Clinical trial NCT03732534
Conditions: Tourette Syndrome
Sponsor: Neurocrine Biosciences
Start date: 2018-10-17; Completion date: 2019-02-18
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, rollover study to collect long-term safety, tolerability, and investigator- and participant-reported pharmacodynamic (PD) data after chronic administration of NBI-98854 in pediatric participants with Tourette Syndrome (TS), as well as to provide open-label access to NBI-98854 for the treatment of TS for pediatric participants who have taken part in a Phase 2 NBI-98854 study.

Detailed description:

Arms: arm 1: NBI-98854 administered once daily for up to 96 weeks
Interventions: intervention 1: NBI-98854
Intervention descriptions: intervention 1: vesicular monoamine transporter 2 (VMAT2) inhibitor

Protocol documents:
Prot_SAP_000.pdf: 
 
  
 
 
C LI NI C A L  S T U D Y  P R O T O C O L 
 
A m e n d m e nt  N o.  2  Fi n al  V ersi o n  D at e:   0 3  D e c e m b er  2 0 1 8 
A m e n d m e nt  N o.  1  Fi n al  V ersi o n  D at e:   0 1  M a y  2 0 1 8 
Ori gi n al  V ersi o n  D at e:    1 9  O ct o b er  2 0 1 7 
 
O p e n -L a b el  R oll o v e r  St u d y f o r  C o nti n ui n g  N BI -9 8 8 5 4  A d mi nist r ati o n f o r 
t h e  T r e at m e nt  of  P e di at ri c  S u bj e cts  wit h  T o u r ett e  S y n d r o m e 
 
St u d y  N o.:   N BI- 9 8 8 5 4- T S 2 0 0 7 
 
D e v el o p m e nt  P h as e:   P h as e  2 
 
S p o ns or:    
N e ur o cri n e  Bi os ci e n c es, I n c.  
 
1 2 7 8 0  El  C a mi n o  R e al 
 
S a n  Di e g o,  C A  9 2 1 3 0 
 
T el e p h o n e:  ( 8 5 8)  6 1 7- 7 6 0 0 
 
F a csi mil e:    ( 8 5 8)  6 1 7- 7 7 0 5 
 
 
C O N FI D E N TI A L  
T his  d o c u m e nt is  a  c o nfi d e nti al  c o m m u ni c ati o n  of  N e ur o cri n e  Bi os ci e n c es, I n c.  It is  a gr e e d t h at 
n o   u n p u blis h e d  i nf or m ati o n  c o nt ai n e d  h er ei n    will   b e   p u blis h e d   or   dis cl os e d    wit h o ut   pri or 
a p pr o v al  fr o m  t h e  s p o ns or.      H o w e v er,  t his   d o c u m e nt  c a n   b e   dis cl os e d  t o   a n   a p pr o pri at e 
I nstit uti o n al  R e vi e w  B o ar d/ Et hi cs  C o m mitt e e (I R B/ E C)  or  a ut h ori z e d r e pr es e nt ati v es  of  n ati o n al 
r e g ul at or y  a ut h oriti es  u n d er t h e  c o n diti o n t h at t h e y r es p e ct its  c o nfi d e nti al  n at ur e. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 
SI G N A T U R E S:  
I  a gr e e t o  c o n d u ct t his st u d y i n  a c c or d a n c e  wit h t h e r e q uir e m e nts  of t his  cli ni c al st u d y  pr ot o c ol 
a n d i n  a c c or d a n c e  wit h t h e f oll o wi n g: 
•   Est a blis h e d  pri n ci pl es  of I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n  of  T e c h ni c al 
R e q uir e m e nts f or  P h ar m a c e uti c als f or  H u m a n  Us e (I C H)  G o o d  Cli ni c al  Pr a cti c es ( G C P)  
•   U nit e d  St at es ( U S)  C o d e  of  F e d er al  R e g ul ati o ns ( C F R);  U S  F o o d  a n d  Dr u g  A d mi nistr ati o n 
( F D A) 
 
C LI NI C A L  S T U D Y  T I T L E : 
O p e n - La b el  R oll o v er  St u d y f or  C o nti n ui n g  N BI- 9 8 8 5 4  A d mi nistr ati o n f or t h e  Tr e at m e nt  of 
P e di atri c  S u bj e cts  wit h  T o ur ett e  S y n dr o m e  
 
P R O T O C O L  N o.:  
N BI - 9 8 8 5 4-T S 2 0 0 7 
 
As  A g r e e d:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pri n ci p al  I n v esti g at or  Si g n at ur e 
D at e  
 
P RI N CI P A L  I N V E S TI G A T O R:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt  Pri n ci p al I n v esti g at or  N a m e) 
 
SI T E:   
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt  Sit e  N a m e) 






N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  5 
T A B L E  O F  C O N T E N T S  
1.  
TI T L E  P A G E  ................................................................................................. 1 
T A B L E  O F  C O N T E N T S  .................................................................................................. 5 
LI S T  O F  T A B L E S  ............................................................................................................ 8 
LI S T  O F  FI G U R E S .......................................................................................................... 8  
2.  
S Y N O P SI S  .................................................................................................... 9 
3.  
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S .............. 1 2 
4.  
E T HI C S  ....................................................................................................... 1 4 
5.  
I N T R O D U C TI O N ....................................................................................... 1 4 
5. 1.  
B a c k gr o u n d .................................................................................................. 1 4  
5. 2.  
N BI - 9 8 8 5 4 ................................................................................................... 1 5 
5. 3.  
St u d y  a n d  D os e  R ati o n al e  ............................................................................ 1 7 
6.  
S T U D Y  O BJ E C TI V E S  ............................................................................... 1 7 
7.  
O V E R VI E W  O F  S T U D Y  D E SI G N  ............................................................ 1 7 
8.  
S T U D Y  P O P U L A TI O N  .............................................................................. 1 9 
8. 1.  
I n cl usi o n  Crit eri a ......................................................................................... 1 9 
8. 2.  
E x cl usi o n  Crit eri a ........................................................................................ 2 1  
8. 3.  
S u bj e ct I d e ntifi c ati o n  a n d  R e pl a c e m e nt  ...................................................... 2 2 
8. 4.  
R a n d o mi z ati o n  ............................................................................................. 2 2 
9.  
S T U D Y  E V A L U A TI O N S  ........................................................................... 2 2 
9. 1.  
S c h e d ul e  of  Ass ess m e nts  ............................................................................. 2 2 
9. 2.  
P h ar m a c o d y n a mi c  Ass ess m e nts  .................................................................. 2 5 
9. 2. 1.  
Cli ni c al  Gl o b al I m pr essi o n  S c al es  ............................................................... 2 5 
9. 2. 2.  
Gill es  d e l a  T o ur ett e  S y n dr o m e - Q u alit y  of  Lif e f or  C hil dr e n  a n d 
A d ol es c e nts  .................................................................................................. 2 5 
9. 3.  
S af et y  Ass ess m e nts  ...................................................................................... 2 5 
9. 3. 1.  
D at a  S af et y  M o nit ori n g  B o ar d ..................................................................... 2 6  
9. 3. 2.  
Vit al  Si g n  M e as ur e m e nts  ............................................................................. 2 6 
9. 3. 3.  
M e di c al  Hist or y  ........................................................................................... 2 6 
9. 3. 4.  
P h ysi c al  E x a mi n ati o n, I n cl u di n g  H ei g ht  a n d  W ei g ht .................................. 2 6 
9. 3. 5.  
El e ctr o c ar di o gr a m  ........................................................................................ 2 6 
9. 3. 6.  
Cli ni c al  La b or at or y  Ass ess m e nts  ................................................................ 2 7 
9. 3. 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 hil dr e n’s  V ersi o ns  ................... 2 7 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  6 
9. 3. 8.  
E xtr a p yr a mi d al  S y m pt o m  R ati n g  S c al e - A b br e viat e d  ................................. 2 8 
9. 3. 9.  
Esti m at e d  T ot al  Bl o o d  S a m pl e  V ol u m e  R e q uir e d  b y  St u d y  ....................... 2 8 
9. 4.  
S p e cifi c  St u d y I nf or m ati o n  .......................................................................... 2 8 
9. 4. 1.  
S cr e e ni n g ( D a ys - 2 8 t o - 1) ........................................................................... 2 8  
9. 4. 2.  
D a y  1 ( B as eli n e  Ass ess m e nts  a n d  St art  of  D osi n g)  ..................................... 2 9 
9. 4. 3.  
W e e ks  2  a n d  4 ( ±  3  d a ys) ............................................................................ 3 0  
9. 4. 4.  
W e e ks  8,  1 6,  3 6,  4 8,  a n d  7 2 ( ±  5  d a ys f or  W e e ks  8  a n d  1 6,  ±  1 4  d a ys f or 
W e e ks   3 6,  4 8,  a n d  7 2) ................................................................................. 3 1 
9. 4. 5.  
W e e ks  1 2,  2 0,  2 4,  6 0,  a n d  8 4 ( ±  5  d a ys f or  W e e ks  1 2,  2 0,  a n d  2 4,  ±  1 4  d a ys 
f or  W e e ks  6 0  a n d  8 4) ................................................................................... 3 2 
9. 4. 6.  
Fi n al  St u d y  Visit/ E arl y  T er mi n ati o n:   W e e k  9 6 ( ±  1 4  d a ys)  ....................... 3 2 
9. 5.  
St u d y  D ur ati o n ............................................................................................. 3 3  
9. 6.  
Pr o hi biti o ns  a n d  R estri cti o ns ....................................................................... 3 3  
9. 6. 1.  
Pri or  a n d  C o n c o mit a nt  M e di c ati o ns ............................................................ 3 3  
9. 6. 2.  
Di et ar y  R estri cti o ns  ..................................................................................... 3 4 
9. 6. 3.  
Ot h er  R estri cti o ns  ........................................................................................ 3 4 
9. 7.  
Wit h dr a w al  Crit eri a  ..................................................................................... 3 4 
9. 7. 1.  
H a n dli n g  of  Wit h dr a w als ............................................................................. 3 5  
9. 7. 2.  
S p o ns or’s  T er mi n ati o n  of  St u d y .................................................................. 3 5  
1 0.  
S T U D Y  D R U G  ............................................................................................ 3 5 
1 0. 1.  
St u d y  Dr u g  S u p pli es  .................................................................................... 3 5 
1 0. 2.  
St u d y  Dr u g  St or a g e...................................................................................... 3 6  
1 0. 3.  
St u d y  Dr u g  P a c k a gi n g  a n d  La b eli n g  ........................................................... 3 6 
1 0. 4.  
Bli n di n g ....................................................................................................... 3 6  
1 0. 5.  
St u d y  Dr u g  A d mi nistr ati o n .......................................................................... 3 6  
1 0. 6.  
Dr u g  C o m pli a n c e  a n d  A c c o u nt a bilit y  ......................................................... 3 7 
1 0. 7.  
St u d y  Dr u g  R et ur n ....................................................................................... 3 7  
1 1.  
A D V E R S E  E V E N T S ................................................................................... 3 7  
1 1. 1.  
D efi niti o n  ..................................................................................................... 3 7 
1 1. 2.  
I nt e nsit y  of  A d v ers e  E v e nts ......................................................................... 3 8 
1 1. 3.  
R el ati o ns hi p t o  St u d y  Dr u g ......................................................................... 3 8  
1 1. 4.  
R e c or di n g  A d v ers e  E v e nts .......................................................................... 3 9  
1 1. 5.  
P ost -St u d y  F oll o w - U p  of  A d v ers e  E v e nts ................................................... 3 9 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  7 
1 1. 6.  
S eri o us  A d v ers e  E v e nts  ............................................................................... 4 0 
1 1. 6. 1.  
D efi niti o n  of  a  S eri o us  A d v ers e  E v e nt  ........................................................ 4 0 
1 1. 6. 2.  
M a n a gi n g  S eri o us  A d v ers e  E v e nts  .............................................................. 4 0 
1 1. 6. 3.  
R e p orti n g  S eri o us  A d v ers e  E v e nts  a n d  Ot h er I m m e di at el y  R e p ort a bl e 
E v e nts  .......................................................................................................... 4 1 
1 1. 6. 4.  
E x p e dit e d  S af et y  R e p orts ............................................................................ 4 1  
1 1. 7.  
Pr e g n a n c y .................................................................................................... 4 1  
1 2.  
D O C U M E N T A TI O N  O F  D A T A ................................................................ 4 2  
1 2. 1.  
C as e  R e p ort  F or m ........................................................................................ 4 2  
1 2. 2.  
D at a  C a pt ur e,  R e vi e w,  a n d  V ali d ati o n  ........................................................ 4 2 
1 2. 3.  
C o di n g  Di cti o n ari es  ..................................................................................... 4 3 
1 3.  
S T A TI S TI C A L  A N D  A N A L Y TI C A L  P L A N  ............................................ 4 3 
1 3. 1.  
A n al ysis  S ets  ................................................................................................ 4 3 
1 3. 2.  
S a m pl e  Si z e  ................................................................................................. 4 3 
1 3. 3.  
H a n d li n g  of  Missi n g  D at a ............................................................................ 4 3 
1 3. 4.  
E nr oll m e nt  a n d  Dis p ositi o n  of  S u bj e cts ...................................................... 4 3  
1 3. 5.  
D e m o gr a p hi cs  a n d  B as eli n e  C h ar a ct eristi cs  ................................................ 4 3 
1 3. 6.  
St u d y  Dr u g  D osi n g  a n d  C o m pli a n c e ........................................................... 4 4  
1 3. 7.  
P h ar m a c o d y n a mi c  D at a  ............................................................................... 4 4 
1 3. 8.  
S af et y  D at a ................................................................................................... 4 4  
1 3. 9.  
S oft w ar e ....................................................................................................... 4 4  
1 3. 1 0.  
I nt eri m A n al ysis ........................................................................................... 4 4  
1 4.  
R E G U L A T O R Y  A N D  E T HI C A L I S S U E S  ................................................ 4 5 
1 4. 1.  
G e n er al  Le g al  R ef er e n c es  ............................................................................ 4 5 
1 4. 2.  
I nstit uti o n al  R e vi e w  B o ar d .......................................................................... 4 5 
1 4. 3.  
Pr ot o c ol  A d h er e n c e  a n d  A m e n d m e nts  ........................................................ 4 5 
1 4. 4.  
R e q uir e d  D o c u m e nts ................................................................................... 4 5  
1 4. 5.  
I nf or m e d  C o ns e nt ........................................................................................ 4 5 
1 4. 6.  
St u d y  M o nit ori n g ......................................................................................... 4 6  
1 4. 7.  
Q u alit y  Ass ur a n c e  ........................................................................................ 4 6 
1 4. 8.  
R e c or d  R et e nti o n ......................................................................................... 4 6  
1 4. 9.  
C o nfi d e nti alit y ............................................................................................. 4 6  
1 5.  
S T U D Y  C O M M E N C E M E N T  A N D  DI S C O N TI N U A TI O N  ..................... 4 7 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  8 
1 6.  
R E F E R E N C E S ............................................................................................ 4 8  
 
LI S T  O F  T A B L E S  
T a bl e   1: 
S c h e d ul e  of  Ass ess m e nts  ............................................................................. 2 3 
T a bl e   2: 
Esti m at e d  T ot al  Bl o o d  S a m pl e  V ol u m e  ...................................................... 2 8 
T a bl e   3: 
I nt e nsit y  of  A d v ers e  E v e nts ......................................................................... 3 8 
T a bl e   4: 
R el ati o ns hi p  of  A d v ers e  E v e nts t o  St u d y  Dr u g ........................................... 3 9  
 
LI S T  O F  FI G U R E S  
Fi g ur e  1:  
St u d y  D esi g n  S c h e m ati c  .............................................................................. 1 9 
 
