A 28-Day Randomized, Placebo-Controlled, Double-Blind, Parallel Groups and Normative Comparison Study to Evaluate the Effect of SAGE-718 on Functioning Capacity in Participants With Huntington's Disease
Phase: PHASE2
Conditions: Huntington Disease
Sponsor: Supernus Pharmaceuticals, Inc.



Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3
C O N FI D E N TI A L  
1  
 
A 2 8 -D A Y  R A N D O MI Z E D , PL A C E B O -C O N T R O L L E D , 
D O U B L E -B LI N D , P A R A L L E L G R O U P S  A N D  
N O R M A TI V E C O M P A RI S O N S T U D Y T O E V A L U A T E  
T H E E F F E C T O F S A G E -7 1 8 O N F U N C TI O NI N G 
C A P A CI T Y I N P A R TI CI P A N T S WI T H H U N TI N G T O N’ S 
DI S E A S E   
S H O R T TI T L E : 2 8 -D A Y P L A C E B O -C O N T R O L L E D 
S T U D Y O F S A G E -7 1 8 O N F U N C TI O NI N G C A P A CI T Y I N 
P A R TI CI P A N T S WI T H H U N TI N G T O N’ S DI S E A S E  
P R O T O C O L N U M B E R: 7 1 8 -CI H -2 0 2  
I N D N U M B E R: 1 4 5 5 6 3 
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  
 P h D 
 
 
Ca m bri d ge, M A 0 2 1 4 2  
P h o ne: 
 
S p o ns or 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: 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3
C O N FI D E N TI A L  
2  
D ate of Ori gi n al Pr ot oc ol  
D ate of A me n d me nt 1  
1 0  J a n uar y 2 0 2 2  
1 5 J ul y 2 0 2 2  
D ate of A me n d me nt 2  
2 6 Ma y 2 0 2 3  
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 -CI H -2 0 2, Versi o n 3
C O N FI D E N TI A L  
3  
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 -CI H -2 0 2
St u d y Title:  
A 2 8 -Da y Ra n d o mize d, Place b o -C o ntr olle d, 
D o u ble -Bli n d, Parallel Gr o u ps a n d N or mati ve 
C o m paris o n St u d y t o E v al uate t he Effect of S A G E -7 1 8 
o n F u ncti o ni n g Ca p acit y i n Partici pa nts wit h 
H u nti n gt o n’s Disease  
Pr ot oc ol V ersi o n a n d D ate  
Versi o n 3 , 2 6 Ma y 2 0 2 3  
{see a p pe n de d electr o nic si g n at ure p a ge} 
 M D 
Date (D D  M o nt h  Y Y Y Y)  
 
{see a p pe n de d electr o nic si g n at ure p a ge} 
 M D, P h D  
Date ( D D  M o nt h  Y Y Y Y)  
 
{see a p pe n de d electr o nic si g n at ure p a ge}  
 P h D 
Date ( D D  M o nt h  Y Y Y Y ) 
 
{see a p pe n de d electr o nic si g n at ure p a ge} 
  
Date ( D D  M o nt h  Y Y Y Y)  
 

Cli nical Pr ot oc ol  
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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4  
 
 
{see a p pe n de d electr o nic si g n at ure p a ge}  
 
 M L A 
 
Date ( D D  M o nt h  Y Y Y Y)  
 
 
 
{see a p pe n de d electr o nic si g n at ure p a ge} 
 
 M S 
 
Date ( D D M o nt h  Y Y Y Y)  
 
 
 
{see a p pe n de d electr o nic si g n at ure p a ge} 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 P h D 
 
Date ( D D  M o nt h  Y Y Y Y)  
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5  
I N V E S TI G A T O R’ S A G R E EM E N T  
 
I ha v e recei ve d a n d rea d t he in vesti gat or’s b r oc h ure f or S A G E-7 1 8. I ha v e rea d t he 7 1 8-CI H -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 h e c o nfi de ntialit y of all 
i nf or mati o n recei ve d or d e vel o pe d i n c o n n ecti 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 o nt h Y Y Y Y)  

Cli nical Pr ot oc ol  
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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
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P R O C E D U R E S I N C A S E O F E M E R G E N C Y  
E mer ge nc y C o nta ct I nf or mati o n  
R ole i n St u d y  
N a me  
A d dress a n d Tele p h o ne N u m ber  
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:  
 
S A E Re p orti n g    
I Q VI A Lifec ycle Safet y 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 
 
 
 
 M D 
  
Pr o d uct C o m plai nts C o ntact  
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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8  
•  
T o e val uate a d diti o nal safet y a n d 
t olera bilit y para meters of S A G E-7 1 8 i n 
partici pa nts wit h H D.  
•  
C ha n ge fr o m Baseli ne a n d bet wee n -gr o u p effects 
( S A G E-7 1 8 a n d  place b o) 
 
, electr ocar di o gra ms ( E C Gs), a n d 
res p o nses o n t he C ol u m bia-S uici de Se verit y 
Rati n g Scale ( C -S S R S).  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
9  
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, parallel gr o u p  st u d y wit h a 2 8 -da y treat me nt 
d urati o n t o e val uate t he effects of S A G E -7 1 8 o n f u ncti o ni n g ca pacit y, safet y , a n d t olera bilit y i n 
partici pa nts wit h earl y ma nifest H D. Partici pa nts will be a d ults wit h ge neticall y -c o nfir me d e x pa nsi o n 
of t he H u nti n gt in ( H T T) ge ne c yt osi ne, a de ni ne, a n d g ua ni ne ( C A G) tri n ucle oti de re peat at S cree ni n g 
w h o meet dia g n ostic criteria detaile d i n t he i ncl usi o n criteria bel o w [i ncl u di n g U nifie d H u nti n gt o n’s 
Disease Rati n g Scale  ( U H D R S) sc ores a n d C A G-A ge -Pr o d uct [ C A P] sc ores wit hi n s pecific ra n ges ]. 
H P  e nr olle d i n t he st u d y will f oll o w t he sa me assess me nt sc he d ule as partici pa nts wit h H D, b ut will 
n ot recei ve S A G E -7 1 8 or place b o, a n d will c o m plete assess me nts o nl y o n perf or ma nce -base d tests 
( H D-C A B
, n ot H D-s pecific meas ures of f u ncti o ni n g a n d H D 
s y m pt o mat ol o g y. 
A n a d ult st u d y part ner f or partici pa nts wit h H D 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 wit h H D 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. F or pr os pecti ve partici pa nts wit h H D a n d st u d y part ners (if a p plica ble), t he 
st u d y will be gi n wit h t he i nf or me d c o nse nt pr ocess. 
Scree ni n g, safet y, a n d efficac y assess me nts will be perf or me d acc or di n g t o t he sc he d ule prese nte d i n 
Ta ble  1  ( H D) a n d Ta ble  2  ( H P). 
 
 
Scree ni n g assess me nts will be perf or me d t o deter mi ne eli gi bilit y. Partici pa nts a n d st u d y part ners (if 
a p plica ble) will recei ve trai ni n g o n t he st u d y pr oce d ures a n d de vices.  
Eli gi ble partici pa nts wit h H D will be ra n d o mize d 1: 1 i n a stratifie d ma n ner base d o n pre vi o us i nta ke of 
a ntise nse oli g o n ucle oti de dr u gs ( yes/ n o) t o recei ve 1. 2 m g of S A G E -7 1 8 or place b o f or u p t o 2 8 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 2 8, partici pa nts wit h H D 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. At cli nic visits, partici pa nts wit h H D will 
ta ke 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, 
 
. Stu 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 nce t o t he 
d osi n g re gi me n will be assesse d at eac h i n -cli nic visit b y e xa mi nati o n of t he use d pac ka gi n g a n d 
c o u nti n g a n y ret ur ne d ca ps ules . 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 1  
Eli gi bilit y C riteri a: 
I ncl usi o n C riteri a 
Eac h eli gi ble partici pa nt m ust:  
F or All  
1.  Be ca pa ble of pr o vi di n g i nf or me d c o nse nt, i n t he o pi ni o n of t he i n vesti gat or.  
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.  A gree t o a d here t o t he st u d y re q uire me nts.  
4.  Be ca pa ble of c o m pl yi n g wit h st u d y pr oce d ures, i n t he o pi ni o n of t he i n vesti gat or.  T he 
i n vesti gat or ma y deter mi ne a partici pa nt’s ca pa bilit y of bei n g a ble t o c o m plete t he Dri vi n g 
Si m ulat or at Scree ni n g base d o n t he o utc o me of t he si m ulat or sic k ness scree ni n g i nter vie w.  
5.  Be at least 2 5 years ol d b ut n o ol der t ha n 6 5 years of a ge at Scree ni n g.  
6.  C urre ntl y h ol d a vali d dri ver’s lice nse, 5 + years dri vi n g e x perie nce, a n d parti ci pa nts o pti n g i n 
t he dri vi n g si m ulat or assess me nt are c urre ntl y dri vi n g  at least  1 × wee kl y.  
7.  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.  
A d diti o nal criteria f or partic i pa nts wit h H D o nl y  
8.  Be a m b ulat or y ( use of assista nce de vices s uc h as a wal ker or ca ne is acce pta ble , as is 
occasi o nal use of w heelc hair.  In di vi d uals re q uiri n g a w heelc hair o n a re g ular basis are 
e xcl u de d), a ble t o tra vel t o t he st u d y ce nter, a n d, j u d ge d b y t he i n vesti gat or, is li kel y t o be a ble 
t o c o nti n ue t o tra vel t o t he st u d y ce nter t o c o m plete st u d y visits f or t he d urati o n of t he st u d y. 
9.  Ha ve:  
a.  Ge neticall y c o nfir me d disease wit h C A G e x pa nsi o n ≥3 6.  
b.  At Scree ni n g, U H D R S T F C > 6  a n d < 1 3, s u g gesti n g n o m ore t ha n a m o derate le vel of 
f u ncti o nal i m pair me nt. 
c. N o feat ures of j u ve nile H D.  
1 0.  C A P sc ore > 7 0, as calc ulate d usi n g t he C A P f or m ula: A G E  ×  ( C A G –  3 0)  / 6. 4 9.  
1 1.  Sc ore of 1 5 t o 2 5 (i ncl usi ve)  o n t he M o C A at Scree ni n g, i n dicati n g t he prese nce of c o g niti ve 
i m pair me nt. 
1 2.  Be willi n g t o i n vite a st u d y part ner, if a vaila ble, w h o is relia ble, c o m pete nt, a n d at least 1 8 years 
of a ge t o partici pate i n t he st u d y.   
1 3.  A gree, if fe male, t o use  at least  o ne met h o d of hi g hl y effecti ve c o ntrace pti o n (refer t o 
Secti o n  9. 2. 4  f or f urt her details o n acce pta ble f or ms 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 1 5 5 da ys f oll o wi n g t he last d ose of I P, 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 g icall y sterile ( h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect 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. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 2  
1 4.  A gree, if male, t o use a n acce pta ble met h o d of effecti ve c o ntrace pti o n f or t he d urati o n of st u d y 
a n d f or 2 15  da ys after recei vi n g t he last d ose of t he 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 w hic h carr y a ris k of pre g na nc y. Acce pta ble met h o ds of effecti ve c o ntrace pti o n 
are liste d i n Secti o n  9. 2. 4 . 
1 5.  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 2 1 5  da ys 
after recei vi n g t he last d ose of I P.  
A d diti o nal criteria f or H P o nl y  
1 6.  Sc ore ≥2 6 o n t he M o C A at Scree ni n g. 
1 7.  Ha ve n o k n o w n fa mil y hist or y of H D; or, ha ve k n o w n fa mil y hist or y of H D b ut ha ve ge netic 
test res ults a vaila ble t hat s h o w a n or mal C A G re peat le n gt h f or b ot h H T T alleles ( < 3 6). 
E xcl usi o n criteri a  
Eac h eli gi ble partici pa nt m ust n ot:  
F or All  
1.  Ha ve bee n dia g n ose d wit h a n d/ or treate d f or a n y t y pe of ca ncer (e xcl u di n g basal cell carci n o ma 
a n d mela n o ma i n sit u) wit hi n t he past year pri or t o Scree ni n g.  
2.  Pla ns t o u n der g o electi ve s ur ger y d uri n g partici pati o n i n t he st u d y.  
3.  Ha ve c urre nt or rece nt s uici dalit y, defi ne d as f oll o ws:  
a. S uici dal i deati o n wit hi n t he past m o nt h, as e vi de nce d b y a “ Yes” o n q uesti o n  4 (acti ve 
s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n) or q uesti o n  5 (acti ve s uici dal 
i deati o n wit h s pecific pla n a n d i nte nt) o n t he C-S S R S.  
b.  S uici dal be ha vi or wit hi n t he past year, as e vi de nce d b y a " Yes" o n a n y of t he C -S S R S 
S uici dal Be ha vi or ite ms (act ual atte m pt, i nterr u pte d atte m pt, a b orte d atte m pt, pre parat or y 
acts or be ha vi or , or s uici dal be ha vi or) o n t he C -S S R S.  
c. Prese nti n g a seri o us ris k of s uici de i n t he o pi ni o n of t he i n vesti gat or.  
4.  T a ke a n y ps yc h otr o pic me dicati o ns, i ncl u di n g a nti de pressa nts a n d a n xi ol ytics, u nless t he d ose 
a n d fre q ue nc y ha ve bee n sta ble f or at l east 3 0 da ys 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 sta ble f or t he d urati o n of t he st u d y.  
5.  Ha ve a n o n g oi n g me dical or ps yc hiatric c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y 
c o m pr o mise t he partici pa nt’s safet y or c o m plia nce wit h st u d y re q uire me nts.  
6.  Ha ve s u pi ne vital si g ns o utsi de of t he f oll o wi n g ra n ges at Scree ni n g or Baseli ne ( vital si g n 
meas ure me nts ma y be re peate d o nce f or i nitial val ues o utsi de t hese ra n ges):  
•  
Heart rate < 5 0 or > 1 0 0 b p m,  
•  
S yst olic bl o o d press ure < 1 0 0 o r > 1 6 0 m m H g, 
•  
Diast olic bl o o d press ure < 6 0 or > 1 0 0 m m H g.  
7.  Ha ve a n alc o h ol or dr u g use dis or der wit hi n t he past 2 years, as assesse d b y t he i n vesti gat or. A 
p ositi ve uri ne dr u g scree n is e xcl usi o nar y u nless dee me d b y t he i n vesti gat or t o reflect a 
prescri be d me dicati o n.  
8.  Ha ve a hist or y of si g nifica nt ha n d i nj ur y t hat w o ul d precl u de eit her writi n g or ra pi d bi ma n ual 
c o m p uterize d res p o n di n g.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 3  
9.  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 0.  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 or he patitis B or C.  
1 1.  Ha ve a hist or y of brai n s ur ger y, a si g nifica nt hea d i nj ur y ca usi n g l oss of c o nsci o us ness greater 
t ha n 3 0 mi n utes, or h os pitalizati o n d ue t o a brai n i nj ur y.  
1 2.  Ha ve a hist or y, prese nce, a n d/ or c urre nt e vi de nce of 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 3.   Ha ve a p ositi ve pre g na nc y test, is lactati n g, or i nte n d t o breastfee d d uri n g t he st u d y. 
1 4.  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). 
1 5.  H a 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 pre vi o us e x p os ure t o ge n e 
t hera p y; or ha ve partici pate d i n a n y H u nti n gt o n’s Disease ( H D) i n vesti gati o nal dr u g, bi ol o gic, 
or de vice trial wit hi n 1 8 0 da ys, or a n o n -H D 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).  
( N ote: Partici pa nts wit h c o nfir mati o n of e nr oll me nt i n t he place b o ar m of t hese trials w o ul d 
n ot be e xcl u de d. ) 
1 6.  Recei ve a n y pr o hi bite d me dicati o ns wit hi n 3 0 da ys of Scree ni n g a n d d uri n g partici pati o n i n 
t he st u d y: 
a. Ot her me dicati o ns gi ve n at d oses or i n c o m bi nati o ns t hat are li kel y t o  ha ve a deleteri o us 
effect o n c o g niti ve perf or ma nce, as deter mi ne d b y t he i n vesti gat or.  
b.  T etra 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. 
1 7.  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 xci pie nts, i ncl u di n g s o y lecit hi n.  
A d diti o nal criteria f or partici pa nts wit h H D o nl y  
1 8.  Ha d gastric b y pass s ur ger y, has a gastric slee ve or la p ba n d, or has ha d a n y relate d pr oce d ures 
t hat i nterfere wit h gastr oi ntesti nal tra nsit. 
1 9.  Recei ve a n y pr o hi bi te d me dicati o ns wit hi n 3 0 da ys of Scree ni n g a n d d uri n g partici pati o n i n t he 
st u d y: 
a. Me 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 ma nta di ne, keta mi ne, c ycl oseri 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 uestra nts ( e g, c olese vela m, c olesti p ol, c h olest yra mi ne).  
2 0.  Ha ve a dia g n osis of a n o n g oi n g ne ur o de ge nerati ve c o n diti o n ot her t ha n H D, i ncl u di n g b ut n ot 
li mite d t o Alz hei mer’s Disease, vasc ular de me ntia, de me ntia wit h Le w y b o dies, or Par ki ns o n’s 
Disease.  
A d diti o nal criteria f or H P o nl y  
2 1.  Ha ve a dia g n osis of a n o n g oi n g ne ur o de ge nerati ve c o n diti o n, i ncl u di n g b ut n ot li mite d t o H D, 
Alz hei mer’s Disease, vasc ular de me ntia, de me ntia wit h Le w y b o dies, or Par ki ns o n’s Disease.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 4  
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 place b o will 
be pr o vi de d as oral s oft gel li pi d ca ps ule f or self -a d mi nistrati o n o nce dail y i n t he m or ni n g.  
Ref ere nce T her a p y, D os a ge, a n d M o de of A d mi nistr ati o n:  N o ne.  
D ur ati o n of Tre at me nt:  2 8 da ys ( 4 wee ks)  
St atistic al Met h o ds:  
Detaile d met h o d ol o g y f or s u m mar y a n d statistical a nal yses of t he data c ollecte d i n t his st u d y will be 
d oc u me nte d i n a statistical a nal ysis pla n  ( S A P), w hic h 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:  
F or t he p ur p ose of all a nal yses w here a p plica ble, 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, u nless state d ot her wise. 
Descri pti ve s u m mar y statistics will  be pr o vi de d f or de m o gra p hics, baseli ne 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 partici 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 
( S D), mi ni m u m val ue, first q uartile ( Q 1), me dia n, t hir d q uartile ( Q 3), a n d ma xi m u m val ue. Cate g orical 
data will be s u m marize d usi n g fre q ue nc y c o u nts a n d perce nta ges.  
A n al ysis Se ts 
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 partici pa nt dis p ositi o n.  
T he Safet y Set  will i ncl u de all partici pa nts  wit h H D  w h o were a d mi nistere d I P or H P a n d will be use d 
t o descri be t he safet y data. T he Safet y Set will be f urt her s u b di vi de d  t o descri be partici pa nts wit h H D 
a n d healt h y partici pa nts se paratel y . 
T he F ull A nal ysis Set  will i ncl u de all partici pa nts w h o meet t he eli gi bilit y criteria a n d ha ve at least 
1  baseli ne assess me nt of H D -C A B  (partici pa nts wit h H D a n d H P).  
T he F ull A nal ysis Set 1 will i ncl u de all partici pa nts w h o i nitiate I P a n d ha ve baseli ne a n d at least 
1  p ost baseli ne efficac y e val uati o n  (partici pa nts wit h H D o nl y).  
T he F ull A nal ysis Set 2 will i ncl u de all partici pa nts wit h H D w h o i nitiate I P or H P w h o meet 
eli gi bilit y criteria a n d ha ve baseli ne a n d at least 1  p ost baseli ne efficac y e val uati o n ( partici pa nts wit h 
H D a n d H P).  
T he Healt h y Partici pa nt Set will i ncl u de all t he healt h y partici pa nts w h o meet t he eli gi bilit y criteria 
a n d ha ve m ore t ha n o ne  e val uati o n ( baseli ne a n d at least o ne p ost baseli ne) . 
Effic ac y A n al ysis  
Baseli ne differe nces bet wee n partici pa nts wit h H D a n d H P will be assesse d acr oss ca n di date e n d p oi nt 
usi n g T -test. T he mea n differe nces, its 9 5 % c o nfi de nce i nter val ( CI) a n d c orres p o n di n g p  val ue will be 
re p orte d. F or a gi ve n e n d p oi nt, if t he 9 5 % CI d oes n ot s pa n zer o, t he n it will be c o ncl u de d  t hat t he 
partici pa nts wit h H D are statisticall y si g nifica ntl y differe nt fr o m t heir h ealt h y co m parat ors at Baseli ne 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 5  
f or t hat e n d p oi nt; ot her wise, it will be c o ncl u ded  t hat t here is n ot e n o u g h e vi de nce t o declare t he m 
statisticall y differe nt.    
 
