha ve o cc urre d after t he start of I P a d mi nistrati o n u ntil 5 ter mi nal half-li ves f oll o wi n g 
t he last a d mi nistrati o n of I P or u ntil t he c o m pleti o n of t he st u d y w hi c he ver is l o n ger. A n y 
pre g na nc y o cc urri n g i n t hat ti me fra me wil l be f oll o we d u ntil deli ver y or ter mi nati o n of t he 
pre g na nc y. T he I n v esti gat or will als o atte m pt t o c ollect pre g na n c y i nf or mati o n o n a n y 
partici pa nt’s part ner w h o bec o mes pre g na nt aft er t he partici pa nt has recei ve d t he first 
a d mi nistrati o n of I P. Aft er o bt ai ni n g t h e necessar y si g ne d i nf or me d c o nse nt fr o m t he pre g na nt 
part ner directl y, t he I n v esti gat or will f oll o w t he sa me pre g na n c y re p orti n g pr oce d ures s pecifi e d 
f or pre g n a nt partici pa nts.  
T he partici pa nt or p artici pa nt’s part ner will be f oll o we d t o deter mi ne t he o utc o me of t he 
pre g na nc y. T he o utc o me of all pre g na n cies (e g, s p o nta ne o us a b orti o n, electi ve a b orti o n, n or mal 
birt h) m ust be f oll o we d a n d d oc u me nte d e v e n if t he partici pa nt was disc o nti n ue d fr o m t he st u d y. 
T he I n vesti gat or will c oll ect f oll o w -u p i nf or m ati o n o n t he partici pa nt or p artici pa nt’s part ner a n d 
t he ne o nate, a n d t he i nf or mati o n will be f or war de d t o Sa ge or desi g nee. Ge n erall y, f oll o w-u p 
will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t h e esti mate d deli ver y d ate. A n y 
ter mi nati o n of pre g na n c y will be re p orte d, re gar dless of fetal stat us ( prese n ce or a bs e nce of 
a n o malies) or i n dicati o n f or t he pr oce d ure.  
Pre g n a nc y i n itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat a n I P ma y ha ve 
i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicati o n. A n y c o m plicati o n d uri n g 
pre g na nc y (e g, a ne mia, i nfecti o ns, pre -ecl a m psia) s h o ul d be re p orte d as a n  A E/ S A E. If t he 
o utc o me of t he pre g na nc y me ets t he criteri a f or i m me diate classificati o n as a n S A E (ie, 
s p o nta ne o us a b orti o n, still birt h, ne o natal deat h,), t he I n vesti gat or s h o ul d f oll o w t he pr oce d ures 
f or re p orti n g a n S A E.  
1 1. 4.  
O ver d ose  
A n o ver d ose is a n y d os e of st u d y tr eat me nt gi ve n t o a partici pa nt or ta ke n b y a p artici pa nt t hat 
e x cee ds t he d ose des cri b e d i n pr ot oc ol. O ver d oses are n ot c o nsi dere d A Es a n d s h o ul d n ot be 
rec or de d as a n A E o n t he eC R F; h o we ver, all o ver d oses m ust be rec or de d o n a n o ver d ose f or m  
a n d se nt t o Sa ge or desi g nee wit hi n 2 4 h o urs of t h e site bec o mi n g a ware of t he o ver d ose. A n 
o ver d ose m ust be re p orte d t o Sa ge or desi g nee e ve n if t he o ver d ose d o es n ot res ult i n a n A E. If 
a n o ver d ose res ults i n a n A E, t he A E m ust be rec or de d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 9  
1 2.  
S T A TI S TI C S  
A  se parate statistical a nal ysis pla n ( S A P) will pr o vi de a detaile d des cri pti o n of t he a nal yses t o be 
perf or me d i n t he st u d y. T he S A P will be fi nalize d a n d a p pr o ve d pri or t o dat a base l oc k.  
1 2. 1.  
D at a A n al ysis Sets  
T he All Ra n d o mize d Set will i ncl u de all partici pa nts w h o ha ve bee n ra n d o mize d a n d will be 
use d t o descri be p artici pa nt dis p ositi o n.  
T he Safet y Set will i ncl u de all partici pa nts w h o were a d mi nistere d at least o ne d ose of t he I P a n d 
will be use d t o descri be t he safet y d ata.  
T he F ull A nal ysis Set w ill i ncl u de all partici pa nts i n t he Safet y Set w h o ha v e baseli ne a n d at 
least 1 p ost baseli ne efficac y e v al uati o n.  
 
 
1 2. 2.  