 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  9 
2.   
S Y N O P SI S  
P r ot o c ol  titl e:  O p e n -L a b el  R oll o v er  St u d y f or  C o nti n ui n g  N BI -9 8 8 5 4  A d mi nistr ati o n f or t h e  Tr e at m e nt 
of  P e di atri c  S u bj e cts  wit h  T o ur ett e  S y n dr o m e  
St u d y  c e nt e rs:   A p pr o xi m at el y  7 5  st u d y  c e nt ers i n t h e  U nit e d  St at es . 
O bj e cti v es:  
•  T o  c oll e ct l o n g -t er m s af et y  a n d t ol er a bilit y  d at a i n  p e di atri c  s u bj e cts r e c ei vi n g  N BI-9 8 8 5 4 
a d mi nist er e d  o n c e  d ail y f or  u p t o  9 6  w e e ks (i e,  a p pr o xi m at el y  2 4  m o nt hs).  
•  T o  pr o vi d e  c o nti n u e d  a c c ess t o  N BI -9 8 8 5 4 f or t h e tr e at m e nt  of  T o ur ett e s y n dr o m e ( T S) i n  u p t o 
a p pr o xi m at el y  2 4 0  p e di atri c  T S s u bj e cts  w h o  h a v e  c o m pl et e d  t h e  P h as e  2 st u d y 
N BI -9 8 8 5 4 -T S 2 0 0 4  or  w er e  d os e d f or  at l e ast  1 6  w e e ks ( ± 3  d a ys)  i n t h e  P h as e  2 st u d y 
N BI -9 8 8 5 4 -T S 2 0 0 5.  
M et h o d ol o g y:   T his st u d y i s  d esi g n e d t o  c oll e ct l o n g -t er m s af et y  a n d t ol er a bilit y  d at a  as  w ell  as 
i n v esti g at or- a n d s u bj e ct -r e p ort e d  p h ar m a c o d y n a mi c ( P D)  d at a f oll o wi n g  c hr o ni c  a d mi nistr ati o n  of 
N BI -9 8 8 5 4 i n  p e di atri c s u bj e cts  wit h  T S.  I n  a d diti o n, t his r oll o v er st u d y  will  pr o vi d e  p e di atri c s u bj e cts 
w h o  h a v e  p arti ci p at e d i n  a  pri or  P h as e  2  N BI -9 8 8 5 4 st u d y  o p e n -l a b el  a c c ess t o  N BI-9 8 8 5 4 f or t h e 
tr e at m e nt  of  T S  u ntil t h e y  c o m pl et e  9 6  w e e ks (i e,  a p pr o xim at el y  2 4  m o nt hs)  of tr e at m e nt.   T his st u d y 
will  all o w  e nr oll m e nt  of  u p t o  a p pr o xi m at el y  2 4 0  m al e  a n d f e m al e  p e di atri c s u bj e ct s ( 6 t o  1 8  y e ars  of 
a g e, i n cl usi v e)  wit h  T S  w h o  h a v e  c o m pl et e d t h e  P h as e  2 st u d y  N BI -9 8 8 5 4 -T S 2 0 0 4  or  w er e  d os e d f or  at 
l e ast  1 6  w e e ks ( ± 3  d a ys) i n t h e  P h as e  2 st u d y  N BI-9 8 8 5 4 -T S 2 0 0 5  a n d  dis c o nti n u e d  d u e t o  a l a c k  of 
effi c a c y  or  a  T E A E  of  w ors e ni n g  of ti cs (s u bj e ct s  w h o  c o m pl et e d t h e  N BI -9 8 8 5 4 -T S 2 0 0 5 st u d y  ar e  al s o 
eli gi bl e) .  S u bj e ct s  w h o  dis c o nti n u e d  pri or t o t h e  e n d  of t h e  N BI -9 8 8 5 4- T S 2 0 0 5  st u d y (i e,  W e e k  4 0) 
m ust  h a v e  c o m pl et e d  a n  e arl y t er mi n ati o n  visit t o  b e  eli gi bl e f or t h e  c urr e nt  st u d y  (t h e  e arl y t er mi n ati o n 
visit  m a y  h a v e  o c c urr e d  at t h e ti m e  of t h e  W e e k  1 6  visit) . 
P ar e nt al  or l e g al  g u ar di a n i nf or m e d  c o ns e nt  wit h si g n e d  a n d  wit n ess e d  p e di atri c  ass e nt f or s u bj e ct s 
≤ 1 7  y e ars  of  a g e,  or  writt e n i nf or m e d  c o ns e nt f or s u bj e cts  1 8  y e ars  of  a g e,  m ust  b e  o bt ai n e d  pri or t o 
c o n d u ct  of  a n y st u d y -r el at e d  pr o c e d ur es. 
S u bj e cts  w h o  h a v e t h eir fi n al  N BI -9 8 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  visit  > 3 0  d a ys  pri or t o 
a nti ci p at e d  b as eli n e ( D a y  1) r e q uir e s cr e e ni n g.   T h es e s u bj e ct s  will  b e s cr e e n e d t o  d et er mi n e  eli gi bilit y 
wit hi n  2 8  d a ys ( D a ys  -2 8  t o -1)  b ef or e  b as eli n e ( D a y  1).   At  b as eli n e ( D a y  1),  eli gi bl e s u bj e cts  will 
r et ur n t o t h e st u d y sit e f or  c oll e cti o n  of  b as eli n e s af et y  a n d P D  ass ess m e nt s.  
S u bj e cts  c a n  h a v e t h eir fi n al  N BI -9 8 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  visit  o n t h e s a m e  d a y  as  D a y  1 
f or t his r oll o v er st u d y  pr o vi d e d t h e y si g n t h e  c urr e nt st u d y’s i nf or m e d  c o ns e nt/ ass e nt  b ef or e t h e fi n al 
N BI - 98 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  visit.   T his  will  all o w  c ert ai n  ass ess m e nts t o  b e  us e d f or  b ot h 
st u di es.   T h e  ass ess m e nt r es ults t h at  c a n  a p pl y t o  b ot h st u di es i n cl u d e  p h ysi c al  e x a mi n ati o ns (i n cl u di n g 
w ei g ht),  vit al si g ns,  el e ctr o c ar di o gr a ms ( E C G) , t h e  Cli ni c al  Gl o b al I m pr essi o n  of  Ti cs-S e v erit y  s c al e 
( C GI-Ti cs -S e v erit y), t h e  E xtr a p yr a mi d al  S y m pt o m  R ati n g  S c al e -A b br e vi at e d ( E S R S -A),  a n d t h e  Gill es 
d e l a  T o ur ett e  S y n dr o m e -Q u alit y  of  Lif e  S c al e f or  C hil dr e n  a n d  A d ol es c e nts ( C & A  G T S -Q O L) s c al e . 
T h e st arti n g  d os e  will  b e  N BI -9 8 8 5 4  2 0  m g f or s u bj e cts  < 5 0  k g  at  b as eli n e  a n d  N BI -9 8 8 5 4  4 0  m g f or 
s u bj e cts  ≥ 5 0  k g  at  b as eli n e.   T h e  d os e  m a y  b e  es c al at e d i n i n cr e m e nts  of  2 0  m g  e v er y  2  w e e ks t o  a 
m a xi m u m  of  6 0  m g f or s u bj e cts  < 5 0  k g  a n d  8 0  m g f or s u bj e cts  ≥ 5 0  k g t o  a c h i e v e  a n  o pti m al  d os e  of 
N BI -9 8 8 5 4 f or  e a c h s u bj e ct.   D os e  es c al ati o ns  will  o c c ur  at t h e  e n d  of  W e e ks  2  a n d  4  b as e d  o n t h e 
f oll o wi n g  2  crit eri a:   1) t h e s u bj e ct’s ti cs  ar e  n ot s uffi ci e ntl y  c o ntr oll e d  p er  p h ysi ci a n i n v esti g at or 
ass ess m e nt;  a n d  2)  a n  e v al u ati o n  b y t h e  p h ysi ci a n i n v esti g at or i n di c at es t h at t h e  s u bj e ct is t ol er ati n g t h e 
st u d y  dr u g  at t h e  c urr e nt  d os e  a n d  w o ul d li k el y  b e  a bl e t o t ol er at e t h e  n e xt  d os e l e v el.   D uri n g t h e first 
4  w e e ks  of t h e tr e at m e nt  p eri o d, t h e  p h ysi ci a n i n v esti g at or  m a y  es c al at e  a s u bj e ct’s  d os e t o t h e  n e xt  d os e 
l e v el,  c o nti n u e  wit h t h e s u bj e ct’s  c urr e nt  d os e,  or r e d u c e t o t h e s u bj e ct’s  pri or t ol er at e d  d os e (i n s u bj e cts 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 0 
w h o  h a v e  h a d  a  d os e  es c al ati o n).  If  a s u bj e ct’s  o pti m al  d os e  h as  alr e a d y  b e e n  est a bli s h e d  at  W e e k  2,  n o 
f urt her  d os e  es c al ati o n  will  b e  all o w e d  d uri n g t h e  d os e  o pti mi z ati o n  p eri o d  a n d t h e s u bj e ct  will  c o nti n u e 
at t h at  d os e  u ntil  W e e k  9 6 ( or  e arl y t er mi n ati o n).   Aft er  W e e k  4, s u bj e cts  will  c o nti n u e t o r e c ei v e t h eir 
o pti mi z e d  d os e  of  N BI -9 8 8 5 4  u ntil  W e e k  9 6 ( or  e ar l y t er mi n ati o n).   At  a n y ti m e  aft er  W e e k  2, t h e 
p h ysi ci a n i n v esti g at or  m a y  d e cr e as e t h e  d os e t o t h e  pr e vi o us  d os e f or  a n y s u bj e ct  w h o  h a d  a  d os e 
es c al ati o n  a n d  w h o is  u n a bl e t o t ol er at e  a  gi v e n  d os e i n cr e as e.   T h e s u bj e ct  will  c o nti n u e  at t h at  d os e 
u ntil t h e  e n d  of t h e tr e at m e nt  p eri o d.   T h e i n v esti g at or  m a y r e d u c e t h e s u bj e ct’s  d os e  o nl y  o n e ti m 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 st arti n g  d os e  or r es u m pti o n  of t h e  pr e vi o us  d os e  will  b e 
dis c o nti n u e d fr o m t h e st u d y.  
E li gi bl e s u bj e cts  will r e c ei v e  a s u p pl y  of  N BI-9 8 8 5 4  o n  D a y  1  a n d  b e gi n  d osi n g  at  b e dti m e  of  D a y   1.  
S u bj e cts  will r et ur n t o t h e st u d y  c e nt er  e v er y  2  t o  1 2  w e e ks f or  ass ess m e nts  a n d  dis p e ns ati o n  of 
N BI -9 8 8 5 4.   T h e fi n al  ass ess m e nts  will  b e  p erf or m e d  at t h e  e n d  of  W e e k  9 6,  or  u p o n  e arl y t er mi n ati o n.  
T h e st u d y  c e nt er  visits  aft er  D a y  1  will  h a v e  wi n d o w s of  ±  3  d a ys f or  visits  at  W e e ks  2  a n d  4,  ±  5  d a ys 
f or  visits  at  W e e ks  8 t hr o u g h  2 4,  a n d  ±  1 4  d a ys f or  visits  at  W e e ks  3 6 t hr o u g h  9 6.   A n i n d e p e n d e nt  D at a 
S af e t y  M o nit ori n g  B o ar d ( D S M B)  will  p eri o di c all y r e vi e w  o n g oi n g  cli ni c al s af et y  d at a t o  e ns ur e t h e 
s af et y  a n d  w ell-b ei n g  of t h e st u d y s u bj e ct s.  
P D  a n d s af et y  ass ess m e nts  will  b e  c oll e ct e d  at s c h e d ul e d ti m es t hr o u g h o ut t h e st u d y.  
St u d y  p o p ul ati o n:   U p t o  a p pr o xi m at el y  2 4 0  m al e  a n d f e m al e  p e di atri c s u bj e cts ( 6 t o  1 8  y e ars  of  a g e, 
i n cl usi v e,  o n  D a y  1 [ b as eli n e])  wit h  a  cli ni c al  di a g n osi s  of  T S  will  b e  e nr oll e d.   T his st u d y  will  o nl y 
e nr oll s u bj e cts  w h o  e x pr ess  a n i nt er est i n  c o nti n ui n g t o r e c ei v e  or r e -i niti at e  NBI -9 8 8 5 4  a n d  h a d 
pr e vi o usl y  c o m pl et e d t h e  P h as e  2 st u d y  N BI -9 8 8 5 4 -T S 2 0 0 4  or  w er e  d os e d f or  at l e ast  1 6  w e e ks 
( ± 3 d a ys) i n t h e  P h as e  2 st u d y  N BI -9 8 8 5 4 -T S 2 0 0 5  a n d  dis c o nti n u e d  d u e t o  a l a c k  of  effi c a c y  or  a  T E A E 
of  w ors e ni n g  of ti cs (s u bj e ct s  w h o  c o m pl et e d t h e  N BI -9 8 8 5 4 -T S 2 0 0 5 st u d y  ar e  al s o  eli gi bl e).   S u bj e cts 
m ust  h a v e  a st a bl e  ps y c hi atri c st at us  as  d et er mi n e d  b y t h e  p h ysi ci a n i n v esti g at or . 
D u r ati o n  of  tr e at m e nt  a n d  st u d y p a rti ci p ati o n:   T h e  e x p e ct e d  d ur ati o n  of st u d y  p arti ci p ati o n f or  e a c h 
s u bj e ct is  u p  t o  1 00  w e e ks, i n cl u di n g  u p t o  4  w e e ks  of s cr e e ni n g  a n d  u p t o  9 6  w e e ks  of st u d y  dr u g 
tr e at m e nt. 
I n v esti g ati o n al  p r o d u ct,  d os e,  a n d  m o d e  of  a d mi nist r ati o n:   N BI -9 8 8 5 4  will  b e s u p pli e d i n  c a ps ul e 
f or m  c o nt ai ni n g  2 0  m g, 4 0  m g ,  6 0  m g,  or  8 0  m g (fr e e  b as e  e q uiv al e nt)  of  N BI -9 8 8 5 4 
 
