Conditions: Huntington Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: yes

Brief summary:
The primary purpose of this study is to assess the magnitude of the baseline difference between participants with early Huntington's Disease (HD) and healthy participants (HP) with respect to measures of cognitive performance.

Detailed description:

Arms:
arm 1: Participants with HD will receive SAGE-718 1.2 milligrams (mg), orally, once daily for up to 28 days. arm 2: Participants with HD will receive SAGE-718-matching placebo, orally, once daily for up to 28 days. arm 3: HP enrolled in this study will not receive any investigational product (IP) (SAGE-718 or placebo).

Interventions: intervention 1: SAGE-718 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-718 oral softgel lipid capsules intervention 2: SAGE-718-matching oral capsules

Protocol document:
Prot_000.pdf: 


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  
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  
 
 
{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  
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  
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  
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 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  
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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 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). 


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 2  
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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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 3  
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). 


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  
5 4  
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 ).  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  


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  
5 5  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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  
5 6  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1 1. 2. 5.  
D ail y M o bile Assess me nt 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  
5 7  
 
 
 
 
 
 
 
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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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 8  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


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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  
5 9  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 1. 3.  
Cli nic al P h ar m ac ol o g y Assess me 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  
6 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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7 1 8 -CI H -2 0 2, Versi o n 3  
C O N FI D E N TI A L  
6 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  
6 2  
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.  


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 3  
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.  


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 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  
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 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  
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 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. 
 
  
 


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 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.  


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 4  
 
 
 
 


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
0 1-J u n- 2 0 2 3 2 0: 4 6: 4 5 G M T + 0 0 0 0
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
0 2-J u n- 2 0 2 3 1 4: 1 9: 4 2 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 1 6: 1 5: 3 9 G M T + 0 0 0 0
e Si g nat ure A p pr o val Tas k
0 5-J u n- 2 0 2 3 1 8: 0 7: 2 1 G M T + 0 0 0 0
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

SAP_001.pdf: 


STATISTICAL ANALYSIS PLAN
METHODS
PROTOCOL NUMBER 718-CIH-202
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
Short Title: 28-Day Placebo-Controlled Study of SAGE-718 on Functioning 
Capacity in Participants with Huntington’s Disease
Phase 2
Author of SAP: 
Version: 1.0
Version Date of SAP: 20 May 2024
Sponsor:
Sage Therapeutics, Inc.
215 First Street
Cambridge, Massachusetts 02142
CONFIDENTIAL
This document contains confidential information.  Any use, distribution, or disclosure 
without the prior written consent of Sage Therapeutics, Inc. is strictly prohibited except to the 
extent required under applicable laws or regulations.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them.


 
 
 
 
 
AUTHORIZATION SIGNATURE PAGE 
 
Author: 
 
 
 
 
 
 
 
 
 
 
 
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Parexel International, Inc 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Sage Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Sage Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Sage Therapeutics, Inc. 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Sage Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Sage Therapeutics, Inc. 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS................................................................... 7 
2. 
INTRODUCTION .................................................................................. 10 
3. 
STUDY OBJECTIVES .......................................................................... 11 
3.1. 
Primary Objective ................................................................................... 11 
3.2. 
Secondary Objectives ............................................................................. 11 
 
 11 
4. 
STUDY ENDPOINTS ............................................................................ 12 
4.1. 
Primary Endpoint .................................................................................... 12 
4.2. 
Secondary Endpoints .............................................................................. 12 
 
 12 
5. 
STUDY DESIGN ................................................................................... 14 
5.1. 
Overall Design ........................................................................................ 14 
5.2. 
Sample Size and Power .......................................................................... 15 
5.3. 
Randomization ........................................................................................ 16 
5.4. 
Blinding and Unblinding ........................................................................ 16 
6. 
MODIFICATIONS ................................................................................. 18 
6.1. 
Modifications from the Approved Clinical Study Protocol .................... 18 
6.2. 
Modifications from the Approved Statistical Analysis Plan .................. 18 
6.3. 
Modifications from the Approved DMC Charter ................................... 19 
7. 
ANALYSIS SETS .................................................................................. 20 
7.1. 
Efficacy Analysis Sets ............................................................................ 20 
7.2. 
Safety Analysis Sets ............................................................................... 20 
7.3. 
Other Analysis Sets ................................................................................. 20 
8. 
STATISTICAL ANALYSIS .................................................................. 21 
8.1. 
General Considerations ........................................................................... 21 
8.2. 
Background Characteristics .................................................................... 22 
8.2.1. 
Participant Disposition ............................................................................ 22 
8.2.2. 
Protocol Deviations ................................................................................ 23 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 23 


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8.2.4. 
Medical History ...................................................................................... 24 
8.2.5. 
Prior and Concomitant Medications ....................................................... 24 
8.2.6. 
Physical Examination ............................................................................. 25 
8.2.7. 
Investigational Product Exposure ........................................................... 25 
8.2.8. 
Investigational Product Adherence ......................................................... 26 
8.3. 
Efficacy Analysis .................................................................................... 27 
8.3.1. 
Definition of Efficacy Variables ............................................................. 27 
8.3.1.1. 
Primary Efficacy Assessment and Estimand .......................................... 27 
 
 33 
8.3.2. 
Visit Windows for Efficacy Analyses .................................................... 48 
8.3.3. 
Analysis of Primary Outcome ................................................................ 49 
8.3.3.1. 
Primary Analysis .................................................................................... 49 
8.3.3.2. 
Sensitivity Analyses for the Primary Outcome ...................................... 50 
 
 50 
 
 
 50 
 
 51 
 
 52 
8.3.4.4. 
Sleep Diary ............................................................................................. 52 
 
 52 
 
 52 
 
 53 
 
 53 
8.4. 
Safety Analysis ....................................................................................... 54 
8.4.1. 
Adverse Events ....................................................................................... 55 
8.4.2. 
Clinical Lab ............................................................................................ 57 
8.4.3. 
12-Lead Electrocardiogram .................................................................... 60 
8.4.4. 
Vital Signs .............................................................................................. 61 
8.4.5. 
Physical Examination ............................................................................. 62 


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8.4.6. 
Columbia Suicide Severity Rating Scale ................................................ 62 
8.4.7. 
Other Safety Analysis ............................................................................. 63 
8.5. 
Other Analysis ........................................................................................ 63 
9. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 65 
10. 
REFERENCES ....................................................................................... 66 
11. 
LIST OF APPENDICES......................................................................... 67 
APPENDIX A. SCHEDULE OF ASSESSMENTS – HUNTINGTON’S DISEASE
 
68 
APPENDIX B. SCHEDULE OF ASSESSMENTS – HEALTHY PARTICIPANTS
 
72 
APPENDIX C. DETAILS OF STATISTICAL METHODOLOGY ...................... 75 
APPENDIX D. HANDLING OF MISSING DATES ............................................. 76 
 
 78 
APPENDIX F. ANTIDOPAMINERGIC MEDICATIONS ................................... 88 
APPENDIX G. TRAIL MAKING TEST: TRIAL B .............................................. 89 
 
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1. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this Statistical Analysis Plan.  
Table 1. Abbreviations and Specialist Terms 
Abbreviation 
Definition 
ADM 
Antidopaminergic Medications 
AE 
Adverse event 
 
 
ASO 
Antisense oligonucleotide 
ATC 
Anatomical therapeutic chemical 
 
 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
 
 
CAG 
Cytosine, adenine, guanine 
 
 
 
 
 
 
CAP 
CAG-Age-Product 
 
 
 
 
 
 
CI 
Confidence Interval 
CS 
Clinically significant 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
 
 
eCRF 
Electronic case report form 
ECGs 
Electrocardiograms 
 
 
ERT 
Emotion Recognition Test 
ET 
Early Termination 
FAS 
Full analysis set 


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Abbreviation 
Definition 
FDA 
Food and Drug Administration 
 
 
HD 
Huntington’s Disease 
HD-CAB 
Huntington’s Disease Cognitive Assessment Battery 
 
 
HEENT 
Head, eye, ear, nose, and throat 
 
 
HP  
Healthy participant(s) 
HPS 
Healthy Participant Set 
 
 
HTT 
Huntingtin gene 
HVLT 
Hopkins Verbal Learning Test-Revised 
 
 
ID 
A participant identification 
IP 
Investigational product 
IRT 
Interactive response technology 
 