 
 
 
 
 
 
 
 
S af et y A n al ysis  
A Es will be c o de d usi n g 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 . T he 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) wi ll 
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 Ter m. T he fre q ue nc y of 
T E A Es will als o be prese nte d b y ma xi m u m se verit y , relati o ns hi p t o I P, a n d b y treat me nt gr o u p. Vital 
si g ns, 
, la b orat or y para meters, E C Gs, a n d C -S S R S data will be 
s u m marize d b y treat me nt gr o u p. 
S a m ple Size  
Usi n g a t w o -si de d al p ha le vel of 0. 0 5, a sa m ple size of at least 8 0  partici pa nts ( 4 0  H P a n d 
4 0  partici pa nts wit h H D) w o ul d pr o vi de at least 8 0 % p o wer t o detect a baseli ne differe nce i n H D -C A B 
c o m p osite sc ore ass u mi n g C o he n’s D effect size e q ual t o 0. 6 3, w hic h is i n t he ra n ge of effect sizes 
re p orte d i n t he literat ure.  
Usi n g a CI a p pr oac h f or sa m ple size esti mati o n  a sa m ple size of 3 2 e val ua ble partici pa nts wit h H D  
( 1 6 per treat me nt ar m) will pr o vi de 8 0 % c o nfi de nce le vel f or esti mati n g t he p o p ulati o n mea n wit h 
0. 5 0  precisi o n or mar gi n of err or.  
Ass u mi n g a 2 0 % dr o p o ut rate  i n partici pa nts wit h H D , a sa m ple size of a p pr o xi matel y 4 0 partici pa nts 
wit h H D will be ra n d o m ize d i n a 1: 1 rati o t o S A G E-7 1 8 a n d place b o t o o btai n 3 2 e val ua ble 
partici pa nts wit h H D. A d diti o nal partici pa nts ma y be ra n d o mize d if t he dr o p o ut rate is hi g her t ha n 
2 0 %.  
E val ua ble partici pa nts  wit h H D  are defi ne d as t h ose ra n d o mize d partici pa nts w h o recei ve I P a n d ha ve 
a vali d baseli ne a n d at least 1 p ost baseli ne efficac y assess me nt.  
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 6  
T a ble  1 : 
Sc he d ule of Assess me nts -H u nti n gt o n ’s Dise ase  
Assess me nts  
Scree ni n g Peri o d  
Tre at me nt Peri o d  
F oll o w -u p  
D a ys -2 8 t o 
-2  
D a y -1  
 
D a y 1  
 
D a y 1 4  
(± 2 
d a ys)  
D a y 2 8  
(± 2 
d a ys)  
D a y 4 2  
( ± 2 d a ys) or 
E T  
I nf or me d c o nse nta 
X  
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
X  
 
 
 
Ra n d o mizati o n b 
 
 
X  
 
 
 
Fa mil y/ me dical hist or y a n d de m o gra p hics c 
X  
 
 
 
 
 
P artici pa nt trai ni n g d 
X  
X  
X  
 
 
 
B o d y wei g ht  
X  
 
 
 
X  
X  
B o d y hei g ht  
X  
 
 
 
 
 
Vital si g ns (i ncl u di n g ort h ostatics) e 
X  
X  
 
X  
X  
X  
P h ysical e xa mi nati o n f 
X  
X  
 
 
X  
X  
C A G test (if n ot c ollecte d as part of me dical 
hist or y) g   
X  
 
 
 
 
 
F S H test h 
X  
 
 
 
 
 
Ser ol o g y  testi 
X  
 
 
 
 
 
1 2 -lea d E C Gj  
X  
X  
 
 
X  
X  
Cli nical la b orat or y assess me nts k  
X  
X  
 
 
X  
X  
Uri ne dr u g test  
X  
X  
X  
X  
X  
X  
Alc o h ol test  
X  
X  
X  
X  
X  
X  
Ci garette/t o bacc o use assess me nt m  
X  
 
X  
X  
X  
X  
Pre g na nc y test n 
X  
 
X  
 
X  
X  
C -S S R S ( Scree ni n g)  
X  
 
 
 
 
 
C -S S R S (si nce last visit)  
 
 
X  
X  
X  
X  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 7  
Assess me nts  
Scree ni n g Peri o d  
Tre at me nt Peri o d  
F oll o w -u p  
D a ys -2 8 t o 
-2  
D a y -1  
 
D a y 1  
 
D a y 1 4  
(± 2 
d a ys)  
D a y 2 8  
(± 2 
d a ys)  
D a y 4 2  
( ± 2 d a ys) or 
E T  
C o g niti ve test ( H D -C A B 
) t 
X  
 
X  
Dail y M o bile Assess me nts x 
 
X ------------------------------------------------------------- X  
I P self-a d mi nistrati o n y 
 
 
X  
( o nce dail y i n t he m or ni n g) 
 
I P dis pe nsati o nz 
 
 
X  
X  
 
 
I P acc o u nta bilit y/ret ur naa 
 
 
 
X  
X  
 
A Es/ S A Es  
X  
(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) 
Pri or a n d c o nc o mita nt me dicati o ns  
X ----------------------------------------------------------------------------- X  
A b bre viati o ns: A E  =  a d verse e ve nt; C A P  =  C A G -A ge -Pr o d uct;  
 
 
; C O VI D-1 9  =  c or o na vir us dise ase 2 0 1 9; C -S S R S  =  C ol u m bi a – S uici de Se verit y 
Rati n g Scale; 
 
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; H D =  H u nti n gt o n’s 
Disease; H D -C A B  =  H u nti n gt o n's Disease C o g niti ve Assess me nt B atter y ; 
 
 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; 
 
 
S A E  =  seri o us a d verse e ve nt; 
 
 
a. 
B ot h partici pa nts a n d st u d y part ners (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.  
b.  Ra n d o mizati o n will ta ke place o n Da y 1 , f oll o wi n g all safet y assess me nts ( vital si g ns, p h ysical e xa mi nati o ns , 
1 2 -lea d E C Gs a n d cli nical la b orat or y), eli gi bilit y re q uire me nts (C -S S R S, uri ne dr u g, alc o h ol a n d pre g na nc y 
testi n g) a n d c o nfir mati o n of i ncl usi o n/e xcl usi o n criteria.  
c. 
I n a d diti o n t o f ull me dical hist or y, all me dicati o ns a n d s u p ple me nts ta ke n wit hi n 8 wee ks pri or t o Scree ni n g, all 
me dicati o ns use d t o treat H 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 o t hera p e utic) use d t o treat or pre ve nt ne ur o ps yc hiatric, f u ncti o nal, a n d c o g niti ve ma nifestati o ns of H D 
will  be rec or de d. I nf or mati o n re gar di n g dia g n osis 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  re gar dless of ti min g . T he f oll o wi n g de m o gra p hics will be c ollect e d: a ge, race, se 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 me nt stat us . 
d.  P artici pa nts a n d st u d y part ners (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 of t he st u d y.  
e. 
Vital si g ns will  i ncl u de te m perat ure, res pirat or y rate, heart r ate, a n d bl o o d press ure. Heart rate a n d bl o o d 
press 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. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 8  
f. 
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 ( Da ys -2 8 t o -2 ) a n d at Da y 4 2 ( ± 2 da ys)/ E T. 
At ot her visits  [e g, Da y 2 8  ( ± 2 da ys) f or partici pa nts wit h H D], p h ysical e xa mi nati o ns 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 a n d 
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 gat or.  
g.  T est res ults of g e neticall y c o nfir me d disease wit h C A G e x p a nsi o n ≥3 6 c ollecte d as part of me dical hist or y is 
acce pta ble i n lie u of ce ntral la b orat or y c o nfir mati o n. F or a n y ge netic c o u nseli n g, t he st u d y sites s h o ul d f oll o w 
t heir l ocal practice. 
h.  Ser 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 a fe male partici pa 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.  
i. 
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 . 
j. 
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.  W he n 
E C G meas ure me nts c oi nci de wit h vital si g ns assess me nt or bl o o d dra ws,  bl o o d dra ws s h o ul d be carrie d o ut  
after E C G a n d vital si g ns . 
k.  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, cli nical c he mistr y, bi oc he mistr y, 
c o a g ulati o n, ge netic testi n g, a n d uri nal ysis. Sa m ples will be c ollecte d ≤2 h o urs pri or t o d osi n g o n Da ys 1 t o 2 8. 
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.  
 
 
 
m.  Data o n ci garette use will b e c ollecte d usi n g t he q uesti o n: “ H o w ma n y pac ks of ci garettes di d y o u s m o ke o ver 
t he past 7 da ys? ” at t he ti me p oi nts s pecifie d. 
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 t hat are n ot p ost me n o pa usal or s ur gicall y 
sterile. 
 
 
 
 
 
 
 
  
 
 
 
 
r. 
T o be a d mi nistere d t o partici pa nt, st u d y part ner (if a p plica bl e), a n d cli nicia n. Meas ures directe d t o st u d y part ner 
ma y be a d mi nistere d re m otel y or i n pers o n.  
s. 
St u d y part ner i n v ol ve me nt is o pti o nal.   
t. 
C o g niti ve tests at all ti me p oi nts will  be perf or me d at t he sa me ti me of da y ( ± 2 h o urs)  a n d will be c o n d ucte d 
pre d ose o n Da y  1  o nl y , 
 T he c o g niti ve tests i ncl u de t he 
H u nti n gt o n's Disease C o g niti ve Assess me nt B atter y ( H D -C A B; S y m b ol Di git M o dalities T est, O ne T o uc h 
St oc ki n gs of Ca m bri d ge, Trail Ma ki n g A a n d Trail Ma ki n g B, H o p ki ns Ver bal Lear ni n g T est _ Re vise d , P ace d 
T a p pi n g T est, a n d E m ot i o n R ec o g niti o n T est) 
 
 
  
 
 
 
 
 
   
 
 
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
1 9  
x.  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 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 t hese assess me nts are 
c o m plete d at a p pr o xi matel y t he sa me ti me ea c h da y, wit hi n 1 h o ur f oll o wi n g I P a d mi nistr ati 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. If i n c o nflict wit h cli nic visit sc he d ule, 
re m ote assess me nt ma y be c o m plete d i n t he cli nic u n der o bser vati o n b y t he st u dy staff . 
y.  O n Da ys 1, 1 4, a n d 2 8  st u d y visits , 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 be c o n d uct e d pri or t o d osi n g . A ll sc he d ul e d c o g niti ve tests 
will b e a d mi nistere d pre d ose o n Da y 1  Visit o nl y a n d p ost d ose o n Da y  1 4  Visit  ( ± 2 da ys) a n d Da y 2 8  Visit  
( ± 2 da ys).  P artici pa nts will re c or d t he date a n d ti me of eac h d ose ta ke n at h o me a n d i n -cli nic  usi n g a n 
ap plicati o n .  
z. 
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. 
aa. 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.  
N ote: O n scree ni n g ( Da ys -2 8 t o -2), Da y 2 8 , a n d  Da y  4 2 , safet y assess me nts 
 ma y be d o ne o n 
se p arate da y(s) t ha n t he c o g niti ve assess me nts, if nee d be, pr o vi de d t hat all assess me nts are c o m plete d wit hi n t he 
s pecifie d visit wi n d o w ( ±2  da ys).   
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 0  
T a ble  2 : 
Sc he d ule of Assess me nts -He alt h y P a rtici p a nts  
Assess me nts  
Scree ni n g Peri o d  
Reli a bilit y Assess me nt Peri o d  
F oll o w -u p  
D a ys -2 8 
t o -2   
D a y -1  
D a y 1  
 
D a y 1 4  
 (± 2 d a ys)  
D a y 2 8  
 (± 2  d a ys)  
D a y 4 2  
 ( ± 2 d a ys) or E T  
I nf or me d c o nse nta 
X  
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
X  
 
 
 
Me dical hist or y a n d 
de m o gra p hics b 
X  
 
 
 
 
 
P artici pa nt trai ni n g c 
X  
X  
X  
 
 
 
B o d y wei g ht  
X  
 
 
 
 
X  
B o d y hei g ht  
X  
 
 
 
 
 