H a n dli n g  of Missi n g D at a  
E ver y atte m pt will be ma de t o a v oi d missi n g data . All partici pa nt s will be use d i n t he a nal yses, 
as per t he a nal ysis p o p ulati o ns, usi n g all n o n missi n g  dat a  a vaila ble. N o i m p utati o n pr ocess will 
be use d t o esti mate missi n g dat a . 
1 2. 3.  
Ge ner al C o n si der ati o ns 
All partici pa nt data, i ncl u di n g t h ose t hat are deri ve d, t hat s u p p ort t he ta bles a n d fi g ures will be 
prese nte d i n t he p artici pa nt data listi n gs. S o me data ma y be prese nte d o nl y i n partici pa nt data 
listi n g, s o me ma y b e pres e nte d wit h a c orres p o n di n g ta ble or fi g ure; t hes e will be i n dicate d i n 
rele va nt se cti o ns bel o w. All s u m maries will be pr o vi de d b y tr eat me nt –  eit her b y ra n d o mize d 
treat me nt or act ual treat me nt recei v e d.  
If a partici pa nt ta kes a n y d ose of S A G E-7 1 8, t he partici pa nt’s act ual treat m e nt is c o nsi dere d as 
S A G E -7 1 8, re gar dless of t he treat me nt t o w hic h t he partici pa nt has b ee n ra n d o mize d.  
F or t he p ur p os e of all a nal yses, w h ere a p plica ble, b aseli ne is defi ne d as t he l ast meas ure me nt pri or 
t o t he first d ose of I P. 
Descri pti ve s u m mar y stat istics will be pr o vi de d f or de m o gra p hics, baseli n e c haracteristics, a n d 
t otal dis p ositi o n, i ncl u di n g t he n u m ber of partici pa nts e nr olle d a n d t he perce nta ge of p artici pa nts 
w h o disc o nti n ue d fr o m t he st u d y, al o n g wit h reas o ns f or disc o nti n uati o ns.  
C o nti n u o us  data will be s u m marize d i n ter ms of t he n u m ber of partici pa nts, mea n, sta n dar d 
de viati o n, mi ni m u m val ue, Q 1, me dia n, Q 3, a n d ma xi m u m val ue. Cate g ori cal dat a will be 
s u m marize d usi n g fre q u e nc y c o u nts a n d perce nt a ges.  
1 2. 4.  
De m o gr a p hics a n d B aseli ne C h ar acteristi cs 
De m o gra p hic d ata, s uc h as a ge, race, a n d et h nicit y, years of e d ucati o n, e m pl o y me nt hist or y, 
c urre nt e m pl o y me nt stat us , a n d baseli ne c h aracteristics, s uc h as hei g ht, wei g ht, a n d b o d y mass 
i n de x ( B MI), will be s u m mariz e d usi n g t he Safet y Set . 
Pre g n a nc y  test res ults a n d dr u g a n d alc o h ol test res ults will be liste d b ut n ot s u m marize d . 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 0  
Me dical hist or y will be s um marize d a n d liste d b y partici pa nt . 
1 2. 5.  
Effic ac y A n al ysis  
T he e n d p oi nts f or eac h c o g niti ve  test, i ncl u di n g i n di vi d ual sc ores f or t he W AI S-IV C o di n g t est 
 are c ha n ge fr o m 
baseli ne sc ores at e ac h p ost baseli ne assess me nt.  Descri pti ve statistics of s c ores a n d c ha n ge fr o m 
baseli ne sc ores will be s u m mariz e d base d o n t he F ull A nal ysis Set. T hese e n d p oi nts will als o be 
a nal yze d usi n g a mi x e d  effects  m o del f or re p eate d meas ures. T h e m o del will i ncl u de c ha n ge 
fr o m baseli ne sc ores as d e pe n de nt varia ble; treat me nt, visit, a n d visit b y tr eat me nt i nteracti o n as 
fi x e d effects; partici p a nts as ra n d o m effects; a n d baseli ne c o g niti ve test sc ores as a c o vari ate; 
M o del -base d p oi nt esti mates (ie,  le ast s q uare mea ns, t heir 9 5 % c o nfi de n ce i nter vals, a n d 
ass ociate d p val u es) at e ac h ti me p oi nt ( visit) will be re p ort e d w here a p plica ble. Li n e pl ots of 
c ha n ge fro m baseli ne s c ores wi ll be pl otte d wit h sta n dar d err or bars. 
 
 will be a nal yze d usi n g 
si milar met h o ds. 
A d diti o nal a nal ys es will be detaile d i n t he S A P . 
1 2. 5. 1.  
M ulti plicit y A dj ust me nt  
N ot a p plica ble.  
