Conditions: Parkinson Disease
Keywords: Parkinson's
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 29
Healthy volunteers: no

Brief summary:
This study assesses the safety, tolerability, pharmacokinetics and efficacy of SAGE-217 in 29 participants with moderate to severe Parkinson's Disease.

Detailed description:
Part A of the study is an open-label design with dosing of Levodopa for 3 days followed by SAGE-217 for 4 days.

Part B of the study is an open-label design with evening dosing of SAGE-217 for 7 days as an adjunct to antiparkinsonian agent(s).

This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.

Arms:
arm 1: Participants on a stable morning dose of levodopa (including carbidopa-levodopa) as antiparkinsonian agent(s) from Days 1 to 3, stopped levodopa and received SAGE-217 at a dose of 30 mg per day, oral solution, for Days 4 to 7 in the morning with food. Stable doses of other antiparkinsonian agents and dose reductions in SAGE-217 were allowed between Days 1 to 7. Participants resumed stable morning dose of levodopa from Days 8 to 14. arm 2: Participants on a stable dose of antiparkinsonian agent(s) received SAGE-217, up to 30 mg per day, capsules, for Days 1 to 7 in the evening with food.

Interventions: intervention 1: SAGE-217 intervention 2: Levodopa intervention 3: Antiparkinsonian Agent(s)
Intervention descriptions: intervention 1: None intervention 2: Levodopa (including carbidopa-levodopa) administered as antiparkinsonian agent(s). intervention 3: Antiparkinsonian agent(s) were administered as a clinical practice as standard of care, which includes levodopa (i.e. levodopa/carbidopa) or dopamine agonists or catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase (BMAO-B) inhibitors.

Protocol document:
SAP_002.pdf: 
 
Offi ci al  Titl e:       A   P h a s e  2,  T  w o  -P art  St u d y t o  E v al u at e t h e  S af et y,  T ol er a bilit y, 
P h ar  m a c o ki n eti c s,  a n d   Effi c a c y  of  S A  G  E  -2 1 7 i n  S u bj e ct s   Wit h 
P ar ki n s o n' s   Di s e a s  e  
N  C T   N u   m b e r:   
N  C T 0 3 0 0 0 5 6 9    
D o c u   m e nt   D at e  :     S A P  V er si o n    1: 0 6 -F e br u ar y -2 0 1 7 
 
 
 


Cli ni c al  St u d y   R e p ort   
 
2 1 7- P  R  K - 2 0 1  P art   A 
1 6. 1  St u d y I nf or  m ati o n 
 
1 
 
 
  
 
9.      
D  O  C  U   M  E  N  T  A  TI  O  N   O F  S  T  A  TI S  TI  C  A  L    M  E  T  H  O  D S   
St atisti c al   A n al ysis  Pl a n  v 1. 0  ( d at e d  0 6 F e b 2 0 1 7) 


S a ge T her a pe utics, I nc.  
S t ati sti c al A n al y si s Pl a n 
M et h o d s 
Pr ot o c ol  Nu m b er  S A G E- 2 1 7- P R K- 2 0 1 
A P H A S E  2, T W O -P A R T  ST U D Y T O E V A L U A T E  TH E  S A F E T Y,  
T O L E R A BI LI T Y,  PH A R M A C O KI N E TI C S,  A N D E F FI C A C Y O F  SA G E - 2 1 7 
O R A L  SO L U TI O N I N PA TI E N T S  WI T H P A R KI N S O N’ S DI S E A S E OF  
M O D E R A T E  S E V E RI T Y R E S P O N DI N G T O  I M M E DI A T E-R E L E A S E  O RA L  
L E V O D O P A/ C A R BI D O P A A N D WI T H D R A W N F R O M  
L E V O D O P A/ C A R BI D O P A  
A ut h or  o f S AP:  
, P h. D. 
Versi o n:  Versi o n 1. 0 
Versi o n  Dat e of  SA P:  0 6 Fe br uar y 2 0 1 7 
Sa ge  T hera pe utics , I nc. 
2 1 5  First Street 
Ca m bri d ge , Massac h usett s 0 2 1 4 2 
C O N FI D E N TI A L  
T hi s  d oc u m e nt  c o nt ai n s  c o nfi d e nti al  inf or m ati o n.   A n y  u se,  distri b uti o n,  or di s cl o s ur e wit h o ut  th e pri or  writt e n 
c o n s e nt  of S a g e T h er a p e uti c s,  In c.  i s stri ctl y  pr ohi bit e d  e xc e pt  t o t h e e xt e nt re q uir e d u n d er  a p pli c a bl e l a w s or 
r e g ul ati o n s.  P er s o n s to w h o m  th e i nf or m ati o n i s di s cl o s e d mu st  be i nf or m e d t h at  th e i nf or m ati o n  is  co nfi d e nti al  
a n d m a y  n ot b e f urt h er  di s cl o s e d b y  th e m.






St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  4 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
9. 4  
S af et y   A n al ysis  .........................................................................................................  1 5 
9. 4. 1  
A d v ers e  E v e nts   .................................................................................................  1 6 
9. 4. 2  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns  .................................................................  1 7 
9. 4. 3  
Cli ni c al  L a b or at or y   ...........................................................................................  1 8 
9. 4. 4  
El e ctr o c ar di o gr a  m  ............................................................................................  1 8 
9. 4. 5  
Vit al  Si g ns   ........................................................................................................  1 8 
9. 4. 6  
P h ys i c al  E x a  mi n ati o n .......................................................................................  1 8 
9. 4. 7  
C ol u  m bi a-  S ui ci d e  S e v erit y   R ati n g  S c al e (  C -S S  R S)  ........................................  1 9 
9. 4. 8  
St a nf or d  Sl e e pi n ess  S c al e  .................................................................................  1 9 
9. 4. 9  
M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n ess/ S e d ati o n (  M  O  A  A/ S)    ..............  1 9 
9. 5  
P h ar  m a c o ki n eti c   A n al ysis  ........................................................................................  1 9 
1 0  S u  m  m a r y  of I nt e ri  m   A n al ys es  ......................................................................................  2 0 
1 1  R ef e r e n c es   .......................................................................................................................  2 0 
1 2  List   of   A p p e n di c es .......................................................................................................... 2 1  
1 2. 1  A p p e n di x   A:  S c h e d ul e  of   Ass ess  m e nts   ....................................................................  2 1 
1 2. 1. 1  
P art   A  ................................................................................................................  2 1 
1 2. 1. 2  
P art   B  ................................................................................................................  2 4 
1 2. 2  A p p e n di x   B:   D et ails  of  St atisti c al   M et h o d ol o g y   ......................................................  2 7 
 
 
 
 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  5 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
2     LI  S T   O F   A  B  B  R  E  VI  A TI  O  N S 
A  B  B  R  E  VI  A  TI  O  N       D  E FI  NI  TI  O  N   O  R   D  E S  C  RI P  TI  O  N   
A E   
a d v ers e  e v e nt  
A  M   
m or ni n g   
A T  C   
A n at o  mi c al  T h er a p e uti c   C h e  mi c al   
 
 
B L  Q   
b el o  w t h e li  mit  of  q u a ntifi c ati o n  
B  MI   
b o d y  m ass i n d e x   
C  -S S  R S  
C ol u  m bi a  -S ui ci d e  S e v erit y   R ati n g  S c al e  
C  B  C   
c o  m pl et e  b l o o d c o u nt  
CI   
c o nfi d e n c e i nt er v al  
C S  R   
c li ni c al st u d y re p ort  
E  C  G  
e l e ctr o c ar di o gr a  m 
e C  R F   
el e ctr o ni c  c as e  re p ort  for  m  
HI  V   
h u  m a n  im  m u n o d efi ci e n c y   v ir us 
I  A 
i nt eri  m  a n al ysis 
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
M  D S  -U P  D  R S       
M o v e  m e nt   Dis or d er  S o ci et y    –  U nit e d  P ar ki ns o n’s   Dis e as e   R ati n g  S c al e   
M  M  R  M   
mi x e d   eff e ct   m o d el r e p e at e d   m e as ur es  
M  O  A  A/ S   
M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n ess/ S e d ati o n    
 
 
P  D  
P ar ki ns o n’s   Dis e as e  
 
 
P  K  
p h ar  m a c o ki n eti c  
P T  
pr ef err e d t er  m  
Q T c F   
Q T  -i nt er v al f or  E  C  G  c orr e ct e d f or  h e art r at e ( Fri d eri ci a) 
S  A E  
seri o us  a d v ers e  e v e nt  
S  A P  
st atisti c al a n al ysis  p l a n 
S  O  C  
S yst e  m   Or g a n  Cl ass   
S S S  
St a nf or d  Sl e e pi n ess  S c al e  
T E  A E  
tr e at  m e nt e m er g e nt   a d v ers e  e v e nt  
U L  O  Q   
u p p er  li  mit  of  q u a ntit ati o n 
W  H  O   -D  D   
W orl d   H e alt h   Or g a ni z ati o n    Dr u g   Di cti o n ar y   


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  6 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
3     I  N T  R  O  D  U  C TI  O  N 
T his st atisti c al  a n al ys e s  pl a n ( S  A P) is f or t h e  i nt eri  m  a n al ysis (I  A) of  P art   A  a n d fi n al  a n al ysis   of t h e 
st u d y ( P art   A  a n d  P art   B)  a n d is  b as e d  o n t h e  a p pr o v e d  cli ni c al st u d y  pr ot o c ol,  d at e d  2 4   O  C T  2 0 1 6, 
V ersi o n  3. 0  , i n c or p or ati n g   A  m e n d  m e nt  2.   
T his  S  A P  a d dr ess es t h e s af et y , effi c a c y,  a n d  p h ar  m a c o ki n eti cs ( P  K)  o bj e cti v es  of t h e st u d y  a n d  d es cri b es 
t h e  pl a n n e d s af et y, effi c a c y ,  a n d  P  K st atisti c al  a n al ys es  a n d  d at a  pr es e nt ati o ns. 
T h e st atisti c al  pl a n  d es cri b e d  h er e aft er is  a n  a  pri ori   pl a n  a n d will  b e   a p pr o v e d  pri or t o  a n y  a n al ysis  of 
d at a  p ert ai ni n g  t o S a g e’s st u d y  2 1 7 -P  R  K - 2 0 1  P art   A  a n d  pri or t o  u n bli n di n g  of  P art   B.   
D at a  pr o c essi n g, t a b ul ati o n  of   d es cri pti v e st atisti cs,  c al c ul ati o n  of i nf er e nti al st atisti cs,  a n d  gr a p hi c al 
r e pr es e nt ati o ns   will  b e  p erf or  m e d  pri  m aril y  usi n g  S  A S (r el e as e  9. 3  or  hi g h er) f or    Wi n d o  ws.  If t h e  us e  of 
ot h er s oft  w ar e is   w arr a nt e d, t h e fi n al st atisti c al   m et h o d ol o g y r e p ort   wil l  d et ail   w h at s oft  w ar e   w as  us e d f or 
w h at  p ur p os es. 
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m ati o n   will  b e  p erf or  m e d  usi n g  P h o e ni x    Wi n  N o nli n ®  s oft  w ar e (  V ersi o n 
6. 4  or l at er;  P h arsi g ht,   C ar y,   N  C)  o n i n di vi d u al  pl as  m a  c o n c e ntr ati o n- ti  m e  d at a. 
W h er e v er  p ossi bl e,    listi n gs   will i n cl u d e  d at a fr o  m  b ot h  P art   A  a n d  P art   B.   S e p ar at e t a bl es  a n d fi g ur es 
will  b e   cr e at e d  f or  P art   A  a n d  P art   B.  T h e r e a d er  of t his  S  A P is  e n c o ur a g e d t o  als o r e a d t h e  cli ni c al 
pr ot o c ol,  a n d  ot h er i d e ntifi e d  d o c u  m e nts, f or  d et ails  o n t h e  pl a n n e d   c o n d u ct  of t his st u d y.    O p er ati o n al 
as p e cts r el at e d t o  c oll e cti o n  a n d ti  mi n g  of  pl a n n e d  cli ni c al  ass ess  m e nts  ar e  n ot r e p e at e d i n t his  S  A P 
u nl ess r el e v a nt t o t h e  pl a n n e d  a n al ysis.  
4     S T  U  D  Y   O  B J  E  C TI  V  E  S    
4. 1     Pri  m ar y   O bj e cti v e   
T h e  pri  m ar y  o bj e cti v e  of t his st u d y  is to  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  S  A  G E - 2 1 7   Or al  S ol uti o n. 
4. 2     S e c o n d ar y   O bj e cti v e s    
T h e s e c o n d ar y  o bj e cti v es  of t his st u d y  ar e:  
•      T o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7   Or al  S ol uti o n  o n t h e s e v erit y  of P ar ki ns o n’s   Dis e as e ( P  D ) 
m ot or s y  m pt o  ms  aft er   wit h dr a  w al  of  L e v o d o p a  or   C ar bi d o p a- L e v o d o p a ( L e v o d o p a/  C ar bi d o p a). 
•      T o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7   Or al  S ol uti o n  e x p os ur e l e n gt h  o n t h e s e v erit y  of  P  D   m ot or 
s y  m pt o  ms  aft er   wit h dr a  w al  of  L e v o d o p a/  C ar bi d o p a. 
•      T o  c o  m p ar e t h e  eff e ct  of  S  A  G E -2 1 7   Or al  S ol uti o n i n  c o  m bi n ati o n   wit h i  m  m e di at e- r el e as e  or al 
L e v o d o p a/  C ar bi d o p a t o  L e v o d o p a/  C ar bi d o p a  al o n e. 
4. 3     Ot h er   O bj e cti v e s   
N ot  a p pli c a bl e.   
5     S T  U  D  Y   E  N  D  P  OI  N T  S   
5. 1     Effi c a c y   E n d p oi nt  s 
5. 1. 1  Pri  m ar y   Effi c a c y   E n d p oi nt   
N ot  a p pli c a bl e.   




St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  8 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
6     S T  U  D  Y   D  E  SI  G  N    
6. 1     O v er all   D e si g n    
T his st u d y is  a  2- p art,   m ulti c e nt er,  P h as e  2 st u d y t o  e v al u at e t h e s af et y, t ol er a bilit y,  P  K,  a n d  effi c a c y  of 
S  A  G E - 2 1 7   Or al  S ol uti o n i n  u p t o  1 8  a d ult s u bj e cts   wit h  P  D  of   m o d er at e s e v erit y   w h o r es p o n d t o 
i  m  m e di at e-r el e as e  or al  L e v o d o p a  a n d  ar e  o n  a st a bl e  d os e.   P art   A  of th e st u d y is  a n  o p e n-l a b el  d esi g n 
wit h   m or ni n g (  A  M)  d osi n g  of  S  A  G E- 2 1 7 f or  4  d a ys.   P art   B  of t h e st u d y is  a  d o u bl e- bli n d, r a n d o  mi z e d, 
pl a c e b o- c o ntr oll e d, t  w o- s e q u e n c e  cr oss o v er  d esi g n.    O n   D a ys  1 t o  4 ( P eri o d  1  of  cr oss o v er), s u bj e cts   will 
r e c ei v e  o p e n-l a bel  L e v o d o p a  pl us  bli n d e d  S  A  G E- 2 1 7  or  pl a c e b o.    O n   D a ys  5 t o  8 ( P eri o d  2  of  cr oss o v er), 
all s u bj e cts   will r e c ei v e  o p e n -l a b el  S  A  G E- 2 1 7   Or al  S ol uti o n  o nl y.  I n  P art   B, s u bj e cts   will r e c ei v e t h eir 
i n di vi d u all y  est a blis h e d t ol er at e d  d os e  of  S  A  G E- 2 1 7   Or al  S ol uti o n fr o  m  P art   A.   S u bj e cts   will  b e  e x p os e d 
t o  S  A  G E- 2 1 7 f or  u p t o  1 2  d a ys ( 4  d a ys i n  P art   A  a n d  u p t o  8  d a ys i n  P art   B)  a n d   will  b e f oll o  w e d f or  a n 
a d diti o n al  7  d a ys i n  P art   A  a n d  a n  a d diti o n al  1 4  d a ys i n  P art   B  aft er t h e  a d  mi nistr ati o n  of t h e l ast  d os e.  
T h er e  ar e t  w o  p arts t o t h e st u d y:  
•      P a rt   A:  O p e n  L a b el   wit h   A  M  d osi n g ( 4  d a ys). 
All s u bj e cts   will  c o nti n u e t o t a k e t h eir  a nti p ar ki ns o ni a n  a g e nts i n cl u di n g i  m  m e di at e  -r el e as e  or al 
L e v o d o p a  o n t h e  d a y  of  a d  missi o n (  D a y - 1)  a n d i n t h e   A  M  o nl y  o n t h e f oll o  wi n g  3  d a ys 
(  D a ys  1 t o  3).   All s u bj e cts   will st o p t h eir i  m  m e di at e-r el e as e  or al  L e v o d o p a  o n   D a y  4  a n d   will 
st art  o n  a  3 0   m g  d os e  of  S  A  G E- 2 1 7   Or al  S ol uti o n  a d  mi nist er e d i n t h e   A  M   wit h f o o d,  as  o utli n e d 
i n  S e cti o n  9. 1. 1  of t h e  pr ot o c ol.  S u bj e cts  n ot t ol er ati n g  3 0   m g   will r e c ei v e  2 0   m g,  a n d s u bj e cts 
n ot t ol er ati n g  2 0   m g   will r e c ei v e  1 0   m g  o n s u bs e q u e nt  d a ys ( S e cti o n  7. 4  of t h e  pr ot o c ol) .  T h e 
d os e r e c ei v e d  o n   D a y  7   will  b e  d efi n e d  as t h e t ol er at e d  d os e f or t h at s u bj e ct.  S u bj e cts  n ot 
t ol er ati n g  1 0   m g   will  n ot  b e  a bl e t o  c o nti n u e i n t h e st u d y  a n d   m a y  b e r e pl a c e d.  S u bj e cts   will  b e 
f oll o  w e d f or  a n  a d diti o n al  7  d a ys (  D a y  1 4)  aft er t h e  a d  mi nistr ati o n  of t h e l ast  d os e.  L e v o d o p a 
tr e at  m e nt   will  b e r es u  m e d  o n   D a y  8  a n d  c o nti n u e t hr o u g h   D a y  1 4.   R es c u e tr e at  m e nt ( or al 
L e v o d o p a  or  ot h er  a nti p ar ki ns o ni a n  a g e nt  at I n v esti g at or’s  dis cr eti o n)   will  b e  all o  w e d, if  n e e d e d, 
o n  all  d a ys (  D a ys  1 t o  7).  P art   A is  d esi g n e d t o  d et er  mi n e t h e t ol er at e d  d os e  of  S  A  G E - 2 1 7   Or al 
S ol uti o n f or  e a c h s u bj e ct  a n d t o  ass ess   w h et h er  S  A  G E- 2 1 7  e x hi bits  effi c a c y i n  s u bj e cts   wit h  P  D 
of   m o d er at e s e v erit y  i n  or d er t o i nf or  m t h e  c o n d u ct  of  P art   B.  
•      P a rt   B:    R a n d o  mi z e d,  pl a c e b o-c o ntr oll e d, t  w o -s e q u e n c e  cr oss o v er   wit h   A  M  d osi n g ( u p t o  8 
d a ys).  P art   B   will  b e i niti at e d  o nl y  aft er r e vi e  w  of t h e  P art   A  I  A  d at a. 
I n  or d er t o q u alif y f or  P art   B  of t h e st u d y,  a s u bj e ct   m ust  h a v e t ol er at e d  a  d os e  of  at l e ast  1 0   m g 
of  S  A  G E - 2 1 7   Or al  S ol uti o n i n  P art   A.  S u bj e cts   w h o  c o  m pl et e  P art   A t hr o u g h   D a y 1 4   will  b e 
r e-a d  mitt e d  o n   D a y  -1  of  P art   B  a n d t h e y   will r e c ei v e t h eir  a nti p ar ki ns o ni a n  a g e nt i n cl u di n g 
i  m  m e di at e-r el e as e  or al  L e v o d o p a.  S u bj e cts   will  b e r a n d o  mi z e d t h e  n e xt  d a y (  D a y  1) i n  a  1: 1 
m a n n er t o  o p e n-l a b el  L e v o d o p a  pl us  bli n d e d  S  A  G E- 2 1 7   Or al  S ol uti o n  or  pl a c e b o  d uri n g  P eri o d  1 
of t h e  cr oss o v er.  All  d os es  of  S  A  G E  - 2 1 7   Or al  S ol uti o n ( or  pl a c e b o)   will  b e  a d  mi nist er e d i n t h e 
m or ni n g   wit h f o o d  as  o utli n e d i n  S e cti o n  9. 1. 2  of t h e  pr ot o c ol.  S u bj e cts r a n d o  mi z e d t o t h e 
L e v o d o p a  pl us  pl a c e b o  ar  m   will r e c ei v e  L e v o d o p a  a n d  pl a c e b o  or al s ol uti o n i n t h e   A  M f or t h e 
first  4  d a ys (  D a ys  1 t o  4). S u bj e cts  r a n d o  mi z e d t o t h e  c o  m bi n ati o n  ar  m  of  L e v o d o p a  a n d  S  A  G E-
2 1 7   Or al  S ol uti o n   will r e c ei v e t his  c o  m bi n ati o n i n t h e  A  M   f or t h e first  4  d a ys (  D a ys  1 t o  4). O n 
D a y  5,  all s u bj e cts   will  cr oss o v er t o  P eri o d  2  a n d   will  o nl y r e c ei v e  o p e n  -l a b el  S  A  G E- 2 1 7   Or al 
S ol uti o n  f or t h e r e  m ai ni n g  4  d a ys (  D a ys  5 t o 8).  S u bj e cts   will r e c ei v e t h eir i n di vi d u all y 
est a blis h e d t ol er at e d  d os e  of  S  A G E  - 2 1 7   Or al  S ol uti o n (fr o  m  P art A).   All s u bj e cts   will  b e  a bl e t o 
r es u  m e  L e v o d o p a fr o  m   D a y  9  o n  w ar ds.  
R es c u e tr e at  m e nt ( at I n v esti g at or’s  dis cr  eti o n)   will  b e  all o  w e d, if  n e e d e d,  o n  all  d a ys 
(  D a ys  1 t o 8).   


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  9 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
R e d u cti o ns i n  d os e  of  S  A  G E  - 2 1 7   will  b e  all o  w e d  d uri n g  b ot h  p arts  of t h e st u d y ( P arts   A  a n d   B). If  at  a n y 
ti  m e t h e  d os e is  n ot t ol er at e d,  ass ess e d  b y  o c c urr e n c e  of  a s e v er e A E   j u d g e d  b y t h e I n v esti g at or t o  b e 
r el at e d t o st u d y  dr u g, t h e  d os e  o n t h e  n e xt  d a y   m ust  b e r e d u c e d t o t h e  n e xt l o  w est  d os e  a n d  c o nti n u e d f or 
t h e r e  m ai n d er  of t h e  d osi n g  p eri o d (i e, s u bj e cts   w h o  ar e  u n a bl e t o t ol er at e t h e  3 0   m g  d os e   will r e c ei v e  a 
d os e  of  2 0   m g,  a n d s u bj e cts   w h o  ar e  u n a bl e t o t ol er at e  2 0   m g   will r e c ei v e  a  1 0   m g  d os e  o n s u bs e q u e nt 
d a ys).  T h e  d os e r e c ei v e d  o n   D a y  7  of t h e  d osi n g  p eri o d i n  P art   A   will  b e  d et er  mi n e d t o  b e  t h e t ol er at e d 
d os e f or t h at s u bj e ct,   wit h t his  d os e t o  b e  us e d  as t h e st arti n g  d os e f or  P art   B  f or t h at s u bj e ct.  S u bj e cts   will 
b e  e x p os e d t o  S  A  G E- 2 1 7   Or al  S ol uti o n f or  u p t o  1 2  d a ys ( 4  d a ys i n  P art   A  a n d  u p t o  8  d a ys i n  P art   B) 
a n d   will  b e f oll o  w e d f or  a n  a d diti o n al  7  d a ys i n  P art   A  a n d  a n  a d diti o n al  1 4  d a ys i n  P art   B  aft er t h e 
a d  mi nistr ati o n  of t h e l ast  d os e.   
Ass ess  m e nts   will  b e  p erf or  m e d  p eri o di c all y  d uri n g t h e st u d y  as  o utli n e d i n t h e  S c h e d ul e  of  E v e nts f or 
P art   A  a n d  P art   B ( s e e S e cti o ns  1 2. 1. 1   a n d 1 2. 1. 2 ). 
6. 2     S a  m pl e   Si z e  a n d   P o  w er   
A p pr o xi  m at el y  1 8 s u bj e cts   will  b e  e nr oll e d i n  P art   A.   A n   I  A is  pl a n n e d  aft er  1 0 s u bj e cts  h a v e  c o  m pl et e d 
P art   A  at l e ast  t hr o u g h   D a y  8 t o i nf or  m t h e  c o n d u ct  of  P art   B. T  w el v e s u bj e cts  ar e  a nti ci p at e d t o  b e 
r a n d o  mi z e d i n  P art   B.  T his  n u  m b er  of s u bj e cts is t h o u g ht t o  b e s uffi ci e nt t o  ass ess  pr eli  mi n ar y s af et y  a n d 
t ol er a bilit y  as   w ell  as  a si g n al  of  effi c a c y  of  S  A  G E-2 1 7   Or al  S ol uti o n i n s u bj e cts   wit h  P  D.  
6. 3     R a n d o  mi z ati o n   
N ot  a  p pli c a bl e  f or P art   A  of t h e st u d y  as it  is o p e n-l a b el,  si n gl e  ar  m. 
P art   B is  a r a n d o  mi z e d,  pl a c e b o- c o ntr oll e d,  t  w o-s e q u e n c e  cr oss o v er st u d y.   S u bj e cts   will  b e r a n d o  ml y 
assi g n e d i n  a  1: 1   m a n n er t o  o n e  of t  w o tr e at  m e nt s e q u e n c es : A  C    or   B  C   w h er e   A  =  L e v o d o p a/  C ar bi d o p a  + 
S  A  G E - 2 1 7,   B  =  L e v o d o p a/  C ar bi d o p a  +  Pl a c e b o,  a n d   C  =  S  A  G E- 2 1 7. 
6. 4     Bli n di n g  a n d   U n bli n di n g   
F or  P art   B, s u bj e cts,  cli ni ci a ns,  a n d t h e st u d y t e a  m   will  b e  bli n d e d t o tr e at  m e nt  all o c ati o n  i n t h e first 
p eri o d .   T h e  p h ar  m a cist,   wh o   will  pr e p ar e t h e  or al s ol uti o n  a c c or di n g t o t h e r a n d o  mi z ati o n s c h e d ul e,   will 
b e  u n bli n d e d. 
D uri n g t h e st u d y, t h e  bli n d is t o  b e  br o k e n  o nl y   w h e n t h e s af et y  of  a s u bj e ct is  at ris k  a n d t h e tr e at  m e nt 
pl a n is  d e p e n d e nt  o n t h e st u d y tr e at  m e nt r e c ei v e d.    U nl ess  a s u bj e ct is  at i  m  m e di at e ris k, t h e I n v esti g at or 
m ust   m a k e  dili g e nt  att e  m pts t o  c o nt a ct t h e  S p o ns or  pri or t o  u n bli n di n g t h e st u d y tr e at  m e nt  a d  mi nist er e d 
t o  a s u bj e ct.   A n y r e q u est fr o  m t h e I n v esti g at or  a b o ut t h e tr e at  m e nt  a d  mi nist er e d t o st u d y s u bj e cts m ust  b e 
dis c uss e d   wit h t h e  S p o ns or. If t h e  u n bli n di n g  o c c urs   wit h o ut t h e  S p o ns or’s  k n o  wl e d g e, t h e I n v esti g at or 
m ust  n otif y t h e  S p o ns or  as s o o n  as  p ossi bl e  a n d  n o l at er t h a n t h e  n e xt  b usi n ess   m or ni n g.   All 
cir c u  mst a n c es s urr o u n di n g  a  pr e  m at ur e  u n bli n di n g   m us t  b e  cl e arl y  d o c u  m e nt e d i n t h e s o ur c e r e c or ds. 
U nl ess  a s u bj e ct is  at i  m  m e di at e ris k,  a n y r e q u est f or t h e  u n bli n di n g  of i n di vi d u al s u bj e cts   m ust  b e   m a d e 
i n   writi n g t o t h e  S p o ns or  a n d  a p pr o v e d  b y t h e  a p pr o pri at e  S p o ns or  p ers o n n el,  a c c or di n g t o st a n d ar d 
o p er ati n g  pr o c e d ur es.  
T h e  bli n di n g  of t h e st u d y   will  b e  br o k e n  aft er t h e  d at a b as e  h as  b e e n l o c k e d.  El e ctr o ni c  c o pi es  of t h e 
r a n d o  mi z ati o n  c o d e   will  b e   m a d e  a v ail a bl e t o t h e l a b or at or y  p erf or  mi n g t h e  bi o a n al yti c al  a n al ys es i n 
or d er t o  all o  w f or li  mit e d  a n al ysi s  of s a  m pl es fr o  m s u bj e cts r e c ei vi n g  pl a c e b o.   
I n  all  c as es   w h er e t h e st u d y  dr u g  all o c ati o n f or  a s u bj e ct is  u n bli n d e d,  p erti n e nt i nf or  m ati o n   m ust  b e 
d o c u  m e nt e d i n t h e s u bj e ct’s r e c or ds  a n d  o n t h e  el e ctr o ni c  c as e r e p ort f or  m ( e  C  R F). If t h e s u bj e ct  or st u d y  
c e nt er  p ers o n n el ( ot h er t h a n  p h ar  m a cist)  h a v e  b e e n  u n bli n d e d, t h e s u bj e ct   will  b e t er  mi n at e d fr o  m t h e 
st u d y. 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 0  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
7 
M  O  DI FI  C  A TI  O  N  S  
7. 1     M o difi c ati o n  s  t o t h e   A p pr o v e d   Cli ni c al   St u d y   Pr ot o c ol 
T h e  pr ot o c ol st at e d t h at  a n  i nt eri  m  a n al ysis   w o ul d  b e  c o n d u ct e d  aft er  1 0 s u bje cts  h a v e  c o  m pl et e d  P art   A 
t hr o u g h   D a y  1 4.   T his t e xt   w as  u p d at e d i n  S e cti o n  6. 2 t o  “A n   I  A is  pl a n n e d  aft er  1 0 s u bj e cts  h a v e 
c o  m pl et e d  P art   A  at l e ast t hr o u g h   D a y  8  t o i nf or  m t h e  c o n d u ct  of  P art   B ”. 
T h er e  ar e   n o ot h er  m o difi c ati o ns fr o  m t h e  cli ni c al st u d y  pr ot o c ol ( v ersi o n   3. 0,  d at e d  2 4   O  C T  2 0 1 6) t h at 
i  m p a ct st atisti c al  a n al ysis.   
7. 2     M o difi c ati o n s t o t h e   A p pr o v e d   St ati sti c al   A n al y si s   Pl a n   
T his is t h e first  v ersi o n  of t h e  S  A P f or t h e i nt eri  m  a n d fi n al  a n al ysis.  
7. 3     M o difi c ati o  n s t o t h e   A p pr o v e d   D  M  C   C h art er  
N ot  a p pli c a bl e.   
8     A  N  A L  Y  S  I  S P  O  P  U L  A TI  O  N  S   
S u bj e cts i n cl u d e d i n t h e  b el o  w  a n al ysis  p o p ul ati o ns ( a n d r e as o n f or  e x cl usi o n, if  a p pli c a bl e)   will  b e 
pr o vi d e d i n  a listi n g.  
8. 1     Effi c a c y   P o p ul ati o n   
T h e  E ffi c a c y P o p ul ati o n   will  c o nsist  of  all s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of st u d y  dr u g  a n d  h a v e 
at l e ast  o n e  p ost d os e   M  D S -U P  D  R S  e v al u ati o n.  S e p ar at e  p o p ul ati o ns  ar e  d efi n e d f or  e a c h  p art  of t h e 
st u d y:  Effi c a c y  P o p ul ati o n ( P art   A)   will i n cl u d e s u bj e cts   w h o f ulfill t h e r e q uir e  m e nts f or  i n cl usi o n i n t h e 
Effi c a c y  P o p ul ati o n  b as e d  o n  P art   A r es ults; si  mil arl y,  Effi c a c y  P o p ul ati o n ( P art   B)   will i n cl u d e s u bj e cts 
w h o f ulfill t h e r e q uir e  m e nts f or i n cl usi o n i n t h e  Effi c a c y  P o p ul ati o n  b as e d  o n  P art   B r es ults.   Effi c a c y 
P o p ul ati o n ( P art   A)  a n d  Effi c a c y  P o p ul ati o n ( P art   B)  will  b e  us e d t o  a n al y z e  effi c a c y  d at a   i n  P arts   A  a n d 
B, r es p e cti v el y  .  
8. 2     S af et y   P o p ul ati o n  
T h e  S af et y  P o p ul ati o n  is  d efi n e d  as  all s u bj e cts   w h o  ar e  a d  mi nist er e d st u d y  dr u g.  T his  p o p ul ati o n will  b e 
us e d t o  pr o vi d e  d es cri pti v e s u  m  m ari e s  of s af et y. S af et y  P o p ul ati o n ( P art   A)  a n d  S af et y  P o p ul ati o n ( P art 
B)   will  b e  us e d t o  a n al y z e s af et y  d at a i n   P arts   A  a n d   B, r es p e cti v el y.  
8. 3     P  K   P o p ul ati o n   
T h e  P  K  P o p ul ati o n   will  c o nsist  of  all s u bj e cts i n t h e s af et y  p o p ul ati o n   wit h  at l e ast  o n e  pl as  m a s a  m pl e 
wit h  q u a ntifi a bl e  c o n c e ntr ati o n  of  S  A  G E  - 2 1 7.   T h e  P  K  p o p ul ati o n   will  b e s e p ar at e d  b y st u d y  p art. P  K 
P o p ul ati o n ( P art   A)   will i n cl u d e s u bj e cts   wit h  at l e ast  o n e  pl as  m a s a  m pl e   wit h  q u a ntifi a bl e  c o n c e ntr ati o n 
of  S  A  G E - 2 1 7 i n  P art   A.   P  K  P o p ul ati o n ( P art   B)   will i n cl u d e s u bj e cts   wit h  at l e ast  o n e  pl as  m a s a  m pl e 
wit h  q u a ntifi a bl e  c o n c e ntr ati o n  of  S  A  G E  - 2 1 7 i n  P art   B.   T h es e  p o p ul ati o ns   will  b e  us e d t o s u  m  m ari z e  P  K 
d at a f or  e a c h r es p e cti v e st u d y  p art.  
9       S T  A TI  S TI  C  A L   A  N  A L  Y  SI  S  
9. 1     G e n er al   C o n si d er ati o n s   
C o nti n u o us ( q u a ntit ati v e)  v ari a bl es   will  b e s u  m  m ari z e d  usi n g t h e  n u  m b er  a n d  pr o p orti o n  of  e a c h  p ossi bl e 
v al u e.  I n  g e n er al, t h e  d e n o  mi n at or f or t h e  p er c e nt a g e  c al c ul ati o n   will  b e  b as e d  u p o n t h e t ot al  n u  m b er  of 
s u bj e cts i n t h e st u d y  p o p ul ati o n f or t h e tr e at m e nt   s e q u e n c e. 
T h e   mi ni  m u  m  a n d   m a xi  m u  m   will  b e r e p ort e d   wit h t h e s a  m e  d e gr e e  of  pr e cisi o n (  i e, t h e s a  m e  n u  m b er  of 
d e ci  m al  pl a c es)  as t h e r a  w  d at a.    M e as ur es  of l o c ati o n (  m e a n  a n d   m e di a n)   will  b e r e p ort e d t o  1  d e gr e e  of 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 1  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
pr e cisi o n   m or e t h a n t h e r a  w  d at a  a n d  m e as ur es  of s pr e a d (st a n d ar d  d e vi ati o n)   will  b e r e p ort e d t o t  w o 
d e gr e es  of  pr e cisi o n   m or e t h a n t h e r a  w  d at a.  
P er c e nt a g es   will  b e  pr es e nt e d t o  o n e  d e ci  m al  pl a c e  u nl ess  ot h er  wis e s p e cifi e d.   Ass ess  m e nts  d o n e  o n 
u ns c h e d ul e d  visits   will  n ot  b e s u  m  m ari z e d  b ut   will  b e list e d.   T h e s af et y  p o p ul ati o n   will  b e  us e d t o 
pr o vi d e  d es cri pti v e s u  m  m ari es  of s af et y.   T h e  effi c a c y  p o p ul ati o n   will  b e  us e d t o  a n al y z e  effi c a c y  d at a.  
T h e  P  K  p o p ul ati o n   will  b e  us e d t o  d eri v e  P  K  d at a.   S af et y s u  m  m ari es f or  P art   A  of t h e st u d y   will  b e 
pr es e nt e d  b y  o v er all s u bj e cts.   S af et y s u  m  m ari es f or  P art   B  of t h e st u d y   will  b e  pr es e nt e d  b y tr e at  m e nt 
s e q u e n c e. 
All fi n al,  pl a n n e d  a n al ys es i d e ntifi e d i n t h e  pr ot o c ol  a n d i n t his  S  A P   will  b e  p erf or  m e d  aft er  all r el e v a nt 
st u d y  d at a  h a v e  b e e n  pr o c ess e d  a n d i nt e gr at e d i nt o t h e  a n al ysis  d at a b as e,  a n al ysis  p o p ul ati o ns  h a v e  b e e n 
fi n ali z e d,  a n d t h e  d at a b as e  h as  b e e n l o c k e d.    A n y  p ost- h o c,  e x pl or at or y  a n al ysis p erf or  m e d  t o s u p p ort 
pl a n n e d st u d y  a n al ys es,   w hi c h   w er e  n ot i d e ntifi e d i n t his  S  A P,   will  b e  d o c u  m e nt e d  a n d r e p ort e d i n 
S e cti o n  9. 8  of t h e   Cli ni c al  St u d y   R e p ort (  C S  R).   A n y r es ults fr o  m t h es e  u n pl a n n e d  a n al ys es ( p ost- h o c) 
will  als o  b e  cl e arl y i d e ntifi e d i n t h e t e xt  of t h e   C S  R.   
All  c oll e ct e d  d at a   will  b e  pr es e nt e d i n listi n gs    a n d   will  b e s ort e d  b y s u bj e ct  a n d st u d y  p art. 
If  p arti al  d at es  o c c ur, t h e  c o n v e nti o n f or r e pl a ci n g   missi n g  d at es f or t h e  p ur p os es  of  c al c ul ati n g  d eri v e d 
v ari a bl es is  as f oll o  ws:  
F or  p arti al  A E    a n d   m e di c ati o n st art  d at es: 
•      If t h e  y e ar is  u n k n o  w n, t h e n  d o  n ot i  m p ut e t h e  d at e  b ut  assi g n  a   missi n g  v al u e. 
•      If t h e y e ar is  k n o  w n,  b ut   m o nt h  or   m o nt h  a n d  d a y  ar e   u n k n o  w n, t h e n: 
o     If t h e  y e ar   m at c h es t h e  y e ar  of first  d os e  d at e, t h e n i  m p ut e t h e   m o nt h  a n d  d a y  of t h e first 
d os e  d at e.  
o     Ot h er  wis e,  assi g n  0 1 J a n u ar y   
•      If t h e y e ar  a n d   m o nt h  ar e  k n o  w n,  b ut  d a y  is  u n k n o  w n, t h e n: 
o     If t h e   m o nt h  a n d  y e ar   m at c h t h e   m o nt h  a n d  y e ar  of t h e first  d os e d at e, t h e n i  m p ut e t h e 
d a y  of t h e first  d os e  d at e. 
o     Ot h er  wis e,  assi g n  0 1   
F or  p arti al  A E    a n d   m e di c ati o n e n d  d at es:  
•      If t h e  y e ar is  u n k n o  w n, t h e n  d o  n ot i  m p ut e t h e  d at e  b ut  assi gn  as   missi n g  v al u e.  
•      If t h e   m o nt h is  u n k n o  w n, t h e n  assi g n t h e l ast  d a y  of t h e  y e ar,  3 1   D e c e  m b er.  If t his r es ults i n a 
d at e  aft er t h e l ast st u d y  d at e,  assi g n t h e  d a y  a n d   m o nt h  of t h e l ast st u d y  d at e. 
•      If t h e  d a y is  u n k n o  w n, t h e n  assi g n t h e l ast  d a y  of t h e   m o nt h. 
If  a n   A E  h as  a   missi n g s e v erit y, it   will  b e i  m p ut e d  as “ S e v er e ”;  a n y   missi n g r el ati o ns hi p t o st u d y  dr u g  of 
a n   A E   will  b e i  m p ut e d  as  “ Pr o b a bl y   R el at e d . ”    N o  ot h er   missi n g d at a  will  b e i  m p ut e d  u nl ess  ot h er  wis e 
s p e cifi e d. 
I n  g e n er al, f or  q u a ntit ati v e l a bor at or y  v al u es r e p ort e d  as ‘ <’  or ‘ ≤’, t h e  l o  w er li  mit  of  q u a ntit ati o n 
( LL  O  Q)  will  b e  us e d f or  a n al ysis   (i e, a  v al u e  of   X   will  b e  us e d i n t h e  a n al ysis f or l a b  v al u es r e p ort e d  as 
‘ <  X’  or ‘≤ X’  ). Si  mil arl y,  f or s af et y q u a ntit ati v e l a b or at or y  v al u es r e p ort e d  as ‘ >  X ’  or ‘≥  X ’, t h e u p p er 
li  mit  of  q u a ntit ati o n (U  L  O  Q)  will  b e  us e d f or  a n al ysis   (i e,  a  v al u e  of   X   will  b e  us e d i n t h e  a n al ysis f or l a b 
v al u es r e p ort e d  as ‘ >  X’  or ‘ ≥  X’).  


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 2  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
F or  a n al ysis  p ur p os es, r e p e at l a b or at or y r est r es ults   will  n ot  b e  us e d  u nl ess t h e  ori gi n al l a b or at or y  v al u e is 
missi n g  or i n di c at e d  as i n v ali d, i n   w hi c h  c as e t h e first  n o n  -missi n g r e p e at l a b or at or y  v al u e   will  b e  us e d 
f or  d at a  a n al ysis. 
F or s af et y  d at a, t h e l ast  o bs er v ati o n r e c or d e d  b ef or e  r e c ei vi n g t h e first  d os e  o n   D a y  1 i n  e a c h st u d y  p art 
will  b e  us e d  as t h e  b as eli n e  o bs er v ati o n f or  all  c al c ul ati o ns  of  c h a n g e fr o  m  b as eli n e.   S e p ar at e  b as eli n es 
will  b e  d eri v e d f or  P art   A  a n d  P art   B.   B as eli n e  v al u es   will  o nl y  b e  dis pl a y e d i n s af et y s u  m  m ari es.   
9. 2     B a c k gr o u n d   C  h ar a ct eri sti c s   
9. 2. 1  S u bj e ct   Di s p o siti o n   
All s u bj e cts   w h o  pr o vi d e i nf or  m e d  c o ns e nt   will  b e  a c c o u nt e d f or i n t his st u d y.   T h e  n u  m b er  of s u bj e cts 
s cr e e n e d  a n d  e nr oll e d   will  b e s u  m  m ari z e d  b y  o v er all s u bj e cts .   T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts 
c o  m pl et e d ,  a n d wit h dr a  w n   fr o  m t h e st u d y,  as   w ell  as r e as o n f or   wit h dr a  w al,   will  b e s u  m  m ari z e d  b y 
o v er all  s u bj e cts i n  P art   A.    A d diti o n all y, t h e  n u  m b er a n d  p er c e nt a g e  of s u bj e cts i n  e a c h  a n al ysis 
p o p ul ati o n   will  b e  s u  m  m ari z e d  o v er all .  P er c e nt a g es   will  b e  c al c ul at e d  usi n g t h e  n u  m b er  of  e nr oll e d 
s u bj e cts.  F o r  P art   B, t h e  n u  m b er  of s u bj e cts r a n d o  mi z e d will  b e s u  m  m ari z e d  b y  o v er all s u bj e cts.   T h e 
n u  m b er  a n d  p er c e nt a g e  of s u bj e cts  c o  m pl et e d,   wit h dr a  w n,  as   w ell  as r e as o ns f or   wit h dr a  w al,  a n d s u bj e cts 
will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt s e q u e n c e f or   P eri o d  1,  P eri o d  2,  a n d  P art   B  o v er all.   T h e  n u  m b er  of 
s u bj e cts i n  e a c h  a n al ysis  p o p ul ati o n   will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt s e q u e n c e.   All  dis p ositi o n 
i nf or  m ati o n   will  b e i n cl u d e d i n  a listi n g. 
9. 2. 2     D e  m o gr a p hi c s  a n d   B a s eli n e   C h ar a ct eri sti c s   
D e  m o gr a p hi cs, s u c h  as  a g e,  g e n  d er,  c hil d - b e ari n g  p ot e nti al, r a c e,  a n d  et h ni cit y,  a n d  b as eli n e 
c h ar a ct eristi cs s u c h  as  h ei g ht,   w ei g ht,  b o d y   m ass i n d e x (  B  MI),  a n d ti  m e ( y e ars) si n c e  P  D  di a g n osis (fr o  m 
i nf or  m e d  c o ns e nt i n  P art   A),   will  b e s u  m  m ari z e d b y  o v er all s u bj e cts  i n  P art   A  a n d  b y tre at  m e nt s e q u e n c e 
i n  P art   B. 
Fr e q u e n c y  a n d  p er c e nt a g e  of  c at e g ori c al s u  m  m ari es, s u c h  as  g e n d er ,  c hil d- b e ari n g  p ot e nti al, r a c e,  a n d 
et h ni cit y ,   will  b e s u  m  m ari z e d b y  o v er all s u bj e cts  i n  P art   A.  I n  P art   B, t h e y   will  b e s u  m  m ari z e d  b y 
tr e at  m e nt s e q u e n c e.    C o nti n u o us s u  m  m ari es, s u c h  as  a g e,  h ei g ht,   w ei g ht, B  MI,   a n d ti  m e si n c e  P  D 
di a g n osis,  will  b e s u  m  m ari z e d  usi n g   m e a n,   st a n d ar d  d e vi ati o n,   m e di a n,   mi ni  m u  m,  a n d   m a xi  m u  m.  A 
d e  m o gr a p hi c t a bl e   will  b e  g e n er at e d f or t h e s af et y  p o p ul ati o n i n  b ot h  p arts  of t h e st u d y. 
H e p atitis,   h u  m a n i  m  m u n o d efi ci e n c y  vir us ( HI  V  ),  a n d  pr e g n a n c y s cr e e ni n g r es ults   will  b e list e d,  b ut  n ot 
s u  m  m ari z e d  as t h e y  ar e  c o nsi d er e d  p art  of t h e i n cl usi o n/ e x cl usi o n  crit eri a.  
M e di c al  hist or y   will  b e list e d.  
9. 2. 3      St u d y   Dr u g   E x p o s ur e    
St u d y  dr u g  d osi n g  i nf or  m ati o n   will  b e list e d. 
9. 2. 4  St u d y   Dr u g   C o  m pli a n c e   
St u d y  dr u g  n o n c o  m pli a n c e s u c h  as   missi n g  visits, i nt err u pti o ns i n t h e s c h e d ul e  of  a d  mi nistr ati o n,  a n d 
n o n p er  mitt e d   m e di c ati o ns   will  b e list e d i n t h e  pr ot o c ol  d e vi ati o ns listi n g.  
9. 3     Effi c a c y    An al y si s   
T h e  pri  m ar y   e n d poi nts  of t his st u d y r el at e t o s af et y  a n d t ol er a bilit y ; t h er e  ar e  n o  pri  m ar y  effi c a c y 
v ari a bl es f or t his st u d y .   
T h e s e c o n d ar y  effi c a c y  v ari a bl es f or t his st u d y i n cl u d e:  
•      M  D S  -U P  D  R S   –  P art III  t ot al s c or e ( P arts   A  a n d   B) 
•      M  D S  -U P  D  R S   –  P arts I -I  V tot al s c or e ( P art   B  o nl y) 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 3  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
T h e  e x pl or at or y  effi c a c y  v ari a bl es f or t his st u d y  ( P art   B  o nl y) i n cl u d e:  
 
 
     
  
     
 
     
 
9. 3. 1  A n al y si s  of   Pri  m ar y   Effi c a c y   V ari a bl e   
N ot  a p pli c a bl e.   
9. 3. 2  A n al y si s  of   S e c o n d ar y   Effi c a c y   V ari a bl e s   
T h e   M  D S -U P  D  R  S i n cl u d es  4 s c al es,   wit h  v ari o us s u bs c al es.  E a c h it e  m is r at e d fr o  m  0 ( n or  m al) t o  4 
(s e v er e).  T h e f o ur   M  D S-U P  D  R S s c al es  ar e:    
P art I:  n o n  m ot or  e x p eri e n c es  of  d ail y li vi n g ( 1 3 it e  ms)  
P art II:   m ot or  e x p eri e n c es  of  d ail y li vi n g ( 1 3 it e  ms)   
P art III:   m ot or  e x a  mi n ati o n ( 3 3 s c or es  b as e d  o n  1 8 it e  ms [s e v er al   wit h ri g ht, l eft  or  ot h er  b o d y 
distri b uti o n s c or es])   
P art I  V:   M ot or  c o  m pli c ati o ns ( 6 it e  ms)   
S c al e f o r t h e    M  D S -U P  D  R S   R ati n g    
D es c ri pti o n    
0  =  n or  m al  
N o s y  m pt o  ms/si g ns  
1  = sli g ht  
S y  m pt o ms/si g ns   wit h s uffi ci e ntl y l o  w fr e q u e n c y 
or i nt e nsit y t o  c a us e  n o i  m p a ct  o n f u n cti o n  
2  =   mil d  
S y  m pt o  ms/si g ns  of fr e q u e n c y  or i nt e nsit y 
s uffi ci e nt t o  c a us e  a   m o d est i  m p a ct  o n f u n cti o n  
3  =   m o d er at e  
S y  m pt o  ms/si g ns s uffi ci e ntl y fr e q u e nt  or i nt e ns e 
t o i  m p a ct  c o nsi d er a bl y,  b ut  n ot  pr e v e nt, f u n cti o n  
4  = s e v er e   
S y  m pt o  ms/si g ns s uffi ci e ntl y fr e q u e nt  or i nt e ns e 
t o i  m p a ct  c o nsi d er a bl y,  b ut  n ot  pr e v e nt, f u n cti o n  
T h e t ot al s c or e f or  P arts I -I  V  c o  m pris es t h e s u  m  of t h e r es ults  of t h e i n di vi d u al it e  m s c or es. P art III 
ass ess es  1 8   m ot or  c at e g ori es, s o  m e  of   w hi c h i n cl u d e ri g ht  a n d l eft   m e as ur e  m e nts: s p e e c h, f a ci al 
e x pr essi o n,  ki n eti c tr e  m or  of  h a n ds, r est tr e  m or  a  m plit u d e,  p ost ur al tr e  m or  of  h a n ds, ri gi dit y  of  n e c k  a n d 
f o ur  e xtr e  miti es, fi n g er t a ps,  h a n d   m o v e  m e nt,  pr o n ati o n/s u pi n ati o n, t o e t a p pi n g,  c o nst a n c y  of r est tr e  m or, 
l e g  a gilit y,  arisi n g fr o  m  c h air,  p ost ur e,  g ait, fr e e zi n g  of  g ait,  p ost ur al st a bilit y,  a n d  gl o b al s p o nt a n eit y  of 
m o v e  m e nt.   T h e  P art III t ot al   s c or e   will  b e  c al c ul at e d  b y t h e s u  m  of s c or es fr o  m t h e  1 8   m ot or  c at e g ori es.  
I n  P art   A, r a  w  v al u es i n t h e   M  D S-U P  D  R S   –  P art III  t ot al s c or e   will  b e s u  m  m ari z e d  b y o v er all s u bj e cts  i n 
t h e  Effi c a c y  P o p ul ati o n ( P art   A).  T h e  P art III t ot al s c or e  at  e a c h ti  m e  p o i nt ( 2,  4,  8,  a n d  1 2  h o urs 
p ost d os e)   will  b e  a v er a g e d  o v er t h e  3 - d a y  p eri o d f or  L/  C  a n d  4- d a y  p eri o d f or  S  A  G E- 2 1 7.    Diff er e n c es 
b et  w e e n  t h e  a v er a g e d P art III t ot al s c or e  at t h e  2,  4,  8,  a n d  1 2  h o ur  p ost d os e ti  m e  p oi nts  b e  a n al y z e d  usi n g 
a  p air e d t -t est.   Th e  a v er a g e d s c or e  a n d t h e  S  A  G E - 2 1 7  – L/  C s u bj e ct l e v el  diff er e n c es  at  e a c h ti  m e  p oi nt 
will  b e s u  m  m ari z e d  a n d  a  S h a pir o-  Wil k  n or  m alit y t est   will  b e r u n  o n t h e  diff er e n c es  pri or t o t h e  p air e d t   -
t est.  If t h e  n or  m alit y  c o n diti o n is  n ot s atisfi e d  at t h e  0. 0 5 si g nifi c a n c e l e v el,  a    Wil c o x o n si g n e d r a n k t est 






St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 6  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
S af et y 
E v al u ati o n 
I n ci d e n c e     R a  w 
V al u e   
C h a n g e 
f r o  m 
B as eli n e   
A b n o r  m alit y/
Cli ni c al 
Si g nifi c a n c e  
A Es   
X     
     
 
 
C  Ms   
X     
     
 
 
L a bs  
     
X     
X        
* 
E  C  G  
     
X     
X 
* 
Vit al  Si g ns       
     
X     
X    
 
P E  
     
*     
 
* 
C- S S  R S      
     
X     
X 
 
S S S  
     
X     
X 
 
M  O  A  A/ S       
     
X     
X 
 
X  =  S af et y   Ass ess  m e nt   will  b e s u  m  m ari z e d i n t a bl es   
*  =  S af et y   Ass ess  m e nt   will  b e s u  m  m ari z e d i n i n di vi d u al s u bj e ct 
d at a listi n gs  
9. 4. 1  A d v er s e  E v e nt s    
A d v ers e  e v e nts   (  A Es) will  b e  c o d e d  usi n g t h e   M e d  D  R  A  c o di n g s yst e  m ( v ersi o n  1 8. 1  or  hi g h er).   T h e 
a n al ysis  of  A Es     will  b e  b as e d  o n t h e  c o n c e pt  of tr e at  m e nt e  m er g e nt   A Es ( T E  A Es ).    A  T E  A E d uri n g  P art 
A   is  d efi n e d  as  a n A E     wit h  o ns et  aft er t h e st art  of  o p e n-l a b el st u d y  dr u g,  or  a n y   w ors e ni n g  of  a  pr e-
e xisti n g   m e di c al  c o n diti o n/ A E   wit h  o ns et  aft er t h e st art  of  o p e n  -l a b el st u d y  dr u g  a n d  u ntil  1 4  d a ys  aft er 
t h e l ast  d os e.  A  T E  A E   d uri n g  P art   B  is  d efi n e d  as  a n   A E   wit h  o ns et  aft er t h e st art  of r a n d o  mi z e d st u d y 
dr u g,  or  a n y   w ors e ni n g  of  a  pr e -e xisti n g   m e di c al  c o n diti o n/  A E   wit h  o ns et  aft er t h e st art  of r a n d o  mi z e d  
st u d y  dr u g  a n d  u ntil  1 4  d a ys  aft er t h e l ast  d os e.   I n  P art   A,  T E  A Es   will  b e  assi g n e d t o tr e at  m e nt  p eri o ds  as 
f oll o  ws: 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  o f  L e v o d o p a  o n   D a y  1  a n d   wit hi n  2 4 
h o urs  aft er t h e l ast  a d  mi nistr ati o n  of  L/  C   m e di c ati o n  a n d  b ef or e t h e first  d os e  of  S  A  G E- 2 1 7  o n 
D a y  4   will  b e  assi g n e d t o t h e  L/  C   D a y  1 t o   D a y  3  p eri o d. 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of  S  A  G E  - 2 1 7  o n   D a y  4  a n d   wit hi n 
2 4  h o urs  aft er t h e l ast  a d  mi nistr ati o n  of  S  A  G E- 2 1 7  o n   D a y  7   will  b e  assi g n e d t o t h e  S  A  G E- 2 1 7 
D a y  4 t o   D a y  7  p eri o d. 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d   m or e t h a n  2 4  h o urs  aft er t h e l ast  d os e  of st u d y  dr u g   will  b e 
assi g n e d t o t h e f oll o  w - u p  p eri o d. 
I n  P art   B,  T E  A Es   will  b e  assi g n e d t o tr e at  m e nt  p eri o ds  as f oll o  ws: 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of   st u d y  dr u g  o n   D a y  1  a n d   wit hi n  2 4 
h o urs  aft er t h e l ast  a d  mi nistr ati o n  of st u d y  dr u g  m e di c ati o n  a n d  b ef or e t h e   first  d os e  of  S  A  G E-
2 1 7  o n   D a y  5  will  b e  assi g n e d t o   t h e  L/  C +  S  A  G E - 2 1 7  or  L/  C  +  Pl a c e b o   D a y  1 t o   D a y  4 p eri o d . 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 7  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of  S  A  G E  - 2 1 7  o n   D a y  5  a n d   wit hi n 
2 4  h o urs  aft er t h e l ast  a d  mi nistr ati o n  of  S  A  G E- 2 1 7  o n  D a y  8   will  b e  assi g n e d t o t h e  S  A  G E  - 2 1 7 
D a y  5 t o   D a y  8  p eri o d. 
•      T E  A Es t h at  o c c urr e d  or   w ors e n e d   m or e t h a n  2 4  h o urs  aft er t h e l ast  d os e  of st u d y  dr u g   will  b e 
assi g n e d t o t h e f oll o  w - u p  p eri o d. 
P art   A,   A Es   will  b e s u  m  m ari z e d  b y tr e at  m e nt  p eri o d  a n d  b y f oll o  w- u p.  I n  P art   B,   A Es   will  b e 
s u  m  m ari z e d  b y tr e at  m e nt  p eri o d  a n d f oll o  w - u p wit hi n tr e at  m e nt s e q u e n c e.   
A s u  m  m ar y  of  T E  A Es   will  b e  pr o vi d e d.  Fr e q u e n ci es  a n d  p er c e nts  of t h e f oll o  wi n g   will  b e i n cl u d e d: 
•      N u  m b er  of s u bj e cts   wit h  at l e ast  o n e  T E  A E   
•      N u  m b er  of s u bj e cts   wit h  at l e ast  o n e  T E  A E l e a di n g t o  dis c o nti n u ati o n   
•      N u  m b er  of s u bj e cts   wit h  a  T E  A E l e a di n g t o  d e at h 
•      N u  m b er  of s u bj e cts   wit h  at l e ast  o n e s eri o us  a d v ers e  e v e nt ( S  A E)   
I n  P art   A, t h e i n ci d e n c e  of  T E  A Es   will  b e s u  m  m ari z e d  b y t h e f oll o  wi n g: 
•      S  O  C  a n d  P T  
•      P T  
•      D os e   ( S  A  G E- 2 1 7  o nl y),   D a y,  a n d  P T 
•      S  O  C,  P T,  a n d   M a xi  m u  m  S e v erit y 
•      S  O  C,  P T,  a n d   R el ati o ns hi p t o  St u d y   Dr u g 
I n P art   B, t h e i n ci d e n c e  of  T E  A Es   will  b e s u  m  m ari z e d  b y t h e f oll o  wi n g: 
•      Tr e at  m e nt s e q u e n c e,  S  O  C,  a n d  P T 
•      Tr e at  m e nt s e q u e n c e  a n d  P T  
•      Tr e at  m e nt s e q u e n c e,  S  O  C,  P T,  a n d   M a xi  m u  m  S e v erit y 
•      Tr e at  m e nt s e q u e n c e,  S  O  C,  P T,  a n d   R el ati o ns hi p t o  St u d y   Dr u g 
All   S  A Es,   A Es l e a di n g t o  dis c o nti n u ati o n,  a n d   A Es  l e a di n g t o  d e at h   will  b e list e d i n  a s e p ar at e t a bl es. 
9. 4. 2     Pri or  a n d   C o n c o  mit a nt   M e di c ati o n s    
C o n c o  mit a nt   m e di c ati o ns   will  b e   c o d e d  usi n g    W orl d   H e alt h   Or g a ni z ati o n   Dr u g   Di cti o n ar y  (   W  H  O-D  D) 
(  V ersi o n  S e pt e  m b er  1,  2 0 1 5  or l at er). 
Fr e q u e n ci es  a n d  p er c e nt a g es  of   m e di c ati o ns  us e d i n t h e st u d y   will  b e s u  m  m ari z e d  as f oll o  ws: 
•      Pri or   m e di c ati o n:   m e di c ati o n t a k e n  pri or t o t h e  d at e  of t h e fir st  d os e  of  o p e n-l a b el st u d y  dr u g i n 
P art   A.  
•      C o n c o  mit a nt   m e di c ati o n: I n  P art   A,  a   m e di c ati o n   wit h  a st art  d at e  o n  or  aft er t h e first  d os e  of 
o p e n-l a b el st u d y  dr u g ( e v e n if  e n d  d at e is   missi n g)  b ut  b ef or e t h e st art  of  P art   B   will  b e 
c o nsi d er e d  c o n c o  mit a nt.   M e di c ati o ns   wit h  a st art  d at e  b ef or e t h e first  d os e  of  o p e n   -l a b el st u d y 
dr u g t h at  ar e  o n g oi n g  or   wit h  a st o p  d at e  o n  or  aft er t h e first  d os e  of  o p e n-l a b el st u d y  dr u g   will  b e 
c o nsi d er e d  c o n c o  mit a nt.  I n  P art   B,  a   m e di c ati o n   wit h  a st art  d at e  o n  or  aft er t h e  first  d os e  of 
r a n d o  mi z e d st u d y  dr u g ( e v e n if  e n d  d at e is   missi n g)   will  b e  c o nsi d er e d  c o n c o  mit a nt.    M e di c ati o ns 
wit h  a st art  d at e  b ef or e t h e first  d os e  of r a n d o  mi z e d st u d y  dr u g t h at  ar e  o n g oi n g  or   wit h  a st o p 
d at e  o n  or  aft er t h e first  d os e  of r a n d o  mi z e d st u d y  dr u g   will  b e  c o nsi d er e d  c o n c o  mit a nt.   If 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 8  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
m e di c ati o n  d at es  ar e i n c o  m pl et e  a n d it is  n ot  cl e ar   w h et h er t h e   m e di c ati o n   w as  c o n c o  mit a nt, it 
will  b e  ass u  m e d t o  b e  c o n c o  mit a nt.   
•      R es c u e   m e di c ati o n:  a n y  or al  L e v o d o p a  or  ot h er  a nti p ar ki ns o n  a g e nt  at t h e I n v e  sti g at or’s 
dis cr eti o n t a k e n  o n  d a ys  1  t o 7 i n  P art   A  or  d a ys  1 t o  8 i n  P art   B t h at is  n ot  p art  of t h e  pl a n n e d 
st u d y tr e at  m e nt   will  b e  c o nsi d er e d r es c u e   m e di c ati o n.  
C o n c o  mit a nt   m e di c ati o ns   will  b e  assi g n e d t o t h e st u d y  p art i n   w hi c h t h e y  ar e  b ei n g t a k e n. If   a 
c o n c o  mit a nt   m e di c ati o n  assi g n e d t o  P art   A  c o nti n u es t o  b e t a k e n t hr o u g h  P art   B, t h e n t h e   m e di c ati o n   will 
b e  assi g n e d t o  b ot h  p arts  of t h e st u d y  as  a p pr o pri at e. If t h e st art  a n d st o p  d at es  of t h e  c o n c o  mit a nt 
m e di c ati o ns  d o  n ot  cl e arl y  d efi n e t h e  p art  d ur  i n g   w hi c h  a   m e di c ati o n   w as t a k e n, it   will  b e  ass u  m e d t o  b e 
t a k e n i n  b ot h  p arts.   D et ails  of  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns   will  b e list e d  b y st u d y  p art, s u bj e ct, st art 
d at e,  a n d  v er b ati  m t er  m.  Pri or  a n d  c o n c o  mit a nt    m e di c ati o ns   will  b e s u  m  m ari z e d  b y   A n at omi c 
T h er a p e uti c   C h e  mi c al (  A T  C)  cl ass  a n d  pr ef err e d t er  m ( P T) .  I n  P art   A,  c o n c o  mit a nt   m e di c ati o ns   will  b e 
s u  m  m ari z e d  u n d er  S  A  G E- 2 1 7,  L e v o d o p a/  C ar bi d o p a f or   D a y  1 t o   D a y  3 ,  a n d f oll o  w- u p.  T h e f oll o  w - u p 
p eri o d  b e gi ns  2 4  h o urs  aft er t h e l ast  d os e  of  S  A  G E- 2 1 7.    M e di c ati o ns t h at  ar e  c o n c o  mit a nt t o  b ot h 
p eri o ds   will  b e s u  m  m ari z e d  u n d er  b ot h tr e at  m e nts.    C o n c o  mit a nt   m e di c ati o ns   will  als o  b e s u  m  m ari z e d  b y 
d os e,  d a y ,  a n d  P T d uri n g t h e  S  A  G E - 2 1 7  p eri o d.  I n  P art   B,  c o n c o  mit a nt   m e di c ati o ns   will b e s u  m  m ari z e d 
u n d er  S  A  G E- 2 1 7,  L/  C  +  Pl a c e b o  or  L/  C  +  S  A  G E - 2 1 7 f or   D a y  1 t o   D a y  4,  a n d f oll o  w- u p.    M e di c ati o ns 
t h at  ar e  c o n c o  mit a nt t o   m ulti pl e  p eri o ds   will  b e s u  m  m ari z e d  u n d er e a c h  p eri o d .   P art   B s u  m  m ari es   will  b e 
wit hi n tr e at  m e nt s e q u e n c e. 
T h e  us e  of r es c u e   m e di c ati o ns   will  b e  list e d  a n d s u  m  m ari z e d i n t h e s a  m e   m a n n er  as  c o n c o  mit a nt 
m e di c ati o ns.    R es c u e   m e di c ati o ns   will  b e s u  m  m ari z e d  b y  P T  o nl y.   
M e di c ati o n s u  m  m ari es   will  b e  b as e d  o n t h e  S af et y  P o p ul ati o n.    
9. 4. 3  Cli ni c al  L a b or at or y  
All st atisti c al  a n al ys es  of l a b or at or y  v al u es   will  b e  p erf or  m e d  usi n g   SI  u nits.    C o nti n u o us  h e  m at ol o g y, 
c h e  mistr y ,  a n d  uri n al ysis r es ults  a n d  c h a n g es fr o  m   B as eli n e  of  P art   A   will  b e s u  m  m ari z e d  b y  o v er all 
s u bj e cts i n  P art   A.    R a  w  v al u es  a n d   m e a n  c h a n g es fr o  m   B as eli n e  of  P art   B   will  b e s u  m  m ari z e d  b y   wit hi n 
r a n d o  mi z e d tr e at  m e nt s e q u e n c e. All  cli ni c al l a b or at or y r es ults   will  b e list e d  b y s u bj e ct  a n d ti  mi n g  of 
c oll e cti o n.  T his listi n g   will i n cl u d e  d at a fr o  m s c h e d ul e d  a n d  u ns c h e d ul e d ti  m e  p oi nts.   Cli ni c all y 
si g nifi c a nt  a b n or  m al fi n di n gs   will  b e r e p ort e d  as A Es  .  
9. 4. 4  El e ctr o c ar di o gr a  m   
T h e f oll o  wi n g  1 2- E  C  G  p ar a  m et ers   will  b e list e d f or  e a c h s u bj e ct:  h e art r at e,  P  R  I nt er v al,   Q  R S D ur ati o n, 
Q T   I nt er v al,  a n d   Q T c F.    A n y  cli ni c all y si g nifi c a nt  a b n or  m aliti es  or  c h a n g es i n  E  C  Gs s h o ul d  b e list e d  as 
a n  A E  .  R a  w  v al u es  , m e a n  c h a n g es fr o  m   B as eli n e  ,  a n d i n v esti g at or i nt er pr et ati o n of  P art   A  r es ults will  b e 
s u  m  m ari z e d  b y o v er all s u bj e cts .    R a  w  v al u es, m e a n  c h a n g es fr o  m   B as eli n e  ,  a n d i n v esti g at or 
i nt er pr et ati o n of  P art   B  r es ults will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt s e q u e n c e. 
9. 4. 5  Vit al  Si g n s  
Vit al si g n r es ults   ( b o d y t e  m p er at ur e,  h e art r at e, r es pir at or y r at e, s u pi n e  a n d st a n di n g  di ast oli c  bl o o d 
pr ess ur e, s u pi n e  a n d st a n di n g s yst oli c  bl o o d  pr ess ur e,  a n d  p uls e  o xi  m etr y ) will  b e list e d  b y s  u bj e ct  a n d 
ti  mi n g  of  c oll e cti on.    R a  w  v al u es  a n d   m e a n  c h a n g es  fr o  m B as eli n e   at  e a c h ti  m e  p oi nt  of  P art   A  will  b e 
s u  m  m ari z e d b y  o v er all s u bj e cts.    R a  w  v al u es  a n d   m e a n  c h a n g es fr o  m   B as eli n e  at  e a c h ti  m e  p oi nt  of  P art 
B   will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt   s e q u e n c e. 
9. 4. 6  P h y si c al  E x a  mi n ati o n   
S cr e e ni n g  p h ysi c al  e x a  mi n ati o n r es ults f or  P art   A  a n d  r es ults f or P art   B  t h at  ar e  cli ni c all y si g nifi c a nt will 
b e list e d  i n t h e   m e di c al  hist or y listi n g.   P ost-s cr e e ni n g  p h ysi c al  e xi  mi n ati o n r es ults f or  P art   A  a n d r es ults 
f or P art   B  t h at  ar e  cli ni ci all y si g nifi c a nt will  b e list e d   i n t h e   A E listi n g. 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  1 9  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
9. 4. 7  C ol u  m bi a -S ui ci d e  S e v erit y   R ati n g   S c al e (  C  -S  S  R  S)  
S ui ci d alit y  w as     m o nit or e d  d uri n g t h e st u d y  usi n g t h e   C-S S  R S.  T his s c al e  c o nsists  of  a  b as eli n e  e v al u ati o n 
t h at  ass ess es t h e lif eti  m e  e x p eri e n c e  of t h e s u bj e ct   wit h s ui ci d al i d e ati o n  a n d  b e h a vi or,  a n d  a  p ost-b as eli n e  
e v al u ati o n t h at f o c us es  o n s ui ci d alit y si n c e t h e l ast s t u d y  visit.  T h e   C-S S  R S i n cl u d es  “ y es ”  or  “ n o ” 
r es p o ns es f or  ass ess  m e nt  of s ui ci d al i d e ati o n  a n d  b e h a vi or  as   w ell  as  n u  m eri c r ati n gs f or s e v erit y  of 
i d e ati o n, if  pr es e nt (fr o  m  1 t o  5,   wit h  5  b ei n g t h e   m ost s e v er e).  
S ui ci d alit y  d at a  c oll e ct e d  o n t h e   C -S S  R S  will  b e list e d f or  all s u bj e cts.    T a bl es  will i n cl u d e  b e h a vi or t y p e 
a n d/ or  c at e g or y f or  S ui ci d al I d e ati o n  a n d  S ui ci d al   B e h a vi or  of t h e   C- S S  R S   pr e-tr e at  m e nt  a n d  p ost-
b as eli n e  e v al u ati o n s.  Fr e q u e n ci es   a n d  p er c e nts f or t h e s u bj e cts   wit h at l e ast  o n e  r es p o ns e of  “  Y es ”  o n t h e 
S ui ci d al I d e ati o n  a n d  S ui ci d al   B e h a vi or  q u esti o ns  pr e -tr e at  m e nt  a n d p ost- b as eli n e    will  b e s u  m  m ari z e d. 
P art   A r es ults  will  b e s u  m  m ari z e d  b y  o v er all s u bj e cts.   P art   B r es ults   will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt 
s e q u e n c e.    R es ults fr o  m  all s e cti o ns  of t h e   C- S S  R S   will  b e list e d.  
9. 4. 8  St a nf or d  Sl e e pi n e s s   S c al e   
T h e  S S S is  a s u bj e ct -r at e d s c al e  d esi g n e d t o  q ui c kl y  ass ess  h o  w  al ert  a s u bj e ct is f e eli n g.   D e gr e es  of 
sl e e pi n ess  a n d  al ert n ess  ar e r at e d  o n  a s c al e  of  1 t o  7,   w h er e t h e l o  w est s c or e  of  1  i n di c at es t h e s u bj e ct is 
“f e eli n g  a cti v e,  vit al,  al ert,  or   wi d e  a  w a k e ”  a n d t h e  hi g h est s c or e  of  7 i n di c at es t h e s u bj e ct is  “ n o l o n g er 
fi g hti n g sl e e p, sl e e p  o ns et s o o n;  h a vi n g  dr e a  m-li k e t h o u g hts ”.  A r es p o ns e  of  “  X ” i n di c at es t h e s u bj e ct is 
asl e e p.   T his r es p o ns e   will  b e s u  m  m ari z e d  c at e g ori c all y  b ut   will  n ot  b e i n cl u d e d i n t h e  n u  m eri c r a  w  v al u e 
a n d  c h a n g e fr o  m  b as eli n e t a bl es.  
S e d ati o n  d at a  c oll e ct e d  o n t h e  S S S   will  b e list e d f or  all s u bj e cts.   T ot al  s c or e  o v er ti  m e will  b e 
r e pr es e nt e d  gr a p hi c all y b y  o v er all s u bj e cts  i n  P art   A  a n d  b y tr e at  m e nt s e q u e n c e i n  P art   B.  R a  w  v al u es   
a n d  c h a n g e fr o  m   B as eli n e  of  P art   A  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d  o v er all s u bj e cts .  R a  w  v al u es 
a n d  c h a n g e fr o  m   B as eli n e  of  P art   B  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt s e q u e n c e.   
Fr e q u e n c y t a bl es  b y  o v er all s u bj e cts i n  P art   A  a n d  b y tr e at  m e nt s e q u e n c e i n  P art   B   will  als o  b e  pr o vi d e d.  
9. 4. 9     M o difi e d   O b s er v er’ s A s s e s s  m e nt  of   Al ert n e s s/  S e d ati o n (  M  O  A  A/  S)  
T h e   M  O  A  A/ S  all o  ws  e x pl or ati o n  of  d e e p er s e d ati o n st at es t h a n t h e  S S S.   If  a   M  O  A  A/ S s c or e  of  3  or l ess 
w as  o bs er v e d, t h e s c or e   w as t o  b e  c o nfir  m e d  b y   w aiti n g  a p pr o xi  m at el y  1 0   mi n ut es  a n d r e-  a d  mi nist eri n g 
t h e   M  O  A  A/ S  ass ess  m e nt. T h e l o  w est s c or e  of  0 i n di c at es t h e s u bj e ct  h as  “  N o r es p o ns e  aft er  p ai nf ul 
tr a p e zi us s q u e ez e ”  a n d t h e  hi g h est s c or e  of  5 i n di c at es t h e s u bj e ct  “  R es p o n ds r e a dil y t o  n a  m e s p o k e n i n 
n or  m al t o n e ”.  
S e d ati o n  d at a  c oll e ct e d  o n t h e   M  O  A  A/ S   will  b e list e d f or  all s u bj e cts.   T ot al  s c or e  o v er ti  m e   will  b e 
r e pr es e nt e d  gr a p hi c all y b y  o v er all s u bj e cts  i n  P art   A  a n d  b y tr e at  m e nt s e q u e n c e i n  P art   B.  R a  w  v al u es 
a n d  c h a n g e fr o  m   B as eli n e  of  P art   A  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d  b y  o v er all s u bj e cts.    R a  w 
v al u es  a n d  c h a n g e fr o  m   B as eli n e  of  P art   B  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d   wit hi n tr e at  m e nt 
s e q u e n c e.   Fr e q u e n cy t a bl es  b y  o v er all s u bj e cts i n  P art   A  a n d  b y tr e at  m e nt s e q u e n c e i n  p art   B   will  als o  b e 
pr o vi d e d.   If  a r e-ass ess  m e nt  at  a ti  m e  p oi nt is r e q uir e d,  o nl y t h e first  ass ess  m e nt   will  b e s u  m  m ari z e d  a n d 
b ot h  ass ess  m e nts   will  b e list e d.  
9. 5     P h ar  m a c o ki n eti c   A n al y si s   
F o r  pl as  m a  c o n c e ntr ati o n  d at a,  all  v al u es  b el o  w t h e li  mit  of  q u a ntifi c ati o n (  B L  Q)   will  b e s et t o  0 f or 
s u  m  m ar y st atisti cs  a n d  gr a p hs. I n di vi d u al  pl as  m a  c o n c e ntr ati o ns  of  S  A  G E - 2 1 7   will  b e s u  m  m ari z e d  at 
e a c h ti  m e  p oi nt  usi n g  d es cri pti v e st atisti cs, i n cl u di n g  n u  m b er ( n),   m e a n, st a n d ar d  d e vi ati o n,   m e di a n, 
m a xi  m u  m,   mi ni  m u  m,   %   c o effi ci e nt  of  v ari ati o n ( C  V  ) a n d  g e o  m etri c   m e a n.  F or  P art   A, s u  m  m ari es   m a y 
b e  d o n e  b y t ol er at e d  d os e  or  b y  o v er all s u bj e cts  o nl y.  I n  P art   B, s u  m  m ari es   m a y  b e  d o n e  b y t ol er at e d 
d os e  or  b y  o v er all s u bj e cts   wit hi n tr e at  m e nt s e q u e n c e.   T h e fi n al  c ol u  m ns i n t h e  P  K t a bl es   will  d e p e n d  o n 
t h e fi n al  d at a  a n d t h e j u d g e  m e nt  of t h e  p h ar  m a c o ki n eti cist.  I n di vi d u al  c o n c e ntr ati o n  pl ots  a n d   m e a n  d at a 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  2 0  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
gr a p hs   will  b e  pr o d u c e d.   All  gr a p hs   will  b e  pr es e nt e d  usi n g  b ot h li n e ar  a n d s e  mi -l o g arit h  mi c s c al es.  T h e 
a b o v e  d es cri pti v e s u  m  m ar y   will  b e  p erf or  m e d f or t h e  P  K  p o p ul ati o n.  
All  S  A  G E  - 2 1 7  pl as  m a  c o n c e ntr ati o ns   will  b e  pr es e nt e d i n  a  b y-s u bj e ct listi n g.  
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m ati o n   will  b e  p erf or  m e d  usi n g  P h o e ni x    Wi n  N o nli n ®  s oft  w ar e (  V ersi o n 
6. 4  or l at er;  P h arsi g ht,   C ar y,   N  C)  o n i n di vi d u al  pl as  m a  c o n c e ntr ati o n- ti  m e  d at a.  F or t h e  P  K  p ar a  m et er 
c al c ul ati o n,   B L  Q  pl as  m a  c o n c e ntr ati o ns  o c c urri n g  b ef or e  tm a x  will  b e s et t o  0,   wit h t h e  e x c e pti o n  of  a 
B L  Q  v al u e  o c c urri n g  b et  w e e n t  w o   m e as ur a bl e  c o n c e ntr ati o ns, i n   w hi c h  c as e it   will  b e s et t o   missi n g. 
B L  Q  pl as  m a  c o n c e ntr ati o ns  o c c urri n g  aft er   tm a x  will  b e s et t o   missi n g.  P h ar  m a c o ki n eti c  p ar a  m et er 
esti  m at es  a n d s u  m  m ari es   will  b e  c o  m pl et e d f or s u bj e cts i n t h e  P  K  p o p ul ati o n  h a vi n g s uffi ci e nt 
m e as ur a bl e  c o n c e ntr ati o ns t o  d efi n e t h e  pr ofil e.    
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m at es, i n cl u di n g   C m a x , tm a x ,  λZ ,   A  U  C0-t ,   A  U  C0-  ∞,   Css, a n d t 1/ 2, w h er e 
a p pr o pri at e  a n d  as  d at a  p er  mit,   will  b e s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs, i n cl u di n g  arit h  m eti c  a n d 
g e o  m etri c   m e a ns,  S  D,   %  C  V,   m e di a n,   mi ni  m u  m,  a n d   m a xi  m u  m.   As t m a x  is  a  c at e g ori c al  v ari a bl e,  o nl y t h e 
m e di a n  a n d   t h e r a n g e   will  b e r e p ort e d.  
W h er e v er  n e c ess ar y  a n d  a p pr o pri at e,  P  K  p ar a  m et ers   m a y  b e  d os e   -a dj ust e d t o  a c c o u nt f or i n di vi d u al 
diff er e n c es i n  d os e. 
A  gr a p h  c o  m p ari n g  c h a n g es i n   M  D S-  U P  D  R S  P art III   t ot al s c or e  a n d  p h ar  m a c o ki n eti c  c o n c e ntr ati o ns  o v er 
ti  m e   will b e  pr o d u c e d f or  o v er all s u bj e cts i n t h e  P  K  P o p ul ati o n.  
1 0     SU  M  M  A  R  Y   O F   I  N T  E  RI  M   A  N  A L  Y  S  E  S 
A n i nt eri  m  a n al ysis   will  b e  c o n d u ct e d  u p o n t h e  c o  m pl eti o n  of  1 0 s u bj e cts i n  P art   A   t o i nf or  m t h e  c o n d u ct 
of  P art   B.   All  P art   A t a bl es, listi n gs,  a n d fi g ur es    e x cl u di n g  a n y  P  K  a n al ysis will  b e  g e n er at e d f or t h e 
i nt eri  m  a n al ysis. 
1 1    R  E F  E  R  E  N  C  E  S   
P et o,   V., J e n ki ns o n,   C.,  Fit z p atri c k,   R.,   &   Gr e e n h all,   R. ( 1 9 9 5).  T h e   D e v el o p  m e nt  of  a  S h ort  
       M e as ur e  of  F u n cti o ni n g  a n d    W ell   B ei n g f or I n di vi d u als   wit h  P ar ki ns o n’s   Dis e as e. Q u alit y  of         
     Lif e  R es e ar c h,  4 ( 3),  2 4 1- 2 4 8.   R etri e v e d fr o  m  htt p://  w  w  w.j st or. or g.


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  2 1  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
1 2    LI  S T   O F   A P  P  E  N  DI  C  E  S  
1 2. 1   A p p e n di x   A:   S c h e d ul e  of   A s s e s s  m e nt s   
1 2. 1. 1   P art   A  
Visit   D a ys   
S c r e e ni n g 
(  D a y -2 8 t o 
D a y   -1)  
A d  mit 
(  D a y -1)  
P a rt   A:    O p e n -L a b el   
F oll o  w -u p  
D a y  1       
D a y  2       
D a y  3       
D a y  4       
D a y  5       
D a y  6       
D a y  7       
D a y  8       
D a y  1 4 ( ± 1)   
I nf or  m e d   C o ns e nt 
X   
     
     
     
     
     
     
     
     
 
 
I n cl usi o n/ E x cl usi o n 
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X       
     
     
     
     
     
     
     
 
 
C o nfi n e d t o   U nit a  
 
X       
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X       
X       
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X   
 
D e  m o gr a p hi cs   
X   
     
     
     
     
     
     
     
     
 
 
M e di c al   Hist or y   
X   
     
     
     
     
     
     
     
     
 
 
P h ysi c al  E x a  mi n ati o n  
X       
X       
X       
     
X       
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X   
 
B o d y    W ei g ht/  H ei g ht   
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C  B  C/ S er u  m   C h e  mistr y b  
X       
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Pr e g n a n c y  T est   
X  -s er u  m     
X  -uri n e      
     
     
     
     
     
     
     
 
 
Uri n al ysis c  
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X   
H e p atitis   &   HI  V s cr e e n       
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Vit al  Si g ns d  
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X   
P uls e   O xi  m etr y e  
 
X       
X       
X       
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X       
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X   
1 2 -L e a d  E  C  G f 
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X   
C  -S S  R S g  
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S S S h  
 
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M  O  A  A/ S
i 
 
     
     
     
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M  D S  -U P  D  R S ( c o  m pl et e) j 
X       
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X       
X   
M  D S  -U P  D  R S ( P art III 
o nl y) k 
 
     
X       
X       
X       
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X       
X       
X       
 
 
Pl as  m a  P  K  S a  m pl es p  
 
     
     
     
     
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X   
A d  mi nist er  L e v o d o p a  or 
C ar bi d o p a  -L e v o d o p a q 
 
     
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X       
X       
     
     
     
     
 
 
A d  mi nist er  S  A  G E  -2 1 7 q     
 
     
     
     
     
X       
X       
X       
X       
 
 
A d v er s e  E v e nts   
X   
Pri or/  C o n c o  mit a nt 
M e di c ati o ns   
X   


Statistical An al ysis Pla n Met h o ds 0 6 Fe br m uy 2 0 1 7 Versi o n 1. 0 
Pr ot oc ol Nu m ber: S A G E- 2 1 7- P R K- 2 0 1 
; C B C = c o m plete bl o o d c o u nt; C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scal e; 
Pa ge 22 
E C G = e ectr ocar 1 0 gra m; HI V = 
u ma n 1 m m u n o eficie nc y vir us; MD S-U
P D R S  = M o ve me nt Dis or der S ociet y - Un i fie d Par ki ns o n's Disease Rati n g Scale; 
M O A AI S = M o di fi e d O bser ver's Assess me nt of Ale11 ness /Se dati o n; 
P K = p ha n nac o ki netic; S S S = Sta nf or d Slee pi ness Scale 
• S u bjects will b e disc har ge d fr o m t he u nit a fter c o m pleti o n of all Da y 8 assess me nts.
b Scree ni n g a n d Sa fet y La b orat m y Tests: Scree ni n g a n d Da y - 1 [ A d missi o n]; pre d ose f or Da y 4 , Da y 6 , a n d Da y 8; Da y 1 4. 
c Uri nal ysis: Scree ni n g a n d A d missi o n ( Da y - 1); Pre d ose f or Da y 4 a n d Da y 7; Da y 1 4. 
Vital Si gn s: Scree ni n g a n d Da y - 1 [ A d missi o n]; pre d ose a n d 1 , 2 , 3 , 4 , 6 , 8 , 1 2 , 1 4 , a n d 1 6 h o urs p ost d ose o n C o nfi ne me nt Da ys 1, 2 , 3 , 4, 5 , 6 , a n d 7; i n A M 
of Da y 8; a n d Da y 1 4. Vital si gn s assess me nts ar e t o b e p erf o1 m e d wit hi n ± l 0 mi n utes of t h e sc he d ule d ti m es t hr o u g h t he 4 h o ur ti m e p oi nt a n d wit hi n ± 1 5 
mi n utes of t he sc he d ule d ti mes t herea fter. 
P ulse O xi met1 y: A d missi o n ( Da y - 1); pre d ose a n d 1, 2, 3, 4, 6, 8, 1 2, 1 4, a n d 1 6 h o urs p ost d ose o n C o n fi ne me nt Da ys 1 , 2, 3, 4 , 5, 6, a n d 7; i n A M of Da y 8; 
a n d Da y 1 4. Pu ls e o xi me tl y is t o b e perf o n ne d wit hi n ± 1 0 mi n utes of t he sc he d ule d ti m es t hr o u g h t he 4 1 0 m ti me p oi nt a n d wit hi n ± 1 5 mi n utes of t h e 
s c h e d ul e d ti mes t herea fter. 
1 2- Lea d E C G: Scree ni n g a n d A d missi o n ( Da y - 1); pre d ose o n Da y 1 a n d Da y 3; pre d ose a n d 1 ( ± 1 0 m i n utes) a n d 1 2 ( ± 1 5 mi n utes) h o urs p ost d ose o n
C o n fi ne me nt Da ys 4 , 5 , 6 , a n d 7; i n A M of Da y 8; a n d Da y 1 4.
g C- S S R S: Scree ni n g a n d A d missi o n ( Da y - 1); 1 2 h o urs p ost d ose o n Da y 1 , Da y 2, a n d Da y 3; pre d ose o n Da y 4, Da y 5, Da y 6, a n d Da y 7 a n d Da y 8 a n d Da y
1 4.; Scree ni n g/ Baseli ne versi o n of C- S S Rs s h o ul d be use d o n da y of scree ni n g a n d Si nce Last Visit versi o n s h o ul d b e use d o n all s u bse q ue nt ti me p oi nts.
S S S: A d missi o n ( Da y - 1); pre d ose a n d 1, 2, 3, 4, 6, 8, 1 2, 1 4, a n d 1 6 h o urs p ost d ose o n C o n fi ne me nt Da ys 1, 2, 3, 4, 5, 6, a n d 7; i n A M of Da y 8; a n d Da y 1 4. 
T he S S S is t o b e perf o n ne d wit hi n ± 1 0 mi n utes of t he sc he d ule d ti mes t hr o u g h t he 4- h o ur t i me p oi nt a n d wit hi n ± 1 5 mi n utes of the sc he d ule d ti mes t herea fter. 
i M O A AI S: Pre d ose a n d 1 , 2 , 3 , 4 , 6 , 8 , 1 2 , 1 4 , a n d 1 6 h o urs p ost d ose o n C o n fi ne me nt Da ys 1 , 2 , 3 , 4 , 5 , 6 , a n d 7; i n A M of Da y 8; a n d Da y 1 4. T he M O A AI S 
is t o b e perf m me d wit h i n ± 1 0 r ni n utes of t he sc he d ule d ti mes t hr o u g h t he 4 h o ur ti n1e p oi nt a n d wit hi n ± 1 5 mi n utes of t he sc he d ule d ti m es t herea fter. 
i MD S- U P D R S   
(c o m plete): Scree ni n g , A d missi o n ( Da y - 1) ( o nl y if ti m e bet wee n Scree ni n g a n d A d missi o n is ""2 7 da ys)] , o n Da y 8 pri or t o res u mi n g Le v o d o pa , 
a n d Da y 1 4. 
k MD S- U P D R S   
( Pa11 III o nl y): 2 ( ± 1 0 mi n utes) , , 4 ( ± 1 0 mi n utes) , 8 ( ± 1 5 mi n utes) , a n d 1 2 ( ± 1 5 mi n utes) h o urs p ost d ose o n Da ys 1 , 2 , 3 , 4 , 5 , 6 , a n d 7. If 
c o m plete MD S- U P D R S   
is n ot c o m plete d o n A dm issi o n d ue t o it ta ki n g place < 7 da ys a fter Scree ni n g, t he n t h e MD S- U P D R S   
Pait III o nl y s h o ul d als o ta ke 
place o n A d missi o n ( Da y - 1). 
Sa ge T hera pe utics In c 
C o n fi de ntial I nf o1 mati o n 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  2 3  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
p   Pl as  m a  P  K s a  m pli n g ti  m e s ( ±  5   mi n ut es):   D a ys  4  pr e p os e  a n d  0. 2 5,  0. 5,  1,  2,  4,  8,  a n d  1 2  h o urs  p ost d os e;  pr e d os e  o n   D a y  5  a n d   D a y  6;  pr e d os e  a n d  0. 2 5,  0. 5, 
1,  2,  4,  8,  a n d  1 2  h o urs  o n   D a y  7; i n   A  M  of   D a y  8;  a n d   D a y  1 4.   P  K s a  m pl e s  ar e t o  b e  c oll e ct e d   wit hi n  ± 5   mi n ut e s  of t h e s c h e d ul e d s a  m pli n g ti  m e.   
q   L e v o d o p a  or   C ar bi d o p a -L e v o d o p a  a n d  S  A  G E -2 1 7  ar e t o  b e  a d  mi nist er e d i n t h e  m or ni n g.   
 