.  S u bj e cts  m ust s w all o w t h e  c a ps ul e  at  b e dti m e  wit h  at l e ast  4  o z.  of  w at er  wit h  or  wit h o ut f o o d.  
R ef e r e n c e  th e r a p y,  d os e,  a n d  m o d e  of  a d mi nist r ati o n:   N ot  a p pli c a bl e.  
C rit e ri a f o r  e v al u ati o n:    
P h a r m a c o d y n a mi cs  
T h e f oll o wi n g  P D  ass ess m e nt s  will  b e  a d mi ni st er e d:  
•  T h e  C GI -Ti cs -S e v erit y  will  b e  c o m pl et e d  b y t h e i n v esti g at or  o n  D a y  1 ( b as eli n e),  a n d  at t h e  e n d 
of  W e e ks  8,  1 6,  2 4,  3 6,  4 8,  7 2,  a n d  9 6 (fi n al st u d y  visit  or  u p o n  e arl y t er mi n ati o n).  
•  T h e  Cli ni c al  Gl o b al I m pr essi o n  of  T o ur ett e  S y n dr o m e -I m pr o v e m e nt s c al e 
( C GI-T S -I m pr o v e m e nt)  will  b e  c o m pl et e d  b y t h e i n v esti g at or  at t h e  e n d  of  W e e ks  8,  1 6,  2 4,  3 6, 
4 8,  7 2,  a n d  9 6 (fi n al st u d y  vi sit  or  u p o n  e arl y t er mi n ati o n).  
•  T h e  C & A -G T S -Q O L  s c al e will  b e  c o m pl et e d  b y t h e s u bj e ct  o n  D a y  1 ( b as eli n e),  a n d  at t h e  e n d 
of  W e e ks  1 2,  2 4,  4 8,  7 2,  a n d  9 6 (fi n al st u d y  vi sit  or  u p o n  e arl y t er mi n ati o n).  
S af et y  
S af et y  a n d t ol er a bilit y  will  b e  m o nit or e d t hr o u g h o ut t h e  st u d y a n d  will i n cl u d e t h e f oll o wi n g 
ass ess m e nt s:  
•  A d v ers e  e v e nt s.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 1 
•  Cli ni c al l a b or at or y t ests ( h e m at ol o g y,  cli ni c al  c h e mi str y,  a n d  uri n al ysis).  
•  Vit al si g ns (i n cl u di n g  ort h ost ati c  bl o o d  pr ess ur e  a n d  p uls e).  
•  P h ysi c al  e x a mi n ati o ns.  
•  1 2 -l e a d  el e ctr o c ar di o gr a m. 
•  E S R S -A.  
•  S ui ci d al i d e ati o n  a n d  b e h a vi or  –  e v al u at e d  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) ,  C hil dr e n’s  V ersi o n. 
St atisti c al  m et h o ds:   P h ar m a c o d y n a mi c, s af et y,  a n d t ol er a bilit y  ass ess m e nts  will  b e s u m m ari z e d  usi n g 
d es cri pti v e st atisti cs.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 2 
3.   
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S     
A D H D  
Att e nti o n -D efi cit  H y p er a cti vit y  Dis or d er  
A E  
A d v ers e  e v e nt  
A L T  
Al a ni n e  a mi n otr a nsf er as e  
A S T  
As p art at e  a mi n otr a nsf er as e  
A U C 0- ∞  
Ar e a  u n d er t h e  pl as m a  c o n c e ntr ati o n  v ers us ti m e  c ur v e  fr o m  0  h o urs 
e xtr a p ol at e d t o i nfi nit y  
β -h C G  
β -h u m a n  c h ori o ni c  g o n a d otr o pi n  
C & A -G T S -Q O L   
Gill es  d e l a  T o ur ett e  S y n dr o m e  –  Q u alit y  of  Lif e  S c al e f or  C hil dr e n 
a n d  A d ol es c e nts  
C F R  
C o d e  of  F e d er al  R e g ul ati o ns  
C GI -Ti cs -S e v erit y   
Cli ni c al  Gl o b al I m pr essi o n  of  Ti cs -S e v erit y s c al e  
C GI -T S -I m pr o v e m e nt  
Cli n i c al  Gl o b al I m pr essi o n  of T o ur ett e  S y n dr o m e -I m pr o v e m e nt 
s c al e 
C m a x   
M a xi m u m  pl as m a  c o n c e ntr ati o n  
C R T  
C o ntr oll e d r o o m t e m p er at ur e  
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 Y P  
C yt o c hr o m e  P 4 5 0  
D S M B  
D at a  S af et y  M o nit ori n g  B o ar d  
D S M -I V  or -5   
Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers , 4 t h or  5t h 
E diti o ns  
D S P V  
Dr u g  S af et y  a n d  P h ar m a c o vi gil a n c e  
E C  
Et hi cs  C o m mitt e e  
E C G  
El e ctr o c ar di o gr a m  
e C R F  
El e ctr o ni c  c as e r e p ort f or m  
E D C  
El e ctr o ni c  d at a  c a pt ur e  
E S R S -A  
E xtr a p yr a mi d al  S y m pt o m  R ati n g  S c al e -A b br e vi at e d  
F D A  
[ U nit e d  St at es]  F o o d  a n d  Dr u g  A d mi nistr ati o n 
G C P  
G o o d  Cli ni c al  Pr a cti c e  
G G T  
G a m m a -gl ut a m yl tr a nsf er as e  
I C F 
I nf or m e d  co ns e nt  for m  
I C H 
I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n  of  T e c h ni c al  R e q uir e m e nts 
f or  P h ar m a c e uti c als f or H u m a n  Us e  
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
M A OI  
M o n o a mi n e  o xi d as e i n hi bit or  
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  
N BI  
N e ur o cri n e  Bi os ci e n c es, I n c.  
P D  
P h ar m a c o d y n a mi cs  
P T  
Pr ef err e d t er m  
Q T c F  
C orr e ct e d  Q T i nt er v al  usi n g  Fri d eri ci a’s  f or m ul a 
S A E  
S eri o us  a d v ers e  e v e nt  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 3 
S A P  
St atisti c al  a n al ysis  pl a n  
S O C  
S yst e m  or g a n  cl ass  
T D  
T ar di v e  d ys ki n esi a  
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  
t½   
A p p ar e nt t er mi n al  h alf -lif e 
tm a x   
Ti m e t o  m a xi m u m  pl as m a  c o n c e ntr ati o n  
T S  
T o ur ett e s y n dr o m e  
T T S  
T ot al  Ti c  S c or e  
U L N  
U p p er li mit  of  n or m al  
U S  
U nit e d  St at es  
V M A T 2  
V esi c ul ar  m o n o a mi n e tr a ns p ort er  2  
W H O  
W orl d  H e alt h  Or g a ni z ati o n  
Y G T S S  
Y al e  Gl o b al  Ti c  S e v erit y  S c al e  
 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 4 
4.   
E T HI C S  
T h e st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h  N e ur o cri n e  Bi os ci e n c es, I n c.  ( N BI) st a n d ar ds 
t h at  m e et r e g ul ati o ns r el ati n g t o  G o o d  Cli ni c al  Pr a cti c e ( G C P).   T h es e st a n d ar ds r es p e ct t h e 
f oll o wi n g  g ui d eli n es: 
•   G o o d  Cli ni c al  Pr a cti c e:   C o ns oli d at e d  G ui d eli n e ( I nt er n ati o n al  C o u n cil f or  H ar m o nis ati o n 
of  T e c h ni c al  R e q uir e m e nts f or  P h ar m a c e uti c als f or  H u m a n  Us e [I C H;  c urr e nt  v ersi o n] ). 
•   U nit e d  St at es ( U S)  C o d e  of  F e d er al  R e g ul ati o ns ( C F R)  d e ali n g  wit h  cli ni c al st u di es 
( 2 1  C F R  p arts  5 0,  5 4,  5 6,  3 1 2,  a n d  3 1 4). 
T h e  et hi c al r e q uir e m e nts  of I nstit uti o n al  R e vi e w  B o ar ds/ Et hi cs  C o m mitt e es (I R Bs/ E Cs)  a n d t h e 
i nf or m e d  c o ns e nt f or ms (I C Fs)  a n d  ass e nt f or ms  ar e  dis c uss e d i n S e cti o n  1 4 . 
5.   
IN T R O D U C TI O N  
5. 1.   
B a c k g r o u n d 
T o ur ett e  s y n dr o m e ( T S) is  a  m o v e m e nt  dis or d er  c h ar a ct eri z e d  b y t h e  pr es e n c e  of  c hr o ni c  m ot or 
a n d  1  or  m or e  v o c al ti cs t h at  oft e n  a p p e ar i n  c hil d h o o d  or  e arl y  a d ol es c e n c e 
(A P A  D S M -I V,  1 9 9 4; A P A  D S M - 5,  2 0 1 3).   Ti cs  ar e  d efi n e d  as r a pi d,  n o n-r h yt h mi c, 
st er e ot y p e d  m ot or  m o v e m e nts  or  v o c ali z ati o ns,  a n d  ar e t y pi c all y  c at e g ori z e d  as si m pl e  or 
c o m pl e x  b as e d  o n t h eir  o v ert f e at ur es.   Si m pl e ti cs  ar e  bri ef,  m e a ni n gl ess  a cti o ns ( e g, f or c ef ul 
bli n ki n g  of t h e  e y es  or  gr u nti n g)  a n d  c o m pl e x ti cs  ar e sl o w er,  m or e  p ur p os ef ul  b e h a vi ors ( e g, 
g yr ati n g  or  utt eri n g  p hr as es;  Le c k m a n  et  al.,  1 9 8 9 ; C a v a n n a  a n d  N a ni,  2 0 1 3 ; 
S h pr e c h er  a n d  K url a n,  2 0 0 9 ).   T h e ti cs f oll o w  a  w a xi n g  a n d  w a ni n g  c o urs e  o v er ti m e,  a n d  m ust 
b e r e c urr e nt f or  a  p eri o d  of  m or e t h a n  1  y e ar t o  q u alif y f or  di a g n o sis.  I n  a d diti o n t o ti c 
p h e n o m e n a,  T S  m a y  als o  pr es e nt  wit h  a  c o nst ell ati o n  of s y m pt o ms t h at  ar e  p art  of  a  br o a d er 
“ T S s p e ctr u m, ”  w hi c h  c a n i n cl u d e  o bs essi v e -c o m p ulsi v e  b e h a vi ors,  att e nti o n -d efi cit  
h y p er a ct i vit y  dis or d er ( A D H D),  a n d i m p ulsi v e  or  a ntis o ci al  b e h a vi or (C h e n  et  al.,  2 0 1 2 ; 
F elli n g   a n d  Si n g er,  2 0 1 1). 
It  h as  b e e n  w ell  est a blis h e d t h at  T S is  pr e d o mi n a ntl y  a  dis or d er  of  c hil d h o o d  wit h  a  m e a n  or 
m e di a n  a g e  of  o ns et  of  a p pr o xi m at el y  6  y e ars  of  a g e ( Le c k m a n  et  al. ,  1 9 9 8; R o b erts o n,  2 0 1 1 ; 
J a n k o vi c  a n d  K url a n,  2 0 1 1 ; S w ai n  et  al. ,  2 0 0 7).   Ti c s y m pt o m at ol o g y  u s u all y  b e c o m es t h e  m ost 
s e v er e  ar o u n d  a g e  1 0  a n d  b y t h e ti m e  a d ult h o o d is  a c hi e v e d  at  1 8  y e ars  of  a g e,  m ost  p ati e nts  ar e 
eit h er ti c -fr e e  or t h eir s y m pto ms  h a v e si g nifi c a ntl y i m pr o v e d ( Le c k m a n  et  al.,  1 9 9 8 ; 
K url a n,  2 0 1 0 ).   T S s y m pt o ms  m a y  als o  o c c ur i n  a d ults a n d  t h es e ti c  p h e n o m e n a  a p p e ar t o  b e  a 
r e-e m er g e n c e  or  a n  e x a c er b ati o n  of  c hil d h o o d  o ns et  T S  (C h o ui n ar d  a n d  F or d,  2 0 0 0 ; J a n k o vi c 
a n d  K url a n,  2 0 1 1). 
P ersist e nt ti cs  c a n  h a v e  a si g nifi c a nt i m p a ct  o n  p ati e nt  q u alit y  of lif e  a n d  oft e n l e a d t o i m p air e d 
ps y c h os o ci al f u n cti o ni n g.   S o m e  of t h es e  pr o bl e ms i n cl u d e s o ci al is ol ati o n,  b ull yi n g,  p h ysi c al 
dis c o mf ort ( wit h  p ai n  or i nj ur y),  a n d  p o or  a c a d e mi c  p erf or m a n c e ( R o ess n er  et  al. ,  2 0 1 3).  
Ps y c h o s o ci al str ess ors  c a n, i n t ur n,  e x a c er b at e ti c s y m pt o m at ol o g y.  It is  u n d er t h es e  c o n diti o ns 
t h at  p h ar m a c ol o gi c al i nt er v e nti o ns  ar e  oft e n  c o nsi d er e d (C h e n  et  al.,  2 0 1 2;  S h pr e c h er  a n d 
K url a n,  2 0 0 9;  R o ess n er  et  al.,  2 0 1 3). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 5 
N e ur o p at h ol o gi c al  m o d els  h a v e  b e e n  pr o p os e d t o  e x pl ai n t h e s y m pt o m ati c f e at ur es  of  T S,  a n d 
c o n v er gi n g li n es  of  e m piri c al  e vi d e n c e  c o nsist e ntl y i m pli c at e  d o p a mi n er gi c  d ysf u n cti o n  a n d 
d ysr e g ul ati o n  wit hi n  pr efr o nt al  c ort e x- b as al  g a n gli a  cir c uitr y ( F elli n g  a n d  Si n g er ,  2 0 1 1; 
P o urf ar  et  al.,  2 0 1 1 ).   F u n cti o n al  n e ur oi m a gi n g  st u di es  h a v e i d e ntifi e d  a  p att er n  of  pr efr o nt al 
c ort e x  h y p er m et a b olis m  a n d r e d u c e d stri at al  a cti vit y i n  T S s u bj e cts  (B a xt er  a n d  G u z e ,  1 9 9 3; 
Br a u n  et  al.,  1 9 9 3 ; P o urf ar  et  al.,  2 0 1 1).   P h ar m a c ot h er a p e uti c  a p pr o a c h es  ai m e d  at  bl o c ki n g 
p osts y n a pti c  d o p a mi n e- 2 r e c e pt ors ( e g,  h al o p eri d ol  a n d  pi m o zi d e)  h a v e  d e m o nstr at e d  effi c a c y 
i n r e d u ci n g  T S s y m pt o ms.  I n t his r e g ar d,  m o d ul ati o n  of  d o p a mi n er gi c t o n e t hr o u g h t h e 
a d mi n istr ati o n  of  a v esi c ul ar  m o n o a mi n e tr a ns p ort er  2 ( V M A T 2 ) i n hi bit or, li k e  N BI- 9 8 8 5 4, 
m a y  als o  b e  a n  eff e cti v e tr e at m e nt  o pti o n f or ti c s u p pr essi o n.  
5. 2.   
N BI - 9 8 8 5 4 
N BI -9 8 8 5 4 ( v al b e n a zi n e t os yl at e) is  a s el e cti v e,  or all y  a cti v e  V M A T 2 i n hi bit or  d e v el o p e d  b y 
N BI.   N BI- 9 8 8 5 4 is  u n d er  d e v el o p m e nt f or t h e tr e at m e nt  of  T S.   N BI - 9 8 8 5 4  w as  a p pr o v e d  b y 
t h e  U S  F o o d  a n d  Dr u g  A d mi nistr ati o n (F D A ) i n  A pril  2 0 1 7 f or t h e tr e at m e nt  of  a d ults  wit h 
t ar di v e  d ys ki n esi a ( T D),  u n d er t h e tr a d e  n a m e I N G R E Z Z A® . 
I n  n o n cli ni c al st u di es,  N BI- 9 8 8 5 4  a p p e ars t o  c a us e littl e  or  n o  c yt o c hr o m e  P 4 5 0 ( C Y P)  e n z y m e 
i n hi biti o n  or i n d u cti o n  at  p h ar m a c ol o gi c all y r el e v a nt  c o n c e ntr ati o ns.   N BI- 9 8 8 5 4 is  a  m o d er at e 
i n hi bit or  of  P- gl y c o pr ot ei n ( P-g p),  b ut  o nl y  at  c o n c e ntr ati o ns t h at  c o ul d  b e  a c hi e v e d i n t h e 
g as tr oi nt esti n al ( GI) tr a ct,  a n d is  n ot  a n i n hi bit or  of  a  p a n el  of  ot h er  dr u g tr a ns p ort ers.  
M et a b olis m  of  N BI - 9 8 8 5 4 is  c h ar a ct eri z e d  b y  h y dr ol ysis  of  N BI- 9 8 8 5 4 t o  N BI- 9 8 7 8 2,  a n d 
C Y P 3 A 4/ 5 - d e p e n d e nt  m o n o-o xi d ati o n t o  N BI - 1 3 6 1 1 0.   N BI- 9 8 7 8 2 is  m et a b oli z e d i n  p art  b y 
C Y P 2 D 6.   All  3  e ntiti es,  n a m el y,  N BI - 9 8 8 5 4,  N BI- 9 8 7 8 2,  a n d  N BI- 1 3 6 1 1 0, c a n   bi n d t o  a n d 
i n hi bit  V M A T 2.   H o w e v er,  N BI- 9 8 7 8 2 is t h e  m ost  p ot e nt  a n d  a p p e ars t o  b e r es p o nsi bl e f or 
m ost   of t h e  o bs er v e d  p h ar m a c ol o gi c al  a cti vit y  of  V M A T 2 i n hi biti o n. 
N BI - 9 8 8 54  a p p e ars t o  b e r a pi dl y  a bs or b e d  wit h  a ti m e t o  m a xi m u m  pl as m a  c o n c e ntr ati o n (t m a x ) 
t y pi c all y r a n gi n g fr o m  a p pr o xi m at el y  0. 5 t o  1. 0  h o urs.   N BI-9 8 8 5 4 r e a c h es st e a d y st at e  wit hi n 
1  w e e k.   T h e  a cti v e  m et a b olit e  N BI - 9 8 7 8 2  gr a d u all y f or ms  wit h  a tm a x   of  4 t o  8  h o urs  a n d  b ot h 
N BI - 9 8 8 5 4  a n d  N BI-9 8 7 8 2  ar e  eli mi n at e d  wit h  a n  a p p ar e nt  t er mi n al  h alf-lif e (t½ ) of  1 5 t o 
2 2  h o urs.   C o a d mi nistr ati o n  of  k et o c o n a z ol e (str o n g  C Y P 3 A 4/ 5 i n hi bit or)  wit h  N BI- 9 8 8 5 4 l e d 
t o  a  1. 5-  a n d  1. 6-f ol d i n cr e as e i n t h e  m a xi m u m  pl as m a  c o n c e ntr ati o n ( Cm a x )  of  N BI- 9 8 8 5 4  a n d 
N BI - 9 8 7 8 2, r es p e cti v el y,  a n d  a  2. 1-f ol d i n cr e as e i n t h e  ar e a  u n d er t h e  pl as m a  c o n c e ntr ati o n 
v ers us ti m e  c ur v e ( A U C) fr o m  0  h o urs  e xtr a p ol at e d t o i nfi nit y ( A U C 0 – ∞)  of  N BI- 9 8 8 5 4  a n d 
N BI - 9 8 7 8 2.   C o a d mi nistr ati o n  of  N BI- 9 8 8 5 4  a n d rif a m pi n (str o n g  C Y P 3 A 4/ 5 i n d u c er) l e d t o  a n 
a p pr o xi m at e  3 0 %  a n d  7 0 %  d e cr e as e i n  C m a x  a n d  A U C 0 – ∞, r es p e cti v el y, f or  N BI- 9 8 8 5 4,  a n d  a n 
a p pr o xi m at e  5 0 %  a n d  8 0 %  d e cr e as e, r es p e cti v el y, f or  N BI- 9 8 7 8 2  c o m p ar e d  wit h  a d mi nistr ati o n 
of  N BI- 9 8 8 5 4  al o n e.   C o a d mi nistr ati o n  of  N BI- 9 8 8 5 4  8 0  m g  a n d  0. 5  m g  di g o xi n r es ult e d i n  a n 
a p pr o xi m at e  1. 9- f ol d i n cr e as e i n t h e C m a x   of  di g o xi n.   T h e  eff e ct  of  N BI- 9 8 8 5 4  o n  di g o xi n 
A U C 0 – ∞ w as  m o d est ( 1. 4-f ol d  i n cr e as e)  a n d t h e  m e a n t½   of  di g o xi n  w as si mil ar  wit h  a n d 
wit h o ut  N BI- 9 8 8 5 4  a d mi nistr ati o n.   Mi d a z ol a m  C m a x  a n d  A U C 0 – ∞ w er e si mil ar  wit h  a n d 
wit h o ut  N BI- 9 8 8 5 4  a d mi nistr ati o n. 
N BI - 9 8 8 5 4 f or t h e tr e at m e nt  of  T S h as  b e e n  e v al u at e d  i n  3  c o m pl et e d  P h as e  1 b  a n d  P h as e  2 
st u di es i n s u bj e cts wit h  T S.   T h es e i n cl u d e  2 st u di es i n  p e di atri c s u bj e cts ( N BI - 9 8 8 5 4- 1 4 0 3  a n d 
N BI - 9 8 8 5 4- 1 5 0 1)  a n d  1 st u d y i n  a d ults (N BI - 9 8 8 5 4- 1 5 0 5).  T h e i niti al  P h as e  1 b,  o p e n -l a b el, 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 6 
m ulti pl e -d os e st u d y  of t h e s af et y, t ol er a bilit y,  p h ar m a c o ki n eti cs ,  a n d p h ar m a c o d y n a mi cs ( P D) 
of  N BI- 9 8 8 5 4 ( N BI- 9 8 8 5 4- 1 4 0 3)  w as  c o n d u ct e d i n  c hil dr e n ( 6 t o  1 1  y e ars  of  a g e)  a n d 
a d ol es c e nts ( 1 2 t o  1 8  y e ars  of  a g e)  wit h  T S .   D os es  of  N BI- 9 8 8 5 4  5  m g  a n d  1 0  m g  w er e 
a d mi nist er e d i n  c hil dr e n  a n d  d os es  of  N BI- 9 8 8 5 4  1 0  m g,  2 5  m g,  or  5 0  m g  w er e  a d mi nist er e d i n 
a d ol es c e nts  d ail y  o v er  a  1 4 -d a y tr e at m e nt  p eri o d f oll o wi n g  a  m ul ti pl e  as c e n di n g  d os e  pr ot o c ol.  
St u d y  N BI- 9 8 8 5 4- 1 5 0 1  w as  a  P h as e  2,  m ulti c e nt er, r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o-
c o ntr oll e d,  p ar all el  gr o u p,  d os e-r a n gi n g  st u d y t o  e v al u at e t h e  effi c a c y, s af et y,  a n d t ol er a bilit y  of 