1 2. 5. 2.  
Se nsiti vit y A n al yses  
N ot a p plica ble.  
1 2. 6.  
S afet y A n a l yses 
Safet y a n d t olera bilit y of S A G E -7 1 8 will be e val u ate d b y t he fre q ue n c y of T E A Es a n d c h a n ge 
fr o m baseli ne i n vital si g ns, cli nical la b orat or y a n al ytes, E C Gs, a n d 
. 
Safet y d ata will be liste d b y partici pa nt a n d s u m m arize d b y tr eat me nt gr o u p, ma xi m u m se verit y , 
a n d relati o ns hi p t o I P. Vital si g ns, la b orat or y para meters, E C Gs, a n d 
 data will be liste d 
b y partici pa nt a n d s u m m arize d b y tr eat me n t gr o u p. All safet y s u m maries will be perf or me d o n 
t he Safet y Set. 
A d diti o nal a nal ys es will be detaile d i n t he S A P.  
1 2. 6. 1.  
A d verse E ve nts  
A E s will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ul at or y Acti vities (Me d D R A ) 
v ersi o n 2 2. 0  or hi g her. A T E A E is defi ne d a s a n A E  wit h o nset after t he first d ose of I P. T h e 
pr o p orti o n of partici pa nts e x perie nci n g T E A Es will be dis pla ye d b y treat me nt gr o u p a n d b y 
s yste m or ga n class a n d preferre d t er m. I n a d diti o n, s u m maries will be pr o vi de d b y i nte nsit y 
( mil d, m o derate, se vere) a n d b y ca usalit y (relate d, n ot relate d) t o I P.  
A n y T E A Es lea di n g t o disc o nti n uati o n or i nterr u pti o n of treat me nt or wit h dra wal fr o m t he st u d y 
a n d a n y treat me nt -e mer ge nt S A Es  wil l be s u m marize d. 
All A Es a n d S A Es (i ncl u di n g t h ose wit h o nset or w orse ni n g bef ore t he start of I P) t hr o u g h t h e 
e n d of t he st u d y will be liste d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 1  
1 2. 6. 2.  
Cli nic al L a b or at or y E v al u ati o ns  
Res ults of cli nical la b orat or y para met ers i n eac h s c he d ule d visit a n d mea n c ha n g es fr o m baseli ne 
will be s u m mariz e d i n sta n dar d u nits. N or mal ra n ges f or eac h para met er will be pr o vi de d b y t he 
la b orat or y; s hift fr o m bas eli ne t o p ost baseli ne val u es i n a b n or malit y of res ults will be pr o vi de d. 
P ote ntiall y C S val ues will be s u m marize d b y t reat me nt. Cli nical la b orat or y res ults will be liste d 
b y partici pa nt a n d ti mi n g of c ollecti o n.  
1 2. 6. 3.  
P h ysic al E x a mi n ati o ns  
A f ull p h ysic al e x a mi nati o n is t o be c o n d ucte d d uri n g Scree ni n g a n d at D a y 4 2 . At ot her visits, 
p h ysical e x a mi nati o ns will i ncl u de a brief a ss ess me nt of ge neral a p peara nce, car di o v asc ular, 
res pirat or y, gastr oi ntesti nal, a n d ne ur ol o gical s yste ms a n d f oll o we d b y a tar get e d p h ysical 
assess me nt as nee de d. A s y m pt o m -direct e d e x a mi nati o n ma y b e c o n d uct e d at a n y ti me at t he 
discreti o n of t he i n vesti g at or. T he occ urre nce of a p h ysical e x a mi nati o n ( yes/ n o) a n d t he dat e 
perf or me d will be liste d b y partici pa nt.  
1 2. 6. 4.  
Vit al Si g ns  
Vital si g ns will i ncl u de b o d y  te m perat ur e, res pir at or y rate, heart rate, a n d bl o o d press ure. H eart 
rate a n d bl o o d pr ess ure t o be c ollecte d i n s u pi ne p ositi o n a n d sta n di n g p ositi o n at all sc he d ule d 
ti me p oi nts. Vital si g n res ults at eac h visit a n d mea n c ha n ges fr o m bas eli ne will be s u m marize d 
b y sc h e d ule d visit. P ote ntiall y C S val ues will be s u m marize d b y treat me nt. Vital si g n res ults wil l 
be liste d b y partici pa nt a n d ti mi n g of c ollecti o n.  
1 2. 6. 5.  
1 2 -Le a d Electr oc a r di o gr a m  
E C G  will be meas ure d after t he partici pa nt h as bee n i n t he s u pi ne p ositi o n f or at least 5 mi n utes. 