Vital si g ns (i ncl u di n g 
ort h ostatics) d 
X  
X  
 
 
 
X  
P h ysical e xa mi nati o n e 
X  
X  
 
 
 
X  
F S H test f 
X  
 
 
 
 
 
Ser ol o g y test g 
X  
 
 
 
 
 
1 2 -lea d E C Gh  
X  
X  
 
 
 
X  
Cli nical la b orat or y assess me nts i 
X  
X  
 
 
 
X  
Uri ne dr u g test  
X  
X  
X  
X  
X  
X  
Alc o h ol test  
X  
X  
X  
X  
X  
X  
Ci garette/t o bacc o use assess me nt j 
X  
 
X  
X  
X  
X  
Pre g na nc y test k 
X  
 
X  
 
 
X  
C -S S R S ( Scree ni n g)  
X  
 
 
 
 
 
M o ntreal C o g niti ve Assess me nt  
X  
 
 
 
X  
 
Dail y M o bile Assess me nts p 
 
X ------------------------------------------------------------------ X  
A Es/ S A Es  
X  
(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)  
Pri or a n d c o nc o mita nt 
me dicati o ns  
X -------------------------------------------------------------------------------- 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 dise ase 2 0 1 9; C -S S R S  =  C ol u m bi a – S uici de Se verit y Rati n g Scale; 
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; H D =  H u nti n gt o n’s 
Disease; H D -C A B  =  H u nti n gt o n's Disease C o g n iti ve Assess me nt B atter y, HI V =  h u ma n i m m u n o deficie nc y vir us; 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 1  
I C F =  i nf or me d c o nse nt f or m; 
  S A E  =  seri o us a d verse 
e ve nt; 
 
 
a. 
P artici pa nts will  be c o nse nte d d uri n g t he Scree ni n g P eri o d.  
b.  I n a d diti o n t o f ull me dical hist or y, all me dicati o ns a n d s u p ple me nts ta ke n wit hi n 8 wee ks pri or t o Scree ni n g. 
I nf or mati o n re gar di n g dia g n osis 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 . T he f oll o wi n g de m o gr a p hics will be c ollecte d: a ge, r ace, se 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 me nt stat us . 
c. 
P artici pa nts 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 of t he st u d y.  
d.  Vital si g ns will  i ncl u de te m perat ure, res pirat or y rate, heart r ate, a n d bl o o d press ure. Heart rate a n d bl o o d 
press 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.  
e. 
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 ( Da ys -2 8 t o -2) a n d at Da y 4 2 ( ± 2 da ys)/ E T. 
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.  
f. 
Ser 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 nts w h o are n ot s ur gicall y sterile t o 
c o nfir m w het her a fe male partici pa 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.  
g.  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.  
h.  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.  
i. 
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, cli nical c he mistr y, bi oc he mistr y, 
c o a g ulati o n, a n d uri nal ysis. Sa m ple c ollecti o n ma y occ ur at a n y ti me.  
j. 
Data o n ci garette use will b e c ollecte d usi n g t he q uesti o n: “ H o w ma n y pac ks of ci garettes di d y o u s m o ke o ver 
t he past 7 da ys? ” at t he ti me p oi nts s pecifie d. 
k.  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 pa rtici pa nts t hat are n ot p ost me n o pa usal or s ur gicall y 
sterile. 
 
 
m.  C o g niti ve tests at all ti me p oi nts will  be perf or me d at t he sa me ti me of da y ( ± 2 h o urs). T he c o g niti ve tests 
i ncl u de t he H u nti n gt o n's Disease C o g niti ve Assess me nt B atter y ( H D-C A B; S y m b ol Di git M o dalities T est, O ne 
T o uc h St oc ki n gs of Ca m bri d ge, Trail Ma ki n g A a n d Trail Ma ki n g B, H o p ki ns Ver bal L ear ni n g T est _ Re vise d , 
P ace d T a p pi n g T est, a n d E m oti o n Rec o g niti o n T est) 
 
 
  
 
 
 
 
 
 
 
 
p.  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 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 c o m plete d 
at a p pr o xi matel y t he sa me ti me eac h da y . 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. If i n c o nfli ct wit h cli nic visit sc he d ule, re m ote assess me nt ma y be c o m plete d i n t he cli nic 
u n der o bser vati o n b y t he st u d y staff . 
N ote: O n Da ys 2 8 a n d 4 2, safet y assess me nts 
 ma y be d o ne o n se par ate da y(s) t ha n t he 
c o g niti ve a ssess me nts, if nee d be, pr o vi de d t hat all assess me nts are c o m plete d wit hi n t he s pecifie d visit wi n d o w 
( ±2  da ys).  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 2  
 

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

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 4  
9.  
T R E A T M E N T O F P A R TI CI P A N T S  .........................................................................4 5  
9. 1.  
Descri pti o n of I n v esti gati o nal Pr o d uct  .......................................................................4 5  
9. 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  ......................................................................................4 5  
9. 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  ..........................................4 5  
9. 2. 2.  
Pr o hi bite d Me dicati o ns  ...............................................................................................4 5  
9. 2. 3.  
Ot her Restricti o ns a n d R ec o m me n dati o ns ..................................................................4 6  
9. 2. 4.  
Acce pt a ble F or ms of C o ntrace pti o n  ...........................................................................4 6  
9. 3.  
I nter ve nti o n After t he E n d of t he St u d y .....................................................................4 7  
9. 4.  
Treat me nt A d h ere n ce  ..................................................................................................4 7  
9. 5.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................4 7  
9. 5. 1.  
E mer ge nc y U n bli n di n g  ...............................................................................................4 8  
1 0.  
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 9  
1 0. 1.  
I n v esti gati o nal Pr o d uct ...............................................................................................4 9  
1 0. 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 9  
1 0. 3.  
I n v esti gati o nal Pr o d uct St ora ge ..................................................................................4 9  
1 0. 4.  
I n v esti gati o nal Pr o d uct Pre parati o n ............................................................................5 0  
1 0. 5.  
I n v esti gati o nal Pr o d uct A d mi nistrati o n ......................................................................5 0  
1 0. 5. 1.  
Me dicati o n A d here nce a n d Re mi n der S yste m  ...........................................................5 0  
1 0. 5. 1. 1.  
O n g oi n g Us e a n d M o nit ori n g of Me dicati o n A d here nce  ...........................................5 0  
1 0. 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 ...............................5 0  
1 0. 7.  
Pr o d uct C o m plai nts  ....................................................................................................5 1  
1 1.  
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 .........................................................................................................5 2  
1 1. 1.  
Scree ni n g Assess me nts  ...............................................................................................5 2  
1 1. 1. 1.  
M o ntreal C o g niti ve Assess me nt  .................................................................................5 2  
1 1. 1. 2.  
Ci garette a n d/ or T o b acc o Use Assess me nt  .................................................................5 2  
1 1. 2.  
Efficac y Assess me nts  .................................................................................................5 3  
1 1 . 2. 1. 
H u nti n gt o n’s Disease -C o g niti ve Assess me nt Batter y I n di vi d ual Assess me nts  .........5 3  
1 1. 2. 1. 1.  
S y m b ol Di git M o dalities Test  .....................................................................................5 3  
1 1. 2. 1. 2.  
O ne T o uc h St oc ki n gs of Ca m bri d ge  ...........................................................................5 3  
1 1. 2. 1. 3.  
Trail Ma ki n g  ...............................................................................................................5 3  
1 1. 2. 1 . 4. 
H o p ki ns Ver bal Lear ni n g Test _ Re vise d  .....................................................................5 3  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 5  
1 1. 2. 1. 5.  
Pace d Ta p pi n g T est  .....................................................................................................5 4  
1 1. 2. 1. 6.  
E m oti o n Rec o g niti o n Tas k  .........................................................................................5 4  
 
5 4  
 
5 4  
 
5 4  
 
5 4  
 
5 5  
 
5 5  
 
5 5  
 
5 5  
 
5 5  
 
5 5  
 
5 6  
 
5 6  
 
5 6  
 
5 6  
1 1. 2. 5.  
Dail y M o bile Ass ess me nts  .........................................................................................5 6  
 
5 6  
 
5 7  
1 1. 2. 5. 3.  
Nati o nal Slee p F o u n d ati o n Slee p Diar y  .....................................................................5 7  
 
5 7  
 
5 7  
 
5 7  
 
5 8  
 
5 8  
 
5 9  
 
5 9  
 
5 9  
1 1. 3.  
Cli nical P har mac ol o g y Assess me nts  ..........................................................................5 9  
 
5 9  
 
6 0  
 
6 0  
1 1. 3. 2.  
P har mac o d y na mic Ass ess me nts  .................................................................................6 0  

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

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

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 8  
LI S T O F T A B L E S  
Ta ble  1:  
Sc he d ule of Assess me nts -H u nti n gt o n’s Disease  .......................................................1 6  
Ta ble  2:  
Sc he d ule of Assess me nts -Healt h y Partici pa nts  .........................................................2 0  
 
 
2 2  
Ta ble 4:  
A b bre viati o ns a n d S peci alist Ter ms  ...........................................................................2 9  
Ta ble 5:  
I n v esti gati o nal Pr o d uct ...............................................................................................4 9  
Ta ble  6:  
S u m mar y of Cli nical La b orat or y A nal ytes  .................................................................6 3  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y Desi g n  ...............................................................................................................3 8  
 
  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
2 9  
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol.  
T a ble 4 : 
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  
 
 
B MI  
b o d y mass i n de x  
 
 
C A G  
c yt osi ne, a de ni ne, a n d g u a ni ne  
 
 
 
 
 
 
C A P  
C A G -A ge -Pr o d uct  
C F R  
C o de of Fe d eral Re g ul ati o ns  
 
 
 
 
 
 
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  
C S  
cli nicall y si g nifica nt  
C -S S R S  
C ol u m bia – S uici de Se verit y Rati n g Scale  
 
 
 
   
 
 
e C R F 
electr o nic case re p ort f or m  
E C G  
electr ocar di o gra m  
E C  
Et hic C o m mittee  
E T  
Earl y Ter mi nati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o ne 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 0  
A b bre vi ati o n  
Defi niti o n  
G C P  
G o o d Cli nical Practice  
 
 
 
 
G M P  
G o o d Ma n ufact uri n g Practice  
 
  
H D  
H u nti n gt o n’s Disease  
H D -C A B  
H u nti n gt o n's Diseas e C o g niti ve Assess me nt Batter y  
 
 
 
  
  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H P  
healt h y p artici pa nt(s)  
 
  
H T T  
H u nti n gt o n ge ne  
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 
a partici pa nt 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 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
 
  
M o C A  
M o ntreal C o g niti ve Assess me nt  
m R N A  
messe n ger ri b o n u cleic aci d  
N C S  
n ot cli nicall y si g nifica nt  
 
 
N M D A  
N -met h yl -D -as p artate  
 
 
N S F  
Nati o nal Slee p F o u n d ati o n  

Cli nical Pr ot oc ol  
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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 1  
A b bre vi ati o n  
Defi niti o n  
P A M  
p ositi ve all osteric m o d ulat or  
 
 
 
 
 
 
P K  
p har mac o ki netic  
P O  
b y  m o ut h  
 
 
 
 
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 D  
sta n dar d de viati o n 
S O C  
s yste m or ga n class 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
St u d y p art ner  
S y n o n y m o us wit h care p art ner  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T F C  
T otal F u ncti o nal Ca pacit y   
T H C  
tetra h y dr oca n na bi n ol  
U H D R S  
U nifie d H u nti n gt o n’s Disease Rati n g Scale  
U P  
u na ntici pate d pr o ble m  
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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 2  
5.  
I N T R O D U C TI O N 
H u nti n gt o n’s D ise ase ( H D) is a rare here ditar y n e ur o de ge nerati ve dise ase c haracterize d b y 
s pecific m ot or s y m pt o ms, i ncl u di n g c h orea a n d ri gi dit y, a n d deteri orati o n of ps yc hiatric a n d 
c o g niti ve f u n cti o n. T he m ot or s y m pt o ms ca n ma nifest at a n y a ge, after w hic h disease 
pr o gressi o n lea ds t o i nca pacitati o n a n d deat h. Bef ore t he a p p eara nce of m ot or s y m pt o ms, 
ps yc hiatric a n d c o g niti ve d ysf u n cti o n pre d o mi nate (Ta b rizi 2 0 1 2). C o g niti ve i m pair me nt is 
al wa ys pres e nt i n t he c o urse of t he dise ase, e v e n i n pre ma nifest ge n e carriers ( Car d os o 2 0 1 7 ). 
T he mec ha nis ms of c o g niti ve c ha n ges i n H D ha v e n ot bee n f ull y d escri b e d, b ut c ha n ges i n 
gl uta mater gic ne ur otra ns missi o n a p pear t o be i n v ol ve d. Re d uce d gl uta mat e i n t he p osteri or 
ci n g ulat e c orte x has bee n c orrel ate d wit h c o g niti ve d ysf u ncti o n i n earl y ma nifest H D 
(U nsc h ul d  2 0 1 2 ). N -m et h yl -D -as partate ( N M D A ) rece pt ors are a s u bt y pe of gl uta mat e rece pt or 
wit h a f u n da me ntal a n d well d oc u me nte d r ole i n re g ulati n g s y n a ptic stre n gt h, healt h, a n d 
plasticit y ( V y klic k y 2 0 1 4 , Ya o  2 0 1 7 ). N M D A rece pt ors ha ve bee n f o u n d t o be d ysf u ncti o nal i n 
t he p ost m orte m brai ns of patie nts wit h H D ( Al bi n 1 9 9 0 ). T o gether, t hes e data s u g gest t hat 
l o were d N M D A rece pt or t o ne ma y c o ntri b ute t o c o g niti ve d ysf u ncti o n i n H D (Pa ul 2 0 1 3 ). 
Precli nical data ill ustrate t hat patie nts wit h H D ha ve re d uce d plas ma le vels of a s pecifi c 
o x yster ol, 2 4( S) -h y dr o x yc h olester ol ( Le o ni 2 0 1 3 ). 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 M D A rece pt or ( Pa ul 2 0 1 3 ) a n d h as bee n c orrelat e d wit h 
perf or ma n ce o n s e veral c o g niti ve tas ks i n H D ( Le wis  2 0 1 9 ). S A G E-7 1 8 is a n o vel 
o x yster ol -base d P A M  o f N M D A rece pt or s wit h t h e p ote ntial t o rest ore N M D A rece pt or t o ne t o 
a meli orate c o g niti ve d efi cits i n H D. S A G E -7 1 8 o nl y affects rece pt or f u n cti o n i n t he prese nce of 
e n d o ge n o us gl uta mate, t h us 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 ociat e d e x cit ot o xicit y.   
T he effect of S A G E -7 1 8 o n c o g niti ve a n d f u ncti o n o utc o mes i n partici pa nts wit h H D will be 
e val uate d i n a ra n d o mize d, place b o -co ntr olle d, d o u ble -bli n d, parallel gr o u p a n d n or mati ve 
c o m paris o n st u d y. A d diti o nal data o n t he effects of S A G E -7 1 8 i n partici pa nts wit h H D will be 
c ollecte d t hr o u g h o ut, i ncl u di n g assess me nts of ne ur o ps yc hiatric a n d m ot or s y m pt o ms.  
5. 1.  
D ose J ust ific ati o n 
S A G E -7 1 8 has bee n well t olerate d i n b ot h healt h y partici pa nts ( H P) a n d a s mall c o h ort of 
partici pa nts wit h H D i n pre vi o us cli nical st u dies. H o we ver, base d o n n o n cli nical fi n di n gs, t he 
U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) i m p ose d a me dia n ma xi m u m c o nce ntrati o n 
( Cma x ) ca p of 4 5 n g/ m L. T o date, cli nical st u dies wit h S A G E -7 1 8  ha ve use d d oses t hat res ulte d i n 
e x p os ures wit hi n t his ca p  a n d n o relate d a d verse e ve nts ( 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 t he e x p os ure ca ps, see t he S A G E -7 1 8 in vesti gat or’s 
b r oc h ure. 
Fr o m a pre vi o us st u d y of S A G E -7 1 8 a d mi nistere d as a n oral s ol uti o n i n healt h y partici pa nts, 
re peat d os es of 1 m g a n d a si n gle d os e of 3 m g de m o nstrate d e vi de nce c o nsiste nt wit h N M D A 
tar get e n ga ge me nt. Fr o m a 1 4-da y st u d y of S A G E -7 1 8 a d mi nistere d as a n oral s ol uti o n i n 
partici pa nts  wit h H D, re p eat d oses of 1 m g s h o we d be neficial effects o n c o g niti o n assess me nts. 
Si milarl y, fr o m a 1 4 -d a y  st u d y of S A G E-7 1 8 a d mi nistere d as a s oli d ta blet i n partici pa nts  wit h 
Par ki ns o n’s D isease, re p eat d oses of 3 m g w he n ta ke n wit h a meal c o ntai ni n g a p pr o xi matel y 
3 0  g of di etar y fat s h o we d be neficial effects o n c o g niti o n assess me nts. T he p har mac o ki netic 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 3  
( P K) e x p os ures i n t he a b o ve sce nari os were si milar, wit h i n di vi d ual C ma x  val ues ra n gi n g fr o m 
1 9. 7 t o 2 9. 7 n g/ m L.  
I n t he prese nt st u d y, S A G E-7 1 8 will be a d mi nistere d as a li pi d base d s oft gel f or m ulati o n at a 
dail y d ose of 1. 2 m g. T h e li pi d f or m ulati o n has i m pr o ve d bi oa vaila bilit y c haracteristics 
c o m pare d t o s ol uti o n a n d ta bl et f or ms. 
 