2  d os es  of  N BI- 9 8 8 5 4 ( 1 0  m g  a n d  2 0  m g i n  c hil dr e n [ 6 t o  1 1  y e ars  of  a g e],  a n d  2 0  m g  a n d 
4 0  m g i n  a d ol es c e nts [ 1 2 t o  1 7  y e ars  of  a g e]) r el ati v e t o  pl a c e b o,  a d mi nist er e d  o n c e  d ail y f or 
6  w e e ks i n   9 8  p e di atri c s u bj e cts  wit h  T S.   S u bj e cts  wit hi n  e a c h  a g e  gr o u p  w er e  r a n d o mi z e d i n  a 
1: 1: 1 r ati o t o  pl a c e b o  or  1  of t h e  2  N BI- 9 8 8 5 4  d os es.   St u d y  N BI - 9 8 8 5 4- 1 5 0 5  w as  a  P h as e  2, 
m ulti c e nt er, r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d,  p ar all el  gr o u p st u d y t o  e v al u at e t h e 
effi c a c y,  s af et y,  a n d t ol er a bilit y  of  2  d o s es  of  N BI- 9 8 8 5 4 ( 4 0  m g  a n d  8 0  m g) r el ati v e t o 
pl a c e b o,  a d mi nist er e d  o n c e  d ail y f or  8  w e e ks i n  1 2 4  a d ult s u bj e cts  wit h  T S.   S u bj e cts  w er e  
r a n d o mi z e d i n  a  1: 1: 1 r ati o t o  pl a c e b o  or  1  of t h e  2  N BI- 9 8 8 5 4  d os es.   
R es ults fr o m  St u d y  N BI- 9 8 8 5 4- 1 4 0 3 r e v e al e d  r e d u cti o ns fr o m  b as eli n e ( D a y - 1) t o  D a y  1 4 i n 
t h e  Y al e  Gl o b al  Ti c  S e v erit y  S c al e (Y G T S S ) t ot al ti c s c or e ( T T S) i n  b ot h  c hil dr e n  a n d 
a d ol es c e nts,  a n d t his  d e cr e as e  w as  o bs er v e d irr es p e cti v e  of  d os e.   T h e  m e a n  p oi nt r e d u cti o n i n 
T T S f or  all s u bj e cts  a cr oss  all  d os es t est e d  w as  - 9. 4  p oi nts  at  D a y  1 4,  w hi c h r e pr es e nts  a  3 1 % 
d e cr e as e fr o m t h e  m e a n  b as eli n e s c or e.   M e a n r e d u cti o ns fr o m  b as eli n e  w er e  als o  o bs er v e d i n 
t h e  Y G T S S i m p air m e nt s c or e f or  b ot h  a g e  gr o u ps.   T h e  P h as e  2,  N BI- 9 8 8 5 4- 1 5 0 1 st u d y i n 
c hil dr e n  a n d  a d ol es c e nts  di d  n ot  m e et its  pri m ar y  effi c a c y  e n d p oi nt  of  a si g nifi c a nt  c h a n g e fr o m 
b as eli n e t o  W e e k  6 i n t h e  T T S  b et w e e n t h e  pl a c e b o  a n d  a cti v e  gr o u ps.   A  c o m pr e h e nsi v e 
e x p os ur e- r es p o ns e  a n al ysis i n di c at e d t h at t h e  d os es s el e ct e d f or t his st u d y  w er e t o o l o w t o 
pr o vi d e  a d e q u at e  pl as m a  e x p os ur es f or ti c r e d u cti o n i n  m ost  p e di atri c s u bj e cts.   F or t h e s u bs et 
of s u bj e cts  wit h  N BI - 9 8 8 5 4 e x p os ur es i n t h e r el e v a nt r a n g e, t h er e  w as  a r e d u cti o n i n ti cs  
(r a n g e:  - 1 1. 3 t o - 1 3. 7  p oi nts  o n t h e  T T S)  c o m p ar e d wit h  t h e s u bs et  of s u bj e cts  wit h s u b-
t h er a p e uti c  e x p os ur es (r a n g e:  - 4. 7 t o - 8. 3  p oi nts  o n t h e  T T S).   Alt h o u g h t h e effi c a c y r es ults i n 
p arti ci p ati n g  a d ults i n t h e  N BI - 9 8 8 5 4- 1 5 0 5 st u d y s h o w e d  a n i m pr o v e m e nt i n  o v er all s y m pt o ms 
of  T S  as  m e as ur e d   b y t h e s e c o n d ar y  e n d p oi nt,  Cli ni c al  Gl o b al I m pr essi o n  of  C h a n g e ( p = 0. 0 1 5 
[ n o mi n al]), t h e  pr e-s p e cifi e d  pri m ar y  e n d p oi nt, t h e  c h a n g e fr o m  b as eli n e i n t h e  Y G T S S  at 
W e e k  8  w as  n ot  m et ( p = 0. 1 8).   
N BI -9 8 8 5 4  h as  b e e n  g e n er all y  w ell t ol er at e d i n si n gl e  d os es  u p t o  3 0 0  m g  a n d i n  m ulti pl e  d os es 
of  u p t o  1 0 0  m g i n  h e alt h y  v ol u nt e ers  a n d  s u bj e cts  wit h  T D.   O v er  8 5 0 s u bj e cts  h a v e  b e e n 
e x p os e d t o  N BI- 9 8 8 5 4 i n  T D  cli ni c al st u di es.  I n  T S s u bj e cts , saf et y r es ults fr o m  St u d y 
N BI - 9 8 8 5 4- 1 4 0 3  s h o w t h at t h e  d os es  w er e  w ell t ol er at e d i n  b ot h  c hil d  a n d  a d ol es c e nt  a g e 
gr o u ps.   T h er e  w er e  n o  d e at hs  or s eri o us  a d v ers e  e v e nts ( S A E s) r e p ort e d  d uri n g t h e st u d y  a n d 
n o  c hil d  dis c o nti n u e d  d u e t o  a n  a d v ers e  e v e nt ( A E ).   T w o  a d ol es c e nts ( b ot h i n t h e  N BI- 9 8 8 5 4 
5 0  m g  gr o u p)  dis c o nti n u e d  d u e t o  A Es.   O n e s u bj e ct  dis c o nti n u e d  o n  D a y  2  d u e t o t h e  A Es  of 
a git ati o n,  h e a d a c h e,  vis u al i m p air m e nt,  v o miti n g,  a n d  w ors e ni n g  of  br a d y c ar di a  a n d t h e  ot h er 
s u bj e ct  dis c o nti n u e d  o n  D a y  4  d u e t o t h e  A Es  of i n cr e as e d  a n xi et y  a n d i ns o m ni a.   Pr eli mi n ar y 
s af et y r es ults fr o m t h e  P h as e  2,  N BI- 9 8 8 5 4- 1 5 0 1  p e di atri c s t u d y s u g g est t h at  all  d os es t est e d 
( N BI- 9 8 8 5 4  1 0  m g  a n d  2 0  m g i n  c hil dr e n  a n d  N BI- 9 8 8 5 4  2 0  m g  a n d  4 0  m g i n  a d ol es c e nts) 
w er e  w ell  t ol er at e d.   T h e  m ost fr e q u e ntl y r e p ort e d  A Es  w er e  h e a d a c h e, s o m n ol e n c e,  u p p er 
r es pir at or y tr a ct i nf e cti o n, i ns o m ni a,  a n d s e d ati o n.   T h er e  w er e  n o  d e at hs  a n d  o nl y  o n e  S A E i n 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 7 
t h e  pl a c e b o  gr o u p ( c o n v ersi o n  dis or d er).  Pr eli mi n ar y r es ults fr o m  St u d y   N BI- 9 8 8 5 4- 1 5 0 5 
s h o w e d t h at t h e  m ost fr e q u e ntl y r e p ort e d  A Es  w er e s o m n ol e n c e ( 2 0. 2 %  N BI- 9 8 8 5 4- tr e at e d 
s u bj e cts  a n d  2. 5 %  of  pl a c e b o s u bj e cts), f ati g u e ( 1 4. 3 %  N BI- 9 8 8 5 4  a n d  2. 5 %  pl a c e b o),  a n d 
a k at hisi a ( 1 3. 1 %  N BI- 9 8 8 5 4  a n d  0 %  pl a c e b o).   S e v e nt e e n s u bj e cts ( 1 3. 7 %)  dis c o nti n u e d fr o m 
t h e st u d y  d u e t o  A Es,  a n d  m ost  of t h es e s u bj e cts r e c ei v e d  N BI- 9 8 8 5 4  8 0  m g ( 1 3/ 1 7 s u bj e cts) 
a n d t h e  m ost  c o m m o n r e as o n f or  A E  dis c o nti n u ati o n  w as  a k at hisi a (r e p ort e d i n  5 s u bj e cts).  
F o ur  s u bj e cts  e x p eri e n c e d  S A Es  d uri n g t h e st u d y;  t h e  S A Es i n cl u d e d  p el vi c i nfl a m m at or y 
dis e as e ( pl a c e b o s u bj e ct;  m o d er at e  a n d  n ot r el at e d t o  N BI - 9 8 8 5 4),  p n e u m ot h or a x ( 80  m g 
s u bj e ct;  m o d er at e  a n d  u nli k el y r el at e d t o  N BI - 9 8 8 5 4),  h y p ers e nsiti vit y ( 8 0  m g  s u bj e ct; 
m o d er at e  a n d  p ossi bl y r el at e d t o  N BI - 9 8 8 5 4),  a n d  p n e u m o ni a str e pt o c o c c al, s e pti c s h o c k, r e n al 
f ail ur e  a c ut e,  a n d  br a c hi al  pl e x us i nj ur y (4 0  m g s u bj e ct; s e v er e  a n d  u nli k el y r el at e d t o 
N BI - 9 8 8 5 4).   
5. 3.   
St u d y  a n d  D os e  R ati o n al e  
All s u bj e cts i n t h e  c urr e nt st u d y  will  h a v e  pr e vi o usl y r e c ei v e d  N BI - 9 8 8 5 4  at  d os es r a n gi n g fr o m 
2 0  m g t o  8 0  m g  d uri n g  a  P h as e  2  p e di atri c  T S  st u d y ( N BI- 9 8 8 5 4- T S 2 0 0 4  or 
N BI - 9 8 8 5 4- T S 2 0 0 5).  I n t h e  c urr e nt r oll o v er st u d y, s u bj e cts  will s elf -a d mi nist er  a  o n c e -d ail y 
d os e  of  N BI- 9 8 8 5 4  2 0  m g t o  8 0  m g  at  h o m e  at  b e dti m e ( q hs) f or  u p t o  9 6  w e e ks (i e, 
a p pr o xi m at el y  2 4  m o nt hs). 
Cli ni c al  d at a fr o m  p e di atri c  T S s u bj e cts  a d mi nist er e d r e p e at e d  d os es  of  N BI - 9 8 8 5 4 fr o m  5  m g 
t o  5 0 m g  p er  d a y i n di c at e t h at  N BI -9 8 8 5 4 is  g e n er all y  w ell t ol er at e d  a n d  ass o ci at e d  wit h 
e x p os ur e- r el at e d  effi c a c y.   T h e  N BI- 9 8 8 5 4  2 0  m g t o  8 0  m g  d os es  h a v e  b e e n s el e ct e d t o  pr o vi d e 
e x p os ur e  ass o ci at e d  wit h  a n  a c c e pt a bl e  s af et y  a n d t ol er a bilit y  pr ofil e.   T his  d os e r a n g e is 
pr e di ct e d t o  pr o vi d e  p ot e nti all y  cli ni c all y  eff e cti v e  e x p os ur es t o  N BI - 9 8 8 5 4 i n s u bj e cts  wit h  T S 
b as e d  o n  c urr e ntl y  a v ail a bl e  d at a . 
6.   
S T U D Y  O B J E C TI V E S  
T h e  o bj e cti v es  of t his  cli ni c al st u d y  ar e  as f oll o ws:  
•   T o  c oll e ct l o n g -t er m s af et y  a n d t ol er a bilit y  d at a i n  p e di atri c s u bj e cts r e c ei vi n g  N BI- 9 8 8 5 4 
a d mi nist er e d  o n c e  d ail y f or  u p t o  9 6  w e e ks (i e,  a p pr o xi m at el y  2 4  m o nt hs). 
•   T o  pr o vi d e  c o nti n u e d  a c c ess t o  N BI- 9 8 8 5 4 f or t h e tr e at m e nt  of  T S i n  u p t o  a p pr o xi m at el y 
2 4 0  p e di atri c  T S s u bj e cts  w h o  h a v e  c o m pl et e d  t h e  P h as e  2 st u d y  N BI- 9 8 8 5 4- T S 2 0 0 4  or 
w er e  d os e d f or  at l e ast  1 6  w e e ks ( ± 3  d a ys) i n t h e  P h as e  2 st u d y  N BI- 9 8 8 5 4- T S 2 0 0 5. 
7.   
O V E R VI E W  O F  S T U D Y  D E SI G N  
T his st u d y is  d esi g n e d t o  c oll e ct l o n g -t er m s af et y  a n d t ol er a bilit y  d at a  as  w ell  as i n v esti g at or- 
a n d s u bj e ct-r e p ort e d  p h ar m a c o d y n a mi c ( P D)  d at a f oll o wi n g  c hr o ni c  a d mi nistr ati o n  of 
N BI - 9 8 8 5 4 i n  p e di atri c s u bj e cts  wit h  T S.  I n  a d diti o n, t his r oll o v er st u d y  will  pr o vi d e  p e di atri c 
s u bj e cts  w h o  h a v e  p arti ci p at e d i n  a  pri or   P h as e  2  N BI- 9 8 8 5 4 st u d y  o p e n-l a b el  a c c ess t o 
N BI - 9 8 8 5 4 f or t h e tr e at m e nt  of  T S  u ntil t h e y  c o m pl et e  9 6  w e e ks (i e,  a p pr o xi m at el y  2 4  m o nt hs) 
of tr e at m e nt.   T his st u d y  will  all o w  e nr oll m e nt  of  u p t o  a p pr o xi m at el y  2 4 0  m al e  a n d f e m al e 
p e di atri c s u bj e cts ( 6 t o  1 8  y e ars  of  a g e, i n cl usi v e)  wit h  T S  w h o  h a v e  w h o  h a v e  c o m pl et e d t h e 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 8 
P h as e  2 st u d y  N BI- 9 8 8 5 4- T S 2 0 0 4  or  w er e  d os e d f or  at l e ast  1 6  w e e ks ( ± 3  d a ys) i n t h e  P h as e  2 
st u d y  N BI- 9 8 8 5 4- T S 2 0 0 5  a n d  dis c o nti n u e d  d u e t o  a l a c k  of  effi c a c y  or  a  T E A E  of  w ors e ni n g  of 
ti cs (s u bj e cts  w h o  c o m pl et e d t h e  N BI- 9 8 8 5 4-T S 2 0 0 5 st u d y  ar e  als o  eli gi bl e).   S u bj e cts  w h o 
dis c o nti n u e d  pri or t o t h e  e n d  of t h e  N BI- 9 8 8 5 4- T S 2 0 0 5 st u d y (i e,  W e e k  4 0)  m ust  h a v e 
c o m pl et e d  a n  e arl y t er mi n ati o n  visit t o  b e  eli gi bl e f or t h e  c urr e nt st u d y (t h e  e arl y t er mi n ati o n 
visit  m a y  h a v e  o c c urr e d  at  t h e ti m e  of t h e  W e e k  1 6  visit). 
P ar e nt al  or l e g al  g u ar di a n i nf or m e d  c o ns e nt  wit h si g n e d  a n d  wit n ess e d  p e di atri c  ass e nt f or 
s u bj e cts  ≤ 1 7  y e ars  of  a g e,  or  writt e n i nf or m e d  c o ns e nt f or s u bj e cts  1 8  y e ars  of  a g e,  m ust  b e 
o bt ai n e d  pri or t o  c o n d u ct  of  a n y  st u d y-r el at e d  pr o c e d ur es. 
S u bj e cts  w h o  h a v e t h eir fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  visit  > 3 0  d a ys  pri or t o 
a nti ci p at e d  b as eli n e ( D a y  1) r e q uir e s cr e e ni n g.   T h es e s u bj e cts  will  b e s cr e e n e d t o  d et er mi n e 
eli gi bilit y  wit hi n  2 8  d a ys ( D a ys  - 2 8 t o -1)  b ef or e  b as eli n e ( D a y  1).   At  b as eli n e ( D a y  1),  eli gi bl e 
s u bj e cts  will r et ur n t o t h e st u d y sit e f or  c oll e cti o n  of  b as eli n e s af et y  a n d  P D  ass ess m e nts.  
S u bj e cts  c a n  h a v e t h eir fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4-T S 2 0 0 5  visit  o n t h e s a m e  d a y 
as  D a y  1 f or t his r oll o v er st u d y  pr o vi d e d t h e y si g n t h e  c urr e nt st u d y’s i nf or m e d  c o ns e nt/ ass e nt 
b ef or e t h e fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  visit.   T his  will  all o w  c ert ai n 
ass ess m e nts t o  b e  us e d f or  b ot h st u di es.   T h e  ass ess m e nt r es ults t h at  c a n  a p pl y t o  b ot h st u di es 
i n cl u d e  p h ysi c al  e x a mi n ati o ns (i n cl u di n g  w ei g ht),  vit al si g ns,  el e ctr o c ar di o gr a ms ( E C G), t h e 
Cli ni c al  Gl o b al I m pr essi o n  of  Ti cs -S e v erit y s c al e ( C GI -Ti cs -S e v erit y), t h e  E xtr a p yr a mi d al 
S y m pt o m  R ati n g  S c al e - A b br e vi at e d ( E S R S-A),  a n d t h e  Gill es  d e  l a  T o ur ett e  S y n dr o m e-Q u alit y 
of  Lif e  S c al e f or  C hil dr e n  a n d  A d ol es c e nts ( C & A  G T S- Q O L) s c al e . 
T h e st arti n g  d os e  will  b e  N BI - 9 8 8 5 4  2 0  m g f or s u bj e cts  < 5 0  k g  at  b as eli n e  a n d  N BI- 9 8 8 5 4 
4 0  m g f or s u bj e cts  ≥ 5 0  k g  at  b as eli n e.   T h e  d os e  m a y  b e  es c al at e d i n  i n cr e m e nts  of  2 0  m g  e v er y 
2  w e e ks t o  a  m a xi m u m  of  6 0  m g f or s u bj e cts  < 5 0  k g  a n d  8 0  m g f or s u bj e cts  ≥ 5 0  k g t o  a c hi e v e 
a n  o pti m al  d os e  of  N BI- 9 8 8 5 4 f or  e a c h s u bj e ct.   D os e  es c al ati o ns  will  o c c ur  at t h e  e n d  of 
W e e ks  2  a n d  4  b as e d  o n t h e f oll o wi n g  2  crit eri a:   1) t h e s u bj e ct’s ti cs  ar e  n ot s uffi ci e ntl y 
c o ntr oll e d  p er  p h ysi ci a n i n v esti g at or  ass ess m e nt;  a n d  2)  a n  e v al u ati o n  b y t h e  p h ysi ci a n 
i n v esti g at or i n di c at es t h at t h e s u bj e ct is t ol er ati n g t h e st u d y  dr u g  at t h e  c urr e nt  d os e  a n d  w o ul d 
li k el y  b e  a bl e t o t ol er at e t h e  n e xt  d os e l e v el.   D uri n g t h e first  4  w e e ks  of t h e tr e at m e nt  p eri o d, 
t h e  p h ysi ci a n i n v esti g at or  m a y  es c al at e  a s u bj e ct’s  d os e t o t h e  n e xt  d os e l e v el,  c o nti n u e  wit h t h e 
s u bj e ct’s  c urr e nt  d os e,  or r e d u c e t o t h e s u bj e ct’s  pri or t ol er at e d  d os e (i n s u bj e cts  w h o  h a v e  h a d 
a  d os e  es c al ati o n).  If  a s u bj e ct’s  o pti m al  d os e  h as  alr e a d y  b e e n  est a blis h e d  at  W e e k  2,  n o 
f urt h er  d os e  es c al ati o n  will  b e  all o w e d  d uri n g t h e  d os e  o pti mi z ati o n  p eri o d  a n d t h e s u bj e ct  will 
c o nti n u e  at t h at  d os e  u ntil  W e e k  9 6 ( or  e arl y t er mi n ati o n) .   Aft er  W e e k  4, s u bj e cts  will  c o nti n u e 
t o r e c ei v e t h eir  o pti mi z e d  d os e  of  N BI- 9 8 8 5 4 u ntil  W e e k  9 6 ( or  e arl y t er mi n ati o n).   At  a n y ti m e 
aft er  W e e k  2, t h e  p h ysi ci a n i n v esti g at or  m a y  d e cr e as e t h e  d os e t o t h e  pr e vi o us  d os e f or  a n y 
s u bj e ct  w h o  h a d  a  d os e es c al ati o n  a n d  w h o is  u n a bl e t o t ol er at e  a  gi v e n  d os e i n cr e as e.   T h e 
s u bj e ct  will  c o nti n u e  at t h at  d os e  u ntil t h e  e n d  of t h e tr e at m e nt  p eri o d.   T h e i n v esti g at or  m a y 
r e d u c e t h e s u bj e ct’s  d os e  o nl y  o n e ti m 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 st arti n g  d os e  or 
r es u m pti o n  of t h e  pr e vi o us  d os e  will  b e  dis c o nti n u e d fr o m t h e st u d y. 
E li gi bl e s u bj e cts  will r e c ei v e  a s u p pl y  of  N BI- 9 8 8 5 4  o n  D a y  1  a n d  b e gi n  d osi n g  at  b e dti m e  of 
D a y  1.   S u bj e cts  will r et ur n t o t h e st u d y  c e nt er  e v er y  2 t o  1 2  w e e ks f or  ass ess m e nts  a n d 
dis p e ns ati o n  of  N BI- 9 8 8 5 4.   T h e fi n al  ass ess m e nts  will  b e  p erf or m e d  at t h e  e n d  of  W e e k  9 6,  or 
u p o n  e arl y t er mi n ati o n.   T h e st u d y  c e nt er  visits  aft er  D a y  1  will  h a v e  wi n d o ws  of  ±  3  d a ys f or 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  1 9 
visits  at  W e e ks  2  a n d  4,  ±  5  d a ys f or  visits  at  W e e ks  8 t hr o u g h  2 4,  a n d  ±  1 4  d a ys f or  visits  at 
W e e ks  3 6 t hr o u g h  9 6.   A n i n d e p e n d e nt  D at a  S af et y  M o nit ori n g  B o ar d ( D S M B)  will 
p eri o di c all y r e vi e w  o n g oi n g  cli ni c al s af et y  d at a t o  e ns ur e t h e s af et y  a n d  w ell - b ei n g  of t h e st u d y 
s u bj e cts. 
P D  a n d s af et y  ass ess m e nts  will  b e  c ol l e ct e d  at s c h e d ul e d ti m es t hr o u g h o ut t h e st u d y. 
A  s c h e m ati c  of t h e st u d y  d esi g n is   s h o w n i n Fi g ur e  1 . 
Fi g u r e   1:  
St u d y  D esi g n  S c h e m ati c  
 