 
 
 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  2 4  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
1 2. 1. 2   P art   B   
 
Visit   D a ys   
S c r e e ni n g 
(  D a y -1 4 t o 
D a y   -1)  
A d  mit 
(  D a y -1)  
P e ri o d  1:    R a n d o  mi z e d,   Bli n d e d  
P e ri o d  2:   O p e n -l a b el 
F oll o  w -u p  
E n d  of 
St u d y  
D a y  1       D a y  2       D a y  3       D a y  4       D a y  5       D a y  6       D a y  7       D a y  8       D a y  9       
D a y  1 5       
D a y  2 2   
I n cl usi o n/ E x cl usi o n 
X       
X       
     
     
     
     
     
     
     
     
 
     
 
C o nfi n e d t o   U nit a 
     
X       
X       
X       
X       
X       
X       
X       
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X       
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M e di c al   Hist or y   
X       
     
     
     
     
     
     
     
     
     
 
     
 
P h ysi c al  E x a  mi n ati o n      
X       
X       
X       
     
X       
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X       
X       
X       
X       
 
B o d y    W ei g ht/  H ei g ht   
X       
     
     
     
     
     
     
     
     
     
 
     
 
C  B  C/ S er u  m   C h e  mistr y b     
X       
X       
X       
     
X       
X       
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X       
X       
X       
 
Pr e g n a n c y  T est   
X  -s er u  m     
X  -uri n e      
     
     
     
     
     
     
     
     
 
     
 
Uri n al ysis c 
X       
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Vit al  Si g ns d 
X       
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P uls e   O xi  m etr y e 
     
X       
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1 2 -L e a d  E  C  G f 
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C  -S S  R S g 
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S S S h 
     
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M  O  A  A/ S
i 
 
     
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M  D S  -U P  D  R S   ( c o  m pl et e)j     
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M  D S  -U P  D  R S ( P art III 
o nl y) k 
 
     
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Pl as  m a  P  K  S a  m pl es q 
 
     
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A d  mi nist er  St u d y   Dr u g 
C o  m bi n ati o n r 
 
     
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A d  mi nist er  S  A  G E  -2 1 7 
o nl y r 
 
     
     
     
     
     
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A d v er s e  E v e nts   
X   
Pri or/  C o n c o  mit a nt 
M e di c ati o ns   
X   
;   C  B  C =  c o  m pl et e  bl o o d  c o u nt;   C -S S  R S  =   C ol u  m bi a -S ui ci d e  S e v erit y   R ati n g  S c al e; 
E  C  G   = el e ctr o c ar di o gr a  m;   HI  V  =  h u  m a n i  m  m u n o d efi ci e n c y  vir us;   M  D S -U P  D  R S  =   M o v e  m e nt   Dis or d er  S o ci et y   - U nifi e d  P ar ki ns o n’s   Dis e as e   R ati n g  S c al e; 
M  O  A  A/ S  =   M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n e ss/ S e d ati o n; 
; 
; 
P  K  =  p h ar  m a c o ki n eti c;  S S S  =  St a nf or d  Sl e e pi n ess  S c al e  




St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6  F e br u ar y  2 0 1 7   V ersi o n  1. 0 
P a g e  2 6  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
q Pl as  m a  P  K s a  m pli n g ti  m e s:   D a ys  1 t o  4  pr e d os e  a n d  0. 2 5,  0. 5,  1,  2,  4,  8,  a n d  1 2  h o urs  p ost d os e;  pr e d os e  o n   D a y  5  a n d   D a y  6;  pr e d os e  a n d  0. 2 5,  0. 5,  1,  2,  4,  8, 
a n d  1 2  h o urs  p ost d os e  o n   D a y  7  a n d   D a y  8; i n   A  M  of   D a y  9;  a n d   D a y  1 5  a n d   D a y  2 2.   P  K s a  m pl es  ar e t o  b e  c oll e ct e d   wit hi n  ± 5   mi n ut e s  of t h e s c h e d ul e d 
s a  m pli n g ti  m e.  
r  St u d y  dr u g is t o  b e  a d  mi nist er e d i n t h e   m or ni n g  
 


St at isti c al   A n al ysis  Pl a n   M et h o ds  0 6 F e br u ar y  2 0 1 7   V ersi o n  1. 0  
P a g e  2 7  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
 
1 2. 2   A p p e n di x   B:   D et ail s  of   St at  i sti c al   M et h o d ol o g y 
N ot  a p pli c a bl e.   

Prot_001.pdf: 
 
 
Official Title: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of SAGE-217 in Subjects With 
Parkinson's Disease 
 
NCT Number: 
NCT03000569 
 
Document Date: 
Protocol Version 5.0: 08-June-2017 
 
Protocol Version 4.0: 06-June-2017 
Protocol Version 3.0: 24-October-2016 
Protocol Version 2.0: 05-October-2016 
Protocol Version 1.0: 28-September-2016 


Clinical Study Report 
16.1 Study Information 
217-PRK-201 Part B 
1 
 
 
 
1. 
PROTOCOL AND AMENDMENTS 
Protocols 
• Protocol V5.0 Amendment 4 dated 08Jun2017 
o Amendment 4 Summary of Changes 
• Protocol V4.0 Amendment 3 dated 06Jun2017 
o Amendment 3 Summary of Changes 
• Protocol V3.0 Amendment 2 dated 24Oct2016 
o Amendment 2 Summary of Changes 
• Protocol V2.0 Amendment 1 dated 05Oct2016 
o Amendment 1 Summary of Changes 
• Protocol V1.0 dated 28Sep2016 
 
Administrative Letters 
• Administrative Letter 1 dated 10Mar2017 
• Administrative Letter 2 dated 24May2017 
• Administrative Letter 3 dated 02Aug2017 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
1 
 
 
 
 
 
 
 
PROTOCOL NUMBER: 217-PRK-201 
A PHASE 2, TWO-PART STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF SAGE-217 IN SUBJECTS WITH 
PARKINSON’S DISEASE 
IND NUMBER: 131,258 
Investigational Product 
SAGE-217 
Clinical Phase 
2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
 
Sponsor Medical Monitor 
 
 
 
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Date of Amendment 4 
, M.D., M.P.H. 
Study Physician 
Phone: 
Email: 
28 September 2016 
5 October 2016 
24 October 2016 
06 June 2017 
08 June 2017 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
Phone: 
Email: 
, M.D., Ph.D. 


Protocol 217-P RK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
 
 
Protocol Number: 
Product: 
IND No.: 
Study Phase: 
Sponsor: 
Date of Amendment 3: 
 
217-PRK-201 
SAGE-217 
131,258 
2 
Sage Therapeutics 
Version 5.0 08 June 2017 
 
 
 
 
 
 
 
 
 
2 
Date (DD /MMMNYYY) 
tJ 
(;Jo L 7- 
Date (DD/MMM/YYYY) 
08 June 2017 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
3 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PRK-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
4 
 
 
CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
  
Address and Telephone Number  
Clinical Research Organization 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
5 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Efficacy of SAGE-217 in Subjects with Parkinson’s Disease (PD) 
Study centers: Up to 12 centers 
Objectives 
Primary: 
Part A: 
• 
To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
Part B: 
• 
To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian agent(s) on the 
severity of PD tremor symptoms. 
Secondary: 
Part A: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
Part B: 
• 
To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian agent(s) on motor 
and non-motor symptoms of PD. 
• 
To evaluate the safety and tolerability of SAGE-217 Capsules. 
Pharmacokinetic: 
• 
Part A: To assess the pharmacokinetic (PK) profile of SAGE-217 Oral Solution in plasma 
samples. 
• 
Part B: To assess the PK profile of SAGE-217 Capsules utilizing a population PK approach. 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
6 
 
 
 
Endpoints 
Primary: 
Part A: 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laboratoiy data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Sevedty 
Rating Scale (C-SSRS). In addition,sleepiness/sedation as assessed by StanfordSleepinessScale 
(SSS) score. 
PartB: 
• 
Improvement in PD tremor as assessed by changes in the MDS UPDRS Pait WIII tremor score 
(defined as the sum of MDS-UPDRSitems 2.10, 3.15, 3.16, 3.17 and 3.18). 
Secondar y: 
Part A: 
• 
Improvement in PD motor symptoms as assessed by changes in the Movement Disorder Society­ 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS)- Pait III (MotorExainination) score. 
PartB: 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS- Pait III total 
score. 
• 
Improvement in PD nonmotor and motor aspects of expeiiences of daily living as assessed by the 
MDS-UPDRS - Pait I and Pait II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - Paits I-IV 
total score. 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laboratoiy data, 
electrocai·diogram (ECG)pai·ametres, and suicidal ideation using the Columbia-SuicideSevedty 
Rating Scale (C-SSRS). 
Pharmacokinetic: 
• 
Plasma concentrations of SAGE-217,and possibly SAGE-217metabolites, will be measured, and 
PK pai·ametres will be derived. 
Exploratory: 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
7 
 
 
 
 
Methodology: 
This study will assess the safety, tolerability, pha1mackoinetics (PK) and effectiveness of SAGE-217. 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referredto as 
Levodopa in this protocol. 
There are two parts , Pait A and Pait B, described below. 
Part A: Open-labelwith AM dosing (4 days). 
All subjects will continue to take their antipai·kinsonian agent(s) including immediate-release oral 
Levodopa on the day of admission (Day -1) and in the AM only the followni g 3 days (Days 1 to 3). 
All subjects will stop theirimmediate-release oral Levodopa on Day 4 and will start on a 30 mg dose 
of SAGE-217 Oral Solutionadministered in the AM with food. Subjects not tolerating 30 mg will 
receive 20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days. Thedose 
received on Day 7 will be defined as the tolerated dose for that subject. Subjects not tolerating 10 mg 
will not be able to continue in the study and may be replaced. Subjects will be followedfor an 
additional 7 days (Day 14) after the administration of the last dose. Levodopa treatment will be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antipai·kinsonian agent at Investigator's discretion) will be 
allowed, if needed,on all days (Days 1 to 7). 
Pait A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each subject and to 
assess whetherSAGE-217exhibits efficacy in subjectswith PD in order to inform the conductof 
Pait B. 
Assessments will be pe1fom1ed periodically during the study as outlined in the Scheduleof Events for 
Pait A (Table 2). 
Part B: Open-label  with evening (PM) dosing,  for 7 days, as an adjunct to antipai·kinsonian  agent(s). 
Subjects on a stable dose of antipaik· insonian agent(s) will continue taking them for the duration of the 
study. Anticholinergics and/or amantadine will be discontinued by Day -6 and Day -10, respectively. 
Screening may occur between Day -28 and Day -2, but subjects must be admittedon Day-1 for 
selected pre-dose assessments (eg, clinical laboratory assessme nts, assessment of tremor).  All subjects 
will take SAGE-217 Capsules, 20 mg, at 8PM on Days 1 and 2. On Day 3, subjects tolerating the 
initial dose (ie, those who do not experience a severe adverse event judged by the Investigator to be 
related to study diug) will receive a dose increase(SAGE-217, 30 mg), at 8PM and continuing each 
subsequent evening at 8PM for the remainder of the dosing pedod (ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by occurrence of a severe 
adverse event judged by the Investigator to be related to study dI11g, th e dose on the next day must be 
reduced to 20 mg and continued for the remainder of the dosing pedod. Subjectswho cannot tolerate 
the 20-mg dose at any time will be discontinued and replaced. 
All doses of SAGE-217 will be adininistered with food. For antipai·kinsonian agents, administration 
with or without food will be determined by the Investigator. 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
8 
 
 
 
Subjects will receive SAGE-217 for up to 7 days and will be followed for an additional 7 days after the 
administration of the last dose. 
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part B (Table 3). 
Number of subjects (planned): 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the conduct of Part B. 
Up to 15 subjects will be enrolled in Part B in order for 10 subjects to complete the study (tolerate at 
least 20 mg SAGE-217 for the duration of the dosing period). 
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Part A: Subjects with PD with a duration of less than 7 years and must meet the criteria for Hoehn 
and Yahr stage 2 or stage 3 (Appendix 2). 
Part B: Subjects with PD and must meet the criteria for Hoehn and Yahr stage 1-4 (Appendix 2) 
assessed during the “on” period (assumed to be within 2 hours of dosing with antiparkinsonian 
agent(s)), and have a tremor with a MDS-UPDRS Part II/III tremor score of ≥8 (sum of items: 2.10, 
3.15, 3.16, 3.17 and 3.18) AND a MDS-UPDRS item score ≥3 in at least one limb (from items 
3.15, 3.16, or 3.17). Inclusion criteria tremor scores must be assessed during “on” periods during 
the screening and Day -1 visit. 
5. Part A: Subject has a stable dose of antiparkinsonian agent(s) including immediate-release oral 
Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month prior to 
the baseline visit) and is expected to remain on this stable dose for the duration of this study. 
Part B: Subject is receiving a stable dose of antiparkinsonian agent(s) (defined as no changes for a 
period of at least 1 month prior to the baseline visit) and is expected to remain on this stable dose 
for the duration of this study. 
6. Part A only: Subject is willing to discontinue his/her treatment with immediate-release oral 
Levodopa or Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. 
7. Part A: Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). 
Part B: Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) by 
Day -6 or amantadine by Day -10. 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been on a stable 
dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
11. Part A: Female subjects must agree to practice a highly effective method of birth control while on 
study through completion of the last follow-up visit. If a subject discontinues early after receiving 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
9 
 
 
 
a dose of SAGE-217, then the subject must continue this method of birth control for at least 7 days 
following the last dose of study drug. Highly effective methods of birth control include combined 
(estrogen and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized 
partner, or sexual abstinence. 
Part B: Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause) and/or 
surgically sterile: 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal 
contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation. 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse). 
12. Male subjects must agree to practice a highly effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with their 
partner's highly effective method. 
13. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. 
14. Part B only: Subjects who participated in Part A and meet all eligibility criteria for Part B must 
have tolerated at least 20 mg SAGE-217 in Part A, otherwise they are ineligible. 
Exclusion Criteria: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major excipient, HPβCD 
(Part A) or SAGE-217 Capsule or its excipients (Part B). 
2. Part A: Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 
4 or stage 5). 
Part B: Subjects with advanced PD (Hoehn and Yahr stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her ability for 
participation. This includes schizophrenia spectrum and other psychotic disorders, substance- 
related and addictive disorders, feeding and eating disorders, bipolar and related disorders, 
structural brain disease including but not limited to history of encephalitis or hydrocephalus and 
history of clinically significant stroke, or anticipating starting psychotherapy or behavior therapy 
during the course of the study or who started psychotherapy or behavior therapy within 30 days 
prior to Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
10 
 
 
 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Part A: Subjects with severe depression as defined by a BDI-II score >19. 
6. Part B: Subject has recent exposure (14 days prior to the Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 4. 
7. Subjects with Type I or Type II diabetes mellitus. 
8. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), metabolic 
identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other atypical 
Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system atrophy). 
9. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
10. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the screening 
or admission visits. NOTE: QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the study. ECG 
may be repeated once if initial values obtained are outside the specified limits. 
11. Subject has a history, presence and/or current evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
12. Subject has exposure to another investigational medication or device within 30 days prior to Day 1. 
13. Subject has donated one or more units of blood or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). 
14. Subject is unwilling or unable to comply with study procedures. 
15. Subjects has used any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug. 
Investigational product, dosage and mode of administration: 
Part A: SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 
Drug Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dose. 
Part B: SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the SAGE-217 Capsules contain croscarmellose 
sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as excipients. For 
Part B, capsules will be available in 5-mg, 10-mg and 20-mg dose strengths. Subjects will be 
administered two capsules per dose. 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
11 
 
 
 
Duration of treatment: 
Part A and Part B: 
Screening Duration: up to 28 days per part 
Treatment Period: 7 days per part 
Follow-up: 7 days per part 
Planned Study Duration per Subject: approximately 42 days if participating in one part only (up to 
84 days if participating in both Parts A and B) 
Reference therapy, dosage, and mode of administration: 
Not applicable; Part A and Part B are open-label with all subjects receiving SAGE-217. 
Criteria for evaluation: 
Safety and tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs, clinical laboratory measures, 
ECGs, physical examinations, concomitant medication usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS in Part A only. 
Efficacy: 
Part A: 
• 
Improvement in PD motor symptoms and overall symptoms will be assessed by changes in the 
MDS UPDRS Part III score and MDS-UPDRS Parts I-IV total score at various time points. 
Part B: 
• 
Improvement in PD tremor as assessed by changes in the MDS UPDRS Part II/III tremor score 
(defined as the sum of MDS-UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS – Part III total 
score. 
• 
Improvement in PD nonmotor and motor aspects of experiences of daily living as assessed by the 
MDS-UPDRS – Part I and Part II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS – Parts I-IV 
total score. 
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and possibly SAGE-217 metabolites 
in Part A and Part B. 
Part A: The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve from time zero to infinity (AUC0-∞), maximum 
plasma concentration (Cmax), time to reach maximum concentration (tmax), the distributional half-life 
and terminal half-life (t1/2), and steady-state drug concentration in the plasma (Css). 
Part B: Area under the curve (AUC), Cmax, and trough concentration (C0h) at steady-state will be 
estimated for each individual using the most recent applicable Population PK model. 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
12 
 
 
 
Statistical Methods: 
Sample Size Calculation 
Approximately 18 subjects will be enrolled in Part A. Up to 15 subjects will be enrolled in Part B in 
order for 10 subjects to complete the study (tolerate at least 20 mg SAGE-217 for the duration of the 
dosing period). The sample size for Part A and Part B was selected based on clinical and not statistical 
considerations. 
Study Populations 
The safety population, defined as all subjects who are administered at least one dose of study drug, will 
be used to provide descriptive summaries of safety. 
The efficacy population, defined as all subjects in the safety population who receive at least one dose 
of study drug and have at least one postdose MDS-UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the safety population with at least one plasma sample 
with sufficient plasma concentrations for PK evaluations and will be used to summarize PK data. 
Separate populations will be defined for each part of the study. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™ (MedDRA). The 
overall incidence of adverse events will be displayed by System Organ Class (SOC), preferred term, 
dose group, and cohort. Incidence of adverse events will also be presented by maximum severity and 
relationship to study drug. Vital signs, clinical laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and total, where applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. Subject listings will be provided for all safety data. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data presentation 
methods where applicable; subject listings will be provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A is planned to inform Part B study conduct. No 
formal interim analysis for Part B subjects is planned. 
Pharmacokinetic Analysis 
Drug concentrations and pharmacokinetic parameters will be summarized using appropriate descriptive 
statistics and listed by subject. 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
13 
 
 
 
Table 2: 
Schedule of Events: Part A (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 
X 


Protocol 217-PRK-201 
Amendment #4, Version 5.0 
Sage Therapeutics 
CONFIDENTIAL 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
; 
; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose for Day 4, Day 6, and Day 8; and Day 14 
c Urinalysis: Screening and Admission (Day -1); predose for Day 4 and Day 7; and Day 14. 
d Vital Signs: Screening and Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM 
of Day 8; and Day 14. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; 
and Day 14. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose on Day 1 and Day 3; predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on 
Confinement Days 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1, Day 2 and Day 3; predose on Day 4, Day 5, Day 6, and Day 7; and Day 8 and 
Day 14. Screening/Baseline version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
h SSS: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
The SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
p 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
Administer Levodopa or 
q 
Carbidopa-Levodopa 
X 
X 
X 
Administer SAGE-217q 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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i MO AAIS: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. The MOAAIS is to 
be perfonned within ±10 minutes of the scheduled times through the 4-how- time point and within ±15 minutes of the scheduled times thereafter. 
j MDS-UPDRS (complete): Screening, Admission (Day -1) (only if time betv.•een Screening and Admission is ?:.7 da ys) , on D a y 8 prior to resmning Levodopa, 
and Day 14. 
I 
 
I 
I 
I 
I 
P P la s ma PK sampling times (±5 minutes): Day 4 predose and 0.25, 0.5, 1, 2, 4,  8, and 12 how-s  po st d ose ; p redo se  D ay 5  and Day 6; predose and 0.25, 0.5, 1, 2, 
4, 8, and 12 how-s on Day 7; in AM of Day 8; and Day 14. PK samples are to be collected within ±5 minutes of the scheduled sampling time. 
q Le vodopa or Carbidopa-Levodopa and SAGE-217 are to be administered in the morning 


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Table 3: 
Schedule of Events: Part B (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -2) 
Admit 
(Day -1) 
Part B:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Confined to Unita 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
X 
CBC/Serum Chemistryb 
X 
Xc 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
X-urine 
Urinalysisd 
X 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
Pulse Oximetryg 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
12-Lead ECGh 
X 
X 
X 
Xf 
X 
Xf 
X 
Xf 
X 
Xf 
X 
C-SSRSi 
X 
X 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
MDS-UPDRS 
(complete)j 
X 
X 
Xf 
Xf 
X 
MDS-UPDRS (Part II 
only)k 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
only)k 
X 
X 
X 
X 
X 
X 
X 


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Visit Days 
Screening 
(Day -28 to 
Day -2) 
Admit 
(Day -1) 
Part B: Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Plasma PK Samplesr 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
Administer SAGE-217s 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
; 
; 
; PK = Pharmacokinetic 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose (within 1 hour of dosing) on Days 4 and 6; and on Days 8 and 14. 
c Two samples will be taken on Day-1: one sample will be sent to the central lab to be analyzed for reporting purposes and one sample to be analyzed locally for 
eligibility with regard to CBC/serum chemistry. 
d Urinalysis: Screening and Admission (Day -1); predose on Days 4 and 6; and on Days 8 and 14. 
e Vital Signs: Screening and Admission (Day -1); predose and 1, 2, and 12 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; and on Day 14. 
Assessments of vital signs are to be performed within ±10 minutes of the 1 and 2-hour time points and within ±15 minutes of the 12-hour time point. 
f Morning assessment only (in the morning of Day 1 or 12 hours [or 13 hours for PK sampling] after the dose from the previous evening). 
g Pulse Oximetry: Admission (Day -1); predose and 1, 2, and 12 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; and on Day 14. Pulse oximetry is to 
be performed within ±10 minutes of the 1 and 2-hour time points and within ±15 minutes of the 12-hour time point. 
h 12-Lead ECG: Screening and Admission (Day -1); predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on Confinement Days 1, 3, 5, and 7; and 
on Day 14. 
i C-SSRS: Screening and Admission (Day -1); predose and 12 hours (±1 hour) postdose on Day 1; and 12 hours (±1 hour) postdose on Day 2, 3, 4, 5, 6, and 7. 
Screening/Baseline version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 


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j MDS-UPDRS (complete, Parts I-IV): Screening, Admission (Day -1) (only if time between Screening and Admission is ?:.7 da ys); at  8AM (±1 hour)  on Day  l; 
12 (±15 1ninutes) hours postdose on Day 7 (ie, 8AM on Day 8); and on Day 14. MDS-UPDRS should take place during the "on" period AND within 2 hours of 
dosing with antiparkinsonianagent(s). 
k MDS-UPDRS (Part II/III only): 12 and 23 (±151ninutes) hours postdose on Confinement Days 1, 2, 3, 4, 5, and 6. MDS-UPDRS Part 11/111s hould take place 
during the "on" period AND within 2 hours of dosing with antiparkinsonian agent(s). 
I 
 
 
I 
 
 
 
I 
I 
I 
I 
r Plasma PK sampling times (±1 hour): predose and 13 hours postdose on Day l; and 13 hours postdose on Days 2 through 7. 
5 SAGE-217 Capsules are to be adrninistered in the evening (8PM ±30 minutes) with food. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............19 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................24 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need .................................26 
5.2. 
SAGE-217 ...................................................................................................................27 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ...........................27 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................27 
5.3.2. 
Clinical Experience .....................................................................................................27 
5.4. 
Potential Risks and Benefits .......................................................................................29 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary Objective .......................................................................................................31 
6.2. 
Secondary Objectives .................................................................................................31 
6.3. 
Pharmacokinetic Objectives .......................................................................................31 
6.4. 
Endpoints ....................................................................................................................31 
6.4.1. 
Primary Endpoints ......................................................................................................31 
6.4.2. 
Secondary Endpoints ..................................................................................................32 
6.4.3. 
Pharmacokinetic Endpoints ........................................................................................32 
6.4.4. 
Exploratory Endpoints ................................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 
7.2. 
Number of Subjects ....................................................................................................35 
7.3. 
Treatment Assignment ................................................................................................35 
7.4. 
Dose Adjustment Criteria ...........................................................................................35 
7.5. 
Criteria for Study Termination ...................................................................................36 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................38 
8.1. 
Subject Inclusion Criteria ...........................................................................................38 
8.2. 
Subject Exclusion Criteria ..........................................................................................39 


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8.3. 
Subject Withdrawal Criteria .......................................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................42 
9.1. 
Description of Study Drug Treatment ........................................................................42 
9.1.1. 
Part A ..........................................................................................................................42 
9.1.2. 
Part B ..........................................................................................................................42 
9.2. 
Concomitant Medications ...........................................................................................42 
9.2.1. 
Prior/Concomitant Medications ..................................................................................42 
9.2.2. 
Prohibited Medications ...............................................................................................43 
9.3. 
Treatment Compliance ................................................................................................43 
9.4. 
Randomization and Blinding ......................................................................................43 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
10.1. 
Study Drug ..................................................................................................................44 
10.1.1. 
SAGE-217 Oral Solution ............................................................................................44 
10.1.2. 
SAGE-217 Capsule .....................................................................................................44 
10.2. 
Study Drug Packaging and Labeling ..........................................................................44 
10.3. 
Study Drug Storage .....................................................................................................44 
10.4. 
Study Drug Preparation ..............................................................................................45 
10.5. 
Administration ............................................................................................................46 
10.6. 
Study Drug Accountability .........................................................................................46 
10.7. 
Study Drug Handling and Disposal ............................................................................46 
11. 
ASSESSMENT OF EFFICACY ................................................................................47 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale ................47 
11.2. 
Exploratory Endpoints ................................................................................................48 
48 
49 
49 
49 
50 
50 
12. 
PHARMACOKINETICS ...........................................................................................52 
12.1. 
Blood Sample Collection ............................................................................................52 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................52 


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12.3. 
Sample Analysis .........................................................................................................52 
13. 
ASSESSMENT OF SAFETY .....................................................................................53 
13.1. 
Safety and Tolerability Parameters .............................................................................53 
13.1.1. 
Demographic/Medical History ...................................................................................53 
13.1.2. 
Vital Signs ..................................................................................................................53 
13.1.3. 
Weight and Height ......................................................................................................53 
13.1.4. 
Physical Examination .................................................................................................53 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................53 
13.1.6. 
Laboratory Assessments .............................................................................................54 
13.1.6.1. 
Hematology .................................................................................................................54 
13.1.6.2. 
Blood Chemistry .........................................................................................................54 
13.1.6.3. 
Urinalysis ....................................................................................................................54 
13.1.6.4. 
Virus Serology ............................................................................................................55 
13.1.6.5. 
Pregnancy Screen ........................................................................................................55 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................55 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................55 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) ...............55 
13.2. 
Adverse and Serious Adverse Events .........................................................................56 
13.2.1. 
Definition of Adverse Events .....................................................................................56 
13.2.1.1. 
Adverse Event .............................................................................................................56 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................56 
13.2.1.3. 
Serious Adverse Event ................................................................................................56 
13.2.1.4. 
Recording Sedation as an Adverse Event ...................................................................57 
13.2.2. 
Pregnancy ...................................................................................................................57 
13.3. 
Relationship to Study Drug .........................................................................................57 
13.4. 
Recording Adverse Events..........................................................................................58 
13.5. 
Reporting Serious Adverse Events .............................................................................58 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................60 
14.1. 
Data Analysis Sets ......................................................................................................60 
14.2. 
Handling of Missing Data ...........................................................................................60 
14.3. 
General Considerations ...............................................................................................60 
14.4. 
Demographics and Baseline Characteristics ...............................................................60 


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14.5. 
Efficacy Endpoints ......................................................................................................60 
14.5.1. 
Secondary Efficacy Endpoints ....................................................................................61 
14.5.2. 
Exploratory Efficacy Endpoints ..................................................................................61 
14.6. 
Safety and Tolerability Analyses ................................................................................61 
14.6.1. 
Adverse Events ...........................................................................................................61 
14.6.2. 
Vital Signs ..................................................................................................................61 
14.6.3. 
Physical Examinations ................................................................................................62 
14.6.4. 
12-Lead ECG ..............................................................................................................62 
14.6.5. 
Clinical Laboratory Evaluations .................................................................................62 
14.6.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................62 
14.6.7. 
Stanford Sleepiness Scale (SSS) .................................................................................62 
14.6.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ........................62 
14.6.9. 
Prior and Concomitant Medications ...........................................................................62 
14.7. 
Pharmacokinetic Analysis ..........................................................................................63 
14.8. 
Determination of Sample Size ....................................................................................63 
14.9. 
Changes From Protocol Specified Analyses...............................................................63 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................64 
15.1. 
Study Monitoring ........................................................................................................64 
15.2. 
Audits and Inspections ................................................................................................64 
15.3. 
Institutional Review Board (IRB) ...............................................................................65 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE..........................................66 
17. 
ETHICS ......................................................................................................................67 
17.1. 
Ethics Review .............................................................................................................67 
17.2. 
Ethical Conduct of the Study ......................................................................................67 
17.3. 
Written Informed Consent ..........................................................................................67 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
18.1. 
Inspection of Records .................................................................................................68 
18.2. 
Retention of Records ..................................................................................................68 
18.3. 
Confidentiality ............................................................................................................68 
19. 
PUBLICATION POLICY ..........................................................................................70 
20. 
LIST OF REFERENCES ............................................................................................71 
21. 
APPENDICES ............................................................................................................73 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA ............................................74 
APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA ..................................................75 
APPENDIX 3. ANTICHOLINERGIC DRUGS .........................................................................76 
APPENDIX 4. TREMOROGENIC DRUGS ..............................................................................77 
APPENDIX 5. MOVEMENT DISORDER SOCIETY-UNIFIED PARKINSON'S 
DISEASE RATING SCALE (MDS-UPDRS) ...................................................79 
80 
83 
86 
87 
APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION AND SINCE LAST VISIT 
VERSION .........................................................................................................90 
APPENDIX 11. STANFORD SLEEPINESS SCALE (SSS) .....................................................96 
APPENDIX 12. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ...........................................................97 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................13 
Table 3: 
Schedule of Events:  Part B (Open-Label) .................................................................16 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................24 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL ..................45 
Table 6: 
Rating Scale for the MDS-UPDRS .............................................................................47 
LIST OF FIGURES 
Figure 1: 
Study Design of Part A ...............................................................................................37 
Figure 2: 
Study Design of Part B ...............................................................................................37 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to 
infinity 
 
 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CS 
clinically significant 
Css 
steady-state drug concentration in the plasma 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EP 
European Pharmacopeia 
GABA 
γ aminobutyric acid 
GABAA 
γ aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Levodopa/Carbidopa 
Levodopa or Carbidopa-Levodopa 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MoCA 
Montreal Cognitive Assessment 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant 
NF 
National Formulary 
PD 
Parkinson’s disease 
 
 
PK 
pharmacokinetic(s) 
PM 
evening 
QTcF 
QT interval calculated using the Fridericia method 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal half-life 
tmax 
time to reach maximum concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need 
Parkinson’s disease (PD) is a chronic progressive neurodegenerative condition that affects the 
motor, autonomic, cognitive, and sensory systems. Parkinson’s disease is the second most 
common neurodegenerative disorder (Bergman 2002) and is associated with a massive loss of 
dopaminergic cells in the substantia nigra, leading to dopamine hypofunction and alteration of 
the basal ganglia circuitry. Dopamine neurons are under the control of the excitatory 
glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. Imbalance between the 
glutamatergic and GABA systems may contribute to excitotoxicity and dopaminergic cell death. 
The motor symptoms of PD have been linked with a loss of dopamine neurons in the substantia 
nigra pars compacta and a consequential reduction in the level of dopamine input in the striatum 
(Siderowf 2012). These symptoms evolve slowly and are characterized by the progression of 
tremor, rigidity, bradykinesia, and postural instability. Tremor caused by PD can appear as 
either a resting tremor or an action tremor. The most typical tremor of PD is a “pill-rolling” rest 
tremor between the thumb and index finger. Not everyone with PD develops a tremor, and those 
who do experience tremor may have symptoms that come and go. Typically, PD tremor starts in 
the fingers of one hand before spreading to affect the rest of the arm. Tremor can also spread to 
affect the foot on the same side of the body and, after several years, the tremor can spread to 
affect the other side of the body. Without treatment, PD tremor usually worsens over time. 
At present, there is no cure for PD. The core symptoms are caused by the degeneration of 
dopamine-producing neurons and, therefore, treatment consists of dopamine replacement. While 
enormous progress has been made in the treatment of PD over the past half century, levodopa 
remains the most potent drug for controlling PD symptoms (Jankovic 2008). The addition of 
carbidopa, a peripheral dopa decarboxylase inhibitor, enhances the therapeutic benefits of 
levodopa.  However, levodopa therapy is frequently associated with motor complications, and 
the appropriate time to initiate levodopa therapy continues to be debated (Stern 2004; 
Weiner 2004). The majority of patients treated with levodopa experience motor fluctuation, 
dyskinesia or other complications after 5 years of treatment (Jankovic 2005). 
Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of 
several neurotransmitter systems. The substantia nigra expresses high concentrations of 
allopregnanolone, a neurosteroid that positively modulates the action of GABA at 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. In PD patients, 
decreased plasma and cerebrospinal fluid levels of the neurosteroid allopregnanolone and 
5α-dihydroprogesterone have been observed (di Michele 2003). 
Parkinson’s disease is the second most common chronic neurodegenerative disease, affecting 
about 1 million people in the United States and more than 4 million people worldwide. It has a 
devastating effect on patients and is often accompanied by tremendous physical and emotional 
burden not only for the patients but also for their families and friends. As the size of the elderly 
population grows, the burden of PD is projected to grow substantially over the next few decades. 
To date, the therapy of PD is symptomatic, aimed at ameliorating motor symptoms. Although 
the goal of therapy is to reverse the functional disability, abolition of all symptoms and signs is 
not currently possible, even with high doses of medication. Thus, there is a growing need for 


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innovative new treatments to prevent, delay onset, or alleviate symptoms of PD. Neurosteroids 
act as neuroprotectants and as GABAA-receptor agonists in the physiology and pathology of the 
basal ganglia, impact dopaminergic cell activity and survival, and may therefore represent 
potential therapeutics in PD. 
 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of PD. 
Two dosage forms of SAGE-217 for oral administration will be used in this study (SAGE-217 
Oral Solution in Part A and SAGE-217 Capsules in Part B). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a non-viscous, clear solution. 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the active, SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies and in toxicology studies. The sedative- 
hypnotic impairments seen with SAGE-217 were typical for GABAA-positive modulators, 
ranging from hyperexcitability and ataxia at the lower doses through deep sedation and 
ultimately anesthesia at higher doses. Depth and duration of sedation demonstrated a clear dose 
response over the range tested, with evidence of tolerance occurring with continued exposure. 
Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 7 days of 
dosing. 
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats. The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. 
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study that was suspected to have been related to exaggerated pharmacology. Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure. 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending. Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food effect, and essential tremor cohorts from Study 217-CLP-101 
and the multiple-ascending dose and drug-drug interaction cohorts from Study 217-CLP-102. 
Discussions of safety data are limited to the single-ascending dose cohorts in Study 
217-CLP-101 and the multiple-ascending dose cohorts in Study 217-CLP-102. In addition, one 


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clinical study of the safety, tolerability, PK, and relative bioavailability SAGE-217 Capsules is 
clinically complete and the final study report is pending. The results of this study (217-CLP- 
103) are briefly described below. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, single- 
ascending dose design in healthy adult volunteers, with the objective of identifying the maximum 
tolerated dose (MTD) and PK profiles of SAGE-217 Oral Solution. Subjects in each of the 
single-ascending dose cohorts received a single dose of study drug, either SAGE-217 Oral 
Solution (six subjects) or placebo (two subjects), with SAGE-217 Oral Solution doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 55 mg, and 66 mg.  Escalation to the 
next dose was undertaken only after safety and PK data were reviewed by the Safety Review 
Committee (SRC) and agreement reached that it was safe to increase the dose. The MTD was 
determined to be 55 mg. Two cohorts, 6 subjects each, received SAGE-217 Oral Solution in an 
open-label manner (one cohort received 50% of the MTD [22 mg] to study the food effects and 
the other cohort received the MTD [55 mg] to study the effects on subjects with essential 
tremor). SAGE-217 Oral Solution was orally bioavailable, demonstrated dose-linear PK from 
the lowest (0.25 mg) through the highest (66 mg) dose, and supported once-daily oral dosing 
with food. In addition, the pharmacodynamic effects of the SAGE-217 Oral Solution MTD were 
assessed in placebo-controlled, blinded, crossover electroencephalogram cohorts of 8 subjects 
each; one cohort received 50% of the MTD (22 mg) and the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers. Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 Oral Solution (nine subjects) or placebo (three subjects), 
once daily for 7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg. 
Escalation to the next dose was undertaken only after safety and PK data were reviewed by the 
SRC and agreement reached that it was safe to increase the dose. The MTD was determined to 
be 30 mg. It was observed that subjects receiving the drug in the evening did better in terms of 
tolerability compared to when they received the drug in the morning. A fourth cohort of 
12 subjects received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug- 
drug interactions. SAGE-217 Oral Solution is not likely to induce the metabolism of cytochrome 
P450 (CYP)2B6 or CYP3A4 substrates. SAGE-217 Oral Solution was orally bioavailable and 
suitable for once-daily oral dosing at night time with food. 
SAGE-217 Oral Solution was generally well tolerated. In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met. Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 
reported in either study. In addition, none of the observed adverse events resulted in 
discontinuation of the study drug. At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure. The most common treatment-emergent 
adverse events (TEAEs) were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, 
and muscle twitching, reported most frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were observed after single doses of 44 mg and 
greater. After multiple doses of 30 mg (morning [AM] or evening [PM]) or 35 mg (AM) over 
7 days, there was no evidence of changes in mean vital sign measures even though Day 7 plasma 


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concentrations approximated that of the highest single dose in the single-ascending dose study. 
Subjects seemed to tolerate SAGE-217 Oral Solution better when given as night time dosing. 
The safety, tolerability, PK, and relative bioavailability of the SAGE-217 Capsules were 
assessed in a Phase 1 randomized, open-label, cross-over study (Study 217-CLP-103). In the 
fasted state, SAGE-217 Capsules demonstrated reduced exposure in terms of maximum (peak) 
plasma concentration (Cmax) and area under the curve from zero to the time of the last 
quantifiable concentration (AUClast) compared to SAGE-217 Oral Solution. SAGE-217 Capsules 
administered in the fed state (with standard and high-fat meal) showed increased exposure 
compared to the fasted state and approximately equivalent exposure in terms of geometric mean 
AUClast compared to SAGE-217 Oral Solution; however, the Cmax for SAGE-217 Capsules was 
reduced by approximately 50% when compared with SAGE-217 Oral Solution. Based on these 
study results, exposures with SAGE-217 Capsules are anticipated to be equal to or less than 
exposures observed at the same dose with SAGE-217 Oral Solution. 
Neuroactive steroids are a class of endogenous and synthetic positive allosteric modulators that 
target both synaptic and extra-synaptic GABAA receptors (Belelli 2002 and confirmed in the 
Sponsor’s in vitro studies). This diverse activity profile suggests that neuroactive steroid 
GABAA receptor-positive allosteric modulators could exhibit robust activity against essential 
tremor. Administration of SAGE-547 injection, a proprietary formulation of the endogenous 
neuroactive steroid, resulted in significant reductions in upper limb kinetic tremor scores 
compared to placebo in a Phase 2 proof‑of‑principle study (IND 122,280). Based on these 
results with SAGE-547, the study design for single-ascending dose study 217-CLP-101 included 
a cohort of subjects with essential tremor (N=6) who received SAGE-217 Oral Solution (55 mg) 
in an open-label manner. Data from this cohort indicate that single doses of SAGE-217 Oral 
Solution resulted in a reduction in the tremor symptoms, suggesting that SAGE-217 might be 
effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral Solution or Capsules in PD, since the 
present study is the first study in this indication. 
 
5.4. 
Potential Risks and Benefits 
Protocol 217-PRK-201 is the first clinical study evaluating the efficacy of SAGE-217 in PD. 
Thus, the potential benefits in this population are unknown, although the risks are likely to be 
similar to those mentioned in the Investigator’s Brochure. GABA compounds that cross the 
blood-brain barrier or increase GABA activity alleviate muscle stiffness caused by a lack of 
GABAergic tone (Winkler 1999), validating this receptor as a therapeutic target. Given the 
promising clinical data with another neuroactive steroid (SAGE-547) in conjunction with the 
shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence 
of anxiolytic activity, and safety data of SAGE-217, it is possible that patients may have a 
clinical benefit at the exposures selected for this study. 
In the 217-CLP-103 study, SAGE-217 Capsules were found to be generally well-tolerated with 
no serious AEs reported during the treatment and follow-up periods. The most frequent AE 
observed was sedation that was mild, transient, and occurred within 1 to 4 hours following 
dosing and generally dissipated by 8 hours. The clinical portion of this study has recently 
completed; the final report is in progress. 


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In view of the few risks associated with administration of SAGE-217 that have been identified to 
date, intra-patient dose-reduction designs have been chosen for Part A and Part B to permit 
reduction in dose based on tolerability (adverse events), specifically sedation, versus treatment 
effect. In Part A, each subject will start with an initial dose of SAGE-217 Oral Solution, 30 mg; 
subjects unable to tolerate 30 mg will receive 20 mg; subjects unable to tolerate 20 mg will 
receive 10 mg. In Part B, each subject will receive SAGE-217 in the evening (PM) starting with 
an initial dose of SAGE-217 Capsules, 20 mg for two days; subjects able to tolerate 20 mg will 
receive 30 mg. If the subject is unable to tolerate 30 mg, the subject will receive 20 mg and 
continue for the remainder of the dosing period. Subjects who cannot tolerate the 20-mg dose at 
any time during Part B will be discontinued and replaced. The tolerated dose for each subject in 
Part A and Part B will be the dose taken on Day 7.  Given the high medical need and potential 
for benefit in PD, there is a favorable benefit-risk evaluation to investigate SAGE-217 in PD. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of Part A is 
• To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
The primary objective of Part B is: 
• To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian 
agent(s) on the severity of PD tremor symptoms. 
 
6.2. 
Secondary Objectives 
The secondary objectives of Part A are: 
• To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor 
symptoms after withdrawal of Levodopa or Carbidopa-Levodopa 
(Levodopa/Carbidopa). 
• To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of 
PD motor symptoms after withdrawal of Levodopa/Carbidopa. 
The secondary objectives of Part B are: 
• To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian 
agent(s) on motor and non-motor symptoms of PD. 
• To evaluate the safety and tolerability of SAGE-217 Capsules. 
6.3. 
Pharmacokinetic Objectives 
The PK objective of Part A is: 
• To assess the PK profile of SAGE-217 Oral Solution in plasma samples. 
The PK objective of Part B is: 
• To assess the PK profile of SAGE-217 Capsules utilizing a population PK approach. 
6.4. 
Endpoints 
6.4.1. 
Primary Endpoints 
Part A: 
• Frequency and severity of adverse events and changes in vital signs, clinical 
laboratory data, electrocardiogram (ECG) parameters, and suicidal ideation using the 
Columbia-Suicide Severity Rating Scale (C-SSRS). In addition, sleepiness/sedation 
as assessed by Stanford Sleepiness Scale (SSS) score. 


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Part B: 
• 
Improvement in PD tremor  as assessed  by changes  in  the  MDS  UPDRS  Pa.ii  II/ III 
tr e m or sco r e (de fin ed as th e s um o f M D S -UP DR S ite m s 2 .1 0, 3 .1 5, 3 .1 6, 3 .1 7 and 
3.18). 
6.4.2. 
Secondary Endpoints 
Part A: 
• 
Improve ment in PD motor symptoms as  assessed  by  changes  in  the  Movement Disorder 
Society-Unified Pai-Icinson's Disease  Rating  Scale  (MDS-UPDRS)  -  Pa.ii  III (Mo tor Exa 
min a ti o n ) to tal score . 
Part B: 
• 
Improve ment in PD motor symptoms as assessed by changes in the MDS-UPDRS - 
Pa.ii III total score. 
• 
Improvement in PD nonmotor and motor aspects of experiences of daily living as 
assessed by the MDS-UPDRS - Pali I and Part II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - 
Paiis I-IV total score. 
• 
Frequency and severity of adverse events and changes in vital signs, clinical 
laboratory data, electrocai·diogram (ECG) parameters, and suicidal ideation using the 
Collllllbia-Suicide Severity Rating Scale (C-SSRS). 
 
6.4.3. 
Pharmacokinetic Endpoints 
• 
Plasma concentratio ns of SAGE -217, and possibly SAGE-217 metabolites, will be 
measured, and PK pai·aineters will be derived. 
 
6.4.4. 
Exploratory Endpoints 
I 
 
I 
 
 
I 


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I 
 
I 


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7. 
INVESTIGATIONAL PLAN 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2 study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217. Part A of the study is an open-label design with morning (AM) dosing of 
SAGE-217 Oral Solution for 4 days in in up to 18 adult subjects with PD of moderate severity 
who respond to immediate-release oral Levodopa and are on a stable dose. Part B of the study is 
an open-label design with evening (PM) dosing of SAGE-217 Capsules for 7 days in up to 
15 adult subjects with PD. Subjects that participate in Part A are eligible to participate in Part B 
if all eligibility criteria for Part B are met and they tolerated at least 20 mg SAGE-217 in Part A. 
Subjects will be followed for an additional 7 days after the administration of the last dose in Part 
A and Part B. 
There are two parts to the study: 
• Part A: Open-label with AM dosing of SAGE-217 Oral Solution (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the 
following 3 days (Days 1 to 3). All subjects will stop their immediate-release oral 
Levodopa on Day 4 and will start on a 30 mg dose of SAGE-217 Oral Solution 
administered in the morning with food, as outlined in Section 9.1.1. Subjects not 
tolerating 30 mg will receive 20 mg, and subjects not tolerating 20 mg will receive 
10 mg on subsequent days (Section 7.4). The dose received on Day 7 will be defined as 
the tolerated dose for that subject. Subjects not tolerating 10 mg will not be able to 
continue in the study and may be replaced.  Subjects will be followed for an additional 
7 days (Day 14) after the administration of the last dose. Levodopa treatment will be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 exhibits efficacy in subjects with PD of 
moderate severity in order to inform the conduct of Part B. 
• Part B: Open-label with PM dosing of SAGE-217 Capsules, for 7 days, as an adjunct 
to antiparkinsonian agent(s). 
Subjects on a stable dose of antiparkinsonian agent(s) will continue taking them for the 
duration of the study.  Anticholinergics and/or amantadine will be discontinued by 
Day -6 and Day -10, respectively. 
Screening may occur between Day -28 and Day -2, but subjects must be admitted on 
Day -1 for selected pre-dose assessments (e.g., clinical laboratory assessments, 
assessment of tremor). All subjects will take SAGE-217 Capsules, 20 mg, at 8PM on 
Days 1 and 2. On Day 3, subjects tolerating the initial dose (i.e., those who do not 


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experience a severe adverse event judged by the Investigator to be related to study 
drug) will receive a dose increase (SAGE 217, 30 mg), at 8PM and continuing each 
subsequent evening at 8PM for the remainder of the dosing period (ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by 
occurrence of a severe adverse event judged by the Investigator to be related to study 
drug, the dose on the next day must be reduced to 20 mg and continued for the 
remainder of the dosing period. Subjects who cannot tolerate the 20-mg dose at any 
time will be discontinued and replaced. 
All doses of SAGE-217 will be administered with food as outline in Section 9.1.2. For 
antiparkinsonian agents, administration with or without food will be determined by the 
Investigator. 
Subjects will receive SAGE-217 for up to 7 days and will be followed for an additional 
7 days after the administration of the last dose. 
 
The study designs of Part A and Part B are displayed in Figure 1 and Figure 2, respectively. 
Assessments will be performed periodically during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and Table 3, respectively). 
7.2. 
Number of Subjects 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14 to inform the conduct of Part B. Up to 
15 subjects will be enrolled in Part B in order for 10 subjects to complete the study (tolerate at 
least 20 mg SAGE-217 for the duration of the dosing period). 
7.3. 
Treatment Assignment 
SAGE-217 will be administered with food in Parts A and B. Food intake will be standardized as 
specified by the Sponsor. If subjects are taking antiparkinsonian agent(s), administration with or 
without food will be determined by the Investigator. 
Parts A and B of the study are open-label. Dose reductions for lack of tolerability will be 
allowed during both parts of the study (Section 7.4). 
 
7.4. 
Dose Adjustment Criteria 
Dose reductions of SAGE-217 for lack of tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part A, as determined by the Investigator, the 
dose on the next day will be reduced to the next lowest dose (ie, subjects who are unable to 
tolerate the 30-mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 
20 mg will receive a 10 mg dose on subsequent days). In Part B, subjects tolerating the initial 
20-mg dose on Days 1 and 2 will receive a 30-mg dose on Day 3 and continue for the remainder 
of the dosing period. If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, the dose 
on the next day must be reduced to 20 mg and continued for the remainder of the dosing period. 


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7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons. In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects. 


37 
 
 
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Figure 1: 
Study Design of Part A 
Figure 2: 
Study Design of Part B 
 
NOTE: Part B will be initiated only after review of the Part A interim analysis (after 10 subjects have completed Part A). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures 
are performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria 
(modified to allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Part A: Subjects with PD with a duration of less than 7 years and must meet the criteria 
for Hoehn and Yahr stage 2 or stage 3 (Appendix 2). 
Part B: Subjects with PD and must meet the criteria for Hoehn and Yahr stage 1-4 
(Appendix 2) assessed during the “on” period (assumed to be within 2 hours of dosing 
with antiparkinsonian agent(s)), and have a tremor with a MDS-UPDRS Part II/III tremor score 
of ≥8 (sum of items: 2.10, 3.15, 3.16, 3.17 and 3.18) AND a MDS-UPDRS item score ≥3 in at 
least one limb (from items 3.15, 3.16, or 3.17). Inclusion criteria tremor scores must be 
assessed during “on” periods during the screening and Day -1 visit. 
5. Part A: Subject has a stable dose of antiparkinsonian agent(s) including immediate- 
release oral Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at 
least 1 month prior to the baseline visit) and is expected to remain on this stable dose for 
the duration of this study. 
Part B: Subject is receiving a stable dose of antiparkinsonian agent(s) (defined as no 
changes for a period of at least 1 month prior to the baseline visit) and is expected to 
remain on this stable dose for the duration of this study. 
6. Part A only: Subject is willing to discontinue his/her treatment with immediate-release 
oral Levodopa or Carbidopa-Levodopa for at least 8 hours prior to dosing with 
SAGE-217. 
7. Part A: Subject is willing to discontinue his/her treatment with anticholinergics 
(Appendix 3) or amantadine at least 5 days prior to the day of admission (Day -1). 
Part B: Subject is willing to discontinue his/her treatment with anticholinergics 
(Appendix 3) by Day -6 or amantadine by Day -10. 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been 
on a stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
11. Part A: Female subjects must agree to practice a highly effective method of birth control 
while on study through completion of the last follow-up visit. If a subject discontinues 


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early after receiving a dose of SAGE-217, then the subject must continue this method of 
birth control for at least 7 days following the last dose of study drug. Highly effective 
methods of birth control include combined (estrogen and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. 
Part B: Female subject agrees to use one of the following methods of contraception 
during participation in the study and for 30 days following the last dose of study drug, 
unless they are postmenopausal (defined as no menses for 12 months without an 
alternative medical cause) and/or surgically sterile: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception 
• associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse). 
12. Male subjects must agree to practice a highly effective method of birth control while on 
study, and for 13 weeks after receiving the last dose of study drug. Effective methods of 
birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with their partner's highly effective method. 
13. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. 
14. Part B only: Subjects who participated in Part A and meet all eligibility criteria for Part 
B must have tolerated at least 20 mg SAGE-217 in Part A, otherwise they are ineligible. 
8.2. 
Subject Exclusion Criteria 
Subjects who met any of the following exclusion criteria will be excluded from the study: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major 
excipient, HPβCD (Part A) or SAGE-217 Capsule or its excipients (Part B). 
2. Part A: Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and 
Yahr stage 4 or stage 5). 
Part B: Subjects with advanced PD (Hoehn and Yahr stage 5). 


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3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia spectrum and other psychotic 
disorders, substance-related and addictive disorders, feeding and eating disorders, bipolar 
and related disorders, structural brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of clinically significant stroke, or anticipating 
starting psychotherapy or behavior therapy during the course of the study, or who started 
psychotherapy or behavior therapy within 30 days prior to Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 
on the C-SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Part A only: Subjects with severe depression as defined by a BDI-II score >19. 
6. Part B only: Subject has recent exposure (14 days prior to the Day -1 visit) to 
tremorogenic drugs, as defined in Appendix 4. 
7. Subjects with Type I or Type II diabetes mellitus. 
8. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other 
atypical Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system 
atrophy). 
9. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease. 
10. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. ECG may be repeated once if initial values obtained are outside the 
specified limits. 
11. Subject has a history, presence and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 and 2. 
12. Subject has exposure to another investigational medication or device within the prior 
30 days. 
13. Subject has donated one or more units of blood or acute loss of an equivalent amount of 
blood within 60 days prior to dosing (1 unit = 450 mL). 
14. Subject is unwilling or unable to comply with study procedures. 
15. Subject has used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 


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Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug. 
8.3. 
Subject Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s). 
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events; 
• Occurrence of pregnancy; 
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance; 
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject fails to attend scheduled assessments during the course of the study, the Investigators 
must determine the reasons and the circumstances as completely and accurately as possible and 
document this in the subject’s source documents. 
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant. Subjects who cannot tolerate the 
10-mg dose at any time during Part A or the 20-mg dose at any time during Part B will be 
withdrawn. Any subject who is withdrawn from the study for any reason is to have the final visit 
assessments performed. 
Subjects who withdraw or are withdrawn from the study may be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug Treatment 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. All doses of SAGE-217 (Oral Solution or Capsule) will be 
administered with food. 
9.1.1. 
Part A 
Subjects participating in Part A of the study will take SAGE-217 Oral Solution in an open-label 
manner. All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the following 3 days 
(Days 1 to 3). On the morning of Day 4, subjects will stop their immediate-release oral 
Levodopa and take SAGE-217 for 4 days (Days 4 to 7) in the AM with food. On Day 4, subjects 
will receive a 30 mg dose of SAGE-217. Subjects not tolerating 30 mg will receive 20 mg the 
next day, and subjects not tolerating 20 mg will receive 10 mg the next day. The dose received 
on Day 7 will be defined as the tolerated dose for that subject. 
Subjects not tolerating 10 mg will not be able to continue in the study and may be replaced. 
Levodopa treatment will be resumed on Day 8 and continue through Day 14. 
9.1.2. 
Part B 
Subjects participating in Part B of the study will take SAGE-217 Capsules in an open-label 
manner. Subjects on a stable dose of antiparkinsonian agent(s) will continue taking them for the 
duration of the study. All subjects will receive SAGE-217, 20 mg, at 8PM on Days 1 and 2. On 
Day 3, subjects tolerating the initial dose (i.e., those who do not experience a severe adverse 
event judged by the Investigator to be related to study drug) will receive a dose increase 
(SAGE-217, 30 mg), at 8PM, continuing each subsequent evening at 8PM for the remainder of 
the dosing period (ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by occurrence of a 
severe adverse event judged by the Investigator to be related to study drug, the dose on the next 
day must be reduced to 20 mg and continued for the remainder of the dosing period. Subjects 
who cannot tolerate the 20-mg dose at any time will be discontinued and replaced. 
9.2. 
Concomitant Medications 
9.2.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.2. 
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
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The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit. Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications. New concomitant medications, ongoing 
concomitant medications with a change in dose, and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified. 
The Investigator will document all doses of Levodopa and Carbidopa-Levodopa taken by the 
subject and the use of rescue medication. 
9.2.2. 
Prohibited Medications 
Subjects who have used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug are to be excluded from the study; these medications/products are 
prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 are not permitted in the 5 days prior to the 
admission visit (Day -1) of Part A and Part B. The list provides non-exhaustive examples of 
each drug class. 
Amantadine is not permitted in the 5 days prior to the admission visit of Part A or 9 days prior to 
the admission visit of Part B. 
The tremorogenic drugs listed in Appendix 4 are not permitted in the 14 days prior to the 
admission visit of Part B. 
 
9.3. 
Treatment Compliance 
Study drug (SAGE-217 Oral Solution or Capsule) will be prepared by the site pharmacist. All 
doses of study drug will be administered by site staff while the subject is confined to the clinical 
unit. The Investigator(s) or designee will record the time and dose of study drug administration 
in the source documents. Any reasons for noncompliance will also be documented, including: 
• Missing visits; 
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. 
 
9.4. 
Randomization and Blinding 
Not applicable; Part A and Part B of the study are open-label. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
SAGE-217 Oral Solution 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dosages. The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient(s) in the Bottle (manufactured under current Good Manufacturing Practice [GMP] 
conditions 
) and further admixed at the clinical site in preparation for dosing. 
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual. 
The Sponsor will not provide Levodopa or Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa-Levodopa. 
10.1.2. 
SAGE-217 Capsule 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 
Capsules contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and 
sodium stearyl fumarate as excipients. Capsules will be available in 5-mg, 10-mg and 20-mg 
dose strengths. Subjects will be administered two capsules per dose. Detailed instructions for 
study drug preparation will be provided in the Pharmacy Manual. 
10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation. SAGE-217 Oral Solution will be provided to the 
site as powder in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy 
at a volume of 125 mL of a 6 mg/mL stock solution and then further diluted to approximately 
40 mL at the identified doses. SAGE-217 Capsules will be provided to the site in appropriately 
labeled bottles. Study drug labels with all required information and conforming to all applicable 
Code of Federal Regulations and GMP/GCP guidelines will be prepared by the clinical research 
organization. 
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217), the Investigator or designee will inspect the materials 
and complete and return the acknowledgment of receipt form enclosed with the parcel. A copy 
of the signed receipt will be kept in the study files. 
The study drug materials for SAGE-217 Oral Solution must be carefully stored at the 
temperature specified in the Pharmacy Manual (eg, clinical dosing solutions stored at 
approximately 2 to 8°C for 11 days with 24 hours of room temperature excursions allowed after 
preparation), safely and separately from other drugs. SAGE-217 Capsules may be stored at room 
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The study drug may not be used for any purpose other than the present study. After the study is 
completed, all unused study drug must be retained, returned as directed, or destroyed on site per 
the Sponsor’s instructions. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies. An accurate, timely record of 
the disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented. This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Study Drug Preparation 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual. The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5. 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
 
Ingredient 
Compendia Specification 
Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations: EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
For the capsule formulation, subjects will swallow two capsules per dose with food. 


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10.5. 
Administration 
SAGE-217 will be administered with food in the morning in Part A and in the evening in Part B. 
Doses of SAGE-217 Oral Solution will be prepared as an approximate 40 mL oral solution to be 
swallowed all at once, followed by approximately 200 mL of water that has been used to rinse 
the dosing bottle. The start time of swallowing the approximately 40 mL oral solution is time 
zero for all assessments. Subjects may have assistance from the clinic staff when taking the 
study drug. 
During Confinement, each subject’s antiparkinsonian agents, including Levodopa or Carbidopa- 
Levodopa, will be administered by site personnel according to the site’s standard operating 
procedures. 
 
10.6. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded. 
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. 
The Investigator will document all doses of Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
 
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding (oral solution only), subsequent admixture of dosing solutions (oral solution only), 
administration of study drug, and for which subject the study drug was intended (ie, record 
subject initials and birth date or other unique identifier). 
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
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11. 
ASSESSMENT OF EFFICACY 
 
 
Assessments will be perfo1med periodicall y dming the study as outlined in 
the Schedule of Events for Pali A and Pali B (Table 2 and Table 3, respectively). 
 
11.1. 
Movement Disorder Society- Unified Parkinson's Disease Rating 
Scale 
The UPDRS is the most commonly used scale in clinical studies of PD (Ramaker 2002). In 
2007, the MDS revised the scale, which was known as the MDS-UPDRS (Goetz 2007), and 
subsequently demonstrated the validity of the MDS-UPDRS for rating PD (Goetz 2008). The 
modified UPDRS includes fom scales, with various subscales. Each item is rated from 0 
(no1m al) to 4 (severe) (Table 6). The fom MDS-UPDRS scales are: 
Pait I: nonmotor experiences of daily living (13 items) 
Pait II: motor experiences of daily living (13 items) 
Pait III: motor examination (33 scores based on 18 items [several with right, left or other body 
distribution scores]) 
Pait IV: Motor complications (6 items) 
Table 6: 
Rating Scale for the MDS-UPDRS 
 
Rating 
Description 
O = n 01mal 
No symptoms /signs 
1 = sligh t 
Symptoms/signs with sufficiently low frequency or intensity to cause no impact on function 
2 = mild 
Symptoms/signs of frequency or intensity sufficient to cause a modest impact on function 
3 = moderate 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
4 = severe 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
Several questions in Pait I and all questions in Pait II can be answered by the patient/caregiver 
and completed without the Investigator's input. The remaining questions in Part I that deal with 
complex behaviors, the objective assessments of parkinsonism (Pait III), and the questions that 
deal with motor fluctuations and dyskinesias (Pait IV) ai·e co m p leted by In vestigator in terview. 
T h e tim e requ ired fo r ad m inistering the MDS-UPDRS is estimated to be less than 10 minutes for 
the interview items of Pait I, 15 minutes for Pait III, and 5 minutes for Paii IV (Goetz 2008). 
The complete MDS-UPDRS is to be administered in Pait A at screening, Admission (Day -1), on 
Day 8 prior to resuming Levodopa, and on Day 14. The complete MDS-UPDRS is to be 
administered in Pait B at screening, Admission (Day -1), in the morning of Days 1 and 8, and on 
Day 14.  In both Paits A and B, the Admission (Day -1) complete MDS-UPDRS is perfo1med 
only if the time between Screening and Admission is ?:.7 days; othe1wise, the MDS-UPDRS 
Pait III only (Pait A) or Pait II and Pait III (Pait B) are perfo1med. 
Pait II of the MDS-UPDRS assesses 13 categories of motor experiences of daily living: speech, 
salivation and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, 


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doing hobbies and other activities, turning in bed, tremor, getting out of bed, car, or deep chair, 
walking and balance, and freezing (Goetz,  2008).  Pa.ii  II  o f  the MDS-UPDRS  (motor 
examination) is to be completed in Pa.ii  B at  12  a n d 23  h o urs postdose on Days 1, 2, 3, 4, 5, and 
6.  If  the complete MDS-UPDRS is not perfo1m ed on Admission due to Admission taking place 
<7 days after Screening, then Pa.ii II s h o ul d also take place on Admission (Day -1) for Part B. 
Pa.ii III of the MDS-UPDRS assesses 18 motor categories, some of which include right and left 
measurements: speech, facial expression, kinetic tremor of hands, rest tremor ainplitude, postural 
tremor of hands, rigidity of neck and four extremities, finger taps, hand movement, 
pronation/supination, toe tapping, constancy of rest tremor, leg agility, arising from chair, 
posture, gait, freezing of gait, postural stability, global spontaneity of movement (Goetz, 2008). 
Pa.ii III of the MDS-UPDRS (motor examination) is to be completed in Pa1i A at 2, 4, 8, and 
12 hours postdose on Days 1, 2, 3, 4, 5, 6, and 7. MDS-UPDRS is to be assessed within ±10 
minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times for the 6-hour through 12-hour time points. Pa1i III of the MDS-UPDRS (motor 
examination) is to be completed in Pa.ii B at 1 2 a n d 23 h o urs postdose on Days 1, 2, 3, 4, 5, and 
6.  If  the complete MDS-UPDRS is not perfo1m ed on Admission due to Admission taking place 
<7 days after Screening, then Pa.ii III should also take place on Admission (Day -1) for both 
Paiis A and B. 
All MDS-UPDRS measurements in Pa.ii B sho uld  b e tak e n  d uring the "on" period (within 
2 hours of dosing with antipai·kinsonian agent(s)). 
The MDS-UPDRS is provided in Appendix 5. 
 
11.2. 
Exploratory Endpoints 
 


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 4; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 7; in AM of Day 8; and Day 14. Samples are to be collected within 
±5 minutes of the scheduled sampling time. 
In Part B, plasma samples for PK analysis will be collected predose and 13 hours postdose on 
Day 1; and 13 hours postdose on Days 2 through 7, and on Day 14. Samples are to be collected 
within ±1 hour of the scheduled sampling time. 
The time of study drug administration is time zero and all post-dosing sampling times are 
relative to this time. The Investigator or designee will arrange to have the plasma samples 
processed, stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events). 
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time. The date and actual time that the blood sample was taken will be 
recorded on the eCRF or electronically with a bar code or other method. 
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70 to -80°C until analyzed. They 
should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours. A specimen-identification form must be completed and 
sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions. 
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of concentrations of SAGE-217 and 
possibly SAGE-217 metabolites will be performed utilizing a validated liquid chromatography- 
tandem mass spectrometry method at a qualified laboratory. Pharmacokinetic parameters will be 
derived such as area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), the 
distributional half-life and terminal half-life (t½), and steady-state drug concentration in the 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS (Part A only) and MOAA/S (Part A only) scores. 
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visits. A full medical 
history, including PD history (e.g., time of diagnosis, Hoehn and Yahr staging) and medication 
history, will be recorded at the Screening visits. 
13.1.2. 
Vital Signs 
Vital signs comprise respiratory rate, temperature, and supine (supine for at least 5 minutes prior 
to the measurement) and standing systolic and diastolic blood pressure and heart rate. 
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 
through 7; in AM of Day 8; and on Day 14. Vital signs and pulse oximetry are to be assessed 
within 
±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times for the 6-hour through 16-hour time points. 
In Part B, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, and 12 hours postdose on Days 1 through 7; and on 
Day 14. Vital signs and pulse oximetry are to be assessed within ±10 minutes of the 1- and 2-
hour time points and within ±15 minutes of the 12-hour time point. 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visits for Parts A and B. 
 
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visits for Parts A and B. Symptom-directed physical examinations will be performed 
during Part A on Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and Day 8. Symptom- 
directed physical examinations will be performed during Part B on Admission (Day -1), Day 1, 
Day 3, Day 4, Day 6, and Day 8. 
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at screening and Admission (Day -1); predose on 
Days 1 and 3; predose and 1 and 12 hours postdose on Days 4, 5, 6, and 7; in AM on Day 8; and 


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Day 14. In Part B, the 12-lead ECG will be assessed at screening and Admission (Day -1); 
predose and 1 and 12 hours postdose on Days 1, 3, 5, and 7, and on Day 14. 
All time points are relative to the time of dosing. ECGs are to be performed within ±10 minutes 
of the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 
13.1.6. 
Laboratory Assessments 
In Part A, blood samples will be collected for hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day -1); predose on Day 4 and Day 7; and on 
Day 14. In Part B, blood and urine samples will be collected at screening and Admission 
(Day -1); predose on Days 4 and 6; and on Day 8 and Day 14. On Day -1 of Part B, two blood 
samples will be taken: one sample will be sent to the central lab to be analyzed for reporting 
purposes and one sample is to be analyzed locally for study eligibility with regard to 
hematology/serum chemistry criteria. 
Serum and urine samples for pregnancy tests (females only) will also be collected. These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3 as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to Section 13.2, 
and recorded in the eCRF. 
 
13.1.6.1. Hematology 
Hematology tests will include complete blood count (CBC), including red blood cells, white 
blood cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), alkaline 
phosphatase (Part B only), total protein, and albumin. 
 
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 


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13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study. 
13.1.6.5. Pregnancy Screen 
Females of childbearing potential will be tested for pregnancy at Parts A and B by serum 
pregnancy test at the Screening visits and by urine pregnancy test on Day -1 (Admissions). For 
Part B, females of childbearing potential will also be tested for pregnancy by urine pregnancy 
test at the follow-up visit on Day 14. 
 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe). 
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be completed on Screening of Parts A and B 
(lifetime history and past 24 months). In Part A, the “Since Last Visit” C-SSRS form will be 
completed on Admission (Day -1); 12 hours postdose on Days 1, 2, and 3; predose on Days 4, 5, 
6, and 7; and on Days 8 and 14. In Part B, the “Since Last Visit” C-SSRS form will be 
completed on Admission (Day -1); predose and 12 hours postdose on Day 1; 12 hours postdose 
on Days 2 through Day 7; and on Day 14. The C-SSRS is provided in Appendix 10. 
 
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling. Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’. 
In Part A, the SSS will be administered on Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in the AM on Day 8; and Day 14. All time 
points are relative to the time of dosing. The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. The SSS should be performed prior to the MOAA/S score. The SSS will not be 
administered in Part B. The SSS is provided in Appendix 11. 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS. If an MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment. In Part A, the MOAA/S assessment should be 


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conducted after other assessments that are scheduled at the same time point. In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 
3, 4, 5, 6, and 7; in AM on Day 8; and Day 14. The MOAA/S will not be performed in Part B. 
The MOAA/S is provided in Appendix 12. 
 
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed. Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher). 
13.2.1. 
Definition of Adverse Events 
 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
All adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, or following the cessation of treatment until the Day 14 Follow-up visit of Parts A and 
B, whether or not they are related to the study, must be recorded on forms provided by Sage 
Therapeutics. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 


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All serious adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, and until the Day 14 Follow-up visit of Parts A and B, whether or not they are related 
to the study, must be recorded on forms provided by Sage Therapeutics. 
 
13.2.1.4. Recording Sedation as an Adverse Event 
In Part A and Part B, sedation will be recorded as an adverse event. Consideration should be 
given to the most appropriate term to describe the sedation characteristics. 
For Part A, in order to standardize the reporting of sedation as adverse events, Investigators must 
record sedation as an adverse event if there is a score of >5 on the SSS and/or a score of ≤2 on 
the MOAA/S. SSS and MOAA/S do not apply to Part B. 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator. The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
The Investigator should request permission to contact the subject, the subject’s spouse/partner (if 
the subject is male and his spouse/partner becomes pregnant) or the obstetrician for information 
about the outcome of the pregnancy (spontaneous miscarriage, elective termination, live birth), 
and in the case of a live birth, about any congenital abnormalities. If a congenital abnormality is 
reported, then it should be recorded in the source documents and reported as a serious adverse 
event. Spontaneous miscarriages should also be reported and handled as serious adverse events. 
Elective abortions without complications should not be handled as adverse events. 
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.” 
 
Not related 
No relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or subject’s clinical 
state. 
Possibly related 
A reaction that follows a plausible temporal sequence from administration of the 
study drug and follows a known response pattern to the suspected study drug. 
Probably related 
The reaction might have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject, but this is not known for sure. 


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If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting. 
 
13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug. 
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted TEAEs. 
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change. 
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe adverse events. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 13.2.1.3. An adverse event 
of severe intensity may not be considered serious. 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 14 Follow-up visit of Parts A and B. Any serious adverse events considered 
possibly or probably related to the investigational product and discovered by the Investigator at 
any time after the study should be reported. All serious adverse events must be reported to the 
Sponsor or Sponsor’s designee immediately by phone and in writing within 24 hours of the first 
awareness of the event. The Investigator must complete, sign and date the serious adverse event 
pages, verify the accuracy of the information recorded on the serious adverse event pages with 
the corresponding source documents, and send a copy to Sage Therapeutics or designee. 
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file. 


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Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 
will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
additional serious adverse events. 


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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered at least one dose of study 
drug. Safety population will be used to provide descriptive summaries of all safety data. 
The efficacy population will consist of all subjects in the safety population who receive at least 
one dose of study drug and have at least one postdose MDS-UPDRS evaluation. The efficacy 
population will be used to analyze all efficacy data. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each part of the study. 
 
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data. No sensitivity analysis of missing data will be performed. 
 
14.3. 
General Considerations 
For the purpose of all safety, efficacy, and exploratory analyses where applicable, baseline is 
defined as the last measurement prior to the start of study drug administration. Continuous 
endpoints will be summarized with n, mean, standard deviation (SD), median, minimum and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts 
and percentages. 
 
14.4. 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, race, and ethnicity, and baseline characteristics, such as 
height, weight, and body mass index (BMI), will be summarized. 
Categorical summaries, such as gender and race, will be summarized by frequency and 
percentage. Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics. 
Hepatitis, HIV, and pregnancy screening results will be listed, but not summarized as they are 
considered part of the inclusion/exclusion criteria. 
Medical history will be listed by subject. 
 
14.5. 
Efficacy Endpoints 
The primary endpoints of Part A relate to safety and tolerability. The primary endpoint for Part 
B is to evaluate the improvement in PD tremor as assessed by changes in the MDS UPDRS Part 
II/III tremor score (defined as the sum of MDS-UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 


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14.5.1. 
Secondary Efficacy Endpoints 
fu Pait A, changes in the MDS-UPDRS- Pait III score will be Sllilllllaii·zed overall and by 
tolerated dose. fu Pait B, MDS-UPDRS Pali III total score, and the MDS-UPDRS - Pa.it s I- IV 
total score will be smmnai·ized overall and by and tolerated dose. 
 
14.5.2. 
Exploratory Efficacy Endpoints 
14.6. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, SSS (Pa.ii A onl y), and 
MOAAIS (Pa1i A only) will be smnmai·ized using descriptive statistics by group and time point, 
where applicable. Continuous endpoints will be Sllilllllai·izedwith nlllllber (n), mean, standai·d 
deviation, median, minimlllll, and maximlllll. fu addition, change from baseline values will be 
calculated at each time point and will be smmnai·ized using descriptive statistics. Out-of-range 
safety endpoints may be categorized as low or high, where applicable. For all categorical 
endpoints, sUilllna ries wi ll include counts and percentages. 
14.6.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher). The 
analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of open-label study drng, or any worsening of a pre­ 
existing medical condition/adverseevent with onset after the strut of ope n-l abe l study diu g and 
until 14 days after the last dose. The incidence of TEAEs will be sUillln ai·ized overall and by 
MedDRA System Organ Class, preferred tenn, and dose group. fucidences will be presented in 
order of decreasing frequency. fu addition, Sllilllllaii·es will be provided by maximlllll severity 
(see Section 13.4) and relationship to study diug (see Section 13.3). 
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the first dose of open-label study diug will also 
be sUillillaii·zed. 
All adverse events and serious adverse events (including those with onset or worsening before 
the staii of open-label study diug) through the Day 14 Follow-up visit of Paii s A and B will be 
listed. 
14.6.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
of Pa.ii A and Pait B in vital signs will be evaluated by time point. 


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14.6.3. 
Physical Examinations 
Screening physical examination results for Part A and Part B will be listed by subject. Any 
clinically significant physical examination will be recorded in medical history. Physical 
examination findings will be listed by subject and visit; abnormal findings will be flagged on the 
listing. 
 
14.6.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event. Electrocardiogram findings will be listed by subject and visit. 
14.6.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline of Parts A and B in clinical laboratory measures will be summarized. 
14.6.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects. Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
14.6.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects in Part A. Changes in score over 
time will be represented graphically, and change from baseline of Part A will be summarized. 
 
14.6.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects in Part A. Changes in 
score over time will be represented graphically, and change from baseline of Part A will be 
summarized. 
14.6.9. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later. 
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant). Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug. Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug. If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant. Details of prior and 
concomitant medications will be listed by study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and summarized. 


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14.7. 
Pharmacokinetic Analysis 
Phaimacokinetic parameters will be Slllllirni.rized u s in g appropriate descriptive statistics. Time to 
reach maximlllll concentration (tma.x) will be summarized using number  (n),  mean,  standai·d 
deviation, median, minimlllll, and maximlllll. All  other  PK pai·ameters  will  be Sllilllllarized  using 
n, geometric mean, coefficient of  vaii·ation,  median,  minimum,  and  maximlllll  and  listed  by 
subject. 
Wherever necessaiy and appropriate, PK pai·ainetres will be dose-adjusted to account for 
individual differences in dose. 
 
 
 
 
and safety. 
 
14.8. 
Determination of Sample Size 
Approximately 18 subjects will be enrolled in Pait A. An interim analysis is planned after 
10 subjects have completed Pait A through Day 14. Up to 15 subjects will be enrolled in Pait B 
in order for 10 subjects to complete the study (tolerate at least 20 mg SAGE-217 for the duration 
of the dosing period). This number of subjects is thought to be sufficient to assess preliminary 
safety and tolerability as well as a signal of efficacy of SAGE-217 in subjects with PD. 
 
14.9. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan. 
Additional exposure-response analyses may be perfo1med for other measures of efficacy 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of <Sponsor> 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between Sage 
Therapeutics and the Investigator. 
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each patient (eg, clinic 
charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to Sage Therapeutics 
or designee and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of a Sage Therapeutics or designee audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs. 
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements. 
 
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan. 
Electronic case report forms will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, and subject status. 
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study. For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available study registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor. It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study. The information obtained from the clinical study will be used 


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towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required. 


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics. No publication or disclosure of study results will be permitted except as 
specified in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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20. 
LIST OF REFERENCES 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neurophan nacology. 2002 
Sep;43(4):651- 61. 
Bergman H, Deuschl G. Pathophysiology of Parkinson's disease: from clinical neurology to 
basic neuroscience and back. Mov Disord. 2002;17:S28-S40. 
 
di Michele F, Longone P, Romeo E, et al. Decreased plasma and cerebrospinal fluid content of 
neuroactive steroids in Parkinson's disease. Neurol Sci. 2003;24(3):172-3. 
Goetz CG, Fahn S, Maitinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, fonnat, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41-4 . 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Pai·kinson's Disease Rating Scale (MDS-UPDRS): Scale presentationand clinimetric 
testing results. Mov Disord. 2008;23(15):2129- 70. 
Hoehn M, Yahr M. Parkinsonism: onset, progression and mo1tality. Neurology. 
1967;17(5):427-42. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Pai·kinson's disease. A clinico-pathological study of 100 cases. JNNP. 1992;55:181-4. 
Jankovic J. Moto r fluctuations and dyskinesia in Parkinson's disease: Clinical manifestations. 
Mov Disord. 2005;11:ll -6. 
Jankovic J. Parkinson's' disease: clinical features and diagnosis. JNNP. 2008;79:368-76. 
Kasten M, Brnggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the 
detection of MCI and dementia in Parkinson disease. Neurology. 2010;75 (5):478-9. 


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Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatiy. 2011;168(12):1266-77. 
Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for 
impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867- 76. 
Siderowf A, Lang AE. Pre-motor Parkinson's disease; concepts and definitions. Mov. Disord 
2012;27, 608-16. 
Stem MB. Dopamine agonists modify the course of Parkinson disease. Arch Neurol. 
2004;61:1969-71. 
Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 
2004;61:1966-9. 
Winkler C, Bentlage C, Nikkhah G, et al. Intracranial transplants of GABA-rich striatal tissue 
induce behavioral recove1y in the rat Parkinson model and promote the effects obtained by 
intrastriatal dopaminergic transplants. Exp. Neurol. 1999;155:165-186. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in the following appendices are for reference only; 
the rating scales and questionnaires reproduced in the eCRFs are to be used for actual subject 
assessment per the Schedule of Events. 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA 
 


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APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA 
The Hoehn and Yahr scale, a commonly used system for describing how the symptoms of 
Parkinson’s disease progress, was first published in 1967 (Hoehn 1967). The original scale 
included 5 disease stages, numbered 1 to 5. 
 
 
Original Hoehn and Yahr Scale 
 
Stage 1 
Unilateral involvement only, usually with minimal or no functional disability 
Stage 2 
Bilateral or midline involvement without impairment of balance 
Stage 3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; 
physically independent 
Stage 4 
Severely disabling disease; still able to walk or stand unassisted 
Stage 5 
Confinement to bed or wheelchair unless aided 


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APPENDIX 3. ANTICHOLINERGIC DRUGS 
The following drugs are not permitted in the 5 days prior to receiving the first dose of study drug 
in Part A and Part B. The list below gives a non-exhaustive list of examples of each drug class. 
A. Antimuscarinic agents 
 
Atropine 
Benzatropine 
Biperiden 
Chlorpheniramine 
Dicyclomine 
Dimenhydrinate 
Diphenhydramine 
Doxepin 
Doxylamine 
Glycopyrrolate 
Hydroxyzine 
Ipratropium 
Orphenadrine 
Oxitropium 
Oxybutynin 
Tolterodine 
Tiotropium 
Tropicamide 
Trihexyphenidyl 
Scopolamine 
Solifenacin 
Tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, trimipramine, 
amoxapine, desipramine, nortriptyline, protriptyline) 
 
B. Antinicotinic agents: 
 
Bupropion 
Dextromethorphan 
Doxacurium 
Hexamethonium 
Mecamylamine 
Tubocurarine 


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APPENDIX 4. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the Day -1 visit and for the 
duration of the study (up to the Day 14 visit). The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
amiodarone, procainamide 
Antiepileptic drugs 
valproic acid, carbamazepine 
Antipsychotic agents 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
lithium at toxic levels 
Antivirals 
acyclovir, vidarabine 
Beta adrenergic agonists 
albuterol, terbutaline 
Calcium Channel blockers 
verapamil 
CNS stimulants 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
cytarabine 
Hormones 
calcitonin, levothyroxine (levothyroxine is allowed if on a stable dose and euythroid) 
Immunomodulatory 
thalidomide 
Immunosuppressants 
cyclosporine, tacrolimus 
Monoamine depleting agents 
tetrabenazine 
Oral hypoglycemic agents 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
metoclopramide 
Tricyclic antidepressants 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
fluoxetine (other SSRIs are allowed) 
Statins 
atorvastatin (other statins are allowed) 


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Sympathomimetics 
epinephrine, pseudoephedrine 
Weight loss medication 
tiratricol 
Xanthine derivatives 
theophylline (caffeine/coffee and theophylline/theobromine/tea require a washout, cocoa 
beans are acceptable) 


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APPENDIX 5. MOVEMENT DISORDER SOCIETY-UNIFIED 
PARKINSON'S DISEASE RATING SCALE (MDS-UPDRS) 
 
Part I: Nonmoto1· A spect s of Experi e nc es of Dail y Li vi ng 
Part II: Motor Expeli ences of Daily Living 
Cognitive impainnent 
Speech 
Hallucinations and psychosis 
Saliva and drooling 
Depressed mood 
Chewing and swallowing 
Anxious mood 
Eating tasks 
Apathy 
Dressing 
Features of dopamine dysregulation syndrome 
Hygiene 
Sleep problems 
Handwriting 
Daytime sleepiness 
Doing hobbies and other activities 
Pain and other sensations 
Tuming in bed 
Urina1y problems 
Tremor impact on activities 
Constipation problems 
Getting in and out of bed 
Lightheadedness on standing 
Walking and balance 
Fatigue 
Freezing 
Part III: Motor Examination 
Part IV: Motor Complications 
Speech 
Time spent with dyskinesias 
Facial expression 
Functional impact of dyskinesias 
Rigidity (neck; right/left upper/lower extremities) 
Painful off state dystonia 
Finger tapping (right/left hands) 
Time spent in the off state 
Hand movements (right/left hands) 
Functional impact of fluctuations 
Pronation-supination movements of right/left hands 
Complexity of motor functions 
Toe tapping (right/left foot) 
Leg agility (right/left leg) 
Arising from chair 
Gait 
Freezing of gait 
Postural instability 
Posture 
Global spontaneity of movement (body bradykinesia) 
Postural tremor of righ t/left hands 
Kinetic tremor of right/left hands 
Rest tremor amplitude: right/left upper/lower extre1niites; lip jaw 
Constancy of rest tremor 


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APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – BASELINE/SCREENING VERSION AND 
SINCE LAST VISIT VERSION 
 
 
 


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APPENDIX 11. STANFORD SLEEPINESS SCALE (SSS) 
 


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APPENDIX 12. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
Modified Observer’s Assessment of Alertness/Sedation Scale 
 
Score 
Responsiveness 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Responds only after painful trapezius squeeze 
0 
No response after painful trapezius squeeze 


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Summary of Changes to 
Protocol 217-PRK-201, Amendment #4 
Date of Amendment: 08 June 2017 
 
The following changes were made in Protocol 217-PRK-201 v5.0, Amendment #4. In addition, minor editorial revisions 
(eg, formatting, punctuation) that are not listed below may have been made throughout the protocol. 
 
Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
Document Header 
Amendment #3, Version 4.0 
Amendment #34, Version 45.0 
Administrative 
update 
Title Page 
Date of Amendment 4 08 June 2017 
Administrative 
update 
Protocol Signature 
Page 
Date of Amendment 3: Version 4.0 06 June 2017 
Date of Amendment 3: Version 45.0 06 8 June 2017 
Administrative 
update 
2. Synopsis, 
Methodology 
This study will assess the safety, tolerability, 
pharmacokinetics (PK) and effectiveness of SAGE- 
217. For ease of discussion, Levodopa alone or 
Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
There are two parts, Part A and Part B, described 
below. Unique subjects will be enrolled in each 
part; subjects from Part A will not continue into Part 
B. 
This study will assess the safety, tolerability, 
pharmacokinetics (PK) and effectiveness of SAGE- 
217. For ease of discussion, Levodopa alone or 
Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
There are two parts, Part A and Part B, described 
below. Unique subjects will be enrolled in each part; 
subjects from Part A will not continue into Part B. 
Removed so subjects 
from Part A may be 
eligible for Part B. 
2. Synopsis, Number 
of subjects (planned); 
Approximately 18 subjects will be enrolled in Part 
A. An interim analysis is planned after 10 subjects 
Approximately 18 subjects will be enrolled in Part A. 
An interim analysis is planned after 10 subjects have 
Changed to reflect 
that subjects from 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
7.2. Number of 
subjects 
have completed Part A through Day 14 to inform the 
conduct of Part B. 
Up to 15 new subjects will be enrolled in Part B in 
order for 10 subjects to complete the study (tolerate 
at least 20 mg SAGE-217 for the duration of the 
dosing period). 
completed Part A through Day 14 to inform the 
conduct of Part B. 
Up to 15 new subjects will be enrolled in Part B in 
order for 10 subjects to complete the study (tolerate at 
least 20 mg SAGE-217 for the duration of the dosing 
period). 
Part A may be 
eligible for Part B. 
2. Synopsis; 
8.1. Subject Inclusion 
Criteria 
14. Part B only: Subjects who participated in Part 
A and meet all eligibility criteria for Part B must 
have tolerated at least 20 mg SAGE-217 in Part A, 
otherwise they are ineligible. 
Added criteria for 
Part B to exclude 
subjects that did not 
tolerate at least 
20 mg dose in Part A 
2. Synopsis, Duration 
of Treatment 
Part A and Part B: 
Screening Duration: up to 28 days 
Treatment Period: 7 days 
Follow-up: 7 days 
Planned Study Duration per Subject: approximately 
42 days 
Part A and Part B: 
Screening Duration: up to 28 days per part 
Treatment Period: 7 days per part 
Follow-up: 7 days per part 
Planned Study Duration per Subject: approximately 
42 days if participating in one part only (up to 84 
days if participating in both Parts A and B) 
Changes made for 
clarification for 
subjects that may 
participate in both 
parts of study 
2. Synopsis, 
Statistical Methods, 
Sample Size 
Calculation 
Approximately 18 subjects will be enrolled in Part 
A. Up to 15 new subjects will be enrolled in Part B 
in order for 10 subjects to complete the study 
(tolerate at least 20 mg SAGE-217 for the duration 
of the dosing period). The sample size for Part A 
and Part B was selected based on clinical and 
not statistical considerations. 
Approximately 18 subjects will be enrolled in Part A. 
Up to 15 new subjects will be enrolled in Part B in 
order for 10 subjects to complete the study (tolerate at 
least 20 mg SAGE-217 for the duration of the dosing 
period). The sample size for Part A and Part B was 
selected based on clinical and not statistical 
considerations. 
Changed to reflect 
that subjects from 
Part A may be 
eligible for Part B. 


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Section Number and 
Title 
Original Text: 
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Rationale: 
Table 3: Schedule of 
Events: Part B 
(Open-Label) 
Added ‘X’ for Day 7 of MDS-UPDRS (Part II only) 
and MDS-UPDRS (Part III only) 
Change made to 
show that MDS- 
UPDRS Part II/III 
only are to be 
performed 12 and 
23 hours following 
the dose on Day 6 
(ie, in the morning 
and evening of 
Day 7) 
7.1 Overall Study 
Design 
This study is a two-part, multicenter, Phase 2 study 
to evaluate the safety, tolerability, PK, and efficacy 
of SAGE-217. Part A of the study is an open-label 
design with morning (AM) dosing of SAGE-217 
Oral Solution for 4 days in in up to 18 adult subjects 
with PD of moderate severity who respond to 
immediate-release oral Levodopa and are on a stable 
dose. Part B of the study is an open-label design 
with evening (PM) dosing of SAGE-217 Capsules 
for 7 days in up to 15 adult subjects with PD. 
Subjects that participate in Part A are not eligible to 
participate in Part B. Subjects will be followed for 
an additional 7 days after the administration of the 
last dose in Part A and Part B. 
This study is a two-part, multicenter, Phase 2 study to 
evaluate the safety, tolerability, PK, and efficacy of 
SAGE-217. Part A of the study is an open-label 
design with morning (AM) dosing of SAGE-217 Oral 
Solution for 4 days in in up to 18 adult subjects with 
PD of moderate severity who respond to immediate- 
release oral Levodopa and are on a stable dose. Part 
B of the study is an open-label design with evening 
(PM) dosing of SAGE-217 Capsules for 7 days in up 
to 15 adult subjects with PD.  Subjects that 
participate in Part A are not eligible to participate in 
Part B if all eligibility criteria for Part B are met 
and they tolerated at least 20 mg SAGE-217 in 
Part A. Subjects will be followed for an additional 7 
days after the administration of the last dose in Part A 
and Part B. 
Changed to reflect 
that subjects from 
Part A may be 
eligible for Part B. 
13.1.2. Vital Signs 
Vital signs comprise respiratory rate, temperature, 
and supine (supine for at least 5 minutes prior to the 
Vital signs comprise respiratory rate, temperature, 
and supine (supine for at least 5 minutes prior to the 
Change made to 
distinguish between 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
measurement) and standing systolic and diastolic 
blood pressure and heart rate. 
Vital signs and pulse oximetry will be performed at 
screening (vital signs only) and Admission (Day -1); 
predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours 
postdose on Days 1 through 7; in AM of Day 8; and 
on Day 14. Vital signs and pulse oximetry are to be 
assessed within ±10 minutes of the scheduled times 
through the 4 hour time point and within ±15 
minutes of the scheduled times for the 6-hour 
through 16-hour time points. 
In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, and 12 
hours postdose on Days 1 through 7; and on Day 14. 
Vital signs and pulse oximetry are to be assessed 
within ±10 minutes of the 1- and 2 hour time points 
and within ±15 minutes of the 12-hour time point. 
measurement) and standing systolic and diastolic 
blood pressure and heart rate. 
In Part A, vVital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 7; in 
AM of Day 8; and on Day 14. Vital signs and pulse 
oximetry are to be assessed within ±10 minutes of the 
scheduled times through the 4 hour time point and 
within ±15 minutes of the scheduled times for the 6- 
hour through 16-hour time points. 
In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, and 12 
hours postdose on Days 1 through 7; and on Day 14. 
Vital signs and pulse oximetry are to be assessed 
within ±10 minutes of the 1- and 2 hour time points 
and within ±15 minutes of the 12-hour time point. 
Part A and Part B 
assessments 
13.2.1.4. Recording 
Sedation as an 
Adverse Event 
In Part A and Part B, sedation will be assessed using 
protocol-specified rating scales. Consideration 
should be given to the most appropriate term to 
describe the sedation characteristics. 
For Part A, in order to standardize the reporting of 
sedation as adverse events, Investigators must record 
sedation as an adverse event if there is a score of >5 
on the SSS and/or a score of ≤2 on the MOAA/S. 
SSS and MOAA/S do not apply to Part B. 
In Part A and Part B, sedation will be assessed using 
protocol specified rating scalesrecorded as an 
adverse event. Consideration should be given to the 
most appropriate term to describe the sedation 
characteristics. 
For Part A, in order to standardize the reporting of 
sedation as adverse events, Investigators must record 
sedation as an adverse event if there is a score of >5 
Clarification 


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Section Number and 
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Original Text: 
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on the SSS and/or a score of ≤2 on the MOAA/S. 
SSS and MOAA/S do not apply to Part B. 
14.8. Determination 
of Sample Size 
Approximately 18 subjects will be enrolled in Part 
A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14. Up to 15 
new subjects will be enrolled in Part B in order for 
10 subjects to complete the study (tolerate at least 20 
mg SAGE-217 for the duration of the dosing 
period). This number of subjects is thought to be 
sufficient to assess preliminary safety and 
tolerability as well as a signal of efficacy of SAGE- 
217 in subjects with PD. 
Approximately 18 subjects will be enrolled in Part A. 
An interim analysis is planned after 10 subjects have 
completed Part A through Day 14. Up to 15 new 
subjects will be enrolled in Part B in order for 10 
subjects to complete the study (tolerate at least 20 mg 
SAGE-217 for the duration of the dosing period). 
This number of subjects is thought to be sufficient to 
assess preliminary safety and tolerability as well as a 
signal of efficacy of SAGE-217 in subjects with PD. 
Changed to reflect 
that subjects from 
Part A may be 
eligible for Part B. 