T he f oll o wi n g E C G p ara meters will be liste d f or eac h E C Gs f or eac h partici pa nt: heart rate, P R, 
Q R S, Q T, a n d Q Tc F. T h e deri ve d me a n of eac h p ara meter will als o be liste d. Mea n E C G d ata 
will be s u m mariz e d b y visit. P ote ntiall y C S val ues of Q Tc F will be s u m marize d b y treat me nt. 
E C G fi n di n gs will be liste d b y p artici pa nt a n d visit  
1 2. 6. 6.  
Pri o r a n d C o nc o mit a nt Me dic ati o ns  
Me dicati o ns will be rec or de d at e ac h st u d y visit d ur i n g t he st u d y a n d will be c o de d usi n g W orl d 
Healt h Or ga niz ati o n -Dr u g dicti o nar y Se pt e m ber 2 0 1 5, or later . 
All me dicati o ns  a n d s u p ple me nts  ta ke n withi n  6 0 da ys  pri or t o  Scree ni n g  t hr o u g h t h e d urati o n of 
t he st u d y will be rec or de d, as well as all me dicati o ns use d t o treat P D  re gar dless of ti mi n g. T h ose 
me dicati o ns ta ke n pri or t o t he first d ose of I P will be de n ote d “ Pri or”. T h os e me dicati o ns ta ke n 
pri or t o t he first d ose of I P a n d c o nti n ui n g be y o n d t he i nitiati o n of t he I P or t h ose me dicati o ns 
starte d at t he sa me ti me or after t h e i nitiati o n of t he I P will be de n ote d “ C o nc o mita nt”.  
Me dicati o ns will be pres e nte d acc or di n g t o w het h er t he y are “ Pri or” or “ C o nc o mita nt” as 
defi ne d a b o v e. If me di cati o n dates are i n c o m plete a n d it is n ot clear w het h er t he me dicati o n was 
c o nc o mita nt, it will be ass u me d t o be c o nc o mita nt.  
Details of pri or a n d c o nc o mita nt me dicati o ns will be liste d b y partici pa nt , start date, a n d 
ver bati m ter m.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 2  
 
 
 
 
 
1 2. 6. 8.  
Ot her S afet y A n al ysis  
N ot a p plica ble . 
1 2. 7.  
Cli nic al  P h ar m ac ol o g y  A n al yses  
 
 
1 2. 8.  
S a m ple Size  a n d P o wer  
Ass u mi n g a pla ce b o -a dj uste d treat me nt effect size of 0. 7 5  (B ur dic k 2 0 1 4 ) i n t he W AI S -I V 
C o di n g test , a t otal sa m ple siz e of 6 0 e val ua ble p artici pa nts ( 3 0 per ar m) will pr o vi de 8 0 % p o wer 
at a t w o-si de d si g nifica n ce le vel α = 0. 0 5. 
A dj usti n g f or a n a ntici pate d 2 0 % dr o p o ut rate, a p pr o xi matel y 7 6 p artici pa nts will be ra n d o ml y 
assi g ne d i n a 1: 1 rati o t o eit her S A G E -7 1 8 or pl ace b o.  
1 2. 8. 1.  
I nteri m a n d D at a M o nit ori n g C o m mittee A n al ysis  
N ot a p plica ble . 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 3  
1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
1 3. 1.  
St u d y M o nit ori n g  
U nless ot her wise wai ve d or a d dress e d i n a n ot her f or u m (e g, i n vesti gat or m eeti n g), bef ore  a n 
i n vesti gati o nal site ca n e nter a partici pa nt i nt o t he st u d y, a re pres e ntati ve of Sa ge will visit t he 
i n vesti gati o nal st u d y site t o: 
•  C o nfir m  t he a de q uac y of t he facilities 
•  Disc uss wit h t he i n vesti gat or(s) a n d ot h er pers o n nel t heir res p o nsi bilities wit h re gar d t o 
pr ot oc ol a d here nce, I P m a na ge me nt, G C P/IC H G C P c o m plia nce, a n d t he res p o nsi bilities 
of Sa ge T hera pe utics or its re prese nt ati ves. A gree d u p o n  site res p o nsi bilities will be 
d oc u me nte d i n a Cli nical Trial A gree me nt bet wee n Sa ge a n d t he i n vesti gat or.  