D O = d os e  o pti mi z ati o n  
a S u bj e cts  w h o  e nt er t h e st u d y  wit hi n  3 0  d a ys  of  h a vi n g t h eir fi n al  N BI -9 8 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  st u d y  visit  ar e  n ot 
r e q uir e d t o  u n d er g o s cr e e ni n g  a n d t h e first  d a y  of t h e st u d y is  D a y  1 ( b as eli n e) f or t h es e s u bj e cts.  
b S u bj e cts  < 5 0  k g  will r e c ei v e  a n  N BI -9 8 8 5 4 st arti n g  d os e  of  2 0  m g,  w hi c h  m a y  b e i n cr e as e d t o  4 0  m g  at  W e e k  2  a n d  6 0  m g  at 
W e e k  4.   S u bj e cts  ≥ 5 0  k g  will r e c ei v e  a n  N BI -9 8 8 5 4 st arti n g  d os e  of  4 0  m g,  w hi c h  m a y  b e i n cr e as e d t o  6 0  m g  at  W e e k  2  a n d 
8 0  m g  at  W e e k  4.  If  a s u bj e ct’s  o pti m al  d os e  h as  alr e a d y  b e e n  est a blis h e d  at  W e e k  2,  n o f urt h er  d os e  es c al ati o n  will  b e 
all o w e d  d uri n g t h e  d os e  o pti mi z ati o n  p eri o d  a n d t h e s u bj e ct  will  c o nti n u e  at t h at  d os e  u ntil t h e  e n d  of t h e tr e at m e nt  p eri o d.   
Aft e r  W e e k  4, s u bj e cts  will  c o nti n u e t o r e c ei v e t h eir  o pti mi z e d  d os e  of  N BI-9 8 8 5 4  u ntil  W e e k  9 6 ( or  e arl y t er mi n ati o n).   At 
a n y ti m e  aft er  W e e k  2, t h e  p h ysi ci a n i n v esti g at or  m a y  d e cr e as e t h e  d os e t o t h e  pr e vi o us  d os e f or  a n y s u bj e ct  w h o  h a d  a  d os e 
es c al ati o n  a n d  w h o is  u n a bl e t o t ol er at e  a  gi v e n  d os e i n cr e as e.   T h e s u bj e ct  will  c o nti n u e  at t h at  d os e  u ntil t h e  e n d  of t h e 
tr e at m e nt  p eri o d. 
8.   
S T U D Y  P O P U L A TI O N  
T his st u d y  will i n cl u d e  u p t o  a p pr o xi m at el y  2 4 0  m al e  a n d f e m al e  p e di atri c s u bj e cts  wit h  a 
cli ni c al  di a g n osis  of  T S.   T his st u d y  will  o nl y  e nr oll s u bj e cts  w h o  e x pr ess  a n i nt er est i n 
c o nti n ui n g t o r e c ei v e  or r e- i niti at e  N BI- 9 8 8 5 4  a n d  h a d  pr e vi o usl y c o m pl et e d t h e  P h as e  2 st u d y 
N BI - 9 8 8 5 4- T S 2 0 0 4  or  w er e  d os e d f or  at l e ast  1 6  w e e ks ( ± 3  d a ys) i n t h e  P h as e  2 st u d y 
N BI - 9 8 8 5 4- T S 2 0 0 5. 
8. 1.   
I n cl usi o n  C rit e ri a  
T o  p arti ci p at e i n t his  st u d y,  s u bj e cts  m ust  m e et t h e f oll o wi n g  crit eri a: 
1.   H a v e  d o c u m e nt ati o n  of  writt e n  a n d  wit n ess e d  ass e nt fr o m t h e s u bj e ct  a n d  writt e n i nf or m e d 
c o ns e nt fr o m t h e s u bj e ct’s  p ar e nt  or l e g al  g u ar di a n f or s u bj e cts  ≤ 1 7  y e ars  of  a g e,  or  writt e n 
i nf or m e d  c o ns e nt fr o m s u bj e cts  1 8  y e ars  of  a g e. 
2.   B e  m al e  or f e m al e,  a g e d  6 t o  1 8  y e ars, i n cl usi v e,  o n  D a y  1 ( b as eli n e).  
3.   H a v e  c o m pl et e d t h e   P h as e  2 st u d y  N BI- 9 8 8 5 4- T S 2 0 0 4  or  w er e  d os e d f or  at l e ast  1 6 w e e ks 
( ± 3  d a ys) i n t h e  P h as e  2 st u d y  N BI- 9 8 8 5 4- T S 2 0 0 5  a n d  dis c o nti n u e d  d u e t o  a l a c k  of 
effi c a c y  or  a  T E A E  of  w or s e ni n g  of ti cs (s u bj e cts  w h o  c o m pl et e d t h e  N BI - 9 8 8 5 4- T S 2 0 0 5 
st u d y  ar e  als o  eli gi bl e).   S u bj e cts  c a n  h a v e t h eir fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or 
N BI - 9 8 8 5 4- T S 2 0 0 5  visit  o n t h e s a m e  d a y  as  D a y  1 f or t his r oll o v er st u d y  pr o vi d e d t h e 
N BI -9 8 8 5 4  Tr e at m e nt  P eri o d
We e k                             2    4     8    1 2   1 6   2 0   2 4          3 6            4 8            6 0                7 2           8 4           9 6/ E T  
D a y  -2 8                   -1  1
D O b
C o nti n u e  N BI -9 8 8 5 4  at  o pti mi z e d  d os e
S cr e e ni n g a