 
 
 
 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 5  
•  T o e val uate a d diti o nal safet y a n d 
t olera bilit y para meters of S A G E-7 1 8 
i n partici pa nts wit h H D. 
•  C ha n ge fr o m Baseli ne a n d bet wee n -gr o u p 
effects ( S A G E -7 1 8 a n d place b o) f or 
, 
electr ocar di o gra ms ( E C Gs), a n d res p o nses o n 
t he C ol u m bia-S uici de Se verit y Rati n g Scal e 
( C-S S R S).  
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 6  
7.  
I N V E S TI G A TI O N A L PL A N  
7. 1.  
O ver all St u d y 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, parallel gr o u p  st u d y wit h a 2 8 -da y 
treat me nt d urati o n t o e val uate t he effects of S A G E-7 1 8 o n f u ncti o ni n g ca p acit y, s afet y, a n d 
t olera bilit y i n partici pa nts wit h earl y ma nifest H D. Partici pa nts will be a d ults wit h 
ge n eticall y -c o nfir me d e x pa nsi o n of t he H u nti n gt in ( H T T) ge n e c yt osi ne, a de ni ne, a n d g ua ni n e 
( C A G) tri n ucle oti de re peat at scree ni n g w h o meet dia g n ostic criteria d etaile d i n t he i ncl usi o n 
criteria b el o w [i ncl u di n g U nifie d H u nti n gt o n’s Disease Rati n g Scale ( U H D R S) sc ores a n d 
C A G -A ge -Pr o d uct [ C A P] sc ores wit hi n s pecific ra n ges).  
H P  e nr olle d i n t he st u d y will f oll o w t he sa me assess me nt sc he d ule as partici pa nts wit h H D, b ut 
will n ot recei ve S A G E -7 1 8 or place b o, a n d will c o m plete assess me nts o nl y o n 
perf or ma n ce -base d tests ( H D -C A B
), n ot H D-s pecific 
meas ures of f u ncti o ni n g a n d H D s y m pt o mat ol o g y.  
A n a d ult st u d y part ner f or p artici pa nts wit h H D 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 wit h H D 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. F or pr os pecti ve p artici pa nts wit h H D a n d st u d y p art ners (if a p plica ble) , 
t he st u d y will be gi n wit h t he i nf or me d c o nse nt pr ocess. 
Scree ni n g, safet y, a n d efficac y ass ess me nts will be perf or me d acc or di n g t o t he sc he d ule 
prese nte d i n Ta bl e  1  ( H D) a n d Ta ble  2  ( HP ). 
 
 
Scree ni n g ass ess me nts will be perf or me d t o  det er mi ne eli gi bilit y. Partici pa nts a n d st u d y part ners 
(if a p plica ble) will recei ve trai ni n g o n t h e st u d y pr oce d ures a n d de vices. 
Eli gi ble partici pa nts wit h H D will be ra n d o mize d 1: 1 i n a stratifie d ma n ner base d o n  pre vi o us 
i nta ke of a ntise nse oli g o n ucle oti de dr u gs ( yes/ n o) t o recei ve 1. 2 m g of S A G E -7 1 8 or place b o f or 
u p t o 2 8 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 2 8, partici p a nts wit h H D will 
self-a d mi nister bli n de d i n vesti gati o nal pr o d u ct (I P) o nce p er da y i n t he m or ni n g. At cli nic visits, 
partici pa nts wit h H D will ta ke t he I P u n der staff s u per visi 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 
ta blets. 
D uri n g  t h e Treat me nt Peri o d, partici pa nts wit h H D will be a ble t o recei ve I P as l o n g as t h ere are 
n o d ose -li miti n g safet y/t olera bilit y c o n cer ns. Partici pa nts wit h H D w h o disc o nti n ue I P earl y 
s h o ul d c o m plete t he re m ai ni n g st u d y visits as sc h e d ule d, u nless t he par tici pa nt wit h H D 
wit h dra ws c o nse nt or l os es t he ca p acit y t o gra nt c o nse nt. If a partici pa nt wit h H D wit h dra ws 
fr o m t he st u d y or st o ps st u d y partici pati o n, a n earl y ter mi nati o n ( E T) visit s h o ul d be c o n d ucte d.  
After c o m pleti n g t he T reat me nt P eri o d or R elia bilit y A ssess me nt P eri o d, all 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 4 2 ( ± 2 da ys) t o c ollect c o nti n ue d safet y a n d 
effic ac y dat a.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 7  
7. 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 parti ci pa nts, 
i ncl u di n g st u d y p art ners f or partici pa nts wit h H D . S u bse q ue nt scree ni n g assess me nts will be 
perf or me d b et wee n Da y  -2 8  a n d Da y -1  f or p artici pa nts wit h H D a n d H P t o deter mi ne eli gi bilit y, 
i ncl u di n g assess me nts of c o g niti ve f u n cti o n. 
7. 1. 2.  
B aseli ne Peri o d  
T he Baseli ne Peri o d will be c o m plete d  b y  Da y 1  f or partici pa nts wit h H D a n d H P . D uri n g t his 
peri o d, 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 s afet y d ata.   
7. 1. 3.  
Tre at me nt Peri o d  
Eli gi b le partici pa nts wit h H D will be ra n d o mize d 1: 1 t o recei ve S A G E -7 1 8, or place b o f or 
2 8  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 t he 4-wee k treat me nt peri o d , partici pa nts 
wit h H D will self -a d mi nister bli n de d 1. 2  m g S A G E -7 1 8 (as 1. 2 -m g s oft gel li pi d ca ps ules) or 
place b o , o nce per da y i n t he m or ni n g. Partici p a nts w h o utilize t he ± 2 da y wi n d o w at Da y 2 8 
s h o ul d c o nti n ue t o self-a d mi nister I P wit hi n t he visit wi n d o w. H P  will n ot recei ve S A G E -7 1 8 or 
p lace b o. 
At cli nic visits, partici pa nts wit h H D will ta ke  t he I P u n der staff s u p er visi o n,  
 
 
 St u d y staff will dis pe nse 
s ufficie nt I P f or d ail 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 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 n e d ta blets .  
D uri n g t h e Treat me nt Peri o d, partici pa nts wit h H D will be a ble t o recei ve I P as l o n g as t h ere are 
n o d ose li miti n g safet y/t olera bilit y c o n cer ns. Partici pa nts wit h H D w h o disc o nti n ue I P earl y 
s h o ul d c o m plete t he re m ai ni n g st u d y visits as sc h e d ule d, u nless t he partici pa nt wit h H D 
wit h dra ws c o nse nt or l os es t he ca p acit y t o gra nt c o nse nt. If a partici pa nt wit h H D wit h dra ws 
fr o m t he st u d y or st o ps st u d y partici pati o n earl y, a n E T  visit s h o ul d be c o n d ucte d.  
7. 1. 4.  
F oll o w -u p Peri o d  
After c o m pleti n g t he T reat me nt P eri o d or R elia bilit y A ssess me nt P eri o d, all 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 4 2 ( ± 2 da ys) t o c ollect c o nti n ue d safet y a n d 
effic ac y dat a  (Ta ble  1  a n d Ta ble  2 ). 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
3 9  
7. 2.  
N u m ber of P artici p a nts  
A p pr o xi matel y 4 0  p artici pa nts wit h earl y H D ( n =  2 0  per treat me nt ar m) will be ra n d o mize d i n 
t he st u d y t o o btai n 3 2  e v al ua ble partici p a nts wit h H D (n  =  1 6 p er treat me nt ar m ). A d diti o nal 
partici pa nts ma y be ra n d o mize 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 ( 2 0 %). 
A p pr o xi matel y 4 0  m atc h e d healt h y partici p a nts (e g. a ge, se x, race a n d e d u cati o n) will be 
e nr olle d i n a n “assess me nt o nl y” ar m a n d will c o m plete s pecific ass ess me nt pr oce d ures 
f oll o wi n g t he sa m e sc he d ule as t he treat me nt ar m partici pa nts.  
7. 3.  
Tre at me nt Assi g n me nt  
Eli gi ble partici pa nts  wit h H D 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 u p t o 2 8  da ys . A d diti o nal details o n ra n d o mizati o n a n d bli n di n g are pr o vi de d i n Secti o n  9. 5 . 
7. 4.  
D ose Criteri a  
D uri n g t h e Treat me nt Peri o d, partici pa nts wit h H D will be a ble t o recei ve I P as l o n g as t h ere are 
n o d ose li miti n g safet y/t olera bilit y c o n cer ns.  
7. 4. 1.  
St o p pi n g C riteri 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 p h y ( E E G ), 
re peat s er u m c he mistr y, uri nal ysis, a n d dr u g/alc o h ol tests.  
7. 5.  
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 nce of A Es or ot her fi n di n gs s u g gesti n g u n acce 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 v e 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 in 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 pati n g partici pa nts.  
7. 6.  
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 partici pa 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 ha ses of t he 
st u d y i ncl u di n g t h e last visit. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 0  
8.  
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  
8. 1.  
P artici p a nt I ncl usi o n Criteri a  
Eac h eli gi ble partici p a nt m ust:  
F or All  
1.  Be ca pa ble of pr o vi di n g i nf or me d c o ns e nt, i n t he o pi ni o n of t he i n vesti gat or.  
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 p ecific pr oce d ures b ei n g 
perf or me d.  
3.  A gree t o a d h ere t o t he st u d y re q uire me nts.  
4.  Be ca pa ble of c o m pl yi n g wit h st u d y pr oce d ures, i n t he o pi ni o n of t he i n vesti gat or.  T h e 
i n vesti gat or ma y d eter mi ne a partici p a nt’s ca p a bil it y of bei n g a bl e t o c o m plete t he 
Dri vi n g Si m ulat or at Scree ni n g base d o n t he  o ut c o me of t he si m ulat or sic k ness scree ni n g 
i nter vie w. 
5.  Be at least 2 5 years ol d b ut n o ol der t ha n 6 5 years of a ge at Scree ni n g.  
6.  C urre ntl y h ol d a v ali d dri ver’s lice ns e, 5 + years dri vi n g e x perie nce, a n d partici pa nts 
o pti n g i n t he dri vi n g si m ulat or assess me nt are c urre ntl y dri vi n g at least 1 × wee kl y.  
7.  A gree t o r efrai 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.  
A d diti o nal criteria for partici pa nts wit h H D o nl y  
8.  Be a m b ulat or y ( use of assista nce de vices s uc h as a wal ker or ca ne is acce pta ble, as is 
occasi o nal use of w heelc hair. I n di vi d uals re q uiri n g a w heel c hair o n a re g ul ar basis are 
e x cl u de d), a ble t o tra v el t o t he  st u d y ce nter, a n d, j u d ge d b y t h e i n vesti gat or, is li kel y t o 
be a ble t o c o nti n ue t o tra vel t o t he st u d y ce nter t o c o m plete st u d y visits f or t he d urati o n 
of t he st u d y.  
9.  Ha ve:  
a.  Ge neticall y c o nfir me d disease wit h C A G e x pa nsi o n ≥3 6.  
b.  At Scree ni n g, U H D R S T F C > 6  a nd < 1 3, s u g gesti n g n o m or e t ha n a m o derate le vel of 
f u ncti o nal i m pair me nt. 
c. N o feat ur es of j u ve nile H D.  
1 0.  C A P sc ore > 7 0, as calc ul ate d usi n g t he C A P f or m ula: A G E  ×  ( C A G –  3 0)  / 6. 4 9.  
1 1.  Sc ore of 1 5 t o 2 5 (i ncl usi ve)  o n t he M o C A at Scree ni n g, i n dicati n g t he pres e n ce of 
c o g niti ve i m pair me nt.  
1 2.  Be willi n g t o i n vite a st u d y part ner, if a vaila ble, w h o is relia ble, c o m pet e nt, a n d at least 
1 8  years of a ge t o partici pate i n t he st u d y .  
1 3.  A gree, if fe male, t o us e at least o ne  met h o d of hi g hl y effecti ve c o ntrace pti o n  (refer t o 
Secti o n  9. 2. 4  f or f urt her details o n acce pta ble f or ms 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 1 5 5 da ys f oll o wi n g t he last d ose of I P, u nless t he y are 
p ost me n o pa usal ( defi n e d as n o me nse s f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 

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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 gicall y 
sterile ( h ysterect o m y, bil ateral sal pi n gect o m y, or bilateral o o p h orect 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 n a nc y. 
1 4.  A gree, if m ale, t o use a n acce pta ble met h o d of effecti ve c o ntr ace pti o n f or t he d urati o n of 
st u d y a n d f or 2 15  da ys after recei vi n g t he last d ose of t he I P, u nl ess t he partici pa nt d oes 
n ot e n ga ge i n se x ual relati o ns w hic h carr y a ris k o f pre g na nc y. Acce pta ble met h o ds of 
effecti ve c o ntr ace pti o n  are liste d i n Secti o n  9. 2. 4 . 
1 5.  A gree, if m ale, t o a bstai n fr o m s per m d o nati o n d uri n g t he Tr eat me nt Peri o d a n d f or 
2 1 5  da ys after recei vi n g t he last d ose of I P.  
A d diti o nal criteria f or H P o nl y  
1 6.  Sc ore ≥2 6 o n t he M o C A at Scree ni n g.  
1 7.  Ha ve n o k n o w n fa mil y hist or y of H D; or, ha v e k n o w n fa mil y hist or y of H D b ut ha ve 
ge n etic test res ults a v aila ble t hat s h o w a n or mal C A G re p eat le n gt h f or b ot h H T T alleles 
( < 3 6). 
8. 2.  
P artici p a nt E xcl usi o n Criteri a  
Eac h eli gi ble partici p a nt m ust n ot:  
F or All  
1.  Ha ve bee n dia g n ose d wit h a n d/ or treat e d f or a n y t y p e of ca n cer (e x cl u di n g s uccessf ull y 
treate d l ocall y e x cise d basal cell c arci n o ma a n d m ela n o ma i n sit u) wit hi n t he past year 
pri or t o Scree ni n g.  
2.  Pla ns t o u n der g o electi ve s ur ger y d uri n g partici pati o n i n t he st u d y.  
3.  Ha ve c urre nt or rece nt s uici dalit y, defi n e d as f oll o ws:  
•  S uici dal i deati o n wit hi n t he past m o nt h, as e vi de nce d b y a “ Yes” o n q uesti o n  4 
(acti ve s uici dal i de ati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n) or q uesti o n 5 
(acti ve s uici dal i de ati o n wit h s pecific pla n a n d i nt e nt) o n t he C-S S R S.  
•  S uici dal be ha vi or wit hi n t he past year, as e vi de nce d b y a " Yes" o n a n y of t h e C -S S R S 
S uici dal Be ha vi or ite ms ( act ual atte m pt, i nterr u pte d atte m pt, a b orte d atte m pt, 
pre parat or y acts  or be ha vi or , or s uici dal be ha vi or) o n t he C -S S R S.  
•  Prese nti n g a seri o us ris k of s uici de i n t he o pi ni o n of t he i n vesti gat or.  
4.  Ta ke a n y ps yc h otr o pic m e di cati 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 ue nc y ha ve bee n sta ble f or at least 3 0 da ys  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 m ai n sta ble f or t he d urati o n of t he st u d y.  
5.  Ha ve a n o n g oi n g me di cal or ps yc hi a tric c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, 
ma y c o m pr o mise t he partici pa nt’s safet y or c o m plia nce wit h st u d y re q uir e m e nts.  
6.  Ha ve s u pi ne vital si g ns o utsi de of t he f oll o wi n g ra n ges at Scree ni n g or Bas eli ne ( vital 
si g n meas ure me nts ma y be re peated o nce f or i niti al val ues o utsi de t hese ra n ges):  
•  Heart rate < 5 0 or > 1 0 0 b p m,  
•  S yst olic bl o o d press ure < 1 0 0 or > 1 6 0 m m H g,  

