Clinical trial NCT05318937
Conditions: Parkinson Disease Cognitive Dysfunction
Sponsor: Sage Therapeutics
Start date: 2022-06-06; Completion date: 2024-02-23
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the effect of SAGE-718 on cognitive performance in participants with Parkinson's disease mild cognitive impairment (PD-MCI).

Detailed description:

Arms: arm 1: Participants received SAGE-718-matching placebo, oral capsules, once daily (QD), in the morning for 42 days. arm 2: Participants received SAGE-718, 1.2 milligrams (mg), oral capsules, QD in the morning for 42 days.
Interventions: intervention 1: SAGE-718-matching placebo intervention 2: SAGE-718
Intervention descriptions: intervention 1: Oral capsules intervention 2: Oral capsules

Protocol documents:
Prot_000.pdf: 
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  
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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  
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  
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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  
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.  


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 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  
 
 
 
 
 
 


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 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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2 8  
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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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 9  
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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3 2  
 
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  
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 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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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
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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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 3  
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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4 4  
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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7 1 8 -C N P -2 0 2, Versi o n 3  
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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  
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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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7 1 8 -C N P -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 8  
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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C O N FI D E N TI A L  
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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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C O N FI D E N TI A L  
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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.  


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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  
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

SAP_001.pdf: 


S T A TI S TI C A L A N A L Y SI S P L A N  
M E T H O D S  
P R O T O C O L N U M B E R 7 1 8 -C N P -2 0 2  
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  
A ut h or of S A P: 
Versi o n:  1. 0  
Versi o n D ate of S A P:  1 4 M arc h 2 0 2 4  
S p o ns or:  
Sa ge  T hera pe utics , I nc. 
2 1 5 First Street  
Ca m bri d ge , Massac h usetts 0 21 4 2  
C O N FI D E N TI A L  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n. A n y use, distri b uti o n, or discl os ure wit h o ut 
t he pri or writte n c o ns e nt of Sa ge T hera pe utics , I nc. is strictl y pr o hi bite d e xce pt t o t he e xte nt 
re q uire d u n der a p plica ble la ws or re g ul ati o ns. Pers o ns t o w h o m t he i nf or mati o n is discl ose d 
m ust be i nf or me d t hat t he i nf or mati o n is c o nfi de ntial a n d ma y n ot be f urt her discl ose d b y 
t he m. 


A U T H O RI Z A TI O N SI G N A T U R E P A G E  
A ut h or:  
 
Date  
 
Pare xel I nter nati o nal, I nc 
A p pr o ve d b y:  
 
Date  
 
Sa ge T hera pe utics, I nc.  
 
Date  
 
Sa ge T hera pe utics, I nc.  
 
Date  
 
Sa ge T hera pe utics, I nc.  


 
Date  
 
 
Sa ge T hera pe utics, I nc.  
  
Date  
 
Sa ge T hera pe utics, I nc.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
2  
T A B L E O F C O N T E N T S  
1.   
LI S T O F A B B R E VI A TI O N S ................................................................... 5  
2.   
I N T R O D U C TI O N .................................................................................... 8  
3. 1.  
Pri mar y O bjecti ve  ..................................................................................... 9  
3. 2.  
Sec o n dar y O bj ecti ves  ............................................................................... 9  
 
 9  
4. 1.  
Efficac y E n d p oi nt  ................................................................................... 1 0  
4. 1. 1.  
Pri mar y Efficac y E n d p oi nt  ..................................................................... 1 0  
 
 1 0  
4. 2.  
Safet y E n d p oi nts  ..................................................................................... 1 1  
 
 1 1  
5. 1.  
O verall Desi g n  ........................................................................................ 1 2  
5. 2.  
Sa m ple Size a n d P o wer  .......................................................................... 1 3  
5. 3.  
Ra n d o mizati o n  ........................................................................................ 1 3  
5. 4.  
Bli n d i n g a n d U n bli n di n g ........................................................................ 1 4  
6. 1.  
M o dificati o ns fr o m t he A p pr o ve d Cli nical St u d y Pr ot oc ol  .................... 1 5  
6. 2.  
M o dificati o ns fr o m t he A p pr o ve d Statistical A nal ysis Pla n  .................. 1 5  
6. 3.  
M o dificati o ns fr o m t he A p pr o ve d D M C C harter  ................................... 1 5  
7. 1.  
All Ra n d o mize d Set  ................................................................................ 1 6  
7. 2.  
Safet y Set  ................................................................................................ 1 6  
7. 3.  
F ull A nal ysis Set  ..................................................................................... 1 6  
7. 4.  
Per Pr ot oc ol Set  ...................................................................................... 1 6  
 
 1 6  
8. 1.  
Ge neral C o nsi derati o ns  ........................................................................... 1 7  
8. 2.  
Bac k gr o u n d C haracteristics  .................................................................... 1 8  
8. 2. 1.  
Partici pa nt Dis p ositi o n  ............................................................................ 1 8  
8. 2. 2.  
Pr ot oc ol De viati o ns  ................................................................................ 1 8  
8. 2. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ........................................... 1 9  
8. 2. 4.  
Me dical Hist or y  ...................................................................................... 2 0  
8. 2. 5.  
Pri or a n d C o nc o mita nt Me dicati o ns/ Pr oce d ures  .................................... 2 0  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3  
 
 
8. 2. 6.  
I n vesti gati o nal Pr o d uct E x p os ure ........................................................... 2 1  
8. 2. 7.  
I n vesti gati o nal Pr o d uct A d here nce ......................................................... 2 1  
8. 3.  
Efficac y A nal ysis  .................................................................................... 2 2  
8. 3. 1.  
Defi niti o n of Efficac y Varia bles  ............................................................. 2 2  
8. 3. 1. 1.  
Pri mar y Efficac y Assess me nt  ................................................................. 2 2  
 
 2 2  
8. 3. 2.  
Visit Wi n d o ws f or Efficac y A nal yses  .................................................... 3 8  
8. 3. 3.  
A nal ysis of Pri mar y Effi cac y Varia ble  ................................................... 4 0  
8. 3. 3. 1.  
Pri mar y A nal ysis  .................................................................................... 4 0  
8. 3. 3. 2.  
M ulti plicit y a dj ust me nt:  .......................................................................... 4 0  
8. 3. 3. 3.  
Se nsiti vit y A nal ysis of Pri mar y E n d p oi nt  .............................................. 4 0  
8. 3. 3. 4.  
S u p p orti ve A nal ysis of Pri mar y E n d p oi nt  .............................................. 4 2  
8. 3. 3. 5.  
S u b gr o u p A nal yses of Pri mar y A nal ysis  ................................................ 4 2  
 
 4 3  
8. 3. 4. 1.  
Wec hsler A d ult I ntelli ge nce Scale -I V C o di n g ....................................... 4 3  
 
 4 3  
 
 4 3  
 
 4 4  
 
 4 4  
8. 3. 4. 6.  
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 ................................................................................................ 4 4  
 
 4 5  
 
 4 5  
 
 4 5  
 
 4 5  
 
 4 6  
 
 4 6  
 
 4 6  
8. 3. 4. 1 4.  
Dail y ( M o bile P h o ne -Base d) Assess me nts  ............................................. 4 7  
8. 4.  
Safet y A nal ysis  ....................................................................................... 4 7  
8. 4. 1.  
A d verse E ve nts  ....................................................................................... 4 8  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4  
 
 
8. 4. 2.  
Cli nical La b orat or y  ................................................................................. 5 0  
8. 4. 3.  
1 2 -Lea d Electr ocar di o gra m  .................................................................... 5 3  
8. 4. 4.  
Vital Si g ns  .............................................................................................. 5 3  
8. 4. 5.  
P h ysical E xa mi nati o n  ............................................................................. 5 4  
 
 5 4  
8. 4. 7.  
Ot her Safet y A nal ysis  ............................................................................. 5 6  
 
 5 6  
 
 5 6  
9.  
S U M M A R Y O F I N T E RI M A N D D M C A N A L Y S E S  .......................... 5 7  
1 0.  
R E F E R E N C E S  ....................................................................................... 5 8  
1 1.  
LI S T O F A P P E N DI C E S ......................................................................... 5 9  
A P P E N D I X A.  S C H E D U L E O F A S S E S S M E N T S  ............................................... 6 0  
A P P E N DI X  B.  D E T AI L S O F S T A TI S TI C A L M E T H O D O L O G Y  ...................... 6 7  
A P P E N DI X  C.  H A N D LI N G O F MI S SI N G D A T E S  ............................................. 7 0  
A P P E N DI X  D.  C O N V E R SI O N F A C T O R S F O R C A L C U L A TI N G L E D  ........... 7 2  
A P P E N DI X  E.  LI S T O F T A B L E S, LI S TI N G S A N D FI G U R E S  .......................... 7 4  
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5  
 
 
1.     
LI S T O F A B B R E VI A TI O N 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 Statistical A nal ysis Pla n  
( S A P).  
T a ble 1 . A b bre vi ati o ns a n d S peci alist Ter ms  
A b bre vi ati o n  Defi niti o n  
A E  
A d verse E ve nt  
A R     
A ut ore gressi ve  
A T C     
A nat o mical T hera pe utic C he mical  
B MI     
B o d y Mass I n de x  
 
 
 
 
 
 
 
 
 
 
C R  
C o ntr olle d R elease  
C S  
Cli nicall y Si g nifica nt  
CI  
C o nfi de nce I nter val  
C O VI D -1 9     
C or o na vir us disease 2 0 1 9  
 
 
 
 
 
 
 
 
D D     
D ail y D ose  
D S S T     
Di git S y m b ol S u bstit uti o n Test  
E B T     
E m oti o nal Bias Tas k  
E C G     
Electr ocar di o gra m  
e C R F    
electr o nic Cas e Re p ort F or m  
E R     
E xte n de d R eleas e  
E R T     
E m oti o n Rec o g niti o n Tas k  
E T  
Earl y Ter mi nati o n  
F A S     
F ull A nal ysis Set  
 
 
G E E     
G e neralize d E sti mati n g E q uati o n  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
6  
 
 
A b bre vi ati o n  Defi niti o n  
I A D L    
Instr u me ntal A cti vities of D ail y L i vi n g 
I P  
I n vesti gati o nal Pr o d uct  
I R 
Im me diate R elease  
I R T    
Interacti ve Re s p o nse T ec h n ol o g y  
L D  
L e v o d o pa D ose  
L E D     
Le v o d o pa E q ui vale nt D ose  
L F T     
Li ver F u ncti o n Test  
L S M     
Least S q uare M ea n  
M A R     
Missi n g at ra n d o m  
Ma x     
Ma xi m u m  
M CI     
Mil d C o g niti ve I m pair me nt  
M D S     
M o ve me nt Dis or der S ociet y  
 
 
Me d D R A     
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
Mi n     
Mi ni m u m  
M M R M     
M i xe d-effects m o del f or re peat e d meas ures 
M N A R     
Missi n g n ot at ra n d o m  
M o C A     
M o ntreal C o g niti ve Assess me nt  
M T T     
M ultitas ki n g Test  
 
 
N C S     
N ot C li nicall y S i g nifica nt 
 
 
 
 
O T S     
O ne T o uc h St oc ki n gs of Ca m bri d ge  
P A L     
Paire d Ass ociates Lear ni n g  
P C S     
P ote ntiall y Cli nicall y Si g nifica nce  
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 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
7  
 
 
A b bre vi ati o n  Defi niti o n  
 
 
P O  
Orall y  
P P S  
Per Pr ot oc ol Set  
P R M     
Patter n Rec o g niti o n Me m or y  
P T  
P referre d T er m  
P V T     
Ps yc h o m ot or Vi gila nce Tas k  
Q 1  
2 5 t h Perce ntile  
Q 3  
7 5 t h Perce ntile  
R L  
Reacti o n Late nc y  
R TI     
Reacti o n Ti me I n de x  
S A P     
S tatistical A nal ysis P la n 
 
 
S D  
Sta n dar d De viati o n  
S E  
S ta n dar d E rr or 
S O C     
S yste m O r ga n C lass 
S S P     
S patial S pa n  
S W M     
S patial W or ki n g Me m or y  
T E A E     
T reat me nt-e mer ge nt A d verse E ve nt  
U N     
U nstr uct ure d  
V R M     
Ver bal Rec o g niti o n Me m or y  
W AI S -I V    
Wec hsler A d ult I ntelli ge nce Scale -I V 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
8  
 
 
2.     
I N T R O D U C TI O N 
T his S A P is f or t he fi nal a nal ysis a n d is base d o n t he f oll o wi n g a p pr o ve d st u d y d oc u me nts: 
•  S t u d y P r ot oc ol, Versi o n 3 . 0 (0 9 A u g ust  2 0 2 2 ) 
•  electr o nic Cas e Re p ort F or m (e C R F), Versi o n 8 . 0 (Dece m ber  2 0 2 3 ) 
T his S A P a d dresses t he o bjecti ves of t he st u d y a n d descri bes t he pla n ne d statistical a nal yses 
a n d data prese ntati o ns. All a nal yses a n d dat a prese ntati o ns will be ge nerate d usi n g S A S ®  
Versi o n 9. 4 or hi g her  S oft ware ( S A S I nstit ute, Car y, N ort h Car oli na, U S A). T his S A P will be 
fi nalize d a n d a p pr o ve d bef ore t h e cli nical data base l oc k. A n y c ha n ges ma de t o t he S A P after 
t he cli nical data base l oc k will be d oc u me nte d a n d disc usse d i n t he cli nical st u d y re p ort f or t his 
st u d y. 
 
 A nal yses of bi o mar kers a n d 
 
. 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
9  
 
 
3.     
S T U D Y O B J E C TI V E S   
3. 1.     
Pri m ar y O bjecti ve  
•  T o e val uate t he effect of S A G E -7 1 8 o n  c o g niti v e 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 ). 
3. 2.     
Sec o n d ar y O bjecti ves   
•  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 . 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 0  
 
 
4.     
S T U D Y E N D P OI N T S  
4. 1.     
Effic ac y E n d p oi nt  
4. 1. 1.     
Pri m ar y Effic ac y E n d p oi nt  
T he p ri mar y e n d p oi nt is cha n ge fr o m b aseli 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.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 1  
 
 
4. 2.     
S afet y E n d p oi nts  
•  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  
o  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 s e verit y of T E A Es. 
o  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 m eters.  
o  C ha n ge fr o m 
Bas eli 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 
. 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 2  
 
 
5.     
S T U D Y D E SI G N  
5. 1.     
O ver all Desi g 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 -M CI . 
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 pec ti ve partici pa nts, 
i ncl u di n g o pti o nal care gi vers. 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 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. 
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 onti 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 vers 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 b ile de vice d uri n g t he Baseli ne Peri o d. 
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 m e nt f or U nite d Ki n gd o m 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 ( 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 -ad 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 the 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 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 h e 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.  
D uri n g t he treat me nt peri 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 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 h e 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 ( E T) 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.  
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 h e 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 safet y, efficac y, a n d     
.  
 




Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 4  
 
 
5. 4.     
Bli n di n g a n d U n bli n di n g  
Partici pa nt s, cli nicia ns, a n d t he st u d y tea m are bli n de d t o treat me nt all ocati o n d uri n g t he st u d y.  
T he ra n d o mizati o n sc he d ules are ke pt strictl y c o nfi de ntial, accessi ble o nl y t o a ut h orize d 
pers o n nel u ntil t he ti me of u n bli n di n g.  
D uri n g t he 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 via t he I R T s yste m o nl y w he n 
t he safet y of a partici 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 partici pa nt is at i m me diate ris k, t he i n vesti gat or 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 st u d y treat me nt a d mi nistere d t o a partici pa nt. T he 
res p o nsi bilit y t o brea k t he treat me nt c o de i n e mer 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 msta nces s urr o u n di n g a pre ma t ure 
u n bli n di n g m ust be clearl y d oc u me nte d i n t he s o urce rec or ds. T he E T  v isit s h o ul d be 
c o m plete d after a partici pa nt 's treat me nt assi g n m e nt has bee n u n bli n de d. 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 5  
 
 
6.     
M O DI FI C A TI O N S  
6. 1.     
M o dific ati o n s fr o m t he A p pr o ve d Cli nic al St u d y Pr ot oc ol 
•  Pr ot oc ol d oes n ot s pec if y t he a nal ysis o bjecti ve of Dail y ( M o bile P h o ne -base d) 
Assess me nts i ncl u di n g Ps yc h o m ot or Vi gila nce Tas k ( P V T), Di git S y m b ol S u bstit uti o n 
Test ( D S S T), a n d Nati o nal Slee p F o u n dati o n Slee p Diar y . T he y will be a naly ze d  t o 
e val uate t he bel o w o bjecti ves. 
o  P V T : T o e val uate t he effect of S A G E -7 1 8 o n m ot or s y m pt o ms i n partici pa nts 
wit h P D -M CI . 
o  D S S T:  T o e val uate t he effect of S A G E -7 1 8 o n a d diti o nal meas ures of gl o bal 
a n d d o mai n -s pecifi c c o g niti ve perf or ma nce i n partici pa nts wit h P D-M CI . 
o  Nati o nal Slee p F o u n dati o n Slee p Diar y : T o e val uate t he effect of S A G E -7 1 8 
o n f u ncti o ni n g i n partici pa nts wit h P D -M CI . 
•  Pr ot oc ol Secti o n 1 0. 6. 1 : 
 
  
•  Pr ot oc ol Secti o n 1 1. 3. 2. 2: 
 
 
  
6. 2.     
M o dific ati o ns fr o m t he A p pr o ve d St atistic al A n al ysis Pl a n 
N ot a p plica ble .  
6. 3.     
M o dific ati o ns fr o m t he A p pr o ve d D M C C h arter 
N ot a p plica ble.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 6  
 
 
7.     
A N A L Y SI S S E T S  
7. 1.     
All R a n d o mize d Set  
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 b e 
use d t o descri be partici pa nt dis p ositi o n.  
7. 2.     
S afet y Set  
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. 
T he Safet y Set  will be use d t o descri be t he safet y data  a n d a nal yses will be base d o n act ual 
treat me nt recei ve d.  
7. 3.     
F ull  A n al ysis Set  
T he F ull A nal ysis Set ( F A S) will i ncl u de all partici pa nts i n t he Safet y Set w h o ha ve baseli ne 
a n d at l east 1 p ost -baseli ne efficac y e val uati o n.  F A S will be use d t o descri be t he efficac y data , 
w hic h is base d u p o n t h e I nte nt-t o-Treat pri nci ple . A nal yses will be base d o n t he pla n ne d 
treat me nt. 
7. 4.     
Per Pr ot oc ol Set  
T he Per Pr ot oc ol Set  ( P P S) is defi ne d as a s u b gr o u p of partici pa nts i n F A S e xcl u di n g:  
•  partici pa nts wit h maj or pr ot oc ol de viati o ns t hat c o ul d affect efficac y  
•  part ici pa nts w h o c o ns u m e d less t ha n 8 0 % of I P  
•  partici pa nts w h o c o ns u m e d i nc orrect I P at a n y ti m e d uri n g st u d y  
•  partici pa nts or st u d y part ner w h o were u n bli n de d t o treat me nt assi g n me nt pri or t o 
t he data base l o c k. 
 
F or f urt her details see  Secti o n  8. 2. 2 .  A  s u p p orti ve a nal ysis will be perf or me d o n t he P P S  t o 
assess t he r o b ust ness of t he st u d y c o ncl usi o ns t o t he c h oice of a nal ysis set f or t he pri mar y 
efficac y varia ble . 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 7  
 
 
8.     
S T A TI S TI C A L  A N A L Y SI S  
8. 1.     
Ge ner al C o nsi der ati o ns  
C o nti n u o us data will be s u m m arize 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  ( S D), mi ni m u m val ue ( mi n), ma xi m u m val ue ( ma x), me dia n, 2 5t h perce ntile ( Q 1) , 
a n d 7 5t h perce ntile ( Q 3 ). T he mi ni m u m a n d ma xi m u m will be re p orte d wit h t he sa me n u m ber 
of deci mal places as t he s o urce (ra w) data . Mea n, me dia n , Q 1, a n d Q 3 will be re p orte d t o 1 
deci mal  place  m ore t ha n t he s o urce (ra w) data . S D a n d sta n dar d err or ( S E), if a p plica ble, will 
be re p orte d t o 2 deci mal places m ore t ha n t he s o urce (ra w) data . Least S q uare  Mea ns  ( L S M) 
will be re p orte d t o 1 deci mal place m ore t ha n t he s o urce (ra w) dat a. C o nfi de nce i nter vals ( CI) 
will be prese nte d t o o ne m ore deci mal place t h a n t he ass ociat e d para meter esti mate. I n ge neral, 
t he ma xi m u m n u m ber of deci mal places re p orte d s hall be f o ur f or a n y s u m mar y statistic. 
A n y val ues t hat re q uire tra nsf or mati o n t o sta n dar d u nits ( metric or SI) will be c o n verte d wit h 
t he a p pr o priat e c orres p o n di n g precisi o n.  
Cate g orical data will be s u m marize d i n ter ms of t he n u m ber of partici pa nts  pr o vi di n g data at 
t he rele va nt ti me p oi nt ( n), fre q ue nc y c o u nts, a n d perce nta ges. Perce nta ges will be prese nte d 
t o 1 deci mal place u nless ot her wise s pecifie d. A n y pla n ne d c olla psi n g of cate g ori es will be 
detaile d i n t he S A P te xt a n d t he data dis pla ys.  
Perce nt a ges will n ot be prese nte d f or zer o c o u nts. Perce nta ges will be calc ulate d usi n g t he 
n u m ber of partici pa nts ( n) as t he de n o mi nat or. A missi n g cate g or y s hall be i ncl u de d o nl y f or 
cate g orical varia bles w here n o data is a vaila ble. T he missi n g cate g or y will be  o mitte d if t here 
are n o missi n g val ues f or t hat varia ble.  
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 b e 
prese nte d i n t he partici 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 be pres e nte d wit h a c orres p o n di n g ta ble or fi g ure; t hese will be i n dicate d i n 
rele va nt s ecti o ns bel o w. All s u m maries will be pr o vi de d b y treat 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 me 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 bee n ra n d o mize d.  
P -val ues will be re p orte d t o f o ur deci mal places, wit h p -val ues less t ha n 0. 0 0 0 1 re p orte d as 
"< 0. 0 0 0 1 ". P -val ues lar ger t ha n 0. 9 9 9 9 will be re p orte d as "> 0. 9 9 9 9 ". 
E ver y atte m pt will be ma de t o a v oi d missi n g data. All partici pa nts 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 data a vaila ble. N o i m p utati o n pr ocess 
will  be use d t o esti mate missi n g data  u nless ot her wise s pecifie d . 
Ge neral defi niti o ns are defi ne d as b el o w:  
•  Baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt pri or t o t he first d ose of I P, 
u nless state d ot her wise. If t he ti me of a n ass ess me nt is c ollect e d, baseli ne will be t he 
latest assess me nt pri or t o first d ose of I P a d mi nistrati o n ti me; if t he ti me of a n 
assess me nt is n ot c ollecte d, t he assess me nt o n Da y 1 is ass u me d t o be pri or t o d osi n g 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 8  
 
 
if t he pr ot oc ol me nti o ns t hat t his assess me nt nee ds t o be bef ore d osi n g or it is c ollecte d 
as "pre -d ose ". 
•  St u d y da y 1 is defi ne d as t he dat e of ra n d o mizati o n f or u ntreate d ra n d o mize d 
partici pa nts or t he dat e of first d ose f or treate d partici pa nts.  
•  St u d y d a y will be calc ulate d relati ve t o t he date of ra n d o mizati o n f or u ntreate d 
ra n d o mize d partici pa nts a n d relati ve t o t he date of first d ose f or treate d partici pa nts. 
o  If e ve nt is pri or t o ra n d o mizati o n or t he first d ose, t he n st u d y da y is calc ulate d as: 
                    Date of E ve nt –  Date of Ra n d o miz ati o n or First D ose  
o  If e ve nt is after ra n d o mizati o n or t he first d ose, t he n st u d y da y is calc ulate d as: 
        Date of E ve nt –  Dat e of Ra n d o mizati o n or First D ose + 1  
8. 2.     
B ac k gr o u n d C h ar acteristics  
8. 2. 1.     
P artici p a nt  Dis p ositi o n  
T his a nal ysis will be base d o n all scree ne d partici pa nts  (i.e., all partici pa nts w h o ha ve si g ne d 
a n i nf or me d c o ns e nt) . 
S u m maries will be pr o vi de d f or all scree ne d partici pa nt s i n t he st u d y i n cl u di n g partici pa nt s 
scree ne d, scree n-faile d, ra n d o mize d, ra n d o mize d b ut n ot d ose d, recei ve d at least o ne d ose of 
I P, c o m plete d I P, disc o nti n ue d st u d y treat me nt  wit h pri mar y reas o n s f or disc o nti n ui n g 
treat me nt, c o m plete d st u d y, a n d disc o nti n ue d st u d y  wit h 
pri mar y reas o ns f or earl y 
disc o nti n uati o n . N u m ber s of partici pa nt s a n d perce nta ges will be base d o n t he partici pa nts w h o  
were ra n d o mize d a n d recei ve d I P ( Safet y Set ). I n a d diti o n, s u m mar y of a nal ysis sets i ncl u di n g 
Safet y Set, F A S, P P S, a n d     
 will be pr o vi de d f or partici pa nts ra n d o mize d. Treat me nt ar m 
assi g n me nt will be s u m marize d acc or di n g t o t he ra n d o mize d treat me nt.  
If a partici pa nt  is rescree ne d beca use t he partici pa nt  has bee n a scree n fail ure t he first ti me, t he 
stat us of t he partici pa nt  will be deter mi ne d fr o m t he sec o n d scree ni n g. I n t he c o u nt of scree ne d 
partici pa nt s, t his partici pa nt  will be c o u nte d o nl y o nce .  
L isti n gs b y treat me nt gr o u p will be pr o vi de d f or dis p ositi o n of partici pa nt s: scree n fail ures, 
i ncl usi o n/e xcl usi o n criteria, c o m pleti o n a n d disc o nti n uati o n fr o m st u d y treat me nt a n d st u d y 
partici pati o n, a n d i ncl usi o n i n a nal ysis sets. 
8. 2. 2.     
Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns will be classifie d as "maj or " or "mi n or " o n o n g oi n g basis b y t he cli nical 
st u d y tea m a n d s p o ns or. 
Maj or pr ot oc ol de viati o ns are defi ne d as t h ose de viati o ns fr o m t he pr ot oc ol li kel y t o ha ve a n 
i m pact o n t he partici pa nt's ri g hts, safet y, well-bei n g, a n d/ or t he vali dit y of t he data f or a nal ysis.  
Mi n or pr ot oc ol de viati o ns i ncl u de all de viati o ns fr o m t he pr ot oc ol e xcl u di n g t he maj or 
pr ot oc ol de viati o ns .   


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
1 9  
 
 
Maj or pr ot oc ol de viati o ns a n d a n y acti o n t o be ta ke n re gar di n g t he e xcl usi o n of partici pa nts or 
affecte d dat a fr o m s pecific a nal yses are defi ne d i n t he pr oject -s pecific Pr ot oc ol De viati o n 
Assess me nt Pla n .  
T he st u d y tea m will i de ntif y t he maj or pr ot oc o l de viati o ns relate d t o efficac y or t hat ma y ha ve 
i m pact o n efficac y t o deter mi ne t he partici pa nts i n t he F A S t o be e xcl u de d fr o m t he PP S pri or 
t o data bas e l oc k i n a bli n de d fas hi o n. S o me maj or pr ot oc ol de viati o ns ma y n ot l ea d t o 
partici pa nts ' data bei n g  excl u de d fr o m t he P P S . 
T he n u m ber a n d perce nt a ge of partici pa nts wit h a maj or pr ot oc ol de viati o n i n t he F A S will be 
s u m marize d b y ra n d o mize d treat me nt gr o u p.  A b y-partici pa nt listi n g of all pr ot oc ol de viati o ns 
will als o be pr o vi de d.  
8. 2. 3.     
De m o gr a p hics a n d B aseli ne C h ar acteristics  
T his a nal ysis will be base d o n t he Safet y Set  a n d F A S . 
De m o gra p hic data, s uc h as a ge  at ra n d o mizati o n , se x, 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 haracteristics, s uc h as hei g ht, 
wei g ht, a n d b o d y m ass  i n de x ( B MI) will be s u m marize d usi n g descri pti ve statistics  b y 
treat me nt gr o u p a n d o verall .  
B aseli ne c haracteristics relate d t o t he dia g n osis a n d treat me nt of PD, c o g niti ve perf or ma nce 
a n d m ot or s y m pt o ms will als o be s u m marize d  f or: 
•  Years si nce i nitial dia g n osis of P D (c o nti n u o us)  
•  Dia g n osis Criteria Le vel f or P D -M CI (cate g ori cal: Le vel 1 
[a b bre viate d ], Le vel 2 
[c o m pre he nsi ve ]) 
•  Me dicati o n f or treati n g P D s y m pt o ms (cate g orical: N o, Yes) 
o  If yes, Cli nical Stat us (cate g orical: O n, Off)   
▪ N ote : O n is t h e t y pical f u ncti o nal state w he n patie nts are recei vi n g 
me dicati o n a n d ha ve a g o o d , a n d Off is t he t y pical f u ncti o nal state w he n 
patie nts ha ve a p o or res p o nse des pite  ta ki n g me dicati o ns. 
•  W AI S -I V C o di n g test sc ore (c o nti n u o us) 
 
 
 
 
 
 
 
 
 
 
 
 
•  T otal dail y Le v o d o pa E q ui vale nt D os e ( L E D) at Scree ni n g (c o nti n u o us) 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 0  
 