 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MoCA 
Montreal Cognitive Assessment 
 
  
 
 
NCS 
Not clinically significant 
 
 
NIH 
National Institute of Health 
 
 
OTS 
One Touch Stockings of Cambridge 
 
 
 
 
 
 


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Abbreviation 
Definition 
 
 
 
 
 
 
 
 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
RMIB 
Reduced Motor Impact Battery 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDMT 
Symbol Digit Modalities Test 
SE 
Standard error 
SEM 
Standard error of the mean 
SOC 
Standard Organ Class 
SS 
Safety set 
 
 
TEAE 
Treatment-emergent adverse event 
 
  
 
 
TMT A 
Trial Making Test: Trial A 
TMT B 
Trial Making Test: Trial B 
UHDRS 
Unified Huntington’s Disease Rating Scale 
 
 
 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis and is based on the following 
approved study documents: 
• Study Protocol Version 3.0, Amendment 2 (26 May 2023) 
• Electronic Case Report Form (eCRF), Version 8.0 (05 February 2024) 
This SAP addresses the objectives of the study and describes the planned statistical analyses 
and data presentations.  All analyses and data presentations will be generated using SAS® 
Version 9.4 or higher version (SAS Institute, Cary, North Carolina, USA).  This SAP has been 
finalized and approved before the clinical database lock.  Any changes made to the SAP after 
the clinical database lock has occurred will be documented and discussed in the clinical study 
report for this study. 
  
 
  
 
 


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
•  To assess the magnitude of the baseline difference between participants with early 
Huntington’s Disease (HD) and healthy participants (HP) with respect to measures of 
cognitive performance. 
3.2. 
Secondary Objectives  
• To evaluate safety and tolerability of SAGE-718 in participants with HD. 
 
 
 
 
 
 
 
 
 
 
 
 
• To evaluate additional safety and tolerability parameters of SAGE-718 in participants 
with HD. 
 
 
 
 
 
 


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4. 
STUDY ENDPOINTS 
4.1. 
Primary Endpoint 
• Difference in baseline measures of the Huntington's Disease Cognitive Assessment 
Battery (HD-CAB) cognitive composite score in participants with HD and HP. 
4.2. 
Secondary Endpoints  
 
• Safety and tolerability of SAGE-718 in HD participants as assessed by the incidence 
of adverse events (AEs)/serious AEs (SAEs), and by changes in vital signs, and clinical 
laboratory parameters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• Change from Baseline and between-group effects (SAGE-718 and placebo) for 
 electrocardiograms (ECGs), and responses on the 
Columbia-Sui cide Severity Rating Scale (C-SSRS).  
 
 
  
 
 
 
 
 
 
 
 
 
 


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5. 
STUDY DESIGN  
5.1. 
Overall Design  
This is a randomized, placebo-controlled, double-blind, parallel group study with a 28-day 
treatment duration to evaluate the effects of SAGE-718 on functioning capacity, safety, and 
tolerability in participants with early manifest HD.  Participants will be adults with genetically 
confirmed expansion of the Huntingtin (HTT) gene cytosine, adenine, and guanine (CAG) 
trinucleotide repeat at screening who meet diagnostic criteria detailed in the inclusion criteria 
(including UHDRS scores and CAG-Age-Product [CAP] scores within specific ranges). 
HP enrolled in the study will follow the same assessment schedule as participants with HD, 
but will not receive SAGE-718 or placebo, and will complete assessments only on 
performance-based tests (HD-CAB
), not HD-specific 
measures of functioning and HD symptomatology. 
An adult study partner for participants with HD is optional but highly recommended for each 
participant with HD to support completion of study activities and to answer questions about 
the participant’s condition.  For prospective participants with HD and study partners (if 
applicable), the study will begin with the informed consent process. 
Screening, safety, and efficacy assessments will be performed according to the schedule 
presented in Appendix A (HD) and Appendix B  (HP).  
 
 
Screening assessments will be performed to determine eligibility.  Participants and study 
partners (if applicable) will receive training on the study procedures and devices. 
Eligible participants with HD will be randomized 1:1 in a stratified manner based on previous 
intake of antisense oligonucleotide drugs (yes/no) to receive 1.2 mg of SAGE-718 or placebo 
for up to 28 days.  Beginning on Day 1 and continuing through Day 28, participants with HD 
will self-administer blinded investigational product (IP) once per day in the morning.  At clinic 
visits, participants with HD will take the IP under staff supervision, 
 
.  Study staff will dispense sufficient IP for daily 
administration until the next scheduled study visit.  Adherence to the dosing regimen will be 
assessed at each in-clinic visit by examination of the used packaging and counting any returned 
tablets. 
During the Treatment Period, participants with HD will be able to receive IP as long as there 
are no dose-limiting safety/tolerability concerns.  Participants with HD who discontinue IP 
early should complete the remaining study visits as scheduled, unless the participant with HD 
withdraws consent or loses the capacity to grant consent.  If a participant with HD withdraws 
from the study or stops study participation, an early termination (ET) visit should be conducted. 




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Using a CI approach for sample size estimation, and assuming a common SD of 1.51 in 
HD-CAB, a sample size of 32 evaluable participants with HD (16 per treatment arm) will 
provide 80% confidence level for estimating the population mean with 0.50 precision or 
margin of error. 
Assuming a 20% dropout rate in participants with HD, a sample size of approximately 40 
participants with HD will be randomized in a 1:1 ratio to SAGE-718 and placebo to obtain 32 
evaluable participants with HD.  Additional participants may be randomized if the dropout rate 
is higher than 20%. 
Evaluable participants with HD are defined as those randomized participants who receive IP 
and have a valid baseline and at least 1 postbaseline efficacy assessment. 
5.3. 
Randomization 
This is a randomized, placebo-controlled, double-blind, parallel group study.  Eligible 
participants with HD will be randomized 1:1 in a stratified manner by previous intake of 
antisense oligonucleotide (ASO) drugs (yes/no) to receive SAGE-718, or matching placebo for 
28 days. Stratified randomization will ensure the treatment balance within each stratum of prior 
antisense oligonucleotide drug intake (yes or no) with the consideration that participants with 
or without prior exposure to antisense oligonucleotide drug may respond to treatment 
differently. Randomization will take place on Day 1. 
Randomization will be performed centrally via an interactive response technology (IRT) 
system.  Randomization schedules will be generated by an independent statistician.  The 
allocation to treatment group will be based on the randomization schedule.   
Similarly for HP on Day 1, site staff will access the IRT and provide the necessary participant 
identifying information, including participant identification (ID) number assigned at Screening 
to register the eligible HP in the IRT system as enrolled status, and set as inactive for treatment 
assignment.  
5.4. 
Blinding and Unblinding 
Participants, clinicians, and the study team will be blinded to treatment allocation during the 
study.  The randomization schedules will be kept strictly confidential, accessible only to 
authorized personnel until the time of unblinding.  The blinding of the study will be broken 
after the database has been locked.  
During the study, the blind can be broken by the investigator via the IRT system only when 
the safety of a participant with HD is at risk and the treatment plan is dependent on the study 
treatment received.  Unless a participant with HD is at immediate risk, the investigator should 
make attempts to contact Sage prior to unblinding the study treatment administered to a 
participant with HD.  The responsibility to break the treatment code in emergency situations 
resides solely with the investigator.  If the unblinding occurs without Sage’s knowledge, the 
investigator must notify Sage within 24 hours of breaking the blind.  All circumstances 
surrounding a premature unblinding must be clearly documented in the source records. 


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In all cases where the study personnel are unblinded, pertinent information (including the 
reason for unblinding) must be documented in the participant’s source documentation and on 
the eCRF. At the time of withdrawal from the study/stopping participation, if possible, an ET 
visit should be conducted. 