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•  Diast olic bl o o d press ure < 6 0 or > 1 0 0 m m H g.  
7.  Ha ve a n alc o h ol or dr u g use dis or der wit hi n t he p ast 2 years, as assesse d b y t he 
i n vesti gat or. A p ositi ve uri ne dr u g scree n is e x cl usi o nar y u nl ess dee me d b y t he 
i n vesti gat or t o r eflect a prescri be d m e dicati o n. 
8.  Ha ve a hist or y of si g nifica nt ha n d i nj ur y t h at w o ul d precl u de eit her writi n g or ra pi d 
bi ma n ual c o m p uteriz e d res p o n di n g.  
9.  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 gle e pis o d e of fe brile 
seiz ures i n c hil d h o o d. 
1 0.  Ha ve a hist or y, prese n ce, 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 or he p atitis B or C.  
1 1.  Ha ve a hist or y of brai n s ur ger y, a si g nifica nt hea d i nj ur y ca usi n g l oss of c o nsci o us ness 
greater t ha n 3 0 mi n utes, or h os pitalizati o n d ue t o a brai n i nj ur y.  
1 2.  Ha ve a hist or y, prese n ce, a n d/ or c urre nt e vi de n ce of i ntracra nial a b n or m alit y (e g, str o ke, 
he m orr ha ge, s pace -oc c u p yi n g lesi o n).  
1 3.   Ha ve a p ositi ve pre g na n c y t est, is lactati n g, or i nte n d t o breastf ee d d uri n g t he st u d y. 
1 4.  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 us e, pare nt, c hil d, or si bli n g w het her bi ol o gical or legall y a d o pt e d).  
1 5.   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 pre vi o us e x p os ure t o 
ge n e t hera p y; or ha v e partici pate d i n a n y H u nti n gt o n’s Disease ( H D) i n vesti gati o nal 
dr u g, bi ol o gic, or d e vice trial wit hi n 1 8 0 da ys, or a n o n -H D dr u g, bi ol o gic, or de vice tri al 
wit hi n 3 0 da ys or 5 h alf -li ves ( w hic he v er is l o n ger). 
( N ote: Partici pa nts wit h c o nfir mati o n of e nr oll me nt i n t he place b o ar m of t hese trials 
w o ul d n ot be e x cl u de d. ) 
1 6.  Recei ve a n y pr o hi bite d me dicati o ns wit hi n 3 0 da ys of Scree ni n g a n d d uri n g partici pati o n 
i n t he st u d y: 
a. Ot her me dicati o ns gi ve n at d oses or i n c o m bi nati o ns t hat are li kel y t o ha ve a 
deleteri o us effect o n c o g niti ve perf or ma n ce, as d eter mi ne d b y t h e i n vesti gat or.  
b.  T etra 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 h er or n ot t he y are prescri b e d. 
1 7.  Is k n o w n t o b e 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.  
A d diti o nal criteria for partici pa nts wit h H D o nl y  
1 8.  Ha d gastric b y p ass s ur ger y, h as a gastri c slee ve or la p ba n d, or has h a d a n y relate d 
pr oce d ures t hat i nterfere wit h gastr oi ntesti nal tra nsit.  
1 9.  Recei ve a n y pr o hi bite d me dicati o ns wit hi n 3 0 da ys of Scree ni n g a n d d uri n g partici pati o n 
i n t he st u d y: 
a. Me dicati o ns wit h p ote nt effects at t he N M D A rece pt or, i ncl u di n g me m a nti ne, 
a ma nta di ne, keta mi ne, c ycl oseri 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).  

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c. 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).  
2 0.  Ha ve a di a g n osis of a n o n g oi n g ne ur o de ge n erati v e c o n diti o n ot her t ha n H D, i ncl u di n g 
b ut n ot li mite d t o Alz hei mer’s Diseas e, vasc ul ar de me ntia, de me ntia wit h Le w y b o dies, 
or Par ki ns o n’s Diseas e.  
A d diti o nal criteria f or H P o nl y  
2 1.  Ha ve a di a g n osis of a n o n g oi n g ne ur o de ge n erati v e c o n diti o n, i ncl u di n g b ut n ot li mite d t o 
H D, Alz hei mer’s Diseas e, vasc ular de me ntia, de me ntia wit h Le w y b o dies, or Par ki ns o n’s 
Disease.  
8. 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/e ntere d i n t he st u d y . A mi ni mal set of scree n 
fail ure i nf or m ati o n will be c ollecte d, i ncl u di n g de m o gra p h y, scree n fail ure details, eli gi bilit y 
criteria, a n d a n y A E or S A E.  
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. Rescree n e d partici pa nts will be 
assi g ne d a ne w p artici pa nt n u m ber . 
8. 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 safet y, 
be ha vi oral, c o m plia n ce, or a d mi nistrati ve reas o ns.  
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 E T  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 st u d y rec or d a n d rec or de d i n t he partici pa nt’s electr o nic case re p ort f or m 
(e C R F).  
T he in vesti gat or m ust n otif y t he sp o ns or a n d/ or t he m e dical m o nit or w he n a parti ci pa nt st o ps 
partici pati o n i n t he st u d y f or a n y reas o n.  
8. 4. 1.  
I n vesti g ati o n al Pr o d uct Disc o nti n u ati o n 
Partici pa nts w h o disc o nti n ue I P will be i n vite d b y t he i n vesti gat or t o c o m plete all of t he 
sc he d ule d st u d y visits a n d assess me nts t hr o u g h t h e e n d of t he Treat me nt P eri o d. T h ose w h o 
decli ne t o c o nti n ue partici pati o n will be as ke d t o c o m plete a n E T  Visit.  
8. 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 E T  visit s h o ul d be 
c o n d ucte d. T he p artici 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.  

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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.  
P ossi ble reas o ns f or st u d y disc o nti n uati o n i ncl u de b ut are n ot li mite d t o t he f oll o wi n g:  
•  A E  
•  Pre g n a nc y  
•  Pr ot oc ol de viati o n  
•  N o n -c o m plia nce wit h st u d y dr u g  
•  L os t t o f oll o w-u p  
•  Wit h dra wal b y s u bject  
•  Scree n fail ure  
•  St u d y t er mi nate d b y s p o ns or  
•  P h ysicia n decisi o n  
•  Ot her  
8. 4. 3.  
L os s 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 at c o ntacti n g t he partici pa nt ha v e 
bee n ma de a n d it has bee n at least 1 m o nt h si nce t he last partici pa nt c o ntact. All atte m pts of  
c o ntact a n d t he 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.  
8. 4. 4.  
Re pl ace me nt of P artici p a nts  
Partici 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, 
ad diti o nal partici pa nts wit h H D ma y b e ra n d o mize d if t he dr o p o ut rate is hi g her t ha n 2 0 %.  

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9.  
T R E A T M E N T O F P A R TI CI P A N T S  
9. 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 oral  soft gel  li pi d ca ps ules are o pa 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 nce.  
9. 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  
9. 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  
All me dicati o ns a n d s u p ple me nts ta ke n wit hi n 8 wee ks pri or t o Scree ni n g, all me dicati o ns use d 
t o treat H 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 ne ur o ps yc hiatric, f u ncti o nal, a n d c o g niti ve 
ma nifestati o ns of H D will  be rec or de d . I nf or mati o n re gar di n g dia g n osis a n d/ or h os pitalizati o n 
d ue t o c or o na vir us diseas e 2 0 1 9 ( 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 n c o mita nt me dicati o n / pr oce d ure c ollecti o n at S cree 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 ha 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 s o urce d o c u me nt. A n y c o n c o mita nt me dicati o n deter mi ne d necessar y f or t he welf are of t he 
partici pa nt wit h H D ma y be gi v e n at t he discreti o n of t he in vesti 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 orta 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. In 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 bilit y a n d t hr o u g h o ut t he st u d y.  
9. 2. 2.  
Pr o hi bite d Me dic ati o ns  
Pr o hi bite d me dicati o ns pri or t o a n d d uri n g t he st u d y i ncl u de:  
•  G e ne t hera p y 
•  H D i n vesti gati o nal dr u g, bi ol o gic, or de vi ce wit hi n 1 8 0 da ys pri or t o Scree ni n g a n d 
u ntil t he fi nal visit  
•  N o n -H D  i n vesti gati o nal dr u g, bi ol o gic, or d e vice wit hi n 3 0 da ys or 5 half -li ves 
( 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 visit 
Use of t he f oll o wi n g me dicat i o ns 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:  
•  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).  

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•  Me dicati o ns wit h p ote nt effects  at t he N M D A rece pt or, i ncl u di n g me m a nti ne, 
a ma nta di ne, c ycl os eri ne, keta mi ne, or relate d c o m p o u n ds.  
•  T H C -c o ntai ni n g s u bsta n ces (a n y r o ute of a d mi nistrati o n), re gar dless of w h et her or 
n ot t he y are prescri b e d   
A n y me di cati o n deter mi n e d necessar y f or t he welf are of t h e partici pa nt ma y be gi v e 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 h e st u d y; h o w e ver, t he us e of a n y pr o hi bite d 
me dicati o ns will be ca pt ure d as a pr ot oc ol de viati o n.  
9. 2. 3.  
Ot her Rest ricti o ns  a n d Rec o m me n d ati 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 ( u nl ess 
dee me d b y t he i n vesti gat or t o reflect a prescri be d me dicati o n) 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.  
Ps yc h otr o pic me di cati o ns  a n d me dicati o ns t hat are k n o w n t o affect c o g niti ve perf or ma nce 
(ie, a nti de pressa nts , a n xi ol ytics, sti m ula nts, be nz o diaze pi nes, a nti ps yc h otics, a ntic h oli ner gics) 
m ust be at a sta ble d ose f or at least 3 0 da ys pri or t o t he first I P a d mi nistrati o n. A d diti o ns a n d/ or 
m o di ficati o ns t o t hese me dicati o ns s h o ul d be mi ni mize d t hr o u g h o ut t he c o urse of t he st u d y. 
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 delet eri o us effect o n c o g niti ve perf or m a nce  are t o be a v oi de d as 
m uc h as p ossi ble .  
A n y a d diti o ns or m o dificati o ns  t o me dicati o ns d uri n g t he c o urse of t he st u d y will be rec or de d i n 
t he c o nc o mita nt me dicati o ns l o g a n d s o urce d o c u me ntati o n.  
9. 2. 4.  
Acce pt a ble F o r ms of C o ntr ace pti o n  
As per t he Cli nical Tr ials Facilitati o n a n d C o or di n ati o n Gr o u p ( C T F G), a fe male is c o nsi dere d of 
c hil d beari n g p ote ntial ( F O C B P) ie, fertile, f oll o wi n g me narc h e a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile. Per ma ne nt steriliz ati o n met h o ds i ncl u de 
h ysterect o m y, bi lateral sal pi n gect o m y a n d bilateral o o p h orect o m y.  
A p ost me n o pa usal state is defi ne d as n o me ns es 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). A hi g h f ollicle 
sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y be use d t o c o nfir m a 
p ost me n o pa usal state i n fe males n ot usi n g h or m o n al c o ntrace pti o n or h or m o nal re place me nt 
t hera p y. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure m e nt is 
i ns ufficie nt.  
A m ale is c o nsi dere d fertile after p u bert y u nless p er ma ne ntl y sterile b y bilateral orc hi d ect o m y.  
Acce pt a ble f or ms of hi g hl y effecti ve c o ntrace pti o n  (ie, ca n ac hie ve a fail ure rate of < 1 % per year 
w he n use d c o nsiste ntl y a n d c orrectl y)  f or p artici p a nts of c hil dbeari n g p ote ntial or f or  a male 
partici pa nt’s  part ner of c hil d beari n g p ot e ntial i ncl u de:  
•  Se x ual a bsti ne nce ; 
•  C o 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 of o v ulati o n ; 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 7  
•  Oral, 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 ; 
•  I ntr a uteri ne d e vice; 
•  I ntr a uteri ne h or m o ne-rel easi n g s yst e m; 
•  Bilateral t u bal li gati 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 S cree ni n g); 
•  Vasect o miz e d part ner ( p erf or me d at least 3 m o nt hs pri or t o S cree 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 d beari 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:  
•  Se x ual a bsti ne nce ; 
•  Hist or y of vasect o m y ( perf or me d at least 3 m o nt hs pri or t o S cree 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) . 
9. 3.  
I nter ve nti o n After t he E n d of t he St u d y 
If eli gi ble, partici pa nts wit h H D w h o c o m plete t his st u d y ma y c o nti n ue or be gi n tr eat me nt wit h 
S A G E -7 1 8 b y p artici pati n g i n  t he l o n g-ter m o pe n -la bel st u d y 7 1 8 -CI H -3 0 1 . 
9. 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 2 8 , partici pa nts wit h H D 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 wit h H D will ta ke t he I P 
u n der staff s u p er visi o n, 
 
 St u d y 
staff will dis pe nse s uffici e 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. I P 
ad here n ce diar y will be c ollecte d dail y via t he 
 a p plicati o n. 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 e C R F, 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. A d here nce will be assesse d d uri n g t h e visit a n d d oc u me nte d. A n y reas o ns f or n o n -
a d here n ce will als o be d o c u me nte d. Det ails a b o ut I P acc o u nta bilit y are i ncl u de d i n Secti o n  1 0. 6 . 
9. 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 , parallel gr o u p st u d y. Eli gi ble 
partici pa nts wit h H D will be ra n d o mize d 1: 1 i n a stratifie d ma n ner b y pre vi o us i nta ke of 
a ntise nse oli g o n u cle oti de dr u gs ( yes/ n o) t o recei ve S A G E-7 1 8, or  matc hi n g  place b o f or 2 8  da ys . 
Stratifie d r a n d o mizati o n will e ns ure t he treat me nt bala nce wit hi n eac h strat u m of pri or a ntise nse 
oli g o n ucle oti de dr u g  i nta ke ( yes or n o) wit h t he c o nsi derati o n t hat partici pa nt s wit h or wit h o ut 
pri or e x p os ure t o a ntise nse oli g o n ucle oti de dr u g ma y res p o n d t o treat me nt differe ntl y . 
Ra n d o mizati o n will ta ke place o n D a y 1.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 8  
Partici pa nts wit h H D , 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 nteracti ve res p o nse tec h n ol o g y (I R T) s yst e m. 
Ra n d o mizati o n sc he d ules will be ge n erat e d b y a n i n de pe n de nt statisticia n. T he all ocati o n t o 
treat me nt gr o u p will be b ase d o n t he ra n d o mizati o n sc he d ule. T he ra n d o mi zati 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 orize d pers o n nel u ntil t he ti 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 data bas e h as bee n l o c ke d.  
Si milarl y f or H P o n Da y 1, site staff will access t he I R T a n d pr o vi de t h e necessar y p artici pa nt 
i de ntif yi n g i nf or mati o n, i ncl u di n g partici pa nt i de ntificati o n (I D) n u m ber assi g ne d at S cree ni n g t o 
re gister t he eli gi ble H P i n t he I R T s yste m as e nr olle d stat us, a n d set as i nacti ve f or treat me nt 
assi g n me nt.  
9. 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 wit h H D is at ris k a n d t he treat me nt pla n is de pen d e nt o n t he st u d y 
treat me nt recei ve d. U nl ess a partici pa nt wit h H D 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 wit h H D . T he res p o nsi bilit y t o brea k t h e treat me nt c o de i n e mer ge n c 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 m at ure u n bli n di n g m ust be clearl y d oc u m e nte d i n t he s o urce rec or ds.  
I n all cases w here t he st u d y pers o n nel are u n bli n de d, perti ne nt i nf or mati o n (i ncl u di n g t he reas o n 
f or u n bli n di n g) m ust be d oc u me nte d i n t he partici p a nt’s s o urce d o c u me ntati o n a n d o n t he e C R F. 
At t he ti me of w it h dra wal fr o m t he st u d y/st o p pi n g partici pati o n, if p ossi ble, a n E T visit s h o ul d 
be c o n d ucte d.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
4 9  
1 0.  
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  
1 0. 1.  
I n vesti g ati o n al Pr o d uct 
S A G E -7 1 8 oral  soft gel  li pi d ca ps ules are o pa 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 n ce. T he ca ps ules are c o m p ose d of S A G E -7 1 8 
d r u g su bsta n ce , 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 urifi e 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 5 : 
I n vesti g ati o n al Pr o d uct 
P r 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  
Pl ace 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  
Place b o   
0. 3, 0. 6, 
0. 9 a n d 
1. 2 m g  
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  
 