 
T otal dail y L E D at Scree ni n g  will be calc ulat e d  base d o n  t he c o n versi o n fact or  prese nte d i n  
A p pe n di x  D . 
B y -partici pa nt lis tin g of  all de m o gra p hics a n d baseli ne c haracteristics will als o be pr o vi de d b y 
treat ment gr o u p . 
8. 2. 4.     
Me dic al Hist or y   
T his a nal ysis will be base d o n t he Safet y Set.  
Me dical hist or y c ollecte d at scree ni n g will be c o de d usi n g t h e 
Me dical Dicti 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.  Me dical hist or y data will be 
s u m marize d b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T).  
Me dical hist or y will be liste d b y treat me nt gr o u p . Als o, b y -partici pa nt listi n g of Par ki ns o n 's 
disease hist or y will be pr o vi de d.  
8. 2. 5.     
Pri or a n d C o nc o mit a nt Me dic ati o ns / Pr oce d ures 
T his a nal ysis will be base d o n t he Safet y Set.  
Me dicati o ns  a n d pr oce d ures  will be rec or de d at eac h st u d y visit d uri 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 nizati o n -Dr u g dicti o nar y Se pte m ber 2 0 1 5 , or later a n d 
Me d D R A Versi o n 2 2. 0 or hi g her , res pecti vel y.  
All me dicati o ns / pr oce d ures ta ke n wit hi n 6 0 da ys pri or t o Scree ni n g t hr o u g h t he 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/ pr oce d ures use d t o treat P D re gar dless of 
ti mi n g. T h ose me dicati o ns / pr oce d ures ta ke n a n d e n de d pri or t o t h e first d ose of I P will be 
de n ote d "Pri or ". T h ose me dicati o ns/ pr oce d ures 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 / pr oce d ures starte d at t he sa me 
ti me or after t he i nitiati on of t he I P will be de n ote d "C o nc o mita nt ". 
Me dicati o ns/ pr oce d ures 
will be prese nte d acc or di n g t o 
w het h er t h e y are 
"Pri or " or 
"C o nc o mita nt " as defi ne d a b o ve.  If me dicati o n/ pr oce d ures dates are i nc o m plete a n d it is n ot 
clear 
w het her t h e 
me dicati o n/ pr oce d ure s are c o nc o mita nt, it 
will be ass u me d t o be 
c o nc o mita nt. 
Missi n g or partial dates will be i m p ute d f or me di cati o n / pr oce d ures.  Al g orit h m f or missi n g or 
partial start /e n d date is d oc u me nte d i n A p pe n di x  C . 
C o nc o mita nt 
me dicati o ns/ pr oce d ures are f urt her cate g orize d as o n -treat me nt a n d p ost-
treat me nt as f oll o ws: 
•  O n -treat me nt c o nc o mita nt me dicati o ns/ pr oce d ures are t h ose t hat ha ve bee n use d 
bet wee n first a n d last d os e of I P ( b ot h i ncl usi ve) as well as me dicati o ns starte d pri or t o 
first d ose of I P a n d c o nti n ue be y o n d t he i nitiati o n of I P. 
•  P ost -treat me nt me dicati o ns/ pr oce d ures are t h ose t hat ha ve bee n starte d after t he last 
d ose of I P.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 1  
 
 
C o nc o mita nt me dicati o n s will be s u m marize d o n t he Safet y Set usi n g A nat o mical T hera pe utic 
C he mical ( A T C ) le vel 1 a n d Sta n dar d 
Me di cati o n Na m e b y act u al treat me nt gr o u p.  
C o nc o mita nt  pr oce d ures  will be s u m marize d o n t he Safet y Set usi n g S O C a n d P T  b y act u al 
treat me nt gr o u p. B y -p a rtici pa nt listi n gs of pri or a n d c o nc o mita nt ( o n -treat me nt a n d p ost-
treat me nt) me dicati o ns  as well as pr oce d ure s will als o be pr o vi de d . 
8. 2. 6.     
I n vesti g ati o n al P r o d uct E x p os ure  
T his a nal ysis will be base d o n t he Safet y Set.  
T otal e x p os ure d urati o n t o I P (i n da ys), t otal dr u g e x p os ure (i n m g), a n d perce nt of pla n ne d 
e x p os ure recei v e d (i n %)  will be s u m marize d b y act ual treat me nt gr o u p . 
T otal e x p os ure d urati o n t o I P (i n da ys) is defi ne d as t he date of t he last d ose mi n us t he  date of 
first d ose pl us  1.  N ote t hat t his d oes n ot e xcl u de da ys w he n t he d ose has bee n misse d.  
T otal dr u g e x p os ure (i n m g)  is defi ne d as t he t ot al I P i n m g f or S A G E-7 1 8 t hat was ta ke n 
d uri n g t he st u d y. T otal dr u g e x p os ure f or partici pa nts ra n d o mize d t o place b o is zer o u nless t he 
partici pa nt has ta ke n S A G E -7 1 8 b y mista ke, i n w hic h case t h e t otal e x p os ure c o m es fr o m 
S A G E -7 1 8 e x p os ure. T he d ose ta ke n will be c o nsi dere d as 0 m g o n da ys t he  partici pa nt s ki ps 
a d ose.   
Perce nt of t he pla n ne d e x p os ure recei ve d  (i n %) is defi ne d as t he t otal dr u g e x p os ure, di vi de d 
b y pla n ne d e x p os ure, ti mes 1 0 0 % . 
•  F or partici pa nts ra n d o mi ze d t o S A G E-7 1 8 w h o c o m plete t he treat me nt peri o d , t he 
pla n ne d e x p os ure  is calc ulate d as f oll ows:  
o  4 0 da ys ti mes 1. 2 m g if St u d y Da y of Da y 4 2  Visit < 4 0  
o  ( Date of Da y 4 2  visit –  First D ose Date + 1 ) ti mes 1. 2 m g if St u d y Da y of Da y 
4 2  Visit  is 4 0 or 4 1  
o  4 2 da ys ti mes 1. 2 m g i f St u d y Da y of Da y 4 2  Visit ≥ 4 2  
•  F or partici pa nts ra n d o mi ze d t o S A G E-7 1 8 w h o disc o nti n ue t he treat me nt earlier t h a n 
Da y 4 2  Visit , t he pla n ne d e x p os ure is ( Last D ose Date –  First D ose Date + 1) ti mes 1. 2 
m g f or partici pa nts ra n d o mize d t o S A G E -7 1 8.  
•  F or partici pa nts ra n d o mi ze d t o place b o, t his meas ure is n ot  a p plica ble.  
B y -partici pa nt  listi n g of I P a d mi nistrati o n a n d e x p os ure will als o be pr o vi de d  i ncl u di n g 
partici pa nt I D, date of d ose, pla n ne d e x p os ure ( m g), a n d act u al e x p os ure ( m g).  
8. 2. 7.     
I n vesti g ati o n al Pr o d uct A d here nce  
T his a nal ysis will be base d o n t he F A S . 
IP a d here nce ( %) is defi ne d as t he n u m ber of ca ps ules ta ke n, di vi de d b y t he n u m ber of ca ps ules 
pla n ne d t o be ta ke n, ti mes 1 0 0 % . T he pla n ne d n u m ber of ca p s ules is defi ne d as si milar wa y as 
pla n ne d e x p os ure.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 2  
 
 
•  F or partici pa nts w h o c o m plete t he treat me nt peri o d,  t he pla n ne d n u m ber of ca ps ules 
ta ke n is defi ne d  as f oll o ws: 
o  4 0 i f St u d y Da y of Da y 4 2  Visit < 4 0  
o  ( Date of Da y 4 2  visit –  First D ose Date + 1 ) if St u d y Da y of Da y 4 2  Visit  is 4 0 
or 4 1  
o  4 2 i f St u d y Da y of Da y 4 2  Visit ≥ 4 2  
•  F or partici pa nts w h o disc o nti n ue t he treat me nt earlier t ha n Da y 4 2 Visit, t he pla n ne d 
e x p os ure is ( Last D ose Date –  First D ose Date + 1 ). 
N u m ber a n d perce nt a ge of partici pa nt s wit h I P a d here nce i n cate g ories ( < 8 0%, 8 0 -1 0 0 %, 
> 1 0 0 % ) will be pr o vi de d.  B y -part ici pa nt listi n g of I P a d here nce will be pr o vi de d. 
8. 3.     
Effic ac y  A n al ysis   
T he F A S a n d P P S will be use d f or all efficac y s u m mar y a n d a nal ysis ta bles. Partici pa nts will 
be a nal yze d acc or di n g t o ra n d o mize d treat me nt.  
8. 3. 1.     
Defi niti o n of Effic ac y  V ari a bles  
8. 3. 1. 1.  
Pri m ar y Effic ac y Assess me nt  
T he W AI S -I V C o di n g test 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 h at c orrel ates wit h real -w orl d f u ncti o nal o ut c o mes ( e. g., t he a bilit y t o 
acc o m plis h e ver y da y tas ks) a n d rec o ver y fr o m f u ncti o nal  disa bilit y. I n -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 uire d 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 ke y a n d write i n t he 
s y m b ol be neat h t he ass ociate d n u m ber. T he 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 ( hi g her sc ores reflecti n g better perf or ma nce).  
W AI S -I V C o di n g Test is c ollecte d at B aseli ne ( Da y -7) , Da y 1  ( pre-d ose) , Da y 1 4, Da y 4 2 a n d 
Da y 7 0.  
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 4  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
8. 3. 1. 2. 5.  P e n n P ar ki ns o n 's D ail y Acti vities Q uesti o n n aire-1 5 K n o wle d ge a ble 
I nf or m a nt  
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 ( P D A Q -1 5 KI)  
is a care gi ver-re p orte d o utc o me t hat meas ures t h e c o g niti ve I A D L i n P D. T he i nstr u me nt is 
c o mplete d b y a KI t o t he patie nt. T he P D A Q -1 5 KI was create d as a n a b bre viate d versi 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 diffic 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" ( 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).  P D A Q -1 5 KI is c ollecte d o n  Baseli ne  ( Da y -7) , Da y 4 2 a n d Da y 7 0. 
T he ke y o utc o me meas ure is a t otal sc ore. Ot her o utc o me meas ures are eac h i n di vi d ual ite ms. 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 5  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
2 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 6  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
8. 3. 1. 2. 1 3.  D ail y ( M o bile P h o ne -B ase d) Assess me nts  
Dail y assess me nts will be deri ve d f or Baseli ne, Da y 1 4, a n d Da y 4 2 usi n g t he mea n of n o n -
missi n g assess me nts f or 7 da ys as descri pte d i n t he Ta ble 2  bel o w. T he baseli ne meas ure m e nt 
will be calc ulate d as t he mea n of da ys i m me diatel y prece di n g t o first d ose da y. T he precisi o n 
le vel of a vera ges is t o kee p o ne deci mal place. Ta ble 2  lists visit de viati o n. If t here are missi n g 
assess me nts f or m ore t h a n 4 da ys a m o n g 7 da ys, t he deri ve d mea n will be c o nsi dere d as 
missi n g.  
T a ble 2 . A n al ysis Visit Deri v ati o n f or D ail y M o bile Assess me nts  
Sc he d ule d Visit   
Deri v ati o n f or a ver a gi n g   
Baseli ne  *  
> Da y -7  a n d ≤ Da y 1   
Da y 1 4  
> Da y 7  a n d ≤ Da y 1 4  
Da y 4 2   
>  Da y 3 5  a n d ≤ Da y 4 2  
* Da y 1 assess me nt will be c ollecte d pri or t o t he first d osi n g per pr ot oc ol. F or P V T a n d D S S T, 
if Da y 1 assess me nt is c ollecte d after t he first d ose or n ot a vaila ble, a vaila ble n o n -missi n g 
assess me nts f or 7 da ys pri or t o t he first d ose will be use d (i.e. , > Da y -8 a n d ≤ Da y -1).    
8. 3. 1. 2. 1 3. 1.  Ps yc h o m ot or Vi gil a nce T as k  
T he P V T has partici pa nts press a b utt o n i n res p o n se 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 he pri mar y meas ure is t he n u m ber of misse d res p o ns es, w hic h descri bes 
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 bil e 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 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). 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 7  
 
 
T he ke y o utc o me meas ures are:  
•  P V T T otal False P ositi ves  
•  P V T T otal Ti me o uts  
•  P V T Sl o pe of Li near Fit  
•  P V T Reacti o n Late nc y ( mea n)  
•  P V T Reacti o n Late nc y ( C oefficie nt of Variati o n)  
•  P V T T otal Hits  
Ot her o utc o me meas ures are:  
•  P V T Reacti o n late nc y ( varia nce)  
•  P V T Mea n Press Le n gt h  
8. 3. 1. 2. 1 3. 2.  Di git S y m b ol S u bstit uti o n Test  
T he 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 ncti o n o ver ti me a n d f or earl y 
detecti o n of c o g niti ve d ysf u ncti o n. T he tas k re q uires partici pa nts t o use a refere nce ke y t o pair 
s pecific n u m bers wit h ge o metric fi gures. T he n u m ber of c orrect pairi n gs ac h ie 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 the 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).   
T he ke y o utc o me meas ures are:  
•  D S T T otal C orrect  
•  D S T T otal I nc orrect  
•  D S T C orrect M o ve me nt Late nc y Mea n  
•  D S T I nc orrect M o ve me nt Late nc y Mea n  
•  D S T C orrect Res p o nse Late nc y Mea n  
•  D S T I nc orrect Res p o nse Late nc y Mea n  
Ot her o utc o me meas ures are:  
•  D S T C orrect M o ve me nt Late nc y S D  
•  D S T I nc orrect M o ve me nt Late nc y S D  
•  D S T C orrect Res p o nse Late nc y S D  
•  D S T I nc orrect Res p o nse Late nc y S D  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 8  
 
 
8. 3. 1. 2. 1 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 ke ni n gs, a n d slee p q ualit y. T hese 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 . T his diar y will be c o m ple te 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 me d i n t h e cli nic u n der o bser va ti 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).  
O utc o me meas ures  are i n di vi d ual ite ms f or slee p l e n gt h, slee p l ate nc y, ni g ht a wa ke ni n gs, a n d 
slee p q ualit y. Slee p le n gt h ( mi n utes) is  c o m p ute d as partici pa nt get o ut of be d t his m or ni n g –  
ti me partici pa nt we nt t o be d last ni g ht. T here is n o ke y o utc o me meas ure.  
8. 3. 2.     
Visit Wi n d o ws f or Effic ac y A n al yses  
T he sc he d ule d visits will n ot be wi n d o we d a n d will be use d at n o mi nal visit val ue f or a nal ysis 
p ur p oses.  T he u nsc he d ul e d a n d E T visit will be ma p pe d t o a sc he d ule d visit f or a nal ysis.  I n 
or der t o acc o m m o dat e as m uc h data as p ossi ble i nt o a nal ysis, t he e xec uti ve wi n d o ws ha ve bee n 
defi ne d as s h o w n i n bel o w ta bles , w hic h ha ve bee n wi de ne d, c o m pare d t o pr ot oc ol-s pecifie d 
o perati o nal wi n d o w s. T hese wi n d o ws will be use d f or a nal ysis p ur p oses o n l y. O nce a nal ysis 
visit wi n d o ws are assi g ne d, all visits, i ncl u di n g sc he d ule d visits, u nsc he d ule d visits, a n d E T 
visits will be eli gi ble f or bei n g fla g ge d as t he "a nal yze d rec or d " wit hi n t he a nal ysis wi n d o w; a 
partici pa nt 's i n di vi d ual a nal ysis visit wi n d o w c o ul d p ote ntiall y c o ntai n m ore t ha n 1 visit.  I n 
t he e ve nt of m ulti ple visits falli n g wit hi n a n a nal ysis wi n d o w or i n case of a tie, t he f oll o wi n g 
r ules will be use d i n s e q ue nce t o deter mi ne t h e "a nal yze d rec or d " f or t h e a nal ysis visit wi n d o w: 
•  If t he data fr o m t he sc he d ule d visit is a vaila ble, t he n t he sc he d ule d visit data will be 
use d.  
•  If n o data fr o m t he sc he d ule d visit is a vaila ble, t he data fr o m u nsc he d ule d visit cl osest 
t o t he sc he d ule d st u d y da y f or t hat wi n d o w will be use d.  
•  If t here is a tie bef ore a n d after t he sc he d ule d da y, t he later data will be use d.  
 