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6.
MODIFICATIONS
6.1. 
Modifications from the Approved Clinical Study Protocol
•
Adding stratification factor of previous intake of antisense oligonucleotide drugs
(yes/no) to all analyses done with 
.
•
Change from baseline in concomitant medications will not be analyzed. Concomitant
medications will be summarized.
•
Full Analysis Set definition was updated to clarify HP and HD participants inclusion.
•
All Randomized Set was replaced by All Enrolled to better describe the study
participants.
•
Two exploratory cognitive batteries were created to separately examine SAGE-718
effects on (1) tests of the executive function domain, referred to as the Executive
Function Focus battery (EFFB) and (2) tests utilizing response formats that minimize
demands on psychomotor speed and coordination, referred to as the Reduced Motor
Impact battery (RMIB). The latter battery is intended to inform the utility of the HD-
CAB in participants where motor symptoms may impede or otherwise confound
performance of certain tests. The EFFB consists of Symbol Digit Modalities Test
(SDMT), Trail Making Test: Trail B (TMT B) and One Touch Stockings of Cambridge
(OTS). The RMIB consists of OTS, Hopkins Verbal Learning Test-Revised (HVLT)
and Emotion Recognition (ERT).
 
 
 
 
 
 
 
 
 
 
 
6.2. 
Modifications from the Approved Statistical Analysis Plan 
This is the first version of the statistical analysis plan for final analysis. 


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6.3. 
Modifications from the Approved DMC Charter 
Not applicable. 


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7.
ANALYSIS SETS
7.1. 
Efficacy Analysis Sets
Full Analysis Set: The Full Analysis set (FAS) will include all randomized HD participants 
and all HP who meet the eligibility criteria and have at least one baseline assessment of HD-
CAB (participants with HD and HP) and will be used in the analysis of primary endpoint.  
Full Analysis Set 1: The Full Analysis Set 1 (FAS1) will include all participants who initiate 
IP and have baseline and at least one postbaseline efficacy evaluation (participants with HD 
only). For participants with HD the efficacy endpoints will be analyzed according to the 
treatment the participant is randomized to. 
Full Analysis Set 2: The Full Analysis Set 2 (FAS2) will include all participants with HD who 
initiate IP or HP who meet eligibility criteria and have baseline and at least one postbaseline 
efficacy evaluation (participants with HD and HP). For participants with HD the efficacy 
endpoints will be analyzed according to the treatment the participant is randomized to. 
Healthy Participants Set: The Healthy Participant Set (HPS) will include all HP who meet 
eligibility criteria and have at least one baseline assessment and one postbaseline assessment 
of at least one of the following tests: HD-CAB
  
7.2. 
Safety Analysis Sets 
Safety Set: The Safety Set (SS) will include all participants with HD who were administered 
IP or HP who met eligibility criteria and will be used to describe the safety data. The Safety 
Set will be further subdivided to describe participants with HD and HP separately. 
Safety Set 1: The Safety Set 1 (SS1) will include all participants with HD in the safety analysis 
set. 
Safety Set 2: The Safety Set 2 (SS2) will include all healthy participants in the safety analysis 
set. 
7.3. 
Other Analysis Sets 
All Enrolled Set:  All Enrolled Set will include all randomized HD participants and all HP 
who meet the eligibility criteria and will be used to describe participant disposition and 
protocol deviations. 
 
 


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8.
STATISTICAL ANALYSIS
8.1. 
General Considerations 
Continuous data will be summarized in terms of the number of participants, mean, standard 
deviation (SD), minimum, and maximum.  The minimum and maximum will be reported to 
the same number of decimal places as the raw data recorded in the database.  The mean and 
median will be reported to one more decimal place, and the SD (and the standard error [SE], if 
applicable) will be reported to two more decimal places, than the raw data recorded in the 
database.  In general, the maximum number of decimal places reported shall be four for any 
summary statistic.  Any values that require transformation to standard units (metric or SI) will 
be converted with the appropriate corresponding precision. 
Categorical data will be summarized in terms of the number of participants providing data at 
the relevant time point (n), frequency counts, and percentages.  Percentages will be reported to 
one decimal place unless otherwise specified.  Any planned collapsing of categories will be 
detailed in the SAP text and the data displays.   
Percentages will not be presented for zero counts.  Percentages will be calculated using the 
number of participants (n) as the denominator.  A missing category shall be included only for 
categorical variables where no data is available.  The missing category will be omitted if there 
are no missing values for that variable. 
For the laboratory results that are “≤ x” or “≥ x”, where x is a number as collected in the data, 
the numeric part of the result will be used in the calculation in the summary tables. If a 
laboratory value contains ‘y <’ then y minus 0.1 for values measured to the first decimal place, 
0.01 for values measured to the second place, 0.001 for values measured to the third decimal 
place, and so on, will be used for the analysis. If a laboratory value contains ‘z >’ then z plus 
0.1 for values measured to the first decimal place, 0.01 for values measured to the second place, 
0.001 for values measured to the third decimal place, and so on, will be used for the analysis. 
The same is true if the result is presented as below limit of quantification (BLQ) and a lower 
limit of quantification (LLOQ) value is provided – LLOQ value will be used for calculation in 
the summary tables. The actual results as collected will be displayed in the listings. 
P-values greater than or equal to 0.0001, in general, will be presented to four decimal places.
P-values less than 0.0001 will be presented as “<0.0001”.  P values greater than 0.9999 will be
presented as “>0.9999”.
Confidence intervals will be presented to one more decimal place than the raw data. 
All summaries and figures will be provided by treatment group – either by randomized 
treatment or actual treatment received depending on the analysis set being used.  Actual 
treatment is defined as: SAGE-718 or Placebo. 
Participants who are randomized to 1.2 mg treatment will be summarized under SAGE-718 
group.  For efficacy data analysis, participants’ data are analyzed by randomization 
assignment.  For safety data analysis, participants’ data are analyzed per the actual treatment 


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received, and this is determined as follows: if a participant received any dose of SAGE-718 at 
any point of time, the participant is assigned to actual treatment of SAGE-718. 
All participant data, including those derived, to support tables and figures will be presented in 
the participant data listings.  In general, the participant data listings will be sorted by participant 
number and assessment visit and date (and time, if applicable).  The treatment will be identified 
for each participant. 
General definitions are defined as below: 
•
Baseline for participants with HD is defined as the last non-missing measurement prior
to the first dose of IP, unless stated otherwise.  If the time of an assessment is collected,
baseline will be the latest assessment prior to first dose of IP administration time; if the
time of an assessment is not collected, the assessment on Day 1 is assumed to be prior
to dosing if the protocol mentions that this assessment needs to be before dosing, or it
is collected as “pre-dose”.
•
Baseline for HP is defined as the last non-missing measurement on or prior to Day 1.
•
Study day 1 is defined as the date of randomization for untreated randomized HD
participants or the date of first dose for treated HD participants.
•
Study day 1 is defined as the date of completion of the baseline assessments for HP.
•
Study day will be calculated relative to Study day 1.
If event is prior to Study day 1, then study day is calculated as:
Date of Event – Date of Study day 1 
If event is after Study day 1, then study day is calculated as: 
        Date of Event – Date of Study day 1 + 1 
8.2. 
Background Characteristics 
8.2.1. 
Participant Disposition 
A clear accounting of the disposition of all participants who enter the study will be provided, 
from screening to study completion. This analysis will be based on All Enrolled Set. 
The summaries of participant disposition on all participants will include: 
•
Number of participants screened (HD and HP)
•
Number of participants screen-failed (HD and HP)
•
Number of participants enrolled (HD and HP)
•
Number of healthy participants (HP) enrolled
•
Number of participants randomized (HD)
•
Number of HD participants randomized but not treated
•
Number and percentage of HD participants received at least one dose of IP


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•
Number and percentage of HD participants completed full treatment period of IP
•
Number and percentage of HD participants discontinued from IP and primary reason
for premature IP discontinuation
•
Number and percentage of participants (HD and HP) completed the study (completed
Day 42 visit)
•
Number and percentage of participants (HD and HP) discontinued from the study and
primary reason for premature study discontinuation
Percentages will be calculated based on the participants that were randomized and received IP 
for HD participants, and percentages will be calculated based on all eligible participants for 
HP, accordingly.  Treatment arm assignment of HD participants will be according to the 
randomized treatment.  If a participant is rescreened because the participant has been a screen 
failure the first time, the status of the participant will be determined from the second screening.  
In the count of screened participants, this participant will be counted only once. 
By-participant listings of disposition details will also be provided. 
8.2.2. 
Protocol Deviations 
This analysis will be based on the All Enrolled Set. 
Protocol deviations will be classified as “major” or “minor” on an ongoing basis by the clinical 
study team and sponsor. 
Major protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the participant’s right, safety, well-being, and/or the validity of the data for analysis.  
Minor protocol deviations include all deviations from the protocol excluding the major 
protocol deviations.   
The number and percentage of participants with a major protocol deviation will be summarized 
by cohort and randomized treatment group.  A by-participant listing of all protocol deviations 
will also be provided. 
8.2.3. 
Demographics and Baseline Characteristics 
This analysis will be based on the Safety Set and FAS. 
Demographic characteristics (age, race, sex, ethnicity, childbearing status, civil/marital status, 
years of education, highest level of education, current employment status, and total years of 
employment) and baseline characteristics, such as height (cm), weight (kg), body mass index 
(BMI) (kg/m2), and HD-CAB composite score, 
 
 and HD-CAB Trail making test B will be summarized by treatment group, overall and 
HP.  
Baseline subgroups will be summarized for the following categories: 
•
Age (<=50, >50)