1 
 
 
Protocol 217-PRK-201 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
 
 
 
 
PROTOCOL NUMBER: 217-PRK-201 
A PHASE 2, TWO-PART STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF SAGE-217 IN SUBJECTS WITH 
PARKINSON’S DISEASE 
IND NUMBER: 131,258 
Investigational Product 
SAGE-217 
Clinical Phase 
2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
 
Sponsor Medical Monitor 
 
 
 
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
, M.D., M.P.H. 
Study Physician 
Phone: 
Email: 
28 September 2016 
5 October 2016 
24 October 2016 
06 June 2017 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
Phone: 
Email: 
, M.D., Ph.D. 


 
Date (DD/MM M/YYYY) 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 
Date (DD/MMMNYYY) 
Protocol 217-PRK-201 
Amendment #3, Version 4.0 
 
PROTOCOL SIGNATURE PAGE 
Sage Therapeutics 
CONFIDENTIAL 
 
 
 
 
Protocol Num ber: 
Product: 
IND No.: 
Study Phase: 
Sponsor : 
Date of Amendment 3: 
 
217 -PRK-201 
SAGE-217 
131,258 
2 
Sage Therapeutics 
Version 4.0 06 June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
 
 
 
 
2 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PRK-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
  
Address and Telephone Number  
Clinical Research Organization 


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2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Efficacy of SAGE-217 in Subjects with Parkinson’s Disease (PD) 
Study centers: Up to 12 centers 
Objectives 
Primary: 
Part A: 
• 
To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
Part B: 
• 
To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian agent(s) on the 
severity of PD tremor symptoms. 
Secondary: 
Part A: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
Part B: 
• 
To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian agent(s) on motor 
and non-motor symptoms of PD. 
• 
To evaluate the safety and tolerability of SAGE-217 Capsules. 
Pharmacokinetic: 
• 
Part A: To assess the pharmacokinetic (PK) profile of SAGE-217 Oral Solution in plasma 
samples. 
• 
Part B: To assess the PK profile of SAGE-217 Capsules utilizing a population PK approach. 


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Endpoints 
Primary: 
Part A: 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laborato1y data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Sevedty 
Rating Scale (C-SSRS). In addition,sleepiness/sedation as assessed by StanfordSleepinessScale 
(SSS) score. 
PartB: 
• 
Improvement in PD tremor as assessed by changes in the MDS UPDRS Pait WIII tremor score 
(defined as the sum of MDS-UPDRSitems 2.10, 3.15, 3.16,3.17 and 3.18). 
Secondar y: 
Part A: 
• 
Improvement in PD motor symptomsas assessed by changes in the Movement Disorder Society­ 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS)- Pait III (Motor Exainination) score. 
PartB: 
• 
Improvement in PD motor symptomsas assessed by changes in the MDS-UPDRS- Pait III total 
score. 
• 
Improvement in PD nonmotor and motor aspects of experiences of daily living as assessed by the 
MDS-UPDRS - Pait I and Part II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - Paits I-IV 
total score. 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laborato1y data, 
electrocai·diogram (ECG)pai·ametres, and suicidal ideation using the Columbia-SuicideSevedty 
Rating Scale (C-SSRS). 
Pharmacokinetic: 
• 
Plasma concentrations of SAGE-217,and possibly SAGE-217metabolites,will be measured, and 
PK paia· meters will be derived. 
Exploratory: 


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Methodology: 
This study will assess the safety, tolerability, pha1macokinetics (PK) and effectivenessof SAGE-217. 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to as 
Levodopa in this protocol. 
There are two parts , Pait A and Pait B, described below. Uniquesubjects will be emolled in each part ; 
subjects from Pait A will not continue into Pait B. 
Part A: Open-label with AM dosing (4 days). 
All subjects will continue to take their antipai·kinsonian agent(s) includingimmediate-release oral 
Levodopa on the day of admission (Day -1) and in the AM only the following 3 days (Days 1 to 3). 
All subjects will stop their immediate-release oral Levodopa on Day 4 and will start on a 30 mg dose 
of SAGE-217 Oral Solutionadministered in the AM with food. Subjects not tolerating 30 mg will 
receive 20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days. The dose 
received on Day 7 will be defined as the tolerated dose for that subject. Subjects not tolerating 10 mg 
will not be able to continue in the study and may be replaced. Subjects will be followedfor an 
additional 7 days (Day 14) after the administrationof the last dose. Levodopa treatmentwill be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antipai·kinsonian agent at Investigator's discretion)will be 
allowed, if needed, on all days (Days 1 to 7). 
Pait A is designed to determine the tolerated dose of SAGE-217 Oral Solutionfor each subject andto 
assess whether SAGE-217 exhibits efficacy in subjects with PD in order to informthe conduct of 
Pait B. 
Assessments will be pe1fo1med periodically during the study as outlined in the Schedule of Events for 
Pait A (Table 2). 
Part B: Open-label with evening (PM) dosing, for 7 days, as an adjunct to antipaik· insonian agent(s). 
Subjects on a stable dose of antipai·kinsonain agent(s) will continue taking them for the duration of the 
study. Anticholinergics and/or amantadine will be discontinuedby Day -6 and Day -10, respectively. 
Screening may occur between Day -28 and Day -2, but subjects must be admittedon Day-1 for 
selected pre-dose assessments (eg, clinical laboratory assessments, assessment of tremor). All subjects 
will take SAGE-217 Capsules, 20 mg, at 8PM on Days 1 and 2. On Day 3, subjects tolerating the 
initial dose (ie, those who do not experience a severe adverse event judgedby the Investigator to be 
related to study diug) will receive a dose increase (SAGE-217, 30 mg), at 8PM and continuing each 
subsequent evening at 8PM for the remainder of the dosing period (endingon Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by occurrence of a severe 
adverse event judgedby the Investigatorto be related to study dI11g, the dose on the next day must be 
reduced to 20 mg and continued for the remainder of the dosing pedod. Subjects who cannot tolerate 
the 20-mg dose at any time will be discontinued and replaced. 
All doses of SAGE-217 will be adininistered with food. For antipai·kinsonian agents, administration 
with or without food will be determined by the Investigator. 


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Subjects will receive SAGE-217 for up to 7 days and will be followed for an additional 7 days after the 
administration of the last dose. 
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part B (Table 3). 
Number of subjects (planned): 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the conduct of Part B. 
Up to 15 new subjects will be enrolled in Part B in order for 10 subjects to complete the study (tolerate 
at least 20 mg SAGE-217 for the duration of the dosing period). 
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Part A: Subjects with PD with a duration of less than 7 years and must meet the criteria for Hoehn 
and Yahr stage 2 or stage 3 (Appendix 2). 
Part B: Subjects with PD and must meet the criteria for Hoehn and Yahr stage 1-4 (Appendix 2) 
assessed during the “on” period (assumed to be within 2 hours of dosing with antiparkinsonian 
agent(s)), and have a tremor with a MDS-UPDRS Part II/III tremor score of ≥8 (sum of items: 2.10, 
3.15, 3.16, 3.17 and 3.18) AND a MDS-UPDRS item score ≥3 in at least one limb (from items 
3.15, 3.16, or 3.17). Inclusion criteria tremor scores must be assessed during “on” periods during 
the screening and Day -1 visit. 
5. Part A: Subject has a stable dose of antiparkinsonian agent(s) including immediate-release oral 
Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month prior to 
the baseline visit) and is expected to remain on this stable dose for the duration of this study. 
Part B: Subject is receiving a stable dose of antiparkinsonian agent(s) (defined as no changes for a 
period of at least 1 month prior to the baseline visit) and is expected to remain on this stable dose 
for the duration of this study. 
6. Part A only: Subject is willing to discontinue his/her treatment with immediate-release oral 
Levodopa or Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. 
7. Part A: Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). 
Part B: Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) by 
Day -6 or amantadine by Day -10. 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been on a stable 
dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
11. Part A: Female subjects must agree to practice a highly effective method of birth control while on 
study through completion of the last follow-up visit. If a subject discontinues early after receiving 


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a dose of SAGE-217, then the subject must continue this method of birth control for at least 7 days 
following the last dose of study drug. Highly effective methods of birth control include combined 
(estrogen and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized 
partner, or sexual abstinence. 
Part B: Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause) and/or 
surgically sterile: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception 
• associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse). 
12. Male subjects must agree to practice a highly effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with their 
partner's highly effective method. 
13. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. 
Exclusion Criteria: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major excipient, HPβCD 
(Part A) or SAGE-217 Capsule or its excipients (Part B). 
2. Part A: Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 
4 or stage 5). 
Part B: Subjects with advanced PD (Hoehn and Yahr stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her ability for 
participation. This includes schizophrenia spectrum and other psychotic disorders, substance- 
related and addictive disorders, feeding and eating disorders, bipolar and related disorders, 
structural brain disease including but not limited to history of encephalitis or hydrocephalus and 
history of clinically significant stroke, or anticipating starting psychotherapy or behavior therapy 
during the course of the study or who started psychotherapy or behavior therapy within 30 days 
prior to Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 


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c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Part A: Subjects with severe depression as defined by a BDI-II score >19. 
6. Part B: Subject has recent exposure (14 days prior to the Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 4. 
7. Subjects with Type I or Type II diabetes mellitus. 
8. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), metabolic 
identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other atypical 
Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system atrophy). 
9. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
10. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the screening 
or admission visits. NOTE: QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the study. ECG 
may be repeated once if initial values obtained are outside the specified limits. 
11. Subject has a history, presence and/or current evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
12. Subject has exposure to another investigational medication or device within 30 days prior to Day 1. 
13. Subject has donated one or more units of blood or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). 
14. Subject is unwilling or unable to comply with study procedures. 
15. Subjects has used any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug. 
Investigational product, dosage and mode of administration: 
Part A: SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 
Drug Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dose. 
Part B: SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the SAGE-217 Capsules contain croscarmellose 
sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as excipients. For 
Part B, capsules will be available in 5-mg, 10-mg and 20-mg dose strengths. Subjects will be 
administered two capsules per dose. 
Duration of treatment: 
Part A and Part B: 
Screening Duration: up to 28 days 
Treatment Period: 7 days 
Follow-up: 7 days 
Planned Study Duration per Subject: approximately 42 days 


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Reference therapy, dosage, and mode of administration: 
Not applicable; Part A and Part B are open-label with all subjects receiving SAGE-217. 
Criteria for evaluation: 
Safety and tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs, clinical laboratory measures, 
ECGs, physical examinations, concomitant medication usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS in Part A only. 
Efficacy: 
Part A: 
• 
Improvement in PD motor symptoms and overall symptoms will be assessed by changes in the 
MDS UPDRS Part III score and MDS-UPDRS Parts I-IV total score at various time points. 
Part B: 
• 
Improvement in PD tremor as assessed by changes in the MDS UPDRS Part II/III tremor score 
(defined as the sum of MDS-UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS – Part III total 
score. 
• 
Improvement in PD nonmotor and motor aspects of experiences of daily living as assessed by the 
MDS-UPDRS – Part I and Part II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS – Parts I-IV 
total score. 
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and possibly SAGE-217 metabolites 
in Part A and Part B. 
Part A: The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve from time zero to infinity (AUC0-∞), maximum 
plasma concentration (Cmax), time to reach maximum concentration (tmax), the distributional half-life 
and terminal half-life (t1/2), and steady-state drug concentration in the plasma (Css). 
Part B: Area under the curve (AUC), Cmax, and trough concentration (C0h) at steady-state will be 
estimated for each individual using the most recent applicable Population PK model. 
Statistical Methods: 
Sample Size Calculation 
Approximately 18 subjects will be enrolled in Part A. Up to 15 new subjects will be enrolled in Part B 
in order for 10 subjects to complete the study (tolerate at least 20 mg SAGE-217 for the duration of the 
dosing period). The sample size for Part A and Part B was selected based on clinical and not statistical 
considerations. 
Study Populations 
The safety population, defined as all subjects who are administered at least one dose of study drug, will 
be used to provide descriptive summaries of safety. 


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The efficacy population, defined as all subjects in the safety population who receive at least one dose 
of study drug and have at least one postdose MDS-UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the safety population with at least one plasma sample 
with sufficient plasma concentrations for PK evaluations and will be used to summarize PK data. 
Separate populations will be defined for each part of the study. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™ (MedDRA). The 
overall incidence of adverse events will be displayed by System Organ Class (SOC), preferred term, 
dose group, and cohort. Incidence of adverse events will also be presented by maximum severity and 
relationship to study drug. Vital signs, clinical laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and total, where applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. Subject listings will be provided for all safety data. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data presentation 
methods where applicable; subject listings will be provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A is planned to inform Part B study conduct. No 
formal interim analysis for Part B subjects is planned. 
Pharmacokinetic Analysis 
Drug concentrations and pharmacokinetic parameters will be summarized using appropriate descriptive 
statistics and listed by subject. 


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Table 2: 
Schedule of Events: Part A (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 
X 


Protocol 217-PRK-201 
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; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose for Day 4, Day 6, and Day 8; and Day 14 
c Urinalysis: Screening and Admission (Day -1); predose for Day 4 and Day 7; and Day 14. 
d Vital Signs: Screening and Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM 
of Day 8; and Day 14. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; 
and Day 14. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose on Day 1 and Day 3; predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on 
Confinement Days 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1, Day 2 and Day 3; predose on Day 4, Day 5, Day 6, and Day 7; and Day 8 and 
Day 14. Screening/Baseline version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
h SSS: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
The SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
p 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
Administer Levodopa or 
q 
Carbidopa-Levodopa 
X 
X 
X 
Administer SAGE-217q 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. The MOAA/S is to 
be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
j MDS-UPDRS (complete): Screening, Admission (Day -1) (only if time between Screening and Admission is ≥7 days), on Day 8 prior to resuming Levodopa, 
and Day 14. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 1, 2, 3, 4, 5, 6, and 7. If 
complete MDS-UPDRS is not completed on Admission due to it taking place <7 days after Screening, then Part III only should also take place on Admission 
(Day -1). 
 
 
 
p Plasma PK sampling times (±5 minutes): Day 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 
4, 8, and 12 hours on Day 7; in AM of Day 8; and Day 14. PK samples are to be collected within ±5 minutes of the scheduled sampling time. 
q Levodopa or Carbidopa-Levodopa and SAGE-217 are to be administered in the morning 


Protocol 217-PRK-201 
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16 
 
 
 
Table 3: 
Schedule of Events: Part B (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -2) 
Admit 
(Day -1) 
Part B:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Confined to Unita 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
X 
CBC/Serum Chemistryb 
X 
Xc 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
X-urine 
Urinalysisd 
X 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
Pulse Oximetryg 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
12-Lead ECGh 
X 
X 
X 
Xf 
X 
Xf 
X 
Xf 
X 
Xf 
X 
C-SSRSi 
X 
X 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
MDS-UPDRS 
(complete)j 
X 
X 
Xf 
Xf 
X 
MDS-UPDRS (Part II 
only)k 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
only)k 
X 
X 
X 
X 
X 
X 


Protocol 217-PRK-201 
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Visit Days 
Screening 
(Day -28 to 
Day -2) 
Admit 
(Day -1) 
Part B: Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Plasma PK Samplesr 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
Administer SAGE-217s 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
; 
; 
PK = Pharmacokinetic 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose (within 1 hour of dosing) on Days 4 and 6; and on Days 8 and 14. 
c Two samples will be taken on Day-1: one sample will be sent to the central lab to be analyzed for reporting purposes and one sample to be analyzed locally for 
eligibility with regard to CBC/serum chemistry. 
d Urinalysis: Screening and Admission (Day -1); predose on Days 4 and 6; and on Days 8 and 14. 
e Vital Signs: Screening and Admission (Day -1); predose and 1, 2, and 12 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; and on Day 14. 
Assessments of vital signs are to be performed within ±10 minutes of the 1 and 2-hour time points and within ±15 minutes of the 12-hour time point. 
f Morning assessment only (in the morning of Day 1 or 12 hours [or 13 hours for PK sampling] after the dose from the previous evening). 
g Pulse Oximetry: Admission (Day -1); predose and 1, 2, and 12 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; and on Day 14. Pulse oximetry is to 
be performed within ±10 minutes of the 1 and 2-hour time points and within ±15 minutes of the 12-hour time point. 
h 12-Lead ECG: Screening and Admission (Day -1); predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on Confinement Days 1, 3, 5, and 7; and 
on Day 14. 
i C-SSRS: Screening and Admission (Day -1); predose and 12 hours (±1 hour) postdose on Day 1; and 12 hours (±1 hour) postdose on Day 2, 3, 4, 5, 6, and 7. 
Screening/Baseline version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 


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j MDS-UPDRS (complete, Parts I-IV): Screening, Admission (Day -1) (only if time between Screening and Admission is ?:.7 da ys); at  8AM (±1 hour)  on Day  l; 
12 (±15 1ninutes) hours postdose on Day 7 (ie, 8AM on Day 8); and on Day 14. MDS-UPDRS should take place during the "on" period AND within 2 hours of 
dosing with antiparkinsonianagent(s). 
k MDS-UPDRS (Part II/III only): 12 and 23 (±151ninutes) hours postdose on Confinement Days 1, 2, 3, 4, 5 , and 6. MDS-UPDRS Part 11/111s hould take place 
during the "on" period AND within 2 hours of dosing with antiparkinsonian agent(s). 
I 
 
 
I 
 
 
 
I 
I 
I 
I 
r Plasma PK sampling times (±1 hour): predose and 13 hours postdose on Day l; and 13 hours postdose on Days 2 through 7. 
5 SAGE-217 Capsules are to be adrninistered in the evening (8PM ±30 minutes) with food. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............19 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................24 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need .................................26 
5.2. 
SAGE-217 ...................................................................................................................27 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ...........................27 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................27 
5.3.2. 
Clinical Experience .....................................................................................................27 
5.4. 
Potential Risks and Benefits .......................................................................................29 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary Objective .......................................................................................................31 
6.2. 
Secondary Objectives .................................................................................................31 
6.3. 
Pharmacokinetic Objectives .......................................................................................31 
6.4. 
Endpoints ....................................................................................................................31 
6.4.1. 
Primary Endpoints ......................................................................................................31 
6.4.2. 
Secondary Endpoints ..................................................................................................32 
6.4.3. 
Pharmacokinetic Endpoints ........................................................................................32 
6.4.4. 
Exploratory Endpoints ................................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 
7.2. 
Number of Subjects ....................................................................................................35 
7.3. 
Treatment Assignment ................................................................................................35 
7.4. 
Dose Adjustment Criteria ...........................................................................................35 
7.5. 
Criteria for Study Termination ...................................................................................36 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................38 
8.1. 
Subject Inclusion Criteria ...........................................................................................38 
8.2. 
Subject Exclusion Criteria ..........................................................................................39 


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8.3. 
Subject Withdrawal Criteria .......................................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................42 
9.1. 
Description of Study Drug Treatment ........................................................................42 
9.1.1. 
Part A ..........................................................................................................................42 
9.1.2. 
Part B ..........................................................................................................................42 
9.2. 
Concomitant Medications ...........................................................................................42 
9.2.1. 
Prior/Concomitant Medications ..................................................................................42 
9.2.2. 
Prohibited Medications ...............................................................................................43 
9.3. 
Treatment Compliance ................................................................................................43 
9.4. 
Randomization and Blinding ......................................................................................43 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
10.1. 
Study Drug ..................................................................................................................44 
10.1.1. 
SAGE-217 Oral Solution ............................................................................................44 
10.1.2. 
SAGE-217 Capsule .....................................................................................................44 
10.2. 
Study Drug Packaging and Labeling ..........................................................................44 
10.3. 
Study Drug Storage .....................................................................................................44 
10.4. 
Study Drug Preparation ..............................................................................................45 
10.5. 
Administration ............................................................................................................46 
10.6. 
Study Drug Accountability .........................................................................................46 
10.7. 
Study Drug Handling and Disposal ............................................................................46 
11. 
ASSESSMENT OF EFFICACY ................................................................................47 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale ................47 
11.2. 
Exploratory Endpoints ................................................................................................48 
48 
49 
49 
49 
50 
50 
12. 
PHARMACOKINETICS ...........................................................................................52 
12.1. 
Blood Sample Collection ............................................................................................52 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................52 


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12.3. 
Sample Analysis .........................................................................................................52 
13. 
ASSESSMENT OF SAFETY .....................................................................................53 
13.1. 
Safety and Tolerability Parameters .............................................................................53 
13.1.1. 
Demographic/Medical History ...................................................................................53 
13.1.2. 
Vital Signs ..................................................................................................................53 
13.1.3. 
Weight and Height ......................................................................................................53 
13.1.4. 
Physical Examination .................................................................................................53 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................53 
13.1.6. 
Laboratory Assessments .............................................................................................54 
13.1.6.1. 
Hematology .................................................................................................................54 
13.1.6.2. 
Blood Chemistry .........................................................................................................54 
13.1.6.3. 
Urinalysis ....................................................................................................................54 
13.1.6.4. 
Virus Serology ............................................................................................................54 
13.1.6.5. 
Pregnancy Screen ........................................................................................................55 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................55 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................55 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) ...............55 
13.2. 
Adverse and Serious Adverse Events .........................................................................56 
13.2.1. 
Definition of Adverse Events .....................................................................................56 
13.2.1.1. 
Adverse Event .............................................................................................................56 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................56 
13.2.1.3. 
Serious Adverse Event ................................................................................................56 
13.2.1.4. 
Recording Sedation as an Adverse Event ...................................................................57 
13.2.2. 
Pregnancy ...................................................................................................................57 
13.3. 
Relationship to Study Drug .........................................................................................57 
13.4. 
Recording Adverse Events..........................................................................................58 
13.5. 
Reporting Serious Adverse Events .............................................................................58 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................60 
14.1. 
Data Analysis Sets ......................................................................................................60 
14.2. 
Handling of Missing Data ...........................................................................................60 
14.3. 
General Considerations ...............................................................................................60 
14.4. 
Demographics and Baseline Characteristics ...............................................................60 


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14.5. 
Efficacy Endpoints ......................................................................................................60 
14.5.1. 
Secondary Efficacy Endpoints ....................................................................................61 
14.5.2. 
Exploratory Efficacy Endpoints ..................................................................................61 
14.6. 
Safety and Tolerability Analyses ................................................................................61 
14.6.1. 
Adverse Events ...........................................................................................................61 
14.6.2. 
Vital Signs ..................................................................................................................61 
14.6.3. 
Physical Examinations ................................................................................................62 
14.6.4. 
12-Lead ECG ..............................................................................................................62 
14.6.5. 
Clinical Laboratory Evaluations .................................................................................62 
14.6.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................62 
14.6.7. 
Stanford Sleepiness Scale (SSS) .................................................................................62 
14.6.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ........................62 
14.6.9. 
Prior and Concomitant Medications ...........................................................................62 
14.7. 
Pharmacokinetic Analysis ..........................................................................................63 
14.8. 
Determination of Sample Size ....................................................................................63 
14.9. 
Changes From Protocol Specified Analyses...............................................................63 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................64 
15.1. 
Study Monitoring ........................................................................................................64 
15.2. 
Audits and Inspections ................................................................................................64 
15.3. 
Institutional Review Board (IRB) ...............................................................................65 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE..........................................66 
17. 
ETHICS ......................................................................................................................67 
17.1. 
Ethics Review .............................................................................................................67 
17.2. 
Ethical Conduct of the Study ......................................................................................67 
17.3. 
Written Informed Consent ..........................................................................................67 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
18.1. 
Inspection of Records .................................................................................................68 
18.2. 
Retention of Records ..................................................................................................68 
18.3. 
Confidentiality ............................................................................................................68 
19. 
PUBLICATION POLICY ..........................................................................................70 
20. 
LIST OF REFERENCES ............................................................................................71 
21. 
APPENDICES ............................................................................................................73 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA ............................................74 
APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA ..................................................75 
APPENDIX 3. ANTICHOLINERGIC DRUGS .........................................................................76 
APPENDIX 4. TREMOROGENIC DRUGS ..............................................................................77 
APPENDIX 5. MOVEMENT DISORDER SOCIETY-UNIFIED PARKINSON'S 
DISEASE RATING SCALE (MDS-UPDRS) ...................................................79 
80 
83 
86 
87 
APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION AND SINCE LAST VISIT 
VERSION .........................................................................................................90 
APPENDIX 11. STANFORD SLEEPINESS SCALE (SSS) .....................................................96 
APPENDIX 12. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ...........................................................97 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................13 
Table 3: 
Schedule of Events:  Part B (Open-Label) .................................................................16 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................24 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL ..................45 
Table 6: 
Rating Scale for the MDS-UPDRS .............................................................................47 
LIST OF FIGURES 
Figure 1: 
Study Design of Part A ...............................................................................................37 
Figure 2: 
Study Design of Part B ...............................................................................................37 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to 
infinity 
 
 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CS 
clinically significant 
Css 
steady-state drug concentration in the plasma 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EP 
European Pharmacopeia 
GABA 
γ aminobutyric acid 
GABAA 
γ aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Levodopa/Carbidopa 
Levodopa or Carbidopa-Levodopa 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MoCA 
Montreal Cognitive Assessment 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant 
NF 
National Formulary 
PD 
Parkinson’s disease 
 
 
PK 
pharmacokinetic(s) 
PM 
evening 
QTcF 
QT interval calculated using the Fridericia method 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal half-life 
tmax 
time to reach maximum concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need 
Parkinson’s disease (PD) is a chronic progressive neurodegenerative condition that affects the 
motor, autonomic, cognitive, and sensory systems. Parkinson’s disease is the second most 
common neurodegenerative disorder (Bergman 2002) and is associated with a massive loss of 
dopaminergic cells in the substantia nigra, leading to dopamine hypofunction and alteration of 
the basal ganglia circuitry. Dopamine neurons are under the control of the excitatory 
glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. Imbalance between the 
glutamatergic and GABA systems may contribute to excitotoxicity and dopaminergic cell death. 
The motor symptoms of PD have been linked with a loss of dopamine neurons in the substantia 
nigra pars compacta and a consequential reduction in the level of dopamine input in the striatum 
(Siderowf 2012). These symptoms evolve slowly and are characterized by the progression of 
tremor, rigidity, bradykinesia, and postural instability. Tremor caused by PD can appear as 
either a resting tremor or an action tremor. The most typical tremor of PD is a “pill-rolling” rest 
tremor between the thumb and index finger. Not everyone with PD develops a tremor, and those 
who do experience tremor may have symptoms that come and go. Typically, PD tremor starts in 
the fingers of one hand before spreading to affect the rest of the arm. Tremor can also spread to 
affect the foot on the same side of the body and, after several years, the tremor can spread to 
affect the other side of the body. Without treatment, PD tremor usually worsens over time. 
At present, there is no cure for PD. The core symptoms are caused by the degeneration of 
dopamine-producing neurons and, therefore, treatment consists of dopamine replacement. While 
enormous progress has been made in the treatment of PD over the past half century, levodopa 
remains the most potent drug for controlling PD symptoms (Jankovic 2008). The addition of 
carbidopa, a peripheral dopa decarboxylase inhibitor, enhances the therapeutic benefits of 
levodopa.  However, levodopa therapy is frequently associated with motor complications, and 
the appropriate time to initiate levodopa therapy continues to be debated (Stern 2004; 
Weiner 2004). The majority of patients treated with levodopa experience motor fluctuation, 
dyskinesia or other complications after 5 years of treatment (Jankovic 2005). 
Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of 
several neurotransmitter systems. The substantia nigra expresses high concentrations of 
allopregnanolone, a neurosteroid that positively modulates the action of GABA at 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. In PD patients, 
decreased plasma and cerebrospinal fluid levels of the neurosteroid allopregnanolone and 
5α-dihydroprogesterone have been observed (di Michele 2003). 
Parkinson’s disease is the second most common chronic neurodegenerative disease, affecting 
about 1 million people in the United States and more than 4 million people worldwide. It has a 
devastating effect on patients and is often accompanied by tremendous physical and emotional 
burden not only for the patients but also for their families and friends. As the size of the elderly 
population grows, the burden of PD is projected to grow substantially over the next few decades. 
To date, the therapy of PD is symptomatic, aimed at ameliorating motor symptoms. Although 
the goal of therapy is to reverse the functional disability, abolition of all symptoms and signs is 
not currently possible, even with high doses of medication. Thus, there is a growing need for 


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innovative new treatments to prevent, delay onset, or alleviate symptoms of PD. Neurosteroids 
act as neuroprotectants and as GABAA-receptor agonists in the physiology and pathology of the 
basal ganglia, impact dopaminergic cell activity and survival, and may therefore represent 
potential therapeutics in PD. 
 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of PD. 
Two dosage forms of SAGE-217 for oral administration will be used in this study (SAGE-217 
Oral Solution in Part A and SAGE-217 Capsules in Part B). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a non-viscous, clear solution. 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the active, SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies and in toxicology studies. The sedative- 
hypnotic impairments seen with SAGE-217 were typical for GABAA-positive modulators, 
ranging from hyperexcitability and ataxia at the lower doses through deep sedation and 
ultimately anesthesia at higher doses. Depth and duration of sedation demonstrated a clear dose 
response over the range tested, with evidence of tolerance occurring with continued exposure. 
Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 7 days of 
dosing. 
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats. The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. 
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study that was suspected to have been related to exaggerated pharmacology. Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure. 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending. Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food effect, and essential tremor cohorts from Study 217-CLP-101 
and the multiple-ascending dose and drug-drug interaction cohorts from Study 217-CLP-102. 
Discussions of safety data are limited to the single-ascending dose cohorts in Study 
217-CLP-101 and the multiple-ascending dose cohorts in Study 217-CLP-102. In addition, one 


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clinical study of the safety, tolerability, PK, and relative bioavailability SAGE-217 Capsules is 
clinically complete and the final study report is pending. The results of this study (217-CLP- 
103) are briefly described below. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, single- 
ascending dose design in healthy adult volunteers, with the objective of identifying the maximum 
tolerated dose (MTD) and PK profiles of SAGE-217 Oral Solution. Subjects in each of the 
single-ascending dose cohorts received a single dose of study drug, either SAGE-217 Oral 
Solution (six subjects) or placebo (two subjects), with SAGE-217 Oral Solution doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 55 mg, and 66 mg.  Escalation to the 
next dose was undertaken only after safety and PK data were reviewed by the Safety Review 
Committee (SRC) and agreement reached that it was safe to increase the dose. The MTD was 
determined to be 55 mg. Two cohorts, 6 subjects each, received SAGE-217 Oral Solution in an 
open-label manner (one cohort received 50% of the MTD [22 mg] to study the food effects and 
the other cohort received the MTD [55 mg] to study the effects on subjects with essential 
tremor). SAGE-217 Oral Solution was orally bioavailable, demonstrated dose-linear PK from 
the lowest (0.25 mg) through the highest (66 mg) dose, and supported once-daily oral dosing 
with food. In addition, the pharmacodynamic effects of the SAGE-217 Oral Solution MTD were 
assessed in placebo-controlled, blinded, crossover electroencephalogram cohorts of 8 subjects 
each; one cohort received 50% of the MTD (22 mg) and the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers. Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 Oral Solution (nine subjects) or placebo (three subjects), 
once daily for 7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg. 
Escalation to the next dose was undertaken only after safety and PK data were reviewed by the 
SRC and agreement reached that it was safe to increase the dose. The MTD was determined to 
be 30 mg. It was observed that subjects receiving the drug in the evening did better in terms of 
tolerability compared to when they received the drug in the morning. A fourth cohort of 
12 subjects received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug- 
drug interactions. SAGE-217 Oral Solution is not likely to induce the metabolism of cytochrome 
P450 (CYP)2B6 or CYP3A4 substrates. SAGE-217 Oral Solution was orally bioavailable and 
suitable for once-daily oral dosing at night time with food. 
SAGE-217 Oral Solution was generally well tolerated. In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met. Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 
reported in either study. In addition, none of the observed adverse events resulted in 
discontinuation of the study drug. At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure. The most common treatment-emergent 
adverse events (TEAEs) were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, 
and muscle twitching, reported most frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were observed after single doses of 44 mg and 
greater. After multiple doses of 30 mg (morning [AM] or evening [PM]) or 35 mg (AM) over 
7 days, there was no evidence of changes in mean vital sign measures even though Day 7 plasma 


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concentrations approximated that of the highest single dose in the single-ascending dose study. 
Subjects seemed to tolerate SAGE-217 Oral Solution better when given as night time dosing. 
The safety, tolerability, PK, and relative bioavailability of the SAGE-217 Capsules were 
assessed in a Phase 1 randomized, open-label, cross-over study (Study 217-CLP-103). In the 
fasted state, SAGE-217 Capsules demonstrated reduced exposure in terms of maximum (peak) 
plasma concentration (Cmax) and area under the curve from zero to the time of the last 
quantifiable concentration (AUClast) compared to SAGE-217 Oral Solution. SAGE-217 Capsules 
administered in the fed state (with standard and high-fat meal) showed increased exposure 
compared to the fasted state and approximately equivalent exposure in terms of geometric mean 
AUClast compared to SAGE-217 Oral Solution; however, the Cmax for SAGE-217 Capsules was 
reduced by approximately 50% when compared with SAGE-217 Oral Solution. Based on these 
study results, exposures with SAGE-217 Capsules are anticipated to be equal to or less than 
exposures observed at the same dose with SAGE-217 Oral Solution. 
Neuroactive steroids are a class of endogenous and synthetic positive allosteric modulators that 
target both synaptic and extra-synaptic GABAA receptors (Belelli 2002 and confirmed in the 
Sponsor’s in vitro studies). This diverse activity profile suggests that neuroactive steroid 
GABAA receptor-positive allosteric modulators could exhibit robust activity against essential 
tremor. Administration of SAGE-547 injection, a proprietary formulation of the endogenous 
neuroactive steroid, resulted in significant reductions in upper limb kinetic tremor scores 
compared to placebo in a Phase 2 proof‑of‑principle study (IND 122,280). Based on these 
results with SAGE-547, the study design for single-ascending dose study 217-CLP-101 included 
a cohort of subjects with essential tremor (N=6) who received SAGE-217 Oral Solution (55 mg) 
in an open-label manner. Data from this cohort indicate that single doses of SAGE-217 Oral 
Solution resulted in a reduction in the tremor symptoms, suggesting that SAGE-217 might be 
effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral Solution or Capsules in PD, since the 
present study is the first study in this indication. 
 
5.4. 
Potential Risks and Benefits 
Protocol 217-PRK-201 is the first clinical study evaluating the efficacy of SAGE-217 in PD. 
Thus, the potential benefits in this population are unknown, although the risks are likely to be 
similar to those mentioned in the Investigator’s Brochure. GABA compounds that cross the 
blood-brain barrier or increase GABA activity alleviate muscle stiffness caused by a lack of 
GABAergic tone (Winkler 1999), validating this receptor as a therapeutic target. Given the 
promising clinical data with another neuroactive steroid (SAGE-547) in conjunction with the 
shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence 
of anxiolytic activity, and safety data of SAGE-217, it is possible that patients may have a 
clinical benefit at the exposures selected for this study. 
In the 217-CLP-103 study, SAGE-217 Capsules were found to be generally well-tolerated with 
no serious AEs reported during the treatment and follow-up periods. The most frequent AE 
observed was sedation that was mild, transient, and occurred within 1 to 4 hours following 
dosing and generally dissipated by 8 hours. The clinical portion of this study has recently 
completed; the final report is in progress. 


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In view of the few risks associated with administration of SAGE-217 that have been identified to 
date, intra-patient dose-reduction designs have been chosen for Part A and Part B to permit 
reduction in dose based on tolerability (adverse events), specifically sedation, versus treatment 
effect. In Part A, each subject will start with an initial dose of SAGE-217 Oral Solution, 30 mg; 
subjects unable to tolerate 30 mg will receive 20 mg; subjects unable to tolerate 20 mg will 
receive 10 mg. In Part B, each subject will receive SAGE-217 in the evening (PM) starting with 
an initial dose of SAGE-217 Capsules, 20 mg for two days; subjects able to tolerate 20 mg will 
receive 30 mg. If the subject is unable to tolerate 30 mg, the subject will receive 20 mg and 
continue for the remainder of the dosing period. Subjects who cannot tolerate the 20-mg dose at 
any time during Part B will be discontinued and replaced. The tolerated dose for each subject in 
Part A and Part B will be the dose taken on Day 7.  Given the high medical need and potential 
for benefit in PD, there is a favorable benefit-risk evaluation to investigate SAGE-217 in PD. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of Part A is 
• To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
The primary objective of Part B is: 
• To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian 
agent(s) on the severity of PD tremor symptoms. 
 
6.2. 
Secondary Objectives 
The secondary objectives of Part A are: 
• To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor 
symptoms after withdrawal of Levodopa or Carbidopa-Levodopa 
(Levodopa/Carbidopa). 
• To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of 
PD motor symptoms after withdrawal of Levodopa/Carbidopa. 
The secondary objectives of Part B are: 
• To evaluate the effect of SAGE-217 Capsules as an adjunct to antiparkinsonian 
agent(s) on motor and non-motor symptoms of PD. 
• To evaluate the safety and tolerability of SAGE-217 Capsules. 
6.3. 
Pharmacokinetic Objectives 
The PK objective of Part A is: 
• To assess the PK profile of SAGE-217 Oral Solution in plasma samples. 
The PK objective of Part B is: 
• To assess the PK profile of SAGE-217 Capsules utilizing a population PK approach. 
6.4. 
Endpoints 
6.4.1. 
Primary Endpoints 
Part A: 
• Frequency and severity of adverse events and changes in vital signs, clinical 
laboratory data, electrocardiogram (ECG) parameters, and suicidal ideation using the 
Columbia-Suicide Severity Rating Scale (C-SSRS). In addition, sleepiness/sedation 
as assessed by Stanford Sleepiness Scale (SSS) score. 


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Part B: 
• 
Improvement in PD tremor  as assessed  by changes  in  the  MDS  UPDRS  Pa.ii  II/ III 
tr e m or sco r e (de fin ed as th e s um o f M D S -UP DR S ite m s 2 .1 0, 3 .1 5, 3 .1 6, 3 .1 7 and 
3.18). 
6.4.2. 
Secondary Endpoints 
Part A: 
• 
Improve ment in PD motor symptoms as  assessed  by  changes  in  the  Movement Disorder 
Society-Unified Pai-Icinson's Disease  Rating  Scale  (MDS-UPDRS)  -  Pa.ii  III (Mo tor Exa 
min a ti o n ) to tal score . 
Part B: 
• 
Improve ment in PD motor symptoms as assessed by changes in the MDS-UPDRS - 
Pa.ii III total score. 
• 
Improvement in PD nonmotor and motor aspects of experiences of daily living as 
assessed by the MDS-UPDRS - Pali I and Part II scores, respectively. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - 
Paiis I-IV total score. 
• 
Frequency and severity of adverse events and changes in vital signs, clinical 
laboratory data, electrocai·diogram (ECG) parameters, and suicidal ideation using the 
Collllllbia-Suicide Severity Rating Scale (C-SSRS). 
 
6.4.3. 
Pharmacokinetic Endpoints 
• 
Plasma concentratio ns of SAGE -217, and possibly SAGE-217 metabolites, will be 
measured, and PK pai·aineters will be derived. 
 
6.4.4. 
Exploratory Endpoints 
I 
 
I 
 
 
I 


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I 
 
I 


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7. 
INVESTIGATIONAL PLAN 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2 study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217. Part A of the study is an open-label design with morning (AM) dosing of 
SAGE-217 Oral Solution for 4 days in in up to 18 adult subjects with PD of moderate severity 
who respond to immediate-release oral Levodopa and are on a stable dose. Part B of the study is 
an open-label design with evening (PM) dosing of SAGE-217 Capsules for 7 days in up to 
15 adult subjects with PD. Subjects that participate in Part A are not eligible to participate in 
Part B. Subjects will be followed for an additional 7 days after the administration of the last dose 
in Part A and Part B. 
There are two parts to the study: 
• Part A: Open-label with AM dosing of SAGE-217 Oral Solution (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the 
following 3 days (Days 1 to 3). All subjects will stop their immediate-release oral 
Levodopa on Day 4 and will start on a 30 mg dose of SAGE-217 Oral Solution 
administered in the morning with food, as outlined in Section 9.1.1. Subjects not 
tolerating 30 mg will receive 20 mg, and subjects not tolerating 20 mg will receive 
10 mg on subsequent days (Section 7.4). The dose received on Day 7 will be defined as 
the tolerated dose for that subject. Subjects not tolerating 10 mg will not be able to 
continue in the study and may be replaced.  Subjects will be followed for an additional 
7 days (Day 14) after the administration of the last dose. Levodopa treatment will be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 exhibits efficacy in subjects with PD of 
moderate severity in order to inform the conduct of Part B. 
• Part B: Open-label with PM dosing of SAGE-217 Capsules, for 7 days, as an adjunct 
to antiparkinsonian agent(s). 
Subjects on a stable dose of antiparkinsonian agent(s) will continue taking them for the 
duration of the study.  Anticholinergics and/or amantadine will be discontinued by 
Day -6 and Day -10, respectively. 
Screening may occur between Day -28 and Day -2, but subjects must be admitted on 
Day -1 for selected pre-dose assessments (e.g., clinical laboratory assessments, 
assessment of tremor). All subjects will take SAGE-217 Capsules, 20 mg, at 8PM on 
Days 1 and 2. On Day 3, subjects tolerating the initial dose (i.e., those who do not 
experience a severe adverse event judged by the Investigator to be related to study 


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drug) will receive a dose increase (SAGE 217, 30 mg), at 8PM and continuing each 
subsequent evening at 8PM for the remainder of the dosing period (ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by 
occurrence of a severe adverse event judged by the Investigator to be related to study 
drug, the dose on the next day must be reduced to 20 mg and continued for the 
remainder of the dosing period. Subjects who cannot tolerate the 20-mg dose at any 
time will be discontinued and replaced. 
All doses of SAGE-217 will be administered with food as outline in Section 9.1.2. For 
antiparkinsonian agents, administration with or without food will be determined by the 
Investigator. 
Subjects will receive SAGE-217 for up to 7 days and will be followed for an additional 
7 days after the administration of the last dose. 
 
The study designs of Part A and Part B are displayed in Figure 1 and Figure 2, respectively. 
Assessments will be performed periodically during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and Table 3, respectively). 
 
7.2. 
Number of Subjects 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14 to inform the conduct of Part B. Up to 
15 new subjects will be enrolled in Part B in order for 10 subjects to complete the study (tolerate 
at least 20 mg SAGE-217 for the duration of the dosing period). 
7.3. 
Treatment Assignment 
SAGE-217 will be administered with food in Parts A and B. Food intake will be standardized as 
specified by the Sponsor. If subjects are taking antiparkinsonian agent(s), administration with or 
without food will be determined by the Investigator. 
Parts A and B of the study are open-label. Dose reductions for lack of tolerability will be 
allowed during both parts of the study (Section 7.4). 
 
7.4. 
Dose Adjustment Criteria 
Dose reductions of SAGE-217 for lack of tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part A, as determined by the Investigator, the 
dose on the next day will be reduced to the next lowest dose (ie, subjects who are unable to 
tolerate the 30-mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 
20 mg will receive a 10 mg dose on subsequent days). In Part B, subjects tolerating the initial 
20- mg dose on Days 1 and 2 will receive a 30-mg dose on Day 3 and continue for the remainder 
of the dosing period. If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, the dose 
on the next day must be reduced to 20 mg and continued for the remainder of the dosing period. 


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7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons. In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects. 


37 
 
 
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Figure 1: 
Study Design of Part A 
Figure 2: 
Study Design of Part B 
 
NOTE: Part B will be initiated only after review of the Part A interim analysis (after 10 subjects have completed Part A). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures 
are performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria 
(modified to allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Part A: Subjects with PD with a duration of less than 7 years and must meet the criteria 
for Hoehn and Yahr stage 2 or stage 3 (Appendix 2). 
Part B: Subjects with PD and must meet the criteria for Hoehn and Yahr stage 1-4 
(Appendix 2) assessed during the “on” period (assumed to be within 2 hours of dosing 
with antiparkinsonian agent(s)), and have a tremor with a MDS-UPDRS Part II/III tremor score 
of ≥8 (sum of items: 2.10, 3.15, 3.16, 3.17 and 3.18) AND a MDS-UPDRS item score ≥3 in at 
least one limb (from items 3.15, 3.16, or 3.17). Inclusion criteria tremor scores must be 
assessed during “on” periods during the screening and Day -1 visit. 
5. Part A: Subject has a stable dose of antiparkinsonian agent(s) including immediate- 
release oral Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at 
least 1 month prior to the baseline visit) and is expected to remain on this stable dose for 
the duration of this study. 
Part B: Subject is receiving a stable dose of antiparkinsonian agent(s) (defined as no 
changes for a period of at least 1 month prior to the baseline visit) and is expected to 
remain on this stable dose for the duration of this study. 
6. Part A only: Subject is willing to discontinue his/her treatment with immediate-release 
oral Levodopa or Carbidopa-Levodopa for at least 8 hours prior to dosing with 
SAGE-217. 
7. Part A: Subject is willing to discontinue his/her treatment with anticholinergics 
(Appendix 3) or amantadine at least 5 days prior to the day of admission (Day -1). 
Part B: Subject is willing to discontinue his/her treatment with anticholinergics 
(Appendix 3) by Day -6 or amantadine by Day -10. 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been 
on a stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. 
11. Part A: Female subjects must agree to practice a highly effective method of birth control 
while on study through completion of the last follow-up visit. If a subject discontinues 


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early after receiving a dose of SAGE-217, then the subject must continue this method of 
birth control for at least 7 days following the last dose of study drug. Highly effective 
methods of birth control include combined (estrogen and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. 
Part B: Female subject agrees to use one of the following methods of contraception 
during participation in the study and for 30 days following the last dose of study drug, 
unless they are postmenopausal (defined as no menses for 12 months without an 
alternative medical cause) and/or surgically sterile: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception 
• associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse). 
12. Male subjects must agree to practice a highly effective method of birth control while on 
study, and for 13 weeks after receiving the last dose of study drug. Effective methods of 
birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with their partner's highly effective method. 
13. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. 
 
8.2. 
Subject Exclusion Criteria 
Subjects who met any of the following exclusion criteria will be excluded from the study: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major 
excipient, HPβCD (Part A) or SAGE-217 Capsule or its excipients (Part B). 
2. Part A: Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and 
Yahr stage 4 or stage 5). 
Part B: Subjects with advanced PD (Hoehn and Yahr stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia spectrum and other psychotic 
disorders, substance-related and addictive disorders, feeding and eating disorders, bipolar 


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and related disorders, structural brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of clinically significant stroke, or anticipating 
starting psychotherapy or behavior therapy during the course of the study, or who started 
psychotherapy or behavior therapy within 30 days prior to Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 
on the C-SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Part A only: Subjects with severe depression as defined by a BDI-II score >19. 
6. Part B only: Subject has recent exposure (14 days prior to the Day -1 visit) to 
tremorogenic drugs, as defined in Appendix 4. 
7. Subjects with Type I or Type II diabetes mellitus. 
8. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other 
atypical Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system 
atrophy). 
9. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease. 
10. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. ECG may be repeated once if initial values obtained are outside the 
specified limits. 
11. Subject has a history, presence and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 and 2. 
12. Subject has exposure to another investigational medication or device within the prior 
30 days. 
13. Subject has donated one or more units of blood or acute loss of an equivalent amount of 
blood within 60 days prior to dosing (1 unit = 450 mL). 
14. Subject is unwilling or unable to comply with study procedures. 
15. Subject has used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug. 


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8.3. 
Subject Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s). 
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events; 
• Occurrence of pregnancy; 
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance; 
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject fails to attend scheduled assessments during the course of the study, the Investigators 
must determine the reasons and the circumstances as completely and accurately as possible and 
document this in the subject’s source documents. 
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant. Subjects who cannot tolerate the 
10-mg dose at any time during Part A or the 20-mg dose at any time during Part B will be 
withdrawn. Any subject who is withdrawn from the study for any reason is to have the final visit 
assessments performed. 
Subjects who withdraw or are withdrawn from the study may be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug Treatment 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. All doses of SAGE-217 (Oral Solution or Capsule) will be 
administered with food. 
9.1.1. 
Part A 
Subjects participating in Part A of the study will take SAGE-217 Oral Solution in an open-label 
manner. All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the following 3 days 
(Days 1 to 3). On the morning of Day 4, subjects will stop their immediate-release oral 
Levodopa and take SAGE-217 for 4 days (Days 4 to 7) in the AM with food. On Day 4, subjects 
will receive a 30 mg dose of SAGE-217. Subjects not tolerating 30 mg will receive 20 mg the 
next day, and subjects not tolerating 20 mg will receive 10 mg the next day. The dose received 
on Day 7 will be defined as the tolerated dose for that subject. 
Subjects not tolerating 10 mg will not be able to continue in the study and may be replaced. 
Levodopa treatment will be resumed on Day 8 and continue through Day 14. 
9.1.2. 
Part B 
Subjects participating in Part B of the study will take SAGE-217 Capsules in an open-label 
manner. Subjects on a stable dose of antiparkinsonian agent(s) will continue taking them for the 
duration of the study. All subjects will receive SAGE-217, 20 mg, at 8PM on Days 1 and 2. On 
Day 3, subjects tolerating the initial dose (i.e., those who do not experience a severe adverse 
event judged by the Investigator to be related to study drug) will receive a dose increase 
(SAGE-217, 30 mg), at 8PM, continuing each subsequent evening at 8PM for the remainder of 
the dosing period (ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose is not tolerated, assessed by occurrence of a 
severe adverse event judged by the Investigator to be related to study drug, the dose on the next 
day must be reduced to 20 mg and continued for the remainder of the dosing period. Subjects 
who cannot tolerate the 20-mg dose at any time will be discontinued and replaced. 
9.2. 
Concomitant Medications 
9.2.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.2. 
Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
taken during the study. 


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The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit. Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications. New concomitant medications, ongoing 
concomitant medications with a change in dose, and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified. 
The Investigator will document all doses of Levodopa and Carbidopa-Levodopa taken by the 
subject and the use of rescue medication. 
9.2.2. 
Prohibited Medications 
Subjects who have used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug are to be excluded from the study; these medications/products are 
prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 are not permitted in the 5 days prior to the 
admission visit (Day -1) of Part A and Part B. The list provides non-exhaustive examples of 
each drug class. 
Amantadine is not permitted in the 5 days prior to the admission visit of Part A or 9 days prior to 
the admission visit of Part B. 
The tremorogenic drugs listed in Appendix 4 are not permitted in the 14 days prior to the 
admission visit of Part B. 
 
9.3. 
Treatment Compliance 
Study drug (SAGE-217 Oral Solution or Capsule) will be prepared by the site pharmacist. All 
doses of study drug will be administered by site staff while the subject is confined to the clinical 
unit. The Investigator(s) or designee will record the time and dose of study drug administration 
in the source documents. Any reasons for noncompliance will also be documented, including: 
• Missing visits; 
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. 
 
9.4. 
Randomization and Blinding 
Not applicable; Part A and Part B of the study are open-label. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
SAGE-217 Oral Solution 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dosages. The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient(s) in the Bottle (manufactured under current Good Manufacturing Practice [GMP] 
conditions 
) and further admixed at the clinical site in preparation for dosing. 
Detailed instructions for study drug preparation will be provided in the Pharmacy Manual. 
The Sponsor will not provide Levodopa or Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa-Levodopa. 
10.1.2. 
SAGE-217 Capsule 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 
Capsules contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and 
sodium stearyl fumarate as excipients. Capsules will be available in 5-mg, 10-mg and 20-mg 
dose strengths. Subjects will be administered two capsules per dose. Detailed instructions for 
study drug preparation will be provided in the Pharmacy Manual. 
10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation. SAGE-217 Oral Solution will be provided to the 
site as powder in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy 
at a volume of 125 mL of a 6 mg/mL stock solution and then further diluted to approximately 
40 mL at the identified doses. SAGE-217 Capsules will be provided to the site in appropriately 
labeled bottles. Study drug labels with all required information and conforming to all applicable 
Code of Federal Regulations and GMP/GCP guidelines will be prepared by the clinical research 
organization. 
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217), the Investigator or designee will inspect the materials 
and complete and return the acknowledgment of receipt form enclosed with the parcel. A copy 
of the signed receipt will be kept in the study files. 
The study drug materials for SAGE-217 Oral Solution must be carefully stored at the 
temperature specified in the Pharmacy Manual (eg, clinical dosing solutions stored at 
approximately 2 to 8°C for 11 days with 24 hours of room temperature excursions allowed after 
preparation), safely and separately from other drugs. SAGE-217 Capsules may be stored at room 
temperature. 


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The study drug may not be used for any purpose other than the present study. After the study is 
completed, all unused study drug must be retained, returned as directed, or destroyed on site per 
the Sponsor’s instructions. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies. An accurate, timely record of 
the disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented. This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Study Drug Preparation 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual. The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5. 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
 
Ingredient 
Compendia Specification 
Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations: EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
For the capsule formulation, subjects will swallow two capsules per dose with food. 


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10.5. 
Administration 
SAGE-217 will be administered with food in the morning in Part A and in the evening in Part B. 
Doses of SAGE-217 Oral Solution will be prepared as an approximate 40 mL oral solution to be 
swallowed all at once, followed by approximately 200 mL of water that has been used to rinse 
the dosing bottle. The start time of swallowing the approximately 40 mL oral solution is time 
zero for all assessments. Subjects may have assistance from the clinic staff when taking the 
study drug. 
During Confinement, each subject’s antiparkinsonian agents, including Levodopa or Carbidopa- 
Levodopa, will be administered by site personnel according to the site’s standard operating 
procedures. 
 
10.6. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded. 
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. 
The Investigator will document all doses of Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
 
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding (oral solution only), subsequent admixture of dosing solutions (oral solution only), 
administration of study drug, and for which subject the study drug was intended (ie, record 
subject initials and birth date or other unique identifier). 
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented. 


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11. 
ASSESSMENT OF EFFICACY 
 
 
Assessments will be perfo1med periodicall y dming the study as outlined in 
the Schedule of Events for Pali A and Pali B (Table 2 and Table 3, respectively). 
 
11.1. 
Movement Disorder Society- Unified Parkinson's Disease Rating 
Scale 
The UPDRS is the most commonly used scale in clinical studies of PD (Ramaker 2002). In 
2007, the MDS revised the scale, which was known as the MDS-UPDRS (Goetz 2007), and 
subsequently demonstrated the validity of the MDS-UPDRS for rating PD (Goetz 2008). The 
modified UPDRS includes fom scales, with various subscales. Each item is rated from 0 
(no1m al) to 4 (severe) (Table 6). The fom MDS-UPDRS scales are: 
Pait I: nonmotor experiences of daily living (13 items) 
Pait II: motor experiences of daily living (13 items) 
Pait III: motor examination (33 scores based on 18 items [several with right, left or other body 
distribution scores]) 
Pait IV: Motor complications (6 items) 
Table 6: 
Rating Scale for the MDS-UPDRS 
 
Rating 
Description 
O = n 01mal 
No symptoms /signs 
1 = sligh t 
Symptoms/signs with sufficiently low frequency or intensity to cause no impact on function 
2 = mild 
Symptoms/signs of frequency or intensity sufficient to cause a modest impact on function 
3 = moderate 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
4 = severe 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
Several questions in Pait I and all questions in Pait II can be answered by the patient/caregiver 
and completed without the Investigator's input. The remaining questions in Part I that deal with 
complex behaviors, the objective assessments of parkinsonism (Pait III), and the questions that 
deal with motor fluctuations and dyskinesias (Pait IV) ai·e co m p leted by In vestigator in terview. 
T h e tim e requ ired fo r ad m inistering the MDS-UPDRS is estimated to be less than 10 minutes for 
the interview items of Pait I, 15 minutes for Pait III, and 5 minutes for Paii IV (Goetz 2008). 
The complete MDS-UPDRS is to be administered in Pait A at screening, Admission (Day -1), on 
Day 8 prior to resuming Levodopa, and on Day 14. The complete MDS-UPDRS is to be 
administered in Pait B at screening, Admission (Day -1), in the morning of Days 1 and 8, and on 
Day 14.  In both Paits A and B, the Admission (Day -1) complete MDS-UPDRS is perfo1med 
only if the time between Screening and Admission is ?:.7 days; othe1wise, the MDS-UPDRS 
Pait III only (Pait A) or Pait II and Pait III (Pait B) are perfo1med. 
Pait II of the MDS-UPDRS assesses 13 categories of motor experiences of daily living: speech, 
salivation and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, 


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doing hobbies and other activities, turning in bed, tremor, getting out of bed, car, or deep chair, 
walking and balance, and freezing (Goetz, 2008). Pa.ii II o f th e MDS-UPDRS (motor 
examination) is to be completed in Pa.ii B at 1 2 a n d 23 h o urs postdose on Days 1, 2, 3, 4, 5, and 
6. If the complete MDS-UPDRS is not perfo1m ed on Admission due to Admission taking place 
<7 days after Screening, then Pa.ii II s h o u ld also take place on Admission (Day -1) for Part B. 
Pa.ii II I o f th e M D S - UPDRS assesses 18 motor categories, some of which include right and left 
measurements: speech, facial expression, kinetic tremor of hands, rest tremor ainplitude, postural 
tremor of hands, rigidity of neck and four extremities, finger taps, hand movement, 
pronation/supination, toe tapping, constancy of rest tremor,  leg agility,  arising  from  chair, 
posture, gait, freezing of gait, postural stability, global  spontaneity of movement  (Goetz,  2008). 
Pa.ii III of the MDS-UPDRS (motor examination) is to be completed in Pa1i A at 2, 4, 8, and 
12 hours postdose on Days 1, 2, 3, 4, 5, 6, and 7. MDS-UPDRS is to be assessed within ±10 
minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times for the 6-hour through 12-hour time points. Pa1i III of the MDS-UPDRS (motor 
examination) is to be completed in Pa.ii B at 1 2 a n d 23 h o urs postdose on Days 1, 2, 3, 4, 5, and 
6. If the complete MDS-UPDRS is not perfo1m ed on Admission due to Admission taking place 
<7 days after Screening, then Pa.ii III should also take place on Admission (Day -1) for both 
Paiis A and B. 
All MDS-UPDRS measurements in Pa.ii B sho  ul d  b e  take n  d uring the "on" period (within  
2 hours of dosing with antipai·kinsonian agent(s)). 
The MDS-UPDRS is provided in Appendix 5. 
 
11.2. 
Exploratory Endpoints 
 


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 4; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 7; in AM of Day 8; and Day 14. Samples are to be collected within 
±5 minutes of the scheduled sampling time. 
In Part B, plasma samples for PK analysis will be collected predose and 13 hours postdose on 
Day 1; and 13 hours postdose on Days 2 through 7, and on Day 14. Samples are to be collected 
within ±1 hour of the scheduled sampling time. 
The time of study drug administration is time zero and all post-dosing sampling times are 
relative to this time. The Investigator or designee will arrange to have the plasma samples 
processed, stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events). 
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time. The date and actual time that the blood sample was taken will be 
recorded on the eCRF or electronically with a bar code or other method. 
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70 to -80°C until analyzed. They 
should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours. A specimen-identification form must be completed and 
sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions. 
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of concentrations of SAGE-217 and 
possibly SAGE-217 metabolites will be performed utilizing a validated liquid chromatography- 
tandem mass spectrometry method at a qualified laboratory. Pharmacokinetic parameters will be 
derived such as area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), the 
distributional half-life and terminal half-life (t½), and steady-state drug concentration in the 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS (Part A only) and MOAA/S (Part A only) scores. 
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visits. A full medical 
history, including PD history (e.g., time of diagnosis, Hoehn and Yahr staging) and medication 
history, will be recorded at the Screening visits. 
13.1.2. 
Vital Signs 
Vital signs comprise respiratory rate, temperature, and supine (supine for at least 5 minutes prior 
to the measurement) and standing systolic and diastolic blood pressure and heart rate. 
Vital signs and pulse oximetry will be performed at screening (vital signs only) and Admission 
(Day -1); predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 through 7; in 
AM of Day 8; and on Day 14. Vital signs and pulse oximetry are to be assessed within 
±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times for the 6-hour through 16-hour time points. 
In Part B, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, and 12 hours postdose on Days 1 through 7; and on 
Day 14. Vital signs and pulse oximetry are to be assessed within ±10 minutes of the 1- and 2-
hour time points and within ±15 minutes of the 12-hour time point. 
 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visits for Parts A and B. 
 
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visits for Parts A and B. Symptom-directed physical examinations will be performed 
during Part A on Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and Day 8. Symptom- 
directed physical examinations will be performed during Part B on Admission (Day -1), Day 1, 
Day 3, Day 4, Day 6, and Day 8. 
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at screening and Admission (Day -1); predose on 
Days 1 and 3; predose and 1 and 12 hours postdose on Days 4, 5, 6, and 7; in AM on Day 8; and 
Day 14. In Part B, the 12-lead ECG will be assessed at screening and Admission (Day -1); 
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All time points are relative to the time of dosing. ECGs are to be performed within ±10 minutes 
of the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 
13.1.6. 
Laboratory Assessments 
In Part A, blood samples will be collected for hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day -1); predose on Day 4 and Day 7; and on 
Day 14. In Part B, blood and urine samples will be collected at screening and Admission 
(Day -1); predose on Days 4 and 6; and on Day 8 and Day 14. On Day -1 of Part B, two blood 
samples will be taken: one sample will be sent to the central lab to be analyzed for reporting 
purposes and one sample is to be analyzed locally for study eligibility with regard to 
hematology/serum chemistry criteria. 
Serum and urine samples for pregnancy tests (females only) will also be collected. These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3 as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to Section 13.2, 
and recorded in the eCRF. 
13.1.6.1. Hematology 
Hematology tests will include complete blood count (CBC), including red blood cells, white 
blood cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
 
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), alkaline 
phosphatase (Part B only), total protein, and albumin. 
 
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 
 
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
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13.1.6.5. Pregnancy Screen 
Females of childbearing potential will be tested for pregnancy at Parts A and B by serum 
pregnancy test at the Screening visits and by urine pregnancy test on Day -1 (Admissions). For 
Part B, females of childbearing potential will also be tested for pregnancy by urine pregnancy 
test at the follow-up visit on Day 14. 
 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe). 
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be completed on Screening of Parts A and B 
(lifetime history and past 24 months). In Part A, the “Since Last Visit” C-SSRS form will be 
completed on Admission (Day -1); 12 hours postdose on Days 1, 2, and 3; predose on Days 4, 5, 
6, and 7; and on Days 8 and 14. In Part B, the “Since Last Visit” C-SSRS form will be 
completed on Admission (Day -1); predose and 12 hours postdose on Day 1; 12 hours postdose 
on Days 2 through Day 7; and on Day 14. The C-SSRS is provided in Appendix 10. 
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling. Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’. 
In Part A, the SSS will be administered on Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in the AM on Day 8; and Day 14. All time 
points are relative to the time of dosing. The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. The SSS should be performed prior to the MOAA/S score. The SSS will not be 
administered in Part B. The SSS is provided in Appendix 11. 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS. If an MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment. In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point. In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 
3, 4, 5, 6, and 7; in AM on Day 8; and Day 14. The MOAA/S will not be performed in Part B. 
The MOAA/S is provided in Appendix 12. 


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13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed. Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher). 
 
13.2.1. 
Definition of Adverse Events 
 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
All adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, or following the cessation of treatment until the Day 14 Follow-up visit of Parts A and 
B, whether or not they are related to the study, must be recorded on forms provided by Sage 
Therapeutics. 
 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, and until the Day 14 Follow-up visit of Parts A and B, whether or not they are related 
to the study, must be recorded on forms provided by Sage Therapeutics. 


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13.2.1.4. Recording Sedation as an Adverse Event 
In Part A and Part B, sedation will be assessed using protocol-specified rating scales. 
Consideration should be given to the most appropriate term to describe the sedation 
characteristics. 
For Part A, in order to standardize the reporting of sedation as adverse events, Investigators must 
record sedation as an adverse event if there is a score of >5 on the SSS and/or a score of ≤2 on 
the MOAA/S. SSS and MOAA/S do not apply to Part B. 
 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator. The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
The Investigator should request permission to contact the subject, the subject’s spouse/partner (if 
the subject is male and his spouse/partner becomes pregnant) or the obstetrician for information 
about the outcome of the pregnancy (spontaneous miscarriage, elective termination, live birth), 
and in the case of a live birth, about any congenital abnormalities. If a congenital abnormality is 
reported, then it should be recorded in the source documents and reported as a serious adverse 
event. Spontaneous miscarriages should also be reported and handled as serious adverse events. 
Elective abortions without complications should not be handled as adverse events. 
 
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.” 
 
Not related 
No relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or subject’s clinical 
state. 
Possibly related 
A reaction that follows a plausible temporal sequence from administration of the 
study drug and follows a known response pattern to the suspected study drug. 
Probably related 
The reaction might have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject, but this is not known for sure. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting. 


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13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug. 
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted TEAEs. 
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change. 
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe adverse events. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 13.2.1.3. An adverse event 
of severe intensity may not be considered serious. 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 14 Follow-up visit of Parts A and B. Any serious adverse events considered 
possibly or probably related to the investigational product and discovered by the Investigator at 
any time after the study should be reported. All serious adverse events must be reported to the 
Sponsor or Sponsor’s designee immediately by phone and in writing within 24 hours of the first 
awareness of the event. The Investigator must complete, sign and date the serious adverse event 
pages, verify the accuracy of the information recorded on the serious adverse event pages with 
the corresponding source documents, and send a copy to Sage Therapeutics or designee. 
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file. 
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 


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will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
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14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered at least one dose of study 
drug. Safety population will be used to provide descriptive summaries of all safety data. 
The efficacy population will consist of all subjects in the safety population who receive at least 
one dose of study drug and have at least one postdose MDS-UPDRS evaluation. The efficacy 
population will be used to analyze all efficacy data. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each part of the study. 
 
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data. No sensitivity analysis of missing data will be performed. 
 
14.3. 
General Considerations 
For the purpose of all safety, efficacy, and exploratory analyses where applicable, baseline is 
defined as the last measurement prior to the start of study drug administration. Continuous 
endpoints will be summarized with n, mean, standard deviation (SD), median, minimum and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts 
and percentages. 
 
14.4. 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, race, and ethnicity, and baseline characteristics, such as 
height, weight, and body mass index (BMI), will be summarized. 
Categorical summaries, such as gender and race, will be summarized by frequency and 
percentage. Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics. 
Hepatitis, HIV, and pregnancy screening results will be listed, but not summarized as they are 
considered part of the inclusion/exclusion criteria. 
Medical history will be listed by subject. 
 
14.5. 
Efficacy Endpoints 
The primary endpoints of Part A relate to safety and tolerability. The primary endpoint for Part 
B is to evaluate the improvement in PD tremor as assessed by changes in the MDS UPDRS Part 
II/III tremor score (defined as the sum of MDS-UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 


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14.5.1. 
Secondary Efficacy Endpoints 
fu Pait A, changes in the MDS-UPDRS- Pait III score will be Sllilllllaii·zed overall and by 
tolerated dose. fu Pait B, MDS-UPDRS Pali III total score, and the MDS-UPDRS - Pa.it s I- IV 
total score will be smmnai·ized overall and by and tolerated dose. 
 
14.5.2. 
Exploratory Efficacy Endpoints 
14.6. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, SSS (Pa.ii A onl y), and 
MOAAIS (Pa11A only) will be smnmai·ized using descriptive statistics by group and time point, 
where applicable. Continuous endpoints will be Sllilllllai·izedwith nlllllber (n), mean, standai·d 
deviation, median, minimlllll, and maximlllll. fu addition, change from baseline values will be 
calculated at each time point and will be smmnai·ized using descriptive statistics. Out-of-range 
safety endpoints may be categorized as low or high, where applicable. For all categorical 
endpoints, sUilllna ries wi ll include counts and percentages. 
14.6.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher). The 
analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of open-label study drng, or any worsening of a pre­ 
existing medical condition/adverseevent with onset after the strut of ope n-l abe l study diu g and 
until 14 days after the last dose. The incidence of TEAEs will be sUillln ai·ized overall and by 
MedDRA System Organ Class, preferred tenn, and dose group. fucidences will be presented in 
order of decreasing frequency. fu addition, Sllilllllaii·es will be provided by maximlllll severity 
(see Section 13.4) and relationship to study diug (see Section 13.3). 
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the first dose of open-label study diug will also 
be sUillillaii·zed. 
All adverse events and serious adverse events (including those with onset or worsening before 
the staii of open-label study diug) through the Day 14 Follow-up visit of Paii s A and B will be 
listed. 
14.6.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
of Pa.ii A and Pait B in vital signs will be evaluated by time point. 


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14.6.3. 
Physical Examinations 
Screening physical examination results for Part A and Part B will be listed by subject. Any 
clinically significant physical examination will be recorded in medical history. Physical 
examination findings will be listed by subject and visit; abnormal findings will be flagged on the 
listing. 
 
14.6.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event. Electrocardiogram findings will be listed by subject and visit. 
14.6.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline of Parts A and B in clinical laboratory measures will be summarized. 
14.6.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects. Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
14.6.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects in Part A. Changes in score over 
time will be represented graphically, and change from baseline of Part A will be summarized. 
 
14.6.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects in Part A. Changes in 
score over time will be represented graphically, and change from baseline of Part A will be 
summarized. 
14.6.9. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later. 
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant). Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug. Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug. If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant. Details of prior and 
concomitant medications will be listed by study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and summarized. 


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14.7. 
Pharmacokinetic Analysis 
Phaimacokinetic parameters will be Slllllirni.rized u s in g appropriate descriptive statistics. Time to 
reach maximlllll concentration (tma.x) will be summarized using number  (n),  mean,  standai·d 
deviation, median, minimlllll, and maximlllll. All  other  PK pai·ameters  will  be Sllilllllarized  using 
n, geometric mean, coefficient of  vaii·ation,  median,  minimum,  and  maximlllll  and  listed  by 
subject. 
Wherever necessaiy and appropriate, PK pai·ainetres will be dose-adjusted to account for 
individual differences in dose. 
 
 
 
 
and safety. 
 
14.8. 
Determination of Sample Size 
Approximately 18 subjects will be enrolled in Pait A. An interim analysis is planned after 
10 subjects have completed Pait A through Day 14. Up to 15 new subjects will be enrolled in 
Pait Bin order for 10 subjects to complete the study (tolerate at least 20 mg SAGE-217 for the 
duration of the dosing period). This number of subjects is thought to be sufficient to assess 
preliminaiy safety and tolerability as well as a signal of efficacy of SAGE-217 in subjects with 
PD. 
14.9. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan. 
Additional exposure-response analyses may be perfo1med for other measures of efficacy 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of <Sponsor> 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between Sage 
Therapeutics and the Investigator. 
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each patient (eg, clinic 
charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to Sage Therapeutics 
or designee and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of a Sage Therapeutics or designee audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs. 
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements. 
 
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan. 
Electronic case report forms will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, and subject status. 
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study. For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available study registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor. It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study. The information obtained from the clinical study will be used 


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towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required. 


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics. No publication or disclosure of study results will be permitted except as 
specified in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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20. 
LIST OF REFERENCES 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neurophan nacology. 2002 
Sep;43(4):651- 61. 
Bergman H, Deuschl G. Pathophysiology of Parkinson's disease: from clinical neurology to 
basic neuroscience and back. Mov Disord. 2002;17:S28-S40. 
 
di Michele F, Longone P, Romeo E, et al. Decreased plasma and cerebrospinal fluid content of 
neuroactive steroids in Parkinson's disease. Neurol Sci. 2003;24(3):172-3. 
Goetz CG, Fahn S, Maitinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, fonnat, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41-4 . 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Pai·kinson's Disease Rating Scale (MDS-UPDRS): Scale presentationand clinimetric 
testing results. Mov Disord. 2008;23(15):2129- 70. 
Hoehn M, Yahr M. Parkinsonism: onset, progression and mo1tality. Neurology. 
1967;17(5):427-42. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Pai·kinson's disease. A clinico-pathological study of 100 cases. JNNP. 1992;55:181-4. 
Jankovic J. Moto r fluctuations and dyskinesia in Parkinson's disease: Clinical manifestations. 
Mov Disord. 2005;11:ll -6. 
Jankovic J. Parkinson's' disease: clinical features and diagnosis. JNNP. 2008;79:368-76. 
Kasten M, Brnggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the 
detection of MCI and dementia in Parkinson disease. Neurology. 2010;75 (5):478-9. 


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Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatiy. 2011;168(12):1266-77. 
Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for 
impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867- 76. 
Siderowf A, Lang AE. Pre-motor Parkinson's disease; concepts and definitions. Mov. Disord 
2012;27, 608-16. 
Stem MB. Dopamine agonists modify the course of Parkinson disease. Arch Neurol. 
2004;61:1969-71. 
Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 
2004;61:1966-9. 
Winkler C, Bentlage C, Nikkhah G, et al. Intracranial transplants of GABA-rich striatal tissue 
induce behavioral recove1y in the rat Parkinson model and promote the effects obtained by 
intrastriatal dopaminergic transplants. Exp. Neurol. 1999;155:165-186. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in the following appendices are for reference only; 
the rating scales and questionnaires reproduced in the eCRFs are to be used for actual subject 
assessment per the Schedule of Events. 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA 
 


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APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA 
The Hoehn and Yahr scale, a commonly used system for describing how the symptoms of 
Parkinson’s disease progress, was first published in 1967 (Hoehn 1967). The original scale 
included 5 disease stages, numbered 1 to 5. 
 
 
Original Hoehn and Yahr Scale 
 
Stage 1 
Unilateral involvement only, usually with minimal or no functional disability 
Stage 2 
Bilateral or midline involvement without impairment of balance 
Stage 3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; 
physically independent 
Stage 4 
Severely disabling disease; still able to walk or stand unassisted 
Stage 5 
Confinement to bed or wheelchair unless aided 


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APPENDIX 3. ANTICHOLINERGIC DRUGS 
The following drugs are not permitted in the 5 days prior to receiving the first dose of study drug 
in Part A and Part B. The list below gives a non-exhaustive list of examples of each drug class. 
A. Antimuscarinic agents 
 
Atropine 
Benzatropine 
Biperiden 
Chlorpheniramine 
Dicyclomine 
Dimenhydrinate 
Diphenhydramine 
Doxepin 
Doxylamine 
Glycopyrrolate 
Hydroxyzine 
Ipratropium 
Orphenadrine 
Oxitropium 
Oxybutynin 
Tolterodine 
Tiotropium 
Tropicamide 
Trihexyphenidyl 
Scopolamine 
Solifenacin 
Tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, trimipramine, 
amoxapine, desipramine, nortriptyline, protriptyline) 
 
B. Antinicotinic agents: 
 
Bupropion 
Dextromethorphan 
Doxacurium 
Hexamethonium 
Mecamylamine 
Tubocurarine 


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APPENDIX 4. TREMOROGENIC DRUGS 
The following drug classes are not permitted in the 14 days prior to the Day -1 visit and for the 
duration of the study (up to the Day 14 visit). The list below gives a non-exhaustive list of 
examples of each drug class. 
Anti-arrhythmics 
amiodarone, procainamide 
Antiepileptic drugs 
valproic acid, carbamazepine 
Antipsychotic agents 
haloperidol, trifluoperazine 
Antimanic agents/mood stabilizer 
lithium at toxic levels 
Antivirals 
acyclovir, vidarabine 
Beta adrenergic agonists 
albuterol, terbutaline 
Calcium Channel blockers 
verapamil 
CNS stimulants 
methylphenidate, amphetamines, cocaine 
Corticosteroids (local injection topical, or inhalation allowed) 
cortisone, hydrocortisone, prednisone 
Cytotoxic agents 
cytarabine 
Hormones 
calcitonin, levothyroxine (levothyroxine is allowed if on a stable dose and euythroid) 
Immunomodulatory 
thalidomide 
Immunosuppressants 
cyclosporine, tacrolimus 
Monoamine depleting agents 
tetrabenazine 
Oral hypoglycemic agents 
metformin, glyburide, glipizide, tolbutamide, pioglitazone, rosiglitazone, acarbose, miglitol 
Prokinetics 
metoclopramide 
Tricyclic antidepressants 
amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, 
nortriptyline, protriptyline 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
fluoxetine (other SSRIs are allowed) 
Statins 
atorvastatin (other statins are allowed) 


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Sympathomimetics 
epinephrine, pseudoephedrine 
Weight loss medication 
tiratricol 
Xanthine derivatives 
theophylline (caffeine/coffee and theophylline/theobromine/tea require a washout, cocoa 
beans are acceptable) 


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APPENDIX 5. MOVEMENT DISORDER SOCIETY-UNIFIED 
PARKINSON'S DISEASE RATING SCALE (MDS-UPDRS) 
 
Part I: Nonmoto1· A spect s of Experi e nc es of Dail y Li vi ng 
Part II: Motor Expeli ences of Daily Living 
Cognitive impainnent 
Speech 
Hallucinations and psychosis 
Saliva and drooling 
Depressed mood 
Chewing and swallowing 
Anxious mood 
Eating tasks 
Apathy 
Dressing 
Features of dopamine dysregulation syndrome 
Hygiene 
Sleep problems 
Handwriting 
Daytime sleepiness 
Doing hobbies and other activities 
Pain and other sensations 
Tuming in bed 
Urina1y problems 
Tremor impact on activities 
Constipation problems 
Getting in and out of bed 
Lightheadedness on standing 
Walking and balance 
Fatigue 
Freezing 
Part III: Motor Examination 
Part IV: Motor Complications 
Speech 
Time spent with dyskinesias 
Facial expression 
Functional impact of dyskinesias 
Rigidity (neck; right/left upper/lower extremities) 
Painful off state dystonia 
Finger tapping (right/left hands) 
Time spent in the off state 
Hand movements (right/left hands) 
Functional impact of fluctuations 
Pronation-supination movements of right/left hands 
Complexity of motor functions 
Toe tapping (right/left foot) 
Leg agility (right/left leg) 
Arising from chair 
Gait 
Freezing of gait 
Postural instability 
Posture 
Global spontaneity of movement (body bradykinesia) 
Postural tremor of righ t/left hands 
Kinetic tremor of right/left hands 
Rest tremor amplitude: right/left upper/lower extre1niites; lip jaw 
Constancy of rest tremor 


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APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – BASELINE/SCREENING VERSION AND 
SINCE LAST VISIT VERSION 
 
 
 


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APPENDIX 11. STANFORD SLEEPINESS SCALE (SSS) 
 


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APPENDIX 12. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
Modified Observer’s Assessment of Alertness/Sedation Scale 
 
Score 
Responsiveness 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Responds only after painful trapezius squeeze 
0 
No response after painful trapezius squeeze 


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Summary of Changes to 
Protocol 217-PRK-201, Amendment #3 
Date of Amendment: 06 June 2017 
 
The following changes were made in Protocol 217-PRK-201 v4.0, Amendment #3. In addition, minor editorial revisions 
(eg, formatting, punctuation) that are not listed below may have been made throughout the protocol. 
 
Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
Document Header 
Version 3.0 24 October 2016 
Amendment #3, Version 34.0 24 October 2016 
CONFIDENTIAL 
Administrative 
update 
Title Page, 
A PHASE 2, TWO-PART STUDY TO 
A PHASE 2, TWO-PART STUDY TO EVALUATE 
a) With the addition 
2. Synopsis 
EVALUATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF 
THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF 
of a capsule 
formulation, the 
SAGE-217 ORAL SOLUTION IN PATIENTS 
WITH PARKINSON’S DISEASE OF MODERATE 
SEVERITY RESPONDING TO IMMEDIATE- 
SAGE-217 ORAL SOLUTION IN PATIENTS 
SUBJECTS WITH PARKINSON’S DISEASE OF 
MODERATE SEVERITY RESPONDING TO 
study is no longer 
specific to SAGE- 
217 Oral Solution 
RELEASE ORAL LEVODOPA/CARBIDOPA 
IMMEDIATE RELEASE ORAL 
b) Update from 
AND WITHDRAWN FROM 
LEVODOPA/CARBIDOPA 
LEVODOPA/CARBIDOPA AND WITHDRAWN 
FROM LEVODOPA/CARBIDOPA 
‘Patients’ to 
‘Subjects’ to adhere 
to company style 
guide 
c) Part B inclusion 
criteria no longer 
considers disease 
severity and does not 
require withdrawal 
from 
levodopa/carbidopa 
Title Page 
Date of Amendment 2 Version 3.0, 24 October 2017 
Date of Amendment 2 Version 3.0, 24 October 20176 
Correction 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
Title Page 
Date of Amendment 3 Version 4.0, 06 June 2017 
Administrative 
update 
Protocol Signature 
Page 
Product: SAGE-217 Oral Solution 
Product: SAGE-217 Oral Solution 
With the addition of 
a capsule 
formulation, the 
study is no longer 
specific to SAGE- 
217 Oral Solution 
Protocol Signature 
Page 
Date of Amendment 2: Version 3.0, 
24 October 2016 
Date of Amendment 23: Version 34.0, 24 October 
201706 June 2017 
Administrative 
update 
Protocol Signature 
Page 
, PhD 
Sage Therapeutics 
, PhD 
MS 
Sage Therapeutics 
Administrative 
update 
2. Synopsis, Name of 
Investigational 
Product 
SAGE-217 Oral Solution 
SAGE-217 Oral Solution 
SAGE-217 Capsules 
Change made to 
accommodate the 
availability of a 
capsule formulation 
2. Synopsis, Study 
centers 
Up to 4 centers 
Up to 4 12 centers 
Change made to 
accommodate more 
centers 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
2. Synopsis, 
Objectives 
Primary: 
• To evaluate the safety and tolerability of 
SAGE-217 Oral Solution. 
Secondary: 
• To evaluate the effect of SAGE-217 Oral 
Solution on the severity of PD motor 
symptoms after withdrawal of Levodopa or 
Carbidopa-Levodopa (Levodopa/Carbidopa). 
• To evaluate the effect of SAGE-217 Oral 
Solution exposure length on the severity of 
PD motor symptoms after withdrawal of 
Levodopa/Carbidopa. 
• To compare the effect of SAGE-217 Oral 
Solution in combination with immediate- 
release oral Levodopa/Carbidopa to 
Levodopa/Carbidopa alone. 
Primary: 
Part A: 
• To evaluate the safety and tolerability of 
SAGE-217 Oral Solution. 
Part B: 
• To evaluate the effect of SAGE-217 
Capsules as an adjunct to antiparkinsonian 
agent(s) on the severity of PD tremor 
symptoms. 
Secondary: 
Part A: 
• To evaluate the effect of SAGE-217 Oral 
Solution on the severity of PD motor 
symptoms after withdrawal of Levodopa or 
Carbidopa-Levodopa (Levodopa/Carbidopa). 
• To evaluate the effect of SAGE-217 Oral 
Solution exposure length on the severity of 
PD motor symptoms after withdrawal of 
Levodopa/Carbidopa. 
• To compare the effect of SAGE 217 Oral 
Solution in combination with immediate 
release oral Levodopa/Carbidopa to 
Levodopa/Carbidopa alone. 
Part B: 
• To evaluate the effect of SAGE-217 
Capsules as an adjunct to antiparkinsonian 
a) Changes made to 
divide the study 
objectives of Part A 
and Part B and make 
efficacy the primary 
objective for Part B; 
b) objectives added 
due to update of 
study design for 
Part B (randomized 
to open-label) and 
availability of 
SAGE-217 Capsule; 
c) added 
Pharmacokinetic 
objectives that were 
inadvertently 
missing from 
previous version 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
agent(s) on motor and non-motor 
symptoms of PD. 
• To evaluate the safety and tolerability of 
SAGE-217 Capsules. 
Pharmacokinetic: 
• Part A: To assess the pharmacokinetic 
(PK) profile of SAGE-217 Oral Solution in 
plasma samples. 
• Part B: To assess the PK profile of 
SAGE-217 Capsules utilizing a population 
PK approach. 
2. Synopsis, 
Primary: 
Primary: 
Part A: 
• 
Frequency and severity of adverse events 
and changes in vital signs, clinical laboratory 
data, electrocardiogram (ECG) parameters, and 
suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) during both Part 
A and Part B. In addition, sleepiness/sedation 
as assessed by Stanford Sleepiness Scale (SSS) 
score. 
Part B: 
• 
Improvement in PD tremor as assessed by 
changes in the MDS UPDRS Part II/III 
tremor score (defined as the sum of MDS- 
UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 
a) Changes made 
Endpoints 
• 
Frequency and severity of adverse events 
and changes in vital signs, clinical laboratory 
data, electrocardiogram (ECG) parameters, and 
suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) during both 
Part A and Part B. 
Secondary: 
Part A: 
due to division of 
study objectives 
between Part A and 
Part B; b) changes 
made due to update 
in study design for 
Part B 
• 
Improvement in PD motor symptoms as 
assessed by changes in the Movement Disorder 
Society-Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) – Part III (Motor 
Examination) score. 
Part B: 


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Title 
Original Text: 
Improvement in PD motor symptoms as 
assessed by changes in the MDS-UPDRS - Part 
III score. 
Improvement in PD overall symptoms as 
assessed by changes in the MDS-UPDRS - 
Parts I-IV total score. 
Sleepiness/sedation as assessed by the 
Stanford Sleepiness Scale (SSS) and Modified 
Observe r's Assessment of Analgesia/Sedation 
(MOAAIS) scores. 
In addition, plasma concentrations of SAGE- 
217 and possibly SAGE-217 metabolites will 
be measured, and pharmacokinetic (PK) 
parameters will be derived. 
Exploratory Endpoints: 
Changed To: 
Secondaiy: 
Part A: 
Improvement in PD motor symptomsas 
assessed by changes in the Movement Disorder 
Society-Unified Par·kinson's Disease Rating 
Scale (MDS-UPDRS) - Part III (Motor 
Examination) score. 
Part B: 
• 
Improvement in PD motor symptoms as 
assessed by changes in the MDS-UPDRS- Part 
III total score. 
• 
Improvement in PD nonmotor and motor 
aspects of experiences of daily living as 
assessed by the MDS-UPDRS - Part I and 
Part II scores, respectively. 
• 
Improvement in PD overall symptoms as 
assessed by changes in the MDS-UPDRS- Parts 
I-IV total score. 
• 
£kepi:Bess/seaatioa as assessed by tl½e 
S B:Bfot'd Sl@@ptn@ss Seal@(£££) end 4odifi@d 
Obse1ver's f.,ssessmeat of Analgesial£edatioa 
(MO,'\f.J£) scores. 
• 
Frequenc y and severity of adverse events 
and changes in vital signs, clinical laboratory 
data, electrocardiogram (ECG) parameters, 
and suicidal ideation using the Columbia­ 
Suicide Severity Rating Scale (C-SSRS). 
Pharmacokinetic: 
• 
lB additioa, f)P lasma concentrations of 
SAGE-217,and possibly SAGE-217 metabolites 
Rationale: 


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Title 
Original Text: 
Changed To: 
will be measured, and f)liftfffi&eekiae ie (PK1 
parameters will be derived. 
Exploratory Endpoi:ras: 
Rationale: 


Protocol 217-PRK-201 
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Section Nmnbe1· and 
7 
 
 
Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Synopsis, 
Methodology 
Original Text: 
 
 
 
 
 
 
 
 
 
 
 
 
This study will assess the safety, tolerability, 
PK, and efficacy of SAGE-217 Oral Solution. 
For ease of discussion, Levodopaalone or 
Carbidopa-Levodopacombination will be 
refened to as Levodopa in this protocol. 
Thereare two pa.its: 
Pait A: Open-label with morning (AM) dosing 
(4 days). 
All subjects will continue to take their 
antiparkinsonian agents including immediate­ 
release oral Levodopa on the day of admission 
(Day -1) and in the AM only the following 3 
days (Days 1 to 3). All subjects will stop their 
immediate-releaseoral Levodopa on Day 4 and 
will strut on a 30 mg dose of SAGE-217Oral 
Solution administered in the AM with food. 
Subjects not tolerating 30 mg will receive 20 
mg, and subjectsnot tolerating 20 mg will 
receive 10 mg on subsequent days. The dose 
received on Day 7 will be defined as the 
tolerateddose for that subject.. Subjects not 
tolerating 10 mg will not be able to continue in 
Changed To: 
 
 
 
 
 
 
 
 
 
 
 
 
Methodology: 
This study will assess the safety, tolerability, 
pharmaco kinetics (PK) and 
efficacyeffectivenessof SAGE-2l74fal. 
£elation.  For ease of discussion, Levodopa 
alone or Carbidopa-Levodopacombni ationwill 
be refened to as Levodopa in this protocol. 
There are two parts.;., Part A and Part B, 
described below. Unique subjects will be 
enrolled in each part; subjects from Part A 
will not con tinue into Part B. 
Pait A: Open-label with momiag (.'\Mt dosing 
(4 days). 
All subjects will continue to take their 
antiparkinsonian agent(s) including immediate­ 
release oral Levodopa on the day of admission 
(Day -1) and in the AM only the followni g 3 
days (Days1 to 3). All subjects will stop their 
immediate-releaseoral Levodopaon Day 4 and 
will strut on a 30 mg dose of SAGE-217 Oral 
Solution administeredin the AM with food. 
Rationale: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changes made due 
to update in study 
design for Pait B 


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Original Text: 
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Rationale: 
the study and may be replaced. Subjects will 
be followed for an additional 7 days (Day 14) 
after the administration of the last dose. 
Levodopa treatment will be resumed on Day 8 
and continue through Day 14. 
Rescue treatment (oral Levodopa or other 
antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all 
days (Days 1 to 7). 
Part A is designed to determine the tolerated 
dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 
exhibits efficacy in subjects with PD in order to 
inform the conduct of Part B. 
Part B: Randomized, placebo-controlled, two- 
sequence crossover with AM dosing (up to 8 
days). Part B will be initiated only after review 
of the Part A interim analysis. 
In order to qualify for Part B of the study, a 
subject must have tolerated a dose of at least 10 
mg of SAGE-217 Oral Solution in Part A. 
Subjects who complete Part A through Day 14 
will be re-admitted on Day -1 of Part B and 
they will receive their antiparkinsonian agent 
including immediate-release oral Levodopa. 
Subjects will be randomized the next day (Day 
1) in a 1:1 manner to open-label Levodopa plus 
blinded SAGE-217 Oral Solution or placebo 
during Period 1 of the crossover. Subjects 
randomized to the combination arm of 
Levodopa and SAGE-217 Oral Solution will 
receive this combination in the morning for the 
Subjects not tolerating 30 mg will receive 20 
mg, and subjects not tolerating 20 mg will 
receive 10 mg on subsequent days. The dose 
received on Day 7 will be defined as the 
tolerated dose for that subject. Subjects not 
tolerating 10 mg will not be able to continue in 
the study and may be replaced. Subjects will be 
followed for an additional 7 days (Day 14) after 
the administration of the last dose. Levodopa 
treatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment (oral Levodopa or other 
antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all 
days (Days 1 to 7). 
Part A is designed to determine the tolerated 
dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 
exhibits efficacy in subjects with PD in order to 
inform the conduct of Part B. 
Assessments will be performed periodically 
during the study as outlined in the Schedule 
of Events for Part A (Table 2). 
Part B: Randomized, placebo controlled, two 
sequence crossover with AM dosing (up to 8 
days). Part B will be initiated only after review 
of the Part A interim analysis. 
In order to qualify for Part B of the study, a 
subject must have tolerated a dose of at least 10 
mg of SAGE 217 Oral Solution in Part A. 
Subjects who complete Part A through Day 14 


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Section Number and 
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Original Text: 
Changed To: 
Rationale: 
first 4 days (Days 1 to 4). Subjects randomized 
to the Levodopa plus placebo arm will receive 
Levodopa and SAGE-217 matching placebo 
oral solution in the AM for the first 4 days 
(Days 1 to 4). On Day 5, all subjects will 
crossover to Period 2 and will only receive 
open-label SAGE-217 Oral Solution for the 
remaining 4 days (Days 5 to 8). Subjects will 
receive their individually established tolerated 
dose of SAGE-217 Oral Solution (from Part A). 
All subjects will be able to resume Levodopa 
from Day 9 onwards. Rescue treatment (at 
Investigator’s discretion) will be allowed, if 
needed, on all days (Days 1 to 8). 
All doses of SAGE-217 Oral Solution (or 
placebo) will be administered in the morning 
with food. If subjects are taking Levodopa as 
opposed to Carbidopa-Levodopa, 
administration with or without food will be 
determined by the Investigator. 
Reductions in dose of SAGE-217 will be 
allowed during both parts of the study (Parts A 
and B). If at any time the dose is not tolerated, 
assessed by occurrence of a severe adverse 
event judged by the Investigator to be related to 
study drug, the dose on the next day must be 
reduced to the next lowest dose and continued 
for the remainder of the dosing period (ie, 
subjects who are unable to tolerate the 30 mg 
dose will receive a dose of 20 mg, and subjects 
who are unable to tolerate 20 mg will receive a 
10 mg dose on subsequent days). The dose 
received on Day 7 of the dosing period in Part 
will be re admitted on Day 1 of Part B and they 
will receive their antiparkinsonian agent 
including immediate release oral Levodopa. 
Subjects will be randomized the next day (Day 
1) in a 1:1 manner to open label Levodopa plus 
blinded SAGE 217 Oral Solution or placebo 
during Period 1 of the crossover. Subjects 
randomized to the combination arm of Levodopa 
and SAGE 217 Oral Solution will receive this 
combination in the morning for the first 4 days 
(Days 1 to 4). Subjects randomized to the 
Levodopa plus placebo arm will receive 
Levodopa and SAGE 217 matching placebo oral 
solution in the AM for the first 4 days (Days 1 to 
4). On Day 5, all subjects will crossover to 
Period 2 and will only receive open label 
SAGE 217 Oral Solution for the remaining 4 
days (Days 5 to 8). Subjects will receive their 
individually established tolerated dose of SAGE 
217 Oral Solution (from Part A). All subjects 
will be able to resume Levodopa from Day 9 
onwards. Rescue treatment (at Investigator’s 
discretion) will be allowed, if needed, on all 
days (Days 1 to 8). 
All doses of SAGE 217 Oral Solution (or 
placebo) will be administered in the morning 
with food. If subjects are taking Levodopa as 
opposed to Carbidopa Levodopa, administration 
with or without food will be determined by the 
Investigator. 
Reductions in dose of SAGE 217 will be 
allowed during both parts of the study (Parts A 
and B).  If at any time the dose is not tolerated, 


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Original Text: 
Changed To: 
Rationale: 
A will be defined as the tolerated dose for that 
subject, with this dose to be used as the starting 
dose for Part B for that subject. 
Subjects will be exposed to SAGE-217 Oral 
Solution for up to 12 days (4 days in Part A and 
up to 8 days in Part B) and will be followed for 
an additional 7 days in Part A and an additional 
14 days in Part B after the administration of the 
last dose. 
Assessments will be performed periodically 
during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and 
Table 3, respectively). 
assessed by occurrence of a severe adverse event 
judged by the Investigator to be related to study 
drug, the dose on the next day must be reduced 
to the next lowest dose and continued for the 
remainder of the dosing period (ie, subjects who 
are unable to tolerate the 30 mg dose will 
receive a dose of 20 mg, and subjects who are 
unable to tolerate 20 mg will receive a 10 mg 
dose on subsequent days). The dose received on 
Day 7 of the dosing period in Part A will be 
defined as the tolerated dose for that subject, 
with this dose to be used as the starting dose for 
Part B for that subject. 
Subjects will be exposed to SAGE 217 Oral 
Solution for up to 12 days (4 days in Part A and 
up to 8 days in Part B) and will be followed for 
an additional 7 days in Part A and an additional 
14 days in Part B after the administration of the 
last dose. 
Open-label with evening (PM) dosing, for 7 
days, as an adjunct to antiparkinsonian 
agent(s). 
Subjects on a stable dose of antiparkinsonian 
agent(s) will continue taking them for the 
duration of the study. Anticholinergics 
and/or amantadine will be discontinued by 
Day -6 and Day -10, respectively. 
Screening may occur between Day -28 and 
Day -2, but subjects must be admitted on Day 
-1 for selected pre-dose assessments (eg, 
clinical laboratory assessments, assessment of 
tremor). All subjects will take SAGE-217 


Protocol 217-PRK-201 
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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
Capsules, 20 mg, at 8PM on Days 1 and 2. On 
Day 3, subjects tolerating the initial dose (ie, 
those who do not experience a severe adverse 
event judged by the Investigator to be related 
to study drug) will receive a dose increase 
(SAGE-217, 30 mg), at 8PM and continuing 
each subsequent evening at 8PM for the 
remainder of the dosing period (ending on 
Day 7). 
If on Day 3 or any time thereafter, the 30-mg 
dose is not tolerated, assessed by occurrence 
of a severe adverse event judged by the 
Investigator to be related to study drug, the 
dose on the next day must be reduced to 20 
mg and continued for the remainder of the 
dosing period. Subjects who cannot tolerate 
the 20-mg dose at any time will be 
discontinued and replaced. 
All doses of SAGE-217 will be administered 
with food. For antiparkinsonian agents, 
administration with or without food will be 
determined by the Investigator. 
Subjects will receive SAGE-217 for up to 7 
days and will be followed for an additional 7 
days after the administration of the last dose. 
Assessments will be performed periodically 
during the study as outlined in the Schedule of 
Events for Parts A and B (Table 2 and Table 3, 
respectively). 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
2. Synopsis, Number 
of patients (planned) 
Number patients (planned) 
Number patients subjects (planned) 
Administrative 
update 
2. Synopsis, Number 
of patients (planned), 
7.2. Number of 
Subjects 
Approximately 18 subjects will be enrolled in Part 
A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the 
conduct of Part B.  Twelve subjects are anticipated 
to be randomized in Part B. 
Approximately 18 subjects will be enrolled in Part A. 
An interim analysis is planned after 10 subjects have 
completed Part A through Day 14 to inform the 
conduct of Part B. Twelve subjects are anticipated to 
be randomized in Part B. 
Up to 15 new subjects will be enrolled in Part B in 
order for 10 subjects to complete the study 
(tolerate at least 20 mg SAGE-217 for the duration 
of the dosing period). 
Changes made due 
to update in study 
design for Part B 
2. Synopsis, 
Diagnosis and main 
criteria for inclusion 
Diagnosis and main criteria for inclusion: All of the 
following inclusion and exclusion criteria will be 
applied during screening for Part A, with some of 
the criteria applied during screening for Part B, as 
indicated. 
Diagnosis and main criteria for inclusion: All of the 
following inclusion and exclusion criteria will be 
applied during screening for Part A, with some of the 
criteria applied during screening for Part B, as 
indicated. 
Changes made due 
to update in study 
design for Part B 
2. Synopsis, 
Diagnosis and main 
criteria for inclusion, 
8.1. Subject Inclusion 
Criteria 
1. Subject has signed an informed consent form 
(ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, 
inclusive. 
3. Subject has a diagnosis of idiopathic PD based 
on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) 
(Hughes 1992; Appendix 1). 
1. Subject has signed an informed consent form 
(ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, 
inclusive. 
3. Subject has a diagnosis of idiopathic PD based 
on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) 
(Hughes 1992; Appendix 1). 
Changes made to 
distinguish criteria 
for Part A and Part B 
and due to updated 
study design for 
Part B 


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Section Number and 
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Original Text: 
Changed To: 
Rationale: 
4. Subjects with PD with a duration of less than 7 
years and must meet the criteria for Hoehn and Yahr 
stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian 
agents including immediate-release oral Levodopa 
or Carbidopa-Levodopa (defined as no changes for a 
period of at least 1 month prior to the baseline visit) 
and is expected to remain on this stable dose for the 
duration of this study. 
6. Subject is willing to discontinue his/her 
treatment with immediate-release oral Levodopa or 
Carbidopa-Levodopa for at least 8 hours prior to 
dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her 
treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of 
admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep 
medication, or neuroleptic must have been on a 
stable dose for at least 1 month prior to the baseline 
visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no 
clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory 
tests. (Part B also) 
4. Part A: Subjects with PD with a duration of less 
than 7 years and must meet the criteria for Hoehn and 
Yahr stage 2 or stage 3 (Appendix 2). 
Part B: Subjects with PD and must meet the 
criteria for Hoehn and Yahr stage 1-4 (Appendix 
2) assessed during the “on” period (assumed to be 
within 2 hours of dosing with antiparkinsonian 
agent(s)), and have a tremor with a MDS-UPDRS 
Part II/III tremor score of ≥8 (sum of items: 2.10, 
3.15, 3.16, 3.17 and 3.18) AND a MDS-UPDRS 
item score ≥3 in at least one limb (from items 3.15, 
3.16, or 3.17). Inclusion criteria tremor scores 
must be assessed during “on” periods during the 
screening and Day -1 visit. 
5. Part A: Subject has a stable dose of 
antiparkinsonian agent(s) including immediate- 
release oral Levodopa or Carbidopa-Levodopa 
(defined as no changes for a period of at least 1 
month prior to the baseline visit) and is expected to 
remain on this stable dose for the duration of this 
study. 
Part B: Subject is receiving a stable dose of 
antiparkinsonian agent(s) (defined as no changes 
for a period of at least 1 month prior to the 
baseline visit) and is expected to remain on this 
stable dose for the duration of this study. 
6. Part A only: Subject is willing to discontinue 
his/her treatment with immediate-release oral 


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Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
11. Female subjects must agree to practice a highly 
effective method of birth control while on study 
through completion of the last follow-up visit. If a 
subject discontinues early after receiving a dose of 
SAGE-217, then the subject must continue this 
method of birth control for at least 7 days following 
the last dose of study drug. Highly effective 
methods of birth control include combined (estrogen 
and progestogen-containing) hormonal 
contraception associated with inhibition of 
ovulation, progestogen-only hormonal contraception 
associated with inhibition of ovulation, intrauterine 
device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner, or 
sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly 
effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study 
drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with 
spermicide (men) in combination with their partner's 
highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm 
donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose 
of study drug. (Part B also) 
Levodopa or Carbidopa-Levodopa for at least 8 hours 
prior to dosing with SAGE-217. (Part B also) 
7. Part A: Subject is willing to discontinue his/her 
treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of 
admission (Day -1). (Part B also) 
Part B: Subject is willing to discontinue his/her 
treatment with anticholinergics (Appendix 3) by 
Day -6 or amantadine by Day -10. 
8. Subjects taking an antidepressant drug, sleep 
medication, or neuroleptic must have been on a stable 
dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no 
clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory 
tests. (Part B also) 
11. Part A: Female subjects must agree to practice a 
highly effective method of birth control while on 
study through completion of the last follow-up visit. 
If a subject discontinues early after receiving a dose 
of SAGE-217, then the subject must continue this 
method of birth control for at least 7 days following 
the last dose of study drug. Highly effective methods 
of birth control include combined (estrogen and 
progestogen-containing) hormonal contraception 
associated with inhibition of ovulation, progestogen- 
only hormonal contraception associated with 


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Original Text: 
Changed To: 
Rationale: 
inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner, or sexual 
abstinence. (Part B also) 
Part B: Female subject agrees to use one of the 
following methods of contraception during 
participation in the study and for 30 days 
following the last dose of study drug, unless they 
are postmenopausal (defined as no menses for 12 
months without an alternative medical cause) 
and/or surgically sterile: 
• 
Combined (estrogen and progestogen 
containing) oral, intravaginal, or transdermal 
hormonal contraception 
• 
associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen- 
only hormonal contraception associated with 
inhibition of ovulation. 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse). 
12. Male subjects must agree to practice a highly 
effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study 


Protocol 217-PRK-201 
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16 
 
 
 
Section Number and 
Title 
Original Text: 
Changed To: 
Rationale: 
drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with 
spermicide (men) in combination with their partner's 
highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm 
donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose 
of study drug. (Part B also) 
2. Synopsis, 
Exclusion criteria, 
8.2. Subject Exclusion 
Criteria 
1. Subjects with a known hypersensitivity to 
SAGE-217 Oral Solution or its major excipient, 
HPβCD. (Part B also) 
2. Subjects with early PD (Hoehn and Yahr 
stage 1) or advanced PD (Hoehn and Yahr stage 4 or 
stage 5). 
3. Subjects with any medical or psychiatric 
condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia 
spectrum and other psychotic disorders, substance- 
related and addictive disorders, feeding and eating 
disorders, bipolar and related disorders, structural 
brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of 
clinically significant stroke, or anticipating starting 
psychotherapy or behavior therapy during the course 
of the study or who started psychotherapy or 
behavior therapy within 30 days prior to Part A Day 
1. 
1. Subjects with a known hypersensitivity to 
SAGE-217 Oral Solution or its major excipient, 
HPβCD. (Part A) or SAGE-217 Capsule or its 
excipients Part B also) 
2. Part A: Subjects with early PD (Hoehn and Yahr 
stage 1) or advanced PD (Hoehn and Yahr stage 4 or 
stage 5). 
Part B: Subjects with advanced PD (Hoehn and 
Yahr stage 5). 
3. Subjects with any medical or psychiatric 
condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia 
spectrum and other psychotic disorders, substance- 
related and addictive disorders, feeding and eating 
disorders, bipolar and related disorders, structural 
brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of 
clinically significant stroke, or anticipating starting 
psychotherapy or behavior therapy during the course 
Changes made to 
distinguish criteria 
for Part A and Part B 
and due to updated 
study design for 
Part B 


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Section Number and 
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Original Text: 
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Rationale: 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain 
stimulation) for PD; 
c. History of suicide attempt within 2 years, or has 
answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has 
current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a 
BDI-II score >19. 
6. Subjects with Type I or Type II diabetes 
mellitus. 
7. Subjects with presence of drug-induced 
parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, 
Wilson's disease), encephalitis, or other atypical 
Parkinsonian syndromes (eg, progressive 
supranuclear palsy, multiple system atrophy). (Part 
B also) 
8. Subject has significant history and/or presence 
of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, 
ophthalmologic, metabolic, or oncological disease. 
(Part B also) 
of the study or who started psychotherapy or behavior 
therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain 
stimulation) for PD; 
c. History of suicide attempt within 2 years, or has 
answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has 
current suicidal ideation; or 
d. Impulse control disorder. 
5. Part A: Subjects with severe depression as 
defined by a BDI-II score >19. 
6. Part B: Subject has recent exposure (14 days 
prior to the Day -1 visit) to tremorogenic drugs, as 
defined in Appendix 4. 
67. Subjects with Type I or Type II diabetes 
mellitus. 
78. Subjects with presence of drug-induced 
parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, 
Wilson's disease), encephalitis, or other atypical 
Parkinsonian syndromes (eg, progressive 
supranuclear palsy, multiple system atrophy). (Part B 
also) 


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9. Subject has clinically significant abnormal 
physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval 
calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be 
the basis for exclusion from the study. ECG may be 
repeated once if initial values obtained are outside 
the specified limits. (Part B also) 
10. Subject has a history, presence and/or current 
evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) 
antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
11. Subject has exposure to another investigational 
medication or device within 30 days prior to Part A 
Day 1. 
12. Subject has donated one or more units of blood 
or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). 
(Part B also) 
13. Subject is unwilling or unable to comply with 
study procedures. (Part B also) 
14. Subjects has used any known strong inhibitors 
and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is 
longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products 
89. Subject has significant history and/or presence of 
hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, 
ophthalmologic, metabolic, or oncological disease. 
(Part B also) 
910.Subject has clinically significant abnormal 
physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval 
calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be 
the basis for exclusion from the study. ECG may be 
repeated once if initial values obtained are outside the 
specified limits. (Part B also) 
101.Subject has a history, presence and/or current 
evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) 
antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
112.Subject has exposure to another investigational 
medication or device within 30 days prior to Part A 
Day 1. 
123.Subject has donated one or more units of blood 
or acute loss of an equivalent amount of blood within 
60 days prior to dosing (1 unit = 450 mL). (Part B 
also) 
134.Subject is unwilling or unable to comply with 
study procedures. (Part B also) 


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containing these within 30 days prior to receiving 
the first dose of study drug. (Part B also) 
145.Subjects has used any known strong inhibitors 
and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is 
longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products 
containing these within 30 days prior to receiving the 
first dose of study drug. (Part B also) 
2. Synopsis, 
Investigational 
product, dosage and 
mode of 
administration 
Investigational product, dosage and mode of 
administration: 
SAGE-217 Oral Solution is available as a 6 mg/mL 
stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% 
sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Investigational product, dosage and mode of 
administration: 
Part A: SAGE-217 Oral Solution is available as a 6 
mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% 
sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Part B: SAGE-217 Capsules are available as hard 
gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug 
Substance, the SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified 
microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. For Part B, capsules will 
be available in 5-mg, 10-mg and 20-mg dose 
strengths. Subjects will be administered two 
capsules per dose. 
Change made to 
accommodate the 
availability of a 
capsule formulation 
for Part B. 
2. Synopsis, Duration 
of treatment 
Duration of treatment: 7 days in Part A; 8 days in 
Part B 
Duration of treatment: 7 days in Part A; 8 days in Part 
BPart A and Part B: 
Changes made due 
to update in study 
design for Part B. 


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Part A: 
Screening duration: up to 28 days; Treatment 
Period: 7 days (SAGE-217 dosing for 4 days); 
Follow-up: 7 days 
Planned participation per subject: approximately 42 
days during Part A. 
Part B: 
Screening duration: up to 14 days; Treatment 
Period: 8 days; Follow-up: 14 days 
Planned participation per subject: approximately 36 
days during Part B. 
Part A: 
Screening dDuration: up to 28 days; Treatment 
Period: 7 days (SAGE 217 dosing for 4 days); 
Follow-up: 7 days 
Planned participation Study Duration per sSubject: 
approximately 42 days during Part A. 
Part B: 
Screening duration: up to 14 days; Treatment Period: 
8 days; Follow up: 14 days 
Planned participation per subject: approximately 36 
days during Part B. 
2. Synopsis, 
Reference therapy, 
dosage and mode of 
administration 
In part B, placebo will be taste-matched to SAGE- 
217 Oral Solution. 
In part B, placebo will be taste  matched to SAGE 
217 Oral Solution.Not applicable; Part A and Part 
B are open-label with all subjects receiving SAGE- 
217. 
Changes made due 
to update in study 
design for Part B. 
2. Synopsis, Criteria 
for evaluation 
Safety and tolerability: 
Safety and tolerability of study drug will be 
evaluated by vital signs, clinical laboratory 
measures, ECGs, physical examinations, 
concomitant medication usage, C-SSRS, and 
adverse event reporting. Sleepiness/sedation will be 
assessed by the SSS and MOAA/S. 
Efficacy: 
Improvement in PD motor symptoms and overall 
symptoms will be assessed by changes in the MDS 
UPDRS Part III score and MDS-UPDRS Parts I-IV 
total score at various time points. 
Safety and tolerability: 
Safety and tolerability of study drug will be evaluated 
by vital signs, clinical laboratory measures, ECGs, 
physical examinations, concomitant medication 
usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS and 
MOAA/Sin Part A only. 
Efficacy: 
Part A: 
Improvement in PD motor symptoms and overall 
symptoms will be assessed by changes in the MDS 
UPDRS Part III score and MDS-UPDRS Parts I-IV 
Changes made due 
to update in study 
objectives and 
endpoints for Part B. 


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total score at various time points. 
Part B: 
• 
Improvement in PD tremor as assessed by 
changes in the MDS UPDRS Part II/III tremor 
score (defined as the sum of MDS-UPDRS items 
2.10, 3.15, 3.16, 3.17 and 3.18). 
• 
Improvement in PD motor symptoms as 
assessed by changes in the MDS-UPDRS – Part III 
total score. 
• 
Improvement in PD nonmotor and motor 
aspects of experiences of daily living as assessed by 
the MDS-UPDRS – Part I and Part II scores, 
respectively. 
• 
Improvement in PD overall symptoms as 
assessed by changes in the MDS-UPDRS – Parts I- 
IV total score. 
2. Synopsis, 
Plasma will be collected to assay for concentrations 
Plasma will be collected to assay for concentrations 
Changes made to 
Pharmacokinetics 
of SAGE-217 and possibly SAGE-217 metabolites. 
of SAGE-217 and possibly SAGE-217 metabolites in 
distinguish PK 
The following PK parameters will be derived from 
the plasma concentrations (where evaluable): area 
Part A and Part B. 
Part A: The following PK parameters will be derived 
objectives for Part A 
and Part B 
under the concentration-time curve from time zero 
to infinity (AUC0-∞), maximum plasma 
concentration (Cmax), time to reach maximum 
concentration (tmax), the distributional half-life and 
terminal half-life (t1/2), and steady-state drug 
concentration in the plasma (Css). 
from the plasma concentrations (where evaluable): 
area under the concentration-time curve from time 
zero to infinity (AUC0-∞), maximum plasma 
concentration (Cmax), time to reach maximum 
concentration (tmax), the distributional half-life and 
terminal half-life (t1/2), and steady-state drug 
concentration in the plasma (Css). 


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Part B: Area under the curve (AUC), Cmax, and 
trough concentration (C0h) at steady-state will be 
estimated for each individual using the most 
recent applicable Population PK model. 
2. Synopsis, 
Statistical methods 
Study Populations 
The safety population, defined as all subjects who 
are administered study drug, will be used to provide 
descriptive summaries of safety. 
The efficacy population, defined as all subjects in 
the safety population who receive at least one dose 
of study drug and have at least one postdose MDS- 
UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the 
safety population with sufficient plasma 
concentrations for PK evaluations and will be used 
to summarize PK data. 
Separate populations will be defined for each part of 
the study. 
General Considerations 
Continuous endpoints will be summarized with 
number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from 
baseline values will be calculated at each time point 
and summarized descriptively. For categorical 
Sample Size Calculation 
Approximately 18 subjects will be enrolled in 
Part A. Up to 15 new subjects will be enrolled in 
Part B in order for 10 subjects to complete the 
study (tolerate at least 20 mg SAGE-217 for the 
duration of the dosing period). The sample size 
for Part A and Part B was selected based on 
clinical and not statistical considerations. 
Study Populations 
The safety population, defined as all subjects who are 
administered at least one dose of study drug, will be 
used to provide descriptive summaries of safety. 
The efficacy population, defined as all subjects in the 
safety population who receive at least one dose of 
study drug and have at least one postdose MDS- 
UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the 
safety population with at least one plasma sample 
with sufficient plasma concentrations for PK 
evaluations and will be used to summarize PK data. 
Changes made due 
to update in study 
design for Part B. 


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endpoints, descriptive summaries will include 
counts and percentages. 
Safety Analysis 
Adverse events will be coded using Medical 
Dictionary for Regulatory Activities™ (MedDRA). 
The overall incidence of adverse events will be 
displayed by System Organ Class (SOC), preferred 
term, dose group, and cohort. Incidence of adverse 
events will also be presented by maximum severity 
and relationship to study drug. Vital signs, clinical 
laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and cohort, where 
applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate 
descriptive statistics and other data presentation 
methods where applicable; subject listings will be 
provided for all efficacy data. 
An interim analysis of 10 subjects completing Part 
A is planned to inform Part B study conduct. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized 
using appropriate descriptive statistics and listed by 
subject. 
Separate populations will be defined for each part of 
the study. 
General Considerations 
Continuous endpoints will be summarized with 
number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from 
baseline values will be calculated at each time point 
and summarized descriptively. For categorical 
endpoints, descriptive summaries will include counts 
and percentages. 
Safety Analysis 
Adverse events will be coded using Medical 
Dictionary for Regulatory Activities™ (MedDRA). 
The overall incidence of adverse events will be 
displayed by System Organ Class (SOC), preferred 
term, dose group, and cohorttotal. Incidence of 
adverse events will also be presented by maximum 
severity and relationship to study drug. Vital signs, 
clinical laboratory measures, ECG, and C-SSRS data 
will be summarized by dose group and cohort, where 
applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. 
Subject listings will be provided for all safety data. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate 
descriptive statistics and other data presentation 


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methods where applicable; subject listings will be 
provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A 
is planned to inform Part B study conduct. No 
formal interim analysis for Part B subjects is 
planned. 
Pharmacokinetic Analysis 
Drug concentrations and pPharmacokinetic 
parameters will be summarized using appropriate 
descriptive statistics and listed by subject. 
2. Synopsis, Table 3 
Removed original table with randomized, placebo- 
controlled design and replaced with open-label design 


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5.2 SAGE-217 
(previously 
5.2 SAGE-217 Oral 
Solution) 
5.2. SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the 
GABAA receptor and thus is expected to be of 
benefit for the treatment of ET. Unlike 
benzodiazepines that are selective for the γ-subunit- 
containing subset of GABAA receptors (Pritchett 
1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α- 
subunit, have a wider range of activity (Belelli 
2002). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w 
aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear 
solution. 
5.2. SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the 
GABAA receptor and thus is expected to be of 
benefit for the treatment of ET. Unlike 
benzodiazepines that are selective for the γ-subunit- 
containing subset of GABAA receptors (Pritchett 
1989, Esmaeili 2009), SAGE-217 and other 
neuroactive steroids, which bind to the ubiquitous α- 
subunit, have a wider range of activity (Belelli 2002). 
Two dosage forms of SAGE-217 for oral 
administration will be used in this study (SAGE- 
217 Oral Solution and SAGE-217 Capsules). 
SAGE-217 Oral Solution 6 mg/mL (40% w/w 
aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a nonviscous, clear 
solution. 
Change made to 
accommodate the 
availability of a 
capsule formulation 
SAGE-217 Capsules are available as hard gelatin 
capsules containing a white to off-white powder. 
In addition to the specified amount of SAGE-217 
Drug Substance, active, SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified 
microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. 
5.3.2 Clinical 
To date, two clinical studies employing SAGE-217 
To date, two clinical studies employing SAGE-217 
Change made to 
Experience 
Oral Solution are clinically complete and final 
clinical study reports are pending. Discussions of 
Oral Solution are clinically complete and final 
clinical study reports are pending. Discussions of 
accommodate the 
availability of a 
pharmacokinetic (PK) data are limited to the single- 
pharmacokinetic (PK) data are limited to the single- 
capsule formulation 


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ascending dose, food effect, and essential tremor 
cohorts from Study 217-CLP-101 and the multiple- 
ascending dose and drug-drug interaction cohorts 
from Study 217-CLP-102. Discussions of safety 
data are limited to the single-ascending dose cohorts 
in Study 217-CLP-101 and the multiple-ascending 
dose cohorts in Study 217-CLP-102. 
Study 217-CLP-101 was a first-in-human, four-part 
study that assessed the effects of a single dose of 
SAGE 217. The study was a double-blind, placebo- 
controlled, single-ascending dose design in healthy 
adult volunteers, with the objective of identifying 
the maximum tolerated dose (MTD) and PK profiles 
of SAGE-217 Oral Solution. Subjects in each of the 
single-ascending dose cohorts received a single dose 
of study drug, either SAGE-217 (six subjects) or 
placebo (two subjects), with SAGE-217 doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 
mg, 55 mg, and 66 mg. Escalation to the next dose 
was undertaken only after safety and PK data were 
reviewed by the Safety Review Committee (SRC) 
and agreement reached that it was safe to increase 
the dose. The MTD was determined to be 55 mg. 
Two cohorts, 6 subjects each received SAGE-217 
Oral Solution in an open-label manner (one cohort 
received 50% of the MTD [22 mg] to study the food 
effects and the other cohort received the MTD [55 
mg] to study the effects on subjects with essential 
tremor). SAGE-217 Oral Solution was orally 
bioavailable, demonstrated dose-linear PK from the 
ascending dose, food effect, and essential tremor 
cohorts from Study 217-CLP-101 and the multiple- 
ascending dose and drug-drug interaction cohorts 
from Study 217-CLP-102. Discussions of safety data 
are limited to the single-ascending dose cohorts in 
Study 217-CLP-101 and the multiple-ascending dose 
cohorts in Study 217-CLP-102. In addition, one 
clinical study of the safety, tolerability, PK, and 
relative bioavailability SAGE-217 Capsules is 
clinically complete and the final study report is 
pending. The results of this study (217-CLP-103) 
are briefly described below. 
Study 217-CLP-101 was a first-in-human, four-part 
study that assessed the effects of a single dose of 
SAGE 217 Oral Solution. The study was a double- 
blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective 
of identifying the maximum tolerated dose (MTD) 
and PK profiles of SAGE-217 Oral Solution. 
Subjects in each of the single-ascending dose cohorts 
received a single dose of study drug, either SAGE- 
217 Oral Solution (six subjects) or placebo (two 
subjects), with SAGE-217 Oral Solution doses of 
0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 
mg, 55 mg, and 66 mg. Escalation to the next dose 
was undertaken only after safety and PK data were 
reviewed by the Safety Review Committee (SRC) 
and agreement reached that it was safe to increase the 
dose. The MTD was determined to be 55 mg. Two 
cohorts, 6 subjects each received SAGE-217 Oral 


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lowest (0.25 mg) through the highest (66 mg) dose, 
and supported once daily oral dosing with food. In 
addition, the pharmacodynamic effects of the 
SAGE-217 Oral Solution MTD were assessed in 
placebo-controlled, blinded, crossover 
electroencephalogram cohorts of 8 subjects each; 
one cohort received 50% of the MTD (22 mg) and 
the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that 
assessed the effects of multiple-ascending doses of 
SAGE 217 Oral Solution. The study was a double- 
blind, placebo-controlled, multiple-ascending dose 
study in healthy adult volunteers.  Subjects in each 
of the multiple-ascending dose cohorts received 
study drug, either SAGE-217 (nine subjects) or 
placebo (three subjects), once daily for 7 days, with 
SAGE-217 Oral Solution doses of 15 mg, 30 mg, 
and 35 mg. Escalation to the next dose was 
undertaken only after safety and PK data were 
reviewed by the SRC and agreement reached that it 
was safe to increase the dose. The MTD was 
determined to be 30 mg. It was observed that 
subjects receiving the drug in the evening did better 
in terms of tolerability compared to when they 
received the drug in the morning. A fourth cohort of 
12 subjects received 30 mg of SAGE-217 Oral 
Solution in an open-label manner to study drug-drug 
interactions. SAGE-217 Oral Solution is not likely 
to induce the metabolism of CYP2B6 or CYP3A4 
substrates. SAGE-217 Oral Solution was orally 
Solution in an open-label manner (one cohort 
received 50% of the MTD [22 mg] to study the food 
effects and the other cohort received the MTD [55 
mg] to study the effects on subjects with essential 
tremor). SAGE-217 Oral Solution was orally 
bioavailable, demonstrated dose-linear PK from the 
lowest (0.25 mg) through the highest (66 mg) dose, 
and supported once daily oral dosing with food. In 
addition, the pharmacodynamic effects of the SAGE- 
217 Oral Solution MTD were assessed in placebo- 
controlled, blinded, crossover electroencephalogram 
cohorts of 8 subjects each; one cohort received 50% 
of the MTD (22 mg) and the other received the MTD 
(55 mg). 
Study 217-CLP-102 was a two-part study that 
assessed the effects of multiple-ascending doses of 
SAGE 217 Oral Solution. The study was a double- 
blind, placebo-controlled, multiple-ascending dose 
study in healthy adult volunteers. Subjects in each of 
the multiple-ascending dose cohorts received study 
drug, either SAGE-217 Oral Solution (nine subjects) 
or placebo (three subjects), once daily for 7 days, 
with SAGE-217 Oral Solution doses of 15 mg, 30 
mg, and 35 mg. Escalation to the next dose was 
undertaken only after safety and PK data were 
reviewed by the SRC and agreement reached that it 
was safe to increase the dose. The MTD was 
determined to be 30 mg. It was observed that 
subjects receiving the drug in the evening did better 
in terms of tolerability compared to when they 


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bioavailable and suitable for once daily oral dosing 
at night time with food. 
SAGE-217 Oral Solution was generally well 
tolerated.  In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the 
stopping criteria were met. Most adverse events 
were reported as mild or moderate in intensity, and 
there were no serious adverse events reported in 
either study. In addition, none of the observed 
adverse events resulted in discontinuation of the 
study drug. At doses planned for further study, the 
observed sedation was mild, transient, and 
associated with daily peak exposure. The most 
common treatment-emergent adverse events 
(TEAEs) were sedation, somnolence, dizziness, 
euphoric mood, fatigue, tremor, and muscle 
twitching, reported most frequently in the highest 
dose group (66 mg). Some changes in mean blood 
pressure and heart rate were observed after single 
doses of 44 mg and greater. After multiple doses of 
30 mg (morning [AM] or evening [PM]) or 35 mg 
(AM) over 7 days, there was no evidence of changes 
in mean vital sign measures even though Day 7 
plasma concentrations approximated that of the 
highest single dose in the single-ascending dose 
study. Subjects seemed to tolerate SAGE-217 better 
when given as night time dosing. 
Neuroactive steroids are a class of endogenous and 
synthetic positive allosteric modulators that target 
received the drug in the morning. A fourth cohort of 
12 subjects received 30 mg of SAGE-217 Oral 
Solution in an open-label manner to study drug-drug 
interactions. SAGE-217 Oral Solution is not likely to 
induce the metabolism of CYP2B6 or CYP3A4 
substrates. SAGE-217 Oral Solution was orally 
bioavailable and suitable for once daily oral dosing at 
night time with food. 
SAGE-217 Oral Solution was generally well 
tolerated. In both Phase 1 studies (217-CLP-101 and 
217-CLP-102), doses were escalated until the 
stopping criteria were met. Most adverse events were 
reported as mild or moderate in intensity, and there 
were no serious adverse events reported in either 
study. In addition, none of the observed adverse 
events resulted in discontinuation of the study drug. 
At doses planned for further study, the observed 
sedation was mild, transient, and associated with 
daily peak exposure. The most common treatment- 
emergent adverse events (TEAEs) were sedation, 
somnolence, dizziness, euphoric mood, fatigue, 
tremor, and muscle twitching, reported most 
frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were 
observed after single doses of 44 mg and greater. 
After multiple doses of 30 mg (morning [AM] or 
evening [PM]) or 35 mg (AM) over 7 days, there was 
no evidence of changes in mean vital sign measures 
even though Day 7 plasma concentrations 
approximated that of the highest single dose in the 


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both synaptic and extra-synaptic GABAA receptors 
(Belelli 2002 and confirmed in the Sponsor’s in 
vitro studies). This diverse activity profile suggests 
that neuroactive steroid GABAA receptor-positive 
allosteric modulators could exhibit robust activity 
against essential tremor. Administration of SAGE- 
547 injection, a proprietary formulation of the 
endogenous neuroactive steroid, resulted in 
significant reductions in upper limb kinetic tremor 
scores compared to placebo in a Phase 2 proof‑of‑ 
principle study (IND 122,280). Based on these 
results with SAGE-547, the study design for single- 
ascending dose study 217-CLP-101 included a 
cohort of subjects with essential tremor (N=6) who 
received SAGE-217 Oral Solution (55 mg) in an 
open-label manner. Data from this cohort indicate 
that single doses of SAGE-217 Oral Solution 
resulted in a reduction in the tremor symptoms, 
suggesting that SAGE-217 might be effective in 
treating PD. 
There are no clinical efficacy data of SAGE-217 
Oral Solution in PD, since the present study is the 
first study in this indication. 
single-ascending dose study. Subjects seemed to 
tolerate SAGE-217 Oral Solution better when given 
as night time dosing. 
The safety, tolerability, PK, and relative 
bioavailability of the SAGE-217 Capsules were 
assessed in a Phase 1 randomized, open-label, 
cross-over study (Study 217-CLP-103). In the 
fasted state, SAGE-217 Capsules demonstrated 
reduced exposure in terms of maximum (peak) 
plasma concentration (Cmax) and area under the 
curve from zero to the time of the last quantifiable 
concentration (AUClast) compared to SAGE-217 
Oral Solution. SAGE-217 Capsules administered 
in the fed state (with standard and high-fat meal) 
showed increased exposure compared to the fasted 
state and approximately equivalent exposure in 
terms of geometric mean AUClast compared to 
SAGE-217 Oral Solution; however, the Cmax for 
SAGE-217 Capsules was reduced by 
approximately 50% when compared with SAGE- 
217 Oral Solution. Based on these study results, 
exposures with SAGE-217 Capsules are 
anticipated to be equal to or less than exposures 
observed at the same dose with SAGE-217 Oral 
Solution. 
Neuroactive steroids are a class of endogenous and 
synthetic positive allosteric modulators that target 
both synaptic and extra-synaptic GABAA receptors 
(Belelli 2002 and confirmed in the Sponsor’s in vitro 


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studies). This diverse activity profile suggests that 
neuroactive steroid GABAA receptor-positive 
allosteric modulators could exhibit robust activity 
against essential tremor. Administration of SAGE- 
547 injection, a proprietary formulation of the 
endogenous neuroactive steroid, resulted in 
significant reductions in upper limb kinetic tremor 
scores compared to placebo in a Phase 2 proof‑of‑ 
principle study (IND 122,280). Based on these 
results with SAGE-547, the study design for single- 
ascending dose study 217-CLP-101 included a cohort 
of subjects with essential tremor (N=6) who received 
SAGE-217 Oral Solution (55 mg) in an open-label 
manner. Data from this cohort indicate that single 
doses of SAGE-217 Oral Solution resulted in a 
reduction in the tremor symptoms, suggesting that 
SAGE-217 might be effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral 
Solution or Capsules in PD, since the present study 
is the first study in this indication. 
5.4. Potential Risks 
and Benefits 
Protocol 217-PRK-201 is the first clinical study 
evaluating the efficacy of SAGE-217 Oral Solution 
in PD. Thus, the potential benefits in this population 
are unknown, although the risks are likely to be 
similar to those mentioned in the Investigator’s 
Brochure. GABA compounds that cross the blood- 
brain barrier or increase GABA activity alleviate 
muscle stiffness caused by a lack of GABAergic 
tone (Winkler 1999), validating this receptor as a 
Protocol 217-PRK-201 is the first clinical study 
evaluating the efficacy of SAGE-217 Oral Solution in 
PD. Thus, the potential benefits in this population are 
unknown, although the risks are likely to be similar to 
those mentioned in the Investigator’s Brochure. 
GABA compounds that cross the blood-brain barrier 
or increase GABA activity alleviate muscle stiffness 
caused by a lack of GABAergic tone (Winkler 1999), 
validating this receptor as a therapeutic target. Given 
a) Change made to 
accommodate the 
availability of a 
capsule formulation; 
b) Changes made 
due to update in 
study design for 
Part B. 


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therapeutic target. Given the promising clinical data 
with another neuroactive steroid (SAGE-547) in 
conjunction with the shared broad receptor 
selectivity profile, oral bioavailability, long half-life, 
preclinical evidence of anxiolytic activity, and safety 
data of SAGE-217, it is possible that patients may 
have a clinical benefit at the exposures selected for 
this study. In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have 
been identified to date, an intra-patient dose- 
reduction design has been chosen to permit 
reduction in dose based on tolerability (adverse 
events), specifically sedation, versus treatment 
effect. Each subject will start with an initial dose of 
30 mg; subjects unable to tolerate 30 mg will receive 
20 mg; subjects unable to tolerate 20 mg will receive 
10 mg. The tolerated dose for each subject will be 
the dose taken on Day 7. Subjects who tolerate at 
least the 10 mg dose on Day 7 will be eligible to 
enroll in Part B. Given the high medical need and 
potential for benefit in PD, there is a favorable 
benefit-risk evaluation to investigate SAGE-217 
Oral Solution in PD. 
In conclusion, selection criteria for the proposed 
study take into account the potential safety risks. 
Continuous safety monitoring, and the 
implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the 
potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being 
the promising clinical data with another neuroactive 
steroid (SAGE-547) in conjunction with the shared 
broad receptor selectivity profile, oral bioavailability, 
long half-life, preclinical evidence of anxiolytic 
activity, and safety data of SAGE-217, it is possible 
that patients may have a clinical benefit at the 
exposures selected for this study. 
In the 217-CLP-103 study, SAGE-217 Capsules 
were found to be generally well-tolerated with no 
serious AEs reported during the treatment and 
follow-up periods. The most frequent AE 
observed was sedation that was mild, transient, 
and occurred within 1 to 4 hours following dosing 
and generally dissipated by 8 hours. The clinical 
portion of this study has recently completed; the 
final report is in progress. 
In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have 
been identified to date, an intra-patient dose- 
reduction designs hasve been chosen for Part A and 
Part B to permit reduction in dose based on 
tolerability (adverse events), specifically sedation, 
versus treatment effect. In Part A, Eeach subject 
will start with an initial dose of SAGE-217 Oral 
Solution, 30 mg; subjects unable to tolerate 30 mg 
will receive 20 mg; subjects unable to tolerate 20 mg 
will receive 10 mg. In Part B, each subject will 
receive SAGE-217 in the evening (PM) starting 
with an initial dose of SAGE-217 Capsules, 20 mg 


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taken in order to ensure the safety of the subjects 
who will be enrolled. 
for two days; subjects able to tolerate 20 mg will 
receive 30 mg. If the subject is unable to tolerate 
30 mg, the subject will receive 20 mg and continue 
for the remainder of the dosing period. Subjects 
who cannot tolerate the 20-mg dose at any time 
during Part B will be discontinued and replaced. 
The tolerated dose for each subject in Part A and 
Part B will be the dose taken on Day 7. Subjects 
who tolerate at least the 10 mg dose on Day 7 will be 
eligible to enroll in Part B. Given the high medical 
need and potential for benefit in PD, there is a 
favorable benefit-risk evaluation to investigate 
SAGE-217 Oral Solution in PD. 
In conclusion, selection criteria for the proposed 
study take into account the potential safety risks. 
Continuous safety monitoring, and the 
implementation of a formal dose-reduction and study 
drug discontinuation scheme also have the potential 
to mitigate risk. From a benefit/risk perspective, the 
appropriate measures are being taken in order to 
ensure the safety of the subjects who will be enrolled. 
6.1. Primary 
Objective 
The primary objective of this study is to evaluate the 
safety and tolerability of SAGE-217 Oral Solution. 
The primary objective of this study is to evaluate the 
safety and tolerability of SAGE 217 Oral 
Solution.Part A is 
• 
To evaluate the safety and tolerability of 
SAGE-217 Oral Solution. 
The primary objective of Part B is: 
Changes made due 
to update in study 
design for Part B and 
availability of a 
capsule formulation. 


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• 
To evaluate the effect of SAGE-217 Capsules 
as an adjunct to antiparkinsonian agent(s) on the 
severity of PD tremor symptoms. 
6.2. Secondary 
Objectives 
The secondary objectives of the study are: 
• 
To evaluate the effect of SAGE-217 Oral 
Solution on the severity of PD motor symptoms 
after withdrawal of Levodopa or Carbidopa- 
Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral 
Solution exposure length on the severity of PD 
motor symptoms after withdrawal of 
Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral 
Solution in combination with immediate-release oral 
Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
The secondary objectives of the study Part A are: 
• 
To evaluate the effect of SAGE-217 Oral 
Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa 
(Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral 
Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE 217 Oral 
Solution in combination with immediate release oral 
Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
The secondary objectives of Part B are: 
• 
To evaluate the effect of SAGE-217 Capsules 
as an adjunct to antiparkinsonian agent(s) on 
motor and non-motor symptoms of PD. 
• 
To evaluate the safety and tolerability of 
SAGE-217 Capsules. 
a) Changes made to 
divide the study 
objectives of Part A 
and Part B and make 
efficacy the primary 
objective for Part B; 
b) objectives added 
due to update of 
study design for 
Part B (randomized 
to open-label) and 
availability of 
SAGE-217 Capsule; 
c) added 
Pharmacokinetic 
objectives that were 
inadvertently 
missing from 
previous version 
New section 
6.3. Pharmacokinetic Objectives 
The PK objective of Part A is: 
• 
To assess the PK profile of SAGE-217 Oral 
Solution in plasma samples. 
Section was 
inadvertently 
missing from 
previous version 


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The PK objective of Part B is: 
• 
To assess the PK profile of SAGE-217 
Capsules utilizing a population PK approach. 
6.3.1. Exploratory 
Endpoints 
6.3.1 Primary Endpoints 
• 
Frequency and severity of adverse events and 
changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal 
ideation using the Columbia-Suicide Severity Rating 
Scale (C-SSRS) during both Part A and Part B. 
6.34.1 Primary Endpoints 
Part A: 
• 
Frequency and severity of adverse events and 
changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal 
ideation using the Columbia-Suicide Severity Rating 
Scale (C-SSRS) during both Part A and Part B. In 
addition, sleepiness/sedation as assessed by 
Stanford Sleepiness Scale (SSS) score. 
Part B: 
• 
Improvement in PD tremor as assessed by 
changes in the MDS UPDRS Part II/III tremor 
score (defined as the sum of MDS-UPDRS items 
2.10, 3.15, 3.16, 3.17 and 3.18). 
a) Changes made 
due to division of 
study objectives 
between Part A and 
Part B; b) changes 
made due to update 
in study design for 
Part B 
6.3.2. Secondary 
Endpoints 
6.3.2 Secondary Endpoints 
Part A: 
• 
Improvement in PD motor symptoms as 
assessed by changes in the Movement Disorder 
Society-Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) – Part III (Motor Examination) 
score. 
6.34.2 Secondary Endpoints 
Part A: 
• 
Improvement in PD motor symptoms as assessed 
by changes in the Movement Disorder Society- 
Unified Parkinson's Disease Rating Scale (MDS- 
UPDRS) – Part III (Motor Examination) total score. 
Part B: 
Changes made due 
to update in study 
objectives and 
design for Part B 


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Part B: 
• 
Improvement in PD motor symptoms as 
assessed by changes in the MDS-UPDRS – Part III 
score. 
• 
Improvement in PD overall symptoms as 
assessed by changes in the MDS-UPDRS – Parts I- 
IV total score. 
• 
Sleepiness/sedation as assessed by the Stanford 
Sleepiness Scale (SSS) and Modified Observer's 
Assessment of Analgesia/Sedation (MOAA/S) 
scores. 
• 
Improvement in PD motor symptoms as assessed 
by changes in the MDS-UPDRS – Part III total score. 
• 
Improvement in PD nonmotor and motor 
aspects of experiences of daily living as assessed by 
the MDS-UPDRS – Part I and Part II scores, 
respectively. 
• 
Improvement in PD overall symptoms as 
assessed by changes in the MDS-UPDRS – Parts I-IV 
total score. 
• 
Frequency and severity of adverse events and 
changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and 
suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS). 
• 
Sleepiness/sedation as assessed by the Stanford 
Sleepiness Scale (SSS) and Modified Observer's 
Assessment of Analgesia/Sedation (MOAA/S) scores. 
New section 
6.4.3 Pharmacokinetic Endpoints 
• 
Plasma concentrations of SAGE-217, and 
possibly SAGE-217 metabolites, will be measured, 
and PK parameters will be derived. 
Section was 
inadvertently 
missing from 
previous version 
6.3.3. Exploratory 
Endpoints 
6.3.3. Exploratory Endpoints 
• 
6.34.34. Exploratory Endpoints 
• 
 


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7.1. Overall Study 
This study is a two-part, multicenter, Phase 2 study 
This study is a two-part, multicenter, Phase 2 study to 
Changes made due 
Design 
to evaluate the safety, tolerability, PK, and efficacy 
of SAGE-217 Oral Solution in up to 18 adult 
evaluate the safety, tolerability, PK, and efficacy of 
SAGE-217 Oral Solution. Part A of the study is an 
to update in study 
design for Part B and 
subjects with PD of moderate severity who respond 
open-label design with morning (AM) dosing of 
availability of 
to immediate-release oral Levodopa and are on a 
stable dose. Part A of the study is an open-label 
SAGE-217 Oral Solution for 4 days in in up to 18 
adult subjects with PD of moderate severity who 
SAGE-217 capsule. 
design with morning (AM) dosing of SAGE-217 for 
respond to immediate-release oral Levodopa and are 
4 days. Part B of the study is a randomized, 
placebo-controlled, two-sequence crossover design. 
on a stable dose. Part A of the study is an open label 
design with morning (AM) dosing of SAGE 217 for 
On Days 1 to 4 (Period 1 of crossover), subjects will 
4 days. Part B of the study is a randomized, placebo  
receive open-label Levodopa plus blinded SAGE- 
217 or placebo. On Days 5 to 8 (Period 2 of 
controlled, two sequence crossover design. On Days 
1 to 4 (Period 1 of crossover), subjects will receive 
crossover), all subjects will receive open-label 
open label Levodopa plus blinded SAGE 217 or 
SAGE-217 Oral Solution only.  In Part B, subjects 
will receive their individually established tolerated 
placebo. On Days 5 to 8 (Period 2 of crossover), all 
subjects will receive open label SAGE 217 Oral 
dose of SAGE 217 Oral Solution from Part A. 
Solution only. In Part B, subjects will receive their 
Subjects will be exposed to SAGE-217 for up to 12 
days (4 days in Part A and up to 8 days in Part B) 
individually established tolerated dose of SAGE 217 
Oral Solution from Part A.  Subjects will be exposed 
and will be followed for an additional 7 days in Part 
to SAGE 217 for up to 12 days (4 days in Part A and 
A and an additional 14 days in Part B after the 
administration of the last dose. 
up to 8 days in Part B) and will be followed for an 
additional 7 days in Part A and an additional 14 days 
There are two parts to the study: 
• 
Part A: Open-label with AM dosing (4 days). 
in Part B after the administration of the last dose. 
Part B of the study is an open-label design with 
evening (PM) dosing of SAGE-217 Capsules for 7 
All subjects will continue to take their 
antiparkinsonian agents including immediate-release 
oral Levodopa on the day of admission (Day -1) and 
days in up to 15 adult subjects with PD. Subjects 
that participate in Part A are not eligible to 
participate in Part B. Subjects will be followed for 


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in the AM only the following 3 days (Days 1 to 3). 
All subjects will stop their immediate-release oral 
Levodopa on Day 4 and will start on a 30 mg dose 
of SAGE-217 Oral Solution administered in the 
morning with food, as outlined in Section 9.1.1. 
Subjects not tolerating 30 mg will receive 20 mg, 
and subjects not tolerating 20 mg will receive 10 mg 
on subsequent days (Section 7.4). The dose  
received on Day 7 will be defined as the tolerated 
dose for that subject. Subjects not tolerating 10 mg 
will not be able to continue in the study and may be 
replaced. Subjects will be followed for an additional 
7 days (Day 14) after the administration of the last 
dose. Levodopa treatment will be resumed on Day 8 
and continue through Day 14. 
Rescue treatment (oral Levodopa or other 
antiparkinsonian agent at Investigator’s discretion) 
will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of 
SAGE-217 Oral Solution for each subject and to 
assess whether SAGE-217 exhibits efficacy in 
subjects with PD of moderate severity in order to 
inform the conduct of Part B. 
• 
Part B: Randomized, placebo-controlled, two- 
sequence crossover with AM dosing (up to 8 days). 
Part B will be initiated only after review of the Part 
A interim analysis. 
an additional 7 days after the administration of 
the last dose in Part A and Part B. 
There are two parts to the study: 
• 
Part A: Open-label with AM dosing of SAGE- 
217 Oral Solution (4 days). 
All subjects will continue to take their 
antiparkinsonian agents including immediate-release 
oral Levodopa on the day of admission (Day -1) and 
in the AM only the following 3 days (Days 1 to 3). 
All subjects will stop their immediate-release oral 
Levodopa on Day 4 and will start on a 30 mg dose of 
SAGE-217 Oral Solution administered in the 
morning with food, as outlined in Section 9.1.1. 
Subjects not tolerating 30 mg will receive 20 mg, and 
subjects not tolerating 20 mg will receive 10 mg on 
subsequent days (Section 7.4). The dose received on 
Day 7 will be defined as the tolerated dose for that 
subject. Subjects not tolerating 10 mg will not be 
able to continue in the study and may be replaced. 
Subjects will be followed for an additional 7 days 
(Day 14) after the administration of the last dose. 
Levodopa treatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment (oral Levodopa or other 
antiparkinsonian agent at Investigator’s discretion) 
will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of 
SAGE-217 Oral Solution for each subject and to 


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In order to qualify for Part B of the study, a subject 
must have tolerated a dose of at least 10 mg of 
SAGE-217 Oral Solution in Part A. Subjects who 
complete Part A will be re-admitted on Day -1 of 
Part B and they will receive their antiparkinsonian 
agent including immediate-release oral Levodopa. 
Subjects will be randomized the next day (Day 1) in 
a 1:1 manner to open-label Levodopa plus blinded 
SAGE-217 Oral Solution or placebo during Period 1 
of the crossover. All doses of SAGE-217 Oral 
Solution (or placebo) will be administered in the 
morning with food as outlined in Section 9.1.2. 
Subjects randomized to the Levodopa plus placebo 
arm will receive Levodopa and SAGE 217 placebo 
oral solution in the AM for the first 4 days (Days 1 
to 4). Subjects randomized to the combination arm 
of Levodopa and SAGE-217 Oral Solution will 
receive this combination in the AM for the first 4 
days (Days 1 to 4). On Day 5, all subjects will 
crossover to Period 2 and will only receive open- 
label SAGE-217 Oral Solution for the remaining 4 
days (Days 5 to 8). Subjects will receive their 
individually established tolerated dose of SAGE-217 
Oral Solution (from Part A). All subjects will be 
able to resume Levodopa from Day 9 onwards. 
Rescue treatment (at Investigator’s discretion) will 
be allowed, if needed, on all days (Days 1 to 8). 
Reductions in dose of SAGE-217 will be allowed 
during both parts of the study (Parts A and B). If at 
assess whether SAGE-217 exhibits efficacy in 
subjects with PD of moderate severity in order to 
inform the conduct of Part B. 
• 
Part B: Randomized, placebo controlled, two 
sequence crossover with AM dosing (up to 8 days). 
Part B will be initiated only after review of the Part A 
interim analysis. 
In order to qualify for Part B of the study, a subject 
must have tolerated a dose of at least 10 mg of 
SAGE 217 Oral Solution in Part A. Subjects who 
complete Part A will be re admitted on Day 1 of Part 
B and they will receive their antiparkinsonian agent 
including immediate release oral Levodopa. Subjects 
will be randomized the next day (Day 1) in a 1:1 
manner to open label Levodopa plus blinded SAGE 
217 Oral Solution or placebo during Period 1 of the 
crossover. All doses of SAGE 217 Oral Solution (or 
placebo) will be administered in the morning with 
food as outlined in Section 9.1.2. Subjects 
randomized to the Levodopa plus placebo arm will 
receive Levodopa and SAGE 217 placebo oral 
solution in the AM for the first 4 days (Days 1 to 4). 
Subjects randomized to the combination arm of 
Levodopa and SAGE 217 Oral Solution will receive 
this combination in the AM for the first 4 days (Days 
1 to 4). On Day 5, all subjects will crossover to 
Period 2 and will only receive open label SAGE 217 
Oral Solution for the remaining 4 days (Days 5 to 8). 
Subjects will receive their individually established 


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any time the dose is not tolerated, assessed by 
occurrence of a severe adverse event judged by the 
Investigator to be related to study drug, the dose on 
the next day must be reduced to the next lowest dose 
and continued for the remainder of the dosing period 
(ie, subjects who are unable to tolerate the 30 mg 
dose will receive a dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will receive a 10 mg 
dose on subsequent days). The dose on Day 7 of the 
dosing period in Part A will be determined to be the 
tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects will be exposed to SAGE-217 for up to 12 
days (4 days in Part A and up to 8 days in Part B) 
and will be followed for an additional 7 days in Part 
A and an additional 14 days in Part B after the 
administration of the last dose. 
The study designs of Part A and Part B are displayed 
in Figure 1 and Figure 2, respectively. Assessments 
will be performed periodically during the study as 
outlined in the Schedule of Events for Part A and 
Part B (Table 2 and Table 3, respectively). 
tolerated dose of SAGE 217 Oral Solution (from Part 
A). All subjects will be able to resume Levodopa 
from Day 9 onwards. 
Rescue treatment (at Investigator’s discretion) will be 
allowed, if needed, on all days (Days 1 to 8). 
Reductions in dose of SAGE 217 will be allowed 
during both parts of the study (Parts A and B). If at 
any time the dose is not tolerated, assessed by 
occurrence of a severe adverse event judged by the 
Investigator to be related to study drug, the dose on 
the next day must be reduced to the next lowest dose 
and continued for the remainder of the dosing period 
(ie, subjects who are unable to tolerate the 30 mg 
dose will receive a dose of 20 mg, and subjects who 
are unable to tolerate 20 mg will receive a 10 mg 
dose on subsequent days). The dose on Day 7 of the 
dosing period in Part A will be determined to be the 
tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects will be exposed to SAGE 217 for up to 12 
days (4 days in Part A and up to 8 days in Part B) and 
will be followed for an additional 7 days in Part A 
and an additional 14 days in Part B after the 
administration of the last dose. Open-label with PM 
dosing of SAGE-217 Capsules, for 7 days, as an 
adjunct to antiparkinsonian agent(s). 
Subjects on a stable dose of antiparkinsonian 
agent(s) will continue taking them for the duration 


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of the study. Anticholinergics and/or amantadine 
will be discontinued by Day -6 and Day -10, 
respectively. 
Screening may occur between Day -28 and Day -2, 
but subjects must be admitted on Day -1 for 
selected pre-dose assessments (e.g., clinical 
laboratory assessments, assessment of tremor). 
All subjects will take SAGE-217 Capsules, 20 mg, 
at 8PM on Days 1 and 2. On Day 3, subjects 
tolerating the initial dose (i.e., those who do not 
experience a severe adverse event judged by the 
Investigator to be related to study drug) will 
receive a dose increase (SAGE 217, 30 mg), at 
8PM and continuing each subsequent evening at 
8PM for the remainder of the dosing period 
(ending on Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose 
is not tolerated, assessed by occurrence of a severe 
adverse event judged by the Investigator to be 
related to study drug, the dose on the next day 
must be reduced to 20 mg and continued for the 
remainder of the dosing period. Subjects who 
cannot tolerate the 20-mg dose at any time will be 
discontinued and replaced. 
All doses of SAGE-217 will be administered with 
food as outline in Section 9.1.2. For 
antiparkinsonian agents, administration with or 


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without food will be determined by the 
Investigator. 
Subjects will receive SAGE-217 for up to 7 days 
and will be followed for an additional 7 days after 
the administration of the last dose. 
The study designs of Part A and Part B are displayed 
in Figure 1 and Figure 2, respectively. Assessments 
will be performed periodically during the study as 
outlined in the Schedule of Events for Part A and Part 
B (Table 2 and Table 3, respectively). 
7.3. Treatment 
Assignment 
SAGE-217 will be administered in the morning with 
food in Parts A and B. Food intake will be 
standardized as specified by the Sponsor. If subjects 
are taking Levodopa as opposed to Carbidopa- 
Levodopa, administration with or without food will 
be determined by the Investigator. 
Part A of the study is open-label. Part B of the study 
is randomized, placebo-controlled, two-sequence 
crossover. Subjects will be randomly assigned in a 
1:1 manner to receive open-label Levodopa plus 
blinded SAGE 217 Oral Solution or placebo for 4 
days (Days 1 to 4, Period 1 of crossover). Subjects, 
clinicians, and the study team will be blinded to 
treatment allocation. The pharmacist, who will 
prepare the oral solutions according to the 
randomization schedule, will be unblinded. For the 
remaining 4 days of Part B (Days 5 to 8, Period 2 of 
crossover), all subjects will discontinue Levodopa 
SAGE-217 will be administered in the morning with 
food in Parts A and B. Food intake will be 
standardized as specified by the Sponsor. If subjects 
are taking Levodopa as opposed to Carbidopa 
Levodopaantiparkinsonian agent(s), administration 
with or without food will be determined by the 
Investigator. 
Parts A and B of the study isare open-label. Part B 
of the study is randomized, placebo controlled, two 
sequence crossover. Subjects will be randomly 
assigned in a 1:1 manner to receive open label 
Levodopa plus blinded SAGE 217 Oral Solution or 
placebo for 4 days (Days 1 to 4, Period 1 of 
crossover). Subjects, clinicians, and the study team 
will be blinded to treatment allocation. The 
pharmacist, who will prepare the oral solutions 
according to the randomization schedule, will be 
unblinded. For the remaining 4 days of Part B (Days 
Changes made due 
to update in study 
design for Part B 


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and will receive their individually established 
tolerated dose of SAGE-217 Oral Solution from Part 
A in an open-label manner. 
Dose reductions for lack of tolerability will be 
allowed during both parts of the study (Section 7.4). 
5 to 8, Period 2 of crossover), all subjects will 
discontinue Levodopa and will receive their 
individually established tolerated dose of SAGE 217 
Oral Solution from Part A in an open label manner. 
Dose reductions for lack of tolerability will be 
allowed during both parts of the study (Section 7.4). 
7.4. Dose Adjustment 
Criteria 
Dose reductions of SAGE-217 for lack of 
tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part 
A, as determined by the Investigator, the dose on the 
next day will be reduced to the next lowest dose (ie, 
subjects who are unable to tolerate the 30 mg dose 
will receive a dose of 20 mg, and subjects who are 
unable to tolerate 20 mg will receive a 10 mg dose 
on subsequent days). The dose received on Day 7 of 
Part A will be determined to be the tolerated dose 
for that subject, with this dose to be used as the 
starting dose for Part B for that subject 
Dose reductions of SAGE-217 for lack of tolerability 
will be allowed during both parts of the study. If at 
any time the dose is not tolerated in Part A, as 
determined by the Investigator, the dose on the next 
day will be reduced to the next lowest dose (ie, 
subjects who are unable to tolerate the 30 mg dose 
will receive a dose of 20 mg, and subjects who are 
unable to tolerate 20 mg will receive a 10 mg dose on 
subsequent days).  The dose received on Day 7 of 
Part A will be determined to be the tolerated dose for 
that subject, with this dose to be used as the starting 
dose for Part B for that subjectIn Part B, subjects 
tolerating the initial 20-mg dose on Days 1 and 2 
will receive a 30-mg dose on Day 3 and continue 
for the remainder of the dosing period. If on Day 
3 or any time thereafter, the 30-mg dose is not 
tolerated, the dose on the next day must be 
reduced to 20 mg and continued for the remainder 
of the dosing period. 
Changes made due 
to update in study 
design for Part B 


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Section Number and 
Title 
Original Text: 
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Rationale: 
Figure 1 footnote 
NOTE: In order to qualify for Part B of the study, a 
subject must tolerate a dose of at least 10 mg of 
SAGE-217 Oral Solution in Part A. 
removed 
Removed due to 
update in study 
design for Part B 
Figure 2 
updated 
Updated figure to 
reflect new study 
design for Part B 
Section 8. Selection 
and Withdrawal of 
Subjects 
It is anticipated that up to 18 subjects will be 
enrolled in Part A at up to 4 study centers.  All of 
the following inclusion and exclusion criteria will be 
applied during screening for Part A, with some of 
the criteria applied during screening for Part B, as 
indicated. 
It is anticipated that up to 18 subjects will be enrolled 
in Part A at up to 4 study centers. All of the 
following inclusion and exclusion criteria will be 
applied during screening for Part A, with some of the 
criteria applied during screening for Part B, as 
indicated. 
Not applicable with 
updated study design 
for Part B. 
8.3. Entrance Criteria 
for Part B 
Removed section 
Not applicable with 
updated study design 
for Part B. 
8.4. (previously 8.3.) 
Subject Withdrawal 
Criteria 
Subjects may be withdrawn from the study if there is 
concern for the subject’s safety or it is determined 
that the subject is no longer a qualified participant. 
Any subject who is withdrawn from the study for 
any reason is to have the final visit assessments 
performed. 
Subjects may be withdrawn from the study if there is 
concern for the subject’s safety or it is determined 
that the subject is no longer a qualified participant. 
Subjects who cannot tolerate the 10-mg dose at 
any time during Part A or the 20-mg dose at any 
time during Part B will be withdrawn. Any subject 
who is withdrawn from the study for any reason is to 
have the final visit assessments performed. 
Change made due to 
update in study 
design for Part B. 


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Section Number and 
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Original Text: 
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Rationale: 
9.1. Description of 
Study Drug 
9.1. Description of Study Drug 
For ease of discussion, Levodopa alone or 
Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
9.1. Description of Study Drug Treatment 
For ease of discussion, Levodopa alone or Carbidopa- 
Levodopa combination will be referred to as 
Levodopa in this protocol. All doses of SAGE-217 
(Oral Solution or Capsule) will be administered 
with food. 
Change made due to 
availability of 
SAGE-217 Capsule 
9.1.1. Part A 
Subjects participating in Part A of the study will 
take study drug (SAGE-217) in an open-label 
Subjects participating in Part A of the study will take 
study drug (SAGE-217) Oral Solution in an open- 
Changes made to 
distinguish between 
manner. All subjects will continue to take their 
label manner. All subjects will continue to take their 
SAGE-217 Oral 
antiparkinsonian agents including immediate-release 
oral Levodopa on the day of admission (Day -1) and 
antiparkinsonian agents including immediate-release 
oral Levodopa on the day of admission (Day -1) and 
Solution and 
Capsule, due to 
in the AM only the following 3 days (Days 1 to 3). 
in the AM only the following 3 days (Days 1 to 3). 
availability and use 
On the morning of Day 4, subjects will stop their 
immediate-release oral Levodopa and take SAGE- 
On the morning of Day 4, subjects will stop their 
immediate-release oral Levodopa and take SAGE- 
of Capsule in Part B. 
217 for 4 days (Days 4 to 7) in the AM with food. 
217 for 4 days (Days 4 to 7) in the AM with food. 
On Day 4, subjects will receive a 30 mg dose of 
SAGE-217. Subjects not tolerating 30 mg will 
On Day 4, subjects will receive a 30 mg dose of 
SAGE-217. Subjects not tolerating 30 mg will 
receive 20 mg the next day, and subjects not 
receive 20 mg the next day, and subjects not 
tolerating 20 mg will receive 10 mg the next day. 
The dose received on Day 7 will be defined as the 
tolerating 20 mg will receive 10 mg the next day. 
The dose received on Day 7 will be defined as the 
tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects not tolerating 10 mg will not be able to 
Subjects not tolerating 10 mg will not be able to 
continue in the study and may be replaced. 
continue in the study and may be replaced. Levodopa 
Levodopa treatment will be resumed on Day 8 and 
treatment will be resumed on Day 8 and continue 
continue through Day 14. 
through Day 14. 


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9.1.1. Part B 
In order to qualify for Part B of the study, a subject 
must tolerate a dose of at least 10 mg of SAGE-217 
Oral Solution. On Day 1 of Part B, subjects will be 
randomized in a 1:1 manner to open-label Levodopa 
plus blinded SAGE-217 Oral Solution or placebo. 
• 
Subjects randomized to the Levodopa plus 
placebo arm will receive Levodopa plus SAGE-217 
placebo oral solution in the AM for the first 4 days 
(Days 1 to 4). 
• 
Subjects randomized to the Levodopa plus 
SAGE-217 Oral Solution arm will receive this 
combination in the AM for the first 4 days (Days 1 
to 4). Subjects will receive their individually 
established tolerated dose of SAGE-217 Oral 
Solution from Part A. 
• 
On Day 5, all subjects will crossover to Period 2 
and will only receive open-label SAGE-217 Oral 
Solution for the remaining 4 days (Days 5 to 8). 
Subjects will receive their individually established 
tolerated dose of SAGE-217 Oral Solution from Part 
A. 
• 
All subjects will be able to resume Levodopa 
from Day 9 onwards. 
In order to qualify for Part B of the study, a subject 
must tolerate a dose of at least 10 mg of SAGE 217 
Oral Solution. On Day 1 of Part B, subjects will be 
randomized in a 1:1 manner to open label Levodopa 
plus blinded SAGE 217 Oral Solution or placebo. 
• 
Subjects randomized 
to the Levodopa plus placebo arm will receive 
Levodopa plus SAGE 217 placebo oral solution in 
the AM for the first 4 days (Days 1 to 4). 
• 
Subjects randomized 
to the Levodopa plus SAGE 217 Oral Solution arm 
will receive this combination in the AM for the first 4 
days (Days 1 to 4). Subjects will receive their 
individually established tolerated dose of SAGE 217 
Oral Solution from Part A. 
• 
On Day 5, all subjects 
will crossover to Period 2 and will only receive open 
label SAGE 217 Oral Solution for the remaining 4 
days (Days 5 to 8). Subjects will receive their 
individually established tolerated dose of SAGE 217 
Oral Solution from Part A. 
• 
All subjects will be 
able to resume Levodopa from Day 9 onwards. 
Subjects participating in Part B of the study will 
take SAGE-217 Capsules in an open-label manner. 
Subjects on a stable dose of antiparkinsonian 
agent(s) will continue taking them for the duration 
Changes made due 
to update in study 
design for Part B. 


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of the study. All subjects will receive SAGE-217, 
20 mg, at 8PM on Days 1 and 2. On Day 3, 
subjects tolerating the initial dose (i.e., those who 
do not experience a severe adverse event judged 
by the Investigator to be related to study drug) 
will receive a dose increase (SAGE-217, 30 mg), at 
8PM, continuing each subsequent evening at 8PM 
for the remainder of the dosing period (ending on 
Day 7). 
If on Day 3 or any time thereafter, the 30-mg dose 
is not tolerated, assessed by occurrence of a severe 
adverse event judged by the Investigator to be 
related to study drug, the dose on the next day 
must be reduced to 20 mg and continued for the 
remainder of the dosing period. Subjects who 
cannot tolerate the 20-mg dose at any time will be 
discontinued and replaced. 
9.2.2. Prohibited 
Medications 
Subjects who have used any known strong inhibitors 
and/or inducers of CYP3A4 within the 14 days or 5 
half-lives (whichever is longer) or consumed 
grapefruit juice, grapefruit, Seville oranges, or St. 
John's Wort or products containing these within 30 
days prior to receiving the first dose of study drug 
are to be excluded from the study; these 
medications/products are prohibited during the 
study. 
The anticholinergic drug classes listed in Appendix 
3 and amantadine are not permitted in the 5 days 
Subjects who have used any known strong inhibitors 
and/or inducers of CYP3A4 within the 14 days or 5 
half-lives (whichever is longer) or consumed 
grapefruit juice, grapefruit, Seville oranges, or St. 
John's Wort or products containing these within 30 
days prior to receiving the first dose of study drug are 
to be excluded from the study; these 
medications/products are prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 
and amantadine are not permitted in the 5 days prior 
to the admission visit (Day -1) of each part of the 
Changes made to 
distinguish between 
Part A and Part B 
and to reflect update 
study design for 
Part B. 


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prior to the admission visit (Day -1) of each part of 
the study. The list provides non-exhaustive 
examples of each drug class. 
studyPart A and Part B. The list provides non- 
exhaustive examples of each drug class. 
Amantadine is not permitted in the 5 days prior to 
the admission visit of Part A or 9 days prior to the 
admission visit of Part B. 
The tremorogenic drugs listed in Appendix 4 are 
not permitted in the 14 days prior to the admission 
visit of Part B. 
9.3. Treatment 
Compliance 
Study drug (SAGE-217 or matched placebo) will be 
prepared by the site pharmacist. 
Study drug (SAGE-217 Oral Solution or matched 
placeboCapsule) will be prepared by the site 
pharmacist. 
Changes made to 
reflect change in 
study design for Part 
B (no longer 
placebo-controlled) 
and accommodate 
availability of 
SAGE-217 Capsule. 
9.4. Randomization 
and Blinding 
Part A of the study is open-label. 
In Part B is a randomized, placebo-controlled, two- 
sequence crossover study. Subjects will be 
randomly assigned in a 1:1 manner to one of two 
treatment groups: open-label Levodopa plus blinded 
SAGE 217 Oral Solution or placebo oral solution. 
Subjects, clinicians, and the study team will be 
blinded to treatment allocation. The pharmacist, 
who will prepare the oral solutions according to the 
randomization schedule, will be unblinded. 
Not applicable; Part A and Part B of the study isare 
open-label. 
In Part B is a randomized, placebo controlled, two 
sequence crossover study. Subjects will be randomly 
assigned in a 1:1 manner to one of two treatment 
groups: open label Levodopa plus blinded SAGE 217 
Oral Solution or placebo oral solution. Subjects, 
clinicians, and the study team will be blinded to 
treatment allocation. The pharmacist, who will 
Changes made to 
reflect change in 
study design for Part 
B (no longer 
randomized, 
placebo-controlled). 


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Original Text: 
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During the study, the blind is to be broken only 
when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment 
received. Unless a subject is at immediate risk, the 
Investigator must make diligent attempts to contact 
the Sponsor prior to unblinding the study treatment 
administered to a subject. Any request from the 
Investigator about the treatment administered to 
study subjects must be discussed with the Sponsor. 
If the unblinding occurs without the Sponsor’s 
knowledge, the Investigator must notify the Sponsor 
as soon as possible and no later than the next 
business morning. All circumstances surrounding a 
premature unblinding must be clearly documented in 
the source records. Unless a subject is at immediate 
risk, any request for the unblinding of individual 
subjects must be made in writing to the Sponsor and 
approved by the appropriate Sponsor personnel, 
according to standard operating procedures. The 
blinding of the study will be broken after the 
database has been locked. Electronic copies of the 
randomization code will be made available to the 
laboratory performing the bioanalytical analyses in 
order to allow for limited analysis of samples from 
subjects receiving placebo. 
In all cases where the study drug allocation for a 
subject is unblinded, pertinent information must be 
documented in the subject’s records and on the 
electronic case report form (eCRF). If the subject or 
study center personnel (other than pharmacist) have 
prepare the oral solutions according to the 
randomization schedule, will be unblinded. 
During the study, the blind is to be broken only when 
the safety of a subject is at risk and the treatment plan 
is dependent on the study treatment received. Unless 
a subject is at immediate risk, the Investigator must 
make diligent attempts to contact the Sponsor prior to 
unblinding the study treatment administered to a 
subject. Any request from the Investigator about the 
treatment administered to study subjects must be 
discussed with the Sponsor. If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator 
must notify the Sponsor as soon as possible and no 
later than the next business morning. All 
circumstances surrounding a premature unblinding 
must be clearly documented in the source records. 
Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in 
writing to the Sponsor and approved by the 
appropriate Sponsor personnel, according to standard 
operating procedures. The blinding of the study will 
be broken after the database has been locked. 
Electronic copies of the randomization code will be 
made available to the laboratory performing the 
bioanalytical analyses in order to allow for limited 
analysis of samples from subjects receiving placebo. 
In all cases where the study drug allocation for a 
subject is unblinded, pertinent information must be 
documented in the subject’s records and on the 


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been unblinded, the subject will be terminated from 
the study. 
electronic case report form (eCRF). If the subject or 
study center personnel (other than pharmacist) have 
been unblinded, the subject will be terminated from 
the study. 
10.1. Study Drug 
10.1. Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL 
stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% 
sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dosages. The 6 
mg/mL stock SAGE-217 Oral Solution will be 
compounded from SAGE-217 Drug Substance 
Powder in the Bottle and Excipient(s) in the Bottle 
(manufactured under current Good Manufacturing 
Practice [GMP] conditions 
) and 
further admixed at the clinical site in preparation for 
dosing.  Placebo will be matched to SAGE-217 
study drug. Detailed instructions for study drug 
preparation will be provided in the Pharmacy 
Manual. 
10.1. Study Drug 
10.1.1. SAGE-217 Oral Solution 
SAGE-217 Oral Solution is available as a 6 mg/mL 
stock aqueous solution of SAGE-217 Drug Substance 
containing 40% HPβCD and 0.0025% sucralose, 
which is further diluted with Sterile Water for 
Injection to achieve the selected dosages. The 6 
mg/mL stock SAGE-217 Oral Solution will be 
compounded from SAGE-217 Drug Substance 
Powder in the Bottle and Excipient(s) in the Bottle 
(manufactured under current Good Manufacturing 
Practice [GMP] conditions 
) and further 
admixed at the clinical site in preparation for dosing. 
Placebo will be matched to SAGE 217 study drug. 
Detailed instructions for study drug preparation will 
be provided in the Pharmacy Manual. 
a) Change made to 
accommodate the 
availability of a 
capsule formulation; 
b) Change made to 
reflect change in 
study design for Part 
B (no longer 
placebo-controlled). 
The Sponsor will not provide Levodopa or 
Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa- 
Levodopa. 
The Sponsor will not provide Levodopa or 
Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa- 
Levodopa. 


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Section Number and 
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Original Text: 
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Rationale: 
10.1.2. SAGE-217 
10.1.2. SAGE-217 Capsule 
Change made to 
Capsules (new 
section) 
SAGE-217 Capsules are available as hard gelatin 
capsules containing a white to off-white powder. 
In addition to the specified amount of SAGE-217 
accommodate the 
availability of a 
capsule formulation 
Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified 
microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. Capsules will be available 
in 5-mg, 10-mg and 20-mg dose strengths. 
Subjects will be administered two capsules per 
dose. Detailed instructions for study drug 
preparation will be provided in the Pharmacy 
Manual. 
10.2. Study Drug 
The composition and pharmaceutical quality of the 
The composition and pharmaceutical quality of the 
Change made to 
Packaging and 
investigational product will be maintained according 
investigational product will be maintained according 
accommodate the 
Labeling 
to the current GMP and Good Clinical Practice 
(GCP) guidelines and available for review in the 
to the current GMP and Good Clinical Practice 
(GCP) guidelines and available for review in the 
availability of a 
capsule formulation 
study medication documentation. Study drug will 
be provided to the site as powder in the bottle and 
excipient(s) in the bottle units to be compounded in 
study medication documentation. Study drugSAGE- 
217 Oral Solution will be provided to the site as 
powder in the bottle and excipient(s) in the bottle 
the pharmacy at a volume of 125 mL of a 6 mg/mL 
units to be compounded in the pharmacy at a volume 
stock solution and then further diluted to 
approximately 40 mL at the identified doses. Study 
of 125 mL of a 6 mg/mL stock solution and then 
further diluted to approximately 40 mL at the 
drug labels with all required information and 
identified doses. SAGE-217 Capsules will be 
conforming to all applicable Code of Federal 
Regulations and GMP/GCP guidelines will be 
provided to the site in appropriately labeled 
bottles. Study drug labels with all required 
prepared by the clinical research organization. 
information and conforming to all applicable Code of 


Protocol 217-PRK-201 
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Section Number and 
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Original Text: 
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Rationale: 
Federal Regulations and GMP/GCP guidelines will 
be prepared by the clinical research organization. 
10.3. Study Drug 
Upon receipt of study drug (SAGE-217 Oral 
Upon receipt of study drug (SAGE-217 Oral Solution 
a) Change made to 
Storage 
Solution and placebo oral solution), the Investigator 
or designee will inspect the materials and complete 
and placebo oral solution), the Investigator or 
designee will inspect the materials and complete and 
accommodate the 
availability of a 
and return the acknowledgment of receipt form 
return the acknowledgment of receipt form enclosed 
capsule formulation; 
enclosed with the parcel. A copy of the signed 
receipt will be kept in the study files. 
with the parcel. A copy of the signed receipt will be 
kept in the study files. 
b) Changes made to 
reflect change in 
The study drug materials for SAGE-217 Oral 
Solution and placebo oral solution must be carefully 
stored at the temperature specified in the Pharmacy 
The study drug materials for SAGE-217 Oral 
Solution and placebo oral solution must be carefully 
stored at the temperature specified in the Pharmacy 
study design for Part 
B (no longer 
placebo-controlled). 
Manual (eg, clinical dosing solutions stored at 
Manual (eg, clinical dosing solutions stored at 
approximately 2 to 8°C for 11 days with 24 hours of 
room temperature excursions allowed after 
approximately 2 to 8°C for 11 days with 24 hours of 
room temperature excursions allowed after 
preparation), safely and separately from other drugs. 
preparation), safely and separately from other drugs. 
SAGE-217 Capsules may be stored at room 
temperature. 
10.4. Study Drug 
Each bottle of SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL 
Change made to 
Preparation 
will be compounded at the clinical pharmacy from 
components manufactured 
and 
will be compounded at the clinical pharmacy from 
components manufactured 
and 
accommodate the 
availability of a 
supplied by the Sponsor per the directions provided 
supplied by the Sponsor per the directions provided 
capsule formulation 
in the Pharmacy Manual.  The batch formula for a 
125 mL solution of the 6 mg/mL stock solution is 
in the Pharmacy Manual.  The batch formula for a 
125 mL solution of the 6 mg/mL stock solution is 
shown in Table 5. 
shown in Table 5. 
Table 5: Batch Formula for 125 mL of Stock SAGE- 
Table 5: Batch Formula for 125 mL of Stock SAGE- 
217 Oral Solution 6 mg/mL 
217 Oral Solution 6 mg/mL 


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Additional excipients may be utilized in placebo to 
match the taste of SAGE-217 Oral Solution. They 
include sucrose octaacetate, tannic acid, and 
ammonium glycyrrhizate. The quantities may vary 
depending on the dose of SAGE-217. 
Additional excipients may be utilized in placebo to 
match the taste of SAGE 217 Oral Solution. They 
include sucrose octaacetate, tannic acid, and 
ammonium glycyrrhizate. The quantities may vary 
depending on the dose of SAGE 217. 
For the capsule formulation, subjects will swallow 
two capsules per dose with food. 
10.5. Administration 
SAGE-217 Oral Solution or placebo oral solution 
SAGE-217 Oral Solution or placebo oral solution will 
a) Change made to 
accommodate the 
availability of a 
capsule formulation; 
b) Changes made to 
reflect change in 
study design for Part 
B (no longer 
placebo-controlled 
and no longer 
morning dosing). 
will be administered in the morning with food. 
be administered with food in the morning with 
Doses of SAGE-217 and placebo for SAGE-217 will 
be prepared as an approximate 40 mL oral solution 
foodin Part A and in the evening in Part B. 
Doses of SAGE-217 and placebo for SAGE 217Oral 
to be swallowed all at once, followed by 
Solution will be prepared as an approximate 40 mL 
approximately 200 mL of water that has been used 
to rinse the dosing bottle. The start time of 
oral solution to be swallowed all at once, followed by 
approximately 200 mL of water that has been used to 
swallowing the approximately 40 mL oral solution is 
rinse the dosing bottle. The start time of swallowing 
time zero for all assessments. Subjects may have 
assistance from the clinic staff when taking the 
the approximately 40 mL oral solution is time zero 
for all assessments. Subjects may have assistance 
study drug. 
from the clinic staff when taking the study drug. 
During Confinement, each subject’s 
antiparkinsonian agents, including Levodopa or 
During Confinement, each subject’s antiparkinsonian 
agents, including Levodopa or Carbidopa-Levodopa, 
Carbidopa-Levodopa, will be administered by site 
will be administered by site personnel according to 
personnel according to the site’s standard operating 
the site’s standard operating procedures. 
procedures. 
10.6. Study Drug 
Accountability 
The study drug provided is for use only as directed 
in this protocol. 
The study drug provided is for use only as directed in 
this protocol. 
Changes made to 
reflect change in 
study design for Part 


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The Investigator or designee must maintain a record 
of all study drug received, used, and discarded. It 
must be clear from the records which subject 
received which dose of active or placebo treatment. 
The Sponsor will be permitted access to the study 
supplies at any time within usual business hours and 
with appropriate notice during or after completion of 
the study to perform drug accountability 
reconciliation. Only unblinded personnel will be 
able to access the study drug and accountability 
documentation from first dosing through database 
hard lock. 
The Investigator will document all doses of 
Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
The Investigator or designee must maintain a record 
of all study drug received, used, and discarded. It 
must be clear from the records which subject received 
which dose of active or placebo treatment. 
The Sponsor will be permitted access to the study 
supplies at any time within usual business hours and 
with appropriate notice during or after completion of 
the study to perform drug accountability 
reconciliation. Only unblinded personnel will be able 
to access the study drug and accountability 
documentation from first dosing through database 
hard lock. 
The Investigator will document all doses of Levodopa 
or Carbidopa-Levodopa taken by the subject, 
including rescue doses. 
B (no longer 
placebo-controlled) 
10.7. Study Drug 
Handling and 
Disposal 
The pharmacist or designee for drug accountability 
is to document the date and time of initial 
compounding, subsequent admixture of dosing 
solutions, administration of study drug, and for 
which subject the study drug was intended (ie, 
record subject initials and birth date or other unique 
identifier). 
At the end of the study, any unused study drug will 
be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s 
directions; disposition of study drug will be 
documented. 
The pharmacist or designee for drug accountability is 
to document the date and time of initial compounding 
(oral solution only), subsequent admixture of dosing 
solutions (oral solution only), administration of 
study drug, and for which subject the study drug was 
intended (ie, record subject initials and birth date or 
other unique identifier). 
At the end of the study, any unused study drug will 
be retained or returned to the Sponsor for destruction 
or destroyed locally per the Sponsor’s directions; 
disposition of study drug will be documented. 
Change made to 
accommodate the 
availability of a 
capsule formulation 


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11. Assessment of 
Efficacy 
Efficacy assessments include evaluation of PD 
periodically during the study as outlined in the 
Schedule of Events (Table 2 and Table 3, 
respectively). 
Efficacy assessments include evaluation of PD 
periodically during the study as outlined in the 
Schedule of Events for Part A and Part B (Table 2 
and Table 3, respectively). 
Clarification for 
respective table 
reference 
11.1 Movement 
Disorder Society – 
Unified Parkinson’s 
Disease Rating Scale 
The UPDRS is the most commonly used scale in 
clinical studies of PD (Ramaker 2002). In 2007, the 
MDS revised the scale, which was known as the 
MDS-UPDRS (Goetz 2007), and subsequently 
demonstrated the validity of the MDS-UPDRS for 
rating PD (Goetz 2008). The modified UPDRS 
includes four scales, with various subscales. Each 
item is rated from 0 (normal) to 4 (severe) (Table 6). 
The four MDS-UPDRS scales are: 
Part I: nonmotor experiences of daily living (13 
items) 
Part II: motor experiences of daily living (13 items) 
Part III: motor examination (33 scores based on 18 
items [several with right, left or other body 
distribution scores]) 
Part IV: Motor complications (6 items) 
Table 6: Rating Scale for the MDS-UPDRS 
Several questions in Part I and all questions in Part 
II can be answered by the patient/caregiver and 
The UPDRS is the most commonly used scale in 
clinical studies of PD (Ramaker 2002). In 2007, the 
MDS revised the scale, which was known as the 
MDS-UPDRS (Goetz 2007), and subsequently 
demonstrated the validity of the MDS-UPDRS for 
rating PD (Goetz 2008). The modified UPDRS 
includes four scales, with various subscales. Each 
item is rated from 0 (normal) to 4 (severe) (Table 6). 
The four MDS-UPDRS scales are: 
Part I: nonmotor experiences of daily living (13 
items) 
Part II: motor experiences of daily living (13 items) 
Part III: motor examination (33 scores based on 18 
items [several with right, left or other body 
distribution scores]) 
Part IV: Motor complications (6 items) 
Table 6: Rating Scale for the MDS-UPDRS 
Several questions in Part I and all questions in Part II 
can be answered by the patient/caregiver and 
a) Changes made to 
reflect change in 
study design for Part 
B; b) added MDS- 
UPDRS Part II text 
due to additional 
endpoint for Part B; 
c) clarified that all 
MDS-UPDRS 
measurements 
should be taken 
during the “on” 
period for Part B and 
defined “on” period; 
d) Added reference 
to appendix 
containing MDS- 
UPDRS (reference 
inadvertently 
symptoms by the MDS-UPDRS, 
Assessments will be performed
symptoms by the MDS-UPDRS, 
. Assessments will be performed


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completed without the Investigator’s input. The 
remaining questions in Part I that deal with complex 
behaviors, the objective assessments of 
parkinsonism (Part III), and the questions that deal 
with motor fluctuations and dyskinesias (Part IV) 
are completed by Investigator interview. The time 
required for administering the MDS-UPDRS is 
estimated to be less than 10 minutes for the 
interview items of Part I, 15 minutes for Part III, and 
5 minutes for Part IV (Goetz 2008). The complete 
MDS-UPDRS is to be administered in Part A at 
screening, Admission (Day -1), on Day 8 prior to 
resuming Levodopa, and on Day 14. The complete 
MDS-UPDRS is to be administered in Part B at 
screening, Admission (Day -1), on Day 9 prior to 
resuming Levodopa; and on Days 15 and 22.  In 
both Parts A and B, the Admission (Day -1) 
complete MDS-UPDRS is performed only if the 
time between Screening and Admission is ≥7 days; 
otherwise, the MDS UPDRS Part III only is 
performed. 
Part III of the MDS-UPDRS assesses 18 motor 
categories, some of which include right and left 
measurements: speech, facial expression, kinetic 
tremor of hands, rest tremor amplitude, postural 
tremor of hands, rigidity of neck and four 
extremities, finger taps, hand movement, 
pronation/supination, toe tapping, constancy of rest 
tremor, leg agility, arising from chair, posture, gait, 
freezing of gait, postural stability, global spontaneity 
completed without the Investigator’s input. The 
remaining questions in Part I that deal with complex 
behaviors, the objective assessments of parkinsonism 
(Part III), and the questions that deal with motor 
fluctuations and dyskinesias (Part IV) are completed 
by Investigator interview. The time required for 
administering the MDS-UPDRS is estimated to be 
less than 10 minutes for the interview items of Part I, 
15 minutes for Part III, and 5 minutes for Part IV 
(Goetz 2008). The complete MDS-UPDRS is to be 
administered in Part A at screening, Admission (Day 
-1), on Day 8 prior to resuming Levodopa, and on 
Day 14. The complete MDS-UPDRS is to be 
administered in Part B at screening, Admission (Day 
-1), on Day 9 prior to resuming Levodopa; and onin 
the morning of Days 15 and 8, and 22on Day 14. In 
both Parts A and B, the Admission (Day -1) complete 
MDS-UPDRS is performed only if the time between 
Screening and Admission is ≥7 days; otherwise, the 
MDS UPDRS Part III only is(Part A) or Part II and 
Part III (Part B) are performed. 
Part II of the MDS-UPDRS assesses 13 categories 
of motor experiences of daily living: speech, 
salivation and drooling, chewing and swallowing, 
eating tasks, dressing, hygiene, handwriting, doing 
hobbies and other activities, turning in bed, 
tremor, getting out of bed, car, or deep chair, 
walking and balance, and freezing (Goetz, 2008). 
Part II of the MDS-UPDRS (motor examination) 
is to be completed in Part B at 12 and 23 hours 
missing in last 
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of movement (Goetz. 2008). Part III of the MDS- 
UPDRS (motor examination) is to be completed in 
Part A at 2, 4, 8, and 12 hours postdose on Days 1, 
2, 3, 4, 5, 6, and 7, and in Part B at 2, 3, 4, 8, and 12 
hours postdose on Days 1, 2, 3, 4, 5, 6, 7, and 9. If 
the complete MDS-UPDRS is not performed on 
Admission due to Admission taking place <7 days 
after Screening, then Part III only should also take 
place on Admission (Day -1) for both Parts A and B. 
MDS-UPDRS is to be assessed within ±10 minutes 
of the scheduled times through the 4 hour time point 
and within ±15 minutes of the scheduled times for 
the 6-hour through 12-hour time points. The MDS- 
UPDRS is provided in Appendix 4. 
postdose on Days 1, 2, 3, 4, 5, and 6. If the 
complete MDS-UPDRS is not performed on 
Admission due to Admission taking place <7 days 
after Screening, then Part II should also take place 
on Admission (Day -1) for Part B. 
Part III of the MDS-UPDRS assesses 18 motor 
categories, some of which include right and left 
measurements: speech, facial expression, kinetic 
tremor of hands, rest tremor amplitude, postural 
tremor of hands, rigidity of neck and four extremities, 
finger taps, hand movement, pronation/supination, 
toe tapping, constancy of rest tremor, leg agility, 
arising from chair, posture, gait, freezing of gait, 
postural stability, global spontaneity of movement 
(Goetz, 2008). Part III of the MDS-UPDRS (motor 
examination) is to be completed in Part A at 2, 4, 8, 
and 12 hours postdose on Days 1, 2, 3, 4, 5, 6, and 7, 
and in Part B at 2, 3, 4, 8, and 12 hours postdose on 
Days 1, 2, 3, 4, 5, 6, 7, and 9. MDS-UPDRS is to be 
assessed within ±10 minutes of the scheduled times 
through the 4 hour time point and within ±15 
minutes of the scheduled times for the 6-hour 
through 12-hour time points. Part III of the MDS- 
UPDRS (motor examination) is to be completed in 
Part B at 12 and 23 hours postdose on Days 1, 2, 3, 
4, 5, and 6. If the complete MDS-UPDRS is not 
performed on Admission due to Admission taking 
place <7 days after Screening, then Part III only 
should also take place on Admission (Day -1) for 
both Parts A and B. MDS UPDRS is to be assessed 


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within ±10 minutes of the scheduled times through 
the 4 hour time point and within ±15 minutes of the 
scheduled times for the 6 hour through 12 hour time 
points. The MDS UPDRS is provided in Appendix 
4. 
All MDS-UPDRS measurements in Part B should 
be taken during the “on” period (within 2 hours of 
dosing with antiparkinsonian agent(s)). 
The MDS-UPDRS is provided in Appendix 5. 
 