T a ble 3 . A n al ysis Visit Wi n d o ws f or W AI S-I V C o di n g Test, 
 
Sc he d ule d Visit   
( +/ 1 wi n d o w d a ys) i n pr ot oc ol    
T ar get St u d y D a y   
St u d y D a y Wi n d o w  f or Visit i n 
A n al ysis  
Baseli ne   
Da y 1 ( pre -d ose)      
Da y 1 ( pre -d ose) or last n o n -missi n g 
assess me nt bef ore t he first d ose of I P   
Da y 1 4 ( ± 2 da ys)  
Da y 1 4  
Da y 2 –  Da y 2 8  
Da y 4 2 ( -2 da ys)   
Da y 4 2   
Da y 2 9 –  Da y 5 6   
Da y 7 0 ( ± 4 da ys)   
Da y 7 0   
Da y 5 7 –  E n d of st u d y   


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
3 9  
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 0  
 
 
8. 3. 3.     
A n al ysis of Pri m ar y Effic ac y V ari a ble  
8. 3. 3. 1.  
Pri m ar y A n al ysis  
Partici pa nts will be a nal yze d acc or di n g t o ra n d o mize d treat me nt. Descri pti ve statistics of 
W AI S -I V C o di n g test sc ore, perce nt c ha n ge fr o m baseli ne a n d c ha n ge fr o m  baseli ne will be 
s u m marize d b y treat me nt gr o u p a n d b y visi t.  
T he pri mar y e n d p oi nt is c ha n ge fr o m baseli ne t o Da y 4 2 i n t he W AI S -I V C o di n g test a n d this 
pri mar y e n d p oi nt will be a nal yze d usi n g a mi xe d -effects m o del f or re peat e d meas ures 
( M M R M). T he m o del will i ncl u de baseli ne 
W AI S-I V C o di n g test sc ore as a c o nti n u o us 
e x pla nat or y varia ble, t reat me nt, visit, a n d visit-b y -treat me nt i nteracti o n as cate g orical 
e x pla nat or y varia bles.  T he Ke n war d -R o ger c orrecti o n t o de grees of free d o m will be a p plie d. 
All e x pla nat or y varia bles will be treat e d as fi xe d effects i n t he m o d el , a n d all p ost-baseli ne 
ti me p oi nts will be i ncl u de d i n t he m o del. A n u nstr uct ure d ( U N) c o varia nce matri x wit h t he 
defa ult Ne wt o n -Ra p hs o n al g orit h m use d b y S A S P R O C MI X E D will be use d t o m o del t he 
wit hi n -s u bject c orrel ati o n. If t his m o del fails t o c o n ver ge –  or, if t he c o n ver ge nce c riteria is 
met b ut t he fi nal Hessia n is n ot p ositi ve defi nit e - t h e Fis her Sc ori n g al g orit h m ( via t he 
S C O RI N G o pti o n of t he P R O C MI X E D state me nt), t he n o -dia g o nal fact or a nal ytic str uct ure 
( via t he T Y P E= F A 0( T ) o pti o n of t he R E P E A T E D state me nt, w here T is t he t otal n u m ber of 
ti me p oi nts), T oe plitz, A ut ore gressi ve ( 1) [ A R ( 1)], C o m p o u n d s y m metr y ( C S) c o varia nce 
str uct ure will be use d, f oll o wi n g t his se q ue nce u ntil c o n ver ge nce is ac hie ve d. If t he m o del still 
d oes n ot c o n ver ge wit h C S str uct ure, n o res ults will be re p orte d. W he n t h e c o varia nce str uct ure 
is n ot U N, t he sa n d wic h esti mat or f or t he varia nce-c o varia nce matri x will be deri ve d, usi n g 
t he E M PI RI C A L o pti o n i n t he P R O C MI X E D state me nt i n S A S. T he pri mar y c o m paris o n will 
be bet wee n S A G E -7 1 8 a n d place b o  at t he Da y 4 2 . L S M a n d S E wit h  9 5 % CI  f or eac h treat me nt 
gr o u p as well as differe nce i n L S M a n d S E wit h 9 5 % CI  will be s u m marize d, a n d t he p -val ue 
fr o m t he h y p ot hesis test of n o differe nce bet wee n t he treat me nt gr o u ps will be als o prese nte d.  
Li ne pl ots w it h L S M  a n d S E bars of  c ha n ge fr o m baseli ne i n W AI S-I V C o di n g test sc ore o ver 
ti me b y treat me nt gr o u p will be pr o vi de d . 
B y -partici pa nt listi n g of  W AI S -I V C o di n g test sc ore b y treat me nt gr o u p a n d b y visit will be 
pr o d uce d .  
8. 3. 3. 2.  
M ulti plicit y a dj ust me nt :  
N ot a p plica ble.  
8. 3. 3. 3.  
Se nsiti vit y A n al ysis of Pri m ar y E n d p oi nt  
If a n y of t he s e nsiti vit y a nal yses yiel ds a res ult t hat is i n a differe nt directi o n fr o m t he res ult of 
t he pri mar y a nal ysis, t he nat ure of t he discre pa nc y will be e xa mi ne d t o clearl y e x pl ai n t he 
discre pa nc y base d o n statistical pri nci ples a n d discre pa nc y will be disc usse d i n t he C S R.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 1  
 
 
8. 3. 3. 3. 1.  C o ntr ol -B ase d P atter n Mi xt ure M o del M ulti ple I m p ut ati o n  
If ≥1 0 % of partici pa nts ha ve missi n g data i n t he pri mar y e n d p oi nt, a se nsiti vit y a nal ysis usi n g 
c o ntr ol-base d Patter n Mi xt ure M o del M ulti ple I m p utati o n ( P M M -MI) u n der t he missi n g n ot 
at ra n d o m ( M N A R) ass u m pti o n will be use d t o i n v esti gate t he i m pact of missi n g data ( Li n gli n g 
2 0 1 9, S A S I nstit ute I nc. ). M N A R ass u mes t he missi n g ness de pe n ds o n t he u n o bser ve d st u d y 
data a n d ca n n ot be pre dicte d s olel y base d o n partici pa nt 's o bser ve d data. 
I n cases w here t here is a missi n g baseli ne val ue, t he missi n g baseli ne val ue will n ot be i m p ute d 
wit h c o ntr ol-base d P M M -MI. I nstea d, t he a vera ge of all a vaila ble baseli ne val ues (re gar dless 
of treat me nt gr o u p) will be  p o p ulate d f or t he missi n g baseli ne val ue.  After t his ste p, t he 
c o ntr ol-base d P M M -MI will be a p plie d.  C o ntr ol -base d P M M -MI u n der M N A R i n v ol ves f o ur 
ste ps as descri be d bel o w. 
Ste p 1.  Assessi n g t he patter n of missi n g data . 
T o i n vesti gate t he patter n of missi n g data, "o ds o ut p ut miss patter n " will be use d i n t he MI 
pr oce d ure of t he S A S s yste m ( P R O C MI).  T he i m p utati o n met h o d will be base d o n t he 
o bser ve d patter n of missi n g data a n d a m o u nt of missi n g data.  T he patter n of missi n g d ata will 
be assesse d as m o n ot o ne or ar bitrar y.  
Ste p 2.  T ur ni n g t he ar bitrar y missi n g patter ns t o m o n ot o ne missi n g patter ns u n der  missi n g at 
ra n d o m (M A R ) ass u m pti o n . 
If a mi xt ure of n o n-m o n ot o ne a n d m o n ot o ne missi n g patter ns e xist i n t he data wit h maj orit y 
of m o n ot o ne missi n g patter ns, t he n t he ar bitrar y missi n g patter ns will be c o n verte d t o 
m o n ot o ne missi n g patter ns u n der M A R ass u m pti o n.  
Ste p 3.  Ge nerati o n of i m p ute d datasets f or A V A L usi n g c o ntr ol -base d patter n i m p utati o n u n der 
M N A R . 
P R O C MI will be use d t o ge nerate m  c o m plete datasets.  T he selecti o n of m  de pe n ds o n t he 
re q uire d c o m p uti n g ti me a n d will be deter mi ne d base d o n t he a m o u nt of missi n g i nf or mati o n 
pri or t o t he last patie nt last visit b ut has bee n rec o m me n de d var yi n g fr o m 5 t o 1 0 0.  
Ste p 4.  C o n vert datasets i nt o l o n g f or mat i n w hic h C H G varia ble r e prese nts all c ha n ge fr o m 
baseli ne wit h differe nt val ues of a visit.  
Ste p 5.  C o n d ucti n g m o del -base d a nal ysis usi n g eac h i m p ute d dataset . 
T he m  c o m plete datasets are a nal yze d usi n g M M R M.  
Ste p 6.  P o oli n g t he res ults fr o m t he i m p ute d m dat asets f or i nfere nce . 
T he res ults fr o m t he m c o m plete datasets are c o m bi ne d t o pr o d uce i nfere ntial res ults.  
8. 3. 3. 3. 2.  Ti p pi n g P oi nt A n al ysis  
If ≥1 0 % of partici pa nts ha ve missi n g data i n t he pri mar y e n d p oi nt , a n ot h er se nsiti vit y a nal ysis 
–  ti p pi n g p oi nt a nal ysis –  will b e c o nsi dere d t o i n vesti gate t he r o b ust ness of t he res ult t o 
de part ures fr o m t he M A R ass u m pti o n of t he M M R M m o del a n d t o i de ntif y t he ti p pi n g p oi nt 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 2  
 
 
w here t he treat me nt effect i n partici pa nts wit h missi n g data o v ert ur ns t he treat me nt effect fr o m 
statisticall y si g nifica nt t o statisticall y n o n-si g nifica nt. 
He nce t he  ti p pi n g p oi nt a nal ysis will o nl y be perf or me d if t he pri mar y efficac y a nal ysis is 
statisticall y si g nifica nt i n treat me nt effect. 
I m ple me nti n g t he ti p pi ng p oi nt a p pr oac h i ncl u des t he f oll o wi n g ste ps  (Y ua n 2 0 1 4 , S A S 
I nstit ute I nc.): 
Ste p 1.  Missi n g baseli ne will be i m p ute d as t he mea n of n o n -missi n g baseli ne f or all ot her 
partici pa nts. F or p ost -bas eli ne , u n der t he M N A R ass u m pti o n, missi n g W AI S -I V C o di n g test 
sc ore u p t o Da y 7 0  will be i m p ute d usi n g P R O C MI u n der M N A R.  
Ste p 2 . T he i m p ute d val ues f or o bser vati o ns i n S A G E -7 1 8 treat me nt gr o u p will be a dj uste d 
directl y usi n g t he s hift para meter ( δ ). 
Ste p 3 . T he i m p ute d datasets wit h t he s hift para meter a p plie d will be a n al yze d usi n g P R O C 
MI X E D.  
Ste p 4 . T he res ults will be c o m bi ne d f or t h e i nfere nce usi n g P R O C MI A N A L Y Z E.  
Ste p 5 . Ste p 1 -4 will be re peate d u ntil t he res ult is n ot statisticall y si g nifica n t. 
Ste p 6 . If nee de d, ste p 1-5 will be re peate d wit h m ore stri n ge nt s hift para meter a p plie d u ntil 
t he res ult is n ot statisticall y si g nifica nt. 
T he s hift para meter ( δ ) val ue will be pr o gressi vel y decrease d , a n d pr ocess re peat e d u ntil n o n -
si g nifica nt p-val ue  is ac hie ve d.  O ne h u n dre d  datasets will be ge nerat e d.  
T he ti p pi n g p oi nt s u m mar y f or eac h pair wise c o m paris o n will i ncl u de L S M differe nce, t he 
9 5 % CI, a n d p -val ue f or eac h of δ  val u e. Iterati o ns i ncl u di n g t he ti p pi n g p oi nt will be 
s u m marize d. 
8. 3. 3. 3. 3.  C o m plete D at a  A n al ysis  
If ≥1 0 % of partici pa nts ha ve missi n g data i n t he pri mar y e n d p oi nt , a se nsiti vit y a nal ysis usi n g 
o nl y partici pa nts w h o ha ve at least baseli ne a n d Da y 4 2  val ues will be perf or me d. T he M M R M 
a nal yses pr o p ose d f or t he a nal ysis of t he pri mar y o utc o me will be pr o vi de d f or c ha n ge fr o m 
baseli ne t o Da y 4 2 .  
8. 3. 3. 4.  
S u p p orti ve  A n al ysis of Pri m ar y E n d p oi nt  
T he pri mar y a nal ysis will be re peate d base d o n t he P P S. T he W AI S -I V c o di n g sc ore after 
ta ki n g t he pr o hi bite d me dicati o n will n ot be i ncl u de d i n t he a nal ysis. N o se nsiti vit y a nal ysis 
will be perf or me d base d o n t he P P S.   
8. 3. 3. 5.  
S u b gr o u p A n al yses  of Pri m ar y A n al ysis  
T he p ri mar y e n d p oi nt will be a nal yze d f or t he f oll o wi n g s u b gr o u ps: 
•  Baseli ne M o difie d H oe h n a n d Ya hr Sta ge: ≤2, > 2  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 3  
 
 
•  
 
•  A ge  at ra n d o mizati o n : ≤6 5 , > 6 5  
S u b gr o u p a nal yses will o nl y occ ur if t here are at l east 1 0 partici pa nts  f or eac h s u b gr o u p.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 4  
 
 
B y -partici pa nt listi n g b y visit will be pr o vi de d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
8. 3. 4. 6.  
Pe n n P ar ki ns o n 's D ail y Acti vities Q uesti o n n aire-1 5 K n o wle d ge a ble 
I nf or m a nt 
F or eac h P D A Q -1 5 KI ite m a n d t otal sc ore, a s u m mar y usi n g descri pti ve statistics o n o bser ve d 
val ues a n d c ha n ges fr o m baseli ne will be pr o vi de d . 
T he c ha n ge fr o m bas eli ne t o Da y 4 2 a n d Da y 7 0 o n t he P D A Q -1 5 KI t otal sc ore will be 
a nal yze d usi n g a si milar M M R M m o del descri be d i n Secti o n 8. 3. 3. 1 . A pl ot s h o wi n g t he L S M 
± S E bar o ver ti me wit hi n eac h treat me nt gr o u p will als o be pr o vi de d.   
B y -partici pa nt listi n g b y visit will be pr o vi de d.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 7  
 