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•
 Race (Black or African American, White, Other)
•
Sex (Male, Female, Unknown/Undifferentiated)
•
 BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2)
•
Country (US, Canada)
•
CAG expansion (<40, ≥40)
•
Previous use of ASO drug (Yes / No)
•
Baseline Trail Making Test B (<240, =240)
•
Use of Antidopaminergic Medications (ADM see Appendix F for details) (Yes /
No)
BMI will be calculated as weight (kg)/height (m2). 
By-participant listing of demographic and other baseline characteristics will also be provided. 
8.2.4. 
Medical History  
This analysis will be based on the Safety Set 1 and Safety Set 2. 
Medical history at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 25.1 and summarized using system organ class and preferred 
term on Safety Set by actual treatment group.  
By-participant listing of medical history will also be provided. 
8.2.5. 
Prior and Concomitant Medications 
This analysis will be based on the Safety Set 1 and Safety Set 2. 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHODrug-Global-B3) September 2022 B3. 
All medications taken within 60 days prior to informed consent through the duration of the 
study will be recorded.  Those medications started and stopped prior to the initiation of the 
start of IP for HD and day 1 for HP will be denoted “Prior”.  Those medications taken prior to 
the initiation of the IP and continuing beyond the initiation of the IP, or those medications 
started at the same time or after the initiation of the IP will be denoted “Concomitant” for HD. 


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Those medications taken prior to day 1 and continuing beyond day 1, or those medications 
started at the same time or after day 1 will be denoted “Concomitant” for HP.  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above.  If medication dates are incomplete and it is not clear whether the medication 
are concomitant, it will be assumed to be concomitant.  
Missing or partial dates will be imputed for medication.  Algorithm for missing or partial start 
/end date is documented in Appendix D. 
Concomitant medications are further categorized as on-treatment and post-treatment as 
follows: 
On-treatment concomitant medications are those that have been used between first and last 
dose of IP (both inclusive) as well as medications started prior to first dose of IP and continue 
beyond the initiation of IP. 
Post-treatment concomitant medications are those that have been started after the last dose of 
IP. 
Concomitant medications will be summarized on Safety Set using Anatomical Therapeutic 
Chemical (ATC) level 1 and preferred term by actual treatment group. 
By-participant listings of prior and concomitant medications, and concomitant procedures will 
also be provided. 
8.2.6. 
Physical Examination 
This analysis will be based on the Safety Set 1 and Safety Set 2. 
Full physical examinations will be performed at Screening and Day 42 (±2 days)/ET, and 
include assessment of body system (eg, head, eye, ear, nose, and throat [HEENT], heart, lungs, 
abdomen, and extremities) 
 
  At other visits (eg, Day 28 for participants with HD), brief physical 
examination will be performed including general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 
Any abnormality in physical examinations will be interpreted by an Investigator as abnormal, 
not clinically significant (NCS); or abnormal and clinically significant (CS) which will be 
reported as an AE. 
By-participant listing of physical examination will be provided. 
8.2.7. 
Investigational Product Exposure  
This analysis will be based on the Safety Set 1. 
Total drug exposure (in mg), total exposure duration to IP (in days), and percent of planned 
exposure received (in %) will be summarized for the Safety Set by actual treatment group. 


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Total drug exposure (in mg) is defined as the total IP in mg for SAGE-718 that was taken 
during the study. Total drug exposure for participants randomized to placebo is zero unless the 
participant has taken SAGE-718 by mistake, in which case the total exposure comes from 
SAGE-718 exposure. If a participant skips a dose on any of the days, the dose taken is 0 mg.  
Total exposure duration to IP (in days) is defined as the date of the last dose minus the date of 
first dose plus 1.  Note that this does not exclude days when the dose has been missed. 
Planned drug exposure (in mg) for completers is defined as 
a) 1.2∙( Study Day of Day 28 visit – Day of the first dose +1) mg, if Study Day of Day 28
visit is in 28±2 window;
b) 1.2∙26 mg, if Study Day of Day 28 visit < 26;
c) 1.2∙30 mg, if Study Day of Day 28 visit > 30.
Planned drug exposure (in mg) for non-completers is 1.2 mg times date of the last dose minus 
the date of first dose plus 1.  
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100. 
By-participant listing of the extent of exposure will also be provided. 
8.2.8. 
Investigational Product Adherence 
This analysis will be based on the FAS1. 
IP adherence (%) is monitored using the medication adherence monitoring platform for all 
participants in the study.  The IP adherence is defined as the number of capsules taken, divided 
by the number of capsules planned to be taken, times 100.  For participants that complete the 
treatment period the planned number of capsules taken is  
a) (Study Day of Day 28 visit – Day of the first dose +1), if Study Day of Day 28 visit is
in 28±2 window;
b) 26, if Study Day of Day 28 visit < 26;
c) 30, if Study Day of Day 28 visit > 30.
For participants that discontinue the treatment early, the planned number of capsules is (Last 
Dose Date – First Dose Date + 1).   
IP adherence will be summarized on Safety Set by treatment group.  Number and percentage 
of participants with IP adherence in categories (<80%, 80-100%, >100%) will be provided.  IP 
adherence will be listed. 


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8.3. 
Efficacy Analysis  
8.3.1. 
Definition of Efficacy Variables 
8.3.1.1. 
Primary Efficacy Assessment and Estimand 
 
The main interest of the primary analysis in this trial is to estimate the baseline differences 
between participants with HD and HP in HD-CAB composite outcome. This is a comparison 
between two populations without establishing a treatment effect and without potential 
intercurrent events. Therefore, we will not present an explicit definition of an estimand in this 
analysis.  
 
The HD-CAB is a cognitive assessment battery developed for HD patients by Stout et al. 
(2014).   The HD-CAB will be assessed on Screening Period (Day -28 to -2), pre-dose on 
Day 1, post-dose on Day 14 and Day 28, and during follow-up on Day 42. 
HD-CAB consists of 6 subtests and each variable will be used to calculate HD-CAB composite 
score as outlined in Table 2.  If at least 1 out of 6 HD-CAB subtests are missing, the HD-CAB 
composite score will be set to missing. 
 