D uri n g t h e st u d y, a m o nit or fr o m Sa ge or re prese ntati ve will ha ve re g ular c o ntacts wit h t he 
i n vesti gati o nal site, f or t h e 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 vesti gat or(s) 
•  C o nfir m t hat facilities re mai n acce pta ble  
•  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 uratel y rec or de d i n t he C R F , a n d t hat I P acc o u nta bilit y c hec ks are bei n g perf or me d 
•  Perf or m s o urce data v erif icati 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 partici pa nt’s me dical rec or ds at t he h os pital or practice, a n d ot her rec or ds 
rele va nt t o t he st u d y. T his will re q uire direct access t o all ori gi nal rec or ds f or eac h 
partici pa nt (e g,  m e dical r ec or ds, s o urce d oc u m e nts , cli nic c harts).  
•  Rec or d a n d re p ort a n y pr ot oc ol de viati o ns n ot pre vi o usl y se nt t o Sa ge T hera pe utics.  
•  C o nfir m A Es a n d S A Es 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 A Es ha ve bee n f or w ar de d t o Sa ge T her a pe utics a n d t h ose S A Es t hat met criteria f or 
re p orti n g ha ve b ee n f or war de d t o t he I R B or I E C. 
T he m o nit or will be a vaila ble bet wee n visits if t he i n vesti gat or(s) or ot her st aff nee ds 
i nf or mati o n or a d vice. 
1 3. 2.  
A u dits a n d I ns pecti o ns  
Sa ge T h era pe utics or a ut h o rize d re pres e ntati ves of Sa ge T hera pe utics, a re g ulat or y a ut h orit y, or 
a n I E C or a n I R B ma y visit t he site t o perf or m a n a u dit(s) or i ns pecti o n(s), i ncl u di n g s o urce data 
verificati o n. T he p ur p ose of a Sa ge T h era p e utics a u dit or a re g ulat or y a ut h orit y i ns pe cti o n is t o 
s yste maticall y a n d i n de p e n de ntl y e x a mi ne all st u d y-relate d acti vities a n d d oc u me nts t o 
deter mi ne w het h er t hese acti vities were c o n d ucte d, a n d data were rec or de d, a nal yze d, a n d 
acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, G C P/ G C P a n d I nter n atio nal C o u ncil f or 
Har m o nizati o n of Tec h ni cal Re q uire me nts f or P har mace uticals f or H u ma n Use (I C H) g ui d eli nes, 
a n d a n y a p plica ble re g ul at or y re q uir e me nts. T he in vesti gat or s h o ul d c o nt act Sa ge T h era p e utics 
i m me diatel y if c o nt acte d b y a re g ulat or y a ge n c y or I RB/I E C a b o ut a n  i ns pe cti o n. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 4  
1 3. 3.  
I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee  
T he p ri nci pal in vesti gat or m ust o btai n I R B ( or IE C) a p pr o val f or t he cli nical st u d y pri or t o 
e nr olli n g a p artici pa nt. I nitial I R B ( or IE C) a p pr o val, a n d all materials a p pr o ve d b y t h e I R B ( or 
E C) f or t his st u d y i ncl u di n g t he p artici pa nt c o ns e nt f or m a n d recr uit me nt materials m ust 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.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 5  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T o e ns ure c o m plia n ce wit h G C P  a n d all a p plica ble re g ulat or y re q uir e me nts, Sa ge T h era pe utics 
ma y c o n d uct a q u alit y ass ura nce a u dit (s) at t he cli nical site. Please see Secti o n  1 3. 2  f or more 
details re gar di n g t he a u dit pr ocess.  
T he i n vesti gat or m ust ha ve a de q u ate q ualit y c o ntr ol practices t o e ns ure t hat t he st u d y is 
perf or me d i n a ma n ner c o nsiste nt wit h t he pr ot oc ol, I C H G C P g ui deli nes, a n d a p plica ble 
re g ulat or y re q uire me nts. T he i n vesti gat or is res p o nsi ble f or re vie wi n g all i de ntifie d pr ot oc ol 
de viati o ns.  P r ot oc ol de viati o ns t hat har m or i ncrease t he p ossi bilit y of har m t o t he ri g hts a n d 
welfare of a p artici pa nt, or a de viati o n ma de wit h o ut pri or I R B/I E C a p pr o val t o eli mi nate a n 
im me diate hazar d t o t he partici pa nt  s h o ul d be re p orte d t o t he I R B/IE C per t he I R B/ IE C’s writte n 
pr oce d ures.  
T he i n vesti gat or is res p o nsi ble f or s u per visi n g a n y in di vi d ual or part y t o w h o m t he i n vesti gat or 
dele gates st u d y-relate d d uties a n d f u ncti o ns c o n d ucte d at t he st u d y site. W he n t he i n vesti gat or 
retai ns t he ser vi ces of a n y i n di vi d ual or part y t o p erf or m st u d y-relate d d uti es a n d f u ncti o ns, t he 
i n vesti gat or m ust e ns ur e t he i n di vi d ual or part y is q ualifie d t o perf or m st u d y-relate d d uties a n d 
f u ncti o ns a n d sh o ul d i m ple me nt pr oce d ures t o e ns ure t he i nte grit y of t he st u d y-relate d d uties a n d 
f u ncti o ns perf or me d,  a n d a n y d ata ge n erat e d.  