 
8. 3. 4. 1 4.  D ail y ( M o bile P h o ne -B ase d) Assess me nts  
F or P V T a n d D S S T, i n vali d data will be fla g ge d after scie nce tea m re vie w b y t he ve n d or a n d 
will n ot be use d f or t he a nal ysis. 
 F or k e y o utc o me meas ures s pecifie d i n  Secti o n  8. 3. 1. 2. 1 3 , the c ha n ge fr o m baseli ne t o Da y 
1 4 a n d Da y 4 2  will be s u m marize d usi n g descri pti ve statistics a n d a nal yze d usi n g a si milar 
M M R M m o del descri be d i n Secti o n 8. 3. 3. 1 . A pl ot s h o wi n g t he L S M ± S E bar o ver ti me 
wit hi n eac h treat me nt gr o u p will als o be pr o vi de d.   
Ot her o utc o me meas ures s pecifie d i n Secti o n  8. 3. 1. 2. 1 3  will be s u m marize d b y visit usi n g 
descri pti ve statistics.  
B y -partici pa nt listi n g b y visit will be pr o vi de d . 
8. 4.     
S afet y A n al ys is 
All safet y s u m maries will be perf or me d o n t he Safet y Set usi n g trea t me nt recei ve d.  
S afet 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 is t he sec o n dar y 
o bjecti ve of t his st u d y a n d will be e val uate d b y t he fre q ue nc y a n d se verit y of T E A Es  a n d 
wit h dra wal d ue t o A Es .  Ot her safet y e n d p oi nts i ncl u de cha n ge fr o m baseli ne i n vital si g ns, 
cli nical la b orat or y a nal yt es, E C Gs, a n d 
.  
T he safet y e n d p oi nts e val uate d at sc he d ule d visits are ta ke n as d o ne i n n o mi nal visit, wit h o ut 
a n y wi n d o wi n g.  If a val ue is a vaila ble f or a n o mi nal sc he d ule d visit, t hat val ue will be use d 
i n s u m mar y b y visit. U nless s pecifie d, u nsc he d ule d meas ure me nt a n d E T m eas ure m e nt will be 
i ncl u de d o nl y if a sc he d ule d meas ure me nt is n ot a vaila ble, a n d t he u nsc he d ule d meas ure me nt 
a n d E T meas ure me nt falls wit hi n t he visit wi n d o w f or t he sc he d ule d visit (sa me as W AI S -I V 
C o di n g Test  i n Ta ble 3 ). If t here are t w o or m ore meas ure me nts i n a visit wi n d o w, t he 
meas ure me nt ta ke n cl osest t o t he st u d y da y tar get will be use d i n a nal ysis.  If t he t w o ha ve 
sa me dista nce fr o m t he tar get st u d y da y, t he latter o ne will be use d. 
A n yti me o n  treat me nt, last val ue o n treat me nt a n d last val ue o n st u d y will be i ncl u de d i n t he 
s u m maries, u nless s pecifie d.  A n yti me o n  treat me nt is defi ne d as meas ure me nt o n or after first 
d ose, o n or bef ore t he date of last d ose. Last val ue o n treat me nt is defi ne d as t he last p ost-
baseli ne val ue bet wee n first d ose of I P a n d u p t o t he date of last d ose of I P (i ncl usi ve).  Last 
val ue o n st u d y is defi ne d as t he last p ost -baseli ne val ue o n or after t he first d ose of I P a n d o n 
or bef ore t he last date of t he st u d y . 
N o statistical h y p ot hesis testi n g will be c o n d ucte d.  
Safet y data will be liste d b y treat me nt gr o u p a n d partici pa nt a n d s u m marize d b y treat me nt 
gr o u p.  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 8  
 
 
T a ble  8 . S u m m ar y of S afet y A n al ysis 
S afet y 
E v al u ati o n  
I nci de nce   
S o urce 
D at a  
C h a n ge 
fr o m 
B aseli ne  
S hift fr o m 
B aseli ne  
P ote nti all y 
Cli nic all y 
Si g nific a nt  
A b n or m alit y/
Cli nic al 
Si g nific a nce  
A Es  
X     
    
 
 
 
 
Cli nical 
La b orat or y  
    
X     
X  
X  
X  
*  
E C G  
    
X     
X  
 
X  
*  
Vital Si g ns     
    
X     
X  
 
X  
 
P h ysical 
E xa m  
    
*     
 
 
 
 
E C G = Electr ocar di o gra ms; 
 
X = Safet y Assess me nt will be s u m marize d i n ta bles 
* = Safet y Assess me nt will be liste d i n i n di vi d ual partici pa nt  data l isti n gs 
8. 4. 1.     
A d verse E ve nts  
A Es will be c o de d usi n g Me d D R A  versi o n 2 2. 0 or hi g her . Inte nsit y /se verit y a n d relati o ns hi p 
of A E will be e val u ate d b y t he i n vesti gat or.  
A T E A E is defi ne d as a n y A E o n or after t he first d ose of I P or a n y w orse 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 he a nal ysis of 
A Es will be base d o n t he c o nce pt of T E A Es. W here t he A E start dat e is missi n g, a d verse e ve nts 
will be ass u me d t o be treat me nt -e mer ge nt, u nless t here is clear e vi de nce (t hr o u g h c o m paris o n 
of partial dates) t o s u g g est t hat t he a d verse e ve nt s tarte d pri or t o t h e first d ose of st u d y 
treat me nt. Missi n g or partial dates will be i m p ute d f or A E . T he a l g orit h m f or missi n g or partial 
start /e n d date is  d oc u me nte d i n A p pe n di x  C . 
A d verse e ve nts are assi g ne d a n A E peri o d base d o n t he o nset dat e/ti me. A E peri o ds are defi ne d 
as f oll o ws:  
•  Pre -treat me nt A E: A E o nset date/ti me bef ore first I P d osi n g date/ti me   
•  T E A E: A E o nset  date/ti me o n or after t he first I P d ose date/ti me (If a n A E st art date 
sa me as I P first d ose date, b ut n o ti me eit her i n A E start or treat me nt start, t he n 
c o nsi der t his A E t o be i n treat me nt peri o d T E A E.)   


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
4 9  
 
 
•  O n -treat me nt T E A E: A E o nset date/ti me o n or after first I P d ose dat e/ti me a n d o n 
or bef ore I P last d ose dat e + 3 0 da ys ( N ote t hat ti me d oes n ot matter f or t he e n d of 
t his peri o d. i.e., if A E occ urre d after t he last d ose b ut o n t he sa me date of last d ose, 
it is c o nsi dere d as o n-treat me nt T E A E) 
•  P ost -treatme nt T E A E: A E o nset date o n or after I P last d ose date + 3 1 da ys  
A n o verall s u m mar y of T E A Es will i ncl u de t he n u m ber a n d perce nta ge of partici pa nts i n t h e 
f oll o wi n g cate g ories: 
•  
A n y T E A E  ( O n-treat me nt, P ost-treat me nt) 
•  
T E A Es b y ma xi m u m se verit y (se vere >  m o derate  >  mil d)  
•  
A n y relate d T E A Es  
•  
A n y relate d T E A Es b y ma xi m u m se verit y  
•  
A n y seri o us T E A Es  
•  
A n y seri o us relate d T E A Es  
•  
A n y T E A Es lea di n g t o deat h  
•  
A n y T E A Es lea di n g t o I P wit h dra wal  
•  
A n y T E A Es lea di n g t o wit h dra wal fr o m t he st u d y  
•  
A n y T E A Es lea di n g t o I P i nterr u pti o n. 
I nci de nce of T E A Es i n f oll o wi n g cate g ories will be pr o vi de d b y S O C a n d P T. A partici pa nt is 
c o u nte d o nl y o nce u n der eac h S O C a n d P T i n case of m ulti ple occ urre nces of t he sa m e A E. 
T hese ta bles will be s orte d b y decreasi n g fre q ue nc y of S O C i n S A G E -7 1 8  gr o u p, t he n i n 
place b o gr o u p, t he n al p h a beticall y first wit hi n S O C , t he n wit hi n P T .  
•  T E A E s 
•  O n -treat me nt T E A Es 
•  P ost -treat me nt T E A Es 
•  T E A Es b y ma xi m u m se verit y 
•  T E A Es b y ca us alit y (relate d, n ot relate d) t o I P  
•  T E A E b y ma xi m u m se verit y a n d ca usalit y  t o I P 
•  Seri o us T E A Es  
•  T E A Es lea di n g t o I P wit h dra wal 
•  T E A Es lea di n g t o wit h dra wal fr o m t he st u d y  
•  T E A Es lea di n g t o I P i nterr u pti o n . 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 0  
 
 
A d diti o nall y, i nci de nce of T E A Es will be s u m marize d b y P T . M ost fre q ue nt T E A Es re p orte d 
> 5 % i n P T of t he c o m bi ne d  treat me nt gr o u p will als o be s u m marize d b y P T. 
F or ma xi m u m se verit y, partici pa nts will be c o u nte d o nl y o nce wit hi n eac h S O C a n d P T at t he 
ma xi m u m se verit y i n t he f oll o wi n g or der: se vere  >  m o derate  >  mil d; a n A E wit h missi n g 
se verit y will be o mitte d fr o m severit y prese ntati o n  a n d will n ot be i m p ute d . F or relati o ns hi p t o 
I P, partici pa nt will be c o u nte d o nl y o nce wit hi n eac h S O C a n d P T wit h  t he str o n gest 
relati o ns hi p t o I P i n t he f oll o wi n g or der: relate d > n ot relate d; a n A E wit h relati o ns hi p missi n g 
is treated as relate d . F or s eri o us ness, a n A E wit h missi n g seri o us ness will n ot be i m p ute d. T he 
i nci de nces will be pres e nte d b y desce n di n g fre q ue nc y of S O C a n d t he n, wit hi n a S O C, b y 
desce n di n g fre q ue nc y of P T base d o n t he partici pa nt c o u nt, a n d i n al p ha betical or d er of P T if 
t he i nci de nce wit hi n a P T is a tie.   
I n a d diti o n, T E A E s u m mar ies b y S O C/ P T will als o be prese nt e d b y t he f oll o wi n g s u b gr o u ps:  
•   Race ( Blac k or Africa n A merica n, W hite, Ot her)  
•  Se x ( Male, Fe male)  
•   B MI ( ≤1 8. 4, 1 8. 5 -2 4. 9, 2 5 -2 9. 9, ≥3 0 k g/ m 2; C ate g ories are defi ne d after r o u n di n g )  
•  A ge at ra n d o mizati o n : ≤6 5 , >6 5  years  
A b y -partici pa nt listi n g of all A Es, 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 E A Es lea di n g t o deat h, T E A Es lea di n g t o I P wit h dra wal  t hr o u g h t he e n d of t he 
st u d y, a n d m ost fre q ue nt ( 5 %) T E A Es will be pr o vi de d . 
8. 4. 2.     
Cli nic al L a b or at or y  
A n y la b res ults c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or will be ca pt ure d as a d verse 
e ve nts, he nce will s h o w u p i n A E dis pla ys . 
F or t he la b orat or y res ults t hat are "≤  x " or "≥ x ", w here x is a n u m ber as c ollecte d i n t he data, 
t he n u meric part of t he res ult will be use d i n t h e calc ulati o n i n t he s u m mar y ta bles. If a 
la b orat or y val u e is re p orte d as "<  y " t he n y mi n us t he mi ni m u m val ue wit h t he sa me precisi o n 
as y (e. g., if y = 1. 3 4 5, t he n use y - 0. 0 0 1 ) will be use d f or t he a nal ysis.  If a la b orat or y val ue is 
re p orte d as ">  y " t he n y  pl us t he mi ni m u m val ue wit h t he sa me precisi o n as y will be use d f or 
t he a nal ysis. T he sa me is tr ue if t h e res ult is prese nte d as bel o w li mit of q ua ntificati o n ( B L Q) 
a n d a l o wer li mit of q ua ntificati o n ( L L O Q) val ue is pr o vi de d ; t he L L O Q val ue will be use d f or 
calc ulati o n i n t he s u m m ar y ta bles. T he act ual res ults as c ollecte d will be dis pla ye d i n t he 
listi n gs. 
Res ults 
of c o nti n u o us cli nical la b orat or y para meters f or he mat ol o g y, bi o c he mistr y, 
c oa g ulati o n, a n d uri ne s a m ples f or uri nal ysis at eac h sc he d ule d visit a n d mea n c ha n ges fr o m 
baseli ne will be s u m marize d i n sta n dar d u nits.  I n a d diti o n, it will als o i ncl u de t he s u m mar y of 
t he last val ue o n treat me nt a n d t he last val ue o n st u d y . 
N or mal ra n ges f or eac h para meter will be pr o vi de d b y t he la b orat or y . S hift fr o m baseli ne t o 
p ost -baseli ne  val u es i n a b n or malit y of he mat ol o g y a n d bi oc he mistr y res ults 
will be 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 1  
 
 
s u m marize d. I n a d diti o n, shift fr o m baseli ne t o w orst p ost -baseli ne val ues i n a b n or malit y of 
res ults at a n y ti me o n treat me nt , t he last val ue o n treat me nt ( o n or after first d ose, o n or bef ore 
last d ose) a n d t he last val ue o n st u d y  (after last d ose, o n or bef ore last da y of t he st u d y) will be 
s u m marize d. If a partici p a nt has b ot h l o w a n d hi g h p ost-baseli ne rec or ds, t he partici pa nt will 
be c o u nte d t wice f or eac h l o w a n d hi g h cell.  
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 ollec ti o n f or eac h 
treat me nt gr o u p. 
T he n u m ber a n d perce nta ge of partici pa nts wit h p ote ntiall y cli nical si g nifica nce ( P C S ) val ues 
f or eac h la b orat or y para meter will be s u m marize d  b y treat me nt f or a n yti me o n treat me nt, t he 
last val ue o n treat me nt a n d t he last val ue o n st u d y. S p o ns or deter mi ne d P C S  val ues will be 
i de ntifie d f or s pecific la b orat or y para meters as o utli ne d i n Ta ble 9  bel o w . 
T a ble 9 . P ote nti all y Cli nic all y Si g nific a nt V al ues f or S pecific L a b or at or y P ar a meters 
L a b or at or y  
P ar a meter     
Se x     
U nits  
Criteri a f or P C S V al ues  
( O bser ve d v al ues) 
 
 
    
Hi g h  
L o w  
He m at ol o g y  
He m o gl o bi n                     
Male     
g/ L     
> 1 8 5  
< 1 1 5  
 
Fe male  
g/ L     
> 1 7 0  
< 1 0 0  
He mat ocrit       
Male     
Fracti o n of 1  
> 0. 5 5  
< 0. 3 8 5  
 
Fe male  
Fracti o n of 1  
> 0. 4 9  
< 0. 3 4 5  
Platelet c o u nt     
    
1 0 ^ 9/ L     
> 6 0 0  
< 1 2 5  
W hite bl o o d cell     
    
1 0 ^ 9/ L     
> 1 5  
< 2. 5  
Bas o p hils     
    
1 0 ^ 9/ L     
> 0. 5  
N A  
E osi n o p hils     
    
1 0 ^ 9/ L     
> 1. 5  
N A  
Ne utr o p hils     
    
1 0 ^ 9/ L     
N A  
< 1. 5  
L y m p h oc ytes     
    
1 0 ^ 9/ L     
> 6. 0  
< 0. 5  
M o n oc ytes     
    
1 0 ^ 9/ L     
> 1. 4  
N A  
Ser u m C he mistr y  
Al b u mi n  
    
g/ L     
> 7 0  
< 2 8  
Bl o o d urea nitr o ge n  
    
m m ol/ L     
> 1 0. 7 1  
N A  
Calci u m  
    
m m ol/ L     
> 2. 7 5  
< 2. 0  
C hl ori de  
    
m m ol/ L     
> 1 2 0  
< 9 0  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 2  
 
 
L a b or at or y  
P ar a meter     
Se x     
U nits  
Criteri a f or P C S V al ues  
( O bser ve d v al ues) 
 
 
    