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Computing HD-CAB composite scores involves following three steps. HD-CAB composite 
scores will be calculated per each visit per each baseline population sample mean as defined 
in the step 2. 
Step 1:  For Trail Making Test B and One Touch Stockings, reverse the score by multiplying 
by -1 to make higher scores indicate better performance across all the 6 subtests (See Recode 
column of Table 2) 
Step 2: For each subtest, compute two z-scores for each participant using the formula: 
𝑧= 𝜒−𝜇
𝜎
where 𝜒 is a participant’s score, 𝜇 is a mean and 𝜎 is a standard deviation at baseline of 
(i)
HD population sample when it is used for efficacy assessment between Sage-718
vs. placebo (if not otherwise is stated);
(ii)
Healthy population sample when it is used for the comparison of HP vs. participants
with HD.
Step 3:  To compute each participant’s composite score, by calculating the average of six 
z-scores for each population sample mean.
The computation of exploratory cognitive batteries will be done as following: 
(i) Executive Function Focus Battery (EFFB) composite score will be calculated as an
average of three z-scores of Symbol Digit Modalities Test (SDMT), Trail Making Test:
Trail B (TMT B) and One Touch Stockings of Cambridge (OTS) for each population;
If any individual subtest score is missing, the EFFB composite score will be set to
missing.
(ii) Reduced Motor Impact Battery (RMIB) composite score will be calculated as an
average of three z-scores of OTS, Hopkins Verbal Learning Test-Revised (HVLT) and
Emotion Recognition (ERT); If any individual subtest score is missing, the RMIB
composite score will be set to missing.
Because the HD cohort in the study is relatively more progressed compared to the HD cohort 
in Stout et al. (2014), some participants may not be able to complete the TMT B test in the 
allotted 240 seconds (see more details in Appendix G). As such, we will explore the following 
approaches: 
(i)
Calculate the outcome of TMT B test as
25 ∙
𝑇𝑖𝑚𝑒
𝐿
, 
where L is an order number of the last symbol reached in TMT B test and 𝑇𝑖𝑚𝑒 is 
the observed time of completion of TMT B. 
The rational for this approach is to estimate the time to completion using the time 
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is equal to 25. This calculated outcome of TMT B test will be recorded by 
multiplying by -1 so that higher values represent better performance.  
(ii)
Calculate the outcome of TMT B test as a speed of completion, which is the number
of symbols done in 1 second as an outcome of TMT B test, and calculate it as
𝐿
𝑇𝑖𝑚𝑒, 
where L is an order number of the last symbol reached in TMT B test and 𝑇𝑖𝑚𝑒 is 
the observed time of completion of TMT B in seconds. 
(iii)
Consider only participants with baseline TMT B values < 240 seconds.
For all sensitivity analyses the calculation of HD-CAB and exploratory composite scores will 
be done accordingly. 
8.3.1.1.1. HD-CAB Symbol Digit Modalities Test 
The Symbol Digit Modalities Test is widely used to monitor changes in cognitive function 
over time and for early detection of cognitive dysfunction.  The task requires participants to 
use a reference key to pair specific numbers with geometric figures.  The number of correct 
pairings (out of 110 possible) achieved within 90 seconds is summed to generate a total score. 
8.3.1.1.2. HD-CAB One Touch Stockings of Cambridge 
One Touch Stockings of Cambridge is a computerized test of executive function.  For this task, 
participants must imagine stacking a set of colored balls to match an example by moving 1 ball 
at a time into 1 of 2 possible locations.  The goal is to perform the task using the smallest 
number of moves possible.  The participant selects that number from the response options on 
the screen. The primary measure for analysis is time to 1st correct response. 
8.3.1.1.3. HD-CAB Trail Making B 
The Trail Making test is a speeded graphomotor test of visual attention and task switching, 
administered in two parts.  Only part B will be used for primary analysis.  Part B includes an 
additional set -switching component, requiring the examinee to connect a series of alternating 
numbers and letters in order from lowest to highest, as in 1-A-2-B-3-C..., in the shortest time 
possible.  The primary measure for analysis is time to completion. 
8.3.1.1.4. HD-CAB Hopkins Verbal Learning Test 
The Hopkins Verbal Learning Test assessed is used to assess verbal learning and memory.  The 
test consists of three learning trials over which a 12-item semantically categorized list is read 
aloud by an examiner.  The examinee is asked to recall as many items as possible from memory 
immediately following each trial (immediate recall) and again following a delay (delayed 
recall).  The learning list items are then presented among additional items that were not 
previously presented, and examinee is asked to identify which items were on the original list 
by responding yes/no to each item (recognition).  The primary measure for analysis is the total 


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words correctly recalled over 4 trials (3 immediate and 1 delayed) with a maximum of 48 
correct. 
8.3.1.1.5. HD-CAB Paced Tapping Test 
In paced tapping, examinees are presented with auditory pacing tones and instructed to 
harmonize their fingertaps with the pacing tones.  A self-paced phase follows, in which the 
auditory pacing cue is removed, and ends with another auditory cue demarking the end of the 
test.  The primary measure of analysis is paced tapping consistency, calculated as 1/SD of the 
intertap interval (1/msec). 
8.3.1.1.6. HD-CAB Emotion Recognition Task 
The Emotion Recognition Task has participants identify the emotions expressed on a series of 
computer-generated human faces (i.e., sadness, happiness, fear, anger, disgust, surprise).  The 
responses can be analyzed by total errors, response latency, and the number of errors for each 
emotion.  The primary measure for analysis is the number of correct negative emotion trials 
(out of 24).  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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8.3.1.2.5.3. National Sleep Foundation Sleep Diary 
Once daily in the morning, participants will briefly answer 5 questions about sleep length, 
sleep latency, night awakenings, and sleep quality.  These questions have been modified from 
version 6 of the National Sleep Foundation Sleep Diary (National Sleep Foundation).  This 
diary will be completed each morning during the Treatment Period using a mobile device.  At 
scheduled clinic visits, the task will be performed in the clinic under observation by study staff, 
otherwise the participant will perform this task remotely (at home). Sleep length will be 
calculated in minutes as a difference between participant get out of bed this morning and time 
participant went to bed last night if the participant went to sleep before the midnight, otherwise 
the difference will be before the out of bed time and the time when participant went to bed in 
this day. Mean sleep diary assessments will be derived based on study days for clinic visit days 
using the mean of non-missing assessments between the previous visit day (exclusive) and the 
current visit day (inclusive). The baseline sleep diary measurement will be calculated as the 
mean of days immediately preceding the first dose day time. The precision level of averages 
to keep one decimal place. Refer to Table 3 above for the visit derivation. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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8.3.2. 
Visit Windows for Efficacy Analyses 
The scheduled visits will not be windowed and will be used at nominal visit value for treatment 
period (Days 14, 28, and 42).  Unscheduled and ET visit will be mapped to a scheduled visit 
for analysis.  Unscheduled measurements and early termination visit will be included only if a 
scheduled measurement is not available, and if the unscheduled measurement falls within the 
visit window or the scheduled visit.  If there are two or more measurements in a visit window, 
the measurement taken closest to the study day target will be used in analysis.  If the two have 
same distance from the target study day, the latter one will be used. 


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Table 4. Analysis Visit Windows for HD-CAB
 
Scheduled Visit 
Study Day of Expected Visit Study Day Window for Visit 
Baseline 
 1 
≤1 
Day 14 (±2 days) 
14 
2 to 20 
Day 28 (±2 days) 
28 
21 to 35 
Day 42 (±2 days) 
42 
≥36 
 
 
 
8.3.3. 
Analysis of Primary Outcome 
The FAS will be used for primary summary tables.  All participants who have baseline 
measures will be analyzed.   
8.3.3.1. 
Primary Analysis 
The primary efficacy endpoint is the difference between participants with HD and HP in 
baseline measures of the HD-CAB composite z-score standardized using mean and standard 
deviation from healthy participants. This primary endpoint will be analyzed using T-test.  The 
mean difference, its standard error (SE) and 95% confidence interval (CI) and corresponding 
p-value will be reported.


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A scatterplot showing the composite scores in two cohorts with mean ± standard error of the 
mean (SEM) bars and a boxplot comparing the distribution in two groups will be provided. 
8.3.3.2. 
Sensitivity Analyses for the Primary Outcome 
Sensitivity analyses of the primary endpoint will be done similarly to the primary analysis 
while the values of TMT B test truncated at 240 seconds will be calculated or eliminated as 
described in Section 8.3.1.1.  Namely, to investigate the influence of stopping patients at 240 
seconds on TMT B test, we will run the following: 
1) Sensitivity Analysis 1 in which we will calculate the value of TMT B outcome as  25 ∙
240
𝐿, where L is the  order number of the last symbol reached in the TMT B test and 
𝑇𝑖𝑚𝑒 is the observed outcome of TMT B; For the HD-CAB and EFFB calculations the 
outcome of the adjusted TMT B test will be multiplied by -1 so that higher values 
represent better performance. 
2) Sensitivity Analysis 2 in which the outcome of TMT B is a speed of completion
calculated as 
𝐿
𝑇𝑖𝑚𝑒, where L is an order number of the last symbol reached in the TMT
B test and 𝑇𝑖𝑚𝑒 is the observed outcome of TMT B;
3) Sensitivity Analysis 3 in which we will run the analysis only among participants with
baseline values of TMT B <240 seconds.
In both analyses the rest of HD-CAB calculations will remain the same. 
Scatterplots showing the composite scores in two cohorts with mean ± standard error of the 
mean (SEM) bars will be provided for sensitivity analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  


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8.3.4.4. 
Sleep Diary 
A summary of sleep diary and sleep length will be presented using descriptive statistics.  
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 