 
 


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. 


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12.1. Blood Sample 
Collection 
In Part A, plasma samples for PK analysis will be 
collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 
hours postdose on Day 4; predose on Day 5 and Day 
6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours 
postdose on Day 7; in AM of Day 8; and Day 14. In 
Part B, plasma samples for PK analysis will be 
In Part A, plasma samples for PK analysis will be 
collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 
hours postdose on Day 4; predose on Day 5 and Day 
6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours 
postdose on Day 7; in AM of Day 8; and Day 14. 
Changes made to 
reflect updated study 
design for Part B. 


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collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 
hours postdose on Days 1 to 4; predose on Day 5 
and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 
hours postdose on Day 7 and Day 8; in the AM on 
Day 9; and on Days 15 and 22. The time of study 
drug administration is time zero and all post-dosing 
sampling times are relative to this time. Samples are 
to be collected within ±5 minutes of the scheduled 
sampling time. The Investigator or designee will 
arrange to have the plasma samples processed, 
stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any 
time if clinically indicated and at the discretion of 
the Investigator (eg, for unusual or severe adverse 
events). 
Each sample will be marked with unique identifiers 
such as the study number, subject number, and the 
nominal sample time. The date and actual time that 
the blood sample was taken will be recorded on the 
eCRF or electronically with a bar code or other 
method. 
Samples are to be collected within ±5 minutes of 
the scheduled sampling time. 
In Part B, plasma samples for PK analysis will be 
collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 
hours postdose on Days 1 to 4; predose on Day 5 and 
Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours 
postdose on Day 7 and Day 8; in the AM on Day 9; 
and on Days 15 and 22.13 hours postdose on Day 1; 
and 13 hours postdose on Days 2 through 7, and 
on Day 14. Samples are to be collected within ±1 
hour of the scheduled sampling time. 
The time of study drug administration is time zero 
and all post-dosing sampling times are relative to this 
time. Samples are to be collected within ±5 minutes 
of the scheduled sampling time. The Investigator or 
designee will arrange to have the plasma samples 
processed, stored, and transported as directed for 
bioanalysis. 
An additional PK sample may be collected at any 
time if clinically indicated and at the discretion of the 
Investigator (eg, for unusual or severe adverse 
events). 
Each sample will be marked with unique identifiers 
such as the study number, subject number, and the 
nominal sample time. The date and actual time that 
the blood sample was taken will be recorded on the 
eCRF or electronically with a bar code or other 
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13.1. Safety and 
Tolerability 
Parameters 
Safety and tolerability of study drug will be 
evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, 
physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS and MOAA/S 
scores. 
Safety and tolerability of study drug will be evaluated 
by adverse event reporting, vital signs measurements, 
clinical laboratory measures, physical examination, 
ECGs, concomitant medication usage, C-SSRS, and 
SSS (Part A only) and MOAA/S (Part A only) 
scores. 
Changes made to 
reflect updated study 
design for Part B. 
13.1.1. 
Demographic/Medical 
History 
Age, gender, race, and ethnic origin will be recorded 
at the Screening visit for Part A. A full medical 
history, including PD history (eg, time of diagnosis, 
staging) and medication history, will be recorded at 
the Screening visit for Part A and updated, as 
needed, as screening for Part B. 
Age, gender, race, and ethnic origin will be recorded 
at the Screening visits for Part A. A full medical 
history, including PD history (eg, time of diagnosis, 
Hoehn and Yahr staging) and medication history, 
will be recorded at the Screening visits for Part A and 
updated, as needed, as screening for Part B. 
Changes made to 
reflect updated study 
design for Part B. 
13.1.2. Vital Signs 
Vital signs comprise respiratory rate, temperature, 
and supine (supine for at least 5 minutes prior to the 
measurement) and standing systolic and diastolic 
blood pressure and heart rate. 
In Part A, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 7; 
in AM of Day 8; and on Day 14. In Part B, vital 
signs and pulse oximetry will be performed at 
screening (vital signs only) and Admission (Day -1); 
predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours 
postdose on Days 1 through 8; in AM on Day 9; and 
on Days 15 and 22. Vital signs and pulse oximetry 
are to be assessed within ±10 minutes of the 
Vital signs comprise respiratory rate, temperature, 
and supine (supine for at least 5 minutes prior to the 
measurement) and standing systolic and diastolic 
blood pressure and heart rate. 
In Part A, vVital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 7; in 
AM of Day 8; and on Day 14. In Part B, vital signs 
and pulse oximetry will be performed at screening 
(vital signs only) and Admission (Day -1); predose 
and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose 
on Days 1 through 8; in AM on Day 9; and on Days 
15 and 22. Vital signs and pulse oximetry are to be 
assessed within ±10 minutes of the scheduled times 
Changes made to 
reflect updated study 
design for Part B. 


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scheduled times through the 4 hour time point and 
within ±15 minutes of the scheduled times for the 6- 
hour through 16-hour time points. 
through the 4 hour time point and within ±15 minutes 
of the scheduled times for the 6-hour through 16-hour 
time points. 
In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, and 12 
hours postdose on Days 1 through 7; and on Day 
14. Vital signs and pulse oximetry are to be 
assessed within ±10 minutes of the 1- and 2 hour 
time points and within ±15 minutes of the 12-hour 
time point. 
13.1.4. Physical 
Examination 
A physical examination of all major body systems 
will be undertaken and recorded at the Screening 
visits for Parts A and B. Symptom-directed physical 
examinations will be performed during Part A on 
Admission (Day -1), Day 1, Day 3, Day 4, Day 6, 
and Day 8. Symptom-directed physical 
examinations will be performed during Part B on 
Admission (Day -1), Day 1, Day 3, Day 4, Day 5, 
Day 7, Day 8, Day 9, and Day 15. 
A physical examination of all major body systems 
will be undertaken and recorded at the Screening 
visits for Parts A and B. Symptom-directed physical 
examinations will be performed during Part A on 
Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and 
Day 8. Symptom-directed physical examinations will 
be performed during Part B on Admission (Day -1), 
Day 1, Day 3, Day 4, Day 5, Day 7, Day 8, Day 96, 
and Day 158. 
Changes made to 
reflect updated study 
design for Part B. 
13.1.5. 
Electrocardiogram 
(ECG) 
A supine 12-lead ECG will be performed at the 
times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at 
screening and Admission (Day -1); predose on Days 
1 and 3; predose and 1 and 12 hours postdose on 
Days 4, 5, 6, and 7; in AM on Day 8; and Day 14. 
A supine 12-lead ECG will be performed at the times 
specified below and the standard intervals recorded as 
well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at 
screening and Admission (Day -1); predose on Days 
1 and 3; predose and 1 and 12 hours postdose on 
Days 4, 5, 6, and 7; in AM on Day 8; and Day 14. In 
Changes made to 
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In Part B, the 12-lead ECG will be assessed at 
screening and Admission (Day -1); predose and 1 
and 12 hours postdose on Days 1 through 8; in AM 
on Day 9; Days 15 and 22. 
All time points are relative to the time of dosing. 
ECGs are to be performed within ±10 minutes of the 
predose and 1-hour time points and within ±15 
minutes of the 12-hour time point. 
Part B, the 12-lead ECG will be assessed at screening 
and Admission (Day -1); predose and 1 and 12 hours 
postdose on Days 1 through 8; in AM, 3, 5, and 7, 
and on Day 9; Days 15 and 2214. 
All time points are relative to the time of dosing. 
ECGs are to be performed within ±10 minutes of the 
predose and 1-hour time points and within ±15 
minutes of the 12-hour time point. 
13.1.6. Laboratory 
Assessments 
In Part A, blood samples will be collected for 
hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, 
and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day 
-1); predose on Day 4 and Day 7; and on Day 14. In 
Part B, blood samples will be collected at screening 
and Admission (Day -1); predose on Days 1, 3, 4, 5, 
6, and 8; on Day 9 and Day 15. Urine samples will 
be collected in Part B at screening and Admission 
(Day -1); predose on Day 4 and Day 8; and on Day 
15. 
Serum and urine samples for pregnancy tests 
(females only) will also be collected. These 
assessments should be performed in accordance with 
the Schedule of Events (Table 2 and Table 3 as 
outlined individually below. 
All clinical laboratory test results outside the 
reference range will be interpreted by the 
Investigator as abnormal, not clinically significant 
In Part A, blood samples will be collected for 
hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, 
and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day - 
1); predose on Day 4 and Day 7; and on Day 14. In 
Part B, blood and urine samples will be collected at 
screening and Admission (Day - 1); predose on Days 
1, 3, 4, 5, 6, and 8; on Day 9 and Day 15. Urine 
samples will be collected in Part B at screening and 
Admission (Day  1); predose on Day 4 and Day 8; 
and on Day 15. 4 and 6; and on Day 8 and Day 14. 
On Day -1 of Part B, two blood samples will be 
taken: one sample will be sent to the central lab to 
be analyzed for reporting purposes and one 
sample is to be analyzed locally for study 
eligibility with regard to hematology/serum 
chemistry criteria. 
Serum and urine samples for pregnancy tests (females 
only) will also be collected. These assessments 
Changes made to 
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(NCS); or abnormal, clinically significant (CS). 
Screening results considered abnormal, CS recorded 
at the Screening visit may make the subject 
ineligible for the study pending review by the 
Medical Monitor. Clinical laboratory results that are 
abnormal, CS during the study but within normal 
range at baseline and/or indicate a worsening from 
baseline will be considered adverse events, assessed 
according to Section 13.2, and recorded in the 
eCRF. 
should be performed in accordance with the Schedule 
of Events (Table 2 and Table 3 as outlined 
individually below. 
All clinical laboratory test results outside the 
reference range will be interpreted by the Investigator 
as abnormal, not clinically significant (NCS); or 
abnormal, clinically significant (CS). Screening 
results considered abnormal, CS recorded at the 
Screening visit may make the subject ineligible for 
the study pending review by the Medical Monitor. 
Clinical laboratory results that are abnormal, CS 
during the study but within normal range at baseline 
and/or indicate a worsening from baseline will be 
considered adverse events, assessed according to 
Section 13.2, and recorded in the eCRF. 
13.1.6.2. 
Serum chemistry tests will include serum 
electrolytes, renal function tests, including 
creatinine, blood urea nitrogen, bicarbonate or total 
carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT), total protein, and 
albumin. 
Serum chemistry tests will include serum electrolytes, 
renal function tests, including creatinine, blood urea 
nitrogen, bicarbonate or total carbon dioxide, liver 
function tests, including total bilirubin, aspartate 
aminotransferase (AST), and alanine 
aminotransferase (ALT), alkaline phosphatase (Part 
B only), total protein, and albumin. 
Changes made to 
reflect updated study 
design for Part B. 
13.1.6.5. Pregnancy 
Screen 
Females of childbearing potential will be tested for 
pregnancy at Parts A and B by serum pregnancy test 
at the Screening visits and by urine pregnancy test 
on Day -1 (Admissions). 
Females of childbearing potential will be tested for 
pregnancy at Parts A and B by serum pregnancy test 
at the Screening visits and by urine pregnancy test on 
Day -1 (Admissions). For Part B, females of 
childbearing potential will also be tested for 
Changes made to 
reflect updated study 
design for Part B. 


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pregnancy by urine pregnancy test at the follow- 
up visit on Day 14. 
13.1.7. Columbia- 
Suicidality will be monitored during the study using 
Suicidality will be monitored during the study using 
Changes made to 
Suicide Severity 
Rating Scale (C- 
the C-SSRS (Posner 2011). This scale consists of a 
baseline evaluation that assesses the lifetime 
the C-SSRS (Posner 2011). This scale consists of a 
baseline evaluation that assesses the lifetime 
reflect updated study 
design for Part B. 
SSRS) 
experience of the subject with suicidal ideation and 
experience of the subject with suicidal ideation and 
behavior, and a post-baseline evaluation that focuses 
on suicidality since the last study visit.  The C-SSRS 
behavior, and a post-baseline evaluation that focuses 
on suicidality since the last study visit.  The C-SSRS 
includes ‘yes’ or ‘no’ responses for assessment of 
includes ‘yes’ or ‘no’ responses for assessment of 
suicidal ideation and behavior as well as numeric 
ratings for severity of ideation, if present (from 1 to 
suicidal ideation and behavior as well as numeric 
ratings for severity of ideation, if present (from 1 to 
5, with 5 being the most severe). 
5, with 5 being the most severe). 
If in the opinion of the Investigator, the subject is 
showing any suicidal tendency, no further study 
If in the opinion of the Investigator, the subject is 
showing any suicidal tendency, no further study drug 
drug will be administered and the subject will be 
will be administered and the subject will be referred 
referred to a psychologist or psychiatrist for further 
to a psychologist or psychiatrist for further 
evaluation. This information will be tracked. 
evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be 
The “Baseline/Screening” C-SSRS form will be 
completed on Screening of Part A (lifetime history 
and past 24 months). In Part A, the “Since Last 
completed on Screening of Parts A and B (lifetime 
history and past 24 months). In Part A, the “Since 
Visit” C-SSRS form will be completed on 
Last Visit” C-SSRS form will be completed on 
Admission (Day 1); 12 hours postdose on Days 1, 
2, and 3; predose on Days 4, 5, 6, and 7; and on 
Admission (Day  1); 12 hours postdose on Days 1, 2, 
and 3; predose on Days 4, 5, 6, and 7; and on Days 8 
Days 8 and 14. In Part B, the “Since Last Visit” C- 
and 14. In Part B, the “Since Last Visit” C-SSRS 
SSRS form will be completed on Admission (Day - 
1); 12 hours postdose on Day 1 through Day 8; and 
form will be completed on Admission (Day -1); 
predose and 12 hours postdose on Day 1; 12 hours 
on Days 9, 15, and 22. The C SSRS is provided in 
postdose on Days 2 through Day 8; and on Days 9, 
Appendix 10. 


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15,7; and 22on Day 14. The C -SSRS is provided in 
Appendix 10. 
13.1.8. 
The SSS is subject-rated scale designed to quickly 
assess how alert a subject is feeling. Degrees of 
sleepiness and alertness are rated on a scale of 1 to 
7, where the lowest score of ‘1’ indicates the subject 
is ‘feeling active, vital, alert, or wide awake’ and the 
highest score of ‘7’ indicates the subject is ‘no 
longer fighting sleep, sleep onset soon; having 
dream-like thoughts’. 
In Part A, the SSS will be administered on 
Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in 
the AM on Day 8; and Day 14. All time points are 
relative to the time of dosing. The SSS is to be 
performed within ±10 minutes of the scheduled 
times through the 4 hour time point and within ±15 
minutes of the scheduled times thereafter. In Part B, 
the SSS will be administered on Admission (Day - 
1); predose on Days 1 through 8; in AM on Day 9; 
and Days 15 and 22. The SSS should be performed 
prior to the MOAA/S score. The SSS is provided in 
Appendix 11. 
The SSS is subject-rated scale designed to quickly 
assess how alert a subject is feeling. Degrees of 
sleepiness and alertness are rated on a scale of 1 to 7, 
where the lowest score of ‘1’ indicates the subject is 
‘feeling active, vital, alert, or wide awake’ and the 
highest score of ‘7’ indicates the subject is ‘no longer 
fighting sleep, sleep onset soon; having dream-like 
thoughts’. 
In Part A, the SSS will be administered on Admission 
(Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 
hours postdose on Days 1 through 7; in the AM on 
Day 8; and Day 14. All time points are relative to the 
time of dosing. The SSS is to be performed within 
±10 minutes of the scheduled times through the 4 
hour time point and within ±15 minutes of the 
scheduled times thereafter. In Part B, the SSS will be 
administered on Admission (Day 1); predose on 
Days 1 through 8; in AM on Day 9; and Days 15 and 
22. The SSS should be performed prior to the 
MOAA/S score. The SSS will not be administered 
in Part B. The SSS is provided in Appendix 11. 
Changes made to 
reflect updated study 
design for Part B. 
13.1.9. 
The MOAA/S allows exploration of deeper sedation 
states than the SSS. If an MOAA/S score of 3 or 
less was observed, the score was to be confirmed by 
waiting approximately 10 minutes and re- 
administering the MOAA/S assessment. In Part A, 
The MOAA/S allows exploration of deeper sedation 
states than the SSS. If an MOAA/S score of 3 or less 
was observed, the score was to be confirmed by 
waiting approximately 10 minutes and re- 
administering the MOAA/S assessment. In Part A, 
Changes made to 
reflect updated study 
design for Part B. 


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the MOAA/S assessment should be conducted after 
other assessments that are scheduled at the same 
time point. In Part A, the MOAA/S will be 
performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 
hours postdose on Days 3, 4, 5, 6, and 7; in AM on 
Day 8; and Day 14. In Part B, the MOAA/S will be 
performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 
hours postdose on Days 1 through 8; in AM on on 
Day 9; and Days 15 and 22. The MOAA/S 
assessments are to be performed within ±10 minutes 
of the scheduled times through the 4-hour time point 
and within ±15 minutes of the scheduled times for 
the 6-hour through 16-hour time points. The 
MOAA/S is provided in Appendix 12. 
the MOAA/S assessment should be conducted after 
other assessments that are scheduled at the same time 
point. In Part A, the MOAA/S will be performed 
predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours 
postdose on Days 3, 4, 5, 6, and 7; in AM on Day 8; 
and Day 14. In Part B, tThe MOAA/S will not be 
performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 
hours postdose on Days 1 through 8; in AM on on 
Day 9; and Days 15 and 22in Part B. The MOAA/S 
assessments are to be performed within ±10 minutes 
of the scheduled times through the 4 hour time point 
and within ±15 minutes of the scheduled times for the 
6 hour through 16 hour time points.in Part B. The 
MOAA/S is provided in Appendix 12. 
13.2.1.1. Adverse 
Events 
An adverse event is the development of an 
undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during 
exposure to a pharmaceutical product, whether or 
not considered casually related to the product. In 
clinical studies, an adverse event can include an 
undesirable medical condition occurring at any time, 
including baseline or washout periods, even if no 
study treatment has been administered. 
All adverse events that occur after any subject has 
been enrolled, before treatment, during treatment, or 
following the cessation of treatment until the Day 22 
Follow-up visit of Part B, whether or not they are 
An adverse event is the development of an 
undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during 
exposure to a pharmaceutical product, whether or not 
considered casually related to the product. In clinical 
studies, an adverse event can include an undesirable 
medical condition occurring at any time, including 
baseline or washout periods, even if no study 
treatment has been administered. 
All adverse events that occur after any subject has 
been enrolled, before treatment, during treatment, or 
following the cessation of treatment until the Day 
2214 Follow-up visit of Parts A and B, whether or 
Changes made to 
reflect updated study 
design for Part B. 


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related to the study, must be recorded on forms 
provided by Sage Therapeutics. 
not they are related to the study, must be recorded on 
forms provided by Sage Therapeutics. 
13.2.1.3. Serious 
Adverse Event 
A serious adverse event is an adverse event 
occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, 
that fulfils one or more of the following: 
• 
It results in death 
• 
It is immediately life-threatening 
• 
It requires inpatient hospitalization or 
prolongation of existing hospitalization 
• 
It results in persistent or significant disability or 
incapacity 
• 
It results in a congenital abnormality or birth 
defect 
• 
It is an important medical event that may 
jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed 
above. 
All serious adverse events that occur after any 
subject has been enrolled, before treatment, during 
treatment, and until the Day 22 Follow-up visit of 
Part B, whether or not they are related to the study, 
must be recorded on forms provided by Sage 
Therapeutics. 
A serious adverse event is an adverse event occurring 
during any study phase and at any dose of the 
investigational product, comparator or placebo, that 
fulfils one or more of the following: 
• 
It results in death 
• 
It is immediately life-threatening 
• 
It requires inpatient hospitalization or 
prolongation of existing hospitalization 
• 
It results in persistent or significant disability or 
incapacity 
• 
It results in a congenital abnormality or birth 
defect 
• 
It is an important medical event that may 
jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed 
above. 
All serious adverse events that occur after any subject 
has been enrolled, before treatment, during treatment, 
and until the Day 2214 Follow-up visit of Parts A 
and B, whether or not they are related to the study, 
must be recorded on forms provided by Sage 
Therapeutics. 
Changes made to 
reflect updated study 
design for Part B. 


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13.2.1.4. Recording 
Sedation as an 
Adverse Event 
Sedation will be assessed using protocol-specified 
rating scales. In order to standardize the reporting 
of sedation as adverse events, Investigators must 
record sedation as an adverse event if there is a 
score of >5 on the SSS and/or a score of ≤2 on the 
MOAA/S. Consideration should be given to the 
most appropriate term to describe the sedation 
characteristics. 
In Part A and Part B, sSedation will be assessed 
using protocol-specified rating scales. 
Consideration should be given to the most 
appropriate term to describe the sedation 
characteristics. 
For Part A, iIn order to standardize the reporting of 
sedation as adverse events, Investigators must record 
sedation as an adverse event if there is a score of >5 
on the SSS and/or a score of ≤2 on the MOAA/S. 
SSS and MOAA/S do not apply to Part B. 
Consideration should be given to the most 
appropriate term to describe the sedation 
characteristics. 
Changes made to 
reflect updated study 
design for Part B. 
13.5. Reporting 
Serious Adverse 
Events 
All serious adverse events (regardless of causality) 
will be recorded from the signing of the ICF until 
the Day 22 Follow-up visit of Part B. Any serious 
adverse events considered possibly or probably 
related to the investigational product and discovered 
by the Investigator at any time after the study should 
be reported. All serious adverse events must be 
reported to the Sponsor or Sponsor’s designee 
immediately by phone and in writing within 24 
hours of the first awareness of the event. The 
Investigator must complete, sign and date the 
serious adverse event pages, verify the accuracy of 
the information recorded on the serious adverse 
event pages with the corresponding source 
All serious adverse events (regardless of causality) 
will be recorded from the signing of the ICF until the 
Day 2214 Follow-up visit of Parts A and B. Any 
serious adverse events considered possibly or 
probably related to the investigational product and 
discovered by the Investigator at any time after the 
study should be reported. All serious adverse events 
must be reported to the Sponsor or Sponsor’s 
designee immediately by phone and in writing within 
24 hours of the first awareness of the event. The 
Investigator must complete, sign and date the serious 
adverse event pages, verify the accuracy of the 
information recorded on the serious adverse event 
pages with the corresponding source documents, and 
send a copy to Sage Therapeutics or designee. 
Changes made to 
reflect updated study 
design for Part B. 


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documents, and send a copy to Sage Therapeutics or 
designee. 
14.1 Data Analysis 
Sets 
The safety population is defined as all subjects who 
are administered study drug. 
The efficacy population will consist of all subjects 
in the safety population who receive at least one 
dose of study drug and have at least one postdose 
MDS-UPDRS evaluation. 
The PK population will consist of all subjects in the 
safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each part of 
the study. 
The safety population is defined as all subjects who 
are administered at least one dose of study drug. 
Safety population will be used to provide 
descriptive summaries of all safety data. 
The efficacy population will consist of all subjects in 
the safety population who receive at least one dose of 
study drug and have at least one postdose MDS- 
UPDRS evaluation. The efficacy population will be 
used to analyze all efficacy data. 
The PK population will consist of all subjects in the 
safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each part of 
the study. 
Updated for 
clarification 
14.3. General 
Considerations 
Added section 
Section was 
inadvertently 
missing in previous 
version 
14.5. Efficacy 
Endpoints 
The primary endpoints of this study relate to safety 
and tolerability. Efficacy assessments include 
evaluation of PD symptoms by the MDS-UPDRS, 
The primary endpoints of this study relate to safety 
and tolerability. Efficacy assessments include 
evaluation of PD symptoms by the MDS UPDRS, 
Part A relate to safety and 
Changes made to 
reflect updated 
endpoints for Part B. 


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tolerability. The primary endpoint for Part B is to 
evaluate the improvement in PD tremor as 
assessed by changes in the MDS UPDRS Part 
II/III tremor score (defined as the sum of MDS- 
UPDRS items 2.10, 3.15, 3.16, 3.17 and 3.18). 
14.5.1. Secondary 
In Part A, changes in the MDS-UPDRS – Part III 
In Part A, changes in the MDS-UPDRS – Part III 
a) Clarification; 
Efficacy Endpoints 
score will be summarized overall and by tolerated 
score will be summarized overall and by tolerated 
b) Change made to 
dose. In Part B, changes in the MDS-UPDRS – Part 
dose. In Part B, changes in the MDS-UPDRS – Part 
reflect updated study
III total score, and the MDS-UPDRS – Parts I-IV 
III total score, and the MDS-UPDRS – Parts I-IV 
design for Part B (no
score will be summarized overall and by randomized
total score will be summarized overall and by 
longer randomized) 
treatment sequence and tolerated dose. 
randomized treatment sequence and tolerated dose. 
14.5.2. Exploratory 
Efficacy Endpoints 


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14.6. Safety and 
Tolerability Analyses 
Data from vital signs, clinical laboratory measures, 
ECG, C-SSRS, SSS, and MOAA/S will be 
summarized using descriptive statistics by group and 
time point, where applicable. Continuous endpoints 
will be summarized with number (n), mean, standard 
deviation, median, minimum, and maximum. In 
addition, change from baseline values will be 
calculated at each time point and will be 
summarized using descriptive statistics. Out-of- 
range safety endpoints may be categorized as low or 
high, where applicable. For all categorical 
endpoints, summaries will include counts and 
percentages. 
Data from vital signs, clinical laboratory measures, 
ECG, C-SSRS, SSS (Part A only), and MOAA/S 
(Part A only) will be summarized using descriptive 
statistics by group and time point, where applicable. 
Continuous endpoints will be summarized with 
number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from 
baseline values will be calculated at each time point 
and will be summarized using descriptive statistics. 
Out-of-range safety endpoints may be categorized as 
low or high, where applicable. For all categorical 
endpoints, summaries will include counts and 
percentages. 
Changes made to 
reflect updated 
endpoints for Part B 
14.6.1. Adverse 
Events 
All adverse events and serious adverse events 
(including those with onset or worsening before the 
start of open-label study drug) through the Day 22 
Follow-up visit of Part B will be listed. 
All adverse events and serious adverse events 
(including those with onset or worsening before the 
start of open-label study drug) through the Day 2214 
Follow-up visit of Parts A and B will be listed. 
Changes made to 
reflect updated study 
design for Part B 


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14.6.7. Stanford 
Sleepiness Scale 
(SSS) 
Sedation data collected on the SSS will be listed for 
all subjects. Changes in score over time will be 
represented graphically, and change from baseline of 
Part A and Part B will be summarized. 
Sedation data collected on the SSS will be listed for 
all subjects in Part A. Changes in score over time 
will be represented graphically, and change from 
baseline of Part A and Part B will be summarized. 
Changes made to 
reflect updated 
endpoints for Part B 
14.6.8. Modified 
Observer’s 
Assessment of 
Alertness/Sedation 
(MOAA/S) 
Sedation data collected on the MOAA/S will be 
listed for all subjects. Changes in score over time 
will be represented graphically, and change from 
baseline of Part A and Part B will be summarized. 
Sedation data collected on the MOAA/S will be listed 
for all subjects in Part A.  Changes in score over 
time will be represented graphically, and change from 
baseline of Part A and Part B will be summarized. 
Changes made to 
reflect updated 
endpoints for Part B 
14.6.9. Prior and 
Concomitant 
Medications 
Medications will be recorded at each study visit 
during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary 
September 2015, or later. 
Medications will be presented according to whether 
they are being taken prior to and/or during the study 
(concomitant). Prior medications are defined as 
those taken during the 4 weeks prior to the date of 
the first dose of open-label study drug. Concomitant 
medications are defined as those with a start date on 
or after the first dose of open-label study drug, or 
those with a start date before the first dose of open- 
label study drug that are ongoing or with a stop date 
on or after the first dose of open-label study drug. If 
medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be 
assumed to be concomitant. 
Medications will be recorded at each study visit 
during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary 
September 2015, or later. 
Medications will be presented according to whether 
they are being taken prior to and/or during the study 
(concomitant). Prior medications are defined as those 
taken during the 4 weeks prior to the date of the first 
dose of open-label study drug. Concomitant 
medications are defined as those with a start date on 
or after the first dose of open-label study drug, or 
those with a start date before the first dose of open- 
label study drug that are ongoing or with a stop date 
on or after the first dose of open-label study drug. If 
medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be 
assumed to be concomitant. 
Changes made to 
reflect updated study 
design for Part B 


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Concomitant medications will be assigned to the 
study part in which they are being taken. If a 
concomitant medication assigned to Part A 
continues to be taken through Part B, then the 
medication will be assigned to both parts of the 
study as appropriate. If the start and stop dates of 
the concomitant medications do not clearly define 
the part during which a medication was taken, it will 
be assumed to be taken in both parts. Details of 
prior and concomitant medications will be listed by 
study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and 
summarized. 
Concomitant medications will be assigned to the 
study part in which they are being taken. If a 
concomitant medication assigned to Part A continues 
to be taken through Part B, then the medication will 
be assigned to both parts of the study as appropriate. 
If the start and stop dates of the concomitant 
medications do not clearly define the part during 
which a medication was taken, it will be assumed to 
be taken in both parts. Details of prior and 
concomitant medications will be listed by study part, 
subject, start date, and verbatim term. 
The use of rescue medication will be recorded and 
summarized. 
14.8. 
Approximately 18 subjects will be enrolled in Part 
A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14. 
Approximately 12 subjects are anticipated to be 
randomized to Part B. This number of subjects is 
thought to be sufficient to assess preliminary safety 
and tolerability as well as a signal of efficacy of 
SAGE-217 Oral Solution in subjects with PD. 
Approximately 18 subjects will be enrolled in Part A. 
An interim analysis is planned after 10 subjects have 
completed Part A through Day 14. Approximately 12 
subjects are anticipated to be randomized to Part 
B.Up to 15 new subjects will be enrolled in Part B 
in order for 10 subjects to complete the study 
(tolerate at least 20 mg SAGE-217 for the duration 
of the dosing period). This number of subjects is 
thought to be sufficient to assess preliminary safety 
and tolerability as well as a signal of efficacy of 
SAGE-217 Oral Solution in subjects with PD. 
a) Changes made to 
reflect updated study 
design for Part B; 
b) change made to 
reflect availability of 
SAGE-217 Capsule 
 
 
 


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Title 
Original Text: 
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Appendix 4. 
Tremorogenic Drugs 
(new appendix) 
New appendix added. 
Added as reference 
for new Exclusion 
Criteria #6 for Part B 
due to updated study 
design 
 
 


Protocol 217-PRK-201 
Version 3.0 24 October 2016 
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1 
 
 
 
 
1. 
TITLE PAGE 
 
PROTOCOL NUMBER: 217-PRK-201 
A PHASE 2, TWO-PART STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF SAGE-217 ORAL SOLUTION IN 
PATIENTS WITH PARKINSON’S DISEASE OF 
MODERATE SEVERITY RESPONDING TO 
IMMEDIATE-RELEASE ORAL 
LEVODOPA/CARBIDOPA AND WITHDRAWN FROM 
LEVODOPA/CARBIDOPA 
IND NUMBER: 131,258 
Investigational Product 
SAGE-217 
Clinical Phase 
2 
Sponsor 
Sage Therapeutics, Inc. 
Sponsor Contact 
, M.D., Ph.D. 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
Medical Monitor 
, M.D., M.P.H. 
Study Physician 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
Date of Original Protocol 
28 September 2016 
Date of Amendment 1 
5 October 2016 


Protocol 217-PRK-201 
Version 3.0 24 October 2016 
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2 
 
 
 
Date of Amendment 2 
24 October 2017 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 


Protocol 217-PRK-20 I 
Versio n 3.0 24 October 2016 
Sage Therapeutics 
3 
 
 
Date (DD /MMM/YYYY) 
Jsozk uotb 
Date (D D/MMM/YYYY) 
Date ( DD/MMWYY YY) 
PROTOCOL SlGNATURE PAGE 
 
 
 
 
Protoco l umber: 
Product: 
IND No.: 
Study Phase: 
Sponsor: 
Date of Amendment 2: 
 
217-PRK-201 
SAGE -217 Oral Solutio n 
131, 258 
2 
Sage Therapeutics 
Version 3.0 24 Oct o ber 20 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
 
 
 
 
 
Sage Therapeutics 
 
 
 
Date (DD/MM:vt/YYYY) 


Protocol 217-PRK-201 
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4 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PRK-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


Protocol 217-PRK-201 
Version 3.0 24 October 2016 
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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone Number 
Clinical Research Organization 
 
 


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2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of SAGE-217 Oral Solution in Patients with Parkinson’s Disease (PD) of Moderate 
Severity Responding to Immediate-Release Levodopa/Carbidopa and Withdrawn from 
Levodopa/Carbidopa 
Study centers: Up to 4 centers 
Objectives: 
Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
Secondary: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral Solution in combination with immediate-release oral 
Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
Endpoints: 
Primary: 
• Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) during both Part A and Part B. 
Secondary: 
Part A: 
• Improvement in PD motor symptoms as assessed by changes in the Movement Disorder Society- 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) – Part III (Motor Examination) score. 


Protocol 217-PRK-201 
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Part B: 
• Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS – Part III score. 
• Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS – Parts I-IV 
total score. 
• Sleepiness/sedation as assessed by the Stanford Sleepiness Scale (SSS) and Modified Observer's 
Assessment of Analgesia/Sedation (MOAA/S) scores. 
In addition, plasma concentrations of SAGE-217 and possibly SAGE-217 metabolites will be 
measured, and pharmacokinetic (PK) parameters will be derived. 
Exploratory Endpoints: 
Methodology: 
This study will assess the safety, tolerability, PK, and efficacy of SAGE-217 Oral Solution. For ease 
of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to as Levodopa 
in this protocol. 
There are two parts: 
Part A: Open-label with morning (AM) dosing (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate-release oral 
Levodopa on the day of admission (Day -1) and in the AM only the following 3 days (Days 1 to 3). 
All subjects will stop their immediate-release oral Levodopa on Day 4 and will start on a 30 mg dose 
of SAGE-217 Oral Solution administered in the AM with food. Subjects not tolerating 30 mg will 
receive 20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days. The dose 
received on Day 7 will be defined as the tolerated dose for that subject. Subjects not tolerating 10 mg 
will not be able to continue in the study and may be replaced. Subjects will be followed for an 
additional 7 days (Day 14) after the administration of the last dose. Levodopa treatment will be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s discretion) will be 
allowed, if needed, on all days (Days 1 to 7). 


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Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each subject and to 
assess whether SAGE-217 exhibits efficacy in subjects with PD in order to inform the conduct of Part 
B. 
Part B: Randomized, placebo-controlled, two-sequence crossover with AM dosing (up to 8 days). 
Part B will be initiated only after review of the Part A interim analysis. 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at least 10 mg of 
SAGE-217 Oral Solution in Part A. Subjects who complete Part A through Day 14 will be re- 
admitted on Day -1 of Part B and they will receive their antiparkinsonian agent including immediate- 
release oral Levodopa. Subjects will be randomized the next day (Day 1) in a 1:1 manner to open- 
label Levodopa plus blinded SAGE-217 Oral Solution or placebo during Period 1 of the crossover. 
Subjects randomized to the combination arm of Levodopa and SAGE-217 Oral Solution will receive 
this combination in the morning for the first 4 days (Days 1 to 4). Subjects randomized to the 
Levodopa plus placebo arm will receive Levodopa and SAGE-217 matching placebo oral solution in 
the AM for the first 4 days (Days 1 to 4). On Day 5, all subjects will crossover to Period 2 and will 
only receive open-label SAGE-217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects 
will receive their individually established tolerated dose of SAGE-217 Oral Solution (from Part A). 
All subjects will be able to resume Levodopa from Day 9 onwards. Rescue treatment (at 
Investigator’s discretion) will be allowed, if needed, on all days (Days 1 to 8). 
All doses of SAGE-217 Oral Solution (or placebo) will be administered in the morning with food. If 
subjects are taking Levodopa as opposed to Carbidopa-Levodopa, administration with or without food 
will be determined by the Investigator. 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). If at 
any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged by the 
Investigator to be related to study drug, the dose on the next day must be reduced to the next lowest 
dose and continued for the remainder of the dosing period (ie, subjects who are unable to tolerate the 
30 mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 20 mg will receive a 
10 mg dose on subsequent days). The dose received on Day 7 of the dosing period in Part A will be 
defined as the tolerated dose for that subject, with this dose to be used as the starting dose for Part B 
for that subject. 
Subjects will be exposed to SAGE-217 Oral Solution for up to 12 days (4 days in Part A and up to 
8 days in Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part A and Part B (Table 2 and Table 3, respectively). 
Number of patients (planned): 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the conduct of Part B. Twelve subjects are 
anticipated to be randomized in Part B. 
Diagnosis and main criteria for inclusion: All of the following inclusion and exclusion criteria will 
be applied during screening for Part A, with some of the criteria applied during screening for Part B, 
as indicated. 
Inclusion criteria: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 


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4. Subjects with PD with a duration of less than 7 years and must meet the criteria for Hoehn and 
Yahr stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral Levodopa 
or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month prior to the 
baseline visit) and is expected to remain on this stable dose for the duration of this study. 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa or 
Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been on a 
stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on study 
through completion of the last follow-up visit. If a subject discontinues early after receiving a 
dose of SAGE-217, then the subject must continue this method of birth control for at least 7 days 
following the last dose of study drug. Highly effective methods of birth control include combined 
(estrogen and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on study, 
and for 13 weeks after receiving the last dose of study drug. Effective methods of birth control 
include sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with 
their partner's highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. (Part B also) 
Exclusion criteria: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major excipient, 
HPβCD. (Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 4 or 
stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her ability 
for participation. This includes schizophrenia spectrum and other psychotic disorders, substance- 
related and addictive disorders, feeding and eating disorders, bipolar and related disorders, 
structural brain disease including but not limited to history of encephalitis or hydrocephalus and 
history of clinically significant stroke, or anticipating starting psychotherapy or behavior therapy 
during the course of the study or who started psychotherapy or behavior therapy within 30 days 
prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 on the 
C SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 


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d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other atypical 
Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system atrophy). (Part B 
also) 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
(Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method (QTcF) 
of >450 msec in males or >470 msec in females will be the basis for exclusion from the study. 
ECG may be repeated once if initial values obtained are outside the specified limits. (Part B also) 
10. Subject has a history, presence and/or current evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
11. Subject has exposure to another investigational medication or device within 30 days prior to Part 
A Day 1. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subjects has used any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug. (Part B also) 
Investigational product, dosage and mode of administration: 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dose. 
Duration of treatment: 7 days in Part A; 8 days in Part B 
Part A: 
Screening duration: up to 28 days; Treatment Period: 7 days (SAGE-217 dosing for 4 days); Follow- 
up: 7 days 
Planned participation per subject: approximately 42 days during Part A. 
Part B: 
Screening duration: up to 14 days; Treatment Period: 8 days; Follow-up: 14 days 
Planned participation per subject: approximately 36 days during Part B. 
Reference therapy, dosage and mode of administration: 
In part B, placebo will be taste-matched to SAGE-217 Oral Solution. 
Criteria for evaluation: 
Safety and tolerability: 


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Safety and tolerability of study drug will be evaluated by vital signs, clinical laboratory measures, 
ECGs, physical examinations, concomitant medication usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS and MOAA/S. 
Efficacy: 
Improvement in PD motor symptoms and overall symptoms will be assessed by changes in the 
MDS-UPDRS Part III score and MDS-UPDRS Parts I-IV total score at various time points. 
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and possibly SAGE-217 
metabolites. The following PK parameters will be derived from the plasma concentrations (where 
evaluable): area under the concentration-time curve from time zero to infinity (AUC0-∞), maximum 
plasma concentration (Cmax), time to reach maximum concentration (tmax), the distributional half-life 
and terminal half-life (t1/2), and steady-state drug concentration in the plasma (Css). 
Statistical methods: 
Study Populations 
The safety population, defined as all subjects who are administered study drug, will be used to 
provide descriptive summaries of safety. 
The efficacy population, defined as all subjects in the safety population who receive at least one dose 
of study drug and have at least one postdose MDS-UPDRS evaluation, will be used to analyze 
efficacy data. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations and will be used to summarize PK data. 
Separate populations will be defined for each part of the study. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™ (MedDRA). The 
overall incidence of adverse events will be displayed by System Organ Class (SOC), preferred term, 
dose group, and cohort. Incidence of adverse events will also be presented by maximum severity and 
relationship to study drug. Vital signs, clinical laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and cohort, where applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data presentation 
methods where applicable; subject listings will be provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A is planned to inform Part B study conduct. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject. 


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Table 2: 
Schedule of Events: Part A (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 
X 


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; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose for Day 4, Day 6, and Day 8; and Day 14 
c Urinalysis: Screening and Admission (Day -1); predose for Day 4 and Day 7; and Day 14. 
d Vital Signs: Screening and Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM 
of Day 8; and Day 14. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; 
and Day 14. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose on Day 1 and Day 3; predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on 
Confinement Days 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1, Day 2 and Day 3; predose on Day 4, Day 5, Day 6, and Day 7; and Day 8 and 
Day 14. Screening/Baseline version of C-SSRS should be used on day of screening and Since Last Visit version should be used on all subsequent time points. 
h SSS: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
The SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. The MOAA/S is to 
be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
p 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
Administer Levodopa or 
q 
Carbidopa-Levodopa 
X 
X 
X 
Administer SAGE-217q 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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. 
j MDS-UPDRS (complete): Screening, Admission (Day -1) (only if time between Screening and Admission is ≥7 days), on Day 8 prior to resuming Levodopa, 
and Day 14. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 1, 2, 3, 4, 5, 6, and 7. If 
complete MDS-UPDRS is not completed on Admission due to it taking place <7 days after Screening, then Part III only should also take place on Admission 
(Day -1). 
 
 
p Plasma PK sampling times (±5 minutes): Day 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 
4, 8, and 12 hours on Day 7; in AM of Day 8; and Day 14. PK samples are to be collected within ±5 minutes of the scheduled sampling time. 
q Levodopa or Carbidopa-Levodopa and SAGE-217 are to be administered in the morning 


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Table 3: 
Schedule of Events: Part B (Randomized, Placebo-Controlled) 
 
Visit Days 
Screening 
(Day -14 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 
X 
X 


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; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 9 assessments. 
b Screening and Safety Laboratory Tests: Screening and Day -1 [Admission]; predose for Day 1, Day 3, Day 4, Day 5, Day 6, and Day 8; and Day 9 and Day 15. 
c Urinalysis: Screening and Admission (Day -1); Predose for Day 4 and Day 8; Day 15. 
d Vital Signs: Screening and Day -1 [Admission]; predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM 
of Day 9; and Days 15 and 22. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; 
and Day 15. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, 
and 8; in AM of Day 9; and Days 15 and 22. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1 through Day 8; Day 9, Day 15 and Day 22. 
h Day -1 [Admission]; predose on Days 1 through Day 8; Day 9, and Day 15 and Day 22. 
i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; and Days 15 and 22. The 
MOAA/S is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -14 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
q 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study Drug 
r 
Combination 
X 
X 
X 
X 
Administer SAGE-217 
onlyr 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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j MDS-UPDRS (complete): Screening, Admission (Day -1) (only if time between Screening and Admission is ≥7 days)], on Day 9 prior to resuming Levodopa, 
and Days 15 and 22. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 3 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 1, 2, 3, 4, 5, 6, 
7, and 8. If complete MDS-UPDRS is not completed on Admission due to it taking place <7 days after Screening, then the MDS-UPDRS Part III only should 
also take place on Admission (Day -1). 
 
 
 
 
 
 
 
 
 
 
q Plasma PK sampling times: Days 1 to 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, 
and 12 hours postdose on Day 7 and Day 8; in AM of Day 9; and Day 15 and Day 22. PK samples are to be collected within ±5 minutes of the scheduled 
sampling time. 
r Study drug is to be administered in the morning. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................25 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need .................................27 
5.2. 
SAGE-217 Oral Solution ............................................................................................28 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................28 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................28 
5.3.2. 
Clinical Experience .....................................................................................................28 
5.4. 
Potential Risks and Benefits .......................................................................................30 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary Objective .......................................................................................................31 
6.2. 
Secondary Objectives .................................................................................................31 
6.3. 
Endpoints ....................................................................................................................31 
6.3.1. 
Primary Endpoints ......................................................................................................31 
6.3.2. 
Secondary Endpoints ..................................................................................................31 
6.3.3. 
Exploratory Endpoints ................................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................33 
7.1. 
Overall Study Design ..................................................................................................33 
7.2. 
Number of Subjects ....................................................................................................34 
7.3. 
Treatment Assignment ................................................................................................34 
7.4. 
Dose Adjustment Criteria ...........................................................................................35 
7.5. 
Criteria for Study Termination ...................................................................................35 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 37 
8.1. 
Subject Inclusion Criteria ...........................................................................................37 
8.2. 
Subject Exclusion Criteria ..........................................................................................38 
8.3. 
Entrance Criteria for Part B ........................................................................................39 
8.4. 
Subject Withdrawal Criteria .......................................................................................39 


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9. 
TREATMENT OF SUBJECTS ..................................................................................41 
9.1. 
Description of Study Drug ..........................................................................................41 
9.1.1. 
Part A ..........................................................................................................................41 
9.1.2. 
Part B ..........................................................................................................................41 
9.2. 
Concomitant Medications ...........................................................................................41 
9.2.1. 
Prior/Concomitant Medications ..................................................................................41 
9.2.2. 
Prohibited Medications ...............................................................................................42 
9.3. 
Treatment Compliance ................................................................................................42 
9.4. 
Randomization and Blinding ......................................................................................42 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
10.1. 
Study Drug ..................................................................................................................44 
10.2. 
Study Drug Packaging and Labeling ..........................................................................44 
10.3. 
Study Drug Storage .....................................................................................................44 
10.4. 
Study Drug Preparation ..............................................................................................45 
10.5. 
Administration ............................................................................................................45 
10.6. 
Study Drug Accountability .........................................................................................46 
10.7. 
Study Drug Handling and Disposal ............................................................................46 
11. 
ASSESSMENT OF EFFICACY ................................................................................47 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale ................47 
11.2. 
Exploratory Endpoints ................................................................................................48 
48 
48 
48 
49 
50 
12. 
PHARMACOKINETICS ...........................................................................................51 
12.1. 
Blood Sample Collection ............................................................................................51 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................51 
12.3. 
Sample Analysis .........................................................................................................51 
13. 
ASSESSMENT OF SAFETY .....................................................................................52 
13.1. 
Safety and Tolerability Parameters .............................................................................52 
13.1.1. 
Demographic/Medical History ...................................................................................52 
13.1.2. 
Vital Signs ..................................................................................................................52 


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13.1.3. 
Weight and Height ......................................................................................................52 
13.1.4. 
Physical Examination .................................................................................................52 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................52 
13.1.6. 
Laboratory Assessments .............................................................................................53 
13.1.6.1. 
Hematology .................................................................................................................53 
13.1.6.2. 
Blood Chemistry .........................................................................................................53 
13.1.6.3. 
Urinalysis ....................................................................................................................53 
13.1.6.4. 
Virus Serology ............................................................................................................53 
13.1.6.5. 
Pregnancy Screen ........................................................................................................53 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................54 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) ...............54 
13.2. 
Adverse and Serious Adverse Events .........................................................................55 
13.2.1. 
Definition of Adverse Events .....................................................................................55 
13.2.1.1. 
Adverse Event .............................................................................................................55 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................55 
13.2.1.3. 
Serious Adverse Event ................................................................................................55 
13.2.1.4. 
Recording Sedation as an Adverse Event ...................................................................56 
13.2.2. 
Pregnancy ...................................................................................................................56 
13.3. 
Relationship to Study Drug .........................................................................................56 
13.4. 
Recording Adverse Events..........................................................................................57 
13.5. 
Reporting Serious Adverse Events .............................................................................57 
14. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................59 
14.1. 
Data Analysis Sets ......................................................................................................59 
14.2. 
Handling of Missing Data ...........................................................................................59 
14.3. 
Demographics and Baseline Characteristics ...............................................................59 
14.4. 
Efficacy Endpoints ......................................................................................................59 
14.4.1. 
Secondary Efficacy Endpoints ....................................................................................59 
14.4.2. 
Exploratory Efficacy Endpoints ..................................................................................59 
14.5. 
Safety and Tolerability Analyses ................................................................................60 
14.5.1. 
Adverse Events ...........................................................................................................60 
14.5.2. 
Vital Signs ..................................................................................................................60 
14.5.3. 
Physical Examinations ................................................................................................60 


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14.5.4. 
12-Lead ECG ..............................................................................................................60 
14.5.5. 
Clinical Laboratory Evaluations .................................................................................61 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................61 
14.5.7. 
Stanford Sleepiness Scale (SSS) .................................................................................61 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ........................61 
14.5.9. 
Prior and Concomitant Medications ...........................................................................61 
14.6. 
Pharmacokinetic Analysis ..........................................................................................61 
14.7. 
Determination of Sample Size ....................................................................................62 
14.8. 
Changes From Protocol Specified Analyses...............................................................62 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................63 
15.1. 
Study Monitoring ........................................................................................................63 
15.2. 
Audits and Inspections ................................................................................................63 
15.3. 
Institutional Review Board (IRB) ...............................................................................64 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
17. 
ETHICS ......................................................................................................................66 
17.1. 
Ethics Review .............................................................................................................66 
17.2. 
Ethical Conduct of the Study ......................................................................................66 
17.3. 
Written Informed Consent ..........................................................................................66 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................67 
18.1. 
Inspection of Records .................................................................................................67 
18.2. 
Retention of Records ..................................................................................................67 
18.3. 
Confidentiality ............................................................................................................67 
19. 
PUBLICATION POLICY ..........................................................................................69 
20. 
LIST OF REFERENCES ............................................................................................70 
21. 
APPENDICES ............................................................................................................72 
APPENDIX 1.   UNITED KINGDOM BRAIN BANK CRITERIA ............................................73 
APPENDIX 2.   HOEHN AND YAHR STAGING CRITERIA...................................................74 
APPENDIX 3.   ANTICHOLINERGIC DRUGS .........................................................................75 
APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED PARKINSON'S 
DISEASE RATING SCALE (MDS-UPDRS) ....................................................76 
77 
78 
81 


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APPENDIX 9. 
84 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION AND SINCE LAST VISIT 
VERSION ...........................................................................................................87 
APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS)........................................................93 
APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ..............................................................94 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................5 
Table 2: 
Schedule of Events:  Part A (Open-Label) .................................................................12 
Table 3: 
Schedule of Events:  Part B (Randomized, Placebo-Controlled) ...............................15 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................25 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL ..................45 
Table 6: 
Rating Scale for the MDS-UPDRS .............................................................................47 


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LIST OF FIGURES 
Figure 1: 
Study Design of Part A ...............................................................................................36 
Figure 2: 
Study Design of Part B ...............................................................................................36 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to 
infinity 
 
 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CS 
clinically significant 
Css 
steady-state drug concentration in the plasma 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EP 
European Pharmacopeia 
GABA 
γ aminobutyric acid 
GABAA 
γ aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Levodopa/Carbidopa 
Levodopa or Carbidopa-Levodopa 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MoCA 
Montreal Cognitive Assessment 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant 
NF 
National Formulary 
PD 
Parkinson’s disease 
 
 
PK 
pharmacokinetic(s) 
PM 
evening 
QTcF 
QT interval calculated using the Fridericia method 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal half-life 
tmax 
time to reach maximum concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need 
Parkinson’s disease (PD) is a chronic progressive neurodegenerative condition that affects the 
motor, autonomic, cognitive, and sensory systems. Parkinson’s disease is the second most 
common neurodegenerative disorder (Bergman 2002) and is associated with a massive loss of 
dopaminergic cells in the substantia nigra, leading to dopamine hypofunction and alteration of 
the basal ganglia circuitry. Dopamine neurons are under the control of the excitatory 
glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. Imbalance between the 
glutamatergic and GABA systems may contribute to excitotoxicity and dopaminergic cell death. 
The motor symptoms of PD have been linked with a loss of dopamine neurons in the substantia 
nigra pars compacta and a consequential reduction in the level of dopamine input in the striatum 
(Siderowf 2012). These symptoms evolve slowly and are characterized by the progression of 
tremor, rigidity, bradykinesia, and postural instability. Tremor caused by PD can appear as 
either a resting tremor or an action tremor. The most typical tremor of PD is a “pill-rolling” rest 
tremor between the thumb and index finger. Not everyone with PD develops a tremor, and those 
who do experience tremor may have symptoms that come and go. Typically, PD tremor starts in 
the fingers of one hand before spreading to affect the rest of the arm. Tremor can also spread to 
affect the foot on the same side of the body and, after several years, the tremor can spread to 
affect the other side of the body. Without treatment, PD tremor usually worsens over time. 
At present, there is no cure for PD. The core symptoms are caused by the degeneration of 
dopamine-producing neurons and, therefore, treatment consists of dopamine replacement. While 
enormous progress has been made in the treatment of PD over the past half century, levodopa 
remains the most potent drug for controlling PD symptoms (Jankovic 2008). The addition of 
carbidopa, a peripheral dopa decarboxylase inhibitor, enhances the therapeutic benefits of 
levodopa.  However, levodopa therapy is frequently associated with motor complications, and 
the appropriate time to initiate levodopa therapy continues to be debated (Stern 2004; 
Weiner 2004). The majority of patients treated with levodopa experience motor fluctuation, 
dyskinesia or other complications after 5 years of treatment (Jankovic 2005). 
Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of 
several neurotransmitter systems. The substantia nigra expresses high concentrations of 
allopregnanolone, a neurosteroid that positively modulates the action of GABA at 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. In PD patients, 
decreased plasma and cerebrospinal fluid levels of the neurosteroid allopregnanolone and 
5α-dihydroprogesterone have been observed (di Michele 2003). 
Parkinson’s disease is the second most common chronic neurodegenerative disease, affecting 
about 1 million people in the United States and more than 4 million people worldwide. It has a 
devastating effect on patients and is often accompanied by tremendous physical and emotional 
burden not only for the patients but also for their families and friends. As the size of the elderly 
population grows, the burden of PD is projected to grow substantially over the next few decades. 
To date, the therapy of PD is symptomatic, aimed at ameliorating motor symptoms. Although 
the goal of therapy is to reverse the functional disability, abolition of all symptoms and signs is 
not currently possible, even with high doses of medication. Thus, there is a growing need for 


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innovative new treatments to prevent, delay onset, or alleviate symptoms of PD. Neurosteroids 
act as neuroprotectants and as GABAA-receptor agonists in the physiology and pathology of the 
basal ganglia, impact dopaminergic cell activity and survival, and may therefore represent 
potential therapeutics in PD. 
 
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of PD. 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a non-viscous, clear solution. 
 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies and in toxicology studies. The sedative- 
hypnotic impairments seen with SAGE-217 were typical for GABAA-positive modulators, 
ranging from hyperexcitability and ataxia at the lower doses through deep sedation and 
ultimately anesthesia at higher doses. Depth and duration of sedation demonstrated a clear dose 
response over the range tested, with evidence of tolerance occurring with continued exposure. 
Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 7 days of 
dosing. 
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats. The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. 
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study that was suspected to have been related to exaggerated pharmacology. Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure. 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending. Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food effect, and essential tremor cohorts from Study 217-CLP-101 
and the multiple-ascending dose and drug-drug interaction cohorts from Study 217-CLP-102. 
Discussions of safety data are limited to the single-ascending dose cohorts in Study 217 CLP 101 
and the multiple-ascending dose cohorts in Study 217-CLP-102. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217. The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution. Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 
55 mg, and 66 mg. Escalation to the next dose was undertaken only after safety and PK data 


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were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose. The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each, 
received SAGE-217 Oral Solution in an open-label manner (one cohort received 50% of the 
MTD [22 mg] to study the food effects and the other cohort received the MTD [55 mg] to study 
the effects on subjects with essential tremor). SAGE-217 Oral Solution was orally bioavailable, 
demonstrated dose-linear PK from the lowest (0.25 mg) through the highest (66 mg) dose, and 
supported once-daily oral dosing with food. In addition, the pharmacodynamic effects of the 
SAGE-217 Oral Solution MTD were assessed in placebo-controlled, blinded, crossover 
electroencephalogram cohorts of 8 subjects each; one cohort received 50% of the MTD (22 mg) 
and the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers. Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 
7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg. Escalation to the next 
dose was undertaken only after safety and PK data were reviewed by the SRC and agreement 
reached that it was safe to increase the dose. The MTD was determined to be 30 mg. It was 
observed that subjects receiving the drug in the evening did better in terms of tolerability 
compared to when they received the drug in the morning.  A fourth cohort of 12 subjects 
received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug-drug 
interactions.  SAGE-217 Oral Solution is not likely to induce the metabolism of cytochrome 
P450 (CYP)2B6 or CYP3A4 substrates. SAGE-217 Oral Solution was orally bioavailable and 
suitable for once-daily oral dosing at night time with food. 
SAGE-217 Oral Solution was generally well tolerated. In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met. Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 
reported in either study. In addition, none of the observed adverse events resulted in 
discontinuation of the study drug. At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure. The most common treatment-emergent 
adverse events (TEAEs) were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, 
and muscle twitching, reported most frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were observed after single doses of 44 mg and 
greater. After multiple doses of 30 mg (morning [AM] or evening [PM]) or 35 mg (AM) over 
7 days, there was no evidence of changes in mean vital sign measures even though Day 7 plasma 
concentrations approximated that of the highest single dose in the single-ascending dose study. 
Subjects seemed to tolerate SAGE-217 better when given as night time dosing. 
Neuroactive steroids are a class of endogenous and synthetic positive allosteric modulators that 
target both synaptic and extra-synaptic GABAA receptors (Belelli 2002 and confirmed in the 
Sponsor’s in vitro studies). This diverse activity profile suggests that neuroactive steroid 
GABAA receptor-positive allosteric modulators could exhibit robust activity against essential 
tremor. Administration of SAGE-547 injection, a proprietary formulation of the endogenous 
neuroactive steroid, resulted in significant reductions in upper limb kinetic tremor scores 
compared to placebo in a Phase 2 proof‑of‑principle study (IND 122,280). Based on these 
results with SAGE-547, the study design for single-ascending dose study 217-CLP-101 included 


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a cohort of subjects with essential tremor (N=6) who received SAGE-217 Oral Solution (55 mg) 
in an open-label manner. Data from this cohort indicate that single doses of SAGE-217 Oral 
Solution resulted in a reduction in the tremor symptoms, suggesting that SAGE-217 might be 
effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral Solution in PD, since the present study is 
the first study in this indication. 
 
5.4. 
Potential Risks and Benefits 
Protocol 217-PRK-201 is the first clinical study evaluating the efficacy of SAGE-217 Oral 
Solution in PD. Thus, the potential benefits in this population are unknown, although the risks 
are likely to be similar to those mentioned in the Investigator’s Brochure. GABA compounds 
that cross the blood-brain barrier or increase GABA activity alleviate muscle stiffness caused by 
a lack of GABAergic tone (Winkler 1999), validating this receptor as a therapeutic target. Given 
the promising clinical data with another neuroactive steroid (SAGE-547) in conjunction with the 
shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence 
of anxiolytic activity, and safety data of SAGE-217, it is possible that patients may have a 
clinical benefit at the exposures selected for this study. In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-reduction design has been chosen to permit reduction in dose based on tolerability (adverse 
events), specifically sedation, versus treatment effect. Each subject will start with an initial dose 
of 30 mg; subjects unable to tolerate 30 mg will receive 20 mg; subjects unable to tolerate 20 mg 
will receive 10 mg. The tolerated dose for each subject will be the dose taken on Day 7. 
Subjects who tolerate at least the 10 mg dose on Day 7 will be eligible to enroll in Part B. Given 
the high medical need and potential for benefit in PD, there is a favorable benefit-risk evaluation 
to investigate SAGE-217 Oral Solution in PD. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution. 
 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms 
after withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD 
motor symptoms after withdrawal of Levodopa/Carbidopa. 
• To compare the effect of SAGE-217 Oral Solution in combination with immediate-release 
oral Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
 
6.3. 
Endpoints 
6.3.1. 
Primary Endpoints 
• Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) during both Part A and Part B. 
 
6.3.2. 
Secondary Endpoints 
Part A: 
• 
Improvement in PD motor symptoms as assessed by changes in the Movement Disorder 
Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) – Part III (Motor 
Examination) score. 
Part B: 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS – Part III 
score. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS – 
Parts I-IV total score. 
• 
Sleepiness/sedation as assessed by the Stanford Sleepiness Scale (SSS) and Modified 
Observer's Assessment of Analgesia/Sedation (MOAA/S) scores. 
 
6.3.3. 
Exploratory Endpoints 
 


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7. 
INVESTIGATIONAL PLAN 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2 study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217 Oral Solution in up to 18 adult subjects with PD of moderate severity who 
respond to immediate-release oral Levodopa and are on a stable dose. Part A of the study is an 
open-label design with morning (AM) dosing of SAGE-217 for 4 days. Part B of the study is a 
randomized, placebo-controlled, two-sequence crossover design. On Days 1 to 4 (Period 1 of 
crossover), subjects will receive open-label Levodopa plus blinded SAGE-217 or placebo. On 
Days 5 to 8 (Period 2 of crossover), all subjects will receive open-label SAGE-217 Oral Solution 
only. In Part B, subjects will receive their individually established tolerated dose of SAGE-217 
Oral Solution from Part A. Subjects will be exposed to SAGE-217 for up to 12 days (4 days in 
Part A and up to 8 days in Part B) and will be followed for an additional 7 days in Part A and an 
additional 14 days in Part B after the administration of the last dose. 
There are two parts to the study: 
• Part A: Open-label with AM dosing (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the 
following 3 days (Days 1 to 3). All subjects will stop their immediate-release oral 
Levodopa on Day 4 and will start on a 30 mg dose of SAGE-217 Oral Solution 
administered in the morning with food, as outlined in Section 9.1.1. Subjects not 
tolerating 30 mg will receive 20 mg, and subjects not tolerating 20 mg will receive 
10 mg on subsequent days (Section 7.4). The dose received on Day 7 will be defined as 
the tolerated dose for that subject. Subjects not tolerating 10 mg will not be able to 
continue in the study and may be replaced.  Subjects will be followed for an additional 
7 days (Day 14) after the administration of the last dose. Levodopa treatment will be 
resumed on Day 8 and continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 exhibits efficacy in subjects with PD of 
moderate severity in order to inform the conduct of Part B. 
• Part B: Randomized, placebo-controlled, two-sequence crossover with AM dosing (up 
to 8 days). Part B will be initiated only after review of the Part A interim analysis. 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at 
least 10 mg of SAGE-217 Oral Solution in Part A. Subjects who complete Part A will 
be re-admitted on Day -1 of Part B and they will receive their antiparkinsonian agent 
including immediate-release oral Levodopa. Subjects will be randomized the next day 
(Day 1) in a 1:1 manner to open-label Levodopa plus blinded SAGE-217 Oral Solution 
or placebo during Period 1 of the crossover. All doses of SAGE-217 Oral Solution (or 


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placebo) will be administered in the morning with food as outlined in Section 9.1.2. 
Subjects randomized to the Levodopa plus placebo arm will receive Levodopa and 
SAGE-217 placebo oral solution in the AM for the first 4 days (Days 1 to 4). Subjects 
randomized to the combination arm of Levodopa and SAGE-217 Oral Solution will 
receive this combination in the AM for the first 4 days (Days 1 to 4). On Day 5, all 
subjects will crossover to Period 2 and will only receive open-label SAGE-217 Oral 
Solution for the remaining 4 days (Days 5 to 8). Subjects will receive their individually 
established tolerated dose of SAGE-217 Oral Solution (from Part A). All subjects will 
be able to resume Levodopa from Day 9 onwards. 
Rescue treatment (at Investigator’s discretion) will be allowed, if needed, on all days 
(Days 1 to 8). 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). 
If at any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged 
by the Investigator to be related to study drug, the dose on the next day must be reduced to the 
next lowest dose and continued for the remainder of the dosing period (ie, subjects who are 
unable to tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to 
tolerate 20 mg will receive a 10 mg dose on subsequent days). The dose on Day 7 of the dosing 
period in Part A will be determined to be the tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects will be exposed to SAGE-217 for up to 12 days (4 days in Part A and up to 8 days in 
Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
The study designs of Part A and Part B are displayed in Figure 1 and Figure 2, respectively. 
Assessments will be performed periodically during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and Table 3, respectively). 
 
7.2. 
Number of Subjects 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14 to inform the conduct of Part B. Twelve 
subjects are anticipated to be randomized in Part B. 
 
7.3. 
Treatment Assignment 
SAGE-217 will be administered in the morning with food in Parts A and B. Food intake will be 
standardized as specified by the Sponsor. If subjects are taking Levodopa as opposed to 
Carbidopa-Levodopa, administration with or without food will be determined by the 
Investigator. 
Part A of the study is open-label. Part B of the study is randomized, placebo-controlled, two- 
sequence crossover. Subjects will be randomly assigned in a 1:1 manner to receive open-label 
Levodopa plus blinded SAGE-217 Oral Solution or placebo for 4 days (Days 1 to 4, Period 1 of 
crossover). Subjects, clinicians, and the study team will be blinded to treatment allocation. The 
pharmacist, who will prepare the oral solutions according to the randomization schedule, will be 
unblinded. For the remaining 4 days of Part B (Days 5 to 8, Period 2 of crossover), all subjects 


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will discontinue Levodopa and will receive their individually established tolerated dose of 
SAGE-217 Oral Solution from Part A in an open-label manner. 
Dose reductions for lack of tolerability will be allowed during both parts of the study 
(Section 7.4). 
 
7.4. 
Dose Adjustment Criteria 
Dose reductions of SAGE-217 for lack of tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part A, as determined by the Investigator, the 
dose on the next day will be reduced to the next lowest dose (ie, subjects who are unable to 
tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 
20 mg will receive a 10 mg dose on subsequent days). The dose received on Day 7 of Part A 
will be determined to be the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject 
 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons. In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects. 


36 
 
 
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Figure 1: 
Study Design of Part A 
 
NOTE: In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of SAGE-217 Oral Solution in Part A. 
Figure 2: 
Study Design of Part B 
 
NOTE: Part B will be initiated only after review of the Part A interim analysis (after 10 subjects have completed Part A). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 18 subjects will be enrolled in Part A at up to 4 study centers. All of 
the following inclusion and exclusion criteria will be applied during screening for Part A, with 
some of the criteria applied during screening for Part B, as indicated. 
 
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures 
are performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria 
(modified to allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Subjects with PD with a duration of less than 7 years and must meet the criteria for 
Hoehn and Yahr stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral 
Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month 
prior to the baseline visit) and is expected to remain on this stable dose for the duration of 
this study. 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa 
or Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217.  (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been 
on a stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on 
study through completion of the last follow-up visit. If a subject discontinues early after 
receiving a dose of SAGE-217, then the subject must continue this method of birth 
control for at least 7 days following the last dose of study drug. Highly effective methods 
of birth control include combined (estrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation, progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on 
study, and for 13 weeks after receiving the last dose of study drug. Effective methods of 


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birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with their partner's highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. (Part B also) 
 
8.2. 
Subject Exclusion Criteria 
Subjects who met any of the following exclusion criteria will be excluded from the study: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major 
excipient, HPβCD. (Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 
4 or stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia spectrum and other psychotic 
disorders, substance-related and addictive disorders, feeding and eating disorders, bipolar 
and related disorders, structural brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of clinically significant stroke, or anticipating 
starting psychotherapy or behavior therapy during the course of the study, or who started 
psychotherapy or behavior therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 
on the C-SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other 
atypical Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system 
atrophy). (Part B also) 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease. (Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. ECG may be repeated once if initial values obtained are outside the 
specified limits. (Part B also) 


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10. Subject has a history, presence and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 and 2. 
11. Subject has exposure to another investigational medication or device within the prior 
30 days. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of 
blood within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subject has used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug. (Part B also) 
 
8.3. 
Entrance Criteria for Part B 
In addition to the inclusion and exclusion criteria determined at screening for Part B indicated in 
Section 8.1 and Section 8.2, respectively, subjects must be able to tolerate at least 10 mg of 
SAGE-217 in Part A in order to be enrolled into Part B. Part B will not be initiated until results 
of the Part A interim analysis have been reviewed. 
 
8.4. 
Subject Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s). 
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events; 
• Occurrence of pregnancy; 
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance; 
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject fails to attend scheduled assessments during the course of the study, the Investigators 
must determine the reasons and the circumstances as completely and accurately as possible and 
document this in the subject’s source documents. 
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant. Any subject who is withdrawn 
from the study for any reason is to have the final visit assessments performed. 


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Subjects who withdraw or are withdrawn from the study may be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
9.1.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner. All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM only the following 3 days 
(Days 1 to 3). On the morning of Day 4, subjects will stop their immediate-release oral 
Levodopa and take SAGE-217 for 4 days (Days 4 to 7) in the AM with food. On Day 4, subjects 
will receive a 30 mg dose of SAGE-217. Subjects not tolerating 30 mg will receive 20 mg the 
next day, and subjects not tolerating 20 mg will receive 10 mg the next day. The dose received 
on Day 7 will be defined as the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject. 
Subjects not tolerating 10 mg will not be able to continue in the study and may be replaced. 
Levodopa treatment will be resumed on Day 8 and continue through Day 14. 
 
9.1.2. 
Part B 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217 Oral Solution. On Day 1 of Part B, subjects will be randomized in a 1:1 manner to 
open-label Levodopa plus blinded SAGE-217 Oral Solution or placebo. 
• Subjects randomized to the Levodopa plus placebo arm will receive Levodopa plus 
SAGE-217 placebo oral solution in the AM for the first 4 days (Days 1 to 4). 
• Subjects randomized to the Levodopa plus SAGE-217 Oral Solution arm will receive 
this combination in the AM for the first 4 days (Days 1 to 4). Subjects will receive 
their individually established tolerated dose of SAGE-217 Oral Solution from Part A. 
• On Day 5, all subjects will crossover to Period 2 and will only receive open-label 
SAGE-217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects will 
receive their individually established tolerated dose of SAGE-217 Oral Solution from 
Part A. 
• All subjects will be able to resume Levodopa from Day 9 onwards. 
9.2. 
Concomitant Medications 
9.2.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.2. 


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Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
taken during the study. 
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit. Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications. New concomitant medications, ongoing 
concomitant medications with a change in dose, and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified. 
The Investigator will document all doses of Levodopa and Carbidopa-Levodopa taken by the 
subject and the use of rescue medication. 
 
9.2.2. 
Prohibited Medications 
Subjects who have used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug are to be excluded from the study; these medications/products are 
prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 and amantadine are not permitted in the 
5 days prior to the admission visit (Day -1) of each part of the study. The list provides non- 
exhaustive examples of each drug class. 
 
9.3. 
Treatment Compliance 
Study drug (SAGE-217 or matched placebo) will be prepared by the site pharmacist. All doses 
of study drug will be administered by site staff while the subject is confined to the clinical unit. 
The Investigator(s) or designee will record the time and dose of study drug administration in the 
source documents. Any reasons for noncompliance will also be documented, including: 
• Missing visits; 
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. 
 
9.4. 
Randomization and Blinding 
Part A of the study is open-label. 
In Part B is a randomized, placebo-controlled, two-sequence crossover study. Subjects will be 
randomly assigned in a 1:1 manner to one of two treatment groups: open-label Levodopa plus 
blinded SAGE-217 Oral Solution or placebo oral solution. Subjects, clinicians, and the study 
team will be blinded to treatment allocation. The pharmacist, who will prepare the oral solutions 
according to the randomization schedule, will be unblinded. 


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During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor. If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures. 
The blinding of the study will be broken after the database has been locked. Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the electronic case report form (eCRF). If the 
subject or study center personnel (other than pharmacist) have been unblinded, the subject will 
be terminated from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dosages. The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient(s) in the Bottle (manufactured under current Good Manufacturing Practice [GMP] 
conditions 
) and further admixed at the clinical site in preparation for dosing. 
Placebo will be matched to SAGE-217 study drug. Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual. 
The Sponsor will not provide Levodopa or Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa-Levodopa. 
 
10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation. Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization. 
 
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 Oral Solution and placebo oral solution), the Investigator 
or designee will inspect the materials and complete and return the acknowledgment of receipt 
form enclosed with the parcel. A copy of the signed receipt will be kept in the study files. 
The study drug materials for SAGE-217 Oral Solution and placebo oral solution must be 
carefully stored at the temperature specified in the Pharmacy Manual (eg, clinical dosing 
solutions stored at approximately 2 to 8°C for 11 days with 24 hours of room temperature 
excursions allowed after preparation), safely and separately from other drugs. The study drug 
may not be used for any purpose other than the present study. After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies. An accurate, timely record of 
the disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 


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• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented. This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Study Drug Preparation 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual. The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5. 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
 
Ingredient 
Compendia Specification 
Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations: EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
Additional excipients may be utilized in placebo to match the taste of SAGE-217 Oral Solution. 
They include sucrose octaacetate, tannic acid, and ammonium glycyrrhizate. The quantities may 
vary depending on the dose of SAGE-217. 
 
10.5. 
Administration 
SAGE-217 Oral Solution or placebo oral solution will be administered in the morning with food. 
Doses of SAGE-217 and placebo for SAGE-217 will be prepared as an approximate 40 mL oral 
solution to be swallowed all at once, followed by approximately 200 mL of water that has been 
used to rinse the dosing bottle. The start time of swallowing the approximately 40 mL oral 
solution is time zero for all assessments. Subjects may have assistance from the clinic staff when 
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During Confinement, each subject’s antiparkinsonian agents, including Levodopa or Carbidopa- 
Levodopa, will be administered by site personnel according to the site’s standard operating 
procedures. 
 
10.6. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded. It must be clear from the records which subject received which dose of active or 
placebo treatment. 
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock. 
The Investigator will document all doses of Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
 
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture of dosing solutions, administration of study drug, and for 
which subject the study drug was intended (ie, record subject initials and birth date or other 
unique identifier). 
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include evaluation of PD symptoms by the MDS-UPDRS, 
 
Assessments will be performed periodically during the study as outlined in 
the Schedule of Events (Table 2 and Table 3, respectively. 
 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating 
Scale 
The UPDRS is the most commonly used scale in clinical studies of PD (Ramaker 2002). In 
2007, the MDS revised the scale, which was known as the MDS-UPDRS (Goetz 2007), and 
subsequently demonstrated the validity of the MDS-UPDRS for rating PD (Goetz 2008). The 
modified UPDRS includes four scales, with various subscales. Each item is rated from 0 
(normal) to 4 (severe) (Table 6). The four MDS-UPDRS scales are: 
Part I: nonmotor experiences of daily living (13 items) 
Part II: motor experiences of daily living (13 items) 
Part III: motor examination (33 scores based on 18 items [several with right, left or other body 
distribution scores]) 
Part IV: Motor complications (6 items) 
Table 6: 
Rating Scale for the MDS-UPDRS 
 
Rating 
Description 
0 = normal 
No symptoms/signs 
1 = slight 
Symptoms/signs with sufficiently low frequency or intensity to cause no impact on function 
2 = mild 
Symptoms/signs of frequency or intensity sufficient to cause a modest impact on function 
3 = moderate 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
4 = severe 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
Several questions in Part I and all questions in Part II can be answered by the patient/caregiver 
and completed without the Investigator’s input. The remaining questions in Part I that deal with 
complex behaviors, the objective assessments of parkinsonism (Part III), and the questions that 
deal with motor fluctuations and dyskinesias (Part IV) are completed by Investigator interview. 
The time required for administering the MDS-UPDRS is estimated to be less than 10 minutes for 
the interview items of Part I, 15 minutes for Part III, and 5 minutes for Part IV (Goetz 2008). 
The complete MDS-UPDRS is to be administered in Part A at screening, Admission (Day -1), on 
Day 8 prior to resuming Levodopa, and on Day 14. The complete MDS-UPDRS is to be 
administered in Part B at screening, Admission (Day -1), on Day 9 prior to resuming Levodopa; 
and on Days 15 and 22. In both Parts A and B, the Admission (Day -1) complete MDS-UPDRS 
is performed only if the time between Screening and Admission is ≥7 days; otherwise, the 
MDS-UPDRS Part III only is performed. 
Part III of the MDS-UPDRS assesses 18 motor categories, some of which include right and left 
measurements: speech, facial expression, kinetic tremor of hands, rest tremor amplitude, postural 


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tremor of hands, rigidity of neck and four extremities, finger taps, hand movement, 
pronation/supination, toe tapping, constancy of rest tremor, leg agility, arising from chair, 
posture, gait, freezing of gait, postural stability, global spontaneity of movement (Goetz. 2008). 
Part III of the MDS-UPDRS (motor examination) is to be completed in Part A at 2, 4, 8, and 
12 hours postdose on Days 1, 2, 3, 4, 5, 6, and 7, and in Part B at 2, 3, 4, 8, and 12 hours 
postdose on Days 1, 2, 3, 4, 5, 6, 7, and 9. If the complete MDS-UPDRS is not performed on 
Admission due to Admission taking place <7 days after Screening, then Part III only should also 
take place on Admission (Day -1) for both Parts A and B. MDS-UPDRS is to be assessed within 
±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times for the 6-hour through 12-hour time points. The MDS-UPDRS is provided in 
Appendix 4. 
11.2. 
Exploratory Endpoints 
 
 
 
 
 
 
 
 


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 4; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 7; in AM of Day 8; and Day 14. In Part B, plasma samples for PK 
analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Days 1 to 4; 
predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Day 7 
and Day 8; in the AM on Day 9; and on Days 15 and 22. The time of study drug administration 
is time zero and all post-dosing sampling times are relative to this time. Samples are to be 
collected within ±5 minutes of the scheduled sampling time. The Investigator or designee will 
arrange to have the plasma samples processed, stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events). 
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time. The date and actual time that the blood sample was taken will be 
recorded on the eCRF or electronically with a bar code or other method. 
 
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70 to -80°C until analyzed. They 
should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours. A specimen-identification form must be completed and 
sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions. 
 
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of concentrations of SAGE-217 and 
possibly SAGE-217 metabolites will be performed utilizing a validated liquid chromatography- 
tandem mass spectrometry method at a qualified laboratory. Pharmacokinetic parameters will be 
derived such as area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), the 
distributional half-life and terminal half-life (t1/2), and steady-state drug concentration in the 
plasma (Css). 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS and MOAA/S scores. 
 
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit for Part A. A full 
medical history, including PD history (eg, time of diagnosis, staging) and medication history, 
will be recorded at the Screening visit for Part A and updated, as needed, as screening for Part B. 
 
13.1.2. 
Vital Signs 
Vital signs comprise respiratory rate, temperature, and supine (supine for at least 5 minutes prior 
to the measurement) and standing systolic and diastolic blood pressure and heart rate. 
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 
through 7; in AM of Day 8; and on Day 14. In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 8; in AM on Day 9; and on Days 15 and 22. 
Vital signs and pulse oximetry are to be assessed within ±10 minutes of the scheduled times 
through the 4-hour time point and within ±15 minutes of the scheduled times for the 6-hour 
through 16-hour time points. 
 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visits for Parts A and B. 
 
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visits for Parts A and B. Symptom-directed physical examinations will be performed 
during Part A on Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and Day 8. Symptom- 
directed physical examinations will be performed during Part B on Admission (Day -1), Day 1, 
Day 3, Day 4, Day 5, Day 7, Day 8, Day 9, and Day 15. 
 
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at screening and Admission (Day -1); predose on 
Days 1 and 3; predose and 1 and 12 hours postdose on Days 4, 5, 6, and 7; in AM on Day 8; and 
Day 14. In Part B, the 12-lead ECG will be assessed at screening and Admission (Day -1); 
predose and 1 and 12 hours postdose on Days 1 through 8; in AM on Day 9; Days 15 and 22. 
All time points are relative to the time of dosing. ECGs are to be performed within ±10 minutes 
of the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 


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13.1.6. 
Laboratory Assessments 
In Part A, blood samples will be collected for hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day -1); predose on Day 4 and Day 7; and on 
Day 14.  In Part B, blood samples will be collected at screening and Admission (Day -1); 
predose on Days 1, 3, 4, 5, 6, and 8; on Day 9 and Day 15. Urine samples will be collected in 
Part B at screening and Admission (Day -1); predose on Day 4 and Day 8; and on Day 15. 
Serum and urine samples for pregnancy tests (females only) will also be collected. These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3 as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to Section 13.2, 
and recorded in the eCRF. 
 
13.1.6.1. Hematology 
Hematology tests will include complete blood count (CBC), including red blood cells, white 
blood cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
 
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), total protein, 
and albumin. 
 
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 
 
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study. 
 
13.1.6.5. Pregnancy Screen 
Females of childbearing potential will be tested for pregnancy at Parts A and B by serum 
pregnancy test at the Screening visits and by urine pregnancy test on Day -1 (Admissions). 


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13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe). 
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be completed on Screening of Part A (lifetime 
history and past 24 months). In Part A, the “Since Last Visit” C-SSRS form will be completed 
on Admission (Day -1); 12 hours postdose on Days 1, 2, and 3; predose on Days 4, 5, 6, and 7; 
and on Days 8 and 14. In Part B, the “Since Last Visit” C-SSRS form will be completed on 
Admission (Day -1); 12 hours postdose on Day 1 through Day 8; and on Days 9, 15, and 22. The 
C SSRS is provided in Appendix 9. 
 
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling. Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’. 
In Part A, the SSS will be administered on Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in the AM on Day 8; and Day 14. All time 
points are relative to the time of dosing. The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. In Part B, the SSS will be administered on Admission (Day -1); predose on Days 1 
through 8; in AM on Day 9; and Days 15 and 22. The SSS should be performed prior to the 
MOAA/S score. The SSS is provided in Appendix 10. 
 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS. If an MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment. In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point. In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 
3, 4, 5, 6, and 7; in AM on Day 8; and Day 14. In Part B, the MOAA/S will be performed 
predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 through 8; in AM on on 
Day 9; and Days 15 and 22. The MOAA/S assessments are to be performed within ±10 minutes 
of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled 
times for the 6-hour through 16-hour time points. The MOAA/S is provided in Appendix 11. 


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13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed. Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher). 
 
13.2.1. 
Definition of Adverse Events 
 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
All adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, or following the cessation of treatment until the Day 22 Follow-up visit of Part B, 
whether or not they are related to the study, must be recorded on forms provided by Sage 
Therapeutics. 
 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, and until the Day 22 Follow-up visit of Part B, whether or not they are related to the 
study, must be recorded on forms provided by Sage Therapeutics. 


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13.2.1.4. Recording Sedation as an Adverse Event 
Sedation will be assessed using protocol-specified rating scales. In order to standardize the 
reporting of sedation as adverse events, Investigators must record sedation as an adverse event if 
there is a score of >5 on the SSS and/or a score of ≤2 on the MOAA/S. Consideration should be 
given to the most appropriate term to describe the sedation characteristics. 
 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator. The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
The Investigator should request permission to contact the subject, the subject’s spouse/partner (if 
the subject is male and his spouse/partner becomes pregnant) or the obstetrician for information 
about the outcome of the pregnancy (spontaneous miscarriage, elective termination, live birth), 
and in the case of a live birth, about any congenital abnormalities. If a congenital abnormality is 
reported, then it should be recorded in the source documents and reported as a serious adverse 
event. Spontaneous miscarriages should also be reported and handled as serious adverse events. 
Elective abortions without complications should not be handled as adverse events. 
 
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.” 
 
Not related 
No relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or subject’s clinical 
state. 
Possibly related 
A reaction that follows a plausible temporal sequence from administration of the 
study drug and follows a known response pattern to the suspected study drug. 
Probably related 
The reaction might have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject, but this is not known for sure. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting. 


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13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug. 
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted TEAEs. 
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change. 
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe adverse events. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 13.2.1.3. An adverse event 
of severe intensity may not be considered serious. 
 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 22 Follow-up visit of Part B. Any serious adverse events considered possibly or 
probably related to the investigational product and discovered by the Investigator at any time 
after the study should be reported. All serious adverse events must be reported to the Sponsor or 
Sponsor’s designee immediately by phone and in writing within 24 hours of the first awareness 
of the event. The Investigator must complete, sign and date the serious adverse event pages, 
verify the accuracy of the information recorded on the serious adverse event pages with the 
corresponding source documents, and send a copy to Sage Therapeutics or designee. 
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file. 
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 


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will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
additional serious adverse events. 


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The primary endpoints of this study relate to safety and tolerability. Efficacy assessments 
include evaluation of PD symptoms by the MDS-UPDRS, 
14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study drug. 
The efficacy population will consist of all subjects in the safety population who receive at least 
one dose of study drug and have at least one postdose MDS-UPDRS evaluation. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each part of the study. 
 
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data. No sensitivity analysis of missing data will be performed. 
 
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, race, and ethnicity, and baseline characteristics, such as 
height, weight, and body mass index (BMI), will be summarized. 
Categorical summaries, such as gender and race, will be summarized by frequency and 
percentage. Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics. 
Hepatitis, HIV, and pregnancy screening results will be listed, but not summarized as they are 
considered part of the inclusion/exclusion criteria. 
Medical history will be listed by subject. 
 
14.4. 
Efficacy Endpoints 
 
14.4.1. 
Secondary Efficacy Endpoints 
In Part A, changes in the MDS-UPDRS – Part III score will be summarized overall and by 
tolerated dose. In Part B, changes in the MDS-UPDRS – Part III score and the MDS-UPDRS – 
Parts I-IV total score will be summarized overall and by randomized treatment sequence and 
tolerated dose. 
 
14.4.2. 
Exploratory Efficacy Endpoints 
 


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14.5. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, SSS, and MOAA/S will be 
summarized using descriptive statistics by group and time point, where applicable. Continuous 
endpoints will be summarized with number (n), mean, standard deviation, median, minimum, 
and maximum. In addition, change from baseline values will be calculated at each time point 
and will be summarized using descriptive statistics. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. For all categorical endpoints, summaries will 
include counts and percentages. 
 
14.5.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher). The 
analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of open-label study drug, or any worsening of a pre- 
existing medical condition/adverse event with onset after the start of open-label study drug and 
until 14 days after the last dose. The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred term, and dose group. Incidences will be presented in 
order of decreasing frequency. In addition, summaries will be provided by maximum severity 
(see Section 13.4) and relationship to study drug (see Section 13.3). 
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the first dose of open-label study drug will also 
be summarized. 
All adverse events and serious adverse events (including those with onset or worsening before 
the start of open-label study drug) through the Day 22 Follow-up visit of Part B will be listed. 
 
14.5.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
of Part A and Part B in vital signs will be evaluated by time point. 
 
14.5.3. 
Physical Examinations 
Screening physical examination results for Part A and Part B will be listed by subject. Any 
clinically significant physical examination will be recorded in medical history. Physical 
examination findings will be listed by subject and visit; abnormal findings will be flagged on the 
listing. 
 
14.5.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event. Electrocardiogram findings will be listed by subject and visit. 


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14.5.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline of Parts A and B in clinical laboratory measures will be summarized. 
 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects. Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
 
14.5.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects. Changes in score over time will 
be represented graphically, and change from baseline of Part A and Part B will be summarized. 
 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects. Changes in score over 
time will be represented graphically, and change from baseline of Part A and Part B will be 
summarized. 
 
14.5.9. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later. 
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant). Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug. Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug. If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant. 
Concomitant medications will be assigned to the study part in which they are being taken. If a 
concomitant medication assigned to Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate. If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts. Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and summarized. 
 
14.6. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics. Time to 
reach maximum concentration (tmax) will be summarized using number (n), mean, standard 
deviation, median, minimum, and maximum. All other PK parameters will be summarized using 
n, geometric mean, coefficient of variation, median, minimum, and maximum and listed by 
subject. 


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Wherever necessary and appropriate, PK parameters will be dose-adjusted to account for 
individual differences in dose. 
 
 
Additional exposure-response analyses may be performed for other measures of efficacy 
and safety. 
 
14.7. 
Determination of Sample Size 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14. Approximately 12 subjects are anticipated 
to be randomized to Part B. This number of subjects is thought to be sufficient to assess 
preliminary safety and tolerability as well as a signal of efficacy of SAGE-217 Oral Solution in 
subjects with PD. 
 
14.8. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan. 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of <Sponsor> 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between Sage 
Therapeutics and the Investigator. 
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each patient (eg, clinic 
charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to Sage Therapeutics 
or designee and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of a Sage Therapeutics or designee audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs. 
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements. 
 
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan. 
Electronic case report forms will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, and subject status. 
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study. For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
 
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
 
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available study registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor. It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study. The information obtained from the clinical study will be used 


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towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required. 


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics. No publication or disclosure of study results will be permitted except as 
specified in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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20. 
LIST OF REFERENCES 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002 
Sep;43(4):651- 61. 
 
 
Bergman H, Deuschl G. Pathophysiology of Parkinson’s disease: from clinical neurology to 
basic neuroscience and back. Mov Disord. 2002;17:S28-S40. 
 
di Michele F, Longone P, Romeo E, et al. Decreased plasma and cerebrospinal fluid content of 
neuroactive steroids in Parkinson’s disease. Neurol Sci. 2003;24(3):172-3. 
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41–4. 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric 
testing results. Mov Disord. 2008;23(15):2129–70. 
Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology. 
1967;17(5):427-42. 
 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP. 1992;55:181-4. 
Jankovic J. Motor fluctuations and dyskinesia in Parkinson’s disease: Clinical manifestations. 
Mov Disord. 2005;11:11-6. 
Jankovic J. Parkinson’s’ disease: clinical features and diagnosis. JNNP. 2008;79:368-76. 
Kasten M, Bruggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the 
detection of MCI and dementia in Parkinson disease. Neurology. 2010;75 (5):478–9. 
 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 


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Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for 
impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867–76. 
Siderowf A, Lang AE. Pre-motor Parkinson’s disease; concepts and definitions. Mov. Disord 
2012;27, 608-16. 
Stern MB. Dopamine agonists modify the course of Parkinson disease. Arch Neurol. 
2004;61:1969-71. 
Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 
2004;61:1966-9. 
Winkler C, Bentlage C, Nikkhah G, et al. Intracranial transplants of GABA-rich striatal tissue 
induce behavioral recovery in the rat Parkinson model and promote the effects obtained by 
intrastriatal dopaminergic transplants. Exp. Neurol. 1999;155:165-186. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in the following appendices are for reference only; 
the rating scales and questionnaires reproduced in the eCRFs are to be used for actual subject 
assessment per the Schedule of Events. 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA 
 


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APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA 
The Hoehn and Yahr scale, a commonly used system for describing how the symptoms of 
Parkinson’s disease progress, was first published in 1967 (Hoehn 1967). The original scale 
included 5 disease stages, numbered 1 to 5. 
 