 
a U S o nl y  
 
1 0. 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 soft gel  li pi d ca ps ules are p ac k a ge d i n blisters usi n g A C L A R ®  ri gi d barrier fil m a n d 
heat seala bl e 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 u al f or 
f urt her det ails).  
T he c o m p ositi o n a n d p har mace utical q ualit y of t h e s oft gel li pi d ca ps ule 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. T he 
site p har macist or desi g n ee will pre pare la bels f or i n di vi d ual d oses. 
1 0. 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 in vesti gat or, or t he 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.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 0  
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 in vesti gat or’s b r oc h ure a n d 
P har mac y Ma n u al. T he I P ma y n ot be use d f or a n y p ur p os e ot her t ha n t he prese nt st u d y. After 
t he st u d y is c o m plete d, all u n use d I P m ust be ret ur ne d per t he sp o ns or’s i nstr ucti o ns or destr o ye d 
l ocall y p er t he site’s pr o ce d ure(s) i n acc or da n ce wit h t he st u d y-s pecific P har mac y Ma n u al.  
T he in vesti gat or or desi 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.  
1 0. 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 will be pr o vi de d as s oft gel li pi d ca ps ules f or self-a d mi nistrati o n 
o nce dail y i n t he m or ni n g  f or u p t o 2 8 d a ys. 
1 0. 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 wit h H D will  s wall o w t he ca ps ules w h ole 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 os es ta ke n i n t he cli nic, site staff will watc h t he p arti ci pa nts wit h H D 
self--a d mi nister t he I P.  
S A G E -7 1 8  or place b o will be self -a d mi nistere d b y partici pa nts wit h H D o n ce dail y i n t he 
m or ni n g . Sites will dis pe nse a 2 -w ee k s u p pl y of I P t o t he partici pa nts wit h H D t o ta ke at h o me 
wit h i nstr ucti o ns f or use (see Ta bl e  1 ).  
I n a d diti o n, t he partici pa nt wit h H D will be i nstr ucte d t o bri n g t h eir d osi n g kit t o t he site as 
o utli ne d i n  Ta ble  1 . All partici pa nts wit h H D s h o ul d be rei nstr ucte d a b o ut t he d osi n g 
re q uire me nts d uri n g st u d y c o nt acts. T he a ut h orize d st u d y pers o n nel c o n d ucti n g t he re -e d u cati o n 
m ust d oc u me nt t he pr ocess i n t he partici pa nt s wit h H D s o urce rec or ds.  
T he i n vesti gat or(s) will r ec or d a n y reas o ns f or n o nc o m plia nce i n t he s o urce d oc u me nts .  
1 0. 5. 1.  
Me dic ati o n A d here nce a n d Re mi n der S yste m  
1 0. 5. 1. 1.  O n g oi n g U se a n d M o nit ori n g of M e dic ati o n A d here nce  
I n cases of misse d d oses, site pers o n nel s h o ul d f oll o w u p wit h t he partici pa nt wit h H D as s o o n as 
p ossi ble t o assess t he reas o n f or n o na d here nce a n d rei nf orce t he i m p orta n ce of c o m pl yi n g wit h 
t he I P d osi n g sc h e d ule.  
Partici pa nts wit h H D w h o are c o nsiste nt l y n o nc o m plia nt wit h st u d y me dicati o n s h o ul d be 
disc usse d wit h t he m e dic al m o nit or.  
1 0. 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  
U p o n recei pt of I P, t he in 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 co 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 in vesti gat or’s 
b r oc h ure a n d ( w h ere a p plica ble) i n t he p har mac y m a n ual. 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.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
5 1  
T he desi g nate d site staff will dis pe nse t h e 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  1 .  
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 D n u m ber f or eac h 
partici pa nt wit h H D a n d H P t hat has si g ne d a n I C F. F or partici pa nts wit h H D, 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 partici 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 n e d at Scree ni n g, t o ra n d o mize t he eli gi ble partici pa nts wit h H D  
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 be dis pe ns e d t o t hat partici pa nt 
wit h H D . T he me dicati o n I D n u m ber a n d t h e n u m ber of ca ps ules dis pe nse d m ust be rec or de d.   
Refer t o Secti o n  9. 5  f or t he I R T assi g n me nt a n d re gistrati o n pr ocess f or H P. 
At t he s u bse q ue nt I P -dis pe nsi n g visit, t he in 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 ned 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 p artici pa nt wit h H D at t his visit m ust be 
rec or de d.  
If dis pe nsi n g err ors or discre pa n cies are disc o vere d b y site staff or sp o ns or’s desi g nee, t he 
sp 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 or aft er c o m pleti o n of t he st u d y t o perf or m dr u g acc o u nta bilit y rec o nciliati o n.  
T he in vesti gat or, p har m acist, 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). 
At t h e e n d of t he st u d y, a n y u n use d I P will be ret ur ne d t o Sa ge T hera pe utics f or destr ucti o n or 
destr o ye d l ocall y per t he site’s pr oce d ures; dis p ositi o n of I P will be d oc 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 in vesti gat or’s b r oc h ure a n d i n t he 
p har mac y ma n u al . 
1 0. 7.  
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 a p pro v e 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 e mer ge n c y c o ntact i nf or mati o n . W here 
p ossi ble, pers o n nel s h o ul d se gre gat e a n d retai n a n y pr o d uct, materials, or pac ka gi n g ass o ciate d 
wit h t he pr o d uct 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 nate d 
re pres e ntati ve(s). 

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1 1.  
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 
 
 
 All assess me nts will  be c o m plete d acc or di n g t o t he Sc he d ules of Assess me nts ( Ta ble  1  
a n d Ta ble  2 ) 
.  
T he eli gi ble p artici pa nts wit h H D i n t his st u d y will be i n t he earliest sta ges of H D a n d are 
e x pecte d t o be a ble t o i n de pe n de ntl y care f or t he msel ves. H o we ver, s o me of t hese assess me nts 
i ncl u de i nf or mati o n pr o vi de d b y care gi vers. F or t he p ur p oses of t his st u d y, t he w or d “care gi ver” 
refers t o t he partici pa nt’s st u d y part n er. 
1 1. 1.  
Scree ni n g Assess me nts  
1 1. 1. 1.  
M o ntre al C o g niti ve Ass ess me nt  
T he M o C A is a meas ur e desi g ne d as a c o g niti ve scree ni n g i nstr u me nt t hat is wi del y use d i n 
cli nical setti n gs. T hi s 1 p a ge, 3 0-p oi nt q uesti o n naire assess es se veral differe nt c o g niti ve 
d o mai ns, i ncl u di n g atte nti o n a n d c o nce ntr ati o n, e x ec uti ve f u ncti o ns, me m or y, la n g u a ge, 
vis u os patial s kills, c o nce pt ual t hi n ki n g, calc ulati o ns, a n d orie ntati o n.  
T he M o ntreal C o g niti ve Ass ess me nt Me m or y T ot al Sc ore i ncl u des all c o g niti ve d o mai ns 
meas ure d a n d re prese nte d gl o bal c o g niti ve f u n cti o n. 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 asre d di ne 2 0 0 5 ). 
A s u bset of M o C A will be a u di o rec or de d a n d re vi e we d wit h t he g oal of mi ni mizi n g t he 
varia bilit y i n assess me nt data. Pers o nal partici pa nt  i de ntifiers s h o ul d n ot be i ncl u de d i n t he 
rec or di n gs.  
T he rec or de d st u d y i nter vie ws will be e ncr y pt e d  a n d st ore d o n t he st u d y d e vices wit h 
pass w or d -pr ot ecte d access f or a ut h orize d users o nl y. Rec or di n gs will be re m o ve d fr o m t he st u d y 
de vices o nce t he y ar e tra nsferre d via sec ure p ort al t o t he st u d y ser ver, w h ere t he y will re mai n 
u ntil st u d y c o m pleti o n w he n Sa ge T hera pe utics pr o vi des destr ucti o n a ut h orizati o n or ot her 
i nstr ucti o ns. 
 
 
Refer  t o Ta bl e  1  a n d Ta ble  2  f or a listi n g of scree ni n g assess me nts.  
1 1. 1. 2.  
Ci g arette a n d/ or T o b acc o Use Assess me nt  
D ata o n ci garette use will be c ollecte d usi n g t he q uesti o n: “ H o w ma n y pac ks of ci garettes di d 
y o u s m o ke o v er t he past 7 da ys? ”.  
N ote: I n a d diti o n t o Scree ni n g, t his assess me nt is als o perf or m e d at a d diti o nal ti me p oi nts , as 
o utli ne d i n Ta ble  1  a n d T a ble  2 . 

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1 1. 2.  
Effic ac y Assess me nts  
T he assess me nts des cri be d  bel o w pr o vi de br o a d ne ur oc o g niti ve e val uati o n acr oss t he d o mai ns of 
e x ec uti ve f u ncti o n, lear ni n g a n d m e m or y, m ot or c o or di nati o n, a n d s ocial c o g niti o n.  
D uri n g t h e Baseli ne Peri o d, partici pa nts will be trai ne d b y st u d y staff o n t h e use of all s oft ware 
a p pli cati o ns a n d de vic es necessar y f or t he c o n d uct of t he st u d y.  
T hese assess me nts will  b e a d mi nistere d pre d ose o n Da y 1 o nl y a n d after t h e dail y d os e of 
S A G E -7 1 8 d uri n g t he Treat me nt Peri o d  o n Da y 1 4  ( ±2 da ys)  a n d Da y 2 8 ( ± 2 da ys) f or 
partici pa nts wit h H D  (T a ble  1 ), a n d at a p pr o xi matel y t he s a 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 wit h H D a n d H P . 
1 1. 2. 1.  
H u nti n gt o n’s D ise ase-C o g niti ve A ssess me nt B atter y  In di vi d u al A ssess me nts 
T he H D -C A B is a c o g niti ve assess me nt batter y d esi g ne d f or cli nical trials i n H D  (St o ut 2 0 1 4 ). 
T he batter y c o nsists of t he 6 f oll o wi n g s u btests : S y m b ol Di git M o dalities Test, O ne T o uc h 
St oc ki n gs of Ca m bri d ge, Trail Ma ki n g, H o p ki ns V er bal Lear ni n g Test _ Re vise d , Pace d T a p pi n g 
Test, a n d E m oti o n Rec o g niti o n Test . 
1 1. 2. 1. 1.  S y m b ol Di git M o d alities Test   
T he S y m b ol  Di git M o dalities  Test 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 dete cti 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 g ures. T h e n u m ber of c orrect pairi n gs 
( o ut of 1 1 0 p ossi ble) ac hi e 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.  
1 1. 2. 1. 2.  O ne T o uc h St oc ki n gs of C a m bri d ge   
O ne T o uc h St oc ki n gs of Ca m bri d ge  is a c o m p uterize d test of e x ec uti ve f u ncti o n. F or t his tas k, 
partici pa nts m ust i ma gi n e stac ki n g a set of c ol ore d balls t o matc h a n e x a m ple b y m o vi n g 1 ball 
at a ti me i nt o 1 of 2 p ossi ble l ocati o ns. T he g oal is t o i ma gi ne t he fe west n u m ber of m o ves 
nee de d t o perf or m t he tas k. T he partici pa nt sel ects t hat n u m ber fr o m t he res p o nse o pti o ns o n t he 
scree n. T h e pri mar y m eas ure f or a nal ysis is ti me t o c orrect res p o nse. 
1 1. 2. 1. 3.  Tr ail M a ki n g  
T he Trail Ma ki n g test is a s pee de d gra p h o m ot or t est of vis ual atte nti o n a n d tas k s witc hi n g, 
a d mi nistere d i n t w o parts. Part A re q uir es t he e x a mi nee t o c o n nect a series of n u m bers i n or de r 
fr o m l o west t o hi g hest as q uic kl y as p ossi ble. Part B i ncl u des a n a d diti o nal set-s witc hi n g 
c o m p o ne nt, re q uiri n g t he e x a mi nee t o c o n nect a s eries of alter nati n g n u m b ers a n d letters i n or der 
fr o m l o west t o hi g hest, as i n 1-A -2 -B -3 -C..., i n t he s h ortest ti m e p ossi ble. T he pri mar y meas ure 
f or a nal ysis is ti me t o c o m pleti o n. 
1 1. 2. 1. 4.  H o p ki ns Ver b al Le ar ni n g Test _ Re vise d   
T he H o p ki ns Ver bal Lear ni n g T est _ Re vise d is use d t o assess ver bal lear ni n g a n d m e m or y. T he 
test c o nsists of t hree lear ni n g trials o ver w hic h a 1 2-ite m se ma nticall y cate g orize d list is rea d 
al o u d b y a n e x a mi ner. T he e x a mi nee is as ke d t o r ecall as ma n y ite ms as p ossi ble fr o m me m or y 
i m me diatel y f oll o wi n g eac h trial (i m me diate recall) a n d a gai n f oll o wi n g a dela y ( dela ye d recall). 

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T he pri mar y me as ure f or a na l ysis is t he t otal w or ds c orrectl y recalle d o ver 4 trials ( 3 i m me diate 
a n d 1 dela ye d) wit h a ma xi m u m of 4 8 c orrect.  
1 1. 2. 1. 5.  P ace d T a p pi n g Test  
I n p ace d t a p pi n g, e x a mi nees are pres e nte d wit h a u dit or y paci n g t o n es a n d i nstr ucte d t o 
har m o nize t heir fi n gerta ps wit h t he paci n g t o n es. A self -pace d p has e f oll o ws, i n w hic h t he 
a u dit or y p aci n g c u e is re m o ve d, a n d e n ds wit h a n ot her a u dit or y c u e de mar ki n g t he e n d of t he 
test. T he pri mar y me as ur e of a nal ysis is pace d ta p pi n g c o nsiste nc y, calc ul ate d as 1/sta n dar d 
de viati o n ( S D ) of t he i nterta p i nter val ( 1/ msec) . 
1 1. 2. 1. 6.  E m oti o n Rec o g niti o n  T as k  
T he E m oti o n Rec o g niti o n Tas k has partici p a nts i de ntif y t he e m oti o ns e x presse d o n a series of 
c o m p uter-ge n erat e d h u ma n faces (ie, s a d ness, ha p pi ness, fear, a n ger, dis g ust, a n d s ur prise). T h e 
res po nses ca n be a n al yze d b y t otal err ors, res p o ns e late nc y, a n d t he n u m ber of err ors f or eac h 
e m oti o n . T he pri mar y me as ure f or a nal ysis is t he n u m ber  of c orrect ne gati v e e m oti o n trials ( o ut 
of 2 4 ).  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  

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1 1. 2. 5.  
D ail y M o bile Assess me nt s 
 
 
 
 
 
 
 
 
  

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1 1. 2. 5. 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 ( Nati o nal Slee p F o u n dati o n ). T his diar y 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 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 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 m e).  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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1 1. 3.  
Cli nic al P h ar m ac ol o g y Assess me nts  
 
 
 
 
 
 
 
 
 
 

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1 1. 3. 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. T he sa m ples a n d t he res ults of t he a nal yses ma y b e use d t o 
hel p desi g n f ut ure cli nic al st u dies, de vel o p c o m p o u n ds, or de vel o p assa ys a n d dia g n ostic or ot h er 
tests. T he s p o ns or will st ore t he dei de ntifie d sa m ples i n a sec ure st ora ge s p ace wit h a de q uate 
meas ures t o pr otect p arti ci pa nt c o nfi de ntialit y. O nl y t he 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 s a m ples a n d ass ociat e d data.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 2.  
S A F E T Y A S S E S S M E N T S  
1 2. 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  1  a n d 
Ta ble  2 ) 
. 
1 2. 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. C o nfir me d 
( ge neticall y teste d) or s us pecte d fa mil y hist or y of H D will als o be d oc u me nte d.  
1 2. 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 2. 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. F ull p h ysic al 
e x a mi nati o ns will be perf or me d at Scree ni n g a n d Da y 4 2  ( ± 2 da ys)/E arl y Ter mi nati o n  (E T ), a n d 
i ncl u de assess me nt of b o d y s yste ms (e g, h ea d, e ye, ear, n ose a n d t hr oat; heart; l u n gs; a b d o me n; 
a n d e xtre mities) as well as c o g niti ve a n d n e ur ol o gi cal e xa mi nati o n , a n d me ntal stat us 
e x a mi nati o n.  At ot her visits  (e g, D a y 2 8 f or p artici pa nts wit h H D), p h ysical e x a mi nati o ns will 
i ncl u de a brief assess me nt of ge n eral a p peara n ce, 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 a n d f oll o we d b y a tar get e d p h ysic al assess me nt as nee de d.  
U nsc he d ule d p h ysic al e x a mi nati o ns ma y als o b e c o n d ucte d per t he in v esti gat or’s discreti o n.  
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 ot 
cli nicall y si g nifica nt ( N C S ); or a b n or mal, cli nicall y si g nif ica nt (C S ) i n s o urce d oc u me nts. 
1 2. 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 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 b e d oc u me nte d as part of me dical hist or y  re gar dless of ti mi n g. I n 
a d diti o n, i nf or mati o n f o c 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 mita 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 2. 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 ol ic bl o o d press ure will  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 ure a n d heart rate will als o be 
meas ure d after t h e partici pa nt has bee n i n t he s u pi ne p ositi o n f or at least 5 m i n utes a n d t he n 
re peat e 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 in 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 me nts.  