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TEAEs.  Where the AE start date is missing, adverse events will be assumed to be treatment-
emergent, unless there is clear evidence (through comparison of partial dates) to suggest that 
the adverse event started prior to the first dose of study treatment.  Missing or partial dates will 
be imputed for AE.  The algorithm for missing or partial start/end date is documented in 
Appendix D. 
Adverse events are assigned an AE period based on the onset date/time.  AE periods are defined 
as follows: 
• Pre-treatment AE: AE onset date before first IP dosing date/time 
• TEAE: AE onset date/time on or after the first IP dose date/time (If an AE start date 
same as IP first dose date, but no time either in AE start or treatment start, then 
consider this AE to be in treatment period TEAE)   
• On-treatment TEAE: AE onset date/time on or after first IP dose date/time and on 
or before IP last dose date + 30 days (Note that time does not matter for the end of 
this period. i.e. if AE occurred after the last dose but on the same date of last dose, 
it is considered as on-treatment TEAE) 
• Post-treatment TEAE: AE onset date on or after IP last dose date + 31 days. An 
overall summary of TEAEs will include the number and percentage of participants 
and number of events in the following categories: Any TEAEs 
• 
Any TEAEs (On-treatment, Post-treatment) 
• 
TEAEs by maximum Severity (severe>moderate>mild) 
• 
Any related TEAEs  
• 
Any related TEAEs by maximum Severity (severe>moderate>mild) 
• 
Any serious TEAEs 
• 
Any serious related TEAEs 
• 
Any TEAEs leading to death 
• 
Any TEAEs leading to IP withdrawal 
• 
Any TEAEs leading to withdrawal from the study 
• 
Any TEAEs leading to IP interruption 
Incidence of TEAEs in following categories will be provided by SOC and PT.  A participant 
is counted only once under each SOC and PT in case of multiple occurrences of the same AE.  
These tables will be sorted by decreasing frequency of System Organ Class (SOC) in 
SAGE-718 group, then in placebo group, then alphabetically first within SOC then within 
preferred term.  
• TEAE 


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• On-treatment TEAE 
• Post-treatment TEAE 
• TEAEs by maximum Severity 
• TEAEs by relationship  
• Serious TEAEs 
• TEAEs leading to IP withdrawal 
• TEAEs leading to withdrawal from the study  
• TEAEs leading to IP interruption 
Additionally, incidence of TEAEs will be summarized by PT.  Most common TEAEs reported 
>5% in either treatment group will also be summarized by PT. 
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe> moderate> mild; an AE with missing 
severity will be omitted from severity presentation and will not be imputed.  For relationship 
to IP, participant will be counted only once within each SOC and PT at the strongest 
relationship to IP in the following order: related > not related; an AE with relationship missing 
is treated as related.  For seriousness, an AE with missing seriousness will not be imputed.  The 
incidences will be presented by descending frequency of SOC and then, within a SOC, by 
descending frequency of PT based on the participant count, and in alphabetical order of PT if 
the incidence within a PT is a tie.   
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
•  Race (Black or African American, White, Other) 
• Sex (Male, Female, Unknown/Undifferentiated) 
•  BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
• Country (US, Rest of World) 
• Age group: ≤50, >50 years 
A by-participant listing of all AEs, SAEs (including those with onset or worsening before the 
start of IP), TEAEs leading to death, TEAEs leading to IP withdrawal through the end of the 
study, TEAEs leading to withdrawal from the study, and most frequent (5%) TEAEs will be 
provided. 
8.4.2. 
Clinical Lab 
Clinical laboratory assessments will include blood samples for hematology, clinical chemistry, 
coagulations, and urinalysis.  Samples will be collected ≤2 hours prior to dosing on dosing 
days. On non dosing days, collection may occur at any time. 


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The actual results as collected will be displayed in the listings. 
All laboratory values will be summarized for the Safety Set using actual treatment received.  
Results of continuous hematology, clinical chemistry parameters, coagulation, and urinalysis 
parameters (quantitative) at each scheduled visit and mean changes from baseline will be 
summarized using standard international (SI) units.  In addition, it will also include the 
summary of last post-baseline value on treatment (on or after first dose, on or before last dose) 
and on study (on or after first dose, on or before last day of the study).   
All laboratory results will be listed in individual participant data listings.  
Normal ranges for each parameter will be provided by the central laboratory.  Shift from 
baseline to worst post-baseline values at any time on treatment, and shift from baseline to the 
last value on treatment (on or after first dose, on or before last dose) and the last value on study 
(on or after first dose, on or before last day of the study) in abnormality of results will be 
summarized.  If a participant has both low and high post-baseline records, the participant will 
be counted twice for each low and high cell. 
The number and percentage of participants with potentially clinically significant (PCS) values 
will be provided in separate displays in hematology, clinical chemistry and liver function tests 
provided for such occurrence for anytime on treatment, last value on treatment, after the last 
dose of treatment (follow-up period).  PCS values will be identified for specific laboratory 
parameters as outlined in Table 12. 
Liver function tests will be monitored closely for PCS values, and will be summarized for 
occurrence anytime post-baseline for the following parameters for these PCS threshold (for 
condition involving more than one parameter, the results need to be from the same timepoint): 
• 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
• 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
• 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, 
>10xULN 
• 
Alkaline Phosphatase: >1.5xULN, >2xULN 
• 
Total Bilirubin: >1.5xULN, >2xULN 
• 
Total 
Bilirubin 
>2xULN 
AND 
(Alanine 
Aminotransferase 
or 
Aspartate 
Aminotransferase >3xULN) [any time post-baseline, does not need to be measured at 
the same time point of assessment] 
• 
[Total Bilirubin >2xULN AND Alkaline Phosphatase <2xULN (any time 
post-baseline, measured at the same time point of assessment)] AND [(Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) AND Alkaline 
Phosphatase <2xULN (any time post-baseline, measured at the same time point of 
assessment)] 










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The assessments for suicidal behavior are ranked as follows with 5 being the worst: 
1.  Preparatory acts or behavior 
2.  Aborted attempt 
3.  Interrupted attempt 
4.  Actual attempt (non-fatal) 
5.  Completed suicide 
Suicidal behavior is considered worse than suicidal ideation.   
Baseline for each question is defined as the worst of the assessments done before the first dose 
of IP, excluding the lifetime version.  This will typically include the ‘past 1-month/past 1-year’ 
version from screening and ‘since last visit version’ from Day 1, as well as any unscheduled 
visits done before the first dose of IP; any Yes will make the baseline value as Yes. 
The number and percentage of participants with at least one response of ‘Yes’ to any C-SSRS 
suicidal ideation or suicidal behavior item, as well as for Participant’s non-suicidal 
self-injurious behavior, will be summarized first by visit, then separately for baseline and 
anytime post-baseline.  
Summary of shift from baseline in C-SSRS suicidal ideation and suicidal behavior will be 
presented for the following categories (no suicidal ideation/behavior, suicidal ideation, and 
suicidal behavior) for each scheduled assessment time point.  If there is no ‘Yes’ response to 
all assessments in suicidal ideation and behavior, then the category for the table is considered 
as ‘No suicidal ideation/behavior’.  If any of the assessments in suicidal behavior is Yes, the 
category is considered as ‘Suicidal behavior’.  If any of the assessments in suicidal ideation is 
Yes but all assessments in suicidal behavior is No, the category is considered as ‘Suicidal 
ideation’.  If the participant has both suicidal ideation as well as suicidal behavior, the 
participant will be counted under suicidal behavior only. 
In addition, a summary of shift in suicidal ideation from baseline maximum rank score for 
anytime post-baseline maximum rank score will be presented.  Maximum score 0 refers to all 
‘No’ for all assessments in the desired period for all 5 questions on suicidal ideation.   A graph 
of distribution of participants with suicide-related events based on the C-SSRS scores over 
time by treatment group will be generated.  A listing of suicidal ideation and suicidal behavior 
will be provided. 
8.4.7. 
Other Safety Analysis 
Not applicable. 
 
 
 


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SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable. 