 
Original Hoehn and Yahr Scale 
 
Stage 1 
Unilateral involvement only, usually with minimal or no functional disability 
Stage 2 
Bilateral or midline involvement without impairment of balance 
Stage 3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; 
physically independent 
Stage 4 
Severely disabling disease; still able to walk or stand unassisted 
Stage 5 
Confinement to bed or wheelchair unless aided 


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APPENDIX 3. ANTICHOLINERGIC DRUGS 
The following drugs are not permitted in the 5 days prior to receiving the first dose of study drug 
in Part A and Part B. The list below gives a non-exhaustive list of examples of each drug class. 
A. Antimuscarinic agents 
 
Atropine 
Benzatropine 
Biperiden 
Chlorpheniramine 
Dicyclomine 
Dimenhydrinate 
Diphenhydramine 
Doxepin 
Doxylamine 
Glycopyrrolate 
Hydroxyzine 
Ipratropium 
Orphenadrine 
Oxitropium 
Oxybutynin 
Tolterodine 
Tiotropium 
Tropicamide 
Trihexyphenidyl 
Scopolamine 
Solifenacin 
Tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, trimipramine, 
amoxapine, desipramine, nortriptyline, protriptyline) 
 
B. Antinicotinic agents: 
 
Bupropion 
Dextromethorphan 
Doxacurium 
Hexamethonium 
Mecamylamine 
Tubocurarine 


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APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED 
PARKINSON'S DISEASE RATING SCALE (MDS-UPDRS) 
 
Part I: Nonmoto1· As pe ct s of Exp e rien c es of Dail y Li ving 
Part II: Motor Experiences of Daily Living 
Cognitive impainnent 
Speech 
Hallucinations and psychosis 
Saliva and drooling 
Depressed mood 
Chewing and swallowing 
Anxious mood 
Eating tasks 
Apathy 
Dressing 
Features of dopamine dysregulation syndrome 
Hygiene 
Sleep problems 
Handwriting 
Daytime sleepiness 
Doing hobbies and other activities 
Pain and other sensations 
Tuming in bed 
Urina1y problems 
Tremor impact on activities 
Constipation problems 
Getting in and out of bed 
Lightheadedness on standing 
Walking and balance 
Fatigue 
Freezing 
Part III: Motor Examination 
Part IV : Motor Complications 
Speech 
Time spent with dyskinesias 
Facial expression 
Functional impact of dyskinesias 
Rigidity (neck; right/left upper/lower extremities) 
Painful off state dystonia 
Finger tapping (right/left hands) 
Time spent in the off state 
Hand movements (right/left hands) 
Functional impact of fluctuations 
Pronation-supination movements of right/left hands 
Complexity of motor functions 
Toe tapping (right/left foot) 
Leg agility (right/left leg) 
Arising from chair 
Gait 
Freezing of gait 
Postural instability 
Posture 
Global spontaneity of movement (body bradykinesia) 
Postural tremor of right/left hands 
Kinetic tremor of right/left hands 
Rest tremor amplitude: right/left upper/lower extremities; lip jaw 
Constancyof rest tremor 


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APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – BASELINE/SCREENING VERSION AND 
SINCE LAST VISIT VERSION 
 
 
 


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APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS) 
 


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APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
Modified Observer’s Assessment of Alertness/Sedation Scale 
 
Score 
Responsiveness 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Responds only after painful trapezius squeeze 
0 
No response after painful trapezius squeeze 


 
 
Summa ry of Changes Page 
Protocol 217-PRK-201 
Date 24 Oct 2016 
The following changes, and the rationale for the changes, were made to the attached protocol in this amendment. 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Title Page 
Title Page 
Date of Original Protocol: 
28 September 2016 
Date of Amendment 1: 
05 October 2016 
Date of Original Protocol: 
28 September 2016 
Date of Amendment 1: 
5 October2016 
Date of Amendment 2: 
20 Octobe1· 2 01 6 
Added the date of Amendment 
2 to the Title Page. 
headers 
headers 
Version 2.0 05 October 2016 Version 3.0 20 October 
Changed Version number and 
date to match those of 
Amendment 2 (version 3.0 
20 October 2016) 
Protocol Signature Page 
Protocol Signature Page 
Date of Amendment 1: 
5 October2016 
Date of Amendment 2: 
20 Octobe1· 2 01 6 
Revised the date of the 
signature page to be the date 
of Amendment 2. 
Protocol Signature Page 
Protocol Signature Page 
Changed the statistical signee. 
Synopsis, Exploratory 
Synopsis, Exploratory 
Endpoints 
Endpoints 
And 
And 
Section 6.3.3, Exploratory 
Endpoints 
Section 6.3.3, Exploratory 
Endpoints 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Synopsis, Methodology 
And 
Section 7.1 Overall Study 
Design (Part A) 
And 
Section 9.1.1, Part A 
Synopsis, Methodology 
And 
Section 7.1 Overall Study 
Design (Part A) 
And 
Section 9.1.1 (Part A) 
All subjects will continue to 
take their antiparkinsonian 
agents including immediate- 
release oral Levodopa on the 
day of admission (Day -1) and 
in the AM the following 3 
days (Days 1 to 3). 
All subjects will continue to 
take their antiparkinsonian 
agents including immediate- 
release oral Levodopa on the 
day of admission (Day -1) and 
in the AM only the following 
3 days (Days 1 to 3). 
Revised text to clarify that 
only the morning dose of 
Levodopa was to be taken on 
Days 1 to 3. 
Synopsis, Methodology 
And 
Section 7.1, Overall Study 
Design (Part B) 
And 
Section 9.1.2, Part B 
Synopsis, Methodology 
And 
Section 7.1, Overall Study 
Design (Part B) 
And 
Section 9.1.2, Part B 
Subjects randomized to the 
Levodopa plus placebo arm 
will receive Levodopa and 
SAGE 217 matching placebo 
oral solution in the AM for the 
first 4 days (Days 1 to 4). 
Subjects randomized to the 
Levodopa plus placebo arm 
will receive Levodopa and 
SAGE 217 placebo oral 
solution in the AM for the first 
4 days (Days 1 to 4). 
Removed “matching” from 
placebo oral solution. 
Synopsis, Inclusion Criteria 
And 
Section 8.1, Inclusion Criteria 
Synopsis, Inclusion Criteria 
And 
Section 8.1, Inclusion Criteria 
11. Female subjects must 
agree to practice a highly 
effective method of birth 
control while on study, and for 
30 days after receiving the last 
dose of study drug. 
11. Female subjects must 
agree to practice a highly 
effective method of birth 
control while on study 
through completion of the 
last follow-up visit. If a 
subject discontinues early 
after receiving a dose of 
SAGE-217, then the subject 
must continue this method of 
birth control for at least 7 
days following the last dose 
of study drug. 
Revised Inclusion Criterion 11 
to clarify timing of highly 
effective method of birth 
control for females during the 
study and if a subject 
prematurely discontinued the 
study. 
Synopsis, Inclusion Criteria 
And 
Section 8.1, Inclusion Criteria 
Synopsis, Inclusion Criteria 
And 
Section 8.1, Inclusion Criteria 
12. Male subjects must agree 
to practice a highly effective 
method of birth control while 
on study, and for 13 weeks 
after receiving the last dose of 
study drug. Effective methods 
of birth control include sexual 
abstinence, vasectomy, or a 
condom with spermicide 
12. Male subjects must agree 
to practice a highly effective 
method of birth control while 
on study, and for 13 weeks 
after receiving the last dose of 
study drug. Effective methods 
of birth control include sexual 
abstinence, vasectomy, or a 
condom with spermicide 
Revised wording of Inclusion 
Criterion 12 to specify that 
males and their partners must 
practice highly effective 
methods of birth control. 


 
 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
(men) in combination with 
female partner's highly 
effective method. 
(men) in combination with 
their partner's highly effective 
method. 
Synopsis, Table 2 
Synopsis, Table 2 
MDS-UPDRS (complete) and 
MDS-UPDRS (complete) and 
MDS-UPDRS (Part III only) 
MDS-UPDRS (Part III only) 
MDS-UPDRS (complete) on 
Days 1,2, 3, 4, 7, and 14. 
MDS-UPDRS (Part III only) 
on Days 5 and 6. 
-- 
Removed performance of 
MDS-UPDRS (complete) on 
Days 1,2, 3, 4, and 7, and 
added it on Day 8. 
Added MDS-UPDRS 
(Pa1·t III  onl y ) to Da ys 1, 2, 
3, 4 ,  and 7, and removed it 
from Day 8. 
The MDS-UPDRS complete is 
to be perfo1m ed weekly, while 
the Part III assessment can be 
perfonned multiple times 
dw-ing a day. 
 
 
 
 
 
Synopsis, Table 2, C-SSRS 
Synopsis, Table 2, C-SSRS 
Added: Screening/Baseline 
Clarified the version of the 
footnote 
footnote 
version of C-SSRS should be 
used on day of screening and 
C-SSRS that should be used at 
each assessment. 
Since Last Visit version 
should be used on all 
subsequent time points. 
Synopsis, Table 2, MDS­ 
Synopsis, Table 2, MDS­ 
Screening, Admission 
Screening, Admission (Day - 
The MDS-UPDRS complete is 
UPDRS (complete) footnote 
UPDRS (complete) footnote 
(Day-1), predose Day 1, Day 
2, Day 3, and Day 4; postdose 
on Day 7; and Day 14 
1) (only if time between 
Screening and Admission is 
7 days), on Day 8 prio1· to 
re s uming Levodopa , and Day 
14 
to be perfo1med weekly ; 
clarified that the MDS­ 
UPDRS complete was to be 
perfo1med on Admission if at 
least 7 days had transpired 
since the screening 
assessment. 
Clarified that the Day 8 
assessment was to be 


 
 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
performed prior to dosing with 
Levodopa. 
Synopsis, Table 2, MDS­ 
UPDRS (Pait III only) 
footnote 
Synopsis, Table 2, MDS­ 
UPDRS (Part III only) 
footnote 
MDS-UPDRS  (Part  III   only): 
2 (± IO minute s) , 4 ( ±I O 
minutes), 8 (±15 minutes), and 
12 (±15 minutes) hours 
postdose on Days 5, 6, and 8. 
MDS-UPDRS (Pait III only): 
2 (±10 minutes), 4 (± IO 
minu te s) , 8 (± 15 minutes), and 
12 (±15 minutes) hours 
postdose on Days 1, 2, 3, 4, 5, 
6, and 7. If complete MDS­ 
UPDRS is not completed on 
Admission due to it taking 
place <7 days afte1· 
S creening , then the MDS­ 
UPDRS Part III only should 
also take place on Admission 
(Day -1). 
The MDS-UPDRS complete is 
to be perfoimed weekly, while 
the Part III assessment can be 
perfonned multiple times 
dw·ing a day; revis ed timing of 
the complete and Pait III only 
assessments to align more 
closely with appropriate 
timing for these assessments. 
Clarified that the MDS­ 
UPDRS Part III only was to 
be perfonned on Admission if 
less than 7 days had transpired 
since the scre.ening 
assess ment. 
Synopsis, Table 3 
Synopsis, Table 3 
MDS-UPDRS (complete) and 
MDS-UPDRS (complete) and 
MDS-UPDRS (Part III only) 
MDS-UPDRS (Part III only) 
MDS-UPDRS (complete) on 
Days I, 4, 8, 15, and 22. 
MDS-UPDRS (Part III only) 
on Days 2, 3, 5, 6, 7, and 9. 
Removed performance of 
MDS-UPDRS (complete) on 
Days 1, 4, and 8, and added 
it on Day 9. 
Added MDS-UPDRS 
(Pa1·t III onl y ) to Da ys 1, 4 , 
and 8, and removed it from 
Day 9. 
The MDS-UPDRS complete is 
to be perfoimed weekly, while 
the Part III assessment can be 
perfonned multiple times 
dw·ing a day; revised timing of 
the complete and Pait III only 
assessments to align more 
closely with appropriate 
timing for these assessments.. 
 
 
 
 
 
 
 
 
 
S o  sis, Table 3, MDS- 
S o sis, Table 3, MDS- 
Screenin , Admission 
Screening, Admission 
The MDS-UPDRS co 
lete is 


 
Part III only should also 
take place on Admission 
a -1 . 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
UPDRS (complete) footnote 
UPDRS (complete) footnote 
(Day-I), predose Day I and 
Day 4; postdose on Day 8; and 
Days 15 and 22 
(Day - I) (only if time 
between Screening and 
Admission is 7 days), on 
Day 9 pri01· to resuming 
Levodopa, and Days 15 and 
22. 
to be perfo1med weekly ; 
clarifi ed that the MDS­ 
UPDRS complete was to be 
perfo1med on Admission if at 
least 7 days had transpired 
since the screening 
assessment. 
Clarified that the Day 9 
assessment was to be 
perfo1med prior to dosing with 
Levodopa. 
Synopsis, Table 3, MDS­ 
Synopsis, Table 3, MDS­ 
MDS-UPDRS (Part III only): 
MDS-UPDRS (Patt III only): Added MDS-UPDRS (Part III 
UPDRS (Pait III only) 
footnote 
UPDRS (Part III only) 
footnote 
2 (± IO tninute s ) , 4 ( ±IO 
minutes), 8 (±15 tninutes), and 
12 (±15 minutes) hours 
postdose on Days 5, 6, and 8. 
2 (±10 tninutes), 3 (±10 
minutes), 4 (±10 minutes), 8 
(±15 minutes), and 12 (±15 
minutes) hours postdose on 
Days 1, 2, 3, 4, 5, 6, and 7. If 
complete MDS-UPDRS is 
not completed on Admission 
due to it taking place <7 
only) assessments to align 
more closely with appropriate 
titning for this assessment; 
clarified that the MDS­ 
UPDRS (Pait III only) was to 
be perfonned on Admission if 
less than 7 days had transpired 
since the scre.ening 
days after Screening, then 
ass essment. 


 
 
Section number and title in 
Section number and title in 
Amendment 1 (05 Oct 2016)    Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
 
Rationale: 
1-----------------,1---------------+ 
---------+ 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 9.1.2, Part B 
Section 9.1.2, Part B 
Subjects randomized to the 
Levodopa plus SAGE-217 
Oral Solution arm will receive 
this combination in the AM 
for the first 4 days (Days 1 to 
4). 
Subjects randomized to the 
Levodopa plus SAGE-217 
Oral Solution arm will receive 
this combination in the AM 
for the first 4 days (Days 1 to 
4).  Subjects will receive 
their individually established 
tolerated dose of SAGE-217 
Oral Solution from Part A. 
Added the statement for 
consistency with next bullet: 
Subjects will receive their 
individually established 
tolerated dose of SAGE-217 
Oral Solution from Part A. 
Section 9.4, Randomization 
and Blinding 
Section 9.4, Randomization 
and Blinding 
Subjects will be randomly 
assigned in a 1:1 manner to 
one of two treatment groups: 
open-label Levodopa plus 
blinded SAGE 217 Oral 
Solution or matching placebo 
oral solution. 
Subjects will be randomly 
assigned in a 1:1 manner to 
one of two treatment groups: 
open-label Levodopa plus 
blinded SAGE 217 Oral 
Solution or placebo oral 
solution. 
Deleted “matching” from 
placebo oral solution. 
Section 10.5, Administration 
Section 10.5, Administration 
SAGE-217 Oral Solution or 
matching placebo will be 
administered in the morning 
with food. 
SAGE-217 Oral Solution or 
placebo oral solution will be 
administered in the morning 
with food. 
Deleted “matching” from 
placebo and added oral 
solution. 
Section 11.1, MDS-UPDRS 
Section 11.1, MDS-UPDRS 
The complete MDS-UPDRS is 
to be administered in Part A at 
screening, Admission (Day - 
1), predose on Days 1, 2, 3, 
and 4; postdose on Day 7; and 
on Day 14. The complete 
MDS-UPDRS is to be 
administered in Part B at 
screening, Admission (Day - 
1), predose on Days 1 and 4; 
postdose on Day 8; and on 
Days 15 and 22. 
The complete MDS-UPDRS is 
to be administered in Part A at 
screening, Admission (Day - 
1), on Day 8 prior to 
resuming Levodopa, and on 
Day 14. The complete MDS- 
UPDRS is to be administered 
in Part B at screening, 
Admission (Day -1), on Day 9 
prior to resuming Levodopa; 
and on Days 15 and 22. In 
both Parts A and B, the 
Admission (Day -1) complete 
MDS-UPDRS is performed 
only if the time between 
Screening and Admission is 
Clarified that the Day 8 
assessment in Part A and the 
Day 9 assessment in Part B 
were to be performed prior to 
dosing with Levodopa. 
The MDS-UPDRS complete is 
to be performed weekly while 
the Part III assessment can be 
performed multiple times 
during a day; clarified that the 
MDS-UPDRS complete was 
to be performed on Admission 
if at least 7 days had 
transpired since the screening 
assessment and the MDS- 
UPDRS (Part III only) was to 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
7 days; otherwise, the MDS be performed on Admission if 
UPDRS Part III only is 
less than 7 days had transpired 
performed. 
since the screening 
assessment. 
Prut III of the MDS-UPDRS 
Added MDS-UPDRS (Part III 
(motor examination) is to be 
only) assessments to align 
completed in Part A at 2, 4, 8, 
more closely with appropriate 
and 12 hours postdose on 
timing for this assessment; 
Days 1, 2, 3, 4, 5, 6, and 7, 
clrui·fied that the MDS­ 
and in Pait B at 2, 3, 4, 8, and 
UPDRS complete was to be 
12 hours  postdose on Days 1, 
perfonned on Admission if at 
2, 3, 4, 5, 6, 7, and 9. If the 
least 7 days had transpired 
complete MDS-UPDRS is 
since the scre.ening ass ess men t 
not performed on Admission and the MDS-UPDRS (Part III 
due to Admission taking 
only) was to be perfonned on 
place <7 days after 
Admission if less than 7 days 
Screening, then Part III only had transpired since the 
should also take place on 
screening assessment. 
Admission (Day -1) for both 
Parts A and B. 


Section number and title in 
Section number and title in 
Amendment 1 (05 Oct 2016) Amendment 2 (24 Oct 2016) 
Original text: 
Rationale: 
Changed to: 
 
 


Sectionnumber and title in 
Section number and title in 
Amendment 1 (05 Oct 2016) Amendment 2 (24 Oct 2016) 
Original text: 
Rationale: 
Changed to: 
 
1-----------------,1---------------1-------------+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 14.4.2, Exploratory 
Efficacy Endpoints 
 
Section 14.4.2, Exploratory 
Efficacy Endpoints 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
 
Original text: 
Changed to: 
 
Rationale: 
 
 
 
 
 
 
Section 20, List of References Section 20, List of References 
Goetz CG, Poewe W, Rasco! 
Deleted this reference. 
The text related to this 
0 , et al. Movement Disorder 
reference was deleted, so the 
Society Task Force Repo1t on 
reference was removed. 
the Hoehn and Yahr Staging 
Scale: Status and 
Recommendations. Mov Dis. 
2004;19(9):I 020-8. 
Appendix 2, Hoehn and Yahr 
Appendix 2, Hoehn and Yahr 
The original scale included 5 
The original scale included 5 
The original scale was to be 
Staging Criteria 
Staging Criteria 
disease stages, numbered I to 
disease stages, numbered 1 to 
used. Deleted sentence about 
5. The scale was later 
5. 
modified scale, deleted 
modified to include two 
reference that was cited, and 
intermediate stages (Goetz 
deleted table displaying 
2004). 
modified scale. 
Table showing the modified 
Hoehn and Yahr Scale 
(includes additional stages of 
0, 1.5, and 2.5) 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
 
Original text: 
Changed to: 
--- 
 
Rationale: 


 
 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Section number and title in 
Amendment 2 (24 Oct 2016) 
 
Original text: 
Changed to: 
 
Rationale: 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
1 
 
 
 
 
 
1. 
TITLE PAGE 
 
 SAGE 
THERAPEUTICS 
 
PROTOCOL NUMBER: 217-PRK-201 
A PHASE 2, TWO-PART STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF SAGE-217 ORAL SOLUTION IN 
PATIENTS WITH PARKINSON'S DISEASE OF 
MODERATE SEVERITY RESPONDING TO 
IMMEDIATE-RELEASE ORAL 
LEVODOPA/CARBIDOPA AND WITHDRAWN FROM 
LEVODOPA/CARBIDOPA 
IND NUMBER: 131,258 
Investigational Product 
Clinical Phase 
Sponsor 
Sponsor Contact 
SAGE-217 
2 
Sage Therapeutics, Inc. 
 
 
 
 
Ph.D. 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
Date of Odginal Protocol 
Date of Amendment 1 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
_ 
, M.D., M.P.H. 
Study Physician 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
28 September 2016 
5 October2016 
, M.D.,


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
2 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
3 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
 
 
Protocol Number: 
Product: 
IND No.: 
Study Phase: 
Sponsor: 
Date of Amendment 1: 
 
 
 
Sponsor Approval 
 
217-PRK-201 
SAGE-217 Oral Solution 
131,258 
2 
Sage Therapeutics 
Version 2.0 05 October 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician 
Sage Therapeutics 
Date (DD/MMMN YYY) 
 
 
 
Date (DD/MMM/YYYY) 
 
 
 
 
Date (DD/MMM/YYYY) 
 
 
 
 
Date (DD/MMM/YYYY) 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
4 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PRK-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
5 
 
 
CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
  
Address and Telephone Number  
Clinical Research Organization 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
6 
 
 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Efficacy of SAGE-217 Oral Solution in Patients with Parkinson’s Disease (PD) of Moderate Severity 
Responding to Immediate-Release Levodopa/Carbidopa and Withdrawn from Levodopa/Carbidopa 
Study centers: Up to 4 centers 
Objectives: 
Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
Secondary: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral Solution in combination with immediate-release oral 
Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
Endpoints: 
Primary: 
• Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) during both Part A and Part B. 
Secondary: 
Part A: 
• Improvement in PD motor symptoms as assessed by changes in the Movement Disorder Society- 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) – Part III (Motor Examination) score. 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
7 
 
 
 
Part B: 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS - Pait III score. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS- Patts I-IV total 
score. 
• 
Sleepiness/sedation as assessed by the StanfordSleepiness Scale (SSS) and Modified Obse1ver's 
Assessment of Analgesia/Sedation (MOAAIS) scores. 
In addition, plasma concentrations of SAGE-217 and possibly SAGE-217metabolites will be measured, 
and PK paia· meters will be derived. 
Exploratory Endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methodology: 
This study will assess the safety, tolerability, pha1macokinetics (PK), and efficacy of SAGE-217 Oral 
Solution. For ease of discussion, Levodopa aloneor Cai·bidopa-Levodopacombination will be refened 
to as Levodopa in this protocol. 
Thereare two paits: 
Part A: Open-label with morning (AM) dosing (4 days). 
All subjectswill continue to take their antipai·lcin so nian agents including immediate-releaseoral 
Levodopa on the day of admission (Day -1) and in the AM the following 3 days (Days 1 to 3). All 
subjects will stop their immediate-release oral Levodopa on Day 4 and will strut on a 30 mg dose of 
SAGE-217Oral Solution administeredin the AM with food. Subjects not tolerating 30 mg will receive 
20 mg, and subjects not tolerating 20 mg will receive IO mg on subsequent days. The dose received on 
Day 7 will be defined as the tolerateddose for that subject. Subjects not tolerating IO mg will not be 
able to continue in the study and may be replaced. Subjects will be followedfor an additional 7 days 
(Day 14) after the administration of the last dose. Levodopatreatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment (oral Levodopaor other antipaik· insonian agent at Investigator's discretion) will be 
allowed, if needed, on all days (Days I to 7). 
Pait A is designed to dete1mine the tolerated dose of SAGE-217Oral Solution for each subjectand to 
assess whether SAGE-217exhibits efficacy in subjectswith PD in order to info1mthe conduct of Pait B. 
   Part B: Randoinized, lacebo-controlled, two-se uence crossover with AM dosin (u to 8 da s). 
 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
8 
 
 
 
Part B will be initiated only after review of the Part A interim analysis. 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at least 10 mg of 
SAGE-217 Oral Solution in Part A. Subjects who complete Part A through Day 14 will be re-admitted 
on Day -1 of Part B and they will receive their antiparkinsonian agent including immediate-release oral 
Levodopa. Subjects will be randomized the next day (Day 1) in a 1:1 manner to open-label Levodopa 
plus blinded SAGE-217 Oral Solution or placebo during Period 1 of the crossover. Subjects randomized 
to the combination arm of Levodopa and SAGE-217 Oral Solution will receive this combination in the 
morning for the first 4 days (Days 1 to 4). Subjects randomized to the Levodopa plus placebo arm will 
receive Levodopa and SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 
to 4). On Day 5, all subjects will crossover to Period 2 and will only receive open-label SAGE-217 Oral 
Solution for the remaining 4 days (Days 5 to 8). Subjects will receive their individually established 
tolerated dose of SAGE-217 Oral Solution (from Part A). All subjects will be able to resume Levodopa 
from Day 9 onwards. Rescue treatment (at Investigator’s discretion) will be allowed, if needed, on all 
days (Days 1 to 8). 
All doses of SAGE-217 Oral Solution (or placebo) will be administered in the morning with food. If 
subjects are taking Levodopa as opposed to Carbidopa-Levodopa, administration with or without food 
will be determined by the Investigator. 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). If at 
any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged by the 
Investigator to be related to study drug, the dose on the next day must be reduced to the next lowest dose 
and continued for the remainder of the dosing period (ie, subjects who are unable to tolerate the 30 mg 
dose will receive a dose of 20 mg, and subjects who are unable to tolerate 20 mg will receive a 10 mg 
dose on subsequent days). The dose received on Day 7 of the dosing period in Part A will be defined as 
the tolerated dose for that subject, with this dose to be used as the starting dose for Part B for that 
subject. 
Subjects will be exposed to SAGE-217 Oral Solution for up to 12 days (4 days in Part A and up to 
8 days in Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part A and Part B (Table 2 and Table 3, respectively). 
Number of patients (planned): 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the conduct of Part B. Twelve subjects are anticipated 
to be randomized in Part B. 
Diagnosis and main criteria for inclusion: All of the following inclusion and exclusion criteria will 
be applied during screening for Part A, with some of the criteria applied during screening for Part B, as 
indicated. 
Inclusion criteria: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Subjects with PD with a duration of less than 7 years and must meet the criteria for Hoehn and Yahr 
stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral Levodopa or 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
9 
 
 
 
Carbidopa-Levodopa (defined as no changes for a period of at least 1 month prior to the baseline 
visit) and is expected to remain on this stable dose for the duration of this study. 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa or 
Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or amantadine 
at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been on a stable 
dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical examination, 
12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on study, and 
for 30 days after receiving the last dose of study drug. Highly effective methods of birth control 
include combined (estrogen and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of 
ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with female 
partner's highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. (Part B also) 
Exclusion criteria: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major excipient, HPβCD. 
(Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 4 or 
stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her ability for 
participation. This includes schizophrenia spectrum and other psychotic disorders, substance-related 
and addictive disorders, feeding and eating disorders, bipolar and related disorders, structural brain 
disease including but not limited to history of encephalitis or hydrocephalus and history of clinically 
significant stroke, or anticipating starting psychotherapy or behavior therapy during the course of the 
study or who started psychotherapy or behavior therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), metabolic 
identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other atypical Parkinsonian 
syndromes (eg, progressive supranuclear palsy, multiple system atrophy). (Part B also) 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
10 
 
 
 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 
(Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the screening 
or admission visits. NOTE: QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the study. ECG 
may be repeated once if initial values obtained are outside the specified limits. (Part B also) 
10. Subject has a history, presence and/or current evidence of serologic positive results for hepatitis B 
surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
11. Subject has exposure to another investigational medication or device within 30 days prior to Part A 
Day 1. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subjects has used any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug. (Part B also) 
Investigational product, dosage and mode of administration: 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Duration of treatment: 7 days in Part A; 8 days in Part B 
Part A: 
Screening duration: up to 28 days; Treatment Period: 7 days; Follow-up: 7 days 
Planned participation per subject: approximately 42 days during Part A. 
Part B: 
Screening duration: up to 14 days; Treatment Period: 8 days; Follow-up: 14 days 
Planned participation per subject: approximately 36 days during Part B. 
Reference therapy, dosage and mode of administration: 
In part B, placebo will be matched to SAGE-217 Oral Solution. 
Criteria for evaluation: 
Safety and tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs, clinical laboratory measures, 
ECGs, physical examinations, concomitant medication usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS and MOAA/S. 
Efficacy: 
Improvement in PD motor symptoms and overall symptoms will be assessed by changes in the 
MDS-UPDRS Part III score and MDS-UPDRS Parts I-IV total score at various time points. 


Sage Therapeutics 
Protocol 217-PRK-201 
Version 2.0 5 October 2016 
11 
 
 
 
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217 and possibly SAGE-217 metabolites. 
The following PK parameters will be derived from the plasma concentrations (where evaluable): area 
under the concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration 
(Cmax), time to reach maximum concentration (tmax), the distributional half-life and terminal half-life 
(t1/2), and steady-state drug concentration in the plasma (Css). 
Statistical methods: 
Study Populations 
The safety population, defined as all subjects who are administered study drug, will be used to provide 
descriptive summaries of safety. 
The efficacy population, defined as all subjects in the safety population who receive at least one dose of 
study drug and have at least one postdose MDS-UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations and will be used to summarize PK data. 
Separate populations will be defined for each part of the study. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time point 
and summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™ (MedDRA). The 
overall incidence of adverse events will be displayed by System Organ Class (SOC), preferred term, 
dose group, and cohort. Incidence of adverse events will also be presented by maximum severity and 
relationship to study drug. Vital signs, clinical laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and cohort, where applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data presentation 
methods where applicable; subject listings will be provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A is planned to inform Part B study conduct. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject. 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
12 
 
 
Table 2: 
Schedule of Events: Part A (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose for Day 4, Day 6, and Day 8; and Day 14 
c Urinalysis: Screening and Admission (Day -1); predose for Day 4 and Day 7; and Day 14. 
d Vital Signs: Screening and Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM 
of Day 8; and Day 14. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; 
and Day 14. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose on Day 1 and Day 3; predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on 
Confinement Days 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1, Day 2 and Day 3; predose on Day 4, Day 5, Day 6, and Day 7; and Day 8 and 
Day 14. 
h SSS: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
The SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
p 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
Administer Levodopa or 
q 
Carbidopa-Levodopa 
X 
X 
X 
Administer SAGE-217q 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
14 
 
 
i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. The MOAA/S is to 
be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
j MDS-UPDRS (complete): Screening, Admission (Day -1), predose Day 1, Day 2, Day 3, and Day 4; postdose on Day 7; and Day 14. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 5, 6, and 8. 
 
 
 
p Plasma PK sampling times (±5 minutes): Day 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 
4, 8, and 12 hours on Day 7; in AM of Day 8; and Day 14. PK samples are to be collected within ±5 minutes of the scheduled sampling time. 
q Levodopa or Carbidopa-Levodopa and SAGE-217 are to be administered in the morning 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
15 
 
 
Table 3: 
Schedule of Events: Part B (Randomized, Placebo-Controlled) 
 
Visit Days 
Screening 
(Day -14 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 
 


Protocol 217-PRK-201 
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16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 9 assessments. 
b Screening and Safety Laboratory Tests: Screening and Day -1 [Admission]; predose for Day 1, Day 3, Day 4, Day 5, Day 6, and Day 8; and Day 9 and Day 15. 
c Urinalysis: Screening and Admission (Day -1); Predose for Day 4 and Day 8; Day 15. 
d Vital Signs: Screening and Day -1 [Admission]; predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM 
of Day 9; and Days 15 and 22. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; 
and Day 15. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, 
and 8; in AM of Day 9; and Days 15 and 22. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1 through Day 8; Day 9, Day 15 and Day 22. 
h Day -1 [Admission]; predose on Days 1 through Day 8; Day 9, and Day 15 and Day 22. 
i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; and Days 15 and 22. The 
MOAA/S is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the scheduled times thereafter. 
j MDS-UPDRS (complete): Screening, Admission (Day -1), predose on Day 1 and Day 4; postdose on Day 8; and Days 15 and 22. 
Visit Days 
Screening 
(Day -14 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
q 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study Drug 
r 
Combination 
X 
X 
X 
X 
Administer SAGE-217 
onlyr 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 2, 3, 5, 6, 7, and 9. 
 
 
 
 
 
q Plasma PK sampling times: Days 1 to 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, 
and 12 hours postdose on Day 7 and Day 8; in AM of Day 9; and Day 15 and Day 22. PK samples are to be collected within ±5 minutes of the scheduled 
sampling time. 
r Study drug is to be administered in the morning. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ............................................................................................................... 1 
2. 
SYNOPSIS .................................................................................................................. 6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .............. 18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 25 
5. 
INTRODUCTION ..................................................................................................... 27 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need ................................ 27 
5.2. 
SAGE-217 Oral Solution ........................................................................................... 28 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 .......................... 28 
5.3.1. 
Nonclinical Studies with SAGE-217 ......................................................................... 28 
5.3.2. 
Clinical Experience .................................................................................................... 28 
5.4. 
Potential Risks and Benefits ...................................................................................... 30 
6. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 31 
6.1. 
Primary Objective ...................................................................................................... 31 
6.2. 
Secondary Objectives ................................................................................................ 31 
6.3. 
Endpoints ................................................................................................................... 31 
6.3.1. 
Primary Endpoints ..................................................................................................... 31 
6.3.2. 
Secondary Endpoints ................................................................................................. 31 
6.3.3. 
Exploratory Endpoints ............................................................................................... 31 
7. 
INVESTIGATIONAL PLAN .................................................................................... 33 
7.1. 
Overall Study Design ................................................................................................. 33 
7.2. 
Number of Subjects ................................................................................................... 34 
7.3. 
Treatment Assignment ............................................................................................... 34 
7.4. 
Dose Adjustment Criteria .......................................................................................... 35 
7.5. 
Criteria for Study Termination .................................................................................. 35 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................. 37 
8.1. 
Subject Inclusion Criteria .......................................................................................... 37 
8.2. 
Subject Exclusion Criteria ......................................................................................... 38 
8.3. 
Entrance Criteria for Part B ....................................................................................... 39 
8.4. 
Subject Withdrawal Criteria ...................................................................................... 39 


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9. 
TREATMENT OF SUBJECTS ................................................................................. 40 
9.1. 
Description of Study Drug ......................................................................................... 40 
9.1.1. 
Part A ......................................................................................................................... 40 
9.1.2. 
Part B ......................................................................................................................... 40 
9.2. 
Concomitant Medications .......................................................................................... 40 
9.2.1. 
Prior/Concomitant Medications ................................................................................. 40 
9.2.2. 
Prohibited Medications .............................................................................................. 41 
9.3. 
Treatment Compliance ............................................................................................... 41 
9.4. 
Randomization and Blinding ..................................................................................... 41 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT .......................................... 43 
10.1. 
Study Drug ................................................................................................................. 43 
10.2. 
Study Drug Packaging and Labeling ......................................................................... 43 
10.3. 
Study Drug Storage .................................................................................................... 43 
10.4. 
Study Drug Preparation.............................................................................................. 44 
10.5. 
Administration ........................................................................................................... 44 
10.6. 
Study Drug Accountability ........................................................................................ 45 
10.7. 
Study Drug Handling and Disposal ........................................................................... 45 
11. 
ASSESSMENT OF EFFICACY ............................................................................... 46 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale ............... 46 
11.2. 
Exploratory Endpoints ............................................................................................... 47 
47 
47 
47 
48 
48 
12. 
PHARMACOKINETICS .......................................................................................... 50 
12.1. 
Blood Sample Collection ........................................................................................... 50 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ................................................. 50 
12.3. 
Sample Analysis ........................................................................................................ 50 
13. 
ASSESSMENT OF SAFETY .................................................................................... 51 
13.1. 
Safety and Tolerability Parameters ............................................................................ 51 
13.1.1. 
Demographic/Medical History .................................................................................. 51 
13.1.2. 
Vital Signs ................................................................................................................. 51 


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13.1.3. 
Weight and Height ..................................................................................................... 51 
13.1.4. 
Physical Examination ................................................................................................ 51 
13.1.5. 
Electrocardiogram (ECG) .......................................................................................... 51 
13.1.6. 
Laboratory Assessments ............................................................................................ 52 
13.1.6.1. 
Hematology ................................................................................................................ 52 
13.1.6.2. 
Blood Chemistry ........................................................................................................ 52 
13.1.6.3. 
Urinalysis ................................................................................................................... 52 
13.1.6.4. 
Virus Serology ........................................................................................................... 52 
13.1.6.5. 
Pregnancy Screen ....................................................................................................... 53 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 53 
13.1.8. 
Stanford Sleepiness Scale (SSS) ................................................................................ 53 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) .............. 53 
13.2. 
Adverse and Serious Adverse Events ........................................................................ 54 
13.2.1. 
Definition of Adverse Events .................................................................................... 54 
13.2.1.1. 
Adverse Event ............................................................................................................ 54 
13.2.1.2. 
Suspected Adverse Reaction ...................................................................................... 54 
13.2.1.3. 
Serious Adverse Event ............................................................................................... 54 
13.2.1.4. 
Recording Sedation as an Adverse Event .................................................................. 55 
13.2.2. 
Pregnancy .................................................................................................................. 55 
13.3. 
Relationship to Study Drug ........................................................................................ 55 
13.4. 
Recording Adverse Events ......................................................................................... 56 
13.5. 
Reporting Serious Adverse Events ............................................................................ 56 
14. 
STATISTICAL METHODS AND CONSIDERATIONS ........................................ 58 
14.1. 
Data Analysis Sets ..................................................................................................... 58 
14.2. 
Handling of Missing Data .......................................................................................... 58 
14.3. 
Demographics and Baseline Characteristics .............................................................. 58 
14.4. 
Efficacy Endpoints ..................................................................................................... 58 
14.4.1. 
Secondary Efficacy Endpoints ................................................................................... 58 
14.4.2. 
Exploratory Efficacy Endpoints ................................................................................. 58 
14.5. 
Safety and Tolerability Analyses ............................................................................... 59 
14.5.1. 
Adverse Events .......................................................................................................... 59 
14.5.2. 
Vital Signs ................................................................................................................. 59 
14.5.3. 
Physical Examinations ............................................................................................... 59 


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14.5.4. 
12-Lead ECG ............................................................................................................. 60 
14.5.5. 
Clinical Laboratory Evaluations ................................................................................ 60 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 60 
14.5.7. 
Stanford Sleepiness Scale (SSS) ................................................................................ 60 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ....................... 60 
14.5.9. 
Prior and Concomitant Medications .......................................................................... 60 
14.6. 
Pharmacokinetic Analysis.......................................................................................... 61 
14.7. 
Determination of Sample Size ................................................................................... 61 
14.8. 
Changes From Protocol Specified Analyses .............................................................. 61 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 62 
15.1. 
Study Monitoring ....................................................................................................... 62 
15.2. 
Audits and Inspections ............................................................................................... 62 
15.3. 
Institutional Review Board (IRB) .............................................................................. 63 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 64 
17. 
ETHICS ..................................................................................................................... 65 
17.1. 
Ethics Review ............................................................................................................ 65 
17.2. 
Ethical Conduct of the Study ..................................................................................... 65 
17.3. 
Written Informed Consent ......................................................................................... 65 
18. 
DATA HANDLING AND RECORDKEEPING ...................................................... 66 
18.1. 
Inspection of Records ................................................................................................ 66 
18.2. 
Retention of Records ................................................................................................. 66 
18.3. 
Confidentiality ........................................................................................................... 66 
19. 
PUBLICATION POLICY ......................................................................................... 68 
20. 
LIST OF REFERENCES ........................................................................................... 69 
21. 
APPENDICES ........................................................................................................... 71 
APPENDIX 1.   UNITED KINGDOM BRAIN BANK CRITERIA ........................................... 72 
APPENDIX 2.   HOEHN AND YAHR STAGING CRITERIA .................................................. 73 
APPENDIX 3.   ANTICHOLINERGIC DRUGS ........................................................................ 74 
APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED PARKINSON'S 
DISEASE RATING SCALE (MDS-UPDRS) ................................................... 75 
76 
77 
80 


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81 
APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION AND SINCE LAST VISIT 
VERSION .......................................................................................................... 84 
APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS) ....................................................... 90 
APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ............................................................. 91 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................. 5 
Table 2: 
Schedule of Events:  Part A (Open-Label) ................................................................ 12 
Table 3: 
Schedule of Events:  Part B (Randomized, Placebo-Controlled) .............................. 15 
Table 4: 
Abbreviations and Specialist Terms .......................................................................... 25 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL ................. 44 
Table 6: 
Rating Scale for the MDS-UPDRS ............................................................................ 46 


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LIST OF FIGURES 
Figure 1: 
Study Design of Part A .............................................................................................. 36 
Figure 2: 
Study Design of Part B .............................................................................................. 36 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
 
 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CS 
clinically significant 
Css 
steady-state drug concentration in the plasma 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EP 
European Pharmacopeia 
GABA 
γ aminobutyric acid 
GABAA 
γ aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Levodopa/Carbidopa 
Levodopa or Carbidopa-Levodopa 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MoCA 
Montreal Cognitive Assessment 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant 
NF 
National Formulary 
PD 
Parkinson’s disease 
 
 
PK 
pharmacokinetic(s) 
PM 
evening 
QTcF 
QT interval calculated using the Fridericia method 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal half-life 
tmax 
time to reach maximum concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need 
Parkinson’s disease (PD) is a chronic progressive neurodegenerative condition that affects the 
motor, autonomic, cognitive, and sensory systems. Parkinson’s disease is the second most 
common neurodegenerative disorder (Bergman 2002) and is associated with a massive loss of 
dopaminergic cells in the substantia nigra, leading to dopamine hypofunction and alteration of 
the basal ganglia circuitry. Dopamine neurons are under the control of the excitatory 
glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. Imbalance between the 
glutamatergic and GABA systems may contribute to excitotoxicity and dopaminergic cell death. 
The motor symptoms of PD have been linked with a loss of dopamine neurons in the substantia 
nigra pars compacta and a consequential reduction in the level of dopamine input in the striatum 
(Siderowf 2012). These symptoms evolve slowly and are characterized by the progression of 
tremor, rigidity, bradykinesia, and postural instability. Tremor caused by PD can appear as 
either a resting tremor or an action tremor. The most typical tremor of PD is a “pill-rolling” rest 
tremor between the thumb and index finger. Not everyone with PD develops a tremor, and those 
who do experience tremor may have symptoms that come and go. Typically, PD tremor starts in 
the fingers of one hand before spreading to affect the rest of the arm. Tremor can also spread to 
affect the foot on the same side of the body and, after several years, the tremor can spread to 
affect the other side of the body. Without treatment, PD tremor usually worsens over time. 
At present, there is no cure for PD. The core symptoms are caused by the degeneration of 
dopamine-producing neurons and, therefore, treatment consists of dopamine replacement. While 
enormous progress has been made in the treatment of PD over the past half century, levodopa 
remains the most potent drug for controlling PD symptoms (Jankovic 2008). The addition of 
carbidopa, a peripheral dopa decarboxylase inhibitor, enhances the therapeutic benefits of 
levodopa.  However, levodopa therapy is frequently associated with motor complications, and 
the appropriate time to initiate levodopa therapy continues to be debated (Stern 2004; 
Weiner 2004). The majority of patients treated with levodopa experience motor fluctuation, 
dyskinesia or other complications after 5 years of treatment (Jankovic 2005). 
Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of 
several neurotransmitter systems. The substantia nigra expresses high concentrations of 
allopregnanolone, a neurosteroid that positively modulates the action of GABA at 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. In PD patients, 
decreased plasma and cerebrospinal fluid levels of the neurosteroid allopregnanolone and 
5α-dihydroprogesterone have been observed (di Michele 2003). 
Parkinson’s disease is the second most common chronic neurodegenerative disease, affecting 
about 1 million people in the United States and more than 4 million people worldwide. It has a 
devastating effect on patients and is often accompanied by tremendous physical and emotional 
burden not only for the patients but also for their families and friends. As the size of the elderly 
population grows, the burden of PD is projected to grow substantially over the next few decades. 
To date, the therapy of PD is symptomatic, aimed at ameliorating motor symptoms. Although 
the goal of therapy is to reverse the functional disability, abolition of all symptoms and signs is 


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not currently possible, even with high doses of medication. Thus, there is a growing need for 
innovative new treatments to prevent, delay onset, or alleviate symptoms of PD. Neurosteroids 
act as neuroprotectants and as GABAA-receptor agonists in the physiology and pathology of the 
basal ganglia, impact dopaminergic cell activity and survival, and may therefore represent 
potential therapeutics in PD. 
 
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of PD. 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a non-viscous, clear solution. 
 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies and in toxicology studies. The sedative- 
hypnotic impairments seen with SAGE-217 were typical for GABAA-positive modulators, 
ranging from hyperexcitability and ataxia at the lower doses through deep sedation and 
ultimately anesthesia at higher doses. Depth and duration of sedation demonstrated a clear dose 
response over the range tested, with evidence of tolerance occurring with continued exposure. 
Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 7 days of 
dosing. 
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats. The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. 
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study that was suspected to have been related to exaggerated pharmacology. Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure. 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending. Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food effect, and essential tremor cohorts from Study 217-CLP-101 
and the multiple-ascending dose and drug-drug interaction cohorts from Study 217-CLP-102. 
Discussions of safety data are limited to the single-ascending dose cohorts in Study 217 CLP 101 
and the multiple-ascending dose cohorts in Study 217-CLP-102. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217. The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution. Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 


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55 mg, and 66 mg. Escalation to the next dose was undertaken only after safety and PK data 
were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose. The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each, 
received SAGE-217 Oral Solution in an open-label manner (one cohort received 50% of the 
MTD [22 mg] to study the food effects and the other cohort received the MTD [55 mg] to study 
the effects on subjects with essential tremor). SAGE-217 Oral Solution was orally bioavailable, 
demonstrated dose-linear PK from the lowest (0.25 mg) through the highest (66 mg) dose, and 
supported once-daily oral dosing with food. In addition, the pharmacodynamic effects of the 
SAGE-217 Oral Solution MTD were assessed in placebo-controlled, blinded, crossover 
electroencephalogram cohorts of 8 subjects each; one cohort received 50% of the MTD (22 mg) 
and the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers. Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 
7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg. Escalation to the next 
dose was undertaken only after safety and PK data were reviewed by the SRC and agreement 
reached that it was safe to increase the dose. The MTD was determined to be 30 mg. It was 
observed that subjects receiving the drug in the evening did better in terms of tolerability 
compared to when they received the drug in the morning.  A fourth cohort of 12 subjects 
received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug-drug 
interactions.  SAGE-217 Oral Solution is not likely to induce the metabolism of cytochrome 
P450 (CYP)2B6 or CYP3A4 substrates. SAGE-217 Oral Solution was orally bioavailable and 
suitable for once-daily oral dosing at night time with food. 
SAGE-217 Oral Solution was generally well tolerated. In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met. Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 
reported in either study. In addition, none of the observed adverse events resulted in 
discontinuation of the study drug. At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure. The most common treatment-emergent 
adverse events (TEAEs) were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, 
and muscle twitching, reported most frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were observed after single doses of 44 mg and 
greater. After multiple doses of 30 mg (morning [AM] or evening [PM]) or 35 mg (AM) over 
7 days, there was no evidence of changes in mean vital sign measures even though Day 7 plasma 
concentrations approximated that of the highest single dose in the single-ascending dose study. 
Subjects seemed to tolerate SAGE-217 better when given as night time dosing. 
Neuroactive steroids are a class of endogenous and synthetic positive allosteric modulators that 
target both synaptic and extra-synaptic GABAA receptors (Belelli 2002 and confirmed in the 
Sponsor’s in vitro studies). This diverse activity profile suggests that neuroactive steroid 
GABAA receptor-positive allosteric modulators could exhibit robust activity against essential 
tremor. Administration of SAGE-547 injection, a proprietary formulation of the endogenous 
neuroactive steroid, resulted in significant reductions in upper limb kinetic tremor scores 
compared to placebo in a Phase 2 proof‑of‑principle study (IND 122,280). Based on these 


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results with SAGE-547, the study design for single-ascending dose study 217-CLP-101 included 
a cohort of subjects with essential tremor (N=6) who received SAGE-217 Oral Solution (55 mg) 
in an open-label manner. Data from this cohort indicate that single doses of SAGE-217 Oral 
Solution resulted in a reduction in the tremor symptoms, suggesting that SAGE-217 might be 
effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral Solution in PD, since the present study is 
the first study in this indication. 
 
5.4. 
Potential Risks and Benefits 
Protocol 217-PRK-201 is the first clinical study evaluating the efficacy of SAGE-217 Oral 
Solution in PD. Thus, the potential benefits in this population are unknown, although the risks 
are likely to be similar to those mentioned in the Investigator’s Brochure. GABA compounds 
that cross the blood-brain barrier or increase GABA activity alleviate muscle stiffness caused by 
a lack of GABAergic tone (Winkler 1999), validating this receptor as a therapeutic target. Given 
the promising clinical data with another neuroactive steroid (SAGE-547) in conjunction with the 
shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence 
of anxiolytic activity, and safety data of SAGE-217, it is possible that patients may have a 
clinical benefit at the exposures selected for this study. In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-reduction design has been chosen to permit reduction in dose based on tolerability (adverse 
events), specifically sedation, versus treatment effect. Each subject will start with an initial dose 
of 30 mg; subjects unable to tolerate 30 mg will receive 20 mg; subjects unable to tolerate 20 mg 
will receive 10 mg. The tolerated dose for each subject will be the dose taken on Day 7. 
Subjects who tolerate at least the 10 mg dose on Day 7 will be eligible to enroll in Part B. Given 
the high medical need and potential for benefit in PD, there is a favorable benefit-risk evaluation 
to investigate SAGE-217 Oral Solution in PD. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution. 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms 
after withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD 
motor symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral Solution in combination with immediate-release 
oral Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
 
6.3. 
Endpoints 
6.3.1. 
Primary Endpoints 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrncardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) during both Part A and Pait B. 
 
6.3.2. 
Secondary Endpoints 
Part A: 
• 
Improvement in PD motor symptoms as assessed by changes in the Movement Disorder 
Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) - Pali III (Motor 
Examination) score. 
Part B: 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS - Pait III 
score. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - 
Palis I-IV total score. 
• 
Sleepiness/sedation as assessed by the Stanford Sleepiness Scale (SSS) and Modified 
Observer's Assessment of Analgesia/Sedation (MOAA/S) scores. 
 
6.3.3. 
Exploratory Endpoints 
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7. 
INVESTIGATIONAL PLAN 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2 study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217 Oral Solution in up to 18 adult subjects with PD of moderate severity who 
respond to immediate-release oral Levodopa and are on a stable dose. Part A of the study is an 
open-label design with morning (AM) dosing of SAGE-217 for 4 days. Part B of the study is a 
randomized, placebo-controlled, two-sequence crossover design. On Days 1 to 4 (Period 1 of 
crossover), subjects will receive open-label Levodopa plus blinded SAGE-217 or placebo. On 
Days 5 to 8 (Period 2 of crossover), all subjects will receive open-label SAGE-217 Oral Solution 
only. In Part B, subjects will receive their individually established tolerated dose of SAGE-217 
Oral Solution from Part A. Subjects will be exposed to SAGE-217 for up to 12 days (4 days in 
Part A and up to 8 days in Part B) and will be followed for an additional 7 days in Part A and an 
additional 14 days in Part B after the administration of the last dose. 
There are two parts to the study: 
• Part A: Open-label with AM dosing (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM the following 
3 days (Days 1 to 3). All subjects will stop their immediate-release oral Levodopa on 
Day 4 and will start on a 30 mg dose of SAGE-217 Oral Solution administered in the 
morning with food, as outlined in Section 9.1.1. Subjects not tolerating 30 mg will 
receive 20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days 
(Section 7.4). The dose received on Day 7 will be defined as the tolerated dose for that 
subject. Subjects not tolerating 10 mg will not be able to continue in the study and may 
be replaced. Subjects will be followed for an additional 7 days (Day 14) after the 
administration of the last dose. Levodopa treatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 exhibits efficacy in subjects with PD of 
moderate severity in order to inform the conduct of Part B. 
• Part B: Randomized, placebo-controlled, two-sequence crossover with AM dosing (up 
to 8 days). Part B will be initiated only after review of the Part A interim analysis. 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at 
least 10 mg of SAGE-217 Oral Solution in Part A. Subjects who complete Part A will 
be re-admitted on Day -1 of Part B and they will receive their antiparkinsonian agent 
including immediate-release oral Levodopa. Subjects will be randomized the next day 


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(Day 1) in a 1:1 manner to open-label Levodopa plus blinded SAGE-217 Oral Solution 
or placebo during Period 1 of the crossover. All doses of SAGE-217 Oral Solution (or 
placebo) will be administered in the morning with food as outlined in Section 9.1.2. 
Subjects randomized to the Levodopa plus placebo arm will receive Levodopa and 
SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 to 4). 
Subjects randomized to the combination arm of Levodopa and SAGE-217 Oral 
Solution will receive this combination in the AM for the first 4 days (Days 1 to 4). On 
Day 5, all subjects will crossover to Period 2 and will only receive open-label SAGE- 
217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects will receive their 
individually established tolerated dose of SAGE-217 Oral Solution (from Part A). All 
subjects will be able to resume Levodopa from Day 9 onwards. 
Rescue treatment (at Investigator’s discretion) will be allowed, if needed, on all days 
(Days 1 to 8). 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). 
If at any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged 
by the Investigator to be related to study drug, the dose on the next day must be reduced to the 
next lowest dose and continued for the remainder of the dosing period (ie, subjects who are 
unable to tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to 
tolerate 20 mg will receive a 10 mg dose on subsequent days). The dose on Day 7 of the dosing 
period in Part A will be determined to be the tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects will be exposed to SAGE-217 for up to 12 days (4 days in Part A and up to 8 days in 
Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
The study designs of Part A and Part B are displayed in Figure 1 and Figure 2, respectively. 
Assessments will be performed periodically during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and Table 3, respectively). 
 
7.2. 
Number of Subjects 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14 to inform the conduct of Part B. Twelve 
subjects are anticipated to be randomized in Part B. 
 
7.3. 
Treatment Assignment 
SAGE-217 will be administered in the morning with food in Parts A and B. Food intake will be 
standardized as specified by the Sponsor. If subjects are taking Levodopa as opposed to 
Carbidopa-Levodopa, administration with or without food will be determined by the 
Investigator. 
Part A of the study is open-label. Part B of the study is randomized, placebo-controlled, two- 
sequence crossover. Subjects will be randomly assigned in a 1:1 manner to receive open-label 
Levodopa plus blinded SAGE-217 Oral Solution or placebo for 4 days (Days 1 to 4, Period 1 of 
crossover). Subjects, clinicians, and the study team will be blinded to treatment allocation. The 
pharmacist, who will prepare the oral solutions according to the randomization schedule, will be 


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unblinded. For the remaining 4 days of Part B (Days 5 to 8, Period 2 of crossover), all subjects 
will discontinue Levodopa and will receive their individually established tolerated dose of 
SAGE-217 Oral Solution from Part A in an open-label manner. 
Dose reductions for lack of tolerability will be allowed during both parts of the study 
(Section 7.4). 
 
7.4. 
Dose Adjustment Criteria 
Dose reductions of SAGE-217 for lack of tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part A, as determined by the Investigator, the 
dose on the next day will be reduced to the next lowest dose (ie, subjects who are unable to 
tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 
20 mg will receive a 10 mg dose on subsequent days). The dose received on Day 7 of Part A 
will be determined to be the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject 
 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons. In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects. 


 
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Figure 1: 
Study Design of Part A 
NOTE: In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of SAGE-217 Oral Solution in Part A. 
Figure 2: 
Study Design of Part B 
NOTE: Part B will be initiated only after review of the Part A interim analysis (after 10 subjects have completed Part A). 
 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 18 subjects will be enrolled in Part A at up to 4 study centers. All of 
the following inclusion and exclusion criteria will be applied during screening for Part A, with 
some of the criteria applied during screening for Part B, as indicated. 
 
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures 
are performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria 
(modified to allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Subjects with PD with a duration of less than 7 years and must meet the criteria for 
Hoehn and Yahr stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral 
Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month 
prior to the baseline visit) and is expected to remain on this stable dose for the duration of 
this study. 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa 
or Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been 
on a stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on 
study, and for 30 days after receiving the last dose of study drug. Highly effective 
methods of birth control include combined (estrogen and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on 
study, and for 13 weeks after receiving the last dose of study drug. Effective methods of 
birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with female partner's highly effective method. (Part B also) 


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13. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. (Part B also) 
 
8.2. 
Subject Exclusion Criteria 
Subjects who met any of the following exclusion criteria will be excluded from the study: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major 
excipient, HPβCD. (Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 
4 or stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia spectrum and other psychotic 
disorders, substance-related and addictive disorders, feeding and eating disorders, bipolar 
and related disorders, structural brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of clinically significant stroke, or anticipating 
starting psychotherapy or behavior therapy during the course of the study, or who started 
psychotherapy or behavior therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 
on the C-SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other 
atypical Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system 
atrophy). (Part B also) 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease. (Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. ECG may be repeated once if initial values obtained are outside the 
specified limits. (Part B also) 
10. Subject has a history, presence and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 and 2. 


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11. Subject has exposure to another investigational medication or device within the prior 
30 days. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of 
blood within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subject has used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug. (Part B also) 
 
8.3. 
Entrance Criteria for Part B 
In addition to the inclusion and exclusion criteria determined at screening for Part B indicated in 
Section 8.1 and Section 8.2, respectively, subjects must be able to tolerate at least 10 mg of 
SAGE-217 in Part A in order to be enrolled into Part B. Part B will not be initiated until results 
of the Part A interim analysis have been reviewed. 
 
8.4. 
Subject Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s). 
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events; 
• Occurrence of pregnancy; 
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance; 
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject fails to attend scheduled assessments during the course of the study, the Investigators 
must determine the reasons and the circumstances as completely and accurately as possible and 
document this in the subject’s source documents. 
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant. Any subject who is withdrawn 
from the study for any reason is to have the final visit assessments performed. 
Subjects who withdraw or are withdrawn from the study may be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
9.1.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner. All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM the following 3 days 
(Days 1 to 3). On the morning of Day 4, subjects will stop their immediate-release oral 
Levodopa and take SAGE-217 for 4 days (Days 4 to 7) in the AM with food. On Day 4, subjects 
will receive a 30 mg dose of SAGE-217. Subjects not tolerating 30 mg will receive 20 mg the 
next day, and subjects not tolerating 20 mg will receive 10 mg the next day. The dose received 
on Day 7 will be defined as the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject. 
Subjects not tolerating 10 mg will not be able to continue in the study and may be replaced. 
Levodopa treatment will be resumed on Day 8 and continue through Day 14. 
 
9.1.2. 
Part B 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217 Oral Solution. On Day 1 of Part B, subjects will be randomized in a 1:1 manner to 
open-label Levodopa plus blinded SAGE-217 Oral Solution or placebo. 
• Subjects randomized to the Levodopa plus placebo arm will receive Levodopa plus 
SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 to 
4). 
• Subjects randomized to the Levodopa plus SAGE-217 Oral Solution arm will receive 
this combination in the AM for the first 4 days (Days 1 to 4). 
• On Day 5, all subjects will crossover to Period 2 and will only receive open-label 
SAGE-217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects will 
receive their individually established tolerated dose of SAGE-217 Oral Solution from 
Part A. 
• All subjects will be able to resume Levodopa from Day 9 onwards. 
9.2. 
Concomitant Medications 
9.2.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.2. 


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Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
taken during the study. 
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit. Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications. New concomitant medications, ongoing 
concomitant medications with a change in dose, and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified. 
The Investigator will document all doses of Levodopa and Carbidopa-Levodopa taken by the 
subject and the use of rescue medication. 
 
9.2.2. 
Prohibited Medications 
Subjects who have used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug are to be excluded from the study; these medications/products are 
prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 and amantadine are not permitted in the 
5 days prior to the admission visit (Day -1) of each part of the study. The list provides non- 
exhaustive examples of each drug class. 
 
9.3. 
Treatment Compliance 
Study drug (SAGE-217 or matched placebo) will be prepared by the site pharmacist. All doses 
of study drug will be administered by site staff while the subject is confined to the clinical unit. 
The Investigator(s) or designee will record the time and dose of study drug administration in the 
source documents. Any reasons for noncompliance will also be documented, including: 
• Missing visits; 
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. 
 
9.4. 
Randomization and Blinding 
Part A of the study is open-label. 
In Part B is a randomized, placebo-controlled, two-sequence crossover study. Subjects will be 
randomly assigned in a 1:1 manner to one of two treatment groups: open-label Levodopa plus 
blinded SAGE-217 Oral Solution or matching placebo oral solution. Subjects, clinicians, and the 
study team will be blinded to treatment allocation. The pharmacist, who will prepare the oral 
solutions according to the randomization schedule, will be unblinded. 


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During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor. If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures. 
The blinding of the study will be broken after the database has been locked. Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the electronic case report form (eCRF). If the 
subject or study center personnel (other than pharmacist) have been unblinded, the subject will 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dosages. The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient(s) in the Bottle (manufactured under current Good Manufacturing Practice [GMP] 
conditions 
) and further admixed at the clinical site in preparation for dosing. 
Placebo will be matched to SAGE-217 study drug. Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual. 
The Sponsor will not provide Levodopa or Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa-Levodopa. 
 
10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation. Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization. 
 
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 Oral Solution and placebo oral solution), the Investigator 
or designee will inspect the materials and complete and return the acknowledgment of receipt 
form enclosed with the parcel. A copy of the signed receipt will be kept in the study files. 
The study drug materials for SAGE-217 Oral Solution and placebo oral solution must be 
carefully stored at the temperature specified in the Pharmacy Manual (eg, clinical dosing 
solutions stored at approximately 2 to 8°C for 11 days with 24 hours of room temperature 
excursions allowed after preparation), safely and separately from other drugs. The study drug 
may not be used for any purpose other than the present study. After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies. An accurate, timely record of 
the disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 


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• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented. This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Study Drug Preparation 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual. The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5. 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
 
Ingredient 
Compendia Specification 
Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations: EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
Additional excipients may be utilized in placebo to match the taste of SAGE-217 Oral Solution. 
They include sucrose octaacetate, tannic acid, and ammonium glycyrrhizate. The quantities may 
vary depending on the dose of SAGE-217. 
 
10.5. 
Administration 
SAGE-217 Oral Solution or matching placebo will be administered in the morning with food. 
Doses of SAGE-217 and placebo for SAGE-217 will be prepared as an approximate 40 mL oral 
solution to be swallowed all at once, followed by approximately 200 mL of water that has been 
used to rinse the dosing bottle. The start time of swallowing the approximately 40 mL oral 
solution is time zero for all assessments. Subjects may have assistance from the clinic staff when 
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During Confinement, each subject’s antiparkinsonian agents, including Levodopa or Carbidopa- 
Levodopa, will be administered by site personnel according to the site’s standard operating 
procedures. 
 
10.6. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded. It must be clear from the records which subject received which dose of active or 
placebo treatment. 
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock. 
The Investigator will document all doses of Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
 
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture of dosing solutions, administration of study drug, and for 
which subject the study drug was intended (ie, record subject initials and birth date or other 
unique identifier). 
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
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11. 
ASSESSMENT OF EFFICACY 
 
 
Assessments will be perfo1med periodicall y dming the study as outlined in 
the Schedule of Events (Table 2 and Table 3). 
 
11.1. 
Movement Disorder Society- Unified Parkinson's Disease Rating 
Scale 
The UPDRS is the most commonly used scale in clinical studies of PD (Ramaker 2002). In 
2007, the MDS revised the scale, which was known as the MDS-UPDRS (Goetz 2007), and 
subsequently demonstrated the validity of the MDS-UPDRS for rating PD (Goetz 2008). The 
modified UPDRS includes four scales, with various subscales. Each item is rated from 0 
(no1m al) to 4 (severe) (Table 6). The four MDS-UPDRS scales are: 
Pait I: nonmotor experiences of daily living (13 items) 
Pait II: motor experiences of daily living (13 items) 
Pait III: motor examination (33 scores based on 18 items [several with right, left or other body 
distribution scores]) 
Pait IV: Motor complications (6 items) 
Table 6: 
Rating Scale for the MDS-UPDRS 
 
Rating 
Description 
0 = no1mal 
No symptoms/signs 
1 = slight 
Symptoms/signs with sufficiently low frequency or intensity to cause no impact on function 
2 = mild 
Symptoms/signs of frequency or intensity sufficient to cause a modest impact on function 
3 = moderate 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
4 = severe 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
Several questions in Pait  I and all  questions in Pait II can be answered by the patient/caregiver 
and completed without the Investigator's input. The remaining questions in Pait I that deal with 
complex behaviors, the objective assessments of parkinsonism (Pait III), and the questions that 
deal with motor fluctuations and dyskinesias (Pait IV) ai·e co m p leted by In vestigato r in te rview. 
Th e tim e requ ired fo r ad m inistering the MDS-UPDRS is estimated to be less than 10 minutes for 
the interview items of Pait I, 15 minutes for Pait III, and 5 minutes for Paii IV (Goetz 2008). 
The complete MDS-UPDRS is to be administered in Pait A at screening, Admission (Day -1), 
predose on Days 1, 2, 3, and 4; postdose on Day 7; and on Day 14. The complete MDS-UPDRS 
is to be administered in Pait B at screening, Admission (Day -1), predoseon Days 1 and 4; 
postdose on Day 8; and on Days 15 and 22. 
Pait III of the MDS-UPDRS assesses 18 motor categories, some of which include right and left 
measurements: speech, facial expression, kinetic tremor of hands, rest tremor amplitude, postural 
tremor of hands, rigidity of neck and four extremities, finger taps, hand movement, 


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I 
I 
I 
I 
I 
pronation/supination, toe tapping, constancy of rest tremor, leg agility, arising from chair, 
posture, gait, freezing of gait, postural stability, global spontaneity of movement (Goetz. 2008). 
Pait III of the MDS-UPDRS (motor examination) is to be completed in Part A at 2, 4, 8, and 
12 hours postdose on Days 5, 6, and 8, and in Pait B at 2, 4, 8, and 12 homs postdose on Days 2, 
3, 5, 6, 7, and 9. MDS-UPDRS is to be assessed within ±10 minutes of the scheduled times 
through the 4-hour time point and within ±15 minutes of the scheduled times for the 6-hour 
through 12-hour time points. The MDS-UPDRS is provided in Appendix 4. 
 
11.2. 
Exploratory Endpoints 
 
 
 


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 4; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 7; in AM of Day 8; and Day 14. In Part B, plasma samples for PK 
analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Days 1 to 4; 
predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Day 7 
and Day 8; in the AM on Day 9; and on Days 15 and 22. The time of study drug administration 
is time zero and all post-dosing sampling times are relative to this time. Samples are to be 
collected within ±5 minutes of the scheduled sampling time. The Investigator or designee will 
arrange to have the plasma samples processed, stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events). 
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time. The date and actual time that the blood sample was taken will be 
recorded on the eCRF or electronically with a bar code or other method. 
 
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed. 
They should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours. A specimen-identification form must be completed and 
sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions. 
 
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of concentrations of SAGE-217 and 
possibly SAGE-217 metabolites will be performed utilizing a validated liquid chromatography- 
tandem mass spectrometry method at a qualified laboratory. Pharmacokinetic parameters will be 
derived such as area under the concentration-time curve from time zero to infinity (AUC0-∞), 
maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), the 
distributional half-life and terminal half-life (t1/2), and steady-state drug concentration in the 
plasma (Css). 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS and MOAA/S scores. 
 
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit for Part A. A full 
medical history, including PD history (eg, time of diagnosis, staging) and medication history, 
will be recorded at the Screening visit for Part A and updated, as needed, as screening for Part B. 
 
13.1.2. 
Vital Signs 
Vital signs comprise respiratory rate, temperature, and supine (supine for at least 5 minutes prior 
to the measurement) and standing systolic and diastolic blood pressure and heart rate. 
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 
through 7; in AM of Day 8; and on Day 14. In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 8; in AM on Day 9; and on Days 15 and 22. 
Vital signs and pulse oximetry are to be assessed within ±10 minutes of the scheduled times 
through the 4-hour time point and within ±15 minutes of the scheduled times for the 6-hour 
through 16-hour time points. 
 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visits for Parts A and B. 
 
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visits for Parts A and B. Symptom-directed physical examinations will be performed 
during Part A on Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and Day 8. Symptom- 
directed physical examinations will be performed during Part B on Admission (Day -1), Day 1, 
Day 3, Day 4, Day 5, Day 7, Day 8, Day 9, and Day 15. 
 
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at screening and Admission (Day -1); predose on 
Days 1 and 3; predose and 1 and 12 hours postdose on Days 4, 5, 6, and 7; in AM on Day 8; and 
Day 14. In Part B, the 12-lead ECG will be assessed at screening and Admission (Day -1); 
predose and 1 and 12 hours postdose on Days 1 through 8; in AM on Day 9; Days 15 and 22. 


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All time points are relative to the time of dosing. ECGs are to be performed within ±10 minutes 
of the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 
 
13.1.6. 
Laboratory Assessments 
In Part A, blood samples will be collected for hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day -1); predose on Day 4 and Day 7; and on 
Day 14.  In Part B, blood samples will be collected at screening and Admission (Day -1); 
predose on Days 1, 3, 4, 5, 6, and 8; on Day 9 and Day 15. Urine samples will be collected in 
Part B at screening and Admission (Day -1); predose on Day 4 and Day 8; and on Day 15. 
Serum and urine samples for pregnancy tests (females only) will also be collected. These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to Section 13.2, 
and recorded in the eCRF. 
 
13.1.6.1. Hematology 
Hematology tests will include complete blood count (CBC), including red blood cells, white 
blood cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
 
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), total protein, 
and albumin. 
 
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 
 
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study. 


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13.1.6.5. Pregnancy Screen 
Females of childbearing potential will be tested for pregnancy at Parts A and B by serum 
pregnancy test at the Screening visits and by urine pregnancy test on Day -1 (Admissions). 
 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe). 
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be completed on Screening of Part A (lifetime 
history and past 24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed 
on Admission (Day -1); 12 hours postdose on Days 1, 2, and 3; predose on Days 4, 5, 6, and 7; 
and on Days 8 and 14. In Part B, the “Since Last Visit” C-SSRS form will be completed on 
Admission (Day -1); 12 hours postdose on Day 1 through Day 8; and on Days 9, 15, and 22. The 
C SSRS is provided in Appendix 9. 
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling. Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’. 
In Part A, the SSS will be administered on Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in the AM on Day 8; and Day 14. All time 
points are relative to the time of dosing. The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. In Part B, the SSS will be administered on Admission (Day -1); predose on Days 1 
through 8; in AM on Day 9; and Days 15 and 22. The SSS should be performed prior to the 
MOAA/S score. The SSS is provided in Appendix 10. 
 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS. If an MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment. In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point. In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 
3, 4, 5, 6, and 7; in AM on Day 8; and Day 14. In Part B, the MOAA/S will be performed 
predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 through 8; in AM on on 
Day 9; and Days 15 and 22. The MOAA/S assessments are to be performed within ±10 minutes 


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of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled 
times for the 6-hour through 16-hour time points. The MOAA/S is provided in Appendix 11. 
 
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed. Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher). 
 
13.2.1. 
Definition of Adverse Events 
 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
All adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, or following the cessation of treatment until the Day 22 Follow-up visit of Part B, 
whether or not they are related to the study, must be recorded on forms provided by Sage 
Therapeutics. 
 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 


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All serious adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, and until the Day 22 Follow-up visit of Part B, whether or not they are related to the 
study, must be recorded on forms provided by Sage Therapeutics. 
 
13.2.1.4. Recording Sedation as an Adverse Event 
Sedation will be assessed using protocol-specified rating scales. In order to standardize the 
reporting of sedation as adverse events, Investigators must record sedation as an adverse event if 
there is a score of >5 on the SSS and/or a score of ≤2 on the MOAA/S. Consideration should be 
given to the most appropriate term to describe the sedation characteristics. 
 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator. The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
The Investigator should request permission to contact the subject, the subject’s spouse/partner (if 
the subject is male and his spouse/partner becomes pregnant) or the obstetrician for information 
about the outcome of the pregnancy (spontaneous miscarriage, elective termination, live birth), 
and in the case of a live birth, about any congenital abnormalities. If a congenital abnormality is 
reported, then it should be recorded in the source documents and reported as a serious adverse 
event. Spontaneous miscarriages should also be reported and handled as serious adverse events. 
Elective abortions without complications should not be handled as adverse events. 
 
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.” 
 
Not related 
No relationship between the experience and the administration of study drug; related 
to other etiologies such as concomitant medications or subject’s clinical state. 
Possibly related 
A reaction that follows a plausible temporal sequence from administration of the 
study drug and follows a known response pattern to the suspected study drug. 
Probably related 
The reaction might have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject, but this is not known for sure. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting. 


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13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug. 
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted TEAEs. 
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change. 
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe adverse events. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 13.2.1.3. An adverse event 
of severe intensity may not be considered serious. 
 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 22 Follow-up visit of Part B. Any serious adverse events considered possibly or 
probably related to the investigational product and discovered by the Investigator at any time 
after the study should be reported. All serious adverse events must be reported to the Sponsor or 
Sponsor’s designee immediately by phone and in writing within 24 hours of the first awareness 
of the event. The Investigator must complete, sign and date the serious adverse event pages, 
verify the accuracy of the information recorded on the serious adverse event pages with the 
corresponding source documents, and send a copy to Sage Therapeutics or designee. 
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file. 
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 


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will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
additional serious adverse events. 


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The primary endpoints of this study relate to safety and tolerabilit 
include evaluation of PD s n toms b the MDS-UPDRS, 
 
14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study diug. 
The efficacy population will consist of all subjects in the safety population who receive at least 
one dose of study drng and have at least one postdose MDS-UPDRS evaluation. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each pa1t of the study. 
 
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data.  No sensitivity analysis of missing data will be perfo1med. 
 
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, race, and ethnicity, and baseline characteristics, such as 
height, weight, and body mass index (BMI), will be summarized. 
Categorical summaries, such as gender and race, will be summarized by frequency and 
percentage. Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics. 
Hepatitis, HIV, and pregnancy screening results will be listed, but not summarized as they are 
considered pait of the inclusion/exclusion criteria. 
Medical histo1y will be listed by subject. 
 
14.4. 
Efficacy Endpoints 
 
14.4.1. 
Secondary Efficacy Endpoints 
In Pait A, changes in the MDS-UPDRS- Pait III score will be summaii·zed overall and by 
tolerated dose. In Pait B, changes in the MDS-UPDRS - Pa1t III score and the MDS-UPDRS - 
Paits I-IV total score will be sUlllln ai·ized overall and by randomized treatment sequence and 
tolerated dose. 
 
14.4.2. 
Exploratory Efficacy Endpoints 


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14.5. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, SSS, and MOAA/S will be 
summarized using descriptive statistics by group and time point, where applicable. Continuous 
endpoints will be summarized with number (n), mean, standard deviation, median, minimum, 
and maximum. In addition, change from baseline values will be calculated at each time point 
and will be summarized using descriptive statistics. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. For all categorical endpoints,summaries will 
include counts and percentages. 
14.5.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher). The 
analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of open-label study drng, or any worsening of a pre­ 
existing medical condition/adverse event with onset after the staii of open-label study chu g and 
until 14 days after the last dose. The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred tenn, and dose group. Incidences will be presented in 
order of decreasing frequency. In addition, summaii·es will be provided by maximum severity 
(see Section 13.4) and relationship to study chu g (see Section 13.3). 
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the first dose of open-label study chu g w ill also 
be summaii·zed. 
All adverse events and serious adverse events (including those with onset or worsening before 
the staii of open-label study chu g) thro ugh the Day 22 Follow-up visit of Paii B will be listed. 
 
14.5.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
of Paii A and Paii B in vital signs will be evaluated by time point. 
 
14.5.3. 
Physical Examinations 
Screening physical examination results for Pa1i A and Paii B will be listed by subject. Any 
clinically significant physical exainination will be recorded in medical histo1y . Physical 
examination findings will be listed by subject and visit; abno1mal findings will be flagged on the 
listing. 


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14.5.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event. Electrocardiogram findings will be listed by subject and visit. 
 
14.5.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline of Parts A and B in clinical laboratory measures will be summarized. 
 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects. Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
 
14.5.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects. Changes in score over time will 
be represented graphically, and change from baseline of Part A and Part B will be summarized. 
 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects. Changes in score over 
time will be represented graphically, and change from baseline of Part A and Part B will be 
summarized. 
 
14.5.9. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later. 
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant). Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug. Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug. If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant. 
Concomitant medications will be assigned to the study part in which they are being taken. If a 
concomitant medication assigned to Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate. If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts. Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and summarized. 


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14.6. 
Pharmacokinetic Analysis 
Phaimacokinetic parameters will be summarized using appropriate descriptive statistics. Time to 
reach maximum concentration (tma.x) will be sunnnarized using number (n), mean, standai·d 
deviation, median, minimum, and maximum. All other PK pai·ameters will be Sllilllllarized using 
n, geometric mean , coefficient of vaii·ation, median, minimum, and maximum and listed by 
subject. 
Wherever necessaiy and appropriate, PK pai·aineters will be dose-adjusted to account for 
individual differences in dose. 
 
 
 
 
and safety. 
 
14.7. 
Determination of Sample Size 
Approximately 18 subjects will be emolled in Pait A. An interim analysis is planned after 
10 subjects have completed Pait A through Day 14. Approximately 12 subjects are anticipated 
to be randomized to Part B. This number of subjects is thought to be sufficient to assess 
preliminaiy safety and tolerability as well as a signal of efficacy of SAGE-217 Oral Solution in 
subjects with PD. 
 
14.8. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan. 
Additional exposure-response analyses may be perfo1med for other measures of efficacy 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of <Sponsor> 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between Sage 
Therapeutics and the Investigator. 
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each patient (eg, clinic 
charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to Sage Therapeutics 
or designee and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of a Sage Therapeutics or designee audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs. 
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements. 
 
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan. 
Electronic case report forms will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, and subject status. 
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study. For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
 
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
 
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available study registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor. It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study. The information obtained from the clinical study will be used 


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towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required. 


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics. No publication or disclosure of study results will be permitted except as 
specified in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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20. 
LIST OF REFERENCES 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neurophan nacology. 2002 
Sep;43(4):651- 61. 
 
Bergman H, Deuschl G. Pathophysiology of Parkinson's disease: from clinical neurology to 
basic neuroscience and back. Mov Disord. 2002;17:S28-S40. 
 
di Michele F, Longone P, Romeo E, et al. Decreased plasma and cerebrospinal fluid content of 
neuroactive steroids in Parkinson's disease. Neurol Sci. 2003;24(3):172-3. 
Goetz CG, Poewe W, Rascol 0 , et al. Movement Disorder Society Task Force Report on the 
Hoehn and Yalu Staging Scale: Status and Recommendations. Mov Dis. 2004;19(9):1020- 8. 
Goetz CG, Fahn S, Maitinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, fonnat, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41-4 . 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Pai·kinson's Disease Rating Scale (MDS-UPDRS): Scale presentationand clinimetric 
testing results. Mov Disord. 2008;23(15):2129- 70. 
Hoehn M, Yahr M. Parkinsonism: onset, progression and mo1tality. Neurology. 
1967;17(5):427-42. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Pai·kinson's disease. A clinico-pathological study of 100 cases. JNNP. 1992;55:181-4. 
Jankovic J. Moto r fluctuations and dyskinesia in Parkinson's disease: Clinical manifestations. 
Mov Disord. 2005;11:ll -6. 
Jankovic J. Parkinson's' disease: clinical features and diagnosis. JNNP. 2008;79:368-76. 
Kasten M, Brnggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the 
detection of MCI and dementia in Parkinson disease. Neurology. 2010;75 (5):478-9. 


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Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for 
impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867–76. 
Siderowf A, Lang AE. Pre-motor Parkinson’s disease; concepts and definitions. Mov. Disord 
2012;27, 608-16. 
Stern MB. Dopamine agonists modify the course of Parkinson disease. Arch Neurol. 
2004;61:1969-71. 
Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 
2004;61:1966-9. 
Winkler C, Bentlage C, Nikkhah G, et al. Intracranial transplants of GABA-rich striatal tissue 
induce behavioral recovery in the rat Parkinson model and promote the effects obtained by 
intrastriatal dopaminergic transplants. Exp. Neurol. 1999;155:165-186. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in the following appendices are for reference only; 
the rating scales and questionnaires reproduced in the eCRFs are to be used for actual subject 
assessment per the Schedule of Events. 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA 
 


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APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA 
The Hoehn and Yahr scale, a commonly used system for describing how the symptoms of 
Parkinson’s disease progress, was first published in 1967 (Hoehn 1967). The original scale 
included 5 disease stages, numbered 1 to 5. The scale was later modified to include two 
intermediate stages (Goetz 2004). 
 
 
Original Hoehn and Yahr Scale 
 
Stage 1 
Unilateral involvement only, usually with minimal or no functional disability 
Stage 2 
Bilateral or midline involvement without impairment of balance 
Stage 3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; 
physically independent 
Stage 4 
Severely disabling disease; still able to walk or stand unassisted 
Stage 5 
Confinement to bed or wheelchair unless aided 
 
 
Modified Hoehn and Yahr Scale 
 
Stage 0 
No signs of disease 
Stage 1 
Symptoms are very mild; unilateral involvement only 
Stage 1.5 
Unilateral and axial involvement 
Stage 2 
Bilateral involvement without impairment of balance 
Stage 2.5 
Mild bilateral disease with recovery on pull test 
Stage 3 
Mild to moderate bilateral disease; some postural instability; physically 
independent 
Stage 4 
Severe disability; still able to walk or stand unassisted 
Stage 5 
Wheelchair bound or bedridden unless aided 


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APPENDIX 3. ANTICHOLINERGIC DRUGS 
The following drugs are not permitted in the 5 days prior to receiving the first dose of study drug 
in Part A and Part B. The list below gives a non-exhaustive list of examples of each drug class. 
A. Antimuscarinic agents 
 
Atropine 
Benzatropine 
Biperiden 
Chlorpheniramine 
Dicyclomine 
Dimenhydrinate 
Diphenhydramine 
Doxepin 
Doxylamine 
Glycopyrrolate 
Hydroxyzine 
Ipratropium 
Orphenadrine 
Oxitropium 
Oxybutynin 
Tolterodine 
Tiotropium 
Tropicamide 
Trihexyphenidyl 
Scopolamine 
Solifenacin 
Tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, trimipramine, 
amoxapine, desipramine, nortriptyline, protriptyline) 
 
B. Antinicotinic agents: 
 
Bupropion 
Dextromethorphan 
Doxacurium 
Hexamethonium 
Mecamylamine 
Tubocurarine 


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APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED 
PARKINSON'S DISEASE RATING SCALE (MDS-UPDRS) 
 
Part I: NomnotorAspects of Experiences of Daily Living 
Part II: Moto1· E xp e 1·ien ces of Dail y Li vi ng 
Cogniti ve impairmen t 
Speech 
Hallucinations and psychosis 
Saliva and drooling 
Depressed mood 
Chewing and swallowing 
Anxious mood 
Eating tasks 
Apathy 
Dressing 
Features of dopamine dysregulation syndrome 
Hygiene 
Sleep problems 
Handwriting 
Daytime sleepiness 
Doing hobbies and other activities 
Pain and other sensations 
Turning in bed 
Urinary problems 
Tremor impact on activities 
Constipation problems 
Getting in and out of bed 
Lightheadedness on standing 
Walking and balance 
Fatigue 
Freezing 
Part III: Motor Examination 
Part IV : Motor Complications 
Speech 
Time spent with dyskinesias 
Facial expression 
Functional impact of dyskinesias 
Rigidity (neck; right/left upper/lo wer extremities) 
Painful off state dystonia 
Finger tapping (right/left hands) 
Time spent in the off state 
Hand movements (right/left hands) 
Functional impact of fluctuations 
Pronation-supination movements of right/left hands 
Complexity of motor functions 
Toe tapping (right/left foot) 
Leg agility (right/left leg) 
Arising from chair 
Gait 
Freezing of gait 
Postural instability 
Posture 
Global spontaneity of movement (body bradykinesia) 
Postural tremor of right/left hands 
Kinetic tremor of right/left hands 
Rest tremor amplitude: right/left upper/lower extremities; lip jaw 
Constancy of rest tremor 


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APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – BASELINE/SCREENING VERSION AND 
SINCE LAST VISIT VERSION 
 
 
 


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APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS) 
 


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APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
Modified Observer’s Assessment of Alertness/Sedation Scale 
 
Score 
Responsiveness 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Responds only after painful trapezius squeeze 
0 
No response after painful trapezius squeeze 


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Summary of Changes Page 
Protocol 217-PRK-201 
Date 05 Oct 2016 
The following changes, and the rationale for the changes, were made to the attached protocol in this amendment. 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Title Page 
Title Page 
Date of Original Protocol: 
28 September 2016 
Date of Original Protocol: 
28 September 2016 
Date of Amendment 1: 
5 October 2016 
Added the date of 
Amendment 1 to the Title 
Page. 
Protocol Signature Page 
Protocol Signature Page 
Date of Original Protocol: 
22 September 2016 
Date of Amendment 1: 
5 October 2016 
Revised the date of the 
signature page to be the date 
of Amendment 1. 
Section 2, Synopsis, 
Endpoints 
Section 2, Synopsis, 
Endpoints 
In addition, plasma 
concentrations of SAGE-217, 
SAGE-217 metabolites, and 
HPβCD will be measured, 
and PK parameters will be 
derived. 
In addition, plasma 
concentrations of SAGE-217 
and possibly SAGE-217 
metabolites will be measured, 
and PK parameters will be 
derived. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 


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Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 2, Synopsis, 
Exploratory Endpoints 
Section 2, Synopsis, 
Exploratory Endpoints 
 
Section 2, Synopsis, 
Pharmacokinetics 
Section 2, Synopsis, 
Pharmacokinetics 
Plasma will be collected to 
assay for concentrations of 
SAGE-217, SAGE-217 
metabolites, and HPβCD 
Plasma will be collected to 
assay for concentrations of 
SAGE-217 and possibly 
SAGE-217 metabolites. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 
Section 2, Synopsis, Schedule 
of Events, Table 2 (Part A) 
Section 2, Synopsis, Schedule 
of Events, Table 2 (Part A) 
 
 
 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Screening (Day -28 to 
Day -1) 
Screening (Day -14 to 
Day -1) 
Corrected timing of screening 
to be from Day -14 (not 
Day -28). 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
 
 
 
. 


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Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 6.3.3, Exploratory 
Endpoints 
Section 6.3.3, Exploratory 
Endpoints 
 
 
 
Section 10.4, Table 5 
Section 10.4, Table 5 
Sucralose concentration 
(mg/mL): 0.029; 
Sucralose amount 
(mg/bottle): 3.569 
Sucralose concentration 
(mg/mL): 0.025; 
Sucralose amount 
(mg/bottle): 3.124 
Corrected the sucralose 
concentration and amount per 
bottle. 
 
 
 
 
 
 
 


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Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
 
 
Section 12.3, Sample 
Analysis 
Section 12.3, Sample 
Analysis 
Bioanalysis of plasma 
samples for the determination 
of concentrations of 
SAGE-217, SAGE-217 
metabolites, and HPβCD will 
be performed utilizing a 
validated liquid 
chromatography-tandem mass 
spectrometry method at a 
qualified laboratory. 
Bioanalysis of plasma 
samples for the determination 
of concentrations of 
SAGE-217 and possibly 
SAGE-217 metabolites will 
be performed utilizing a 
validated liquid 
chromatography-tandem mass 
spectrometry method at a 
qualified laboratory. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 


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Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 20, List of References 
Section 20, List of References 
Pritchett DB, Sontheimer H, 
Shivers BD, et al. 
Importance of a novel 
GABAA receptor subunit for 
benzodiazepine 
pharmacology. Nature. 
1989;338(6216):582-5. 
Deleted Pritchett et al., 1989 
This reference was not cited 
within the text and was 
removed. 
Appendix 9 
Appendix 9 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Baseline, Version 1/14/09 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Baseline/Screening Version 
1/14/09 
Replaced the Baseline version 
of the C-SSRS with the 
Baseline/Screening version of 
the C-SSRS. 


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Summary of Changes Page 
Protocol 217-PRK-201 
Date 05 Oct 2016 
The following changes, and the rationale for the changes, were made to the attached protocol in this amendment. 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Title Page 
Title Page 
Date of Original Protocol: 
28 September 2016 
Date of Original Protocol: 
28 September 2016 
Date of Amendment 1: 
5 October 2016 
Added the date of 
Amendment 1 to the Title 
Page. 
Protocol Signature Page 
Protocol Signature Page 
Date of Original Protocol: 
22 September 2016 
Date of Amendment 1: 
5 October 2016 
Revised the date of the 
signature page to be the date 
of Amendment 1. 
Section 2, Synopsis, 
Endpoints 
Section 2, Synopsis, 
Endpoints 
In addition, plasma 
concentrations of SAGE-217, 
SAGE-217 metabolites, and 
HPβCD will be measured, 
and PK parameters will be 
derived. 
In addition, plasma 
concentrations of SAGE-217 
and possibly SAGE-217 
metabolites will be measured, 
and PK parameters will be 
derived. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
2 
 
 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 2, Synopsis, 
Exploratory Endpoints 
Section 2, Synopsis, 
Exploratory Endpoints 
 
Section 2, Synopsis, 
Pharmacokinetics 
Section 2, Synopsis, 
Pharmacokinetics 
Plasma will be collected to 
assay for concentrations of 
SAGE-217, SAGE-217 
metabolites, and HPβCD 
Plasma will be collected to 
assay for concentrations of 
SAGE-217 and possibly 
SAGE-217 metabolites. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 
Section 2, Synopsis, Schedule 
of Events, Table 2 (Part A) 
Section 2, Synopsis, Schedule 
of Events, Table 2 (Part A) 
 
 
. 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Screening (Day -28 to 
Day -1) 
Screening (Day -14 to 
Day -1) 
Corrected timing of screening 
to be from Day -14 (not 
Day -28) 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
Section 2, Synopsis, Schedule 
of Events, Table 3 (Part B) 
 
 
 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
3 
 
 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
 
Changed to: 
Rationale: 
Section 6.3.3, Exploratory 
Endpoints 
Section 6.3.3, Exploratory 
Endpoints 
 
 
 
Section 10.4, Table 5 
Section 10.4, Table 5 
Sucralose concentration 
(mg/mL): 0.029; 
Sucralose amount 
(mg/bottle): 3.569 
Sucralose concentration 
(mg/mL): 0.025; 
Sucralose amount 
(mg/bottle): 3.124 
Corrected the sucralose 
concentration and amount per 
bottle. 
 
 
 
 
 
 
 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
4 
 
 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
 
Section 12.3, Sample 
Analysis 
Section 12.3, Sample 
Analysis 
Bioanalysis of plasma 
samples for the determination 
of concentrations of 
SAGE-217, SAGE-217 
metabolites, and HPβCD will 
be performed utilizing a 
validated liquid 
chromatography-tandem mass 
spectrometry method at a 
qualified laboratory. 
Bioanalysis of plasma 
samples for the determination 
of concentrations of 
SAGE-217 and possibly 
SAGE-217 metabolites will 
be performed utilizing a 
validated liquid 
chromatography-tandem mass 
spectrometry method at a 
qualified laboratory. 
Clarified that plasma might 
be assayed for concentrations 
of SAGE-217 metabolites and 
removed assay of HPβCD. 


Protocol 217-PRK-201 
Version 2.0 5 October 2016 
Sage Therapeutics 
5 
 
 
 
Section number and title in 
Protocol (28 Sep 2016) 
Section number and title in 
Amendment 1 (05 Oct 2016) 
Original text: 
Changed to: 
Rationale: 
Section 20, List of References 
Section 20, List of References 
Pritchett DB, Sontheimer H, 
Shivers BD, et al. 
Importance of a novel 
GABAA receptor subunit for 
benzodiazepine 
pharmacology. Nature. 
1989;338(6216):582-5. 
Deleted Pritchett et al., 1989 
This reference was not cited 
within the text and was 
removed. 
Appendix 9 
Appendix 9 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Baseline, Version 1/14/09 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Baseline/Screening Version 
1/14/09 
Replaced the Baseline version 
of the C-SSRS with the 
Baseline/Screening version of 
the C-SSRS. 