T he i n vesti gat or m ust mai ntai n a de q uate a n d acc urate s o urce d oc u me nt s a n d st u d y rec or ds t hat 
i ncl u de all perti ne nt o bser vati o ns o n eac h of t he site’s st u d y p artici pa nts. S o urce dat a  m ust be 
attri b uta ble, le gi ble, c o nt e m p ora ne o us, ori gi nal, acc urat e, a n d c o m plet e. C ha n ges t o s o urce data 
s h o ul d be tracea ble, s h o ul d n ot o bsc ure t he ori gi nal e ntr y, a n d s h o ul d be e x plai ne d , if necessary  
t o pr o vi de clarificati o n. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 6  
1 5.  
E T HI C S  
1 5. 1.  
Et hics Re vie w  
T he fi nal st u d y pr ot oc ol, i ncl u di n g t he fi nal v ersi o n of t he I C F, m ust be gi v e n a writte n a n d 
date d a p pr o val or fa v ora ble o pi ni o n b y a n I R B or IE C as a p pr o pri ate. T he in vesti gat or m ust 
o btai n a n d d oc u me nt  a ppr o val bef ore he or s he ca n e nr oll a n y partici p a nt  i nt o t he st u d y. T he I R B  
or IE C  m ust  s u p pl y t o t he s p o ns or a list of t he I R B/IE C  me m bers hi p a n d a state me nt t o c o nfir m 
t hat t he I R B/IE C  is or ga niz e d a n d o perates acc or di n g t o G C P a n d a p plica bl e la ws a n d 
re gulati o ns.  
T he p ri nci pal in vesti gat or is res p o nsi ble f or i nf or mi n g t he I R B or IE C of a n y a m e n d me nt t o t he 
pr ot oc ol i n acc or da nce wit h l ocal re q uire me nts. I n a d diti o n, t he I R B or IE C m ust a p pr o ve all 
a d vertisi n g us e d t o recr uit partici pa nt s f or t he st u d y. T he pr ot oc ol m ust be re-a p pr o ve d b y t he 
I R B or IE C u p o n r ecei pt of a me n d me nts a n d a n n u all y, as l oc al re g ul ati o ns re q uire.  
T he p ri nci pal i n vesti gat or is als o res p o nsi ble f or pr o vi di n g t he I R B or IE C wit h re p orts of a n y 
re p orta ble s eri o us a dvers e dr u g reacti o ns fr o m a n y ot her st u d y c o n d ucte d wit h t he I P. Sa ge 
T hera p e utics will pr o vi de t his i nf or mati o n t o t he p ri nci pal in vesti gat or.  
Pr o gress re p orts a n d n otificati o ns of seri o us a d v erse dr u g reacti o ns will be pr o vi de d t o t he I R B 
or IE C acc or di n g t o l ocal re g ulati o ns a n d g ui deli n es.  I n a d diti o n, t he p ri nci pal in vesti gat or m ust 
i nf or m t he I R B/IE C  a n d s p o ns or of a n y c h a n ges si g nifica ntl y affecti n g t h e c o n d uct of t he st u d y 
a n d/ or i ncreasi n g t h e ris k t o partici pa nt s (e g, vi olati o ns t o t he pr ot oc ol or  ur ge nt safet y meas ures 
ta ke n f or p artici pa nt  safet y). 
1 5. 2.  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be p erf or me d i n acc or da nce wit h et hical pri nci ples t hat ha v e t heir ori gi n i n t he 
Declarati o n of Helsi n ki a n d are c o nsiste nt wit h I C H  a n d G C P g ui deli nes, as w ell as all  
a p plica ble re gi o nal or nati o nal re g ulat or y re q uire m e nts. 
1 5. 3.  
Writte n I nf or me d C o nse nt  
Pri or t o e nr olli n g a st u d y partici pa nt, t he i n vesti gat or(s) will e ns ure t hat t he partici pa nt  is gi v e n 
f ull a n d a de q uat e oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k a n d 
be nefit of t he st u d y . Parti ci pa nt s m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he 
st u d y at a n y ti me. T h e partici pa nt  s h o ul d be gi v e n t he o p p ort u nit y t o as k q u esti o ns a n d all o we d 
ti me t o c o nsi der t he i nf or mati o n pr o vi de d. 