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 0 
c urr e nt st u d y’s i nf or m e d  c o ns e nt/ ass e nt  is si g n e d b ef or e t h e fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or 
N BI - 9 8 8 5 4-T S 2 0 0 5  visit.  
4.   S u bj e cts  m ust  h a v e  a st a bl e  ps y c hi atri c st at us (s u c h  as  T S s p e ctr u m  di a g n os es [ e g, 
o bs essi v e -c o m p ulsi v e  dis or d er,  A D H D])  as  cli ni c all y  d et er mi n e d  b y t h e i n v esti g at or.  
5.   If  m e di c ati o ns  ar e  b ei n g  us e d t o tr e at  T S s y m pt o ms  a n d/ or  T S s p e ctr u m  di a g n os es, s u bj e cts 
m ust  b e  o n st a bl e  d os es  of t h es e  m e di c ati o ns f or  a  mi ni m u m  of  3 0  d a ys  b ef or e  D a y  1 
( b as eli n e),  a n d t h e  m e di c ati o n r e gi m e n is  e x p e ct e d t o r e m ai n st a bl e t hr o u g h o ut t h e st u d y 
p eri o d.   T h e  us e  of  c o n c o mit a nt  d o p a mi n e  a nt a g o nists ( e g,  pi m o zi d e,  h al o p eri d ol, 
ari pi pr a z ol e)  a n d/ or t etr a b e n a zi n e / d e ut etr a b e n a zi n e t o tr e at  T S s y m pt o ms is  pr o hi bit e d.  
Ot h er  n o n d o p a mi n er gi c ti c s u p pr essi o n t h er a p y ( e g,  cl o ni di n e,  g u a nf a ci n e) is  all o w e d 
d uri n g t h e st u d y  p eri o d if t h e  d os e r e gi m e n  h as  b e e n st a bl e f or  a  mi ni m u m  of  3 0  d a ys  b ef or e 
D a y  1 ( b as eli n e). 
6.   S u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  c o ntr a c e pti o n  c o nsist e ntl y fr o m  D a y   1 
( b as eli n e)  u ntil  3 0  d a ys (f e m al es)  or  9 0  d a ys ( m al es)  aft er t h e l ast  d os e  of st u d y  dr u g.   A 
f e m al e s u bj e ct  of  c hil d b e ari n g  p ot e nti al is  d efi n e d  as  a f e m al e  c a p a bl e  of  b e c o mi n g 
pr e g n a nt,  w hi c h i n cl u d es s u bj e cts  w h o  h a v e  h a d t h eir first  m e nstr u al  c y cl e (i e,  m e n ar c h e) 
a n d  ar e  n ot s ur gi c all y st eril e (i e,  bil at er al  o o p h or e ct o m y,  h yst er e ct o m y  or  bil at er al t u b al 
li g ati o n f or  at l e ast  3  m o nt hs  pri or t o  D a y  1 [ b as eli n e]).   A  mal e s u bj e ct  of  c hil d b e ari n g 
p ot e nti al is  d efi n e d  as  a s u bj e ct  w h o  h as r e a c h e d s p er m ar c h e  a n d  h as  n ot  b e e n  v as e ct o mi z e d 
f or  at l e ast  3  m o nt hs  pri or t o D a y  1 ( b as eli n e) . 
A c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n i n cl u d e t h e f oll o wi n g:  
•   C o n d o m  wit h s p er mi ci d e ( cr e a m, s pr a y, f o a m,  g el, s u p p osit or y,  or  p ol y m er fil m). 
•   Di a p hr a g m  wit h s p er mi ci d e ( wit h  or  wit h o ut  c o n d o m). 
•   C er vi c al  c a p  wit h s p er mi ci d e ( wit h  or  wit h o ut  c o n d o m).  
•   V a gi n al s p o n g e i m pr e g n at e d  wit h s p er mi ci d e  us e d  wit h  a  c o n d o m.  
•   I ntr a ut eri n e  d e vi c e (I U D). 
•   H or m o n al  c o ntr a c e pti o n t a k e n f or  at l e ast  3  m o nt hs  pri or t o  D a y  1 ( b as eli n e) . 
S u bj e cts  w h o  pr a cti c e t ot al  a bsti n e n c e fr o m s e x u al i nt er c o urs e  as t h e  pr ef err e d lif est yl e  ar e 
n ot r e q uir e d t o  us e  c o ntr a c e pti o n ( p eri o di c  a bsti n e n c e is  n ot  a c c e pt a bl e).   
7.   F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  h a v e  a  n e g ati v e s er u m  β - h u m a n  c h ori o ni c 
g o n a d otr o pi n ( β- h C G)  pr e g n a n c y t est  at s cr e e ni n g (if  a p pli c a bl e)  a n d  n e g ati v e  uri n e 
pr e g n a n c y t est  o n  D a y  1 ( b as eli n e). 
8.   H a v e  a  b o d y  w ei g ht (i n  k g)  gr e at er t h a n  or  e q u al t o t h e  5t h  p er c e ntil e  of  his/ h er  a g e -  a n d 
g e n d er- m at c h e d  w ei g ht  p er c e ntil e  o n  D a y  1 ( b as eli n e) . 
9.   B e i n  g o o d  g e n er al  h e alt h  a n d  e x p e ct e d t o  c o m pl et e t h e  st u d y  as  d esi g n e d. 
1 0.  B e  willi n g  a n d  a bl e t o  a d h er e t o t h e st u d y r e gi m e n  a n d st u d y  pr o c e d ur es  d es cri b e d i n t h e 
pr ot o c ol  a n d i nf or m e d  c o ns e nt/ ass e nt f or ms, i n cl u di n g  all r e q uir e m e nts  at t h e st u d y  c e nt er 
a n d r et ur n f or t h e  fi n al st u d y visit.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 1 
8. 2.   
E x cl usi o n  C rit e ri a  
S u bj e cts  will  b e  e x cl u d e d fr o m t h e st u d y  if t h e y: 
1.   H a v e  a n  u nst a bl e  m e di c al  c o n diti o n  or  c hr o ni c  dis e as e (i n cl u di n g si g nifi c a nt  n e ur ol o gi c al, 
h e p ati c, r e n al,  c ar di o v as c ul ar,  g astr oi nt esti n al,  p ul m o n ar y,  or  e n d o cri n e  dis e as e),  or 
m ali g n a n c y t h at  c o ul d  c o nf o u n d i nt er pr et ati o n  o f st u d y  o ut c o m e. 
2.   H a d  a  m e di c all y  si g nifi c a nt ill n ess  wit hi n  3 0  d a ys  of  D a y  1 ( b as eli n e) . 
3.   H a v e  a  hist or y  of s u b st a n c e ( dr u g  or  al c o h ol)  d e p e n d e n c e  or  a b us e  wit hi n t h e  3  m o nt hs 
b ef or e  D a y  1 ( b as eli n e),  as  d efi n e d i n t h e  Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al 
Dis or d ers ( D S M) -I V ( S u bst a n c e  D e p e n d e n c e  or  A b us e)  or  D S M- 5  ( S u bst a n c e  Us e 
Dis or d er). 
4.   H a v e  a si g nifi c a nt ris k  of s ui ci d al  or  vi ol e nt  b e h a vi or.   S u bj e cts  wit h  a n y lif eti m e s ui ci d al 
b e h a vi or,  or s ui ci d al i d e ati o n  of t y p e  4 ( a cti v e s ui ci d al i d e ati o n  wit h s o m e i nt e nt t o  a ct, 
wit h o ut s p e cifi c  pl a n)  or t y p e  5 ( a cti v e s ui ci d al i d e ati o n  wit h s p e cifi c  pl a n  a n d i nt e nt) i n t h e 
p ast  y e ar  b as e d  o n t h e  “ B as eli n e/ S cr e e ni n g  v ersi o n ”  of 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) ( ass ess e d  at  b as eli n e [ D a y  1])  will  b e  e x cl u d e d . 
5.   H a v e  a  k n o w n  hist or y  of  n e ur ol e pti c  m ali g n a nt s y n dr o m e. 
6.   H a v e  a  k n o w n  hist or y  of l o n g  Q T s y n dr o m e  or  c ar di a c  arr h yt h mi a. 
7.   H a v e  a  s cr e e ni n g (if  a p pli c a bl e)  or  D a y  1 ( b as eli n e)  a v er a g e tri pli c at e  el e ctr o c ar di o gr a m 
( E C G) c orr e ct e d  Q T i nt er v al  usi n g  Fri d eri ci a's f or m ul a ( Q T c F)  of  > 4 5 0  ms e c  or t h e 
pr es e n c e  of  a n y  cli ni c all y si g nifi c a nt  c ar di a c  a b n or m alit y.  
8.   R e c ei v e  a n y  e x cl u d e d  c o n c o mit a nt  m e di c ati o n  as  d et ail e d i n  S e cti o n  9. 6. 1 . 
9.   E x c essi v e  us e  of t o b a c c o  a n d/ or  ni c oti n e- c o nt ai ni n g  pr o d u cts ( b as e d  o n t h e i n v esti g at or's 
ass ess m e nt)  wit hi n  3 0  d a ys  of  D a y  1 ( b as eli n e). 
1 0.  H a v e  a  h e m at ol o gi c  m ali g n a n c y  or s oli d t u m or  di a g n os e d  wit hi n  3  y e ars  pri or t o  D a y   1 
( b as eli n e),  e x c e pt f or l o c ali z e d s ki n  c a n c er  or  c ar ci n o m a i n sit u  of t h e  c er vi x. 
1 1.  H a v e  r e c ei v e d  a n i n v esti g ati o n al  dr u g ( ot h er t h a n  N BI- 9 8 8 5 4)  wit hi n  3 0  d a ys  b ef or e  D a y  1 
( b as eli n e)  or  5  h alf-li v es  of t h e i n v esti g ati o n al  dr u g (if  k n o w n),  w hi c h e v er is l o n g er,  or  pl a n 
t o  us e  a n i n v esti g ati o n al  dr u g ( ot h er t h a n  N BI- 9 8 8 5 4)  d uri n g t h e st u d y. 
1 2.  H a v e  a  bl o o d l oss  ≥ 2 5 0  m L  or  d o n at e d  bl o o d  wit hi n  5 6  d a ys  or  d o n at e d  pl as m a  wit hi n 
7  d a ys  of  D a y  1 ( b as eli n e). 
1 3.  H a v e  a n  all er g y,  h y p ers e nsiti vit y,  or i nt ol er a n c e t o  V M A T 2 i n hi bit ors ( e g, t etr a b e n a zi n e , 
d e ut etr a b e n a zi n e ). 
1 4.  Ar e  c urr e ntl y  p arti ci p ati n g i n  a n ot h er  N BI - 9 8 8 5 4  T S st u d y. 
1 5.  H a v e  a  hist or y  of  or s u s p e ct e d  p o or  c o m pli a n c e i n  cli ni c al r es e ar c h st u di es.  
1 6.  H a v e  hist or y  of  s e v er e  h e p ati c i m p air m e nt  or  h a v e  c hr o ni c  el e v ati o n  of  as p art at e 
a mi n otr a nsf er as e ( A S T)  or  al a ni n e  a mi n otr a nsf er as e ( A L T)  > 1 . 5 ti m es  u p p er li mit  of  n or m al 
( U L N). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 2 
1 7.  F o r s u bj e cts  w h o  r e q ui r e  a s c r e e ni n g  visit :  H a v e s er u m  cr e ati ni n e l e v els  gr e at er t h a n t h e 
U L N  at s cr e e ni n g,  or  as p art at e  a mi n otr a nsf er as e ( A S T),  al a ni n e  a mi n otr a nsf er as e ( A L T), 
g a m m a -gl ut a m yl tr a nsf er as e ( G G T),  or t ot al  bilir u bi n  > 1. 5 ti m es t h e  U L N  at s cr e e ni n g.  
S u bj e cts  wit h  a  d o c u m e nt e d  di a g n osis  of  Gil b ert's s y n dr o m e  ar e  n ot r e q uir e d t o  m e et t h e 
bilir u bi n  crit eri a.  
8. 3.   
S u bj e ct  I d e ntifi c ati o n  a n d  R e pl a c e m e nt  
S u bj e cts  will  b e i d e ntifi e d  b y t h eir  u ni q u e s u bj e ct  n u m b er  a n d i niti als (firs t,  mi d dl e, l ast;  a 
h y p h e n  m a y  b e  us e d if t h e s u bj e ct  h as  n o  mi d dl e  n a m e).   T h e s u bj e ct i niti als  a n d s u bj e ct 
n u m b er  will  b e  n ot e d  o n  el e ctr o ni c  c as e r e p ort f or ms ( e C R Fs),  all s o ur c e  d o c u m e nt ati o n, 
l a b or at or y  d o c u m e nts,  a n d  E C G tr a ci n gs.   S u bj e cts  w h o  dis c o nti n u e fr o m t h e st u d y  will  n ot  b e 
r e pl a c e d. 
8. 4.   
R a n d o mi z ati o n 
T his is  a n  o p e n -l a b el st u d y. 
9.   
S T U D Y  E V A L U A TI O N S  
9. 1.   
S c h e d ul e  of  Ass ess m e nts  
A  s c h e d ul e  of  ass ess m e nts t h at s u m m ari z es t h e fr e q u e n c y  a n d ti mi n g  of  all  ass ess m e nts is 
pr o vi d e d i n  T a bl e   1.   N o  pr ot o c ol-r el at e d  pr o c e d ur es s h o ul d  b e  p erf or m e d  b ef or e  p ar e nt al  or 
l e g al  g u ar di a n i nf or m e d  c o ns e nt  wit h si g n e d  a n d  wit n ess e d  p e di atri c  asse nt  ar e  pr o vi d e d f or 
s u bj e cts  ≤ 1 7  y e ars  of  a g e,  or  writt e n i nf or m e d  c o ns e nt is  pr o vi d e d f or s u bj e cts  1 8  y e ars  of  a g e.  
S u bj e ct -r el at e d  e v e nts  a n d  a cti viti es i n cl u di n g s p e cifi c i nstr u cti o ns,  pr o c e d ur es,  c o n c o mit a nt 
m e di c ati o ns,  dis p e nsi n g  of st u d y  dr u g,  a n d  d es cri pti o ns  of  A Es s h o ul d  b e r e c or d e d i n t h e 
a p pr o pri at e s o ur c e  d o c u m e nts  a n d  e C R Fs. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 3 
T a bl e  1:  
S c h e d ul e  of  Ass ess m e nt s  
P r o c e d u r e  
S c r e e ni n g a 
B as eli n e
b  
O p e n -L a b el  N B I -9 8 8 5 4  T r e at m e nt  P e ri o d  
W e e k  
D a y  -2 8  
t o -1  
D a y  1   
2   
4   
8   
1 2   
1 6   
2 0   
2 4   
3 6   
4 8   
6 0   
7 2   
8 4  
9 6/ E T
c 
Visit d   
1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
1 2   
1 3   
1 4  
I nf or m e d  c o ns e nt/ ass e nte 
X  
X f  
  