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
1 
 
 
 
 
1. 
TITLE PAGE 
 
 SAGE 
THERAPEUTICS 
 
PROTOCOL NUMBER: 217-PRK-201 
A PHASE 2, TWO-PART STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF SAGE-217 ORAL SOLUTION IN 
PATIENTS WITH PARKINSON'S DISEASE OF 
MODERATE SEVERITY RESPONDING TO 
IMMEDIATE-RELEASE ORAL 
LEVODOPA/CARBIDOPA AND WITHDRAWN FROM 
LEVODOPA/CARBIDOPA 
IND NUMBER: 131,258 
Investigational Product 
Clinical Phase 
Sponsor 
Sponsor Contact 
SAGE-217 
2 
Sage Therapeutics, Inc. 
 
 
 
 
Ph.D. 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
Date of Odginal Protocol 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
_ 
, M.D., M.P.H. 
Study Physician 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Phone: 
Email: 
28 September 2016 
, M.D.,


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
2 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 


 
Protocol 217-P RK-201 
Version I.0 28 September 20I6 
PROTOCOLSIGNATURE PAGE 
Sage Therapeutics 
 
 
 
Pro tocol Number: 
Product: 
IND No.: 
Study Ph;ise: 
217-PRK-20l 
SAGE-217 Oral Solution 
131,258 
2 
Sponsor: 
Sage Therapeutics 
Date of Origim1l Pr otocol: Version 1.0 22 September 2016 
 
 
 
 
 
Statist ician 
Sage Therapeutics 
 
 
 
 
3 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 
I 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
4 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PRK-201 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
5 
 
 
CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
  
Address and Telephone Number  
Clinical Research Organization 


Protocol 217-PRK-201 
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6 
 
 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 2, Two-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Efficacy of SAGE-217 Oral Solution in Patients with Parkinson’s Disease (PD) of Moderate Severity 
Responding to Immediate-Release Levodopa/Carbidopa and Withdrawn from Levodopa/Carbidopa 
Study centers: Up to 4 centers 
Objectives: 
Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 Oral Solution. 
Secondary: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms after 
withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD motor 
symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral Solution in combination with immediate-release oral 
Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
Endpoints: 
Primary: 
• Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrocardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) during both Part A and Part B. 
Secondary: 
Part A: 
• Improvement in PD motor symptoms as assessed by changes in the Movement Disorder Society- 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) – Part III (Motor Examination) score. 


Protocol 217-PRK-201 
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7 
 
 
 
Part B: 
• 
Improvementin PD motor symptoms as assessed by changes in the MDS-UPDRS - Pait III score. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - Patts I-IV total 
score. 
• 
Sleepiness/sedation as assessed by the Stanford SleepinessScale (SSS) and Modified Obse1ver's 
Assessment of Analgesia/Sedation(MOAAIS) scores. 
In addition, plasma concentrations of SAGE-217, SAGE-217 metabolites, and hydroxypropyl-beta­ 
cyclodextiin (HPPCD) will be measured, and PK pai·amteers will be derived. 
Exploratory Endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methodology: 
This study will assess the safety, tolerability, pha1macokinetics (PK), and efficacy of SAGE-217 Oral 
Solution. For ease of discussion, Levodopa alone or Cai·bidopa-Levodopacombination will be refened 
to as Levodopa in this protocol. 
There ai·e two pa1t:s 
Part A: Open-label with morning (AM) dosing (4 days). 
All subjects will continue to take their antipai·lcinso nian agents includingimmediate-releaseoral 
Levodopa on the day of admission(Day -1) and in the AM the following 3 days (Days 1 to 3). All 
subjects will stop their immediate-release oral Levodopa on Day 4 and will strut on a 30 mg dose of 
SAGE-217 Oral Solution administered in the AM with food. Subjects not tolerating 30 mg will receive 
20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days. The dose received on 
Day 7 will be defined as the tolerateddose for that subject. Subjects not tolerating 10 mg will not be 
able to continue in the study and may be replaced. Subjects will be followedfor an additional 7 days 
(Day 14) after the administration of the last dose. Levodopatreatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment(oral Levodopa or other antipail·cinso nian agent at Investigator's discretion)will be 
allowed, if needed, on all days (Days 1 to 7). 
Pait A is designed to dete1mine the tolerated dose of SAGE-217 Oral Solution for each subject and to 
assess whether SAGE-217 exhibits efficacy in subjects with PD in order to info1m the conduct of Pait B. 
Part B: Randomized, placebo-controlled, two-sequence crossover with AM dosing (up to 8 days). 
Pait B will be initiated only after review of the Pait A interim analysis. 


Protocol 217-PRK-201 
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Sage Therapeutics 
8 
 
 
 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at least 10 mg of 
SAGE-217 Oral Solution in Part A. Subjects who complete Part A through Day 14 will be re-admitted 
on Day -1 of Part B and they will receive their antiparkinsonian agent including immediate-release oral 
Levodopa. Subjects will be randomized the next day (Day 1) in a 1:1 manner to open-label Levodopa 
plus blinded SAGE-217 Oral Solution or placebo during Period 1 of the crossover. Subjects randomized 
to the combination arm of Levodopa and SAGE-217 Oral Solution will receive this combination in the 
morning for the first 4 days (Days 1 to 4). Subjects randomized to the Levodopa plus placebo arm will 
receive Levodopa and SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 
to 4). On Day 5, all subjects will crossover to Period 2 and will only receive open-label SAGE-217 Oral 
Solution for the remaining 4 days (Days 5 to 8). Subjects will receive their individually established 
tolerated dose of SAGE-217 Oral Solution (from Part A). All subjects will be able to resume Levodopa 
from Day 9 onwards. Rescue treatment (at Investigator’s discretion) will be allowed, if needed, on all 
days (Days 1 to 8). 
All doses of SAGE-217 Oral Solution (or placebo) will be administered in the morning with food. If 
subjects are taking Levodopa as opposed to Carbidopa-Levodopa, administration with or without food 
will be determined by the Investigator. 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). If at 
any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged by the 
Investigator to be related to study drug, the dose on the next day must be reduced to the next lowest dose 
and continued for the remainder of the dosing period (ie, subjects who are unable to tolerate the 30 mg 
dose will receive a dose of 20 mg, and subjects who are unable to tolerate 20 mg will receive a 10 mg 
dose on subsequent days). The dose received on Day 7 of the dosing period in Part A will be defined as 
the tolerated dose for that subject, with this dose to be used as the starting dose for Part B for that 
subject. 
Subjects will be exposed to SAGE-217 Oral Solution for up to 12 days (4 days in Part A and up to 
8 days in Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
Assessments will be performed periodically during the study as outlined in the Schedule of Events for 
Part A and Part B (Table 2 and Table 3, respectively). 
Number of patients (planned): 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 10 subjects 
have completed Part A through Day 14 to inform the conduct of Part B. Twelve subjects are anticipated 
to be randomized in Part B. 
Diagnosis and main criteria for inclusion: All of the following inclusion and exclusion criteria will 
be applied during screening for Part A, with some of the criteria applied during screening for Part B, as 
indicated. 
Inclusion criteria: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures are 
performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria (modified to 
allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Subjects with PD with a duration of less than 7 years and must meet the criteria for Hoehn and Yahr 
stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral Levodopa or 
Carbidopa-Levodopa (defined as no changes for a period of at least 1 month prior to the baseline 
visit) and is expected to remain on this stable dose for the duration of this study. 


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
9 
 
 
 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa or 
Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or amantadine 
at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been on a stable 
dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical examination, 
12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on study, and 
for 30 days after receiving the last dose of study drug. Highly effective methods of birth control 
include combined (estrogen and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of 
ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on study, and 
for 13 weeks after receiving the last dose of study drug. Effective methods of birth control include 
sexual abstinence, vasectomy, or a condom with spermicide (men) in combination with female 
partner's highly effective method. (Part B also) 
13. Males must be willing to abstain from sperm donation and females from donating eggs while on 
study through 13 weeks after receiving the last dose of study drug. (Part B also) 
Exclusion criteria: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major excipient, HPβCD. 
(Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 4 or 
stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her ability for 
participation. This includes schizophrenia spectrum and other psychotic disorders, substance-related 
and addictive disorders, feeding and eating disorders, bipolar and related disorders, structural brain 
disease including but not limited to history of encephalitis or hydrocephalus and history of clinically 
significant stroke, or anticipating starting psychotherapy or behavior therapy during the course of the 
study or who started psychotherapy or behavior therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 on the C 
SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), metabolic 
identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other atypical Parkinsonian 
syndromes (eg, progressive supranuclear palsy, multiple system atrophy). (Part B also) 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease. 


Protocol 217-PRK-201 
Version 1.0 28 September 2016 
Sage Therapeutics 
10 
 
 
 
(Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the screening 
or admission visits. NOTE: QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the study. ECG 
may be repeated once if initial values obtained are outside the specified limits. (Part B also) 
10. Subject has a history, presence and/or current evidence of serologic positive results for hepatitis B 
surface antigen (HbsAg), hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) 
antibodies 1 and 2. 
11. Subject has exposure to another investigational medication or device within 30 days prior to Part A 
Day 1. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of blood 
within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subjects has used any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 
within the 14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug. (Part B also) 
Investigational product, dosage and mode of administration: 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile Water 
for Injection to achieve the selected dose. 
Duration of treatment: 7 days in Part A; 8 days in Part B 
Part A: 
Screening duration: up to 28 days; Treatment Period: 7 days; Follow-up: 7 days 
Planned participation per subject: approximately 42 days during Part A. 
Part B: 
Screening duration: up to 14 days; Treatment Period: 8 days; Follow-up: 14 days 
Planned participation per subject: approximately 36 days during Part B. 
Reference therapy, dosage and mode of administration: 
In part B, placebo will be matched to SAGE-217 Oral Solution. 
Criteria for evaluation: 
Safety and tolerability: 
Safety and tolerability of study drug will be evaluated by vital signs, clinical laboratory measures, 
ECGs, physical examinations, concomitant medication usage, C-SSRS, and adverse event reporting. 
Sleepiness/sedation will be assessed by the SSS and MOAA/S. 
Efficacy: 
Improvement in PD motor symptoms and overall symptoms will be assessed by changes in the 
MDS-UPDRS Part III score and MDS-UPDRS Parts I-IV total score at various time points. 


Protocol 217-PRK-201 
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11 
 
 
 
Pharmacokinetics: 
Plasma will be collected to assay for concentrations of SAGE-217, SAGE-217 metabolites, and HPβCD. 
The following PK parameters will be derived from the plasma concentrations (where evaluable): area 
under the concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration 
(Cmax), time to reach maximum concentration (tmax), the distributional half-life and terminal half-life 
(t1/2), and steady-state drug concentration in the plasma (Css). 
Statistical methods: 
Study Populations 
The safety population, defined as all subjects who are administered study drug, will be used to provide 
descriptive summaries of safety. 
The efficacy population, defined as all subjects in the safety population who receive at least one dose of 
study drug and have at least one postdose MDS-UPDRS evaluation, will be used to analyze efficacy 
data. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations and will be used to summarize PK data. 
Separate populations will be defined for each part of the study. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time point 
and summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Safety Analysis 
Adverse events will be coded using Medical Dictionary for Regulatory Activities™ (MedDRA). The 
overall incidence of adverse events will be displayed by System Organ Class (SOC), preferred term, 
dose group, and cohort. Incidence of adverse events will also be presented by maximum severity and 
relationship to study drug. Vital signs, clinical laboratory measures, ECG, and C-SSRS data will be 
summarized by dose group and cohort, where applicable. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data presentation 
methods where applicable; subject listings will be provided for all efficacy data. 
An interim analysis of 10 subjects completing Part A is planned to inform Part B study conduct. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics and listed by 
subject. 


Protocol 217-PRK-201 
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12 
 
 
Table 2: 
Schedule of Events: Part A (Open-Label) 
 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis & HIV screen 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 


Protocol 217-PRK-201 
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13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
; CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 8 assessments. 
b Screening and Safety Laboratory Tests: Screening and Admission (Day -1); predose for Day 4, Day 6, and Day 8; and Day 14 
c Urinalysis: Screening and Admission (Day -1); predose for Day 4 and Day 7; and Day 14. 
d Vital Signs: Screening and Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM 
of Day 8; and Day 14. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; 
and Day 14. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose on Day 1 and Day 3; predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on 
Confinement Days 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1, Day 2 and Day 3; predose on Day 4, Day 5, Day 6, and Day 7; and Day 8 and 
Day 14. 
Visit Days 
Screening 
(Day -28 to 
Day -1) 
Admit 
(Day -1) 
Part A:  Open-Label 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 14 (±1) 
p 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
Administer Levodopa or 
q 
Carbidopa-Levodopa 
X 
X 
X 
Administer SAGE-217q 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


Protocol 217-PRK-201 
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14 
 
 
h SSS: Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. 
The SSS is to be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
i  MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 3, 4, 5, 6, and 7; in AM of Day 8; and Day 14. The MOAA/S is to 
be performed within ±10 minutes of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times thereafter. 
j MDS-UPDRS (complete): Screening, Admission (Day -1), predose Day 1, Day 2, Day 3, and Day 4; postdose on Day 7; and Day 14. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 5, 6, and 8. 
 
 
 
 
p Plasma PK sampling times (±5 minutes): Day 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 
4, 8, and 12 hours on Day 7; in AM of Day 8; and Day 14. PK samples are to be collected within ±5 minutes of the scheduled sampling time. 
q Levodopa or Carbidopa-Levodopa and SAGE-217 are to be administered in the morning 


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15 
 
 
Table 3: 
Schedule of Events: Part B (Randomized, Placebo-Controlled) 
 
Visit Days 
Screening 
(Day -28 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
Inclusion/Exclusion 
X 
X 
a 
Confined to Unit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight/Height 
X 
b 
CBC/Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X-serum 
X-urine 
c 
Urinalysis 
X 
X 
X 
X 
X 
d 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
f 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
g 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
SSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
i 
MOAA/S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS 
j 
(complete) 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS (Part III 
k 
only) 
X 
X 
X 
X 
X 
X 


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16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC = complete blood count; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; HIV = human immunodeficiency virus; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; 
MOAA/S = Modified Observer’s Assessment of Alertness/Sedation; 
; 
PK = pharmacokinetic; SSS = Stanford Sleepiness Scale 
a Subjects will be discharged from the unit after completion of all Day 9 assessments. 
b Screening and Safety Laboratory Tests: Screening and Day -1 [Admission]; predose for Day 1, Day 3, Day 4, Day 5, Day 6, and Day 8; and Day 9 and Day 15. 
c Urinalysis: Screening and Admission (Day -1); Predose for Day 4 and Day 8; Day 15. 
d Vital Signs: Screening and Day -1 [Admission]; predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM 
of Day 9; and Days 15 and 22. Vital signs assessments are to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within 
±15 minutes of the scheduled times thereafter. 
e Pulse Oximetry: Admission (Day -1); predose and 1, 2, 3, 4, 6 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; 
and Day 15. Pulse oximetry is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the 
scheduled times thereafter. 
f 12-Lead ECG: Screening and Admission (Day -1); predose and 1 (±10 minutes) and 12 (±15 minutes) hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, 
and 8; in AM of Day 9; and Days 15 and 22. 
g C-SSRS: Screening and Admission (Day -1); 12 hours postdose on Day 1 through Day 8; Day 9, Day 15 and Day 22. 
h Day -1 [Admission]; predose on Days 1 through Day 8; Day 9, and Day 15 and Day 22. 
i MOAA/S: Predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Confinement Days 1, 2, 3, 4, 5, 6, 7, and 8; in AM of Day 9; and Days 15 and 22. The 
MOAA/S is to be performed within ±10 minutes of the scheduled times through the 4 hour time point and within ±15 minutes of the scheduled times thereafter. 
Visit Days 
Screening 
(Day -28 
to Day -1) 
Admit 
(Day -1) 
Period 1: Randomized, Blinded 
Period 2: Open-label 
Follow-up 
End of 
Study 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 15 
Day 22 
q 
Plasma PK Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study Drug 
r 
Combination 
X 
X 
X 
X 
Administer SAGE-217 
onlyr 
X 
X 
X 
X 
Adverse Events 
X 
Prior/Concomitant 
Medications 
X 


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17 
 
 
j MDS-UPDRS (complete): Screening, Admission (Day -1), predose on Day 1 and Day 4; postdose on Day 8; and Days 15 and 22. 
k MDS-UPDRS (Part III only): 2 (±10 minutes), 4 (±10 minutes), 8 (±15 minutes), and 12 (±15 minutes) hours postdose on Days 2, 3, 5, 6, 7, and 9. 
 
 
 
 
q Plasma PK sampling times: Days 1 to 4 predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, 
and 12 hours postdose on Day 7 and Day 8; in AM of Day 9; and Day 15 and Day 22. PK samples are to be collected within ±5 minutes of the scheduled 
sampling time. 
r Study drug is to be administered in the morning. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ............................................................................................................... 1 
2. 
SYNOPSIS .................................................................................................................. 6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .............. 18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 25 
5. 
INTRODUCTION ..................................................................................................... 27 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need ................................ 27 
5.2. 
SAGE-217 Oral Solution ........................................................................................... 28 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 .......................... 28 
5.3.1. 
Nonclinical Studies with SAGE-217 ......................................................................... 28 
5.3.2. 
Clinical Experience .................................................................................................... 28 
5.4. 
Potential Risks and Benefits ...................................................................................... 30 
6. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 31 
6.1. 
Primary Objective ...................................................................................................... 31 
6.2. 
Secondary Objectives ................................................................................................ 31 
6.3. 
Endpoints ................................................................................................................... 31 
6.3.1. 
Primary Endpoints ..................................................................................................... 31 
6.3.2. 
Secondary Endpoints ................................................................................................. 31 
6.3.3. 
Exploratory Endpoints ............................................................................................... 31 
7. 
INVESTIGATIONAL PLAN .................................................................................... 33 
7.1. 
Overall Study Design ................................................................................................. 33 
7.2. 
Number of Subjects ................................................................................................... 34 
7.3. 
Treatment Assignment ............................................................................................... 34 
7.4. 
Dose Adjustment Criteria .......................................................................................... 35 
7.5. 
Criteria for Study Termination .................................................................................. 35 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................. 37 
8.1. 
Subject Inclusion Criteria .......................................................................................... 37 
8.2. 
Subject Exclusion Criteria ......................................................................................... 38 
8.3. 
Entrance Criteria for Part B ....................................................................................... 39 
8.4. 
Subject Withdrawal Criteria ...................................................................................... 39 


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9. 
TREATMENT OF SUBJECTS ................................................................................. 40 
9.1. 
Description of Study Drug ......................................................................................... 40 
9.1.1. 
Part A ......................................................................................................................... 40 
9.1.2. 
Part B ......................................................................................................................... 40 
9.2. 
Concomitant Medications .......................................................................................... 40 
9.2.1. 
Prior/Concomitant Medications ................................................................................. 40 
9.2.2. 
Prohibited Medications .............................................................................................. 41 
9.3. 
Treatment Compliance ............................................................................................... 41 
9.4. 
Randomization and Blinding ..................................................................................... 41 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT .......................................... 43 
10.1. 
Study Drug ................................................................................................................. 43 
10.2. 
Study Drug Packaging and Labeling ......................................................................... 43 
10.3. 
Study Drug Storage .................................................................................................... 43 
10.4. 
Study Drug Preparation.............................................................................................. 44 
10.5. 
Administration ........................................................................................................... 44 
10.6. 
Study Drug Accountability ........................................................................................ 45 
10.7. 
Study Drug Handling and Disposal ........................................................................... 45 
11. 
ASSESSMENT OF EFFICACY ............................................................................... 46 
11.1. 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale ............... 46 
11.2. 
Exploratory Endpoints ............................................................................................... 47 
47 
47 
47 
48 
48 
12. 
PHARMACOKINETICS .......................................................................................... 50 
12.1. 
Blood Sample Collection ........................................................................................... 50 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ................................................. 50 
12.3. 
Sample Analysis ........................................................................................................ 50 
13. 
ASSESSMENT OF SAFETY .................................................................................... 51 
13.1. 
Safety and Tolerability Parameters ............................................................................ 51 
13.1.1. 
Demographic/Medical History .................................................................................. 51 
13.1.2. 
Vital Signs ................................................................................................................. 51 


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13.1.3. 
Weight and Height ..................................................................................................... 51 
13.1.4. 
Physical Examination ................................................................................................ 51 
13.1.5. 
Electrocardiogram (ECG) .......................................................................................... 51 
13.1.6. 
Laboratory Assessments ............................................................................................ 52 
13.1.6.1. 
Hematology ................................................................................................................ 52 
13.1.6.2. 
Blood Chemistry ........................................................................................................ 52 
13.1.6.3. 
Urinalysis ................................................................................................................... 52 
13.1.6.4. 
Virus Serology ........................................................................................................... 52 
13.1.6.5. 
Pregnancy Screen ....................................................................................................... 53 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 53 
13.1.8. 
Stanford Sleepiness Scale (SSS) ................................................................................ 53 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) .............. 53 
13.2. 
Adverse and Serious Adverse Events ........................................................................ 54 
13.2.1. 
Definition of Adverse Events .................................................................................... 54 
13.2.1.1. 
Adverse Event ............................................................................................................ 54 
13.2.1.2. 
Suspected Adverse Reaction ...................................................................................... 54 
13.2.1.3. 
Serious Adverse Event ............................................................................................... 54 
13.2.1.4. 
Recording Sedation as an Adverse Event .................................................................. 55 
13.2.2. 
Pregnancy .................................................................................................................. 55 
13.3. 
Relationship to Study Drug ........................................................................................ 55 
13.4. 
Recording Adverse Events ......................................................................................... 56 
13.5. 
Reporting Serious Adverse Events ............................................................................ 56 
14. 
STATISTICAL METHODS AND CONSIDERATIONS ........................................ 58 
14.1. 
Data Analysis Sets ..................................................................................................... 58 
14.2. 
Handling of Missing Data .......................................................................................... 58 
14.3. 
Demographics and Baseline Characteristics .............................................................. 58 
14.4. 
Efficacy Endpoints ..................................................................................................... 58 
14.4.1. 
Secondary Efficacy Endpoints ................................................................................... 58 
14.4.2. 
Exploratory Efficacy Endpoints ................................................................................. 58 
14.5. 
Safety and Tolerability Analyses ............................................................................... 59 
14.5.1. 
Adverse Events .......................................................................................................... 59 
14.5.2. 
Vital Signs ................................................................................................................. 59 
14.5.3. 
Physical Examinations ............................................................................................... 59 


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14.5.4. 
12-Lead ECG ............................................................................................................. 60 
14.5.5. 
Clinical Laboratory Evaluations ................................................................................ 60 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 60 
14.5.7. 
Stanford Sleepiness Scale (SSS) ................................................................................ 60 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) ....................... 60 
14.5.9. 
Prior and Concomitant Medications .......................................................................... 60 
14.6. 
Pharmacokinetic Analysis.......................................................................................... 61 
14.7. 
Determination of Sample Size ................................................................................... 61 
14.8. 
Changes From Protocol Specified Analyses .............................................................. 61 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 62 
15.1. 
Study Monitoring ....................................................................................................... 62 
15.2. 
Audits and Inspections ............................................................................................... 62 
15.3. 
Institutional Review Board (IRB) .............................................................................. 63 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................... 64 
17. 
ETHICS ..................................................................................................................... 65 
17.1. 
Ethics Review ............................................................................................................ 65 
17.2. 
Ethical Conduct of the Study ..................................................................................... 65 
17.3. 
Written Informed Consent ......................................................................................... 65 
18. 
DATA HANDLING AND RECORDKEEPING ...................................................... 66 
18.1. 
Inspection of Records ................................................................................................ 66 
18.2. 
Retention of Records ................................................................................................. 66 
18.3. 
Confidentiality ........................................................................................................... 66 
19. 
PUBLICATION POLICY ......................................................................................... 68 
20. 
LIST OF REFERENCES ........................................................................................... 69 
21. 
APPENDICES ........................................................................................................... 71 
APPENDIX 1.   UNITED KINGDOM BRAIN BANK CRITERIA ........................................... 72 
APPENDIX 2.   HOEHN AND YAHR STAGING CRITERIA .................................................. 73 
APPENDIX 3.   ANTICHOLINERGIC DRUGS ........................................................................ 74 
APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED PARKINSON'S 
DISEASE RATING SCALE (MDS-UPDRS) ................................................... 75 
76 
77 
80 


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81 
APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION AND SINCE LAST VISIT 
VERSION .......................................................................................................... 84 
APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS) ....................................................... 90 
APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) ............................................................. 91 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................. 5 
Table 2: 
Schedule of Events:  Part A (Open-Label) ................................................................ 12 
Table 3: 
Schedule of Events:  Part B (Randomized, Placebo-Controlled) .............................. 15 
Table 4: 
Abbreviations and Specialist Terms .......................................................................... 25 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL ................. 44 
Table 6: 
Rating Scale for the MDS-UPDRS ............................................................................ 46 


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LIST OF FIGURES 
Figure 1: 
Study Design of Part A .............................................................................................. 36 
Figure 2: 
Study Design of Part B .............................................................................................. 36 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
ALT 
alanine aminotransferase 
AM 
morning 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
 
 
BMI 
body mass index 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CS 
clinically significant 
Css 
steady-state drug concentration in the plasma 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EP 
European Pharmacopeia 
GABA 
γ aminobutyric acid 
GABAA 
γ aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Levodopa/Carbidopa 
Levodopa or Carbidopa-Levodopa 
MDS 
Movement Disorder Society 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson's Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MoCA 
Montreal Cognitive Assessment 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant 
NF 
National Formulary 
PD 
Parkinson’s disease 
 
 
PK 
pharmacokinetic(s) 
PM 
evening 
QTcF 
QT interval calculated using the Fridericia method 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal half-life 
tmax 
time to reach maximum concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Parkinson’s Disease and Unmet Medical Need 
Parkinson’s disease (PD) is a chronic progressive neurodegenerative condition that affects the 
motor, autonomic, cognitive, and sensory systems. Parkinson’s disease is the second most 
common neurodegenerative disorder (Bergman 2002) and is associated with a massive loss of 
dopaminergic cells in the substantia nigra, leading to dopamine hypofunction and alteration of 
the basal ganglia circuitry. Dopamine neurons are under the control of the excitatory 
glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. Imbalance between the 
glutamatergic and GABA systems may contribute to excitotoxicity and dopaminergic cell death. 
The motor symptoms of PD have been linked with a loss of dopamine neurons in the substantia 
nigra pars compacta and a consequential reduction in the level of dopamine input in the striatum 
(Siderowf 2012). These symptoms evolve slowly and are characterized by the progression of 
tremor, rigidity, bradykinesia, and postural instability. Tremor caused by PD can appear as 
either a resting tremor or an action tremor. The most typical tremor of PD is a “pill-rolling” rest 
tremor between the thumb and index finger. Not everyone with PD develops a tremor, and those 
who do experience tremor may have symptoms that come and go. Typically, PD tremor starts in 
the fingers of one hand before spreading to affect the rest of the arm. Tremor can also spread to 
affect the foot on the same side of the body and, after several years, the tremor can spread to 
affect the other side of the body. Without treatment, PD tremor usually worsens over time. 
At present, there is no cure for PD. The core symptoms are caused by the degeneration of 
dopamine-producing neurons and, therefore, treatment consists of dopamine replacement. While 
enormous progress has been made in the treatment of PD over the past half century, levodopa 
remains the most potent drug for controlling PD symptoms (Jankovic 2008). The addition of 
carbidopa, a peripheral dopa decarboxylase inhibitor, enhances the therapeutic benefits of 
levodopa.  However, levodopa therapy is frequently associated with motor complications, and 
the appropriate time to initiate levodopa therapy continues to be debated (Stern 2004; 
Weiner 2004). The majority of patients treated with levodopa experience motor fluctuation, 
dyskinesia or other complications after 5 years of treatment (Jankovic 2005). 
Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of 
several neurotransmitter systems. The substantia nigra expresses high concentrations of 
allopregnanolone, a neurosteroid that positively modulates the action of GABA at 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. In PD patients, 
decreased plasma and cerebrospinal fluid levels of the neurosteroid allopregnanolone and 
5α-dihydroprogesterone have been observed (di Michele 2003). 
Parkinson’s disease is the second most common chronic neurodegenerative disease, affecting 
about 1 million people in the United States and more than 4 million people worldwide. It has a 
devastating effect on patients and is often accompanied by tremendous physical and emotional 
burden not only for the patients but also for their families and friends. As the size of the elderly 
population grows, the burden of PD is projected to grow substantially over the next few decades. 
To date, the therapy of PD is symptomatic, aimed at ameliorating motor symptoms. Although 
the goal of therapy is to reverse the functional disability, abolition of all symptoms and signs is 


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not currently possible, even with high doses of medication. Thus, there is a growing need for 
innovative new treatments to prevent, delay onset, or alleviate symptoms of PD. Neurosteroids 
act as neuroprotectants and as GABAA-receptor agonists in the physiology and pathology of the 
basal ganglia, impact dopaminergic cell activity and survival, and may therefore represent 
potential therapeutics in PD. 
 
5.2. 
SAGE-217 Oral Solution 
SAGE-217 is a positive allosteric modulator of the GABAA receptor and thus is expected to be 
of benefit for the treatment of PD. 
SAGE-217 Oral Solution 6 mg/mL (40% w/w aqueous hydroxypropyl-β-cyclodextrin [HPβCD] 
with 0.025 mg/mL sucralose) is a non-viscous, clear solution. 
 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 
5.3.1. 
Nonclinical Studies with SAGE-217 
In nonclinical studies of SAGE-217, sedative-hypnotic effects were consistently observed at 
higher doses in both in vivo pharmacology studies and in toxicology studies. The sedative- 
hypnotic impairments seen with SAGE-217 were typical for GABAA-positive modulators, 
ranging from hyperexcitability and ataxia at the lower doses through deep sedation and 
ultimately anesthesia at higher doses. Depth and duration of sedation demonstrated a clear dose 
response over the range tested, with evidence of tolerance occurring with continued exposure. 
Tolerance to the effects of SAGE-217 on motor incoordination was not observed after 7 days of 
dosing. 
The compound has been assessed in 14-day rat and dog toxicology studies with daily 
administration of SAGE-217 as a solution in HPβCD in dogs and Labrasol® in rats. The no 
observed adverse effect level was 3 mg/kg (females) and 22.5 mg/kg (males) in rats and 
2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. 
A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic 
study that was suspected to have been related to exaggerated pharmacology. Additional 
toxicology and pharmacology information is provided in the Investigator’s Brochure. 
 
5.3.2. 
Clinical Experience 
To date, two clinical studies employing SAGE-217 Oral Solution are clinically complete and 
final clinical study reports are pending. Discussions of pharmacokinetic (PK) data are limited to 
the single-ascending dose, food effect, and essential tremor cohorts from Study 217-CLP-101 
and the multiple-ascending dose and drug-drug interaction cohorts from Study 217-CLP-102. 
Discussions of safety data are limited to the single-ascending dose cohorts in Study 217 CLP 101 
and the multiple-ascending dose cohorts in Study 217-CLP-102. 
Study 217-CLP-101 was a first-in-human, four-part study that assessed the effects of a single 
dose of SAGE-217. The study was a double-blind, placebo-controlled, single-ascending dose 
design in healthy adult volunteers, with the objective of identifying the maximum tolerated dose 
(MTD) and PK profiles of SAGE-217 Oral Solution. Subjects in each of the single-ascending 
dose cohorts received a single dose of study drug, either SAGE-217 (six subjects) or placebo 
(two subjects), with SAGE-217 doses of 0.25 mg, 0.75 mg, 2 mg, 5.5 mg, 11 mg, 22 mg, 44 mg, 


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55 mg, and 66 mg. Escalation to the next dose was undertaken only after safety and PK data 
were reviewed by the Safety Review Committee (SRC) and agreement reached that it was safe to 
increase the dose. The MTD was determined to be 55 mg.  Two cohorts, 6 subjects each, 
received SAGE-217 Oral Solution in an open-label manner (one cohort received 50% of the 
MTD [22 mg] to study the food effects and the other cohort received the MTD [55 mg] to study 
the effects on subjects with essential tremor). SAGE-217 Oral Solution was orally bioavailable, 
demonstrated dose-linear PK from the lowest (0.25 mg) through the highest (66 mg) dose, and 
supported once-daily oral dosing with food. In addition, the pharmacodynamic effects of the 
SAGE-217 Oral Solution MTD were assessed in placebo-controlled, blinded, crossover 
electroencephalogram cohorts of 8 subjects each; one cohort received 50% of the MTD (22 mg) 
and the other received the MTD (55 mg). 
Study 217-CLP-102 was a two-part study that assessed the effects of multiple-ascending doses of 
SAGE-217 Oral Solution. The study was a double-blind, placebo-controlled, multiple-ascending 
dose study in healthy adult volunteers. Subjects in each of the multiple-ascending dose cohorts 
received study drug, either SAGE-217 (nine subjects) or placebo (three subjects), once daily for 
7 days, with SAGE-217 Oral Solution doses of 15 mg, 30 mg, and 35 mg. Escalation to the next 
dose was undertaken only after safety and PK data were reviewed by the SRC and agreement 
reached that it was safe to increase the dose. The MTD was determined to be 30 mg. It was 
observed that subjects receiving the drug in the evening did better in terms of tolerability 
compared to when they received the drug in the morning.  A fourth cohort of 12 subjects 
received 30 mg of SAGE-217 Oral Solution in an open-label manner to study drug-drug 
interactions.  SAGE-217 Oral Solution is not likely to induce the metabolism of cytochrome 
P450 (CYP)2B6 or CYP3A4 substrates. SAGE-217 Oral Solution was orally bioavailable and 
suitable for once-daily oral dosing at night time with food. 
SAGE-217 Oral Solution was generally well tolerated. In both Phase 1 studies (217-CLP-101 
and 217-CLP-102), doses were escalated until the stopping criteria were met. Most adverse 
events were reported as mild or moderate in intensity, and there were no serious adverse events 
reported in either study. In addition, none of the observed adverse events resulted in 
discontinuation of the study drug. At doses planned for further study, the observed sedation was 
mild, transient, and associated with daily peak exposure. The most common treatment-emergent 
adverse events (TEAEs) were sedation, somnolence, dizziness, euphoric mood, fatigue, tremor, 
and muscle twitching, reported most frequently in the highest dose group (66 mg). Some 
changes in mean blood pressure and heart rate were observed after single doses of 44 mg and 
greater. After multiple doses of 30 mg (morning [AM] or evening [PM]) or 35 mg (AM) over 
7 days, there was no evidence of changes in mean vital sign measures even though Day 7 plasma 
concentrations approximated that of the highest single dose in the single-ascending dose study. 
Subjects seemed to tolerate SAGE-217 better when given as night time dosing. 
Neuroactive steroids are a class of endogenous and synthetic positive allosteric modulators that 
target both synaptic and extra-synaptic GABAA receptors (Belelli 2002 and confirmed in the 
Sponsor’s in vitro studies). This diverse activity profile suggests that neuroactive steroid 
GABAA receptor-positive allosteric modulators could exhibit robust activity against essential 
tremor. Administration of SAGE-547 injection, a proprietary formulation of the endogenous 
neuroactive steroid, resulted in significant reductions in upper limb kinetic tremor scores 
compared to placebo in a Phase 2 proof‑of‑principle study (IND 122,280). Based on these 


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results with SAGE-547, the study design for single-ascending dose study 217-CLP-101 included 
a cohort of subjects with essential tremor (N=6) who received SAGE-217 Oral Solution (55 mg) 
in an open-label manner. Data from this cohort indicate that single doses of SAGE-217 Oral 
Solution resulted in a reduction in the tremor symptoms, suggesting that SAGE-217 might be 
effective in treating PD. 
There are no clinical efficacy data of SAGE-217 Oral Solution in PD, since the present study is 
the first study in this indication. 
 
5.4. 
Potential Risks and Benefits 
Protocol 217-PRK-201 is the first clinical study evaluating the efficacy of SAGE-217 Oral 
Solution in PD. Thus, the potential benefits in this population are unknown, although the risks 
are likely to be similar to those mentioned in the Investigator’s Brochure. GABA compounds 
that cross the blood-brain barrier or increase GABA activity alleviate muscle stiffness caused by 
a lack of GABAergic tone (Winkler 1999), validating this receptor as a therapeutic target. Given 
the promising clinical data with another neuroactive steroid (SAGE-547) in conjunction with the 
shared broad receptor selectivity profile, oral bioavailability, long half-life, preclinical evidence 
of anxiolytic activity, and safety data of SAGE-217, it is possible that patients may have a 
clinical benefit at the exposures selected for this study. In view of the few risks associated with 
administration of SAGE-217 Oral Solution that have been identified to date, an intra-patient 
dose-reduction design has been chosen to permit reduction in dose based on tolerability (adverse 
events), specifically sedation, versus treatment effect. Each subject will start with an initial dose 
of 30 mg; subjects unable to tolerate 30 mg will receive 20 mg; subjects unable to tolerate 20 mg 
will receive 10 mg. The tolerated dose for each subject will be the dose taken on Day 7. 
Subjects who tolerate at least the 10 mg dose on Day 7 will be eligible to enroll in Part B. Given 
the high medical need and potential for benefit in PD, there is a favorable benefit-risk evaluation 
to investigate SAGE-217 Oral Solution in PD. 
In conclusion, selection criteria for the proposed study take into account the potential safety 
risks. Continuous safety monitoring, and the implementation of a formal dose-reduction and 
study drug discontinuation scheme also have the potential to mitigate risk. From a benefit/risk 
perspective, the appropriate measures are being taken in order to ensure the safety of the subjects 
who will be enrolled. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution. 
6.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate the effect of SAGE-217 Oral Solution on the severity of PD motor symptoms 
after withdrawal of Levodopa or Carbidopa-Levodopa (Levodopa/Carbidopa). 
• 
To evaluate the effect of SAGE-217 Oral Solution exposure length on the severity of PD 
motor symptoms after withdrawal of Levodopa/Carbidopa. 
• 
To compare the effect of SAGE-217 Oral Solution in combination with immediate-release 
oral Levodopa/Carbidopa to Levodopa/Carbidopa alone. 
 
6.3. 
Endpoints 
6.3.1. 
Primary Endpoints 
• 
Frequency and severity of adverse events and changes in vital signs, clinical laboratory data, 
electrncardiogram (ECG) parameters, and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) during both Part A and Pait B. 
 
6.3.2. 
Secondary Endpoints 
Part A: 
• 
Improvement in PD motor symptoms as assessed by changes in the Movement Disorder 
Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) - Pali III (Motor 
Examination) score. 
Part B: 
• 
Improvement in PD motor symptoms as assessed by changes in the MDS-UPDRS - Pait III 
score. 
• 
Improvement in PD overall symptoms as assessed by changes in the MDS-UPDRS - 
Palis I-IV total score. 
• 
Sleepiness/sedation as assessed by the Stanford Sleepiness Scale (SSS) and Modified 
Observer's Assessment of Analgesia/Sedation (MOAA/S) scores. 
 
6.3.3. 
Exploratory Endpoints 
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7. 
INVESTIGATIONAL PLAN 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2 study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217 Oral Solution in up to 18 adult subjects with PD of moderate severity who 
respond to immediate-release oral Levodopa and are on a stable dose. Part A of the study is an 
open-label design with morning (AM) dosing of SAGE-217 for 4 days. Part B of the study is a 
randomized, placebo-controlled, two-sequence crossover design. On Days 1 to 4 (Period 1 of 
crossover), subjects will receive open-label Levodopa plus blinded SAGE-217 or placebo. On 
Days 5 to 8 (Period 2 of crossover), all subjects will receive open-label SAGE-217 Oral Solution 
only. In Part B, subjects will receive their individually established tolerated dose of SAGE-217 
Oral Solution from Part A. Subjects will be exposed to SAGE-217 for up to 12 days (4 days in 
Part A and up to 8 days in Part B) and will be followed for an additional 7 days in Part A and an 
additional 14 days in Part B after the administration of the last dose. 
There are two parts to the study: 
• Part A: Open-label with AM dosing (4 days). 
All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM the following 
3 days (Days 1 to 3). All subjects will stop their immediate-release oral Levodopa on 
Day 4 and will start on a 30 mg dose of SAGE-217 Oral Solution administered in the 
morning with food, as outlined in Section 9.1.1. Subjects not tolerating 30 mg will 
receive 20 mg, and subjects not tolerating 20 mg will receive 10 mg on subsequent days 
(Section 7.4). The dose received on Day 7 will be defined as the tolerated dose for that 
subject. Subjects not tolerating 10 mg will not be able to continue in the study and may 
be replaced. Subjects will be followed for an additional 7 days (Day 14) after the 
administration of the last dose. Levodopa treatment will be resumed on Day 8 and 
continue through Day 14. 
Rescue treatment (oral Levodopa or other antiparkinsonian agent at Investigator’s 
discretion) will be allowed, if needed, on all days (Days 1 to 7). 
Part A is designed to determine the tolerated dose of SAGE-217 Oral Solution for each 
subject and to assess whether SAGE-217 exhibits efficacy in subjects with PD of 
moderate severity in order to inform the conduct of Part B. 
• Part B: Randomized, placebo-controlled, two-sequence crossover with AM dosing (up 
to 8 days). Part B will be initiated only after review of the Part A interim analysis. 
In order to qualify for Part B of the study, a subject must have tolerated a dose of at 
least 10 mg of SAGE-217 Oral Solution in Part A. Subjects who complete Part A will 
be re-admitted on Day -1 of Part B and they will receive their antiparkinsonian agent 
including immediate-release oral Levodopa. Subjects will be randomized the next day 


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(Day 1) in a 1:1 manner to open-label Levodopa plus blinded SAGE-217 Oral Solution 
or placebo during Period 1 of the crossover. All doses of SAGE-217 Oral Solution (or 
placebo) will be administered in the morning with food as outlined in Section 9.1.2. 
Subjects randomized to the Levodopa plus placebo arm will receive Levodopa and 
SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 to 4). 
Subjects randomized to the combination arm of Levodopa and SAGE-217 Oral 
Solution will receive this combination in the AM for the first 4 days (Days 1 to 4). On 
Day 5, all subjects will crossover to Period 2 and will only receive open-label SAGE- 
217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects will receive their 
individually established tolerated dose of SAGE-217 Oral Solution (from Part A). All 
subjects will be able to resume Levodopa from Day 9 onwards. 
Rescue treatment (at Investigator’s discretion) will be allowed, if needed, on all days 
(Days 1 to 8). 
Reductions in dose of SAGE-217 will be allowed during both parts of the study (Parts A and B). 
If at any time the dose is not tolerated, assessed by occurrence of a severe adverse event judged 
by the Investigator to be related to study drug, the dose on the next day must be reduced to the 
next lowest dose and continued for the remainder of the dosing period (ie, subjects who are 
unable to tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to 
tolerate 20 mg will receive a 10 mg dose on subsequent days). The dose on Day 7 of the dosing 
period in Part A will be determined to be the tolerated dose for that subject, with this dose to be 
used as the starting dose for Part B for that subject. 
Subjects will be exposed to SAGE-217 for up to 12 days (4 days in Part A and up to 8 days in 
Part B) and will be followed for an additional 7 days in Part A and an additional 14 days in 
Part B after the administration of the last dose. 
The study designs of Part A and Part B are displayed in Figure 1 and Figure 2, respectively. 
Assessments will be performed periodically during the study as outlined in the Schedule of 
Events for Part A and Part B (Table 2 and Table 3, respectively). 
 
7.2. 
Number of Subjects 
Approximately 18 subjects will be enrolled in Part A. An interim analysis is planned after 
10 subjects have completed Part A through Day 14 to inform the conduct of Part B. Twelve 
subjects are anticipated to be randomized in Part B. 
 
7.3. 
Treatment Assignment 
SAGE-217 will be administered in the morning with food in Parts A and B. Food intake will be 
standardized as specified by the Sponsor. If subjects are taking Levodopa as opposed to 
Carbidopa-Levodopa, administration with or without food will be determined by the 
Investigator. 
Part A of the study is open-label. Part B of the study is randomized, placebo-controlled, two- 
sequence crossover. Subjects will be randomly assigned in a 1:1 manner to receive open-label 
Levodopa plus blinded SAGE-217 Oral Solution or placebo for 4 days (Days 1 to 4, Period 1 of 
crossover). Subjects, clinicians, and the study team will be blinded to treatment allocation. The 
pharmacist, who will prepare the oral solutions according to the randomization schedule, will be 


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unblinded. For the remaining 4 days of Part B (Days 5 to 8, Period 2 of crossover), all subjects 
will discontinue Levodopa and will receive their individually established tolerated dose of 
SAGE-217 Oral Solution from Part A in an open-label manner. 
Dose reductions for lack of tolerability will be allowed during both parts of the study 
(Section 7.4). 
 
7.4. 
Dose Adjustment Criteria 
Dose reductions of SAGE-217 for lack of tolerability will be allowed during both parts of the 
study. If at any time the dose is not tolerated in Part A, as determined by the Investigator, the 
dose on the next day will be reduced to the next lowest dose (ie, subjects who are unable to 
tolerate the 30 mg dose will receive a dose of 20 mg, and subjects who are unable to tolerate 
20 mg will receive a 10 mg dose on subsequent days). The dose received on Day 7 of Part A 
will be determined to be the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject 
 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons. In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator. Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects. 


 
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Figure 1: 
Study Design of Part A 
NOTE: In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of SAGE-217 Oral Solution in Part A. 
Figure 2: 
Study Design of Part B 
NOTE: Part B will be initiated only after review of the Part A interim analysis (after 10 subjects have completed Part A). 
 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
It is anticipated that up to 18 subjects will be enrolled in Part A at up to 4 study centers. All of 
the following inclusion and exclusion criteria will be applied during screening for Part A, with 
some of the criteria applied during screening for Part B, as indicated. 
 
8.1. 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria for enrollment in the study: 
1. Subject has signed an informed consent form (ICF) before any study-specific procedures 
are performed. 
2. Subject is between 40 and 75 years of age, inclusive. 
3. Subject has a diagnosis of idiopathic PD based on modified UK Brain Bank Criteria 
(modified to allow individuals with a family history of PD) (Hughes 1992; Appendix 1). 
4. Subjects with PD with a duration of less than 7 years and must meet the criteria for 
Hoehn and Yahr stage 2 or stage 3 (Appendix 2). 
5. Subject has a stable dose of antiparkinsonian agents including immediate-release oral 
Levodopa or Carbidopa-Levodopa (defined as no changes for a period of at least 1 month 
prior to the baseline visit) and is expected to remain on this stable dose for the duration of 
this study. 
6. Subject is willing to discontinue his/her treatment with immediate-release oral Levodopa 
or Carbidopa-Levodopa for at least 8 hours prior to dosing with SAGE-217. (Part B also) 
7. Subject is willing to discontinue his/her treatment with anticholinergics (Appendix 3) or 
amantadine at least 5 days prior to the day of admission (Day -1). (Part B also) 
8. Subjects taking an antidepressant drug, sleep medication, or neuroleptic must have been 
on a stable dose for at least 1 month prior to the baseline visit. 
9. Subjects must have a MoCA score of >22. 
10. Subject is in good physical health and has no clinically significant findings on physical 
examination, 12-lead ECG, or clinical laboratory tests. (Part B also) 
11. Female subjects must agree to practice a highly effective method of birth control while on 
study, and for 30 days after receiving the last dose of study drug. Highly effective 
methods of birth control include combined (estrogen and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence. (Part B also) 
12. Male subjects must agree to practice a highly effective method of birth control while on 
study, and for 13 weeks after receiving the last dose of study drug. Effective methods of 
birth control include sexual abstinence, vasectomy, or a condom with spermicide (men) 
in combination with female partner's highly effective method. (Part B also) 


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13. Males must be willing to abstain from sperm donation and females from donating eggs 
while on study through 13 weeks after receiving the last dose of study drug. (Part B also) 
 
8.2. 
Subject Exclusion Criteria 
Subjects who met any of the following exclusion criteria will be excluded from the study: 
1. Subjects with a known hypersensitivity to SAGE-217 Oral Solution or its major 
excipient, HPβCD. (Part B also) 
2. Subjects with early PD (Hoehn and Yahr stage 1) or advanced PD (Hoehn and Yahr stage 
4 or stage 5). 
3. Subjects with any medical or psychiatric condition that jeopardizes/compromises his/her 
ability for participation. This includes schizophrenia spectrum and other psychotic 
disorders, substance-related and addictive disorders, feeding and eating disorders, bipolar 
and related disorders, structural brain disease including but not limited to history of 
encephalitis or hydrocephalus and history of clinically significant stroke, or anticipating 
starting psychotherapy or behavior therapy during the course of the study, or who started 
psychotherapy or behavior therapy within 30 days prior to Part A Day 1. 
4. Subjects with a history of: 
a. Electroconvulsive therapy; 
b. Stereotaxic brain surgery (deep brain stimulation) for PD; 
c. History of suicide attempt within 2 years, or has answered YES to questions 3, 4, or 5 
on the C-SSRS at the screening or Day -1 visits, or has current suicidal ideation; or 
d. Impulse control disorder. 
5. Subjects with severe depression as defined by a BDI-II score >19. 
6. Subjects with Type I or Type II diabetes mellitus. 
7. Subjects with presence of drug-induced parkinsonism (eg, metoclopramide, flunarizine), 
metabolic identified neurogenetic disorders (eg, Wilson's disease), encephalitis, or other 
atypical Parkinsonian syndromes (eg, progressive supranuclear palsy, multiple system 
atrophy). (Part B also) 
8. Subject has significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or 
oncological disease. (Part B also) 
9. Subject has clinically significant abnormal physical examination OR 12-lead ECG at the 
screening or admission visits. NOTE: QT interval calculated using the Fridericia method 
(QTcF) of >450 msec in males or >470 msec in females will be the basis for exclusion 
from the study. ECG may be repeated once if initial values obtained are outside the 
specified limits. (Part B also) 
10. Subject has a history, presence and/or current evidence of serologic positive results for 
hepatitis B surface antigen (HbsAg), hepatitis C (HCV) antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 and 2. 


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11. Subject has exposure to another investigational medication or device within the prior 
30 days. 
12. Subject has donated one or more units of blood or acute loss of an equivalent amount of 
blood within 60 days prior to dosing (1 unit = 450 mL). (Part B also) 
13. Subject is unwilling or unable to comply with study procedures. (Part B also) 
14. Subject has used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug. (Part B also) 
 
8.3. 
Entrance Criteria for Part B 
In addition to the inclusion and exclusion criteria determined at screening for Part B indicated in 
Section 8.1 and Section 8.2, respectively, subjects must be able to tolerate at least 10 mg of 
SAGE-217 in Part A in order to be enrolled into Part B. Part B will not be initiated until results 
of the Part A interim analysis have been reviewed. 
 
8.4. 
Subject Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s). 
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events; 
• Occurrence of pregnancy; 
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance; 
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject fails to attend scheduled assessments during the course of the study, the Investigators 
must determine the reasons and the circumstances as completely and accurately as possible and 
document this in the subject’s source documents. 
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant. Any subject who is withdrawn 
from the study for any reason is to have the final visit assessments performed. 
Subjects who withdraw or are withdrawn from the study may be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
For ease of discussion, Levodopa alone or Carbidopa-Levodopa combination will be referred to 
as Levodopa in this protocol. 
 
9.1.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner. All subjects will continue to take their antiparkinsonian agents including immediate- 
release oral Levodopa on the day of admission (Day -1) and in the AM the following 3 days 
(Days 1 to 3). On the morning of Day 4, subjects will stop their immediate-release oral 
Levodopa and take SAGE-217 for 4 days (Days 4 to 7) in the AM with food. On Day 4, subjects 
will receive a 30 mg dose of SAGE-217. Subjects not tolerating 30 mg will receive 20 mg the 
next day, and subjects not tolerating 20 mg will receive 10 mg the next day. The dose received 
on Day 7 will be defined as the tolerated dose for that subject, with this dose to be used as the 
starting dose for Part B for that subject. 
Subjects not tolerating 10 mg will not be able to continue in the study and may be replaced. 
Levodopa treatment will be resumed on Day 8 and continue through Day 14. 
 
9.1.2. 
Part B 
In order to qualify for Part B of the study, a subject must tolerate a dose of at least 10 mg of 
SAGE-217 Oral Solution. On Day 1 of Part B, subjects will be randomized in a 1:1 manner to 
open-label Levodopa plus blinded SAGE-217 Oral Solution or placebo. 
• Subjects randomized to the Levodopa plus placebo arm will receive Levodopa plus 
SAGE-217 matching placebo oral solution in the AM for the first 4 days (Days 1 to 
4). 
• Subjects randomized to the Levodopa plus SAGE-217 Oral Solution arm will receive 
this combination in the AM for the first 4 days (Days 1 to 4). 
• On Day 5, all subjects will crossover to Period 2 and will only receive open-label 
SAGE-217 Oral Solution for the remaining 4 days (Days 5 to 8). Subjects will 
receive their individually established tolerated dose of SAGE-217 Oral Solution from 
Part A. 
• All subjects will be able to resume Levodopa from Day 9 onwards. 
9.2. 
Concomitant Medications 
9.2.1. 
Prior/Concomitant Medications 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
Section 9.2. 


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Record the name, start date (if known), indication for use and whether ongoing or stopped of 
medications/treatments taken within 2 weeks prior to study entry as well as any medications 
taken during the study. 
The charts of all study participants will be reviewed for new concomitant medications through 
discharge from the unit. Chart reviews will include examination of nursing and physician 
progress notes, vital signs, and medication records in order to identify adverse events that may be 
associated with new concomitant medications. New concomitant medications, ongoing 
concomitant medications with a change in dose, and medical procedures ordered (eg, laboratory 
assessments, computed tomography or magnetic resonance imaging scans) will be reviewed to 
determine if they are associated with an adverse event not previously identified. 
The Investigator will document all doses of Levodopa and Carbidopa-Levodopa taken by the 
subject and the use of rescue medication. 
 
9.2.2. 
Prohibited Medications 
Subjects who have used any known strong inhibitors and/or inducers of CYP3A4 within the 
14 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving the 
first dose of study drug are to be excluded from the study; these medications/products are 
prohibited during the study. 
The anticholinergic drug classes listed in Appendix 3 and amantadine are not permitted in the 
5 days prior to the admission visit (Day -1) of each part of the study. The list provides non- 
exhaustive examples of each drug class. 
 
9.3. 
Treatment Compliance 
Study drug (SAGE-217 or matched placebo) will be prepared by the site pharmacist. All doses 
of study drug will be administered by site staff while the subject is confined to the clinical unit. 
The Investigator(s) or designee will record the time and dose of study drug administration in the 
source documents. Any reasons for noncompliance will also be documented, including: 
• Missing visits; 
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. 
 
9.4. 
Randomization and Blinding 
Part A of the study is open-label. 
In Part B is a randomized, placebo-controlled, two-sequence crossover study. Subjects will be 
randomly assigned in a 1:1 manner to one of two treatment groups: open-label Levodopa plus 
blinded SAGE-217 Oral Solution or matching placebo oral solution. Subjects, clinicians, and the 
study team will be blinded to treatment allocation. The pharmacist, who will prepare the oral 
solutions according to the randomization schedule, will be unblinded. 


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During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact the Sponsor prior to unblinding the 
study treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with the Sponsor. If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor as soon as possible 
and no later than the next business morning. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. Unless a subject is at immediate 
risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor personnel, according to standard operating procedures. 
The blinding of the study will be broken after the database has been locked. Electronic copies of 
the randomization code will be made available to the laboratory performing the bioanalytical 
analyses in order to allow for limited analysis of samples from subjects receiving placebo. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the electronic case report form (eCRF). If the 
subject or study center personnel (other than pharmacist) have been unblinded, the subject will 
be terminated from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dosages. The 6 mg/mL stock SAGE-217 Oral 
Solution will be compounded from SAGE-217 Drug Substance Powder in the Bottle and 
Excipient(s) in the Bottle (manufactured under current Good Manufacturing Practice [GMP] 
conditions 
) and further admixed at the clinical site in preparation for dosing. 
Placebo will be matched to SAGE-217 study drug. Detailed instructions for study drug 
preparation will be provided in the Pharmacy Manual. 
The Sponsor will not provide Levodopa or Carbidopa-Levodopa during the study; subjects will 
use their prescribed Levodopa or Carbidopa-Levodopa. 
 
10.2. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation. Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  Study drug labels with all required information and conforming to all 
applicable Code of Federal Regulations and GMP/GCP guidelines will be prepared by the 
clinical research organization. 
 
10.3. 
Study Drug Storage 
Upon receipt of study drug (SAGE-217 Oral Solution and placebo oral solution), the Investigator 
or designee will inspect the materials and complete and return the acknowledgment of receipt 
form enclosed with the parcel. A copy of the signed receipt will be kept in the study files. 
The study drug materials for SAGE-217 Oral Solution and placebo oral solution must be 
carefully stored at the temperature specified in the Pharmacy Manual (eg, clinical dosing 
solutions stored at approximately 2 to 8°C for 11 days with 24 hours of room temperature 
excursions allowed after preparation), safely and separately from other drugs. The study drug 
may not be used for any purpose other than the present study. After the study is completed, all 
unused study drug must be retained, returned as directed, or destroyed on site per the Sponsor’s 
instructions. 
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies. An accurate, timely record of 
the disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 


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• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
A copy of the inventory record and a record of any clinical supplies that have been destroyed 
must be documented. This documentation must include at least the information below or as 
agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.4. 
Study Drug Preparation 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual. The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5. 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
 
Ingredient 
Compendia Specification 
Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD 
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.029 
3.569 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations: EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
Additional excipients may be utilized in placebo to match the taste of SAGE-217 Oral Solution. 
They include sucrose octaacetate, tannic acid, and ammonium glycyrrhizate. The quantities may 
vary depending on the dose of SAGE-217. 
 
10.5. 
Administration 
SAGE-217 Oral Solution or matching placebo will be administered in the morning with food. 
Doses of SAGE-217 and placebo for SAGE-217 will be prepared as an approximate 40 mL oral 
solution to be swallowed all at once, followed by approximately 200 mL of water that has been 
used to rinse the dosing bottle. The start time of swallowing the approximately 40 mL oral 
solution is time zero for all assessments. Subjects may have assistance from the clinic staff when 
taking the study drug. 


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During Confinement, each subject’s antiparkinsonian agents, including Levodopa or Carbidopa- 
Levodopa, will be administered by site personnel according to the site’s standard operating 
procedures. 
 
10.6. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded. It must be clear from the records which subject received which dose of active or 
placebo treatment. 
The Sponsor will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock. 
The Investigator will document all doses of Levodopa or Carbidopa-Levodopa taken by the 
subject, including rescue doses. 
 
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture of dosing solutions, administration of study drug, and for 
which subject the study drug was intended (ie, record subject initials and birth date or other 
unique identifier). 
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented. 


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11. 
ASSESSMENT OF EFFICACY 
 
 
Assessments will be perfoimed periodicall y dming the study as outlined in 
the Schedule of Events (Table 2 and Table 3). 
 
11.1. 
Movement Disorder Society- Unified Parkinson's Disease Rating 
Scale 
The UPDRS is the the most commonly used scale in clinical studies of PD (Ramaker 2002). In 
2007, the MDS revised the scale, which was known as the MDS-UPDRS (Goetz 2007), and 
subsequently demonstrated the validity of the MDS-UPDRS for rating PD (Goetz 2008). The 
modified UPDRS includes four scales, with various subscales. Each item is rated from 0 
(noimal) to 4 (severe) (Table 6). The four MDS-UPDRS scales are: 
Pait I: nonmotor experiences of daily living (13 items) 
Pait II: motor experiences of daily living (13 items) 
Pait III: motor exainination (33 scores based on 18 items [several with right, left or other body 
distribution scores]) 
Pait IV: Motor complications (6 items) 
Table 6: 
Rating Scale for the MDS-UPDRS 
 
Rating 
Description 
0 = no1mal 
No symptoms/signs 
1 = slight 
Symptoms/signs with sufficiently low frequency or intensity to cause no impact on function 
2 = mild 
Symptoms/signs of frequency or intensity sufficient to cause a modest impact on function 
3 = moderate 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
4 = severe 
Symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent, function 
Several questions in Pait I and all questions in Pait II can be answered by the patient/caregiver 
and completed without the Investigator's input. The remaining questions in Pait I that deal with 
complex behaviors, the objective assessments of parkinsonism (Pait III), and the questions that 
deal with motor fluctuations and dyskinesias (Pait IV) ai·e co m p leted by In vestigator in terview. 
Th e tim e requ ired fo r ad m inistering the MDS-UPDRS is estimated to be less than 10 minutes for 
the interview items of Pait I, 15 minutes for Pait III, and 5 minutes for Pait IV (Goetz 2008). 
The complete MDS-UPDRS is to be administered in Pait A at screening, Admission (Day -1), 
predose on Days 1, 2, 3, and 4; postdose on Day 7; and on Day 14. The complete MDS-UPDRS 
is to be administered in Pait B at screening, Admission (Day -1), predoseon Days 1 and 4; 
postdose on Day 8; and on Days 15 and 22. 
Pait III of the MDS-UPDRS assesses 18 motor categories, some of which include right and left 
measurements: speech, facial expression, kinetic tremor of hands, rest tremor amplitude, postural 
tremor of hands, rigidity of neck and four extremities, finger taps, hand movement, 


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I 
I 
I 
I 
I 
 
pronation/supination, toe tapping, constancy of rest tremor, leg agility, arising from chair, 
posture, gait, freezing of gait, postural stability, global spontaneity of movement (Goetz. 2008). 
Pait III of the MDS-UPDRS (motor examination) is to be completed in Part A at 2, 4, 8, and 
12 hours postdose on Days 5, 6, and 8, and in Pait B at 2, 4, 8, and 12 homs postdose on Days 2, 
3, 5, 6, 7, and 9. MDS-UPDRS is to be assessed within ±10 minutes of the scheduled times 
through the 4-hour time point and within ±15 minutes of the scheduled times for the 6-hour 
through 12-hour time points. The MDS-UPDRS is provided in Appendix 4. 
 
11.2. 
Exploratory Endpoints 
 
 
 


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
In Part A, plasma samples for PK analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 4; predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 
12 hours postdose on Day 7; in AM of Day 8; and Day 14. In Part B, plasma samples for PK 
analysis will be collected predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Days 1 to 4; 
predose on Day 5 and Day 6; predose and 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose on Day 7 
and Day 8; in the AM on Day 9; and on Days 15 and 22. The time of study drug administration 
is time zero and all post-dosing sampling times are relative to this time. Samples are to be 
collected within ±5 minutes of the scheduled sampling time. The Investigator or designee will 
arrange to have the plasma samples processed, stored, and transported as directed for bioanalysis. 
An additional PK sample may be collected at any time if clinically indicated and at the discretion 
of the Investigator (eg, for unusual or severe adverse events). 
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time. The date and actual time that the blood sample was taken will be 
recorded on the eCRF or electronically with a bar code or other method. 
 
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70°C to -80°C until analyzed. 
They should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours. A specimen-identification form must be completed and 
sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions. 
 
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of concentrations of SAGE-217, SAGE-217 
metabolites, and HPβCD will be performed utilizing a validated liquid chromatography-tandem 
mass spectrometry method at a qualified laboratory. Pharmacokinetic parameters will be derived 
such as area under the concentration-time curve from time zero to infinity (AUC0-∞), maximum 
plasma concentration (Cmax), time to reach maximum concentration (tmax), the distributional half- 
life and terminal half-life (t1/2), and steady-state drug concentration in the plasma (Css). 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by adverse event reporting, vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, and SSS and MOAA/S scores. 
 
13.1.1. 
Demographic/Medical History 
Age, gender, race, and ethnic origin will be recorded at the Screening visit for Part A. A full 
medical history, including PD history (eg, time of diagnosis, staging) and medication history, 
will be recorded at the Screening visit for Part A and updated, as needed, as screening for Part B. 
 
13.1.2. 
Vital Signs 
Vital signs comprise respiratory rate, temperature, and supine (supine for at least 5 minutes prior 
to the measurement) and standing systolic and diastolic blood pressure and heart rate. 
In Part A, vital signs and pulse oximetry will be performed at screening (vital signs only) and 
Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 
through 7; in AM of Day 8; and on Day 14. In Part B, vital signs and pulse oximetry will be 
performed at screening (vital signs only) and Admission (Day -1); predose and at 1, 2, 3, 4, 6, 8, 
12, 14, and 16 hours postdose on Days 1 through 8; in AM on Day 9; and on Days 15 and 22. 
Vital signs and pulse oximetry are to be assessed within ±10 minutes of the scheduled times 
through the 4-hour time point and within ±15 minutes of the scheduled times for the 6-hour 
through 16-hour time points. 
 
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visits for Parts A and B. 
 
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visits for Parts A and B. Symptom-directed physical examinations will be performed 
during Part A on Admission (Day -1), Day 1, Day 3, Day 4, Day 6, and Day 8. Symptom- 
directed physical examinations will be performed during Part B on Admission (Day -1), Day 1, 
Day 3, Day 4, Day 5, Day 7, Day 8, Day 9, and Day 15. 
 
13.1.5. 
Electrocardiogram (ECG) 
A supine 12-lead ECG will be performed at the times specified below and the standard intervals 
recorded as well as any abnormalities. 
In Part A, the 12-lead ECG will be assessed at screening and Admission (Day -1); predose on 
Days 1 and 3; predose and 1 and 12 hours postdose on Days 4, 5, 6, and 7; in AM on Day 8; and 
Day 14. In Part B, the 12-lead ECG will be assessed at screening and Admission (Day -1); 
predose and 1 and 12 hours postdose on Days 1 through 8; in AM on Day 9; Days 15 and 22. 


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All time points are relative to the time of dosing. ECGs are to be performed within ±10 minutes 
of the predose and 1-hour time points and within ±15 minutes of the 12-hour time point. 
 
13.1.6. 
Laboratory Assessments 
In Part A, blood samples will be collected for hematology and serum chemistry at the Screening 
visit, on Admission (Day -1), predose on Days 4, 6, and 8; and on Day 14. Urine samples will be 
collected in Part A at screening and Admission (Day -1); predose on Day 4 and Day 7; and on 
Day 14.  In Part B, blood samples will be collected at screening and Admission (Day -1); 
predose on Days 1, 3, 4, 5, 6, and 8; on Day 9 and Day 15. Urine samples will be collected in 
Part B at screening and Admission (Day -1); predose on Day 4 and Day 8; and on Day 15. 
Serum and urine samples for pregnancy tests (females only) will also be collected. These 
assessments should be performed in accordance with the Schedule of Events (Table 2 and 
Table 3) and as outlined individually below. 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS); or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to Section 13.2, 
and recorded in the eCRF. 
 
13.1.6.1. Hematology 
Hematology tests will include complete blood count (CBC), including red blood cells, white 
blood cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio. 
 
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes, renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide, liver function tests, including total 
bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), total protein, 
and albumin. 
 
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 
 
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study. 


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13.1.6.5. Pregnancy Screen 
Females of childbearing potential will be tested for pregnancy at Parts A and B by serum 
pregnancy test at the Screening visits and by urine pregnancy test on Day -1 (Admissions). 
 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe). 
If in the opinion of the Investigator, the subject is showing any suicidal tendency, no further 
study drug will be administered and the subject will be referred to a psychologist or psychiatrist 
for further evaluation. This information will be tracked. 
The “Baseline/Screening” C-SSRS form will be completed on Screening of Part A (lifetime 
history and past 24 months).  In Part A, the “Since Last Visit” C-SSRS form will be completed 
on Admission (Day -1); 12 hours postdose on Days 1, 2, and 3; predose on Days 4, 5, 6, and 7; 
and on Days 8 and 14. In Part B, the “Since Last Visit” C-SSRS form will be completed on 
Admission (Day -1); 12 hours postdose on Day 1 through Day 8; and on Days 9, 15, and 22. The 
C SSRS is provided in Appendix 9. 
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling. Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’. 
In Part A, the SSS will be administered on Admission (Day -1); predose and 1, 2, 3, 4, 6, 8, 12, 
14, and 16 hours postdose on Days 1 through 7; in the AM on Day 8; and Day 14. All time 
points are relative to the time of dosing. The SSS is to be performed within ±10 minutes of the 
scheduled times through the 4-hour time point and within ±15 minutes of the scheduled times 
thereafter. In Part B, the SSS will be administered on Admission (Day -1); predose on Days 1 
through 8; in AM on Day 9; and Days 15 and 22. The SSS should be performed prior to the 
MOAA/S score. The SSS is provided in Appendix 10. 
 
13.1.9. 
Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) 
The MOAA/S allows exploration of deeper sedation states than the SSS. If an MOAA/S score of 
3 or less was observed, the score was to be confirmed by waiting approximately 10 minutes and 
re-administering the MOAA/S assessment. In Part A, the MOAA/S assessment should be 
conducted after other assessments that are scheduled at the same time point. In Part A, the 
MOAA/S will be performed predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 
3, 4, 5, 6, and 7; in AM on Day 8; and Day 14. In Part B, the MOAA/S will be performed 
predose and 1, 2, 3, 4, 6, 8, 12, 14, and 16 hours postdose on Days 1 through 8; in AM on on 
Day 9; and Days 15 and 22. The MOAA/S assessments are to be performed within ±10 minutes 


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of the scheduled times through the 4-hour time point and within ±15 minutes of the scheduled 
times for the 6-hour through 16-hour time points. The MOAA/S is provided in Appendix 11. 
 
13.2. 
Adverse and Serious Adverse Events 
Adverse events will be collected after the ICF has been signed. Medical conditions that occur 
after the ICF has been signed will be captured on the adverse event eCRF. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (version 18.1 or higher). 
 
13.2.1. 
Definition of Adverse Events 
 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
All adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, or following the cessation of treatment until the Day 22 Follow-up visit of Part B, 
whether or not they are related to the study, must be recorded on forms provided by Sage 
Therapeutics. 
 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 


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All serious adverse events that occur after any subject has been enrolled, before treatment, during 
treatment, and until the Day 22 Follow-up visit of Part B, whether or not they are related to the 
study, must be recorded on forms provided by Sage Therapeutics. 
 
13.2.1.4. Recording Sedation as an Adverse Event 
Sedation will be assessed using protocol-specified rating scales. In order to standardize the 
reporting of sedation as adverse events, Investigators must record sedation as an adverse event if 
there is a score of >5 on the SSS and/or a score of ≤2 on the MOAA/S. Consideration should be 
given to the most appropriate term to describe the sedation characteristics. 
 
13.2.2. 
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of notification of the 
Investigator. The Investigator will promptly notify the Medical Monitor and withdraw the 
subject from the study. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
The Investigator should request permission to contact the subject, the subject’s spouse/partner (if 
the subject is male and his spouse/partner becomes pregnant) or the obstetrician for information 
about the outcome of the pregnancy (spontaneous miscarriage, elective termination, live birth), 
and in the case of a live birth, about any congenital abnormalities. If a congenital abnormality is 
reported, then it should be recorded in the source documents and reported as a serious adverse 
event. Spontaneous miscarriages should also be reported and handled as serious adverse events. 
Elective abortions without complications should not be handled as adverse events. 
 
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, possibly related or probably related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event should be classified as “unrelated.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “related.” 
 
Not related 
No relationship between the experience and the administration of study drug; related 
to other etiologies such as concomitant medications or subject’s clinical state. 
Possibly related 
A reaction that follows a plausible temporal sequence from administration of the 
study drug and follows a known response pattern to the suspected study drug. 
Probably related 
The reaction might have been produced by the subject’s clinical state or other 
modes of therapy administered to the subject, but this is not known for sure. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting. 


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13.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event or lead to discontinuation of administration of 
study drug. 
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted TEAEs. 
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change. 
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe adverse events. Severity is a measure of 
intensity whereas seriousness is defined by the criteria under Section 13.2.1.3. An adverse event 
of severe intensity may not be considered serious. 
 
13.5. 
Reporting Serious Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 22 Follow-up visit of Part B. Any serious adverse events considered possibly or 
probably related to the investigational product and discovered by the Investigator at any time 
after the study should be reported. All serious adverse events must be reported to the Sponsor or 
Sponsor’s designee immediately by phone and in writing within 24 hours of the first awareness 
of the event. The Investigator must complete, sign and date the serious adverse event pages, 
verify the accuracy of the information recorded on the serious adverse event pages with the 
corresponding source documents, and send a copy to Sage Therapeutics or designee. 
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the CRF and/or study file. 
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 


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will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
additional serious adverse events. 


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The primary endpoints of this study relate to safety and tolerabilit 
include evaluation of PD s n toms b the MDS-UPDRS, 
 
 
14. 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1. 
Data Analysis Sets 
The safety population is defined as all subjects who are administered study diug. 
The efficacy population will consist of  all subjects  in the  safety  population  who  receive at least 
one dose of study di11g a n d h ave at lea s t on e po st dose MDS-UPDRS evaluation. 
The PK population will consist of all subjects in the safety population with sufficient plasma 
concentrations for PK evaluations. 
Separate populations will be defined for each pa1t of the study. 
 
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data. No sensitivity analysis of missing data will be perfo1med. 
 
14.3. 
Demographics and Baseline Characteristics 
Demographics, such as age, gender, race, and ethnicity, and baseline characteristics, such as 
height, weight, and body mass index (BMI), will be summarized. 
Categorical summaries, such as gender and race, will be summarized by frequency and 
percentage. Continuous summaries, such as age, height, weight, BMI, and baseline vital signs, 
will be summarized using descriptive statistics. 
Hepatitis, HIV, and pregnancy screening results will be listed, but not summarized as they are 
considered pait of the inclusion/exclusion criteria. 
Medical histo1y will be listed by subject. 
 
14.4. 
Efficacy Endpoints 
 
14.4.1. 
Secondary Efficacy Endpoints 
In Pait A, changes in the MDS-UPDRS - Pait III score will be summaii·zed overall and by 
tolerated dose. In Pait B, changes in the MDS-UPDRS-Pa1t III score and the MDS-UPDRS - 
Paits I-IV total score will be sUffiln ai·ized overall and by randomized treatment sequence and 
tolerated dose. 
 
14.4.2. 
Exploratory Efficacy Endpoints 


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14.5. 
Safety and Tolerability Analyses 
Data from vital signs, clinical laboratory measures, ECG, C-SSRS, SSS, and MOAA/S will be 
summarized using descriptive statistics by group and time point, where applicable. Continuous 
endpoints will be summarized with number (n), mean, standard deviation, median, minimum, 
and maximum. In addition, change from baseline values will be calculated at each time point 
and will be summarized using descriptive statistics. Out-of-range safety endpoints may be 
categorized as low or high, where applicable. For all categorical endpoints,summaries will 
include counts and percentages. 
14.5.1. 
Adverse Events 
Adverse events will be coded using the MedDRA coding system (version 18.1 or higher). The 
analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of open-label study drng, or any worsening of a pre­ 
existing medical condition/adverse event with onset after the strut of ope n-l abe l study chu g and 
until 14 days after the last dose. The incidence of TEAEs will be summarized overall and by 
MedDRA System Organ Class, preferred tenn, and dose group. Incidences will be presented in 
order of decreasing frequency. In addition, summaii·es will be provided by maximum severity 
(see Section 13.4) and relationship to study chu g (see Section 13.3). 
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the first dose of open-label study chu g w ill also 
be summaii·zed. 
All adverse events and serious adverse events (including those with onset or worsening before 
the strut of open-label study chu g) thro ugh the Day 22 Follow-up visit of Pait B will be listed. 
 
14.5.2. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
of Pait A and Pait B in vital signs will be evaluated by time point. 
 
14.5.3. 
Physical Examinations 
Screening physical examination results for Pait A and Pait B will be listed by subject. Any 
clinically significant physical exainination will be recorded in medical histo1y . Physical 
examination findings will be listed by subject and visit; abno1mal findings will be flagged on the 
listing. 


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14.5.4. 
12-Lead ECG 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an 
adverse event. Electrocardiogram findings will be listed by subject and visit. 
 
14.5.5. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline of Parts A and B in clinical laboratory measures will be summarized. 
 
14.5.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS will be listed for all subjects. Listings will include 
behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the C-SSRS. 
 
14.5.7. 
Stanford Sleepiness Scale (SSS) 
Sedation data collected on the SSS will be listed for all subjects. Changes in score over time will 
be represented graphically, and change from baseline of Part A and Part B will be summarized. 
 
14.5.8. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
Sedation data collected on the MOAA/S will be listed for all subjects. Changes in score over 
time will be represented graphically, and change from baseline of Part A and Part B will be 
summarized. 
 
14.5.9. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization (WHO)-Drug dictionary September 2015, or later. 
Medications will be presented according to whether they are being taken prior to and/or during 
the study (concomitant). Prior medications are defined as those taken during the 4 weeks prior to 
the date of the first dose of open-label study drug. Concomitant medications are defined as those 
with a start date on or after the first dose of open-label study drug, or those with a start date 
before the first dose of open-label study drug that are ongoing or with a stop date on or after the 
first dose of open-label study drug. If medication dates are incomplete and it is not clear whether 
the medication was concomitant, it will be assumed to be concomitant. 
Concomitant medications will be assigned to the study part in which they are being taken. If a 
concomitant medication assigned to Part A continues to be taken through Part B, then the 
medication will be assigned to both parts of the study as appropriate. If the start and stop dates 
of the concomitant medications do not clearly define the part during which a medication was 
taken, it will be assumed to be taken in both parts. Details of prior and concomitant medications 
will be listed by study part, subject, start date, and verbatim term. 
The use of rescue medication will be recorded and summarized. 


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14.6. 
Pharmacokinetic Analysis 
Phaimacokinetic parameters will be summarized using appropriate descriptive statistics. Time to 
reach maximum concentrntion (tma.x) will be summarized using number (n), mean, standai·d 
deviation, median, minimum, and maximum. All other PK pai·ameters will be summarized using 
n, geometric mean, coefficient of vaii·ation, median, minimum, and maximum and listed by 
subject. 
Wherever necessaiy and appropriate, PK pai·aineters will be dose-adjusted to account for 
individual differences in dose. 
 
 
 
 
and safety. 
 
14.7. 
Determination of Sample Size 
Approximately 18 subjects will be enrolled in Pait A. An interim analysis is planned after 
10 subjects have completed Pait A through Day 14. Approximately 12 subjects are anticipated 
to be randomized to Part B. This number of subjects is thought to be sufficient to assess 
preliminaiy safety and tolerability as well as a signal of efficacy of SAGE-217 Oral Solution in 
subjects with PD. 
 
14.8. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan. 
Additional exposure-response analyses may be perfo1med for other measures of efficacy 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of <Sponsor> 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between Sage 
Therapeutics and the Investigator. 
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each patient (eg, clinic 
charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to Sage Therapeutics 
or designee and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of a Sage Therapeutics or designee audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines of the International Council on 
Harmonisation (ICH), and any applicable regulatory requirements. The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs. 
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics or designee will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and the most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements. 
 
17.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan. 
Electronic case report forms will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, adverse 
events, and subject status. 
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study. For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
 
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
 
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available study registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor. It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study. The information obtained from the clinical study will be used 


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towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required. 


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics. No publication or disclosure of study results will be permitted except as 
specified in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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20. 
LIST OF REFERENCES 
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the 
interaction of neurosteroids with GABA(A) receptors. Neurophan nacology. 2002 
Sep;43(4):651- 61. 
 
Bergman H, Deuschl G. Pathophysiology of Parkinson's disease: from clinical neurology to 
basic neuroscience and back. Mov Disord. 2002;17:S28-S40. 
 
di Michele F, Longone P, Romeo E, et al. Decreased plasma and cerebrospinal fluid content of 
neuroactive steroids in Parkinson's disease. Neurol Sci. 2003;24(3):172-3. 
Goetz CG, Poewe W, Rascol 0 , et al. Movement Disorder Society Task Force Report on the 
Hoehn and Yalu Staging Scale: Status and Recommendations. Mov Dis. 2004;19(9):1020- 8. 
Goetz CG, Fahn S, Maitinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, fonnat, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41-4 . 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Pai·kinson's Disease Rating Scale (MDS-UPDRS): Scale presentationand clinimetric 
testing results. Mov Disord. 2008;23(15):2129- 70. 
Hoehn M, Yahr M. Parkinsonism: onset, progression and mo1tality. Neurology. 
1967;17(5):427-42. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Pai·kinson's disease. A clinico-pathological study of 100 cases. JNNP. 1992;55:181-4. 
Jankovic J. Moto r fluctuations and dyskinesia in Parkinson's disease: Clinical manifestations. 
Mov Disord. 2005;11:ll -6. 
Jankovic J. Parkinson's' disease: clinical features and diagnosis. JNNP. 2008;79:368-76. 
Kasten M, Brnggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the 
detection of MCI and dementia in Parkinson disease. Neurology. 2010;75 (5):478-9. 


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Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Pritchett DB, Sontheimer H, Shivers BD, et al. Importance of a novel GABAA receptor subunit 
for benzodiazepine pharmacology. Nature. 1989;338(6216):582-5. 
Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for 
impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867–76. 
Siderowf A, Lang AE. Pre-motor Parkinson’s disease; concepts and definitions. Mov. Disord 
2012;27, 608-16. 
Stern MB. Dopamine agonists modify the course of Parkinson disease. Arch Neurol. 
2004;61:1969-71. 
Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 
2004;61:1966-9. 
Winkler C, Bentlage C, Nikkhah G, et al. Intracranial transplants of GABA-rich striatal tissue 
induce behavioral recovery in the rat Parkinson model and promote the effects obtained by 
intrastriatal dopaminergic transplants. Exp. Neurol. 1999;155:165-186. 


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21. 
APPENDICES 
Copies of scales and questionnaires included in the following appendices are for reference only; 
the rating scales and questionnaires reproduced in the eCRFs are to be used for actual subject 
assessment per the Schedule of Events. 


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APPENDIX 1. UNITED KINGDOM BRAIN BANK CRITERIA 
 


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APPENDIX 2. HOEHN AND YAHR STAGING CRITERIA 
The Hoehn and Yahr scale, a commonly used system for describing how the symptoms of 
Parkinson’s disease progress, was first published in 1967 (Hoehn 1967). The original scale 
included 5 disease stages, numbered 1 to 5. The scale was later modified to include two 
intermediate stages (Goetz 2004). 
 
 
Original Hoehn and Yahr Scale 
 
Stage 1 
Unilateral involvement only, usually with minimal or no functional disability 
Stage 2 
Bilateral or midline involvement without impairment of balance 
Stage 3 
Bilateral disease: mild to moderate disability with impaired postural reflexes; 
physically independent 
Stage 4 
Severely disabling disease; still able to walk or stand unassisted 
Stage 5 
Confinement to bed or wheelchair unless aided 
 
 
Modified Hoehn and Yahr Scale 
 
Stage 0 
No signs of disease 
Stage 1 
Symptoms are very mild; unilateral involvement only 
Stage 1.5 
Unilateral and axial involvement 
Stage 2 
Bilateral involvement without impairment of balance 
Stage 2.5 
Mild bilateral disease with recovery on pull test 
Stage 3 
Mild to moderate bilateral disease; some postural instability; physically 
independent 
Stage 4 
Severe disability; still able to walk or stand unassisted 
Stage 5 
Wheelchair bound or bedridden unless aided 


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APPENDIX 3. ANTICHOLINERGIC DRUGS 
The following drugs are not permitted in the 5 days prior to receiving the first dose of study drug 
in Part A and Part B. The list below gives a non-exhaustive list of examples of each drug class. 
A. Antimuscarinic agents 
 
Atropine 
Benzatropine 
Biperiden 
Chlorpheniramine 
Dicyclomine 
Dimenhydrinate 
Diphenhydramine 
Doxepin 
Doxylamine 
Glycopyrrolate 
Hydroxyzine 
Ipratropium 
Orphenadrine 
Oxitropium 
Oxybutynin 
Tolterodine 
Tiotropium 
Tropicamide 
Trihexyphenidyl 
Scopolamine 
Solifenacin 
Tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, trimipramine, 
amoxapine, desipramine, nortriptyline, protriptyline) 
 
B. Antinicotinic agents: 
 
Bupropion 
Dextromethorphan 
Doxacurium 
Hexamethonium 
Mecamylamine 
Tubocurarine 


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APPENDIX 4. MOVEMENT DISORDER SOCIETY-UNIFIED 
PARKINSON'S DISEASE RATING SCALE (MDS-UPDRS) 
 
Part I: NomnotorAspects of Experiences of Daily Living 
Part II: Moto1· E xp e 1·ien ces of Dail y Li vi ng 
Cogniti ve impairment 
Speech 
Hallucinations and psychosis 
Saliva and drooling 
Depressed mood 
Chewing and swallowing 
Anxious mood 
Eating tasks 
Apathy 
Dressing 
Features of dopamine dysregulation syndrome 
Hygiene 
Sleep problems 
Handwriting 
Daytime sleepiness 
Doing hobbies and other activities 
Pain and other sensations 
Turning in bed 
Urinary problems 
Tremor impact on activities 
Constipation problems 
Getting in and out of bed 
Lightheadedness on standing 
Walking and balance 
Fatigue 
Freezing 
Part III: Motor Examination 
Part IV : Motor Complications 
Speech 
Time spent with dyskinesias 
Facial expression 
Functional impact of dyskinesias 
Rigidity (neck; right/left upper/lo wer extremities) 
Painful off state dystonia 
Finger tapping (right/left hands) 
Time spent in the off state 
Hand movements (right/left hands) 
Functional impact of fluctuations 
Pronation-supination movements of right/left hands 
Complexity of motor functions 
Toe tapping (right/left foot) 
Leg agility (right/left leg) 
Arising from chair 
Gait 
Freezing of gait 
Postural instability 
Posture 
Global spontaneity of movement (body bradykinesia) 
Postural tremor of right/left hands 
Kinetic tremor of right/left hands 
Rest tremor amplitude: right/left upper/lower extremities; lip jaw 
Constancy of rest tremor 


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APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – BASELINE/SCREENING VERSION AND 
SINCE LAST VISIT VERSION 
 
 
 


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APPENDIX 10. STANFORD SLEEPINESS SCALE (SSS) 
 


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APPENDIX 11. MODIFIED OBSERVER’S ASSESSMENT OF 
ALERTNESS/SEDATION (MOAA/S) 
 
Modified Observer’s Assessment of Alertness/Sedation Scale 
 
Score 
Responsiveness 
5 
Responds readily to name spoken in normal tone 
4 
Lethargic response to name spoken in normal tone 
3 
Responds only after name is called loudly and/or repeatedly 
2 
Responds only after mild prodding or shaking 
1 
Responds only after painful trapezius squeeze 
0 
No response after painful trapezius squeeze 


P (617) 299-8380 • F (617) 299-8379 • 215 First Street, Cambridge. MA 02142 
 
 
 
 
• SAGE 
w w w . sa g e r x. c o rn 
T H E R A P E U T I C S 
 
 
 
 
 
March I0, 2017 
 
 
 
 
 
217-PRK-201 Protocol Administrative Letter #01 
 
 
This administrative letter is to clarify the following in Protocol 217-PRK-201 
Version 3.0 dated 24 October 2016 (Amendment 2): 
 
• Timepoints of the Montreal Cognitive Assessment (MoCA) Table 2 (Part 
A) footnote "l" and Table 3 (Part B) footnote "I": TheMoCA should be 
conducted in Part A on Days 1, 3, and 4 and in Part Bon Days 1, 4, and 9, 
two (2) hours post dose ±30 minutes. All other timepoints on days not 
specified herein can be administered at any time. 
 
• End of Study Visit for subjects who tenninate early in Pa1i A or Part B: 
Section 8.4 (page 39), Subject Withdrawal Criteria, states that any subject 
who is withdrawn from the study for any reason is to have the final visit 
assessments performed. Final visit assessments for Part A are the 
assessments for the day of early termination (Days 1-8) plus any additional 
assessments required for Day 14 (only assessments that are not collected 
under the assessments on the day of early tennination). If early termination 
occurs on Part A Days 9-14, then Day 14 is the Final Visit. Final visit 
assessments for Part B are the Part B, Day 15 assessments. If a subject 
tenninates early on Part B Days 16-22 then EOS Day 22 is the Final Visit. 
 
• Table 2 (Pa1i A) Row 8 and Table 3 (Part B) Row 6 is identified as 
"CBC/Semm Chemistry": This refers to Hematology and Blood Chemistry 
as described in Sections 13.1.6.1 and 13.1.6.2 of the Protocol. 
 
• Section 13.1.6.3. Urinalysis (page 53) states "Urinalysis will include 
assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific 
gravity." Bile is used as a synonym for bilimbin; urine bilirubin should be 
tested as part of the urinalysis. 
 
• In Part A on Day -1 duplicate samples are to be collected for Hematology, 
Blood Chemistry and Urinalysis with one set of samples being sent to a 


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• SAGE 
www sagerx corn 
THERAPEUTICS 
 
 
 
local lab for confirmationof eligibility based on results prior to dosing on 
Day I and on a second set of samples being sent to the  central  lab  for 
ana l ysis. 
 
These clarifications will be included in a future amendment to the protocol. 
 
 
 
 
 
Sage Therapeutics 


P ( 6 1 7 ) 299-8380 • F ( 617) 299-8379 • 215 First S tr e e t. Cambridge. MA 0214 2 
 
 
• SAGE 
w w w . s a g e r x . c o m 
THERAPEUTICS 
 
 
May24,2017 
 
 
217-PRK-201 Protocol Administrative Letter #02 
 
 
This administrative letter is to give you a quick update on SAGE 217-PRK-201 
clinical study. You will recall that this study had two phases: Part A and Part B. 
An interim analysis was conducted on twelve subjects after they completed their 
dosing in Part A to inform the methodology and conduct of Part B. 
 
In the five subjects with overt tremor (tremor score over five at baseline), an 
approximate 20-30% improvement in tremor symptoms was observed on the four 
days of SAGE-217 open-label treatment, as assessed by change in the MDS­ 
UPDRS Part III tremor score. This improvement in tremor score during the 
SAGE-217 dosing phase was longer-lasting than the effect on tremor observed in 
these subjects during the levodopa/carbidopa-only phase. Administration of 
SAGE-217 during the day was found to be generally well-tolerated with no serious 
adverse events or discontinuations reported. Similar to findings in the Phase I 
clinical program, the most common adverse events were sedation and somnolence 
(occurring 2 to 4 hours post dose). While dosing was initiated at the 30 mg per day 
maximum tolerated dose established in the Phase 1 program, the majority of 
patients were down-titrated to 10 or 20 mg of SAGE-217 per day. 
 
Based on the signal of activity in reducing Parkinsonian tremor in these patients, 
Sage plans to proceed to an open-label Part B study evaluating SAGE-217 as an 
adjunctive treatment to anti-Parkinso nian agents in tremor-predominant patients. 
 
As a result, Part B of this study has been revamped to include the following key 
eligibility criteria: 
 
1. Subjects with PD, who meet the criteria for Hoehn &  Yahr stage 1-4  
assessed during the "on" period, andhave a tremor with a total score of 2::.10 
(sum ofMDS-UPDRS Part 2 and 3 tremor items: 2.10, 3.15, 3.16, 3.17 and 
3.18) AND a score 2::.3 in one lim b (from items 3.15, 3.16, or 3.17) AND a 
constancy of rest tremor score of 2::.3 (item 3.18). Inclusion criteria tremor 
scores must be assessed during "on" periods assumed  to  be within 2  hours 
of dosing with antiparkinsonian agent(s) during the screening and Day -1 
visit. 
2. Subjects will continue on their stable dose(s) of antiparkinsonian agent(s) 
and will receive Sage-217 capsules oral once a day at night time for a 


P (617) 299·8380 • F (617) 299·8379 • 215 Fir sI Stree t. Cambri dg e. MA 0 2 1 42 
 
 
 
 
• SAGE 
w w w. s a g e r x . c o m 
THEPAPEUTICS 
 
 
period of 7 days. Subjects will receive SAGE-217 capsules 20 mg total 
dose on Days 1 and 2 and if tolerated, the total daily dose will be escalated 
to 30 mg on Day 3. 
 
Based upon the tremor scores in the first 12 subjects at admission for Part A of the 
study, it is unlikely that these subjectswill qualify for the revised Part B. To the 
extent subjects from Part A meet the aforementioned key entry criteria for the 
amended Part B, they remain eligible. Please assess these subjects for their tremor 
scores during the "on" period. If the subject does not meet these criteria, they are 
ineligible for Part B. 
 