W he n t he partici pa nt deci des t o partici pate i n t he st u d y, t he partici pa nt   m ust  pr o vi de  si g ne d a n d 
date d i nf or me d c o nse nt . T he writte n c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y 
pr oce d ures.  T he i n vesti gat or m ust d oc u me nt t he c o nse nt pr ocess i n t he partici pa nt’s s o urce 
rec or ds. T h e i n vesti gat or m ust mai ntai n t he ori gi nal, si g n e d I C F. A c o p y of t he si g ne d I C F m ust 
be gi v e n t o t he partici pa nt . 
T hr o u g h o ut t he st u d y pa rtici pa nts s h o ul d be i nf or me d of a n y c h a n ges ma de t o t he st u d y a n d as 
ne w safet y a n d or ris k i nf or mati o n bec o mes k n o w n . T he pr o visi o n of t his i nf or mati o n  will be 
d oc u me nte d  i n t he partici pa nt’s s o urce rec or ds, a n d w he n a p plica bl e, a n u p date d I C F will be 
pr o vi de d . 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 7  
1 5. 4.  
D at a Pr otecti o n  
•  Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt 
rec or ds or datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; 
partici pa nt na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici p a nt i de ntifia ble 
will n ot be tra nsferre d.  
•  T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d d ata (i ncl u di n g 
b ut n ot li mite d t o, retai ne d bi ol o gical sa m ples, i ma ges a n d/ or rec or di n gs) will be use d  
b y t he s p o ns or i n acc or da nce wit h  l ocal dat a pr otecti o n la w. T he le vel of discl os ure 
m ust als o be e x plai ne d t o t he partici pa nt w h o will be re q uir e d t o gi v e c o nse nt f or  
t heir data t o be use d as d escri be d i n t he i nf or me d c o nse nt. 
•  T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds  ma y be e x a mi ne d b y  
Sa ge Q ualit y Ass ura n ce a u dit ors or ot her a ut h oriz e d pers o n nel a p p oi nte d b y t he  
s p o ns or, b y a p pr o priat e I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 8  
1 6.  
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 6. 1.  
I ns pecti o n of Rec or ds 
Sa ge T h era pe uti cs or its r e prese nt ati ve(s)  will be all o we d t o c o n d uct visits at t he i n vesti gati o n 
site a n d s u p p orti n g facilities f or t he p ur p os e of m o nit ori n g a n y as p ect of t he st u d y. T he 
i n vesti gat or a grees t o all o w t he m o nit or t o i ns pect t he facilit y, dr u g st ora ge area, dr u g 
acc o u nta bilit y rec or ds, p artici pa nt  me dical r ec or ds  a n d st u d y s o urce d oc u me nts, a n d ot her 
rec or ds relati ve t o st u d y c o n d uct. 
Ins p ecti o n  of t he st u d y b y a re g ulat or y aut h orit y ma y o cc ur at a n y ti me. T he i n vesti gat or m ust 
a gree t o t he i ns p ecti o n of st u d y-relate d rec or ds a n d s o urce d oc u m e nts  b y t h e re g ulat or y aut h orit y  
re pres e ntati ve(s). 
1 6. 2.  
Rete nti o n of Rec or ds  
T he p ri nci pal i n vesti gat or m ust mai ntai n all d oc u me ntati o n relati n g t o t he st u d y f or t h e peri o d 
o utli ne d i n t he site c o ntract, or f or a p eri o d of 2  ye ars after t he last mar keti n g a p plicati o n 
a p pr o val , a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o n s i n a n I C H 
re gi o n or at least 2 years ha ve ela ps e d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt  
of t he I P. Sa ge is res p o nsi ble  t o i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n st u d y d o c u me nts 
n o l o n ger nee d t o be retai ne d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 9  
1 7.  
P U B LI C A TI O N P O LI C Y  
All i nf or mati o n c o ncer ni n g S A G E -7 1 8  is c o nsi dere d c o nfi d e ntial a n d s hall re mai n t he s ole 
pr o pert y of Sa ge T hera pe uti cs. T he i n vesti gat or a grees t o use t his i nf or mati o n o nl y i n c o n d ucti n g 
t he st u d y a n d s h all n ot use it f or a n y ot her p ur p oses wit h o ut writte n a p pr o val fr o m Sa ge 
T hera p e utics. N o p u blicati o n or discl os ure of st u d y res ults will be per mitte d e x ce pt as s pecifie d 
i n a se parate, writte n, a gree me nt bet w ee n Sa ge T h era pe utics a n d t he i n vesti gat or. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 0  
1 8.  