  
  
  
  
  
  
  
  
  
  
  
 
I n cl usi o n/ e x cl u si o n  crit eri a 
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
M e di c al  hist or y  
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
P h ysi c al  e x a mi n ati o n (i n cl u di n g 
w ei g ht)  
X   
X   
  
  
  
X   
  
  
X   
  
  
X   
  
  
X  
H ei g ht  
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
Vit al si g ns  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
1 2 -le a d  el e ctr o c ar di o gr a m g 
X   
X   
X   
X   
  
X   
  
  
X   
  
  
X   
  
  
X  
Pr e g n a n c y t est h 
X (s)   
X (s, u)  
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X ( u)  
Cli ni c al l a b or at or y t est s  
X   
X   
  
  
  
X   
  
  
X   
  
  
X   
  
  
X  
C -S S R S i 
  
X i  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
E S R S -A  
  
X   
  
  
X   
  
X   
  
X   
  
X   
  
X   
  
X  
C GI -Ti c s -S e v erit y  
  
X   
  
  
X   
  
X   
  
X   
X   
X   
  
X   
  
X  
C GI -T S -I m pr o v e m e nt 
 
  
  
  
X   
  
X   
  
X   
X   
X   
  
X   
  
X  
C & A -G T S -Q O L  
  
X   
  
  
  
X   
  
  
X   
  
X   
  
X   
  
X  
St u d y  dr u g  d o si n g  at  h o m e j 
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Dis p e ns e st u d y  dr u g  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
St u d y  dr u g  a c c o u nt a bilit y k  
 
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
A d v ers e  e v e nt  m o nit ori n g  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Pri or  a n d  c o n c o mit a nt 
m e di c ati o ns  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
O ut p ati e nt st u d y  c e nt er  visit  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
D efi niti o ns:   C & A -G T S -Q O L = Gill es  d e l a  T o ur ett e  S y n dr o m e -Q u alit y  of  Lif e f or  C hil dr e n  a n d  A d ol es c e nts;  C GI -Ti cs -S e v erit y = Cli ni c al  Gl o b al  I m pr essi o n  of  Ti cs-S e v erit y 
s c al e;  C GI-T S -I m pr o v e m e nt =  Cli ni c al  Gl o b al I m pr essi o n  of  T o ur ett e  S y n dr o m e-I m pr o v e m e nt s c al e;  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 S R S -A = E xtr a p yr a mi d al 
S y m pt o m  R ati n g  S c al e -A b br e vi at e d;  E T = e arl y t er mi n ati o n;  Q T c F = c orr e ct e d  Q T i nt er v al  usi n g  Fri d eri ci a’s f or m ul a; s =s er u m;  u  = uri n e.  
F o ot n ot es  a p p e ar  o n t h e f oll o wi n g  p a g e . 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 4 
a S cr e e ni n g is  n ot r e q uir e d f or s u bj e cts  w h o  h a d t h eir l ast  N BI -9 8 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  st u d y  visit wit hi n  3 0  d a ys  pri or t o  b as eli n e ( D a y  1).  
b D a y  1 is t h e  d a y  of  b as eli n e  ass ess m e nts.   D a y  1 is  als o t h e first  d a y  of  d osi n g; st u d y  dr u g  will  b e  a d mi nist er e d  at  h o m e  at  b e dti m e ( u n d er t h e s u p er visi o n  of  p ar e nt/l e g al  g u ar di a n 
f or s u bj e cts  ≤ 1 7  y e ars  of  a g e).   F or s u bj e cts w h o  h a v e t h eir  fi n al  N BI-9 8 8 5 4 -T S 2 0 0 4  or  N BI -9 8 8 5 4 -T S 2 0 0 5  visit  o n t h e s a m e  d a y  as  D a y  1, t h e  N BI -9 8 8 5 4 -T S 2 0 0 4  or 
N BI -9 8 8 5 4 -T S 2 0 0 5  ass ess m e nts f or  p h ysi c al  e x a mi n ati o n (i n cl u di n g  w ei g ht),  vit al si g ns,  E C G ,  E S R S-A,  C GI -Ti cs -S e v erit y,  a n d  C & A -G T S -Q O L s c al e  will  b e  us e d f or  D a y  1.  
c Fi n al st u d y  visit f or s u bj e cts  w h o  c o m pl et e t h e st u d y ( or  e arl y t er mi n ati o n).  
d T h e st u d y  c e nt er  visits  aft er  D a y  1  will  h a v e  wi n d o ws  of  ±  3  d a ys f or  visits  at  W e e ks  2  a n d  4,  ±  5  d a ys f or  visits  at  W e e ks  8  t hr o u g h  2 4,  a n d  ±  1 4  d a ys f or  visits  at  W e e ks  3 6 
t hro u g h  9 6.  
e P ar e nt al  or l e g al  g u ar di a n i nf or m e d  c o ns e nt  wit h si g n e d  a n d  wit n ess e d  p e di atri c  ass e nt f or s u bj e cts  ≤ 1 7  y e ars  of  a g e,  writt e n  i nf or m e d  c o ns e nt f or s u bj e cts  1 8 y e ars  of  a g e.  
f N ot r e q uir e d f or s u bj e cts  w h o  u n d er w e nt s cr e e ni n g.  
g A st a n d ar d  1 2 -l e a d  E C G  will  b e  c o n d u ct e d i n tri pli c at e ( at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5  mi n ut es)  aft er t h e  s u bj e ct  h as r est e d s u pi n e f or  at l e ast  5  mi n ut es.   T h e  E C G 
p ar a m et ers  will  b e  b as e d  o n t h e  E C G  m a c hi n e r e a di n gs ( Q T c F  m a y  b e  c al c ul at e d).  
h Pr e g n a n c y t ests  ar e r e q uir e d f or  all f e m al es  of  c hil d b e ari n g  p ot e nti al.   S er u m  pr e g n a n c y t ests  will  b e  c o n d u ct e d  at s cr e e ni n g ( if  a p pli c a bl e)  a n d  D a y  1.   A  uri n e  pr e g n a n c y t est 
will  b e  c o n d u ct e d  o n  D a y  1  a n d  at  all s u bs e q u e nt  visits.   T h e  uri n e  pr e g n a n c y t es t r es ult  o n  D a y  1  will  b e  us e d t o  c o nfir m  eli gi bilit y. 
i T h e  " S cr e e ni n g/ B as eli n e"  v ersi o n  will  b e  a d mi nist er e d  o n  D a y  1  a n d t h e  “ Si n c e  L ast  Visit ”  v ersi o n  will  b e  us e d  at  all  ot h er t i m e p oi nts. 
j St u d y  dr u g  will  b e  a d mi nist er e d  o n c e  d ail y  at t h e s u bj e ct’s  b e dti m e  at  h o m e ( u n d er t h e s u p er visi o n  of t h eir  p ar e nt/ g u ar di a n f or s u bj e cts  ≤ 1 7  y e ars  of  a g e).   T h e  d at e  a n d ti m e  of 
t h e first  d os e  aft er  a  visit  a n d t h e l ast  d os e  pri or t o t h e  n e xt  visit s h o ul d  b e r e c or d e d  o n t h e  pr o vi d e d s u bj e ct r e mi n d er  c ar ds. 
k S u bj e cts  will r et ur n  all  us e d  a n d  u n us e d st u d y  dr u g,  a n d  a  c o m pli a n c e  c h e c k  will  b e  p erf or m e d  b y  c o u nti n g t h e  c a ps ul es r et ur n e d  at  e a c h st u d y  visit.