Hi g h  
L o w  
Creati ni ne     
    
m m ol/ L     
> 3 x U L N or > 3 x Baseli ne  
 
Ga m ma Gl uta m yl 
Tra nsferase  
    
 
> 3 x U L N  
 
Gl uc ose  
    
m m ol/ L     
> 1 3. 9  
< 2. 8  
S o di u m  
    
m m ol/ L     
> 1 5 0  
< 1 3 2  
P otassi u m     
    
m m ol/ L     
> 5. 4  
< 3. 3  
Pr otei n  
    
g/ L     
 
< 4 5  
Bicar b o nate     
    
m m ol/ L     
> 3 4  
< 1 8  
P h os p h or us     
    
m m ol/ L     
> 1. 9 4  
< 0. 6 1  
C o a g ul ati o n  
Pr ot hr o m bi n ti me     
    
 
≥1. 1 1 x U L N  
N A  
Partial 
t hr o m b o plasti n ti me 
    
 
> 1. 5 x U L N  
N A  
Li ver f u ncti o n tests will be m o nit ore d cl osel y f or P C S  val ues, a n d will be s u m marize d f or 
occ urre nce a n y ti me p ost -baseli ne f or t he f oll o wi n g para meters f or t hese P C S t hres h ol d:  
•  
Ala ni ne A mi n otra nsferas e: > 3 x U L N, > 5 x U L N, > 1 0 x U L N  
•  
As partate A mi n otra nsferase: > 3 x U L N, > 5 x U L N, > 1 0 x U L N  
•  
Ala ni ne 
A mi n otra nsferase or 
As partat e 
A mi n otra nsferase: > 3 x U L N, > 5 x U L N, 
> 1 0 x U L N  
•  
Al kali ne P h os p hatase: > 1. 5 x U L N, > 2 x U L N  
•  
T otal Bilir u bi n: > 1. 5 x U L N, > 2 x U L N  
•  
T otal  
Bilir u bi n 
> 2 x U L N 
A N D  
( Ala ni ne  
A mi n otra nsferase 
or  
As partate 
A mi n otra nsferase > 3 x U L N)  [a n y ti me p ost-baseli ne, d oes n ot nee d t o be meas ure d at 
t he sa me ti me p oi nt of assess me nt] 
•  
[( T otal Bilir u bi n > 2 x U L N) A N D  Al kali ne P h os p hatase < 2 x U L N (a n y ti me p ost -
baseli ne, meas ure d at t he sa me ti me p oi nt of assess me nt)] A N D  [( A L T or A S T 
> 3 x U L N) A N D  Al kali ne P h os p hatase < 2 x U L N  (a n y ti me p ost -baseli ne, meas ure d at  
t he sa me ti me p oi nt of assess me nt)] 
N ote:  T he c o n diti o n s i n t he first pair  of brac kets d o  n ot ne e d t o occ ur a t t he sa me 
ti mep oi nt as t he c o n diti o n s i n t he sec o n d pair  of brac kets.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 3  
 
 
B y -partici pa nt listi n g of F S H a n d ser ol o g y test res ults at scree ni n g will be pr o vi de d.  
B y -partici pa nt listi n g of uri ne dr u g scree n a n d breat h alc o h ol test will als o be pr o vi de d.  
8. 4. 3.     
1 2 -Le a d  Electr oc ar di o gr a m  
A si n gle 1 2 -lea d E C G u n der Pr ot oc ol A me n d me nt 2 a n d tri plicate 1 2 -lea d E C G u n der Ori gi nal 
Pr ot oc ol a n d Pr ot oc ol A me n d me nt 1 will be perf or me d  after t he partici pa nt has bee n resti n g 
i n t he s u pi ne p ositi o n f or at least 5 mi n utes. If t h e m ulti ple  1 2 -lea d E C G are perf or me d, t he 
a vera ge of all val ues  o n t he sa me date will be use d i n t he s u m mar y.  If t here are b ot h sc he d ule d 
visit a n d u nsc he d ule d visit o n t he sa me date, all t he assess me nts o n t hat date are c o nsi dere d as 
t he sc he d ule d visit f or t he s u m mar y. A s u m mar y of t he o bser ve d val ues ( ra w val ues f or t he 
si n gle E C G; a vera ge val ues  f or t he m ulti ple E C G  o n t he sa me date ) a n d c ha n ge fr o m baseli ne 
val ues will be s u m marize d b y eac h sc he d ule d visit f or t he f oll o wi n g E C G para m eters: heart 
rate, P R, Q R S, Q T, a nd Q Tc F i nter val. T his s u m mar y will als o i ncl u de t he last val ues o n 
treat me nt a n d o n st u d y.  A b y-partici pa nt listi n g of 1 2 lea d E C G will als o be pr o vi de d f or eac h 
of t he E C G meas ure me nts.  
E C G is e val uate d b y i n vesti gat or as "n or mal ", "a b n or mal, n ot cli nicall y si g nifica nt" a n d 
"a b n or mal, cli nicall y si g nifica nt ".  T he n u m b er a n d perce nta ge of partici pa nts wit h eac h 
cate g or y  will be pr o vi de d at bas eli ne a n d eac h p ost -baseli ne sc he d ule d assess me nt ti me p oi nt.  
If t here are m ore t ha n o ne e val uati o n at t he sa me time p oi nt , t he latest assess me nt fr o m E C G 
ve n d or will be use d f or t he s u m mar y . 
P ote ntiall y cli nicall y si g nifica nt val ues of Q Tc F as o utli ne d i n Ta ble 1 0  will be s u m marize d 
b y treat me nt f or a n yti me o n treat me nt, t he last val ue o n treat me nt a n d t h e last val ue o n st u d y .   
T a ble 1 0 . P ote nti all y Cli nic all y Si g nific a nt  ( P C S) V al ues f or 1 2 -Le a d E C G P ar a meter  
1 2 -Le a d 
E C G     
U nits  
Criteri a f or P C S V al ues 
( O bser ve d v al ues) 
Criteri a f or P C S C v al u es 
( C h a n ge fr o m B aseli ne) 
Hi g h     
L o w     
I ncre ase    
Decre ase  
Q Tc F     
msec     
> 4 5 0 b ut ≤4 8 0  
> 4 8 0 b ut ≤5 0 0  
> 5 0 0  
N A     
≥3 0 t o 6 0  
> 6 0  
N A  
8. 4. 4.     
Vit al Si g ns  
Vital si g ns will i ncl u de oral te m perat ure  (˚C), res pirat or y rate ( breat hs per mi n ute), heart rate 
( beats per mi n ute [ b p m]), a n d bl o o d press ure ( m m H g).  Heart rate a n d bl o o d press ure were 
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 a n d mea n c ha n ges fr o m baseli ne will be s u m marize d b y sc he d ule d visit.  It 
will als o i ncl u de t h e s u m mar y of last val ues o n treat me nt a n d o n st u d y assess me nts. P ote ntiall y 
cli nicall y si g nifica nt val ues as o utli ne d i n Ta ble 1 1  will be s u m marize d b y treat me nt f or 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 4  
 
 
a n yti me o n treat me nt, t he last val ue o n treat me nt a n d t he last val ue o n st u d y .  B y-partici pa nt 
listi n g of vital si g ns will als o be pr o vi de d. 
T a ble 1 1 . P ote nti all y Cli nic all y Si g nific a nt  ( P C S) V al ues f or Vit al Si g n P ar a meters  
Vit al Si g n  
U nits  
Criteri a f or P C S 
V al ues ( O bser ve d 
v al ues)  
Criteri a f or P C S v al ues 
( C h a n ge fr o m B aseli ne 
v al ues)  
Hi g h     
L o w     
I ncre ase    
Decre ase  
Heart rate (s u pi ne a n d sta n di n g)   
Beats/ mi n   
> 1 2 0     
< 4 0     
N A     
N A  
Res pi rat or y rate 
Breat hs/ mi n  > 2 0     
< 8     
 
 
S yst olic bl o o d press ure (s u pi ne 
a n d sta n di n g)  
m m H g  
> 1 8 0     
< 9 0     
≥3 0     
≥3 0  
Diast olic bl o o d press ure (s u pi ne 
a n d sta n di n g)  
m m H g  
> 1 1 0     
< 5 0     
≥2 0     
≥2 0  
S u pi ne –  Sta n di n g *  S yst olic 
Bl o o d Press ure  
m m H g  
≥2 0     
    
 
 
S u pi ne –  Sta n di n g *  Diast olic 
Bl o o d Press ure  
m m H g  
≥1 0     
    
 
 
Ort h ostatic h y p ote nsi o n: s u pi ne –  
sta n di n g*  S B P a n d D B P  
m m H g  
S B P ≥2 0 a n d 
D B P ≥1 0  
    
 
 
P ossi ble ort h ostatic h y p ote nsi o n: 
s u pi ne –  sta n di n g*  S B P a n d D B P  
m m H g  
S B P ≥2 0 or 
D B P ≥1 0  
    
 
 
* S u pi ne –  Sta n di n g mea ns t he differe nce of res ults bet wee n s u pi ne a n d sta n di n g p ositi o ns.  
8. 4. 5.     
P h ysic al E x a mi n ati o n  
A f ull p h ysical e xa 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 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 vasc 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 get e d p h ysical assess me nt as deter mi n e d b y t he 
i n vesti gat or. U nsc he d ul e d, s y m pt o m directe d e xa 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 n vesti gat or.  A n y baseli ne a b n or malities will be rec or de d o n t he me dical 
hist or y f or m. A n y p ost -baseli ne a b n or malities or baseli ne c o n diti o ns t hat w orse ne d p ost -
baseli ne will be rec or de d o n t he a d verse e ve nts f or m.  
T he occ urre nce of a p h ysical e xa mi nati o n ( yes/ n o) a n d t he date perf or me d will be liste d b y 
partici pa nt.   
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 5  
 
 
 
 
   
  
 
 
  
 
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 6  
 
 
 
 
 
 
 
 
 
  
 
8. 4. 7.     
Ot her S afet y A n al ysis  
N ot a p plica ble.  
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 7  
 
 
9.     
S U M M A R Y O F  I N T E RI M A N D D M C A N A L Y S E S 
N ot a p plica ble.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0 1 4 Marc h 2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2 ( Versi o n 3. 0 0 9 A u g ust 2 0 2 2)     
C O N FI D E N TI A L  
 
 
5 8  
 
 
1 0.     
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 ve 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.  
 
Sc ha de, S., M olle n ha uer, B., & Tre n k wal der, C. ( 2 0 2 0). Le v o d o pa e q ui vale nt d ose 
c o n versi o n fact ors: A n u p date d pr o p osal i nc l u di n g o pica p o ne a n d safi na mi de. M o ve me nt 
Dis or ders Cli nical Practi ce, 7( 3), 3 4 3 – 3 4 5.   
 
Stefa nie T. J ost, P h D  et al. Le v o d o pa D ose E q ui vale nc y i n Par ki ns o n 's Disease: U p date d 
S yste matic Re vie w a n d Pr o p osals . M o ve me nt Dis or ders, V ol. 3 8, N o. 7, 2 0 2 3 . 
 
"T he MI Pr oce d ure ". S A S ® 9. 4 a n d S A S ® Vi ya ® 3. 4 Pr o gra m mi n g D oc u me ntati o n . S A S 
I nstit ute I nc., 2 0 1 9, 
htt ps:// d oc u me ntati o n.sas.c o m/ d oc/e n/ p g msasc dc/ 9. 4 _ 3. 4/stat u g/stat u g _ mi _ details 6 1. ht m . 
 
Y ua n Y Se nsiti vit y A nal ysis i n M ulti ple I m p utati o n f or Missi n g Data.  S A S I nstit ute I nc. , 
2 0 1 4, htt ps://s u p p ort.sas.c o m/res o urces/ pa pers/ pr ocee di n gs 1 4/ S A S 2 7 0 -2 0 1 4. p df . 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
5 9  
 
 
1 1.     
LI S T O F A P P E N DI C E S  
A P P E N DI X  A.  S C H E D U L E O F A S S E S S M E N T S  
A P P E N DI X  B.   D E T AI L S O F S T A TI S TI C A L M E T H O D O L O G Y  
A P P E N DI X  C.  H A N D LI N G O F MI S SI N G D A T E S  
A P P E N DI X  D.   C O N V E R SI O N F A C T O R S F O R C A L C U L A TI N G L E D  
A P P E N DI X  E.  LI S T O F T A B L E S, LI S TI N G S A N D FI G U R E S  
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 0  
 
 
A P P E N DI X  A.  S C H E D U L E O F A S S E S S M E N T S  
T a ble 1 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 ns e 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     
    
    
    
    
 
 
Partici pa nt trai ni n g g 
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  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 1  
 
 
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  
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 res earc h 
sa m ple o 
X     
    
    
X     
    
X  
 
O pti o nal ge netic res earc h 
sa m ple o 
X     
    
    
    
    
 
 
M o difie d H oe h n a n d Ya hr sta ge 
scale 
X     
    
    
    
    
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 2  
 
 
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  
W AI S -I V C o di n g Test  
    
X     
X     
X     
    
X  
X  
 
 
 a n d P D A Q -1 5  
K n o wle d gea bl e I nf or ma nt )r 
    
X     
    
    
    
X  
X  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 3  
 
 
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 n w  
 
    
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  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 4  
 
 
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 Test; 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 =  Par ki ns o n 's 
Disease; 
; P D A Q-1 5 KI = Pe n n Par ki ns o n 's Disease A cti 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 Tas k ; S A E = seri o us a d verse e ve nt; 
 
 W AI S-I V = Wec hsler A d ult I ntelli ge nce Scale-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 Peri o d, a n d a t 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 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 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 vers (if a p plica ble) will  be c o nse nte d d uri n g t he Scree ni n g Peri o d . 
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 dia g n osis, is ol ati o n, a n d/ or h os pitalizati o n d ue 
t o C O VI D-1 9 will be 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 Partici pa nts a n d care gi vers (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 perat ure, res pirat or 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 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 , at all sc he d ule 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 vasc 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 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 ga t 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 male 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 patitis B a n d C scree 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 least 5 mi n utes . 




Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
6 6  
 
 
T a ble 1 3 . Sc he d ule of 
, Bi oc he mic al, a n d Ge netic 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 y) 
D a y 4 2  
(-2 d a y)  
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 Scree ni n g. O n Da ys 1 4 a n d 4 2, t he 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.  
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
6 7  
 
 
A P P E N DI X  B.  D E T AI L S O F S T A TI S TI C A L M E T H O D O L O G Y  
S a m ple S A S C o de f or M M R M 
pr oc mi xe d data = data;  
class trt 0 1 p n(ref = '1 ') a visit n us u bji d; 
m o del C H G = trt 0 1 p n base a visit n trt 0 1 p n *a visit n/ d df m = kr;  
re peat e d a visit n / s u bject = us u bji d t y pe = U N; 
ls mea ns trt 0 1 p n *a visit n / diff =all cl al p ha = 0. 0 5; 
r u n; 
 
S a m pl e S A S C o de f or G E E  
pr oc ge n m o d data = data;  
class trt 0 1 p n(ref = '1 ') a visit n us u bji d; 
m o del A V A L C =  bas e  trt 0 1 p n a visit n trt 0 1 p n *a visit n / dist = bi n li n k =l o git; 
re peat e d a visit n /s u bject = us u bji d t y pe = U N; 
ls mea ns treat me nt *a visit / diff e x p cl; 
r u n; 
 
S a m ple S A S C o de f or A N C O V A  
pr oc mi xe d data = data;  
class trt 0 1 p n(ref = '1 '); 
m o del C H G = trt 0 1 p n base / s ol uti o n cl;  
ls mea ns trt 0 1 p n / cl diffs; 
r u n; 
 
S a m ple S A S C o de f or P M M -MI u n der M N A R  
Ste p 1.  Assessi n g t he patter n of missi n g data  
pr oc mi data = n o n _ m o n o see d = x x x ni m p ute = 0;  
var trt 0 1 p n base y 1 -y 3; * y 1 = Da y 1 4, y 2 = Da y 4 2 , y 3 = Da y 7 0 ; 
o ds o ut p ut miss patter n = patter n;  
r u n; 
Ste p 2.  T ur ni n g t he ar bitrar y missi n g patter ns t o m o n ot o ne missi n g patter ns u n der M A R 
ass u m pti o n  
pr oc mi data = n o n _ m o n o o ut = m o n o see d = x x x ni m p ute = m  
mi n =. . x x x  
ma x =. . y y y;  * peri o d (.) mea ns n o i m p utati o n nee de d;  
var trt 0 1 p n base y 1 y 2 y 3;  
mc mc c hai n = m ulti ple  i m p ute = m o n ot o ne; 
r u n; 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
6 8  
 
 
Ste p 3.  Ge nerati o n of i m p ute d datasets f or A V A L usi n g c o ntr ol -base d patt er n i m p utati o n 
u n der M N A R  
pr oc mi data = m o n o see d = x x x ni m p ute = m o ut =i m p ute d;  
mi n =. . x x x;  
ma x =. . y y y;  
b y _i m p utati o n _;  
class trt 0 1 p n;  
var y 1 y 2 y 3;  
m o n ot o ne  re g(/ details); 
m nar m o del( y 1 y 2 y 3/ m o del o bs =(trt 0 1 p n = '1 ')); * o nl y c o ntr ol gr o u p is use d t o deri ve 
t he i m p utati o n m o del; 
r u n; 
Ste p 4 -1.  Calc ulate C H G 1 4, C H G 4 2 , a n d C H G7 0 . 
Ste p 4 -2.  C o n vert datasets i nt o l o n g f or mat i n w hic h C H G varia bl e re prese nts all c ha n ge 
fr o m baseli ne wit h differe nt val ues of a visit. 
Ste p 5.  C o n d ucti n g m o del -base d a nal ysis usi n g eac h i m p ute d dataset  
pr oc mi xe d data = i m p ute d;  
b y _i m p utati o n _;  
class s u bji d trt 0 1 p n (ref ='1 ') a visit n; 
m o del c h g = trt 0 1 p n base a visit n trt 0 1 p n *a visit n / d df m = ke n war dr o ger;  
re peat e d a visit n / s u bject = us u bji d t y pe = U N; 
ls mea ns trt 0 1 p n *a visit n / diff =all cl al p ha = 0. 0 5; 
o ds o ut p ut ls mea ns =ls mea ns diffs = diffs;  
r u n; 
Ste p 6.  P o oli n g t he res ults fr o m t he i m p ute d m dat asets f or i nfere nce  
pr oc s ort data =ls mea ns;  
b y trt 0 1 p n a visit n _i m p utat oi n _;  
r u n; 
 
pr oc mia nal yze par ms =ls mea ns;  
m o deleffects esti mate;  
o ds o ut p ut Para meter Esti mates =l ms;  
b y treat me nt a visit;  
r u n; 
 
pr oc s ort data = diffs;  
b y a visit _i m p utat oi n _;  
r u n; 
 
pr oc mia nal yze par ms = diffs;  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
6 9  
 
 
m o deleffects esti mate;  
o ds o ut p ut Para meter Esti mates = dif;  
b y a visit;  
r u n; 
 
S a m ple S A S C o de f or Ti p pi n g P oi nt A n al ysis  
/ *----------------------------------------------------------------*/  
/ *--- Ge nerat e i m p ute d data set f or s p ecifie d s hift para meters ---*/  
 / *--- data = i n p ut data set ---*/  
 / *--- s mi n = mi n s hift para meter ---*/  
 / *--- s ma x = ma x s hift para meter ---*/  
/ *--- si nc = i ncre me nt of t he s hift para meter ---*/  
 / *--- o ut = o ut p ut i m p ute d data set ---*/  
/ *----------------------------------------------------------------*/  
% macr o mi data( data =, s mi n =, s ma x =, si nc =, o ut =);  
data & o ut;  
 set _ n ull _; 
r u n;  
 
/ *------------ # of s hift val ues ------------*/  
%let ncase = %s yse valf( ( &s ma x -&s mi n)/ &si nc, ceil );  
/ *------- I m p ute d data f or eac h s hift -------*/  
% d o jc = 0 %t o & ncase;  
%let sj = %s yse valf( &s mi n + &jc * &si nc);  
pr oc mi data = & data see d = x x x ni m p ute = m o ut = o ut mi;  
class trt 0 1 p n; 
m o n ot o ne re g( y 1 y 2 y 3 ); 
m nar a dj ust( y 1 y 2 y 3  / s hift = &sj a dj ust o bs =(trt 0 1 p n ='1 ') ); *acti ve treat me nt is use d; 
var trt 0 1 p n y 1 y 2 y 3 ; 
r u n; 
 
data o ut mi;  
set o ut mi; 
S hift = &sj;  
r u n; 
 
data & o ut;  
set & o ut o ut mi; 
r u n; 
%e n d;  
% me n d mi data;  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
7 0  
 
 
A P P E N DI X  C.  H A N D LI N G O F MI S SI N G D A T E S  
A d verse E ve nts  
If t he A E start date is c o m pletel y missi n g, d o n ot i m p ute a date b ut c o nsi der it as T E A E, u nless 
t he A E e n d dat e is bef ore t he i nitiati o n of treat me nt, i n w hic h case t he A E will be c o nsi dere d 
pri or.  
F or partial A E  start dates:  
•  W he n t he year is pres e nt, b ut t he  m o nt h a n d da y are missi n g, t he n:  
− If t he year is t he sa m e as t he year of t he first d ose date, t he n i m p ute as t he m o nt h 
a n d da y of t he first d ose date.  
− Ot her wise, i m p ute t he m o nt h a n d da y as Ja n uar y 1
st.  
•  If t he year a n d m o nt h are prese nt, b ut t he da y is missi n g, t he n:  
− If t he year a n d m o nt h of A E start are t he sa m e as t he year a n d m o nt h of i niti ati o n 
of t he treat me nt, t he i m p ute as t he date of t he first d ose.  
− Ot her wise, i m p ute as t he 1 st da y of t he m o nt h.  
•  If t he i m p ute d A E start date is after t he A E e n d date, t he n t he start date will be s et 
t o t he e n d date. 
•  W he n t he year a n d da y are prese nt a n d t he m o nt h is missi n g, treat it as if t he da y is 
missi n g, a n d o nl y year is prese nt.   F oll o w t he i m p utati o n r ules f or "year  is prese nt, 
b ut t he m o nt h a n d da y are missi n g ". 
F or partial A E  e n d dat es:  
•  D o n ot i m p ute t he A E e n d date.  
D ates i n Dise ase Hist or y ( D ates of di a g n osis, c urre nt e pis o de, first e pis o de)  
•  If t he year is pres e nt a n d t he m o nt h a n d da y are missi n g, t he n t he m o nt h a n d da y 
will be set t o Ja n uar y 1 st. 
− If t he year a n d da y are prese nt a n d t he m o nt h is missi n g, t he n t he m o nt h will be 
set t o Ja n uar y. 
•  If t he year a n d m o nt h are prese nt a n d t he da y is missi n g, t he n t he da y will be set t o 
t he 1st da y of m o nt h . 
Pri or a n d C o nc o mit a nt Me dic ati o ns /Pr oce d ures  
If t he me dicati o n start date is c o m pletel y missi n g, d o n ot i m p ute a date b ut c o nsi der it as 
c o nc o mita nt, u nless t he me dicati o n e n d date is bef ore t he i nitiati o n of treat me nt, i n w hic h case 
t he me dicati o n will be c o nsi dere d pri or. A p pl y t he sa me r ule t o t he c o m pletel y missi n g case 
of me dicati o n e n d dat e.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
7 1  
 
 
F or t he partial start date of me dicati o n:  
•  If t he year is prese nt, b ut t he m o nt h a n d da y are missi n g, t he n t he m o nt h a n d da y 
will be set t o Ja n uar y 1 st u nless t he year is t he sa me as t he first d ose date , t he n 
i m p ute t he first d ose. 
− If t he year a n d da y are prese nt, b ut t he m o nt h is missi n g, t he n treat it as if t he da y 
is missi n g a n d o nl y year is prese nt. F oll o w t he i m p utati o n r ule f or "t he year is 
prese nt , b ut t he m o nt h a n d da y are missi n g". 
•  If t he year a n d m o nt h are prese nt a n d t he da y is missi n g, t he n t he da y will be set t o 
t he 1st da y of m o nt h, u nl ess t he year a n d m o nt h are t he sa me as t he year a n d m o nt h  
of t he first d ose , t he n i m p ute as t he date of t he first d ose. 
− If t he i m p ute d start date of me dicati o n is after t he n o n-i m p ute d e n d date of 
me dicati o n, t he n t he start date will be set t o t he e n d date of me dicati o n.  
F or t he partial e n d dat e of me dicati o n:  
•  If t he year is prese nt, b ut t he m o nt h a n d da y are missi n g, t he n t he m o nt h a n d da y 
will be set t o Dece m ber 3 1 st. 
− If t he year a n d da y are prese nt, b ut t he m o nt h is missi n g, t he n treat it as if t he da y 
is missi n g a n d o nl y year is prese nt. F oll o w t he i m p utati o n r ule f or "t he year is 
prese nt, b ut t he m o nt h a n d da y are missi n g ". 
•  If t he year a n d m o nt h are prese nt, b ut t he da y is missi n g, t he n t he da y will be set t o 
t he last da y of t he m o nt h. 
A p pl y t he sa me r ule t o t h e pr oce d ures wit h missi n g or partial dates.  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
7 2  
 
 
A P P E N DI X  D.  C O N V E R SI O N F A C T O R S F O R C A L C U L A TI N G L E D  
T a ble 1 4 . C o n versi o n f act ors f or c alc ul ati n g L E D  
Dr u g Cl ass     
Ge neric N a me  
Tr a de N a me  
C o n versi o n 
F act or/ R ati o  
L -d o pa  I R    
Car bi d o pa -le v o d o pa    
Si ne met  
D D × 1  
 
Car bi d o pa -le v o d o pa 
( orall y disi nte grati n g 
ta blet) 
Parc o pa  I R 
D D × 1  
 
Le v o d o pa  I n halati o n 
p o w der  
I n brija 
D D x 0. 6 9  
 
Car bi d o pa/ Le v o d o pa 
E ntaca p o ne  
Stale v o  
D D x 1. 3 3  
 
Car bi d o pa -le v o d o pa-
e ntaca p o ne (e nt eral 
s us pe nsi o n) 
D u o pa ( U S)  
D u o d o pa ( E U)  
D D x 1. 1 1 
( m or ni n g d ose); 
D D x 1. 4 6 
( mai nte na nce 
a n d e xtra d oses)  
L -d o pa  C R  
Car bi d o pa -le v o d o pa 
(c o ntr olle d rel ease) 
Si ne met C R  
D D × 0. 7 5  
L -d o pa  E R  
Car bi d o pa -le v o d o pa 
(e xte n de d release 
ca ps ules)  
R ytar y  
D D × 0. 5  
 
Car bi d o pa -le v o d o pa 
(e xte n de d release) 
N ot R ytar y  
D D × 0. 7 5  
C atec h ol-o -
met h yl -
tra nsferase 
i n hi bit ors 
E ntaca p o ne  
C o mta n  
L D × 0. 3 3  
 
T olca p o ne  
Tas mar  
L D × 0. 5  
 
O pica p o ne  
O n ge nt ys  
L D × 0. 5  
M o n oa mi ne 
o xi dase -B 
i n hi bit ors 
Sele gili ne  
El de pr yl  
D D × 1 0  
 
Sele gili ne ( orall y 
disi nte grati n g ta blet)  
Zela par  
D D × 8 0  
 
Rasa gili ne  
Azilect  
D D × 1 0 0  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4     
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 )    
C O N FI D E N TI A L  
 
 
7 3  
 
 
Dr u g Cl ass     
Ge neric N a me  
Tr a de N a me  
C o n versi o n 
F act or/ R ati o  
M o n oa mi ne 
o xi dase -B 
i n hi bit ors 
Safi na mi de  
Xa da g o  
L E D = 1 5 0 m g  
D o pa mi ne 
A g o nists  
Pra mi pe x ole  
Mira pe x  
D D x 1 0 0  
 
Pra mi pe x ole (e xte n de d 
releas e) 
Mira pe x E R  
D D x 1 0 0  
 
R o pi nir ole  
Re q ui p  
D D x 2 0  
 
R o pi nir ole 
(e xte n de d release) 
Re q ui p X L  
D D x 2 0  
 
A p o m or p hi ne 
(s u bc uta ne o us i njecti o n) 
A p o k y n  
D D x 1 0  
 
A p o m or p hi ne s u bli n g ual 
fil m 
K y n m o bi  
D D x 1. 5  
 
R oti g oti ne 
(tra ns der mal patc h)  
Ne u pr o  
D D x 3 0. 3  
A de n osi ne 2 A 
a nta g o nist  
Istra def ylli ne 
N o uria nz  
L D x 0. 2  
A ntic h oli ner gic  Tri he x y p he ni d yl     
Arta ne  
L E D = 1 0 0 m g  
 
Be nztr o pi ne  
C o ge nti n  
L E D = 1 0 0 m g  
Ot her     
A ma nta di ne  
A ma nta di ne  
D D × 1  
 
Z o nisa mi de  
Z o nisa mi de  
L E D = 1 0 0 m g  
N ote:  I R = i m me diate rel ease, C R  =  c o ntr olle d rel ease , E R  =  e xte n de d release , D D  =  dail y 
d ose , L D = le v o d o pa d os e, L E D  =  le v o d o pa eq ui v ale nt  d ose.  L D is t he s u bt otal L E D of 
le v o d o pa-c o ntai ni n g me dicati o ns .