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1 2. 1. 6.  
Electr oc a r di o gr a m  
A 1 2 -lea d E C G will be p erf or me d at t he time p oi nts descri be d i n  Ta ble  1  a n d Ta ble  2 . T he 
sta n dar d i nter vals ( h eart rate, P R, Q R S, Q T, a n d Q T c orrecte d acc or d i n g t o Fri deri cia’s f or m ula 
(Q Tc F) as w ell 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 m will b e 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 vital si g ns assess me nt or bl o o d 
dra ws,  bl o o d dra ws s h o ul d be carrie d o ut aft er E C G a n d vital si g ns. 
All 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 2. 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 es s 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  6 . 
T a ble  6 : 
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, c h olester ol ( L D L, H D L), creati ne p h os p h o ki nase, T S H a n d 
refle x t o free T 3/ T 4 if T S H is a b n or mal 
He m at ol o g y  
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 (M C V, M C H, a n d M C H C)   
Uri n al ysis  
P r 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  
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, HI V -1 a n d -2 a nti b o d y  
Ge netic test 
(scree ni n g o nl y) 
C A G test a 
A b bre viati o ns: C A G = c yt osi ne, a d e ni ne, a n d g ua ni ne , H D L = hi g h de nsit y li p o pr otei n, HI V = h u ma n 
i m m u n o deficie nc y vir us, L D L = l o w de nsit y li p o pr otei n, M C H = mea n c or p usc ular he m o gl o bi n , M C H C = mea n 
c or p usc ular he m o gl o bi n c o nce ntrati o n , M C V = mea n c or p us c ular v ol u me , R B C = Re d bl o o d cell, 
T 3  =  trii o d ot h yr o ni ne, T 4 = th yr o xi ne , T S H = t h yr oi d-sti m ul ati n g h or m o ne. 
a Ge neticall y c o nfir me d disease wit h C A G e x pa nsi o n ≥3 6 c ollecte d as part of me dical hist or y is acce pta ble i n lie u 
of ce ntral la b orat or y c o nfir mati o n. F or a n y ge netic c o u nseli n g, t he st u d y sites s h o ul d  f oll o w t heir l ocal practice. 
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 
in vesti 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.  
Ser u m F S H test will be c o n d ucte d at Scree ni n g f or t he fe mal e parti ci 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.  

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C O N FI D E N TI A L  
6 4  
1 2. 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 sel ecte d dr u gs of a b use (a m p heta mi nes, bar bit urates, 
be nz o diaze pi nes, c ocai ne, T H C, 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.  
1 2. 1. 7. 2.  Pre g n a nc y Testi n g  
A s er u m pre g n a nc y tests 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 ests will be c o n d ucte d at ot her sc he d ule d ti me p oi nts f or fe mal e partici pa nts t hat are 
n ot p ost me n o pa usal or s ur gic all y st erile . 
1 2. 1. 8.  
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
S uici dalit y will be m o nit ore d d uri n g t he st u d y usi n g t he C -S S R S ( P os ner 2 0 1 1 ). T his scale 
c o nsists of a baseli ne e v al uati o n t hat assesses t he lifeti me e x perie nce of t he partici pa nt wit h 
s uici dal i deati o n a n d be h a vi or, a n d a p ost bas eli ne e val uati o n t hat f oc us es o n s uici dalit y si nce t he 
last st u d y visit. T he C-S S R S i ncl u des ‘ yes’ or ‘ n o’ res p o nses f or assess me nt of s uici dal i deati o n 
a n d be ha vi or as well as n u meric rati n gs f or s e verit y of i deati o n, if pres e nt (fr o m 1 t o 5, wit h 5 
bei n g t he m ost s e v ere).  
T he “ Baseli ne/ Scree ni n g” C -S S R S f or m will be c o m plete d at S cree ni n g (lifeti me, past 1  year  
a n d past m o nt h ) (Ta ble  1  a n d Ta ble  2 ). T h e “ Si nce Last Visit” C-S S R S f or m will be c o m plete d 
at all s u bse q ue nt ti me p oi nts o utli ne d i n  Ta ble  1 .  
1 2. 2.  
A d verse a n d Seri o us A d verse E ve nts  
1 2. 2. 1.  
A d verse E ve nt Defi niti o n  
A n A E is a n y u nt o war d me dical occ urre n ce 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 u ct a n d t hat d o es n ot necessaril y h a ve a ca usal r elati 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 bl e 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 la b orat or y fi n di n g), s y m pt o m or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct w het her or n ot relate d t o t he me dici n al (i n vesti gati o nal) 
pr o d uct. I n cli nical st u dies, a n A E ca n i n cl u de a n u n desira 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 baseli ne or was h o ut peri o ds, e v e 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 in v esti 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 an  S A E s h o ul d be re p orte 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 
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).  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 5  
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 her 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 her a p e utics.  
Partici pa nt s 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 in 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 in vesti 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 nresol 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 in 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 sp o ns or or 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 2. 2. 2.  
Seri o us A d verse E ve nt 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 di sa 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 in vesti gat or 
ma y je o p ar dize 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 h e 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 in v esti 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 
in vesti gat or, b et wee n t h e 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. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 6  
1 2. 2. 3.  
Rel ati o ns hi p t o I n vesti g ati o n al Pr o d uct  
T he in vesti gat or m ust ma ke t he deter mi nati o n of relati o ns hi p t o t he I P f or eac h A E  ( n ot relate 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 relate d ” t o t he use of t he I P if t here is n ot a 
reas o na bl e p ossi bilit y t h at t he e ve nt has bee n ca us e d b y t h e I P. Fact ors 
p oi nti n g t o war ds t his ass ess 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 v e nt, t he 
prese nce of bi ol o gicall y i m pla usi ble relati o ns hi p bet wee n t he pr o d uct a n d t he 
A E, or t he pres e nce of a m ore li kel y alter na ti 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 h ere is a reas o n a ble 
p ossi bilit y t hat t he e v e nt ma y h a ve bee n ca use 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 are n ot 
li mite d t o: a p ositi ve rec halle n ge, a reas o n a ble te m p oral se q ue n ce bet w ee n 
a d mi nistrati o n of t he dr u g a n d t h e 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 u cti o n, a 
bi ol o gicall y pla usi ble  rel ati o ns hi p bet wee n t he dr u g a n d t h e A E, or a lac k of 
alter nati ve e x pla nati o n f or t he A E . 
1 2. 2. 4.  
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 ncrease d 
fre q ue n c y of A Es 
•  halti 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 D A G ui da nce 2 1 C F R Part 3 1 2. 6 6, s o me re porte d e ve nts ma y q ualif y as a n 
u na ntici pate d pr o ble m ( U P), defi ne d as a n y i nci d e 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 n at ure, se v erit y, or fre q ue 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 S M or U P m ust be re p orte d wit hi n 2 4 h o urs via e mail t o sa ge.safet y @I Q VI A.c o m u p o n 
disc o ver y d ue t o t he ur ge nt re p orti n g re q uir e me nts t o re g ul at ors a n d I R B(s)/ E Cs(s).  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 7  
1 2. 2. 5.  
Rec or di n g A d verse E ve nts  
A Es  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 n ol o g y w he n 
p ossi ble. F or eac h A E, t h e in vesti gat or will e val uate 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; pr escri 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 pitaliz e 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 here as seri o us ness is defi ne d b y t h e criteria u n der Secti o n  1 2. 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 2. 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). T he in vesti gat or m ust c o m pl ete,  si g n a n d date t he S A E re p ort f or m, v erif 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 p e utics  a n d 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 b le, 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 de si 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.   
Sa ge T h era pe utics , or desi 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 p ri nci pal in 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.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 8  
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 in vesti gat ors i n a bli n de d fas hi o n.  
 
 
1 2. 3.  
Pre g n a nc y  
If a partici pa nt 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 will 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 in vesti 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 btai 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 in vesti 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 in vesti gat or will c ollect 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 preg 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 in 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 2. 4.  
O ver d ose  
O ver d ose is des cri be d i n Secti o n  1 2. 5 .  
1 2. 5.  
S peci al C o nsi der ati o ns  
Dr u g a b use is t he p ersiste nt or s p ora dic, i nte nti o n al e xcessi ve use of I P w hic h is acc o m pa nie d b y 
har mf ul p h ysical or ps yc h ol o gical effects i n t he partici pa nt. If a n e ve nt of dr u g a b use occ urs 
d uri n g t he st u d y it m ust be re p ort e d t o t he s p o n s or a n d/ or desi g nee usi n g t he S pecial 
C o nsi derati o ns  for m wit hi n 2 4 h o urs of t he site bec o mi n g a ware of t he e ve nt(s). If t he dr u g 
a b use res ults i n a n A E  or S A E , t he A E or S A E m ust als o be rec or de d a n d re p orte d as descri be d 
i n Secti o n  1 2. 2. 5  a n d Secti o n  1 2. 2. 6 , res pecti vel y. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 9  
Dr u g mis use refers t o sit uati o ns w here I P is i nte nti o nall y a n d i na p pr o priatel y use d n ot i n 
acc or da nce wit h t he i nte n de d use as s pecifie d i n t he pr ot oc ol. If a n e ve nt of dr u g mis use occ urs 
d uri n g t he st u d y , it m ust be re p ort e d t o t he s p o ns or a n d/ or desi g nee usi n g t he S pecial 
C o nsi derati o ns f or m wit hi n 2 4 h o urs of t he site bec o mi n g a ware of t he e ve nt(s). If t he dr u g 
mis use res ults i n a n A E  or a S A E , t he A E or S A E m ust als o be rec or de d a n d re p orte d as 
descri be d  i n Secti o n  1 2. 2. 5  a n d Secti o n  1 2. 2. 6 , res pecti vel y. 
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 part ici 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 t he 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 C R F; h o we ver, all o ver d oses m ust be rec or de d o n t he S pecial 
C o nsi derati o ns f or m a n d se nt t o Sa ge a n d/ 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 v er d ose. A n o ver d ose m ust be re p orte d t o Sa ge a n d desi g nee e ve n if t he o ver d ose 
d oes 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  or a S A E , t h e A E or S A E  m ust be 
rec or de d a n d re p orte d as descri be d i n Secti o n  1 2. 2. 5  a n d Secti o n  1 2. 2. 6 , res pecti vel y.   
A me dicati o n err or is a n y pre ve nta ble e ve nt t hat m a y ca use or lea d t o i na p pr o priate me dicati o n 
use or partici pa nt h ar m w hile t he me dicati o n is i n t he c o ntr ol of t he h ealt hcar e pr ofessi o nal, 
partici pa nt, or c o ns u mer. All me dicati o n err ors m ust be rec or de d o n t he S p ecial C o nsi derati o ns 
f or m a n d se nt t o t he s p o ns or a n d/ or desi g nee wit hi n 2 4 h o urs of t he site bec o mi n g a ware of t he 
me dicati o n err or. T he me dicati o n err or m ust be re p orte d t o t he s p o ns or a n d/ or desi g n ee e v e n if 
t he me dicati o n err or d oes n ot res ult i n a n A E. If a me dicati o n err or res ults i n a n A E or S A E , t he 
A E or S A E m ust be rec or de d a n d re p orte d as descri be d i n  Secti o n  1 2. 2. 5  a n d Secti o n  1 2. 2. 6 , 
res pecti vel y. 
 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 0  
1 3.  
S T A TI S TI C S  
Detaile d descri pti o n of t he a nal yses t o be p erf or me d i n t he st u d y will be pr o vi de d i n t he 
statistical a nal ysis pla n ( S A P). 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 o c k. 
A n y c ha n ges/ a d diti o ns t o t he S A P f oll o wi n g data base l oc k will be des cri be d i n detail i n t he 
cli nical st u d y re p ort.  
1 3. 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 I P or H P a n d will be use d t o 
descri be t he s afet y d ata.  
T he F ull A nal ysis Set  will i ncl u de all partici pa nts w h o meet t he eli gi bilit y criteria a n d h a ve at 
least 1  baseli ne ass ess me nt of H D -C A B (partici p a nts wit h H D a n d H P).  
T he F ull A nal ysis Set 1 will i ncl u de all  partici pa nts w h o i niti ate I P a n d ha ve baseli ne a n d at least 
1  p ost baseli ne effi cac y e val uati o n  (partici pa nts wit h H D o nl y) . 
T he F ull A nal ysis Set 2 will i ncl u de all partici pa nts wit h H D w h o i nitiate I P or H P w h o meet 
eli gi bilit y criteria a n d h a ve baseli ne a n d at least 1  p ost bas eli ne effi cac y e val uati o n ( partici pa nts 
wit h H D a n d H P) . 
T he Healt h y Partici p a nt Set will i ncl u de all t he healt h y partici pa nts w h o m eet t he eli gi bilit y 
criteria a n d ha ve m or e t h a n o ne  e v al uati o n ( baseli ne a n d at  least o ne p ost baseli ne). 
1 3. 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 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. I m p ut ati o n pr ocess will be 
a p plie d a n d descri be d i n t he S A P  if nee de d. 
1 3. 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 n al yses , w here a p plica bl e, B aseli ne is defi ne d as t h e last meas ure m e nt 
pri or t o t he first d ose of I P , u nless state d ot her wise. 
Descri pti ve s u m mar y statistics will be pr o vi de d f or de m o gra p hics, b aseli ne 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 partici 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 dis c o nti n uati o ns.  

Cli nical Pr ot oc ol  
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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 1  
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 p artici pa nts, mea n, S D , mi ni m u m 
val ue, first q uartile (Q 1 ), me dia n, t hir d q uartile (Q 3 ), a n d ma xi m u m val ue. Cate g orical data will 
be s u m mariz e d usi n g fre q ue nc y c o u nts a n d p erce nta g es. 
1 3. 4.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hic d ata, s uc h as a ge, race, a n d et h nicit y, a n d b aseli ne c h aracteristics, s uc h as hei g ht, 
wei g ht, a n d  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 r es ults a n d dr u g s cree n res ults will b e liste d b ut n ot s u m marize d.  
Me dical hist or y will be liste d b y p artici pa nt.  
1 3. 5.  
Effic ac y A n al ysis  
Efficac y data will be s u m mariz e d usi n g a p pr o priat e descri pti ve statistics a n d ot her data 
prese ntati o n met h o ds , w here a p plica ble; partici p a nt  listi n gs will be pr o vi de d f or all efficac y data. 
Partici pa nt s will be a nal yze d acc or di n g t o r a n d o mize d treat me nt.  
Baseli ne differe nces bet wee n partici pa nts wit h H D a n d H P will be assesse d acr oss ca n di date 
e n d p oi nt base d o n e nr oll me nt set usi n g T -test. T h e mea n differe n ces, its 9 5 % c o nfi de n ce i nter val 
( CI) a n d c orres p o n di n g p  val ue will be re p orte d. F or a gi ve n e n d p oi nt, if t h e 9 5 % CI d oes n ot 
s pa n zer o, t he n it will be c o ncl u ded  t hat t he p artici pa nts wit h H D are st atisticall y si g nifica ntl y 
differe nt fr o m t heir h ealt h y co m p a rat ors at Baseli ne f or t hat e n d p oi nt; ot her wise, it will be 
c o ncl u ded  t hat t here is n ot e n o u g h e vi de nce t o declare t he m statisticall y differe nt.  
 
 
 
 
.  
 