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10. 
REFERENCES 
 
  
 
 
 
 
 
SAS® Version 9.4 of the SAS System for Personal Computers. Copyright ©2013. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
Stout JC, Queller S, Baker KN, et al. HD-CAB: a cognitive assessment battery for clinical 
trials in Huntington's disease. Mov Disord. 2014;29(10):1281-8. 
Carlozzi NE, Victorson D, Sung V, et al. HD-PRO-TRIADTM validation: A patient-reported 
instrument for the symptom triad of Huntington’s disease. Tremor Other Hyperkinet Mov. 
2014; 4. doi: 10.7916/D8PN93NZ 
 
 
 
 
 
 
 
 
 
 
 


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11. 
LIST OF APPENDICES 


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APPENDIX A. SCHEDULE OF ASSESSMENTS – HUNTINGTON’S 
DISEASE 
 
Assessments  
Screening Period 
Treatment Period 
Follow-up 
Days -28 to 
-2 
Day-1 
 
Day 1 
 
Day 14  
(±2 days) 
Day 28  
(±2 days) 
Day 42  
(±2 days) or 
ET  
Informed consenta 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
Randomizationb 
 
 
X 
 
 
 
Family/medical history and 
demographicsc 
X 
 
 
 
 
 
Participant trainingd 
X 
X 
X 
 
 
 
Body weight 
X 
 
 
 
X 
X 
Body height 
X 
 
 
 
 
 
Vital signs (including orthostatics)e 
X 
X 
 
X 
X 
X 
Physical examinationf 
X 
X 
 
 
X 
X 
CAG test (if not collected as part of 
medical history)g  
X 
 
 
 
 
 
FSH testh 
X 
 
 
 
 
 
Serology testi 
X 
 
 
 
 
 
12-lead ECGj  
X 
X 
 
 
X 
X 
Clinical laboratory assessmentsk  
X 
X 
 
 
X 
X 
Urine drug test
X 
X 
X 
X 
X 
X 
Alcohol test
X 
X 
X 
X 
X 
X 
Cigarette/tobacco use assessmentm 
X 
 
X 
X 
X 
X 
Pregnancy testn 
X 
 
X 
 
X 
X 
C-SSRS (Screening) 
X 
 
 
 
 
 
C-SSRS (since last visit) 
 
 
X 
X 
X 
X 


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Assessments  
Screening Period 
Treatment Period 
Follow-up 
Days -28 to 
-2 
Day-1 
 
Day 1 
 
Day 14  
(±2 days) 
Day 28  
(±2 days) 
Day 42  
(±2 days) or 
ET  
Cognitive test (HD-CAB
)t 
X 
 
X 
X 
X 
X 
Daily Mobile Assessmentsx 
 
X-------------------------------------------------------------X 
IP self-administrationy 
 
X  
(once daily in the morning) 
 
IP dispensationz 
 
 
X 
X 
 
 
IP accountability/returnaa 
 
 
 
X 
X 
 
AEs/SAEs 
X 
(from time of ICF throughout the duration of participation) 
Prior and concomitant medications 
X-----------------------------------------------------------------------------X 
Abbreviations: AE = adverse event; CAP = CAG-Age-Product; 
 
 COVID-19 = coronavirus disease 2019; 
C-SSRS = Columbia–Suicide Severity Rating Scale; 
 
 ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating 
hormone; HD = Huntington’s Disease; HD-CAB = Huntington's Disease Cognitive Assessment Battery; 
 
 
 HIV = human immunodeficiency virus; ICF = informed consent form; 
IP = investigational product; 
 O = optional; 
 SAE = serious adverse event; 
 
 
a. 
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b. Randomization will take place on Day 1, following all safety assessments (vital signs, physical 
examinations, 12-lead ECGs and clinical laboratory), eligibility requirements (C-SSRS, urine drug, alcohol 
and pregnancy testing) and confirmation of inclusion/exclusion criteria.  
c. 
In addition to full medical history, all medications and supplements taken within 8 weeks prior to 
Screening, all medications used to treat HD regardless of timing, and all nonpharmacological methods (eg, 
psychosocial, psychotherapeutic) used to treat or prevent neuropsychiatric, functional, and cognitive 
manifestations of HD will be recorded. Information regarding diagnosis and/or hospitalization due to 
COVID-19 will be documented as part of medical history regardless of timing. The following 
demographics will be collected: age, race, sex, ethnicity, years of education, employment history, and 
current employment status. 
d. Participants and study partners (if applicable) will be trained by study staff on the use of software 
applications and devices necessary for the conduct of the study. 
e. 
Vital signs will include temperature, respiratory rate, heart rate, and blood pressure. Heart rate and blood 
pressure to be collected in supine position and standing position at all scheduled time points. 
f. 
A full physical examination is to be conducted during Screening (Days -28 to -2) and at Day 42 (±2 
days)/ET. At other visits [eg, Day 28 (±2 days) for participants with HD], physical examinations will 
include a brief assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and 
neurological systems and followed by a targeted physical assessment as needed. A symptom-directed 
examination may be conducted at any time at the discretion of the investigator. 
g. Test results of genetically confirmed disease with CAG expansion ≥36 collected as part of medical history 
is acceptable in lieu of central laboratory confirmation. For any genetic counseling, the study sites should 
follow their local practice. 
h. Serum FSH test will be conducted at Screening for the female participants who are not surgically sterile to 
confirm whether a female participant with ≥12 months of spontaneous amenorrhea meets the protocol-
defined criteria for being postmenopausal. 
i. 
To include hepatitis B and C screening tests, HIV-1 and -2 antibody. 
j. 
A single ECG will be measured after the participant has been in the supine position for at least 5 minutes. 
When ECG measurements coincide with vital signs assessment or blood draws, blood draws should be 
carried out after ECG and vital signs. 
k. Clinical laboratory assessments will include blood samples for hematology, clinical chemistry, 
biochemistry, coagulation, genetic testing, and urinalysis. Samples will be collected ≤2 hours prior to 
dosing on Days 1 to 28. On nondosing days, collection may occur at any time. 
 
 
 
m. Data on cigarette use will be collected using the question: “How many packs of cigarettes did you smoke 
over the past 7 days?” at the time points specified. 
n. Serum pregnancy tests will be conducted for all female participants at Screening; urine pregnancy tests will 
be conducted at other scheduled time points for female participants that are not postmenopausal or 
surgically sterile. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  


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t. 
Cognitive tests at all time points will be performed at the same time of day (±2 hours) and will be 
conducted predose on Day 1 only, and postdose on Day 14 (±2 days) 
. The cognitive 
tests include the Huntington's Disease Cognitive Assessment Battery (HD-CAB; Symbol Digit Modalities 
Test, One Touch Stockings of Cambridge, Trail Making A and Trail Making B, Hopkins Verbal Learning 
Test_Revised, Paced Tapping Test, and Emotion Recognition Test) 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
x. Daily reminders will be sent to participants via a mobile device to complete assessments on remote device. 
Daily assessments include 
 
 the National Sleep Foundation Sleep Diary. It is recommended that these 
assessments are completed at approximately the same time each day, within 1 hour following IP 
administration. Daily mobile assessments should be completed in a quiet area of participant’s home. If in 
conflict with clinic visit schedule, remote assessment may be completed in the clinic under observation by 
the study staff. 
y. On Days 1, 14, and 28 study visits, participants will self-administer IP in the clinic under the supervision of 
study staff. All scheduled safety assessments will be conducted prior to dosing. All scheduled cognitive 
tests will be administered predose on Day 1 Visit only and postdose on Day 14 Visit (±2 days) and Day 28 
Visit (±2 days). Participants will record the date and time of each dose taken at home and in-clinic using an 
application.  
z. 
Study staff will dispense enough IP for the participant to take daily at home until the next scheduled visit. 
aa. Participants will bring all used packaging and unused IP to the clinic at each visit for study staff to review 
and document. 
Note: On screening (Days -28 to -2), Day 28, and Day 42, safety assessments 
 
 may be done on separate day(s) than the cognitive assessments, if need be, 
provided that all assessments are completed within the specified visit window (±2 days). 