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 4  
 
 
A P P E N DI X  E.  LI S T O F T A B L E S, LI S TI N G S A N D FI G U R E S  
T a bles  
Ta ble 1 4. 1. 1 S u m mar y of Dis p ositi o ns  ( All Scree ne d Partici pa nts) 
Ta ble 1 4. 1. 2 S u m mar y of Maj or Pr ot oc ol De viati o ns ( F ull A nal ysis Set)  
Ta ble 1 4. 1. 3 S u m mar y of A nal ysis Sets ( All Ra n d o mize d Set)  
Ta ble 1 4. 1. 4. 1. 1 S u m mar y of De m o gra p hi cs a n d Baseli ne C haracteristics ( F ull A nal ysis Set)  
Ta ble 1 4. 1. 4. 1. 2 S u m mar y of De m o gra p hi cs a n d Baseli ne C haracteristics ( Safet y Set)  
Ta ble 1 4. 1. 5. 1 S u m mar y of Me dical Hist or y ( Safet y Set)  
Ta ble 1 4. 1. 6. 1 S u m mar y of C o nc o mita nt Me dicati o ns  ( Safet y Set) 
Ta ble 1 4. 1. 6. 2 S u m mar y of C o nc o mita nt Pr oce d ures ( Safet y Set)  
Ta ble 1 4. 1. 7 S u m mar y of I n vesti gati o nal Pr o d uct E x p os ure ( Safet y Set)  
Ta ble 1 4. 1. 8 S u m mar y of I n vesti gati o nal Pr o d uct A d here nce ( F ull A nal ysis Set)  
 
Ta ble 1 4. 2. 1. 1. 1 A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult I ntelli g e nce Scal e –  I V ( W AI S-I V) C o di n g Test Sc ore 
b y Visit ( F ull A nal ysis Set)  
Ta ble 1 4. 2. 1. 1. 2 A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult I ntelli ge nce Scal e –  I V ( W AI S-I V) C o di n g Test Sc ore 
b y Visit a n d S u b gr o u p Baseli ne M o difie d H oe h n a n d Ya hr Sta ge ( F ull A nal ysis Set)  
Ta ble 1 4. 2. 1. 1. 3 A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult I ntelli ge nce Scal e -I V ( W AI S-I V) C o di n g Test Sc ore 
b y Visit a n d 
 ( F ull A nal ysis Set) 
Ta ble 1 4. 2. 1. 1. 4 A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult I ntelli ge nce Scal e -I V ( W AI S-I V) C o di n g Test Sc ore 
b y Visit a n d S u b gr o u p A ge ( F ull A nal ysis Set)  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 5  
 
 
T a bles  
Ta ble 1 4. 2. 1. 2. 1 Se nsiti vit y A nal ysis usi n g C o ntr ol -Base d Patter n Mi xt ure M o del M ulti ple I m p utati o n –  A nal ysis of C h a n ge 
fr o m Baseli ne o 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 Sc ore b y Visit ( F ull A nal ysis Set) 
Ta ble 1 4. 2. 1. 2. 2 Se nsiti vit y A nal ysis usi n g Ti p pi n g P oi nt –  A nal ysis of C ha n ge fr o m Baseli ne o 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 Sc ore b y Visit ( F ull A nal ysis Set) 
Ta ble 1 4. 2. 1. 2. 3 Se nsiti vit y A nal ysis usi n g C o m plete Data –  A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult 
I ntelli ge nce Scal e-I V ( W AI S-I V) C o di n g Test Sc ore b y Visit ( F ull A nal ysis Set) 
Ta ble 1 4. 2. 1. 2. 4 Se nsiti vit y A nal ysis usi n g t he Per Pr ot oc ol Set –  A nal ysis of C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult 
I ntelli ge nce Scal e-I V ( W AI S-I V) C o di n g Test Sc ore b y Visit ( Per Pr ot oc ol A nal ysis Set) 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 6  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 7  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 8  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
7 9  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 0  
 
 
T a bles  
Ta ble 1 4. 2. 4. 5. 1 A nal ysis of C ha n ge fr o m Baseli ne o n t he Ps yc h o m ot or Vi gila nce Tas k ( P V T) b y Visit –  Ke y O utc o me Meas ures 
( F ull A nal ysis Set) 
Ta ble 1 4. 2. 4. 5. 2 S u m mar y of C ha n ge fr o m Baseli ne o n t he Ps yc h o m ot or Vi gila n ce Tas k ( P V T) b y Visit –  Ot her O utc o me 
Meas ures ( F ull A nal ysis Set)  
Ta ble 1 4. 2. 4. 6. 1 A nal ysis of C ha n ge fr o m Baseli ne o n t he Di git S y m b ol S u bstit uti o n Test ( D S S T) b y Visit –  Ke y O utc o me 
Meas ures ( F ull A nal ysis Set)  
Ta ble 1 4. 2. 4. 6. 2 S u m mar y of C ha n ge fr o m Baseli ne o n t he Di git S y m b ol S u bstit uti o n Test ( D S S T) b y Visit –  Ot her O utc o me 
Meas ures ( F ull A nal ysis Set)  
Ta ble 1 4. 2. 4. 7 S u m mar y of C ha n ge fr o m Baseli ne o n t he Nati o nal Slee p F o u n dati o n Slee p Diar y b y Visit ( F ull A nal ysis Set)  
Ta ble 1 4. 3. 1. 1 O verall S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts ( Safet y Set)  
Ta ble 1 4. 3. 1. 2. 1. 1 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 1. 2. 1. 2 S u m mar y of O n -Treat me nt Treat me nt -E mer ge nt A d vers e E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m 
( Safet y Set) 
Ta ble 1 4. 3. 1. 2. 1. 3 S u m mar y of P ost -Treat me nt Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m 
( Safet y Set) 
Ta ble 1 4. 3. 1. 2. 2 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m a n d S u b gr o u p 
Race ( Safet y Set)  
Ta ble 1 4. 3. 1. 2. 3 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m S u b gr o u p Se x 
( Safet y Set) 
Ta ble 1 4. 3. 1. 2. 4 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m S u b gr o u p B MI 
( Safet y Set) 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 1  
 
 
T a bles  
Ta ble 1 4. 3. 1. 2. 5 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m S u b gr o u p A ge 
( Safet y Set) 
Ta ble 1 4. 3. 1. 3 S u m mar y o f Treat me nt-E mer ge nt A d verse E ve nts b y S yste m Or ga n Class, Preferre d Ter m, Ma xi m u m Se verit y 
a n d Ca usalit y t o I P ( Safet y Set)  
Ta ble 1 4. 3. 1. 4 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y S yste m Or ga n Class, Preferre d Ter m, a n d Ca usalit y t o I P 
( Safet y Set) 
Ta ble 1 4. 3. 1. 5 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts b y Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 1. 6 S u m mar y of M ost Fre q ue nt ( > 5 %) Treat me nt -E mer ge nt A d verse E ve nts b y Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 2. 1 S u m mar y of Seri o us Treat me nt -E mer g e nt A d verse E ve nts b y S yste m Or ga n Class a n d Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 2. 3 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts Lea di n g t o I n vesti gati o nal Pr o d uct Wit h dra wal b y S yste m 
Or ga n Class a n d Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 2. 4 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts Lea di n g t o Wit h dra wal fr o m t he St u d y b y S yste m Or ga n Class 
a n d Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 2. 5 S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts Lea di n g t o I n vesti gati o nal Pr o d uct I nterr u pti o n b y S yste m 
Or ga n Class a n d Preferre d Ter m ( Safet y Set)  
Ta ble 1 4. 3. 4. 1. 1 S u m mar y of He mat ol o g y La b orat or y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 4. 1. 2 S u m mar y of C he mistr y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 4. 1. 3 S u m mar y of Q ua ntitati ve Uri nal ysis La b orat or y Para meters  ( Safet y Set) 
Ta ble 1 4. 3. 4. 1. 4 S u m mar y of Q ua ntitati ve C oa g ul ati o n La b orat or y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 4. 2. 1 S u m mar y of P ote ntiall y Cli nicall y Si g nifica nt He mat ol o g y La b orat or y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 4. 2. 2 S u m mar y of P ote ntiall y Cli nicall y Si g nifica nt C he mistr y a n d C oa g ulati o n La b orat or y Para meters ( Safet y Set)  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 2  
 
 
T a bles  
Ta ble 1 4. 3. 4. 2. 3 S u m mar y of P ote ntiall y Cli nicall y Si g nifica nt Li ver F u ncti o n Tests ( Safet y Set)  
Ta ble 1 4. 3. 4. 3. 1 S u m mar y of A b n or malit y S hift fr o m Baseli ne i n He mat ol o g y La b orat or y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 4. 3. 2 S u m mar y of A b n or malit y S hift fr o m Baseli ne i n C he mistr y a n d C oa g ulati o n La b orat or y Para meters ( Safet y Set)  
Ta ble 1 4. 3. 5. 1 S u m mar y of 1 2 -Lea d Electr ocar di o gra ms ( E C G) ( Safet y Set)  
Ta ble 1 4. 3. 5. 2 S u m mar y of P ote ntiall y Cli nicall y Si g nifica nt Q Tc F ( Safet y Set)  
Ta ble 1 4. 3. 5. 3 S u m mar y of E C G I nter pretati o n b y I n vesti gat or ( Safet y Set)  
Ta ble 1 4. 3. 6. 1 S u m mar y of Vital Si g ns ( Safet y Set)  
Ta ble 1 4. 3. 6. 2 S u m mar y of P ote ntiall y Cli nicall y Si g nifica nt Vital Si g ns ( Safet y Set)  
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 3  
 
 
Listi n gs  
Listi n g 1 6. 1. 7 Partici pa nt Ra n d o mizati o n ( Ra n d o mize d Set)  
Listi n g 1 6. 2. 1. 1 Partici pa nt Dis p ositi o n ( Ra n d o mize d Set)  
Listi n g 1 6. 2. 1. 2 Partici pa nts w h o Disc o nti n ue d Treat me nt a n d/ or St u d y ( Ra n d o mize d Set)  
Listi n g 1 6. 2. 2. 1 Pr ot oc ol De viati o ns ( Ra n d o mize d Set)  
Listi n g 1 6. 2. 3. 1 Assi g n me nt t o A nal ysis Sets ( Ra n d o mize d Set)  
Listi n g 1 6. 2. 3. 2 I ncl usi o n/ E xcl usi o n Criteria Vi olati o ns a n d Re -scree ni n g ( All Scree ne d Partici pa nts) 
Listi n g 1 6. 2. 4. 1 De m o gra p hics ( Safet y Set)  
Listi n g 1 6. 2. 4. 2 Baseli ne C haracteristics ( Safet y S et)  
Listi n g 1 6. 2. 4. 3 Par ki ns o n 's Disease Hist or y ( Safet y Set) 
Listi n g 1 6. 2. 4. 4 Me dical Hist or y ( Safet y Set)  
Listi n g 1 6. 2. 4. 5 Pri or/ C o nc o mita nt/ P ost -Treat me nt Me dicati o ns ( Safet y Set)  
Listi n g 1 6. 2. 4. 6 Pri or/ C o nc o mita nt/ P ost -Treat me nt Pr oce d ures ( Safet y Set)  
Listi n g 1 6. 2. 5. 1 I n vesti gati o nal Pr o d uct A d mi nistrati o n ( Safet y Set)  
Listi n g 1 6. 2. 5. 2 I n vesti gati o nal Pr o d uct E x p os ure ( Safet y Set)  
Listi n g 1 6. 2. 5. 3 I n vesti gati o nal Pr o d uct C o m plia nce ( Safet y Set)  
 
Listi n g 1 6. 2. 6. 1 Wec hsler A d ult I nt elli ge nce Scale –  I V ( W AI S-I V) C o di n g Test ( F ull A nal ysis Set) 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 4  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 5  
 
 
Listi n gs  
Listi n g 1 6. 2. 6. 1 2 Ps yc h o m ot or Vi gila nce Tas k ( P V T) ( F ull A nal ysis Set)  
Listi n g 1 6. 2. 6. 1 3 Di git S y m b ol S u bstit uti o n Test ( D S S T) ( F ull A nal ysis Set)  
Listi n g 1 6. 2. 6. 1 4 Nati o nal Slee p F o u n dati o n Slee p Diar y ( F ull A nal ysis Set)  
Listi n g 1 6. 2. 7. 1 A d verse E ve nts ( Safet y Set)  
Listi n g 1 6. 2. 7. 2 Seri o us A d verse E ve nts ( Safet y Set)  
Listi n g 1 6. 2. 7. 3 Treat me nt -E mer ge nt A d verse E ve nts Lea di n g t o Deat h ( Safet y Set)  
Listi n g 1 6. 2. 7. 4 Treat me nt -E mer ge nt A d verse E ve nts Lea di n g t o I n vesti gati o nal Pr o d uct Wit h dra wal a n d/ or St u d y Wit h dra wal 
( Safet y Set) 
Listi n g 1 6. 2. 7. 5 M ost Fre q ue nt( > 5 %) Treat me nt -E mer ge nt A d verse E ve nts ( Safet y Set)  
Listi n g 1 6. 2. 8. 1. 1 He mat ol o g y La b orat or y Para meters ( Safet y Set)  
Listi n g 1 6. 2. 8. 1. 2 Cli nical C he mistr y La b orat or y Para meters ( Safet y Set)  
Listi n g 1 6. 2. 8. 1. 3 Uri nal ysis La b orat or y Para meters ( Safet y Set)  


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 6  
 
 
Listi n gs  
Listi n g 1 6. 2. 8. 1. 4 C oa g ulati o n La b orat or y Para meters ( Safet y Set)  
Listi n g 1 6. 2. 8. 2. 1 P ote ntiall y Cli nicall y Si g nifica nt He mat ol o g y La b orat or y Para meters ( Safet y Set)  
Listi n g 1 6. 2. 8. 2. 2 P ote ntiall y Cli nicall y Si g nifica nt Cli nical C he mistr y La b orat or y Para m eters ( Safet y Set)  
Listi n g 1 6. 2. 8. 2. 3 P ote ntiall y Cli nicall y Si g nifica nt Li ver  F u ncti o n Tests ( Safet y Set)  
Listi n g 1 6. 2. 8. 3 Pre g na nc y Test ( Safet y Set)  
Listi n g 1 6. 2. 8. 4 F S H a n d Ser ol o g y/ HI V/ He patitis ( Safet y Set)  
Listi n g 1 6. 2. 8. 5 Uri ne Dr u g Scree n a n d Breat h Al c o h ol Test ( Safet y Set)  
Listi n g 1 6. 2. 9. 1. 1 1 2 -Lea d Electr ocar di o gra m ( E C G) ( Safet y Set)  
Listi n g 1 6. 2. 9. 1. 2 P ote ntiall y Cli nicall y Si g nifica nt Q Tc F Val ues ( Safet y Set)  
Listi n g 1 6. 2. 9. 2. 1 Vital Si g ns ( Safet y Set)  
Listi n g 1 6. 2. 9. 2. 2 P ote ntiall y Cli nicall y Si g nifica nt Vital Si g ns ( Safet y Set)  
Listi n g 1 6. 2. 9. 3 P h ysical E xa mi nati o ns ( Safet y Set)  
 
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 7  
 
 
Fi g ures  
Fi g ure 1 4. 2. 1. 1 Pl ot of L S Mea n +/ - S E i n C ha n ge fr o m Baseli ne o n t he Wec hsler A d ult I ntelli ge nce Scale -I V C o di n g Test 
Sc ore b y Visit ( F ull A nal ysis Set)  
Fi g ure 1 4. 2. 1. 2 F orest Pl ot of Differe nce i n L S Mea ns ( 9 5 % CI) f or C ha n ge fr o m Baseli ne o 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 Sc ore f or S u b gr o u ps at Da y 4 2 b y Treat me nt Gr o u p ( F ull A nal ysis Set) 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 8  
 
 


Statistical A nal ysis Pla n Met h o ds Versi o n 1. 0  1 4 Marc h  2 0 2 4  
Sa ge T hera pe utics, I nc.  
Pr ot oc ol N u m ber: 7 1 8 -C N P -2 0 2  ( Versi o n 3 . 0 0 9 A u g ust  2 0 2 2 ) 
C O N FI D E N TI A L  
 
 
8 9  
 
 
Fi g ures  
Fi g ure 1 4. 2. 4. 5 Pl ot of L S Mea n +/ - S E i n C ha n ge fr o m Baseli ne o n t he Ps yc h o m ot or Vi gila nce Tas k ( P V T) b y Visit - Ke y 
O utc o me Meas ures ( F ull A nal ysis Set)  
Fi g ure 1 4. 2. 4. 6 Pl ot of L S Mea n +/ - S E i n C ha n ge fr o m Baseli ne o n t he Di git S y m b ol S u bstit uti o n Test ( D S S T) b y Visit - Ke y 
O utc o me Meas ures ( F ull A nal ysis Set)