 
 
 
 
 
 
  
A d diti o nal a nal ys es will be detaile d i n t he S A P . 
1 3. 6.  
S afet y A n al 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 res p o nses o n t he C-S S R S. 
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 C -S S R S data 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. All safet y s u m maries will be perf or me d o n 
t he Safet y Set. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 2  
1 3. 6. 1.  
A d verse E ve nts  
A Es  will be c o de d usi n g Me dical Dicti o nar y f or R e g ul at 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 a nal ysis of A Es 
will be base d o n t he c o n ce pt of T E A Es. T he pr o p orti o n of s u bjects e x perie n ci n g T E A Es will be 
dis pla ye d b y tr eat me nt gr o u p  a n d b y S yste m Or ga n Class ( S O C) a n d P referre 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 r elate 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 of treat me nt or wit h dra wal 
fr o m t he st u d y a n d a n y tr eat 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 h e 
e n d of t he st u d y will be liste d.  
1 3. 6. 2.  
Cli nic al L a b or at or y E v al u ati o ns  
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, cli n ical c he mistr y, 
a n d uri nal ysis. Sa m ples will be c ollecte d ≤2 h o urs pri or t o d osi n g o n d osi n g da ys. 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.  
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 ges fr o m baseli ne 
will be  s u m marize 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 treat me nt. Cli nical la b or at 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 3. 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  Da y 4 2  ( ± 2 da ys). At 
ot her visits (e g, Da y 2 8 f or partici pa nts wit h H D),  p h ysical e x a mi nati o ns will i ncl u de a brief 
assess me nt of ge n eral a p peara 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 a n d f oll o w e d b y a tar gete d p h ysi cal assess me nt as nee de d. A s y m pt o m -directe d 
e x a mi nati o n ma y be c o n d ucte d a t a n y ti me at t he discreti o n of t he i n vesti gat 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 date perf or me d will be liste d b y partici pa nt.  
1 3. 6. 4.  
Vit al Si g ns  
Vital si g ns will i ncl u de te m perat ur e, res pir at or y rate, heart rate, a n d bl o o d press ure. He art rate 
a n d bl o o d press ure t o b e 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 h a n ges fr o m bas eli ne will be s u m marize d b y 
sc he d ule d visit. P ote ntiall y C S  val ues will be s u m mariz e d b y tr eat me nt. Vital si g n res ults will be 
liste d b y partici p a nt a n d ti mi n g of c ollecti o n. 
1 3. 6. 5.  
1 2 -Le a d Electr oc a r di o gr a m  
A si n gle E C G will be me as ure d after t he p artici 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. T he f oll o wi n g E C G para meters w ill be liste d f or eac h p artici pa nt: heart rat e, P R, 
Q R S, Q T, a n d Q Tc F. E C G data will be s u m marize d b y visit. P ote ntiall y C S  val ues of Q Tc F will 
be s u m mariz e d b y tr eat m e nt. E C G  fi n di n gs will b e liste d b y partici pa nt a n d visit. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 3  
1 3. 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 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 niz ati o n -Dr u g dicti o nar y ( W H O -D D) Se pte 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 wit hi n 8 wee ks pri or t o Scree ni n g, all me dicat i o ns use d 
t o treat H 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 ne ur o ps yc hiatric, f u ncti o nal, a n d c o g niti ve 
ma nifestati o ns of H D will be rec or de d. T h ose m e dicati o ns ta ke n pri or t o t he i nitiati o n of t he start 
of I P will be d e n ote d “ Pri or”. T h ose me dicati o ns ta ke n pri or t o t he i nitiati o n of t he 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 he i nitiati o n of t he I P will be den ote d “ C o nc o mita nt”.  
I nf or mati o n re gar di n g di a g n osis a n d/ or h os pitalizati 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 me nte d as part of m e 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.  
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.  
1 3. 6. 7.  
C ol u m bi a S uici de Se verit y  R ati n g Sc ale  
S uici dalit y d ata c ollecte d o n t he C -S S R S at B aseli ne f or partici pa nts wit h H D a n d H P  a n d b y 
visit d uri n g t he Treat me nt Peri o d a n d F oll o w -u p f or partici pa nts wit h H D will be liste d a n d 
s u m marize d. Listi n gs will i ncl u de be ha vi or t y pe a n d/ or cate g or y f or S uici d al I d eati o n a n d 
S uici dal Be ha vi or of t he C -S S R S.  
1 3. 6. 8.  
Ot her S afet y A n al ysis  
N ot a p plica ble . 
 
 
 
 
1 3. 8.  
S a m ple Size a n d P o wer  
  
Usi n g a t w o -si de d al p ha l e vel of 0. 0 5, a s a m ple siz e of at least 8 0 p artici pa nts ( 4 0 H P a n d 
4 0  partici pa nts wit h H D) w o ul d pr o vi de at least 8 0 % p o wer t o det ect baseli ne differe nce i n 
H D -C A B c o m p osite sc ore ass u mi n g C o he n’s D effect size e q ual t o 0. 6 3, w hic h is i n t he ra n ge of 
effect sizes  o bser ve d f or i n di vi d ual tests fr o m H D -C A B (St o ut 2 0 1 4 ). 
Usi n g  a CI  a p pr oac h f or sa m ple siz e esti mati o n  a sa m ple siz e of  3 2  e val ua ble partici pa nts wit h 
H D ( 1 6  per treat me nt ar m)  will  pr o vi de  8 0 %  c o nfi de nce le vel  f or esti mati n g t he p o p ulati o n mea n 
wit h 0. 5 0  precisi o n  or mar gi n of err or.  

Cli nical Pr ot oc ol  
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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 4  
Ass u mi n g a 2 0 % dr o p o ut rate i n partici pa nts wit h H D, a sa m ple siz e of a p pr o xi matel y 
4 0  partici pa nts wit h H D will be ra n d o mize d i n a 1: 1 rati o t o S A G E-7 1 8 a n d place b o  t o o btai n 
3 2  e val ua ble p artici pa nt s wit h H D. A d diti o nal partici pa nts ma y be ra n d o mi ze d if t he dr o p o ut rate 
is hi g her t ha n 2 0 %.  
E val ua ble partici pa nts wit h H D are d efi ne d as t h ose ra n d o mize d partici pa nts w h o recei ve I P a n d 
ha ve a v ali d baseli ne a n d at least 1 p ost baseli ne efficac y assess me n t. 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 5  
1 4.  
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 4. 1.  
St u d y M o nit ori n g  
Bef ore a n i n v esti 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 
T hera p e utics will visit t he i n vesti gati o nal st u d y site per Sa ge st a n dar d o perati n g pr oce d ures t o: 
•  Deter mi ne 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, a n d t he res p o nsi bilities of Sa ge T hera pe utics or its re prese ntati ves. 
T his will be d oc u me nte d i n a Cli ni cal Trial A gree me nt bet wee n Sa ge T hera pe utics 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 T hera pe uti cs or re prese ntati ve will ha ve re g ul ar c o nt acts 
wit h t he i n vesti gati o nal site, f or t he f oll o wi n g:  
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he i n v esti gat or(s)  
•  C o nfir m t hat facilities re mai n acce pta ble  
•  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 e C R Fs , 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 erifi cati o n. T his i ncl u des a c o m paris o n of t he data i n t he eC R Fs  
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, cli ni c 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 hera pe utics a n d t h ose S A Es t hat met criteria f or 
rep orti n g ha ve b ee n f or war de d t o t he I R B or et hics c o m mittee.  
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 4. 2.  
A u dits a n d I ns pecti o ns  
Sa ge T h era pe utics or a ut h orize 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 pecti o n is t o 
s yste maticall y a n d i n dep 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/ I nter n ati o nal C o u ncil f or Har m o nizati o n of 
Tec h nical  Re q uir e me nts f or P har mace uticals f or H u ma n Use  (I C H) G C P g ui deli nes, a n d a n y 
a p plica ble re g ulat or y re q uire me nts. T he in vesti gat or s h o ul d c o ntact Sa ge T hera pe 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 R B/IE 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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 6  
1 4. 3.  
I nstit uti o n al Re vie w B o ar d or 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 Et hics C o m mittee ( E 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 partici pa nt. I nitial I R B ( or E C) a p pr o val, a n d all materials a p pr o v e d b y 
t he I R B ( or E C) f or t his stu d y i ncl u di n g t he partici pa nt c o nse nt f or m a n d recr uit me nt materials 
m ust be mai ntai ne d b y t h e in 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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 7  
1 5.  
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 4. 2  f or m ore 
details re gar di n g t he a u dit pr ocess.  
T he in 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, G C P/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 in 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. Si g nifica nt pr ot oc ol de viati o ns s h o ul d be re p ort e d t o t he I R B/ E C per t he I R B/ E C’s 
writte n pr oce d ures.  
T he in vesti gat or is res p o nsi ble f or s u per visi n g a n y i n di vi d ual or part y t o w h o m t he i n vesti gat or 
dele gates trial -relate d d uties a n d f u ncti o ns c o n d uct e d at t he trial site. W he n t he in 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 trial-relate d d uties a n d f u ncti o ns, t he 
in 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 trial -relate d d uties a n d 
f u ncti o ns a n d s h 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 tri al-relat e 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 in vesti gat or m ust mai ntai n a de q uate a n d acc urate  s o urce d oc u me nts a n d trial rec or ds t h at 
i ncl u de all perti ne nt o bser vati o ns o n eac h of t he site’s trial partici 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 necessar y, 
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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 8  
1 6.  
E T HI C S  
1 6. 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 IC 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 E C as a p pr o priate. T he in vesti gat or m ust 
o btai n a n d d oc u me nt a p pr 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 E 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/ E 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/E C is or ga ni ze 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 g ulati 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 E 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 E C m ust  a p pr o ve all 
a d vertisi n g us e d t o recr uit partici pa nts f or t he st u d y. T he pr ot oc ol m ust be re -a p pr o ve d b y t he 
I R B or E C u p o n recei 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 in 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 E C wit h re p orts of a n y 
re p orta ble s eri o us a d vers 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 rea cti o ns will be pr o vi de d t o t he I R B 
or E C acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes. 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/ E 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 he c o n d uct of t he trial 
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 6. 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 well 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 6. 3.  
Writte n I nf or me d C o nse nt  
Pri or t o e nr olli n g a tri al partici pa nt, t he in vesti gat or(s) will e ns ure t h at t he p artici pa nt is gi v e n 
f ull a n d a de quat 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 nts 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 trial, t he partici pa nt ( or t he partici pa nt’s, p are nt 
or le gall y a ut h orize d re prese ntati ve) m ust pr o vi de si g ne d a n d date d i nf or m e 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 u cti n g a n y st u d y pr oce d ures. T he in 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 in vesti gat or m ust mai ntai n 
t he ori gi nal, si g ne d I C F. A c o p y of t he si g ne d I nf or me d C o nse nt F or m m ust be gi ve n t o t he 
partici pa nt or t o t he partici pa nt’s pare nt or le gall y a ut h orize d re pres e ntati ve.  
T hr o u g h o ut t he tri al parti ci pa nts s h o ul d be i nf or m e d of a n y c h a n ges ma d e 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 p r o visi o n of t his i nf or mati o n will be 

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
7 9  
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.  
1 6. 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 ns e 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 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8 0  
1 7.  
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 7. 1.  
I ns pecti o n of Rec or ds 
Sa ge T h era pe utics or its re prese nt ati ve(s) will be all o we d t o c o n d uct site visits at t he 
i n vesti gati o n facilities f or t he p ur p ose of m o nit ori n g a n y as pect of t he st u d y. T he in v esti 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 or a ge area, dr u g acc o u nta bilit y rec or ds, 
partici pa nt c harts a n d st u d y s o ur ce d oc u m e nts, a n d ot her rec or ds rel ati ve t o st u d y c o n d u ct.  
I ns p ecti o n of t he st u d y b y a Re g ul at or y A ut 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 ul at or y 
A ut h orit y re pres e ntati ve(s).  
1 7. 2.  
Rete nti o n of Rec or ds  
T he p ri nci pal in 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 k eti 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 ns 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 I P. Sa ge T hera pe utics  is res p o nsi ble t o i nf or m t he in vesti gat or/i nstit uti o n as t o w he n st u d y 
d oc u me nts n o l o n ger nee d t o be retai ne d. 
 
  
 

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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8 1  
1 8.  
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 utics. T he in 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 in vesti gat or.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8 2  
1 9.  
LI S T O F R E F E R E N C E S  
Al bi n R L, Y o u n g A B, Pe n ne y J B, et al. A b n or malities of striatal pr ojecti o n ne ur o ns a n d 
N -met h yl -D -as p artate rece pt ors i n pres y m pt o mati c H u nti n gt o n's diseas e. N E n gl J Me d. 
1 9 9 0; 3 2 2( 1 8): 1 2 9 3 -1 2 9 8.  
 
 
 
 
 
 
 
  
Car d os o, F. N o n m ot or S y m pt o ms i n H u nti n gt o n Disease. I nt Re v Ne ur o bi ol. 
2 0 1 7; 1 3 4: 1 3 9 7 -1 4 0 8 . 
 
 
 
 
 
 
 
Le o ni V, L o n g J D, Mills J A,  et al. P R E DI C T-H D st u d y gr o u p. Plas ma 2 4 S h y dr o x yc h olester ol 
c orrel ati o n wit h mar kers of H u nti n gt o n diseas e pr o gressi o n. Ne ur o bi ol Dis. 2 0 1 3; 5 5: 3 7 -4 3.  
Le wis et al. C o g niti ve Deficits i n H u nti n gt o n’s Disease a n d Altere d 2 4( S) H y dr o x yc h olester ol.  
P oster at  H S G A n n ual M eeti n g . 2 0 1 9.  
Nasre d di ne Z S, P hilli ps N A, Bé diria n V, et al. T he M o ntreal C o g niti ve Assess me nt, 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 Geriatr S oc. 2 0 0 5 ; 5 3( 4): 6 9 5 -6 9 9.  
N S F Slee p Diar y, t h e nsf. or g, Re v -2 , 2 0 2 1.  
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: 1 7 2 9 0 -1 7 3 0 0.  
P os ner K, Br o w n G K, St a nle y B, et al. T he C ol u m bia -S uici de Se verit y Rati n g Scal e: i nitial 
vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d 
a d ults. A m J Ps yc hiatr y. 2 0 1 1 Dec; 1 6 8( 1 2): 1 2 6 6 -1 2 7 7 . 
St o ut  J C, Q ueller S, Ba ker K N, et al. H D-C A B: a c o g niti ve assess me nt batt er y f or cli nical trials 
i n H u nti n gt o n's disease. M o v Dis or d. 2 0 1 4; 2 9( 1 0): 1 2 8 1-1 2 8 8.  
Ta brizi SJ, Reil ma n n R, R o os R A, et al. P ote ntial e n d p oi nts f or cli nical trials i n pre ma nifest a n d 
earl y H u nti n gt o n's dis eas e i n t he T R A C K -H D st u d y: a nal ysis of 2 4 m o nt h o bser vati o nal data. 
La n cet N e ur ol. 2 0 1 2; 1 1( 1): 4 2 -5 3.  

Cli nical Pr ot oc ol  
Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
8 3  
 
  
U nsc h ul d P G, E d de n R A, Carass A, et al. Brai n meta b olite alterati o ns a n d c o g niti ve d ysf u ncti o n 
i n earl y H u nti n gt o n's dis ease. M o v Dis or d. 2 0 1 2; 2 7( 7): 8 9 5-9 0 2.  
V y klic k y V, K ori ne k M, S mej kal o va T, et al. Str uct ure, f u ncti o n, a n d p har mac ol o g y of N M D A 
rece pt or c ha n n els. P h ysi ol Res. 2 0 1 4; 6 3 S u p pl 1: S 1 9 1-S 2 0 3.  
Ya o L, Z h o u Q. E n h a nci n g N M D A rece pt or fu n cti o n: rece nt p r o gress o n all osteric m o d ulat ors. 
Ne ural Plast. 2 0 1 7;  2 0 1 7: 2 8 7 5 9 0 4.  

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Sa ge T h era pe utics, I n c.  
7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
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Si g nat ure Pa ge f or V V- C LI N- 0 0 2 6 5 1 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 0 2 6 5 1 v 1. 0
e Si g nat ure A p pr o val Tas k
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e Si g nat ure A p pr o val Tas k
0 1-J u n- 2 0 2 3 2 1: 0 0: 1 0 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
0 2-J u n- 2 0 2 3 0 0: 3 7: 3 6 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
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e Si g nat ure A p pr o val Tas k
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e Si g nat ure A p pr o val Tas k
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e Si g nat ure A p pr o val Tas k
0 6-J u n- 2 0 2 3 1 4: 2 3: 3 8 G M T + 0 0 0 0