These clarifications will be included in a future amendment to the protocol. 
 
Sage Therapeutics 


P ( 61 7} 299-8380 • F ( 617 ) 2 99 -8 3 79 • 215 Fi r s t S tr ee t. C a mb r i dg e. MA 02 142 
 
 
• SAGE 
w w w . s a g e r x . c o m 
THERAPEUTICS 
 
 
 
 
 
August 2, 2017 
 
 
 
 
217-PRK-201 Protocol Administrative Letter #03 
 
 
This memo is to clarify the following: 
 
• 
Pharmacokinetic sample storage conditions 
• 
Errors in Table 3: Schedule of Events: Part B (Open-Label) 
o 
MDS-UPDRS Complete 
o 
MDS-UPDRS Part Il only and Part ill only 
o 
Footnote "p" 
o 
Footnote "q" 
 
Section 12.2 of Protocol 217-PRK-201, Amendment 4, Version 5.0 states that plasma samples 
should be kept frozen at approximately -70°C to -80°C until analyzed. This letter defines an 
acceptable range of -l 5°C to -30°C for sample storage prior to being shipped for bioanalysis. 
 
MDS-UPDRS Complete is to be done in the morning on Day l (8:00 AM ±1 hour) and Day 8 
(approximately 12 hours ±15 minutes after the Day 7 dose). MDS-UPDRS Parts II & III are to be 
done on Days 2, 3, 4, 5, 6, and 7 in the morning and evening at approximately 12 and 23 hours 
(±15 minutes) following the SAGE-217 dose from the previous Day. 
 
Footnote "p" which corresponds to the PDSS-2 does not reference a Screening timepoint. This is 
correctly marked with an "X" in Table 3. The PDSS-2 should be done at Screening, on Day l at 
8:00 AM (1 hour), Day 8 (12 hours ±15 minutes post Day 7 dose), and on Day 14. 
 
Footnote "q" which corresponds to the BDI-11 incorrectly lists Admission (Day -1). The BDI-11 
should be done at Screening and on Days 1, 8, and 14. 
 

SAP_000.pdf: 
Offi ci al  Titl e:      A   P h a s e  2,  T  w o  -P art  St u d y t o  E v al u at e t h e  S af et y,  T ol er a bilit y, 
P h ar  m a c o ki n eti c s,  a n d   Effi c a c y  of  S A  G  E  -2 1 7 i n  S u bj e ct s   Wit h 
P ar ki n s o n' s   Di s e a s  e  
N  C T   N u   m b e r:      N  C T 0 3 0 0 0 5 6 9    
D o c u m e nt  D at e : 
S A P  V er si o n  2:  0 2 - Au g u st - 20 1 7 


Cli ni c al  St u d y   R e p ort   
2 1 7- P  R  K - 2 0 1  P art   B
1 6. 1  St u d y I nf or  m ati o n 
1 
9.   
S  T  A  TI S  TI  C  A  L    M  E  T  H  O  D S  I  N  T  E  RI   M   A  N  A  L  Y SI S  P  L  A N
T h e  St atisti c al   A n al ysis  Pl a n   M et h o ds   w er e   m o difi e d  o n c e;  V ersi o n  2. 0 ( d at e d  0 1   A u g ust  2 0 1 7)   
is  pr o vi d e d. 


S a ge T her a pe utics, I nc.  
St atis tic al A n al ysis  Pl an  
Met h o ds 
Pr ot oc ol 2 1 7 - P RK - 2 01
A P H A S E  2, T W O -P A R T  ST U D Y T O E V A L U A T E  TH E  S A F E T Y,  
T O L E R A BI LI T Y,  PH A R M A C O KI N E TI C S,  A N D E F FI C A C Y O F  SA G E - 2 1 7 
I N SU BJ E C T S  WI T H P A R KI N S O N’ S DI S E A S E 
A ut h or  o f S AP:  
 P h. D. 
Versi o n:  V ersi o n 2. 0 
D ate  of SA P:  0 1 A u g us t 2 0 1 7 
S p o ns or:  
Sa ge  T he ra pe utics, I nc. 
2 1 5  First Street 
Ca m bri d ge , Massac h usetts 0 2 1 4 2 
C O N FI D E N TI A L  
T his  doc u me n t c o ntai ns co nfi de ntial i nf or mati o n.   A n y  use,  distri b uti o n,  or discl os ure wit h o u t t he pri or wr itte n 
c o nse nt  of Sa ge T hera pe utics,  I nc. is strictl y p r o hi bite d exce p t t o t he exte nt re q uire d  un der  ap plic a ble laws  o r 
re g ulati o ns.  P ers o ns to  w h o m  t he inf or mati o n  is discl ose d m ust be inf or me d t hat  the  inf or mati o n  is co nfi de ntial  
a nd ma y  n ot  be  furt h er discl ose d b y the m.






St atisti c al   A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0  
P a g e  4 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
9. 3. 3. 6  
Ti  m e t o  First   R es c u e   M e di c ati o n  ...............................................................  1 6 
9. 4  
S af et y   A n al ysis  .........................................................................................................  1 6 
9. 4. 1  
A d v ers e  E v e nts   .................................................................................................  1 7 
9. 4. 2  
Pr i or  a n d   C o n c o  mit a nt   M e di c ati o ns .................................................................  1 8 
9. 4. 3  
Cli ni c al  L a b or at or y   ...........................................................................................  1 8 
9. 4. 4  
El e ctr o c ar di o gr a  m  ............................................................................................  1 9 
9. 4. 5  
Vit al  Si g ns   ........................................................................................................  1 9 
9. 4. 6  
P h ys i c al  E x a  mi n ati o n .......................................................................................  1 9 
9. 4. 7  
C ol u  m bi a-  S ui ci d e  S e v erit y   R ati n g  S c al e (  C -S S  R S)  ........................................  1 9 
9. 4. 8  
St a nf or d  Sl e e pi n ess  S c al e  .................................................................................  1 9 
9. 4. 9  
M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n ess/ S e d ati o n (  M  O  A  A/ S)    ..............  2 0 
9. 5  
P h ar  m a c o ki n eti c   A n al ysis  ........................................................................................  2 0 
1 0  S u  m  m a r y  of I nt e ri  m   A n al ys es  ......................................................................................  2 0 
1 1  R ef e r e n c es   .......................................................................................................................  2 1 
1 2  List   of   A p p e n di c es .......................................................................................................... 2 2  
1 2. 1  A p p e n di x   A:  S c h e d ul e  of   Ass ess  m e nts   ....................................................................  2 2 
1 2. 1. 1  
P art   A  ................................................................................................................  2 2 
1 2. 1. 2  
P art   B  ................................................................................................................  2 5 


St atisti c al   A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0  
P a g e  5 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
2     LI S  T   O F   A B  B  R  E  VI  A  TI  O  N  S 
A  B  B  R  E  VI  A  TI  O  N      D  E FI  NI  TI  O  N   O  R   D  E S  C  RI P  TI  O  N   
A E   
a d v ers e  e v e nt  
A  M   
m or ni n g   
A T  C   
A n at o  mi c al  T h er a p e uti c   C h e  mi c al   
 
 
B L  Q   
b el o  w t h e li  mit  of  q u a ntifi c ati o n  
B  MI   
b o d y   m ass i n d e x  
C  -S S  R S  
C ol u  m bi a  -S ui ci d e  S e v erit y   R ati n g  S c al e  
C  B  C   
c o  m pl et e  b l o o d c o u nt  
CI   
c o nfi d e n c e i nt er v al  
C S  R   
c li ni c al st u d y re p ort  
E  C  G  
e l e ctr o c ar di o gr a  m 
e C  R F   
el e ctr o ni c  c as e  re p ort  for  m  
HI  V   
h u  m a n  im  m u n o d efi ci e n c y   v ir us 
I  A 
i nt eri  m  a n al ysis 
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
M  D S  -U P  D  R S      
M o v e  m e nt   Dis or d er  S o ci et y    –  U nit e d  P ar ki ns o n’s   Dis e as e   R ati n g  S c al e   
M  M  R  M   
mi x e d   eff e ct   m o d el r e p e at e d   m e as ur es  
M  O  A  A/ S   
M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n ess/ S e d ati o n    
 
 
P  D  
P ar ki ns o n’s   Dis e as e  
 
 
 
 
P  K  
p h ar  m a c o ki n eti c  
P T  
pr ef err e d t er  m  
Q T c F   
Q T  -i nt er v al f or  E  C  G  c orr e ct e d f or  h e art r at e ( Fri d eri ci a) 
S  A E  
seri o us  a d v ers e  e v e nt  
S  A P  
st atisti c al a n al ysis  p l a n 
S  O  C  
S yst e  m   Or g a n   Cl ass  
S S S  
St a nf or d  Sl e e pi n ess  S c al e  
T E  A E  
tr e at  m e nt e m er g e nt   a d v ers e  e v e nt  
U L  O  Q   
u p p er  li  mit  of  q u a ntit ati o n 
W  H  O   -D  D   
W orl d   H e alt h    Or g a ni z ati o n   Dr u g   Di cti o n ar y   


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  6 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
3     I  N  T  R  O  D  U  C  TI  O  N 
T his  a  m e n d e d  st atisti c al  a n al yse s pl a n ( S  A P) is f or t h e  fi n al  a n al ysis of t h e  st u d y ( P art   A  a n d  P art   B) a n d 
is  b as e d  o n t h e  a p pr o v e d  cli ni c al st u d y  pr ot o c ol,  d at e d  0 8 J  U  N  2 0 1 7,   V ersi o n 5. 0 , i n c or p or atin g 
A  m e n d  m e nt  4   
T his  S  A P  a d dr ess es t h e s af et y , effi c a c y,  a n d  p h ar  m a c o ki n eti cs ( P  K)  o bj e cti v es  of t h e st u d y  a n d  d es cri b es 
t h e  pl a n n e d s af et y, effi c a c y ,  a n d  P  K st atisti c al  a n al ys es  a n d  d at a  pr es e nt ati o ns. 
T h e st atisti c al  pl a n  d es cri b e d  h er e aft er is  a n  a  pri ori   pl a n  a n d will  b e   a p pr o v e d  pri or t o  a n y  a n al ysis  of 
d at a  p ert ai ni n g  t o S a g e’s st u d y  2 1 7- P  R  K - 2 0 1  P art   A  a n d  pri or t o  a n y  a n al ysis  of  d at a  p ert ai ni n g t o P art   B .   
D at a  pr o c essi n g, t a b ul ati o n  of  d es cri pti v e st atisti cs,  c al c ul ati o n  of i nf er e nti al st atisti cs,  a n d  gr a p hi c al 
r e pr es e nt ati o ns   will  b e  p erf or  m e d  pri  m aril y  usi n g  S  A S (r el e as e  9. 3  or  hi g h er) f or    Wi n d o  ws.  If t h e  us e  of 
ot h er s oft  w ar e is   w arr a nt e d, t h e fi n al st atisti c al   m et h o d ol o g y r e p ort   will  d et ail   w h at s oft  w ar e   w as  us e d f or 
w h at  p ur p os es. 
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m ati o n   will  b e  p erf or  m e d  usi n g  P h o e ni x    Wi n  N o nli n ®  s oft  w ar e (  V ersi o n 
6. 4  or l at er;  P h arsi g ht,   C ar y,   N  C)  o n i n di vi d u al  pl as  m a  c o n c e ntr ati o n- ti  m e  d at a. 
S e p ar at e listi n gs, t a bl es,  a n d fi g ur es   will  b e  cr e at e d f or  P art   A  a n d  P art   B.   T h e r e a d er  of t his  S  A P is 
e n c o ur a g e d t o  als o r e a d t h e  cli ni c al  pr ot o c ol,  a n d  ot h er i d e ntifi e d  d o c u  m e nts, f or  d et ails  o n t h e  pl a n n e d 
c o n d u ct  of t his st u d y.   O p er ati o n al  as p e cts r el at e d t o  c oll e cti o n  a n d ti  mi n g  of  pl a n n e d  cli ni c al  ass ess  m e nts 
ar e  n ot r e p e at e d i n t his  S  A P  u nl ess r el e v a nt t o t h e  pl a n n e d  a n al ysis.  
4     S  T  U  D  Y   O  B J  E  C  TI  V  E S   
4. 1     P ri  m a r y   O bj e cti v e  
T h e  pri  m ar y  o bj e cti v e  of  P art   A  is t o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  S  A  G E- 2 1 7   Or al  S ol uti o n. 
T h e  pri  m ar y  o bj e cti v e  of  P art   B is t o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7  c a ps ul es  as  a n  a dj u n ct t o 
a nti p ar ki ns o ni a n  a g e nt(s)  o n t h e s e v erit y  of  P ar ki ns o n’s   Dis e as e ( P  D ) tr e  m or s y  m pt o  ms. 
4. 2     S e c o n d a r y   O bj e cti v es   
T h e s e c o n d ar y  o bj e cti v es  of  P art   A  ar e:  
•     T o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7   Or al  S ol uti o n  o n t h e s e v erit y  of  P  D   m ot or s y  m pt o  ms  aft er 
wit h dr a  w al  of  L e v o d o p a  or   C ar bi d o p a- L e v o d o p a ( L e v o d o p a/  C ar bi d o p a). 
•     T o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7   Or al  S ol uti o n  e x p os ur e l e n gt h  o n t h e s e v erit y  of  P  D   m ot or 
s y  m pt o  ms  aft er   wit h dr a  w al  of  L e v o d o p a/  C ar bi d o p a. 
T h e s e c o n d ar y  o bj e cti v es  of  P art   B  ar e:  
•     T o  e v al u at e t h e  eff e ct  of  S  A  G E - 2 1 7  c a ps ul es  as  a n  a dj u n ct t o  a nti p ar ki ns o ni a n  a g e nt(s)  o n   m ot or 
a n d  n o n-  m ot or s y  m pt o  ms  of  P  D. 
•     T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  S  A  G E- 2 1 7   C a ps ul es. 
4. 3  
P h a r  m a c o ki n eti c  O bj e cti v es   
•     P a rt   A:  T o  ass ess t h e  p h ar  m a c o ki n eti c ( P  K)  pr ofil e  of  S  A  G E - 2 1 7   Or al  S ol uti o n i n 
pl as  m a s a  m pl es.  
•     P a rt   B:  T o  ass ess t h e  P  K  pr ofil e  of  S  A  G E- 2 1 7   C a ps ul es  utili zi n g  a  p o p ul ati o n  P  K 
a p pr o a c h. 




St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  8 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
p ar a  m et ers ,  a n d sui ci d al i d e ati o n  usi n g t h e   C ol u  m bi a -S ui ci d e  S e v erit y   R ati n g  S c al e (  C -S S  R S).  I n 
a d diti o n, sl e e pi n ess/s e d ati o n  as  ass ess e d  b y  St a nf or d  Sl e e pi n ess  S c al e.  
T h e s e c o n d ar y s af et y  e n d p oi nt  of  P art   B is t h e fr e q u e n c y  a n d s e v erit y  of   A Es    a n d  c h a n g es i n  vit al si g ns, 
cli ni c al l a b or at or y  d at a,  E  C  G  p ar a  m et ers,  a n d s ui ci d al i d e ati o n  usi n g t h e   C ol u  m bi a- S ui ci d e  S e v erit y 
R ati n g  S c al e (  C  -S S  R S).  
5. 3     Ot h e r   E n d p oi nts   
Pl as  m a  c o n c e ntr ati o ns  of  S  A  G E - 2 1 7,  a n d  p ossi bl y  S  A  G E- 2 1 7   m et a b olit es,   will  b e   m e as ur e d,  a n d  P  K 
p ar a  m et ers   will  b e  d eri v e d.  
6     S  T  U  D  Y   D  E SI  G  N   
6. 1     O v e r all   D esi g n    
T his st u d y is  a  2- p art,   m ulti c e nt er,  P h as e  2 st u d y t o  e v al u at e t h e s af et y, t ol er a bilit y,  P  K,  a n d  effi c a c y  of 
S  A  G E - 2 1 7.   P art   A  of t h e st u d y is  a n  o p e n-l a b el  d esi g n   wit h   m or ni n g (  A  M)  d osi n g  of  S  A  G E- 2 1 7 f or  4 
d a ys  i n  u p t o  1 8  a d ult s u bj e cts   wit h  P  D  of   m o d er at e s e v erit y   w h o r es p o n d t o i  m  m e di at e-r el e as e  or al 
L e v o d o p a  a n d  ar e  o n st a bl e  d os e.   P art   B  of t h e st u d y is  a n  o p e n-l a b el  d esi g n   wit h  e v e ni n g ( P  M)  d osi n g 
of  S  A  G E - 2 1 7   C a ps ul es f or  7  d a ys i n  u p t o  1 5  a d ult s u bj e cts   wit h  P  D.   S u bj e cts t h at  p arti ci p at e i n  P art   A 
ar e  eli gi bl e t o  p arti ci p at e i n  P art   B if  all  eli gi bilit y  crit eri a f or  P art   B  ar e   m et  a n d t h e y t ol er at e d  at l e ast  2 0 
m g  S  A  G E  - 2 1 7 i n  P art   A.  S u bj e cts   will  b e f oll o  w e d f or  a n  a d diti o n al  7  d a ys  aft er t h e  a d  mi nistr ati o n  of t h e 
l ast  d os e i n  P art   A  a n d  P art   B. 
T h er e  ar e t  w o  p arts t o t h e st u d y: 
•     P a rt   A:  O p e n  L a b el   wit h   A  M  d osi n g ( 4  d a ys  ). 
All s u bj e cts   will  c o nti n u e t o t a k e t h eir  a nti p ar ki ns o ni a n  a g e nts i n cl u di n g i  m  m e di at e  -r el e as e  or al 
L e v o d o p a  o n t h e  d a y  of  a d  missi o n (  D a y - 1)  a n d i n t h e   A  M  o nl y  o n t h e f oll o  wi n g  3  d a ys 
(  D a ys  1 t o  3).   All s u bj e cts   will st o p t h eir i  m  m e di at e-r el e as e  or al  L e vo d o p a  o n   D a y  4  a n d   will 
st art  o n  a  3 0   m g  d os e  of  S  A  G E- 2 1 7   Or al  S ol uti o n  a d  mi nist er e d i n t h e   A  M   wit h f o o d,  as  o utli n e d 
i n  S e cti o n  9. 1. 1  of t h e  pr ot o c ol.  S u bj e cts  n ot t ol er ati n g  3 0   m g   will r e c ei v e  2 0   m g,  a n d s u bj e cts 
n ot t ol er ati n g  2 0   m g   will r e c ei v e  1 0   m g  o n s u bs e q u e nt  d a ys  ( S e cti o n  7. 4  of t h e  pr ot o c ol).  T h e 
d os e r e c ei v e d  o n   D a y  7   will  b e  d efi n e d  as t h e t ol er at e d  d os e f or t h at s u bj e ct.  S u bj e cts  n ot 
t ol er ati n g  1 0   m g   will  n ot  b e  a bl e t o  c o nti n u e i n t h e st u d y  a n d   m a y  b e r e pl a c e d.  S u bj e cts   will  b e 
f oll o  w e d f or  an  a d diti o n al  7  d a ys (  D a y  1 4)  aft er t h e  a d  mi nistr ati o n  of t h e l ast  d os e.  L e v o d o p a 
tr e at  m e nt   will  b e r es u  m e d  o n   D a y  8  a n d  c o nti n u e t hr o u g h   D a y  1 4.  
R es c u e tr e at  m e nt ( or al  L e v o d o p a  or  ot h er  a nti p ar ki ns o ni a n  a g e nt  at I n v esti g at or’s  dis cr eti o n)   will 
b e  all o  w e d, if  n e e d e d,  o n  all  d a ys (  D a ys  1 t o  7).  
P art   A is  d esi g n e d t o  d et er  mi n e t h e t ol er at e d  d os e  of  S  A  G E - 2 1 7   Or al  S ol uti o n f or  e a c h s u bj e ct 
a n d t o  ass ess   w h et h er  S  A  G E - 2 1 7  e x hi bits  effi c a c y i n s u bj e cts   wit h  P  D of   m o d er at e s e v erit y  i n 
or d er t o i nf or  m t h e  c o n d u ct  o f  P art   B.  
•     P a rt   B:  O p e n  -l a b el   wit h  P  M  d osi n g  of  S  A  G E- 2 1 7   C a ps ul es, f or  7  d a ys,  as  a n  a dj u n ct t o 
a nti p ar ki ns o ni a n  a g e nt(s).  
S u bj e cts  o n  a st a bl e  d os e  of  a nti p ar ki ns o ni a n  a g e nt(s)   will  c o nti n u e t a ki n g t h e  m f or t h e  d ur ati o n 
of t h e st u d y.    A nti c h oli n er gi cs  a n d/ or  a  m a nt a di n e   will  b e  dis c o nti n u e d  b y   D a y - 6  a n d   D a y - 1 0, 
r es p e cti v el y. 
S cr e e ni n g   m a y  o c c ur  b et  w e e n   D a y  - 2 8  a n d   D a y - 2,  b ut s u bj e cts   m ust  b e  a d  mitt e d  o n   D a y - 1 f or 
s el e ct e d  pr e-d os e  ass ess  m e nts ( e g,  cli ni c al l a b or at or y  ass ess  m e nts,  ass ess  m e nt  of tr e  m or ).    All 
s u bj e cts   will t a k e  S  A  G E- 2 1 7   C a ps ul es,  2 0   m g,  at  8 P  M  o n   D a ys  1  a n d  2.   O n   D a y  3, s u bj e cts 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  9 
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
t ol er ati n g t h e i niti al  d os e (i e, t h os e   w h o  d o  n ot  e x p eri e n c e  a s e v er e A E   j u d g e d  b y t h e I n v esti g at or 
t o  b e r el at e d t o st u d y  dr u g)   will r e c ei v e  a  d os e i n cr e as e ( SA  G E  - 2 1 7,  3 0   m g),  at  8 P  M  a n d 
c o nti n ui n g  e a c h s u bs e q u e nt  e v e ni n g  at  8 P  M f or t h e r e  m ai n d er  of t h e  d osi n g  p eri o d ( e n di n g  o n 
D a y  7).   
If  o n   D a y  3  or  a n y ti  m e t h er e aft er, t h e  3 0   m g  d os e is  n ot t ol er at e d,  ass ess e d  b y  o c c urr e n c e  of  a 
s e v er e A E   j u d g e d  b y t h e I n v esti g at or t o  b e r el at e d t o st u d y  dr u g, t h e  d os e  o n t h e  n e xt  d a y   m ust  b e 
r e d u c e d t o  2 0   m g  a n d  c o nti n u e d f or t h e r e  m ai n d er  of t h e  d osi n g  p eri o d.   S u bj e cts   w h o  c a n n ot 
t ol er at e t h e  2 0   m g  d os e  at  a n y ti  m e   will  b e  dis c o nti n u e d  a n d r e pl a c e d. 
All  d os es  of  S  A  G E  - 2 1 7   will  b e  a d  mi nist er e d   wit h f o o d  as  o utli n e d i n  S e cti o n  9. 1. 2  of t h e 
pr ot o c ol.   F or  a nti p ar ki ns o ni a n  a g e nts,  a d  mi nistr ati o n   wit h  or   wit h o ut f o o d   will  b e  d et er  mi n e d  b y 
t h e I n v esti g at or. 
S u bj e cts   will r e c ei v e  S  A  G E - 2 1 7 f or  u p t o  7  d a ys  a n d   will  b e f oll o  w e d f or  a n a d diti o n al  7  d a ys 
aft er t h e  a d  mi nistr ati o n  of t h e l ast  d os e.  
Ass ess  m e nts   will  b e  p erf or  m e d  p eri o di c all y  d uri n g t h e st u d y  as  o utli n e d i n t h e  S c h e d ul e  of  E v e nts f or 
P art   A  a n d  P art   B ( s e e S e cti o ns  1 2. 1. 1   a n d 1 2. 1. 2 ). 
6. 2     S a  m pl e  Si z e  a n d  P o  w e r  
A p pr o xi  m at el y  1 8 s u bj e cts   will  b e  e nr oll e d i n  P art   A.   A n   i nt eri  m  a n al ysis is  pl a n n e d  aft er  1 0 s u bj e cts 
h a v e  c o  m pl et e d  P art   A  at l e ast  t hr o u g h   D a y  1 4 t o i nf or  m t h e  c o n d u ct  of  P art   B.   U p t o  1 5 s u bj e cts   will  b e 
e nr oll e d i n  P art   B i n  or d er f or  1 0 s u bj e cts t o  c o  m pl et e t h e st u d y (t ol er at e  at l e ast  2 0   m g  S  A  G E- 2 1 7 f or t h e 
d ur ati o n  of t h e  d osi n g  p eri o d).  
6. 3     R a n d o  mi z ati o n 
N ot  a p pli c a bl e  as  P art   A  a n d  P art   B  ar e    o p e n-l a b el, si n gl e  ar  m. 
6. 4     Bli n di n g  a n d   U n bli n di n g   
N ot  a p pli c a bl e  as  P art   A  a n d  P art   B  ar e  o p e n  -l a b el. 
7  
M  O  DI FI  C  A  TI  O  N S  
7. 1     M o difi c ati o ns t o t h e   A p p r o v e d   Cli ni c al  St u d y  P r ot o c ol 
T h e  p r ot o c ol   w as  a  m e n d e d t o  v ersi o n  5. 0,  d at e d  0 8 J  U  N  2 0 1 7.   P art   B   w as  c h a n g e d fr o  m  a r a n d o  mi z e d 
d esi g n t o  o p e n- l a b el.   T h e i n cl usi o n/ e x cl usi o n  crit eri a,  d osi n g s c h e d ul e,  a n d  ass ess  m e nt ti  m e  p oi nts   w er e 
u p d at e d.   S u bj e cts  ar e  all o  w e d t o r e  m ai n  o n  a nti p ar ki ns o ni a n  a g e nt(s)   w hi c h  eli  mi n at es  t h e  n e e d f or 
r es c u e   m e di c ati o ns i n  P art   B.  T h e   M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n ess/ S e d ati o n  S c al e 
(  M  O  A  A/ S)  a n d  St a nf or d  Sl e e pi n ess  S c al e ( S S S)  ass ess  m e nts   w er e r e  m o v e d fr o  m  P art   B     
 
 
7. 2     M o difi c ati o ns t o t h e   A p p r o v e   d  St atisti c al   A n al ysis  Pl a n  
T h e  P art   B s e cti o ns  of t his  S  A P   w er e  u p d at e d  aft er  pr ot o c ol  v ersi o n  5. 0,  d at e d  0 8  J  U  N  2 0 1 7.   P art   B 
s u  m  m ari es   will  b e  d o n e  b y  o v er all s u bj e cts i nst e a d  of  b y tr e at  m e nt s e q u e n c e.   S e cti o ns f or t h e    
 
   M  D S-U P  D  R S  P art II/III   tr e  m or s c or e   w er e  a d d e d.   T h e  P art   B M  O  A  A/ S,  S S S,   M  M  R  M  , a n d r es c u e 
m e di c ati o n  a n al ysis   w as r e  m o v e d.    S e p ar at e listi n gs  a n d t a bl es  ar e  n o  w  b ei n g  pr o d u c e d f or  P art   A  a n d 
P art   B.  
7. 3     M o difi c ati o ns t o t h e   A p p r o v e d   D   M  C   C h a rt e r    
N ot  a p pli c a bl e.   


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 0  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
S a g e  T h er a p e ut ics I n c  
C o nfi d e nti al I nf or  m ati o n   
8     A  N  A  L  Y S  I S P  O P  U  L  A  T I  O  N S  
S u bj e cts i n cl u d e d i n t h e  b el o  w  a n al ysis  p o p ul ati o ns ( a n d r e as o n f or  e x cl usi o n, if  a p pli c a bl e)   will  b e 
pr o vi d e d i n  a listi n g.  
8. 1     Effi c a c y   P o p ul ati o n 
T h e  E ffi c a c y P o p ul ati o n   will  c o nsist  of  all s u bj e cts   w h o r e c ei v e  at l e ast  o n e  d os e  of st u d y  dr u g  a n d  h a v e 
at l e ast  o n e  p ost d os e   M  D S -U P  D  R S  e v al u ati o n.  S e p ar at e  p o p ul ati o ns  ar e  d efi n e d f or  e a c h  p art  of t h e 
st u d y:  Effi c a c y  P o p ul ati o n ( P art   A)   will i n cl u d e s u bj e cts   w h o f ulfill t h e r e q uir e  m e nts f or i n cl usi o n i n t h e 
Effi c a c y  P o p ul ati o n  b as e d  o n  P art   A r es ults; si  mil arl y,  Effi c a c y  P o p ul ati o n ( P art   B)   will i n cl u d e s u bj e cts 
w h o f ulfill t h e r e q uir e  m e nts f or i n cl usi o n i n t h e  Effi c a c y  P o p ul ati o n  b as e d  o n  P art   B r es ults.   Effi c a c y 
P o p ul ati o n ( P art   A)  a n d  Effi c a c y  P o p ul ati o n ( P art   B)  will  b e  us e d t o  a n al y z e  effi c a c y  d at a   i n  P arts A  a n d 
B, r es p e cti v el y  .  
8. 2     S af et y  P o p ul ati o n  
T h e  S af et y  P o p ul ati o n  is  d efi n e d  as  all s u bj e cts   w h o  ar e  a d  mi nist er e d st u d y  dr u g i n  a st u d y  p art.  T his 
p o p ul ati o n  will  b e  us e d t o  pr o vi d e  d es cri pti v e s u  m  m ari es  of s af et y.   S af et y  P o p ul ati o n ( P art   A)  a n d  S af et y 
P o p ul ati o n ( P art   B)   will  b e  us e d t o  a n al y z e s af et y  d at a i n  P arts   A  a n d   B, r es p e cti v el y.  
8. 3     P  K  P o p ul ati o n 
T h e  P  K  P o p ul ati o n   will  c o nsist  of  all s u bj e cts i n t h e s af et y  p o p ul ati o n   wit h  at l e ast  o n e  pl as  m a s a  m pl e 
wit h  q u a ntifi a bl e  c o n c e ntr ati o n  of  S  A  G E  - 2 1 7.   T h e  P  K  p o p ul ati o n   will  b e s e p ar at e d  b y st u d y  p art. P  K 
P o p ul ati o n ( P art   A)   will i n cl u d e s u bj e cts   wit h  at l e ast  o n e  pl as  m a s a  m pl e   wit h  q u a ntifi a bl e  c o n c e ntr ati o n 
of  S  A  G E -2 1 7 i n  P art   A.   P  K  P o p ul ati o n ( P art   B)   will i n cl u d e s u bj e cts   wit h  at l e ast  o n e  pl as  m a s a  m pl e 
wit h   q u a ntifi a bl e  c o n c e ntr ati o n  of  S  A  G E - 2 1 7 i n  P art   B.   T h es e  p o p ul ati o ns   will  b e  us e d t o s u  m  m ari z e  P  K 
d at a f or  e a c h r es p e cti v e st u d y  p art.  
9     S T  A  TI S  TI  C  A  L   A  N  A  L  Y SI S   
9. 1     G e n e r al   C o nsi d e r ati o ns   
C o nti n u o us ( q u a ntit ati v e)  v ari a bl es   will  b e s u  m  m ari z e d  usi n g t h e  n u  m b er  a n d  pr o p orti o n  of  e a c h  p ossi bl e 
v al u e.  I n  g e n er al, t h e  d e n o  mi n at or f or t h e  p er c e nt a g e  c al c ul ati o n   will  b e  b as e d  u p o n t h e t ot al  n u  m b er  of 
s u bj e cts i n t h e st u d y p o p ul ati o n.    A n  e x c e pti o n t o t his   will  b e t h e  b y  d os e  A E   a n d   m e di c ati o n t a bl es.   T h e 
d e n o  mi n at or f or  p er c e nt a g e   will  b e t h e  n u  m b er  of s u bj e cts  d os e d  at  a  S  A  G E- 2 1 7   m g l e v el  o n  a  p arti c ul ar 
st u d y  d a y.   T h e  d e n o  mi n at or f or  p er c e nt a g e i n  c at e g ori c al  p ar a  m et er  uri n al ysis l a b or at or y t a bl es   will  b e 
t h e  n u  m b er  of s u bj e cts   wit h  a n  ass ess  m e nt  at  a  gi v e n ti  m e  p oi nt. 
T h e   mi ni  m u  m  a n d   m a xi  m u  m   will  b e r e p ort e d   wit h t h e s a  m e  d e gr e e  of  pr e cisi o n (  i e, t h e s a  m e  n u  m b er  of 
d e ci  m al  pl a c es)  as t h e  o bs er v e d  d at a.    M e as ur es  of l o c ati o n (  m e a n  a n d   m e di a n)   w ill  b e r e p ort e d t o  1 
d e gr e e  of  pr e cisi o n   m or e t h a n t h e  o bs er v e d  d at a  a n d   m e as ur es  of s pr e a d (st a n d ar d  d e vi ati o n)   will  b e 
r e p ort e d t o t  w o  d e gr e es  of  pr e cisi o n   m or e t h a n t h e o bs er v e d  d at a.  
P er c e nt a g es   will  b e  pr es e nt e d t o  o n e  d e ci  m al  pl a c e  u nl ess  ot h er  wis e s p e cifi e d.   Ass ess  m e nts  d o n e  o n 
u ns c h e d ul e d  visits   will  n ot  b e s u  m  m ari z e d  b ut   will  b e list e d.   T h e s af et y  p o p ul ati o n   will  b e  us e d t o 
pr o vi d e  d es cri pti v e s u  m  m ari es  of s af et y.   T h e  effi c a c y  p o p ul ati o n   will  b e  us e d t o  a n al y z e  effi c a c y  d at a.  
T h e  P  K  p o p ul ati o n   will  b e  us e d t o  d eri v e  P  K  d at a.   S af et y s u  m  m ari es f or  P art   A  of t h e st u d y   will  b e 
pr es e nt e d  b y  o v er all s u bj e cts.   S af et y s u  m  m ari es f or  P art   B  of t h e st u d y   will  b e  pr es e nt e d  b y  o v er all 
s u bj e cts. 
All fi n al,  pl a n n e d  a n al ys es i d e ntifi e d i n t h e  pr ot o c ol  a n d i n   t his  S  A P   will  b e  p erf or  m e d  aft er  all r el e v a nt 
st u d y  d at a  h a v e  b e e n  pr o c ess e d  a n d i nt e gr at e d i nt o t h e  a n al ysis  d at a b as e,  a n al ysis  p o p ul ati o ns  h a v e  b e e n 
fi n ali z e d,  a n d t h e  d at a b as e  h as  b e e n l o c k e d.    A n y  p ost- h o c,  e x pl or at or y  a n al ysis p erf or  m e d  t o s u p p ort 
pl a n n e d st u d y  a n al ys es,   w hi c h   w er e  n ot i d e ntifi e d i n t his  S  A P,   will  b e  d o c u  m e nt e d  a n d r e p ort e d i n 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 1  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
S e cti o n  9. 8  of t h e   Cli ni c al  St u d y   R e p ort (  C S  R).   A n y r es ults fr o  m t h es e  u n pl a n n e d  a n al ys es ( p ost- h o c) 
will  als o  b e  cl e arl y i d e ntifi e d i n t h e t e xt  o  f t h e   C S  R. 
All  c oll e ct e d  d at a   will  b e  pr es e nt e d i n listi n gs    a n d   will  b e s ort e d  b y s u bj e ct  a n d st u d y  p art. 
If  p arti al  d at es  o c c ur, t h e  c o n v e nti o n f or r e pl a ci n g   missi n g  d at es f or t h e  p ur p os es  of  c al c ul ati n g  d eri v e d 
v ari a bl es  wit hi n  e a c h st u d y  p art   is  as f ollo  ws:  
F or  p arti al  A E    a n d   m e di c ati o n st art  d at es: 
•     If t h e  y e ar is  u n k n o  w n, t h e n  d o  n ot i  m p ut e t h e  d at e  b ut  assi g n  a   missi n g  v al u e. 
•     If t h e y e ar is  k n o  w n,  b ut   m o nt h  or   m o nt h  a n d  d a y  ar e   u n k n o  w n, t h e n: 
o     If t h e  y e ar   m at c h es t h e  y e ar  of first  d os e  d at e, t h e n i  m p ut e t h e   m o nt h  a n d  d a y  of t h e first 
d os e  d at e  i n t h e st u d y  p art. 
o     Ot h er  wis e,  assi g n  0 1 J a n u ar y   
•     If t h e y e ar  a n d   m o nt h  ar e  k n o  w n,  b ut  d a y is  u n k n o  w n, t h e n: 
o     If t h e   m o nt h  a n d  y e ar   m at c h t h e   m o nt h  a n d  y e ar  of t h e first  d os e d at e, t h e n i  m p ut e t h e 
d a y  of t h e first  d os e  d at e i n t h e st u d y  p art. 
o     Ot h er  wis e,  assi g n  0 1   
F or  p arti al  A E    a n d   m e di c ati o n e n d  d at es:  
•     If t h e  y e ar is  u n k n o  w n, t h e n  d o  n ot i  m p ut e t h e  d at e  b ut  assi g n  as   missi n g  v al u e. 
•     If t h e   m o nt h is  u n k n o  w n, t h e n  assi g n t h e l ast  d a y  of t h e  y e ar,  3 1   D e c em b er.    If t his r es ults i n a 
d at e  aft er t h e l ast  st u d y  p art d at e,  assi g n t h e  d a y  a n d   m o nt h  of t h e l ast st u d y  d at e. 
•     If t h e  d a y is  u n k n o  w n, t h e n  assi g n t h e l ast  d a y  of t h e   m o nt h. 
If  a n   A E  h as  a   missi n g s e v erit y or r el ati o ns hi p, it   will  b e l eft  as   missi n g.   N o   ot h er   missi n g  d at a  will  b e 
i  m p ut e d  u nl ess  ot h er  wis e s p e cifi e d. 
I n  g e n er al, f or  q u a ntit ati v e l a b or at or y  v al u es r e p ort e d  as ‘ <’  or ‘ ≤’, t h e l o  w er li  mit  of  q u a ntit ati o n 
( LL  O  Q)  will  b e  us e d f or  a n al ysis   (i e, a  v al u e  of   X   will  b e  us e d i n t h e  a n al ysis f or l a b  v al u es r e p ort e d  as 
‘ <  X’  or ‘≤ X’  ). Si  mil arl y,  f or s af et y q u a ntit ati v e  l a b or at or y  v al u es r e p ort e d  as ‘ >  X’  or ‘≥  X ’, t h e u p p er 
li  mit  of  q u a ntit ati o n (U  L  O  Q)  will  b e  us e d f or  a n al ysis   (i e,  a  v al u e  of   X   will  b e  us e d i n t h e  a n al ysis f or l a b 
v al u es r e p ort e d  as ‘ >  X’  or ‘ ≥  X’).  
F or  a n al ysis  p ur p os es, r e p e at l a b or at or y r est r es ults   will  n ot  b e  us e d  u nl ess t h e  ori gi n al l a b or at or y  v al u e is 
missi n g  or i n di c at e d  as i n v ali d, i n   w hi c h  c as e t h e first  n o n  -missi n g r e p e at l a b or at  or y  v al u e   will  b e  us e d 
f or  d at a  a n al ysis. 
F or s af et y  d at a, t h e l ast  o bs er v ati o n r e c or d e d  b ef or e  r e c ei vi n g t h e first  d os e  o n   D a y  1 i n  e a c h st u d y  p art 
will  b e  us e d  as t h e  b as eli n e  o bs er v ati o n f or  all  c al c ul ati o ns  of  c h a n g e fr o  m  b as eli n e.   S e p ar at e  b as eli n es 
will  b e  d eri v e d f or  P art   A  a n d  P art   B.   B as eli n e  v al u es   will  o nl y  b e  dis pl a y e d i n s af et y s u  m  m ari es.   
S e p ar at e t a bl es,  fi g ur es,  a n d listi n gs   will  b e  pr o d u c e d f or  P art   A  a n d  P art   B. 
9. 2     B a c k g r o u n d   C  h a r a ct e risti cs   
9. 2. 1  
S u bj e ct   Dis p ositi o n  
All s u bj e cts   w h o  pr o vi d e i nf or  m e d  c o ns e nt i n  e a c h st u d y  p art   will  b e  a c c o u nt e d f or i n t his st u d y.   T  h e 
n u  m b er  of s u bj e cts s cr e e n e d  a n d  e nr oll e d i n  e a c h st u d y  p art  will  b e s u  m  m ari z e d   b y  o v er all s u bj e cts .   T h e 
n u  m b er  a n d  p er c e nt a g e  of s u bj e cts  c o  m pl et e d,  a n d   wit h dr a  w n  fr o  m t h e st u d y,  as   w ell  as r e as o n f or 
wit h dr a  w al,   will  b e s u  m  m ari z e d  b y  o v er all   s u bj e cts i n e a c h st u d y  p art .    A d diti o n all y, t h e  n u  m b er a n d 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 2  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
p er c e nt a g e  of s u bj e cts i n  e a c h  a n al ysis  p o p ul ati o n   will  b e  s u  m  m ari z e d  o v er all  f or e a c h  st u d y  p art.  
P er c e nt a g es   will  b e  c al c ul at e d  usi n g t h e  n u  m b er  of  e nr oll e d s u bj e cts.     All  dis p ositi o n i nf or  m ati o n   will  b e 
i n cl u d e d i n  a listi n g. 
9. 2. 2     D e  m o g r a p hi cs  a n d   B as eli n e   C h a r a ct e risti cs   
D e  m o gr a p hi cs, s u c h  as  a g e,  g e n d er,   c hil d - b e ari n g  p ot e nti al, r a c e,  a n d  et h ni cit y,  a n d b as eli n e 
c h ar a ct eristi cs s u c h  as  h ei g ht,   w ei g ht,  b o d y   m ass i n d e x (  B  MI),  a n d ti  m e ( y e ars) si n c e  P  D  di a g n osis (fr o  m 
i nf or  m e d  c o ns e nt),   will  b e s u  m  m ari z e d b y  o v er all s u bj e cts  i n e a c h st u d y  p art . 
Fr e q u e n c y  a n d  p er c e nt a g e  of  c at e g ori c al s u  m  m ari es, s u c h  as  g e n d e r,  c hil d- b e ari n g  p ot e nti al, r a c e,  a n d 
et h ni cit y ,   will  b e s u  m  m ari z e d b y  o v er all s u bj e cts  i n  e a c h st u d y  p art.  C o nti n u o us s u  m  m ari es, s u c h  as  a g e, 
h ei g ht,   w ei g ht,  B  MI,   a n d ti  m e si n c e  P  D  di a g n osis,    will  b e s u  m  m ari z e d  usi n g   m e a n, st a n d ar d  d e vi ati o n, 
m e di a n,   mi n  i  m u  m,  a n d   m a xi  m u  m.  S e p ar at e  d e  m o gr a p hi c t a bl e s   will  b e  g e n er at e d f or t h e s af et y 
p o p ul ati o n i n  b ot h  p arts  of t h e st u d y. 
H e p atitis,   h u  m a n i  m  m u n o d efi ci e n c y  vir us ( HI  V  ),  a n d  pr e g n a n c y s cr e e ni n g r es ults   will  b e list e d,  b ut  n ot 
s u  m  m ari z e d  as t h e y  ar e  c o nsi d er e d  p art  of t h e i n cl usi o n/ e x cl usi o n  crit eri a.  
M e di c al  hist or y   will  b e list e d.  
9. 2. 3      St u d y   D r u g   E x p os u r e   
St u d y  dr u g  d osi n g i nf or  m ati o n   will  b e list e d. 
9. 2. 4  
St u d y   D r u g   C o  m pli a n c e  
St u d y  dr u g  n o n c o  m pli a n c e s u c h  as   missi n g  visits, i nt err u pti o ns i n t h e s c h e d ul e  of  a d  mi nistr ati o n,  a n d 
n o n p er  mitt e d   m e di c ati o ns   will  b e list e d i n t h e  pr ot o c ol  d e vi ati o ns listi n g.  
9. 3     Effi c a c y     A n al ysis  
T h e  pri  m ar y  e n d p oi nts  of  P art   A  r el at e t o s af et y  a n d t ol er abilit y ; t h er e  ar e  n o  pri  m ar y  effi c a c y  v ari a bl es 
f or P art   A .   
T h e  pri  m ar y  effi c a c y  v ari a bl e f or  P art   B  is t h e   M  D S-U P  D  R S  P art II/III tr e  m or s c or e.   
T h e s e c o n d ar y  effi c a c y  v ari a bl es f or t his st u d y i n cl u d e:  
•     M  D S  -U P  D  R S   –  P art III  t ot al s c or e ( P arts   A  a n d   B) 
•     M  D S  -U P  D  R S   –  P art I  a n d II t ot al s c or es ( P art   B  o nl y)  
•     M  D S  -U P  D  R S   –  P arts I -I  V t ot al s c or e ( P art   B  o nl y) 
T h e  e x pl or at or y  effi c a c y  v ari a bl es f or t his st u d y  i n cl u d e:  
 
 
 
 
 
 
 
 
 
 
9. 3. 1  
A n al ysis  of  P ri  m a r y   Effi c a c y   V a ri a bl e 
T h e   M  D S -U P  D  R S i n cl u d es  4 s c al es,   wit h  v ari o us s u bs c al es.  E a c h it e  m is r at e d fr o  m  0 ( n or  m al) t o  4 
(s e v er e).  T h e f o ur   M  D S-U P  D  R S s c al es  ar e:    
P art I:  n o n  m ot or  e x p eri e n c es  of  d ail y li vi n g ( 1 3 it e  ms)  


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 3  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
P art II:   m ot or  e x p eri e n c es  of  d ail y li vi n g ( 1 3 it e  ms)   
P art III:   m ot or  e x a  mi n ati o n ( 3 3 s c or es  b as e d  o n  1 8 it e  ms [s e v er al   wit h ri g ht, l eft  or  ot h er  b o d y 
distri b uti o n s c or es])   
P art I  V:   M ot or  c o  m pli c ati o ns ( 6 it e  ms)   
S c al e f o r t h e    M  D S -U P  D  R S   R ati n g    
D es c ri pti o n    
0  =  n or  m al  
N o s y  m pt o  ms/si g ns  
1  = sli g ht  
S y  m pt o  ms/si g ns   wit h s uffi ci e ntl y l o  w fr e q u e n c y 
or i nt e nsit y t o  c a us e  n o i  m p a ct  o n f u n cti o n  
2  =   mil d  
S y  m pt o  ms/si g ns  of fr e q u e n c y  or i nt e nsit y 
s uffi ci e nt t o  c a us e  a   m o d est i  m p a ct  o n f u n cti o n  
3  =   m o d er at e  
S y  m pt o  ms/si g ns s uffi ci e ntl y fr e q u e nt  or i nt e ns e 
t o i  m p a ct  c o nsi d er a bl y,  b ut  n ot  pr e v e nt, f u n cti o n  
4  = s e v er e   
S y  m pt o  ms/si g ns s uffi ci e ntl y fr e q u e nt  or  i nt e ns e 
t o i  m p a ct  c o nsi d er a bl y,  b ut  n ot  pr e v e nt, f u n cti o n  
T h e   M  D S -U P  D  R S  P art II/III tr e  m or s c or e  c o  m pris es t h e s u  m  of   M  D S  -  U P  D  R S it e  ms  2. 1 0,  3. 1 5,  3. 1 6, 
3. 1 7,  a n d  3. 1 8  a n d  ass ess es t h e s e v erit y i n  P  D tr e  m or.   
P art  A  A n al ysis  
N ot  a p pli c a bl e.   
P art  B  A n al y sis 
I n  P art   B,  o bs er v e d v al u es  a n d  c h a n g e fr o  m  b as eli n e  i n t h e tr e  m or s c or e   will  b e s u  m  m ari z e d  b y  o v er all 
s u bj e cts i n t h e  Effi c a c y  P o p ul ati o n ( P art   B).  
9. 3. 2  
A n al ysis  of  S e c o n d a r y   Effi c a c y   V a ri a bl es 
T h e t ot al s c or e f or  P arts I -I  V  c o  m pris es t h e s u  m  of t h e r es ults  of t h e i n di vi d u al it e  m s c or es. P art III 
ass ess es  1 8   m ot or  c at e g ori es, s o  m e  of   w hi c h i n cl u d e ri g ht  a n d l eft   m e as ur e  m e nts: s p e e c h, f a ci al 
e x pr essi o n,  ki n eti c tr e  m or  of  h a n ds, r est tr e  m or  a  m plit u d e,  p ost ur al tr e  m or  of  h a n ds, ri gi dit y  of  n e c k  a n d 
f o ur  e xtr e  miti es, fi n g er t a ps,  h a n d   m o v e  m e nt,  pr o n ati o n/s u pi n ati o n, t o e t a p pi n g,  c o nst a n c y  of r est tr e  m or, 
l e g  a gilit y,  arisi n g fr o  m  c h air,  p ost ur e,  g ait, fr e e zi n g  of  g ait,  p ost ur al st a bilit y,  a n d  gl o b al s p o nt a n eit y  of 
m o v e  m e nt.   T h e  P art III t ot al s c or e   will  b e  c al c ul at e d  b y t h e s u  m  of s c or es fr o  m t h e  1 8   m ot or  c at e g ori es.    
P art  A  A n al ysis  
I n  P art   A,  o bs er v e d v al u es  i n t h e   M  D S-U P  D  R S   –  P art III  t ot al s c or e a n d i n t h e  i n di vi d u al s c or es will  b e 
s u  m  m ari z e d  b y  ov er all s u bj e cts  i n t h e  Effi c a c y  P o p ul ati o n ( P art   A).  T h e  P art III t ot al s c or e  at  e a c h ti  m e 
p oi nt ( 2,  4,  8,  a n d  1 2  h o urs  p ost d os e)   will  b e  a v er a g e d  o v er t h e  3- d a y  p eri o d f or  L/  C  a n d  4- d a y  p eri o d f or 
S  A  G E - 2 1 7.    Diff er e n c es  b et  w e e n t h e  a v er a g e d P art III t ot al s c or e  at t h e  2,  4,  8,  a n d  1 2  h o ur  p ost d os e ti  m e 
p oi nts  b e  a n al y z e d  usi n g  a  p air e d t -t est.  T h e  a v er a g e d s c or e  a n d t h e  S  A  G E - 2 1 7  – L/  C s u bj e ct l e v el 
diff er e n c es  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d  a n d  a  S h a pir o -Wil k  n or  m alit y t est   will  b e r u   n  o n t h e 
diff er e n c es  pri or t o t h e  p air e d t -t est.  If t h e  n or  m alit y  c o n diti o n is  n ot s atisfi e d  at t h e  0. 0 5 si g nifi c a n c e 
l e v el,  a    Wil c o x o n si g n e d r a n k t est   will  b e  us e d t o  c o  m p ar e t h e ti  m e  p oi nts.  T h e s a  m e  a n al ysis   will  b e 
p erf or  m e d  o n t h e  P art III i n di vi d u al s c or es.    








St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 7  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
S af et y 
E v al u ati o n 
I n ci d e n c e     O bs e r
v e d 
V al u e   
C h a n g e 
f r o  m 
B as eli n e   
A b n o r  m alit y/
Cli ni c al 
Si g nifi c a n c e  
X  =  S af et y   Ass ess  m e nt   will  b e s u  m  m ari z e d i n t a bl es   
*  =  S af et y   Ass ess  m e nt   will  b e s u  m  m ari z e d i n i n di vi d u al s u bj e ct 
d at a listi n gs  
9. 4. 1  
A d v e rs e  E v e nts    
A d v ers e  e v e nts   (  A Es) will  b e  c o d e d  usi n g t h e   M e d  D  R  A  c o di n g s yst e  m ( v ersi o n  1  9. 1  or  hi g h er).   T h e 
a n al ysis  of  A Es     will  b e  b as e d  o n t h e  c o n c e pt  of tr e at  m e nt e  m er g e nt   A Es ( T E  A Es ).    A  T E  A E d uri n g  P art 
A   a n d  P art   B is  d efi n e d  as  a n  A E   wit h  o ns et  aft er t h e st art    of  o p e n-l a b el st u d y  dr u g i n t h e r es p e cti v e st u d y 
p art,  or  a n y   w ors e ni n g  of  a  pr e- e xisti n g   m e di c al  c o n diti o n/ A E   wit h  o ns et  aft er t h e st art  of  o p e n  -l a b el 
st u d y  dr u g  a n d  u ntil  1 4  d a ys  aft er t h e l ast  d os e.   I n  P art   A,  T E  A Es   will  b e  assi g n e d t o tr e at  m e nt p eri o ds  as 
f oll o  ws: 
•     T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of  L e v o d o p a  o n   D a y  1  a n d   wit hi n  2 4 
h o urs  aft er t h e l ast  a d  mi nistr ati o n  of  L/  C   m e di c ati o n  a n d  b ef or e t h e first  d os e  of  S  A  G E- 2 1 7  o n 
D a y  4   will  b e  assi g n e d t o t h e  L/  C   D a y  1 t o   D a y   3  p eri o d. 
•     T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of  S  A  G E  - 2 1 7  o n   D a y  4  a n d   wit hi n 
2 4  h o urs  aft er t h e l ast  a d  mi nistr ati o n  of  S  A  G E- 2 1 7  o n   D a y  7   will  b e  assi g n e d t o t h e  S  A  G E- 2 1 7 
D a y  4 t o   D a y  7  p eri o d. 
•     T E  A Es t h at  o c c urr e d  or   w ors e n e d   m or e t h a n  2 4  h o urs  aft er t h e l ast  d os e  of st u d y  dr u g   will  b e 
assi g n e d t o t h e f oll o  w - u p  p eri o d. 
I n  P art   B,  T E  A Es   will  b e  assi g n e d t o tr e at  m e nt  p eri o ds  as f oll o  ws: 
•     T E  A Es t h at  o c c urr e d  or   w ors e n e d  o n  or  aft er t h e first  d os e  of   st u d y  dr u g  o n   D a y  1  a n d   wit hi n  2 4 
h o urs  aft er t h e l ast  a d  mi nistr ati o n  of st u d y  dr u g  m e di c ati o n  o n     D a y  7   will  b e  assi g n e d t o t h e 
S  A  G E - 2 1 7   D a y  1 t o   D a y  7  p eri o d. 
•     T E  A Es t h at  o c c urr e d  or   w ors e n e d   m or e t h a n  2 4  h o urs  aft er t h e l ast  d os e  of st u d y  dr u g   will  b e 
assi g n e d t o t h e f oll o  w - u p  p eri o d. 
I n P art  A  a n d  P art   B,   A Es   will  b e s u  m  m ari z e d  b y   tr e at  m e nt p eri o d  a n d  b y f oll o  w- u p. 
A s u  m  m ar y  of  T E  A Es   will  b e  pr o vi d e d.  Fr e q u e n ci es  a n d  p er c e nts  of t h e f oll o  wi n g   will  b e i n cl u d e d: 
•     N u  m b er  of s u bj e cts   wit h  at l e ast  o n e  T E  A E   
•     N u  m b er  of s u bj e cts   wit h  at l e ast  o n e  T E  A E   l e a di n g t o  dis c o nti n u ati o n 
•     N u  m b er  of s u bj e cts   wit h  a  T E  A E l e a di n g t o  d e at h 
•     N u  m b er  of s u bj e cts   wit h  at l e ast  o n e s eri o us  a d v ers e  e v e nt ( S  A E)   
I n  P art   A  a n d  P art   B, t h e i n ci d e n c e  of  T E  A Es   will  b e s u  m  m ari z e d  b y t h e f oll o  wi n g: 
•     S  O  C  a n d  P T  
•     P T  
•     D os e   ( S  A  G E- 2 1 7  o nl y),   D a y,  a n d  P T 
•     S  O  C,  P T,  a n d   M a xi  m u  m  S e v erit y 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 8  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
•     S  O  C,  P T,  a n d   R el ati o ns hi p t o  St u d y   Dr u g 
All   S  A Es,   A Es l e a di n g t o  dis c o nti n u ati o n,  a n d   A Es  l e a di n g t o  d e at h   will  b e list e d i n  a s e p ar at e t a bl es. 
9. 4. 2     P ri o r  a n d   C o n c o  mit a nt    M e di c ati o ns   
C o n c o  mit a nt   m e di c ati o ns   will  b e  c  o d e d  usi n g    W orl d   H e alt h   Or g a ni z ati o n   Dr u g   Di cti o n ar y  (   W  H  O-D  D) 
(  V ersi o n  S e pt e  m b er  1,  2 0 1 6 or l at er).  
Fr e q u e n ci es  a n d  p er c e nt a g es  of   m e di c ati o ns  us e d i n t h e st u d y   will  b e s u  m  m ari z e d  as f oll o  ws: 
•     Pri or   m e di c ati o n:   m e di c ati o n t a k e n  pri or t o t h e  d at e  of t h e firs t  d os e  of  o p e n-l a b el st u d y  dr u g i n 
P art   A.  
•     C o n c o  mit a nt   m e di c ati o n: I n  P art   A  a n d  P art   B  ,  a   m e di c ati o n   wit h  a st art  d at e  o n  or  aft er t h e first 
d os e  of  o p e n-l a b el st u d y  dr u g  wit hi n t h e st u d y  p art   ( e v e n if  e n d  d at e is   missi n g)   will  b e 
c o nsi d er e d  c o n c o  mit a nt.   M e di c ati o ns   wit h  a st art  d at e  b ef or e t h e first  d os e  of  o p e n   -l a b el st u d y 
dr u g t h at  ar e  o n g oi n g  or   wit h  a st o p  d at e  o n  or  aft er t h e first  d os e  of  o p e n-l a b el st u d y  dr u g   will  b e 
c o nsi d er e d  c o n c o  mit a nt.   If   m e di c ati o n  d at es  ar e i n c o  m pl et e  a n d it is  n ot  cl e ar   wh et h er t h e 
m e di c ati o n   w as  c o n c o  mit a nt, it   will  b e  ass u  m e d t o  b e  c o n c o  mit a nt.   
•     R es c u e   m e di c ati o n:  a n y  or al  L e v o d o p a  or  ot h er   a nti p ar ki ns o ni a n  a g e nt  at t h e I n v esti g at or’s 
dis cr eti o n t a k e n  o n  d a ys  1  t o 7 i n  P art   A t h at is  n ot  p art  of t h e  pl a n n e d st u d y tr e at  m e nt   will  b e 
c o nsi d er e d r es c u e   m e di c ati o n.   R es c u e   m e di c ati o ns  ar e  n ot  a p pli c a bl e t o  P art   B.   
C o n c o  mit a nt   m e di c ati o ns   will  b e  assi g n e d t o t h e st u d y  p art i n   w hi c h t h e y  ar e  b ei n g t a k e n. If  a 
c o n c o  mit a nt   m e di c ati o n  assi g n e d t o  P art   A  c o nti n u es t o  b e t a k e n t hr o u g h  P art   B, t h e n t h e   m e di c ati o n   will 
b e  assi g n e d t o  b ot h  p arts  of t h e st u d y  as  a p pr o pri at e.   D et ails  of  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns   will  b e 
list e d  b y st u d y  p art, s u bj e ct, st art  d at e,  a n d  v er b ati  m t er  m.  Pri or  a n d  c o n c o  mit a nt m e di c ati o ns   will  b e 
s u  m  m ari z e d  b y   A n at o  mi c  T h er a p e uti c   C h e  mi c al (  A T  C)  cl ass  a n d  pr ef err e d t er  m ( P T) .  I n  P art   A, 
c o n c o  mit a nt   m e di c ati o ns   wil l  b e s u  m  m ari z e d  u n d er  S  A  G E- 2 1 7,  L e v o d o p a/  C ar bi d o p a f or   D a y  1 t o   D a y  3, 
a n d f oll o  w- u p.   T h e f oll o  w- u p  p eri o d  b e gi ns  2 4  h o urs  aft er t h e l ast  d os e  of  S  A  G E - 2 1 7.  M e di c ati o ns t h at 
ar e  c o n c o  mit a nt t o  b ot h  p eri o ds   will  b e s u  m  m ari z e d  u n d er  b ot h tr e at  m e nts.    C o n c o  mit a nt   m e di c ati o ns 
will  als o  b e s u  m  m ari z e d  b y  d os e,   d a y ,  a n d  P T  d uri n g t h e  S  A  G E- 2 1 7  p eri o d.  I n  P art   B,  c o n c o  mit a nt 
m e di c ati o ns   will  b e s u  m  m ari z e d  u n d er  S  A  G E-  2 1 7  a n d f oll o  w - u p.   T h e f oll o  w- u p  p eri o d  b e gi ns  2 4  h o urs 
aft er t h e l ast  d os e  of  S  A  G E - 2 1 7.    C o n c o  mit a nt   m e di c ati o ns   will  als o  b e s u  m  m ari z e d  b y  d os e,  d a y,  a n d  P T 
d uri n g t h e  S  A  G E- 2 1 7  p eri o d.   
T h e  us e  of r es c u e   m e di c ati o ns  i n  P art   A will  b e list e d  a n d s u  m  m ari z e d i n t h e s a  m e   m a n n er  as  c o n c o  mit a nt 
m e di c ati o ns.    R es c u e   m e di c ati o ns   will  b e s u  m  m ari z e d  b y  P T  o nl y.   
M e di c ati o n s u  m  m ari es   will  b e  b as e d  o n t h e  S af et y  P o p ul ati o n.    
9. 4. 3  
Cli ni c al  L a b o r at o r y  
All   st atisti c al  a n al ys es  of l a b or at or y  v al u es   will  b e  p erf or  m e d  usi n g  SI  u nits.    C o nti n u o us  h e  m at ol o g y, 
c h e  mistr y ,  a n d  uri n al ysis r es ults a n d  c h a n g es fr o  m  b as eli n e  of  P art   A  a n d  P art   B    will  b e s u  m  m ari z e d  b y 
o v er all s u bj e cts    wit hi n  e a c h st u d y  p art.  All  cli ni c al l a b or at or y r es ults   will  b e list e d  b y s u bj e ct  a n d ti  mi n g 
of  c oll e cti o n.  T his listi n g   will i n cl u d e  d at a fr o  m s c h e d ul e d  a n d  u ns c h e d ul e d ti  m e  p oi nts.   Cli ni c all y 
si g nifi c a nt  a b n or  m al fi n di n gs   will  b e r e p ort e d  as  A Es  .  
I n  P art   B, t h e  n u  m b er  of s u bj e cts   wit h  c h e  mistr y  a n d  h e  m at ol o g y  v al u es  b el o  w,   wit hi n,  or  a b o v e t h e 
n or  m al r a n g e  b y ti  m e  p oi nt  a n d i n r el ati o n t o  b as eli n e   will  b e t a b ul at e d i n  a s hift t a bl e   wit hi n  e a c h 
p ar a  m et er  b y  o v er all s u bj e cts .   T h e  n u  m b er  of  n or  m al  a n d  a b n or  m al  uri n al ysis  v al u es  b y ti  m e  p oi nt  a n d i n 
r el ati o n t o  b as eli n e   will  b e t a b ul at e d i n  a s hift t a bl e   wit hi n  e a c h  p ar a  m et er  b y o v er all s u bj e cts . 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  1 9  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
9. 4. 4  
El e ct r o c a r di o g r a  m   
T h e f oll o  wi n g  1 2- E  C  G  p ar a  m et ers   will  b e list e d f or  e a c h s u bj e ct:  h e art r at e,  P  R  I nt er v al, Q  R S   D ur ati o n, 
Q T   I nt er v al,  a n d   Q T c F.    A n y  cli ni c all y si g nifi c a nt  a b n or  m aliti es  or  c h a n g es i n  E  C  Gs s h o ul d  b e list e d  as 
a n  A E  .  O bs er v e d   v al u es , m e a n  c h a n g es fr o  m   b as eli n e ,  a n d i n v esti g at or i nt er pr et ati o n of  P art   A  a n d  P art 
B   r es ults will  b e   s u  m  m ari z e d  b y o v er all s u bj e cts  wit hi n  e a c h  p art  . 
9. 4. 5  
Vit al  Si g ns  
Vit al si g n r es ults   ( b o d y t e  m p er at ur e,  h e art r at e, r es pir at or y r at e, s u pi n e  a n d st a n di n g  di ast oli c  bl o o d 
pr ess ur e, s u pi n e  a n d st a n di n g s yst oli c  bl o o d  pr ess ur e,  a n d  p uls e  o xi  m etr y ) will  b e list e d  b y s u bj e ct  a n d 
ti  mi n g  of  c oll e cti on.   O bs er v e d   v al u es  a n d   m e a n  c h a n g es  fr o  m b as eli n e  at  e a c h ti  m e  p oi nt  of  P art   A   a n d 
P art   B  will  b e s u  m  m ari z e d   b y  o v er all s u bj e cts    wit hi n  e a c h st u d y  p art. 
I n  P art   B, t h e  n u  m b er  of  p uls e  o xi  m etr y  v al u es  cl assifi e d  as  n or  m al,  a b n or  m al ( n ot cli ni c all y  si g nifi c a nt), 
a n d  a b n or  m al ( cli ni c all y si g nifi c a nt)  b y ti  m e  p oi nt  a n d i n r el ati o n t o  b as eli n e   will  b e t a b ul at e d i n  a s hift 
t a bl e  b y  o v er all s u bj e cts. 
9. 4. 6  
P h ysi c al  E x a  mi n ati o n   
S cr e e ni n g  p h ysi c al  e x a  mi n ati o n r es ults f or  P art   A  a n d  r es ults f or P art   B  t h at  ar e  cli ni c all y si g nifi c a nt will 
b e list e d  i n t h e   m e di c al  hist or y listi n g.   P ost-s cr e e ni n g  p h ysi c al  e x a  mi n ati o n  r es ults f or  P art   A  a n d p ost-
s cr e e ni n g r es ults f or  P art   B t h at  ar e cli ni c all y  si g nifi c a nt will  b e   pr es e nt e d  i n t h e   A E listi n gs. 
9. 4. 7  
C ol u  m bi a -S ui ci d e  S e v e rit y   R ati n g  S c al e (  C- S S  R S)  
S ui ci d alit y  w as     m o nit or e d  d uri n g t h e st u d y  usi n g t h e   C-S S  R S.  T his s c al e  c o nsists  of  a  b as eli n e  e v al u ati o n 
t h at  ass ess es t h e lif eti  m e  e x p eri e n c e  of t h e s u bj e ct   wit h s ui ci d al i d e ati o n  a n d  b e h a vi or,  a n d  a  p ost-b as eli n e  
e v al u ati o n t h at f o c us es  o n s ui ci d alit y si n c e t h e l ast st u d y  visit.  T h e   C -S S  R S i n cl u d es  “ y es ”  or  “ n o ” 
r es p o ns es f or  ass ess  m e nt  of s ui ci d al i d e ati o n  a n d  b e h a vi or  as   w ell  as  n u  m eri c r ati n gs f or s e v erit y  of 
i d e ati o n, if  pr es e nt (fr o  m  1 t o  5,   wit h  5  b ei n g t h e   m ost s e v er e).  
S ui ci d alit y  d at a  c oll e ct e d  o n t h e   C -S S  R S   will  b e list e d f or  all s u bj e cts.   T a bl es  will i n cl u d e  b e h a vi or t y p e 
a n d/ or  c at e g or y f or  S ui ci d al I d e ati o n  a n d  S ui ci d al   B e h a vi or  of t h e   C- S S  R S   pr e-tr e at  m e nt  a n d  p ost-
b as eli n e  e v al u ati o n s.  Fr e q u e n ci es  a n d  p er c e nts  f or t h e s u bj e cts   wit h at l e ast  o n e  r es p o ns e  of  “  Y es ”  o n t h e 
S ui ci d al I d e ati o n  a n d  S ui ci d al   B e h a vi or  q u esti o ns  pr e -tr e at  m e nt  a n d p ost- b as eli n e    will  b e s u  m  m ari z e d. 
P art   A  a n d  P art   B  r es ults will  b e s u  m  m ari z e d  b y  o v er all s u bj e cts     wit hi n  e a c h st u d y  p art.  R es ults fr o  m  all 
s e cti o ns  of t h e   C-S S  R S   will  b e list e d.  
9. 4. 8  
St a nf o r d  Sl e e pi n ess  S c al e  
T h e  S S S is  a s u bj e ct -r at e d s c al e  d esi g n e d t o  q ui c kl y  ass ess  h o  w  al ert  a s u bj e ct is f e eli n g.   D e gr e es  of 
sl e e pi n ess  a n d  al ert n ess  ar e r at e d  o n  a s c al e   of  1 t o  7,   w h er e t h e l o  w est s c or e  of  1 i n di c at es t h e s u bj e ct is 
“f e eli n g  a cti v e,  vit al,  al ert,  or   wi d e  a  w a k e ”  a n d t h e  hi g h est s c or e  of  7 i n di c at es t h e s u bj e ct is  “ n o l o n g er 
fi g hti n g sl e e p, sl e e p  o ns et s o o n;  h a vi n g  dr e a  m-li k e t h o u g hts ”.  A r es p o ns e  of  “  X ”   i n di c at es t h e s u bj e ct is 
asl e e p.    T his r es p o ns e   will  b e s u  m  m ari z e d  c at e g ori c all y  b ut   will  n ot  b e i n cl u d e d i n t h e n u  m eri c  o bs er v e d 
v al u e  a n d  c h a n g e fr o  m  b as eli n e t a bl es.  
S e d ati o n  d at a  c oll e ct e d  o n t h e  S S S   will  b e list e d f or  all s u bj e cts.   T ot al  s c or e  o v er t i  m e will  b e 
r e pr es e nt e d  gr a p hi c all y b y  o v er all s u bj e cts  i n P art   A.   O bs er v e d   v al u es  a n d  c h a n g e fr o  m  b as eli n e  of  P art 
A   at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d  o v er all s u bj e cts.   Fr e q u e n c y t a bl es  b y  o v er all s u bj e cts i n  P art   A  
will  als o  b e  pr o vi d e d.   
T his  ass ess  m e nt  is  us e d i n  P art   A  o nl y. 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 0  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
9. 4. 9     M o difi e d   O bs e r v e r’s Ass ess  m e nt  of   Al e rt n ess/ S e d ati o n (   M  O  A  A/ S)  
T h e   M  O  A  A/ S  all o  ws  e x pl or ati o n  of  d e e p er s e d ati o n st at es t h a n t h e  S S S. If  a   M  O  A  A/ S s c or e  of  3  or l ess 
w as  o bs er v e d, t h e s c or e   w as t o  b e  c o nfir  m e d  b y   w aiti n  g  a p pr o xi  m at el y  1 0   mi n ut es  a n d r e- a d  mi nist eri n g 
t h e   M  O  A  A/ S  ass ess  m e nt. T h e l o  w est s c or e  of  0 i n di c at es t h e s u bj e ct  h as  “  N o r es p o ns e  aft er  p ai nf ul 
tr a p e zi us s q u e ez e ”  a n d t h e  hi g h est s c or e  of  5 i n di c at es t h e s u bj e ct  “  R es p o n ds r e a dil y t o  n a  m e s p o k e n i n 
n or  m al  t o n e”.  
S e d ati o n  d at a  c oll e ct e d  o n t h e   M  O  A  A/ S   will  b e list e d f or  all s u bj e cts.   T ot al  s c or e  o v er ti  m e   will  b e 
r e pr es e nt e d  gr a p hi c all y b y  o v er all s u bj e cts  i n  P art   A.  O bs er v e d    v al u es  a n d  c h a n g e fr o  m  bas eli n e  of  P art 
A  at  e a c h ti  m e  p oi nt   will  b e s u  m  m ari z e d   b y  o v er all s u bj e cts.   Fr e q u e n c y t a bl es  b y  o v er all s u bj e cts i n  P art 
A   will  als o  b e  pr o vi d e d.    If  a r e-ass ess  m e nt  at  a ti  m e  p oi nt is r e q uir e d,  o nl y t h e first  ass ess  m e nt   will  b e 
s u  m  m ari z e d  a n d  b ot h  ass ess  m e nts   will  b e list e d.  
T his  ass ess  m e nt is  us e d i n  P art   A  o nl y.  
9. 5     P h a r  m a c o ki n eti c    A n al ysis 
F or  pl as  m a  c o n c e ntr ati o n  d at a,  all  v al u es  b el o  w t h e li  mit  of  q u a ntifi c ati o n (  B L  Q)   will  b e s et t o  0 f or 
s u  m  m ar y st atisti cs  a n d  gr a p hs. I n di vi d u al  pl as  m a  c o n c e ntr ati o ns  of  S  A  G E - 2 1 7   will  b e s u  m  m ari z e d  at 
e a c h ti  m e  p oi nt  usi n g  d es cri pti v e st atisti cs, i n cl u di n g  n u  m b er ( n),   m e a n, st a n d ar d  d e vi ati o n,   m e di a n, 
m a xi  m u  m,   mi ni  m u  m,   %   c o effi ci e nt  of  v ari ati o n ( C  V  ) a n d  g e o  m etri c   m e a n.  F or  P art   A  a n d  P art   B, 
s u  m  m ari es   m a y  b e  d o n e  b y t ol er at e d  d os e  or  b y  o v er all s u bj e cts  o nl y   wit hi n  e a c h st u d y  p art.   T h e fi n al 
c ol u  m ns i n t h e  P  K t a bl es   will  d e p e n d  o n t h e fi n al  d at a  a n d t h e j u d g e  m e nt  of t h e  p h ar  m a c o ki n eti cist.  
I n di vi d u al  c o n c e ntr ati o n  pl ots  a n d   m e a n  d at a  gr a p hs   will  b e  pr o d u c e d.   All  gr a p hs   will  b e  pr es e nt e d  usi n g 
b ot h li n e ar  a n d s e  mi -l o g arit h  mic s c al es.  T h e  a b o v e  d es cri pti v e s u  m  m ar y   will  b e  p erf or  m e d f or t h e  P  K 
p o p ul ati o n.  
All  S  A  G E  - 2 1 7  pl as  m a  c o n c e ntr ati o ns   will  b e  pr es e nt e d i n  a  b y-s u bj e ct listi n g.  
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m ati o n   will  b e  p erf or  m e d  usi n g  P h o e ni x    Wi n  N o nli n ®  s oft  w ar e (  V ersi o n 
6. 4  or l at er;  P h arsi g ht,   C ar y,   N  C)  o n i n di vi d u al  pl as  m a  c o n c e ntr ati o n- ti  m e  d at a.  F or t h e  P  K  p ar a  m et er 
c al c ul ati o n,   B L  Q  pl as  m a  c o n c e ntr ati o ns  o c c urri n g  b ef or e  tm a x  will  b e s et t o  0,   wit h t h e  e x c e pti o n  of  a 
B L  Q  v al u e  o c c urri n g  b et  w e e n t  w o   m e as ur a bl e  c o n c e  ntr ati o ns, i n   w hi c h  c as e it   will  b e s et t o   missi n g. 
B L  Q  pl as  m a  c o n c e ntr ati o ns  o c c urri n g  aft er   tm a x  will  b e s et t o   missi n g.  P h ar  m a c o ki n eti c  p ar a  m et er 
esti  m at es  a n d s u  m  m ari es   will  b e  c o  m pl et e d f or s u bj e cts i n t h e  P  K  p o p ul ati o n  h a vi n g s uffi ci e nt 
m e as ur a bl e  c o n c e ntr ati o ns t o  d efi n e t h e  pr ofil e.    
P h ar  m a c o ki n eti c  p ar a  m et er  esti  m at es, i n cl u di n g   C m a x ,  λZ ,   A  U  C0-t ,   A  U  C0-  ∞,  a n d t1/ 2, w h er e  a p pr o pri at e 
a n d  as  d at a  p er  mit,   will  b e s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs, i n cl u di n g  arit h  m eti c  a n d  g e o  m etri c 
m e a ns,  S  D,   %  C  V,   m e di a n,   mi ni  m u  m,  a n d   m a xi  m u  m.   Ot h er  p ar a  m et ers   m a y  b e  a d d e d  at t h e  dis cr eti o n  of 
t h e  p h ar  m a c o ki neti cist.   
W h er e v er  n e c ess ar y  a n d  a p pr o pri at e,  P  K  p ar a  m et ers   m a y  b e  d os e   -a dj ust e d t o  a c c o u nt f or i n di vi d u al 
diff er e n c es i n  d os e. 
A  gr a p h  c o  m p ari n g   M  D S-  U P  D  R S  P art III t ot al s c or e  a n d  p h ar  m a c o ki n eti c  c o n c e ntr ati o ns  o v er ti  m e   will 
b e  pr o d u c e d f or  o v er all s u bj e cts i n t h e  P  K  P o p ul ati o n  i n  P art   A  a n d  P art   B. 
A  gr a p h  c o  m p ari n g   M  D S-  U P  D  R S  P art II/III tr e  m or s c or e  a n d  p h ar  m a c o ki n eti c  c o n c e ntr ati o ns  o v er ti  m e 
will  b e  pr o d u c e d f or  o v er all s u bj e cts i n t h e  P  K  P o p ul ati o n i n  P art   B. 
1 0    S U   M   M  A  R  Y   O F   I  N  T  E  RI   M   A  N  A  L  Y S  E S  
A n i nt eri  m  a n al ysis   will  b e  c o n d u ct e d  u p o n t h e  c o  m pl eti o n  of  1 0 s u bj e cts i n  P art   A   t o i nf or  m t h e  c o n d u ct 
of  P art   B.   All  P art   A t a bl es, listi n gs,  a n d fi g ur es    e x cl u di n g  a n y  P  K  a n al ysis will  b e  g e n er at e d f or t h e 
i nt eri  m  a n al ysis. 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 1  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
1 1    R  E F  E  R  E  N  C  E S   
P et o,   V., J e n ki ns o n,   C.,  Fit z p atri c k,   R.,   &   Gr e e n h all,   R. ( 1 9 9 5).  T h e   D e v el o p  m e nt  of  a  S h ort  
       M e as ur e  of  F u n cti o ni n g  a n d    W ell   B ei n g f or I n di vi d u als   wit h  P ar ki ns o n’s   Dis e as e. Q u alit y  of         
     Lif e  R es e ar c h,  4 ( 3),  2 4 1- 2 4 8.   R etri e v e d fr o  m  htt p://  w  w  w.j st or. or g.


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 2  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
1 2    LI S  T   O F   A P P  E  N  DI  C  E S   
1 2. 1   A p p e n di x   A:  S c h e d ul e  of   Ass ess  m e nts   
1 2. 1. 1    P a rt   A  
Visit   D a ys   
S c r e e ni n g 
(  Da y  -2 8 t o 
D a y   -1)  
A d  mit 
(  D a y -1)  
P a rt   A:    O p e n -L a b el   
F oll o  w -u p  
D a y  1      
D a y  2      
D a y  3      
D a y  4      
D a y  5      
D a y  6      
D a y  7      
D a y  8      
D a y  1 4 ( ± 1)   
I nf or  m e d   C o ns e nt 
X   
    
    
    
    
    
    
    
    
 
 
I n cl usi o n/ E x cl usi o n 
X      
X      
    
    
    
    
    
    
    
 
 
C o nfi n e d t o   U nit a  
 
X      
X      
X      
X      
X      
X      
X      
X      
X   
 
D e  m o gr a p hi cs   
X   
    
    
    
    
    
    
    
    
 
 
M e di c al   Hist or y   
X   
    
    
    
    
    
    
    
    
 
 
P h ysi c al  E x a  mi n ati o n  
X      
X      
X      
    
X      
X      
    
X      
    
X   
 
B o d y    W ei g ht/  H ei g ht   
X   
    
    
    
    
    
    
    
    
 
 
C  B  C/ S er u  m   C h e  mistr y b  
X      
X      
    
    
    
X      
    
X      
    
X      
X   
Pr e g n a n c y  T est   
X  -s er u  m    
X  -uri n e     
    
    
    
    
    
    
    
 
 
Uri n al ysis c  
X      
X      
    
    
    
X      
    
    
X      
 
X   
H e p atitis   &   HI  V s cr e e n      
X   
    
    
    
    
    
    
    
    
 
 
Vit al   Si g ns d  
X      
X      
X      
X      
X      
X      
X      
X      
X      
X      
X   
P uls e   O xi  m etr y e  
 
X      
X      
X      
X      
X      
X      
X      
X      
X      
X   
1 2 -L e a d  E  C  G f 
X      
X      
X      
    
X      
X      
X      
X      
X      
X      
X   
C  -S S  R S g  
X      
X      
X      
X      
X      
X      
X      
X      
X      
X      
X   
S S S h  
 
X      
X      
X      
X      
X      
X      
X      
X      
X      
X   
M  O  A  A/ S
i 
 
    
    
    
X      
X      
X      
X      
X      
X      
X   
M  D S  -U P  D  R S ( c o  m pl et e) j 
X      
X      
    
    
    
    
    
    
    
X      
X   
M  D S  -U P  D  R S ( P art III 
o nl y) k 
 
    
X      
X      
X      
X      
X      
X      
X      
 
 
Pl as  m a  P  K  S a  m pl es p  
 
    
    
    
    
X      
X      
X      
X      
X      
X   
A d  mi nist er  L e v o d o p a  or 
C ar bi d o p a  -L e v o d o p a q 
 
    
X      
X      
X      
    
    
    
    
 
 
A d  mi nist er  S  A  G E  -2 1 7 q    
 
    
    
    
    
X      
X      
X      
X      
 
 
A d v er s e  E v e nts   
X   
Pri or/  C o n c o  mit a nt 
M e di c ati o ns   
X   


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 3  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
;   C  B  C  =  c o  m pl et e  bl o o d  c o u nt;   C-S S  R S  =   C ol u  m bi a -S ui ci d e  S e v erit y   R ati n g  S c al e; 
E  C  G   = el e ctr o c ar di o gr a  m;   HI  V  =  h u  m a n i  m  m u n o d efi ci e n c y  vir us;   M  D S -U P  D  R S  =   M o v e  m e nt   Dis or d er  S o ci et y   - U nifi e d  P ar ki ns o n’s   Dis e as e   R ati n g  S c al e; 
M  O  A  A/ S  =   M o difi e d   O bs er v er’s   Ass ess  m e nt  of   Al ert n e ss/ S e d ati o n; 
; 
P  K  =  p h ar  m a c o ki n eti c;  S S S  =  St a nf or d  Sl e e pi n ess  S c al e  
a  S u bj e cts   will  b e  dis c h ar g e d fr o  m t h e  u nit  aft er  c o  m pl eti o n  of  all   D a y  8  ass ess  m e nts.  
b S cr e e ni n g  a n d  S af et y  L a b or at or y  T ests:  S cr e e ni n g  a n d   D a y  -1 [  A d  missi o n];  pr e d os e  f or   D a y  4, D a y  6,  a n d   D a y  8;   D a y   1 4 . 
c  Uri n al ysis:  S cr e e ni n g  a n d   A d  missi o n (  D a y   -1);  Pr e d os e f or   D a y  4  a n d   D a y  7 ;   D a y 1 4 . 
d Vit al  Si g  ns:  S cr e e ni n g  a n d   D a y  -1 [  A d  missi o n];  pr e d os e  a n d  1,  2,  3,  4,  6,  8,  1 2,  1 4,  a n d  1 6  h o urs  p ost d os e  o n   C o nfi n e  m e nt   D a ys  1,  2,  3,  4,  5,  6,  a n d  7; i n   A  M 
of   D a y  8 ;  a n d   D a y1 4 .    Vit al si g ns  ass e ss  m e nts  ar e t o  b e  p erf or  m e d   wit hi n  ± 1 0   mi n ut es  of t h e s c h e d ul e d ti  m es t hr o u g h t h e  4  h o ur ti  m e  p oi nt  a n d   wit hi n  ± 1 5 
mi n ut e s  of t h e s c h e d ul e d ti  m e s t h er e aft er.   
e  P uls e   O xi  m etr y:   A d  missi o n (  D a y  -1);  pr e d os e  a n d  1,  2,  3,  4,  6 , 8,  1 2,  1 4,  a n d  1 6  h o urs  p ost d os e  o n   C o nfi n e  m e nt   D a ys  1,  2,  3,  4,  5,  6,  a n d  7; i n   A  M  of   D a y  8 ; 
a n d   D a y  1 4 .   P uls e  o xi  m etr y is t o  b e  p erf or  m e d   wit hi n  ± 1 0   mi n ut e s  of t h e s c h e d ul e d ti  m e s t hr o u g h t h e  4  h o ur ti  m e  p oi nt  a n d   wit hi n  ± 1 5   mi n ut e s  of t h e 
s c h e d ul e d ti  m e s t h er e aft er.  
f  1 2 -L e a d  E  C  G:  S cr e e ni n g  a n d   A d  missi o n (  D a y   -1);   pr e d os e  o n   D a y  1  a n d   D a y  3;  pr e d os e  a n d  1 ( ± 1 0   mi n ut es)  a n d  1 2 ( ± 1 5   mi n ut es)  h o urs  p ost d os e  o n 
C o nfi n e  m e nt   D a ys  4,  5,  6,   a n d  7; i n   A  M  of   D a y  8 ;  a n d   D a y 1 4 . 
g   C-S S  R S:  S cr e e ni n g  a n d   A d  missi o n (  D a y  -1);  1 2  h o urs  p ost d os e  o n   D a y  1 , D a y  2,  a n d   D a y  3;  pr e d os e  o n   D a y  4,   D a y  5,   D a y  6,  a n d   D a y  7  a n d   D a y  8  a n d   D a y 
1 4. ; S cr e e ni n g/  B as eli n e  v ersi o n  of   C -S S  Rs s h o ul d  b e us e d  o n  d a y  of  s cr e e ni n g  a n d  Si n c e  L ast   Visit  v ersi o n s h o ul d  b e  us e d  o n  all s u bs e q u e nt ti  m e  p oi nts.  
h S S S:   A d  missi o n (  D a y  -1);  pr e d os e  a n d  1,  2,  3,  4,  6,  8,  1 2,  1 4,  a n d  1 6  h o urs  p ost d os e  o n   C o nfi n e  m e nt   D a ys  1,  2,  3,  4,  5,  6,  a n d  7; i n   A  M  of   D a y  8;  a n d   D a y  1 4. 
T h e  S S S is t o  b e  p erf or  m e d   wit hi n  ± 1 0   mi n ut es  of t h e s c h e d ul e d ti  m e s t hr o u g h t h e  4  -h o ur ti  m e  p oi nt  a n d   wit hi n  ± 1 5   mi n ut es  of t h e s c h e d ul e d ti  m e s t h er e aft er.   
i  M  O  A  A/ S:  Pr e d os e  a n d  1,  2,  3,  4,  6,  8,  1 2,  1 4,  a n d  1 6  h o urs  p ost d os e  o n   C o nfi n e  m e nt   D a ys  1,  2,  3,  4,  5,  6   ,  a n d 7; i n   A  M  of   D a y  8 ;  a n d   D a y 1 4 .   T h e   M  O  A  A/ S 
is t o  b e  p erf or  m e d   wit hi n  ± 1 0   mi n ut e s  of t h e s c h e d ul e d ti  m e s t hr o u g h t h e  4  h o ur ti  m e  p oi nt  a n d   wit hi n  ± 1 5   mi n ut e s  of t h e s c h e d ul e d ti  m es t h er e aft er. 
j  M  D S  -U P  D  R S ( c o  m pl et e):  S cr e e ni n g,   A d  missi o n (  D a y   -1) ( o nl y if ti  m e  b et  w e e n  S cr e e ni n g  a n d   A d  missi o n is  ≥ 7  d a ys)],  o n   D a y  8  pri or t o r es u  mi n g  L e v o d o p a, 
a n d   D a y  1 4 . 
k M  D S  -U P  D  R S ( P art III  o nl y):  2 ( ± 1 0   mi n ut es), ,  4 ( ± 1 0   mi n ut es),  8 ( ± 1 5   mi n ut e s),  a n d  1 2 ( ± 1 5   mi n ut e s)  h o urs  p ost d os e  o n   D a ys  1,  2,   3,  4 ,  5,  6, a n d  7.  If 
c o  m pl et e   M  D S -U P  D  R S is  n ot  c o  m pl et e d  o n   A d  missi o n  d u e t o it t a ki n g  pl a c e  < 7  d a ys  aft er  S cr e e ni n g, t h e n t h e   M  D S  -U P  D  R S  P art III  o nl y  s h o ul d  als o t a k e 
pl a c e  o n   A d  missi o n (  D a y  -1).    
 
 
 
 
 
   
 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 4  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
p   Pl as  m a  P  K s a  m pli n g ti  m e s ( ±  5   mi n ut es):   D a ys  4  pr e p os e  a n d  0. 2 5,  0. 5,  1,  2,  4,  8,  a n d  1 2  h o urs  p ost d os e;  pr e d os e  o n   D a y  5  a n d   D a y  6;  pr e d os e  a n d  0. 2 5,  0. 5, 
1,  2,  4,  8,  a n d  1 2  h o urs  o n   D a y  7;  i n   A  M  of   D a y  8;  a n d   D a y  1 4.   P  K s a  m pl e s  ar e t o  b e  c oll e ct e d   wit hi n  ± 5   mi n ut e s  of t h e s c h e d ul e d s a  m pli n g ti  m e.  
q   L e v o d o p a  or   C ar bi d o p a -L e v o d o p a  a n d  S  A  G E -2 1 7  ar e t o  b e  a d  mi nist er e d i n t h e   m or ni n g.  
 
 


St atisti c al  A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0   
P a g e  2 5  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
1 2. 1. 2  P a rt   B  
Visit   D a ys   
S c r e e ni n g 
(  D a y -2 8 t o 
D a y   -2)  
A d  mit 
(  D a y -1)  
P a rt   B:    O p e n -L a b el   
F oll o  w -u p  
D a y  1      
D a y  2      
D a y  3      
D a y  4      
D a y  5      
D a y  6      
D a y  7      
D a y  8      
D a y  1 4 ( ± 1)   
I nf or  m e d   C o ns e nt 
X 
    
    
    
    
    
    
    
    
 
 
I n cl usi o n/ E x cl usi o n 
X 
X    
    
    
    
    
    
    
    
 
 
C o nfi n e d t o   U nit   
 
X    
X    
X    
X    
X    
X    
X    
X    
X 
 
D e  m o gr a p hi cs   
X 
    
    
    
    
    
    
    
    
 
 
M e di c al   Hist or y   
X 
    
    
    
    
    
    
    
    
 
 
P h ysi c al  E x a  mi n ati o n  
X 
X    
X    
    
X    
X    
    
X    
    
X 
 
B o d y    W ei g ht/  H ei g ht   
X 
X    
    
    
    
    
    
    
    
 
 
C  B  C/ S er u  m   C h e  mistr y   
X 
X      
    
    
    
X    
    
X    
    
X 
X 
Pr e g n a n c y  T est  
X-  s er u  m    
X-  uri n e     
    
    
    
    
    
    
    
    
X-  uri n e  
Uri n al ysis d 
X 
X    
    
    
    
X    
    
X    
    
X 
X 
H e p atitis   &   HI  V s cr e e n   
X 
    
    
    
    
    
    
    
    
 
 
Vit al   Si g ns e 
X 
X    
X    
X    
X    
X    
X    
X    
X    
X f    
X 
P uls e   O xi  m etr y g 
 
X    
X    
X    
X    
X    
X    
X    
X    
X f    
X 
1 2 -L e a d  E  C  G h 
X 
X    
X    
X f    
X    
X f    
X    
X f    
X    
X f    
X 
C-  S S  R S i 
X 
X    
X    
X f    
X f    
X f    
X f    
X f    
X f    
X f    
X 
M  D S  -U P  D  R S ( c o  m pl et e) j    
X 
X    
X f    
    
    
    
    
    
    
X f    
X 
M  D S  -U P  D  R S ( P art II 
o nl y) k 
 
    
X    
X    
X    
X    
X    
X 
 
 
 
M  D S  -U P  D  R S ( P art III 
o nl y) k 
 
    
X    
X    
X    
X    
X    
X 
 
 
 






St atisti c al   A n al ysis  Pl a n   M et h o ds  0 1   A u g ust  2 0 1 7   V ersi o n  2. 0  
P a g e  2 8  
Pr ot o c ol   N u  m b er:  S  A  G E -2 1 7 -P  R  K -2 0 1  
 
S a g e  T h er a p e uti cs I n c  
C o nfi d e nti al I nf or  m ati o n   
 
 
1 2. 2   A p p e n di x   B:   D et ails  of  St atisti c al    M et h o d o  l o g y 
N ot  a p pli c a bl e.