LI S T O F R E F E R E N C E S  
B ur dic k DJ, C h olert o n B, Wats o n G S et al. Pe o ple wit h Par ki ns o n’s Disease a n d n or mal M M S E 
sc ore ha v e a br oa d ra n ge of c o g niti ve perf or ma nce M o ve me nt Dis or ders. 2 0 1 4; 2 9( 1 0): 1 2 5 8 -6 4.  
 
  
C h olert o n B A, Za b etia n C P, Q ui n n J F  et al. Pacifi c N ort h west U d all Ce nter of e x celle nce 
cli nical c o ns orti u m: st u d y desi g n a n d baseli ne c o h ort c haracteristics. J Par ki ns o ns Dis. 
2 0 1 3; 3( 2): 2 0 5 -1 4.  
C olli n gri d ge G L, V olia ns kis A, Ba n nister N, et al. T he N M D A rece pt or as a tar get f or c o g niti ve 
e n ha nce me nt. Ne ur o p har mac ol o g y. 2 0 1 3 ; 6 4: 1 3-2 6.  
 
 
Di Natale C, M o nac o A, Pe d o ne C, et al. T he le vel of 2 4 -h y dr o x yc h olester yl esters decreas es i n 
pl as ma of patie nts wit h Par ki ns o n's disease.  Ne ur osci Lett. 2 0 1 8 A pr 1 3; 6 7 2: 1 0 8 -1 1 2.  
G oetz C G, P oe we W, Rasc ol O, et al. M o ve me nt Dis or der S ociet y Tas k F orce o n Rati n g Scales 
f or Par ki ns o n’s Dise ase. M o ve me nt Dis or der S oci et y T as k F orce re p ort o n t he H oe h n a n d Ya hr 
sta gi n g scale: stat us a n d rec o m me n dati o ns. M o v Dis or d. 2 0 0 4; 1 9( 9): 1 0 2 0 -8.  
 
 
 
 
 
Lit va n I, Aarsla n d D, A dler C H, et al. M D S Tas k F orce o n mil d c o g niti ve i m pair me nt i n 
Par ki ns o n's diseas e: criti cal re vie w of P D -M CI. M o v Dis or d. 2 0 1 1; 2 6( 1 0): 1 8 1 4 – 2 4.  
Marras C, Bec k J C, B o w er J H  et al; Par ki ns o n’s F o u n dati o n P 4 Gr o u p. Pre vale nce of 
Par ki ns o n's diseas e acr oss N o rt h A merica. N PJ Par ki ns o ns Dis. 2 0 1 8; 4: 2 1. 
Marti nez -H orta  S  a n d K ulise vs k y J. Mil d c o g niti ve i m pair me nt i n Par ki ns o n’s disease. J Ne ural 
Tra ns m  ( Vie n n a) ( 2 0 1 9;1 2 6 [7 ]): 8 9 7-9 0 4  
Nasre d di ne Z S , P hilli ps N A, Be diria n V, et al. T he M o ntreal C o g niti ve Assess me n t, M o C A: A 
Brief Scree ni n g T o ol f or Mil d C o g niti ve I m pair me nt. J A m Ger S oc. 2 0 0 5;5 3 (4 ): 6 9 5-9.  
Par ki ns o n ’s F o u n dati o n, 2 0 2 1. A vaila ble fr o m: htt ps:// w w w. par ki ns o n. or g  
Pa ul S M, D o hert y  JJ, R o bic ha u d AJ , et al. T he maj or brai n c h ol ester ol meta b olite 
2 4( S) -h y dr o x yc h olest er ol is a p ote nt all osteric m o d ulat or of N -met h yl -D -as partate rece pt ors. 
J Ne ur osci. 2 0 1 3; 3 3 ( 4 4): 1 7 2 9 0-3 0 0.  
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 1  
S u ni, E. Nati o nal Slee p F o u n dati o n. Slee p Diar y. 2 5 Fe br uar y 2 0 2 1. A vaila ble fr o m: 
w w w.slee pf o u n d ati o n. or g/articl es/ nsf -offi cial -sle e p-diar y.  
 
 

Si g nat ure Pa ge f or V V- C LI N- 0 0 1 6 9 3 v 2. 0
Si g nat ure Pa ge f or V V- C LI N- 0 0 1 6 9 3 v 2. 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 4: 0 5: 4 4 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 4: 1 0: 4 7 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 4: 1 3: 1 0 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 4: 1 5: 4 4 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 4: 3 5: 0 4 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
2 1- Se p- 2 0 2 2 1 5: 0 3: 2 1 G M T + 0 0 0 0