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APPENDIX B. SCHEDULE OF ASSESSMENTS – HEALTHY 
PARTICIPANTS 
Assessments  
Screening Period 
Reliability Assessment Period 
Follow-up 
Days -
28 to -2  
Day -1 
Day 1 
 
Day 14 
 (±2 days) 
Day 28 
 (±2 days) 
Day 42 
 (±2 days) or ET  
Informed consenta 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
Medical history and 
demographicsb 
X 
 
 
 
 
 
Participant trainingc 
X 
X 
X 
 
 
 
Body weight 
X 
 
 
 
 
X 
Body height 
X 
 
 
 
 
 
Vital signs (including 
orthostatics)d 
X 
X 
 
 
 
X 
Physical examinatione 
X 
X 
 
 
 
X 
FSH testf 
X 
 
 
 
 
 
Serology testg 
X 
 
 
 
 
 
12-lead ECGh  
X 
X 
 
 
 
X 
Clinical laboratory assessmentsi 
X 
X 
 
 
 
X 
Urine drug test 
X 
X 
X 
X 
X 
X 
Alcohol test 
X 
X 
X 
X 
X 
X 
Cigarette/tobacco use 
assessmentj 
X 
 
X 
X 
X 
X 
Pregnancy testk 
X 
 
X 
 
 
X 
C-SSRS (Screening) 
X 
 
 
 
 
 
Daily Mobile Assessmentsp 
 
X------------------------------------------------------------------X 
AEs/SAEs 
X  
(from time of ICF throughout the duration of participation)  


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Assessments  
Screening Period 
Reliability Assessment Period 
Follow-up 
Days -
28 to -2  
Day -1 
Day 1 
 
Day 14 
 (±2 days) 
Day 28 
 (±2 days) 
Day 42 
 (±2 days) or ET  
Prior and concomitant 
medications 
X--------------------------------------------------------------------------------X 
Abbreviations: AE = adverse event; 
 
COVID-19 = coronavirus disease 2019; C-SSRS = Columbia–Suicide Severity Rating Scale; 
ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; HD = Huntington’s 
Disease; HD-CAB = Huntington's Disease Cognitive Assessment Battery, HIV = human immunodeficiency 
virus; ICF = informed consent form; 
  SAE = serious 
adverse event; 
 
 
a. Participants will be consented during the Screening Period. 
b. In addition to full medical history, all medications and supplements taken within 8 weeks prior to 
Screening. Information regarding diagnosis and/or hospitalization due to COVID-19 will be documented as 
part of medical history. The following demographics will be collected: age, race, sex, ethnicity, years of 
education, employment history, and current employment status. 
c. 
Participants will be trained by study staff on the use of software applications and devices necessary for the 
conduct of the study. 
d. Vital signs will include temperature, respiratory rate, heart rate, and blood pressure. Heart rate and blood 
pressure to be collected in supine position and standing position at all scheduled time points. 
e. 
A full physical examination is to be conducted during Screening (Days -28 to -2) and at Day 42 (±2 
days)/ET. A symptom-directed examination may be conducted at any time at the discretion of the 
investigator. 
f. 
Serum FSH test will be conducted at Screening for the female participants who are not surgically sterile to 
confirm whether a female participant with ≥12 months of spontaneous amenorrhea meets the protocol-
defined criteria for being postmenopausal. 
g. To include hepatitis B and C screening tests, HIV-1 and -2 antibody. 
h. A single ECG will be measured after the participant has been in the supine position for at least 5 minutes. 
i. 
Clinical laboratory assessments will include blood samples for hematology, clinical chemistry, 
biochemistry, coagulation, and urinalysis. Sample collection may occur at any time. 
j. 
Data on cigarette use will be collected using the question: “How many packs of cigarettes did you smoke 
over the past 7 days?” at the time points specified. 
k. Serum pregnancy tests will be conducted for all female participants at Screening; urine pregnancy tests will 
be conducted at other scheduled time points for female participants that are not postmenopausal or 
surgically sterile. 
 
 
m. Cognitive tests at all time points will be performed at the same time of day (±2 hours). The cognitive tests 
include the Huntington's Disease Cognitive Assessment Battery (HD-CAB; Symbol Digit Modalities Test, 
One Touch Stockings of Cambridge, Trail Making A and Trail Making B, Hopkins Verbal Learning 
Test_Revised, Paced Tapping Test, and Emotion Recognition Test) 
 
 
  
 
 
 
 
 
 
 
 


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p. Daily reminders will be sent to participants via a mobile device to complete assessments on remote device. 
Daily assessments include 
 
 the National Sleep Foundation Sleep Diary. It is recommended that assessments 
are completed at approximately the same time each day. Daily mobile assessments should be completed in 
a quiet area of participant’s home. If in conflict with clinic visit schedule, remote assessment may be 
completed in the clinic under observation by the study staff. 
Note: On Days 28 and 42, safety assessments 
 may be done on separate day(s) than the 
cognitive assessments, if need be, provided that all assessments are completed within the specified visit window 
(±2 days). 
 


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APPENDIX C. DETAILS OF STATISTICAL METHODOLOGY 
 
Sample SAS Code for T-test 
      proc ttest data=data sides=2 alpha=0.05 h0=0 test=diff; 
            class subjgrp; 
            var aval; 
            ods output statistics=statistics ttests=ttests equality=equality;  
      run; *Note: if probf > 0.05 reading results from pooled method, if probf > 0.05 reading 
results from satterthwaite method; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D. HANDLING OF MISSING DATES 
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged.  
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
• When the year is known, but the month and day is unknown, then: 
− If the year matches the year of first dose date and the end date (if present) is 
after first dose date, or AE is ongoing, then impute as the month and day of 
the first dose date + 1 day. 
− If the year of AE onset < year of initiation of the treatment, then the month 
and day will be set to December 31st.  
− If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
• If the year and month are known, but the day is unknown, then: 
− If the year of AE onset = the year of initiation of the treatment and:  
− the month of AE onset = the month of initiation of the treatment, then the day 
will be set to the day of initiation of the treatment. 
− the month of AE onset < the month of initiation of the treatment, then the day 
will be set to the last day of month. 
− if the month of AE onset > the month of initiation of the treatment, then the 
day will be set to the 1st day of month. 
− If the year of AE onset < the year of initiation of the treatment, then the day 
will be set to the last day of month. 
− If the year of AE onset > the year of initiation of the treatment, then the day 
will be set to the 1st day of month. 
If the imputed AE onset date is after the AE stop date, then the onset date will be set to the 
stop date. 


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• When the year and day are present and the month is missing, treat it as if the day 
is missing, and only year is present.  Follow the imputation rules for “year is 
known, but the month and day is unknown”. 
• When the year is missing, but the month and/or day is known, treat this date as 
missing; do not impute. 
 
Prior and Concomitant Medications 
If the medication start date is completely missing, do not impute a date but consider it as 
concomitant, unless the medication end date is before the initiation of IP for HD or day 1 for 
HP, in which case the medication will be considered prior. 
For the partial start date of medication: 
• If the year is present and the month and day are missing, then the month and day 
will be set to January 1 unless the year is the same as the first dose date then 
impute the first dose date. 
• If the year and day are present and the month is missing, then t treat it as if the 
day is missing and only year is present. Follow the imputation rules for “year is 
known, but the month and day is unknown”. 
• If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month unless the month is the same as the date of the first dose 
then impute as the date of the first dose. 
• If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
If the medication end date is completely missing, do not impute a date but consider it as 
concomitant. 
For the partial end date of medication: 
• If the year is present and the month and day are missing, then the month and day 
/will be set to December 31. 
• If the year and month are present and the day is missing, then the day will be set 
to the last day of the month. 
• If the year and day are present and the month is missing, then treat it as if the day 
is also missing.  Impute the month and day to be December 31.   
 
 
 


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APPENDIX F. ANTIDOPAMINERGIC MEDICATIONS  
A list of neuroleptics and anti-chorea medications which are commonly referred collectively 
as Antidopaminergic Medications (ADM) in the HD community.  
Neuroleptics: 
Aripiprazole 
Quetiapine 
Olanzapine 
Risperidone 
Clozapine 
Ziprasidone Hydrochloride 
 
Anti-Chorea Meds: 
Valbenazine 
Tetrabenazine 
Deutetrabenazine 
 
 
 
 
 
 
 
 


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APPENDIX G. TRAIL MAKING TEST: TRIAL B 
An example of the Trail Making Test: Trial B (TMT B) is presented below. The number in 
the path can be ordered as 1 is 1st, A is 2nd, 2 is 3rd, B is 4 th, …, 13 is 25th. As you can see, 
the test has 25 symbols and their numbers of order will be used in the calculations of TMT B 
outcomes as defined in Section 8.3.1.1. 
 
 
 
 


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