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 5 
9. 2.   
P h a r m a c o d y n a mi c  Ass ess m e nts  
9. 2. 1.   
Cli ni c al  Gl o b al I m p r essi o n  S c al es  
T h e  C GI- Ti cs – S e v erit y  a n d  Cli ni c al  Gl o b al I m pr essi o n  of  T o ur ett e  S y n dr o m e- I m pr o v e m e nt 
s c al e (C GI -T S – I m pr o v e m e nt) will  b e  us e d t o r at e t h e s u bj e ct’s  o v er all s e v erit y  of ti cs  a n d 
o v er all i m pr o v e m e nt  of  T S.    
T h e  C GI -Ti cs - Se v erit y  will  b e  us e d t o  ass ess  o v er all s e v erit y  o n  a  7- p oi nt s c al e (r a n g e; 
1 = n or m al,  n ot  at  all ill t o  7 = a m o n g t h e  m ost  e xtr e m el y ill s u bj e cts ).  T h e  C GI -Ti cs -S e v erit y 
will  b e  ass ess e d  b y t h e i n v esti g at or  ( or  d esi g n e e)  o n D a y  1 ( b as eli n e)  ( n ot r e q uir e d f or s u bj e cts 
w h o  h a v e t h eir fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  st u d y  visit  o n  D a y  1) , a n d  at 
W e e ks  8,  1 6,  2 4,  3 6,  4 8,  7 2 ,  a n d  at t h e fi n al st u d y visit ( W e e k  9 6),  or  e arl y t er mi n ati o n.   If 
p ossi bl e, t h e s a m e  p ers o n s h o ul d r at e t h e  C GI- Ti cs -S e v erit y  at  all  visits.   
T h e  C GI -T S – I m pr o v e m e nt  will  b e  us e d t o  ass ess  o v er all i m pr o v e m e nt si n c e t h e i niti ati o n  of 
st u d y  dr u g  d osi n g  o n  a  7 -p oi nt s c al e (r a n g e;  1 = v er y  m u c h i m pr o v e d t o  7 = v er y  m u c h  w ors e) .  
C GI -T S -I m pr o v e m e nt  will  b e  ass ess e d  b y t h e i n v esti g at or ( or  d esi g n e e) at  W e e ks  8,  1 6,  2 4,  3 6, 
4 8,  7 2,  a n d  at t h e fi n al st u d y  visit ( W e e k  9 6),  or  e arl y t er mi n ati o n .  If  p ossi bl e, t h e s a m e  p ers o n 
s h o ul d r at e t h e  C GI-T S -I m pr o v e m e nt  at  all  visits. 
9. 2. 2.   
Gill es  d e l a  T o u r ett e  S y n d r o m e - Q u alit y  of  Lif e f o r  C hil d re n  a n d  A d ol es c e nts  
T h e  C & A -G T S -Q O L  is  a  v ali d  a n d r eli a bl e i nstr u m e nt t o  ass ess t h e  q u alit y  of lif e i n  c hil dr e n 
a n d  a d ol es c e nts  wit h  T S ( C a v a n n a  et  al.,  2 0 1 3 ; S u  et  al.,  2 0 1 7 ).  It  c o nsists  of  2 7 it e ms  a n d  4 
s u bs c al es ( ps y c h ol o gi c al,  p h ysi c al,  o bs essi v e -c o m p ulsi v e,  a n d  c o g niti v e).   E a c h it e m is r at e d 
a cr oss  5  r es p o ns e  o pti o ns:   “ N e v er, ”  “ R ar el y, ”  “ S o m eti m es, ”  “ Oft e n, ”  a n d  “ Al w a ys. ”  T h er e  ar e 
2  v ersi o ns  of t his i nstr u m e nt:   1  v ersi o n f or  c hil dr e n  a g e d  6 t o  1 2  y e ars  a n d  1  v ersi o n f or 
a d ol es c e nts  a g e d  1 3 t o  1 8  y e ars.   T h e  C & A -G T S -Q O L  als o i n cl u d es  a  vis u al  a n al o g s c al e, 
ass essi n g  h o w s atisfi e d t h e s u bj e ct f e els  wit h  his/ h er lif e (r a n g e  of  0  t o  1 0 0,  wit h  1 0 0 
r e pr es e nti n g t h e  gr e at est s atisf a cti o n). 
T h e  s u bj e ct will  c o m pl et e  t h e  C & A-G T S -Q O L  o n  D a y  1  ( b as eli n e) ( n ot r e q uir e d f or s u bj e cts 
w h o  h a v e t h eir fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  st u d y  visit  o n  D a y  1) ,  a n d at 
W e e ks   1 2,  2 4,  4 8,  7 2,  a n d  at t h e fi n al st u d y visit ( W e e k  9 6),  or  e arl y t er mi n ati o n .  T h e s u bj e ct 
c a n r e c ei v e  assist a n c e filli n g  o u t t h e  q u esti o n n air e if  n e e d e d.  
9. 3.   
S af et y  Ass ess m e nts  
C o n c o mit a nt  m e di c ati o n  us e  a n d  A Es  will  b e  m o nit or e d t hr o u g h o ut t h e st u d y  as  d es cri b e d i n 
S e cti o n  9. 6. 1  a n d  S e cti o n  1 1 , r es p e cti v el y.   A d diti o n al s af et y  ass ess m e nts  ar e  d es cri b e d i n t h e 
f oll o wi n g s e cti o ns. 
F or  a n y  a b n or m al s af et y  ass ess m e nt  d e e m e d  cli ni c all y si g nifi c a nt, t h e i n v esti g at or  will  p erf or m 
a p pr o pri at e f oll o w- u p  ass ess m e nts ( e g, r e p e at  a n al ysis),  u ntil t h e  c a us e  of t h e  a b n or m alit y is 
d et er mi n e d  a n d/ or  u ntil t h e  v al u e r et ur ns t o  b as eli n e ( or  wit hi n  n or m al li mits),  or t h e 
i n v esti g at or  d e e ms t h e  a b n or m alit y t o  b e  of  n o  cli ni c al si g nifi c a n c e. 
A p pr o pri at e  ps y c hi atri c  e v al u ati o n  a n d i nt er v e nti o n  will  b e  pr o vi d e d f or  a n y tr e at m e nt -
e m er g e nt s ui ci d al  b e h a vi or  or  cli ni c all y si g nifi c a nt s ui ci d al i d e ati o n.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 6 
9. 3. 1.   
D at a  S af et y  M o nit o ri n g  B o a r d 
A n i n d e p e n d e nt  D S M B  will  p eri o di c all y r e vi e w  o n g oi n g  cli ni c al s af et y  d at a t o  e ns ur e t h e s af et y 
a n d  w ell -b ei n g  of t h e st u d y s u bj e cts.   T h e s af et y  d at a r e vi e w  m a y r es ult i n r e c o m m e n d ati o n f or 
e arl y t er mi n ati o n  of  t h e st u d y  or  c h a n g es t o t h e  pr ot o c ol  a n d i nf or m e d  c o ns e nt.   A  D S M B 
c h art er  will  d es cri b e t h e r es p o nsi biliti es, ti mi n g  of  m e eti n gs,  a n d  d at a r e vi e w  pr o c e d ur es f or t h e 
m e m b ers t o f oll o w.  
9. 3. 2.   
Vit al  Si g n  M e as u r e m e nt s  
Vit al si g ns  will i n cl u d e  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e,  ort h ost ati c  p uls e r at e, 
r es pir at or y r at e (r e c or d e d  o nl y  s u pi n e),  a n d  or al  b o d y t e m p er at ur e.   Bl o o d  pr ess ur e  will  b e 
m e as ur e d  usi n g  a  c ali br at e d  a ut o m ati c  bl o o d  pr ess ur e  c uff  aft er t h e s u bj e ct  h as  b e e n s u pi n e f or 
at l e ast  5  mi n u t es  a n d  aft er  a p pr o xi m at el y  2  mi n ut es  of st a n di n g. 
Vit al si g n  m e as ur e m e nts  will  b e  c oll e ct e d  at s cr e e ni n g (if  a p pli c a bl e),   o n D a y  1 ( b as eli n e)  ( n ot 
r e q uir e d f or s u bj e cts  w h o  h a v e t h eir fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4-T S 2 0 0 5 st u d y  visit 
o n  D a y  1),  a n d  a t  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  3 6,  4 8,  6 0,  7 2,  8 4,  a n d  at t h e fi n al st u d y visit 
( W e e k  9 6),  or  e arl y t er mi n ati o n.  Vit al si g n  m e as ur e m e nts  will  b e  o bt ai n e d  b ef or e  a n y 
s c h e d ul e d  bl o o d s a m pl e  c oll e cti o n . 
9. 3. 3.   
M e di c al  Hist o r y  
A  m e di c al  hist or y  will  b e t a k e n  at s c r e e ni n g (if  a p pli c a bl e)  a n d  o n  D a y 1.   T h e  a g e  at  T S 
di a g n osis  will  b e  d o c u m e nt e d f or  all s u bj e cts; if  n e c ess ar y,  s u bj e ct  a g e  at  T S  o ns et  c a n  b e 
esti m at e d  b y t h e i n v esti g at or  b as e d  u p o n  a v ail a bl e  cli ni c al i nf or m ati o n.  
9. 3. 4.   
P h y si c al  E x a mi n ati o n,  I n cl u di n g  H ei g ht   a n d  W ei g ht 
T h e  c o m pl et e  p h ysi c al  e x a mi n ati o n  will  c o nsist  of  a n  ass ess m e nt  of  g e n er al  a p p e ar a n c e, s ki n 
a n d  m u c os a e,  h e a d,  e y es,  e ars,  n os e, t hr o at,  n e c k (i n cl u di n g t h yr oi d), l y m p h  n o d es,  c h est/l u n gs, 
c ar di o v as c ul ar,  a b d o m e n,  e xtr e miti es,  m us c ul os k el et al,  a n d  n e ur ol o gi c al s yst e m.   A  c o m pl et e 
p h ysi c al  e x a mi n ati o n i n cl u di n g  w ei g ht  will  b e  p erf or m e d  at s cr e e ni n g (if  a p pli c a bl e),   o n D a y  1 
( b as eli n e) ( n ot r e q uir e d f or s u bj e cts  w h o  h a v e t h eir fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or 
N BI - 9 8 8 5 4- T S 2 0 0 5  st u d y  visit  o n  D a y  1), a n d  a t  W e e ks 1 2,  2 4,  6 0,  a n d  at t h e  fi n al st u d y visit 
( W e e k  9 6),  or  e arl y t er mi n ati o n.  H ei g ht  will  b e  m e as ur e d  at s cr e e ni n g (if  a p pli c a bl e)  a n d  o n 
D a y  1  ( n ot r e q uir e d f or s u bj e cts  w h o  u n d er w e nt s cr e e ni n g).   H ei g ht  a n d  w ei g ht  will  b e 
m e as ur e d  wit h s u bj e cts  n ot  w e ari n g s h o es. 
9. 3. 5.   
El e ct r o c a r di o g r a m  
A  st a n d ar d  1 2- l e a d  E C G  will  b e r e c or d e d i n tri pli c at e ( at l e ast  1  mi n ut e  a p art  a n d  wit hi n 
1 5  mi n ut es)  aft er t h e s u bj e ct  h as r est e d s u pi n e f or  at l e ast  5  mi n ut es.   T h e  E C G  p ar a m et ers t h at 
will  b e  ass ess e d i n cl u d e  h e art r at e  ( H R),  P R i nt er v al,  Q R S  d ur ati o n, c orr e ct e d  Q T  i nt er v al,  a n d 
Q T c F ( m a c hi n e r e a di n gs  or  c al c ul at e d).   A d diti o n all y, t h e  o c c urr e n c e  of  d e -  a n d r e-p ol ari z ati o n 
a n d r h yt h m  dis or d ers  or  ot h er  a b n or m aliti es  will  b e  ass ess e d.   B as e d  o n t h e r e vi e w  of t h es e 
p ar a m et ers, t h e i n v esti g at or  or  d esi g n e e  will  n ot e if t h e  E C G is  N or m al,  A b n or m al  n ot 
Cli ni c all y  Si g nifi c a nt,  or  A b n or m al  Cli ni c all y  Si g nifi c a nt.  If t h e  E C G is  A b n or m al  Cli ni c all y 
Si g nifi c a nt, t h e i n v esti g at or  or  d esi g n e e  will  pr o vi d e  a  d es cri pti o n  of t h e  a b n or m a lit y r e c or d e d 
o n t h e  A E  e C R F. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 7 
T h e  1 2- l e a d  E C G r e c or di n gs  will  b e  c o n d u ct e d at s cr e e ni n g (if  a p pli c a bl e),   o n D a y  1 ( b as eli n e)  
( n ot r e q uir e d f or s u bj e cts  w h o  h a v e t h eir fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5 st u d y 
visit  o n  D a y  1),  a n d  at  W e e ks   2,  4,  1 2,  2 4,  6 0,  a n d  at t h e fi n al st u d y  visit ( W e e k  9 6),  or  e arl y 
t er mi n ati o n. 
9. 3. 6.   
Cli ni c al  L a b o r at o r y  Ass ess m e nts  
All  cli ni c al l a b or at or y  ass ess m e nts  will  b e  p erf or m e d  b y  a  c e ntr al l a b or at or y,  w hi c h  will 
pr o vi d e i nstr u cti o ns  a n d s u p pli es t o t h e st u d y st aff  b ef or e  st u d y i niti ati o n.   T h e i nstr u cti o ns  will 
b e i n cl u d e d i n  a l a b or at or y  m a n u al.   T h e l a b or at or y t est  b att er y  will i n cl u d e r o uti n e  a n d 
s cr e e ni n g l a b or at or y t ests. 
Cli ni c al s af et y l a b or at or y  ass ess m e nts  will  b e  p erf or m e d  at s cr e e ni n g (if  a p pli c a bl e),   o n D a y  1 
(b as eli n e) ,  a n d at  W e e ks  1 2,  2 4,  6 0,  a n d  at t h e  fi n al st u d y visit ( W e e k  9 6),  or  e arl y t er mi n ati o n.  
T h er e  ar e  n o f asti n g r e q uir e m e nts f or l a b or at or y  ass ess m e nts.  
T h e f oll o wi n g  cli ni c al s af et y l a b or at or y  ass a ys  will  b e  p erf or m e d:  
H e m at ol o g y :  c o m pl et e  bl o o d  c o u nt i n cl u di n g  w hit e  bl o o d  c ell ( W B C)  c o u nt  wit h  diff er e nti al, 
r e d  bl o o d  c ell  c o u nt,  h e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  m e a n  c or p us c ul ar  h e m o gl o bi n 
( M C H),  m e a n  c or p us c ul ar  h e m o gl o bi n  c o n c e ntr ati o n ( M C H C),  m e a n  c or p us c ul ar  v ol u m e 
( M C V), r e d  c ell  distri b uti o n  wi dt h ( R D W), a n d  m e a n  pl at el et  v ol u m e ( M P V).    A  s a m pl e f or 
gl y c at e d  h e m o gl o bi n ( H b A 1 c)  will  als o  b e  c oll e ct e d ( a n  a d diti o n al  2  m L s a m pl e).  
Cli ni c al  C h e mistr y :  s o di u m,  p ot assi u m,  c al ci u m,  m a g n esi u m,  c hl ori d e,  bl o o d  ur e a  nitr o g e n, 
bi c ar b o n at e,  cr e at i ni n e,  uri c  a ci d,  al b u mi n,  al k ali n e  p h os p h at as e, l a ct at e  d e h y dr o g e n as e,  A L T, 
A S T,  G G T,  cr e ati n e  ki n as e, t ot al  bilir u bi n, t ot al  c h ol est er ol, tri gl y c eri d es, t ot al  pr ot ei n ,  a n d 
gl u c os e.  
Uri n al ysis :  s p e cifi c  gr a vit y,  nitrit e s,  k et o n es,  pr ot ei n,  ur o bili n o g e n,  gl u c os e,  bilir u bi n, 
l e u k o c yt e  est er as e,  o c c ult  bl o o d,  a n d  p H;  mi cr os c o pi c  e x a mi n ati o n  of s e di m e nt  will  b e 
p erf or m e d  o nl y if t h e r es ults  of t h e  uri n al ysis  di psti c k  e v al u ati o n  ar e  p ositi v e f or  nitrit es, 
pr ot ei n, l e u k o c yt e  est er as e,  or  bl o o d. 
T h e f oll o wi n g  a d diti o n al l a b or at or y t ests  will  b e  p erf or m e d:  
Pr e g n a n c y  T ests:   A  pr e g n a n c y t est  will  b e  c o n d u ct e d f or f e m al e s u bj e cts  of  c hil d b e ari n g 
p ot e nti al.   A s er u m  pr e g n a n c y t est  will  b e  c o n d u ct e d  at s cr e e ni n g (if  a p pli c a bl e)  a n d  o n  D a y  1 
( b as eli n e) a n d  a  uri n e  pr e g n a n c y t est  will  b e  c o n d u ct e d  o n  D a y   1 ( b as eli n e; t o  c o nfir m 
eli gi bilit y ), at  W e e ks   2,  4,  8,  1 2,  1 6,  2 0,  2 4,  3 6,  4 8,  6 0,  7 2,  8 4,  a n d  at t h e fi n al st u d y visit 
( W e e k  9 6),  or  e arl y t er mi n ati o n. 
9. 3. 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 hil d r e n’s  V e rsi o ns  
T h e  C -S S R S is  a  v ali d at e d i nstr u m e nt t o  pr os p e cti v el y  ass ess s ui ci d al i d e ati o n  a n d  b e h a vi or 
( htt p:// w w w. cssrs. c ol u m bi a. e d u).   T h er e  ar e  v ersi o ns  of t h e  q u esti o n n air e  d esi g n e d f or  us e  at 
s cr e e ni n g ( C hil dr e n’s B as eli n e/ S cr e e ni n g  v ersi o n)  a n d  at  visits t hr o u g h o ut t h e st u d y ( C hil dr e n’s 
Si n c e  Last  Visit  v ersi o n).   All  v ersi o ns  of t h e  C - S S R S i n cl u d e  a s eri es  of s cr e e ni n g  q u esti o ns 
r el at e d t o 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.   S u bj e ct r es p o ns es  of “ y es ” t o  o n e  or  m or e 
s cr e e ni n g  q u esti o ns  will  pr o m pt  a d diti o n al  q u esti o ns t h at  e v al u at e fr e q u e n c y  a n d i nt e nsit y  of 
s ui ci d al i d e ati o n  a n d/ or  b e h a vi or.   S u bj e cts  wit h  a n y lif eti m e s ui ci d al  b e h a vi or  or s ui ci d al 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 8 
i d e ati o n  of t y p e  4 ( a cti v e s ui ci d al i d e ati o n  wit h s o m e i nt e nt t o  a ct,  wit h o ut s p e cifi c  pl a n) or 
t y p e 5 ( a cti v e s ui ci d al i d e ati o n  wit h s p e cifi c  pl a n  a n d i nt e nt) i n t h e  1  y e ar   b ef or e D a y   1 
( b as eli n e) b as e d  o n t h e  C -S S R S  C hil dr e n’s  B as eli n e/ S cr e e ni n g   v ersi o n s h o ul d  b e  e x cl u d e d (s e e 
e x cl usi o n  crit eri o n   #4 ). 
T h e  C -S S R S  will  b e  a d mi nist er e d  a n d s c or e d  b y t h e i n v esti g at or  or  q u alifi e d st u d y  c e nt er 
p ers o n n el  o n  D a y  1 ( b as eli n e) , at  W e e ks  2,   4,  8,  1 2,  1 6,  2 0,  2 4,  3 6,  4 8,  6 0,  7 2,  8 4,  a n d  at t h e 
fi n al st u d y visit ( W e e k  9 6),  or  e arl y t er mi n ati o n .  
9. 3. 8.   
E xt r a p y r a mi d al  S y m pt o m  R ati n g  S c al e- A b b r e vi at e d  
T h e  E S R S -A is  a  ps y c h o m etri c all y  v ali d at e d i nstr u m e nt t h at  ass ess es  4  t y p es  of  m o v e m e nt 
dis or d ers:   p ar ki ns o nis m,  a k at hisi a,  d yst o ni a,  a n d  d ys ki n esi a ( C h o ui n ar d  a n d  M ar g ol es e,  2 0 0 5 ).  
T h e i n v esti g at or ( or  d esi g n e e)  will  a d mi nist er t h e  E S R S -A  o n  D a y  1 ( b as eli n e)  ( n ot r e q uir e d f or 
s u bj e cts  w h o  h a v e t h eir fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  st u d y  visit  o n  D a y  1), 
at  W e e ks  8,  1 6,  2 4,  4 8,  7 2,  a n d  at t h e  fi n al st u d y visit ( W e e k  9 6),  or  e arl y t er mi n ati o n . 
9. 3. 9.   
Esti m at e d  T ot al  Bl o o d  S a m pl e  V ol u m e  R e q ui r e d  b y  St u d y 
T h e  esti m at e d t ot al  bl o o d s a m pl e  v ol u m e f or  e a c h s u bj e ct is  pr es e nt e d i n  T a bl e   2.   T h es e 
esti m at es i n cl u d e s a m pl es t o  b e  c oll e ct e d  d uri n g t h e tr e at m e nt  p eri o d  a n d t h e fi n al  st u d y visit 
(W e e k  9 6  or  u p o n  e arl y t er mi n ati o n). 
T a bl e  2:    
Esti m at e d  T ot al  Bl o o d  S a m pl e  V ol u m e 
P a r a m et e r  
N u m b e r  of  S a m pl es 
R e q ui r e d  
A p p r o xi m at e  
V ol u m e ( m L)  
A p p r o xi m at e  T ot al 
V ol u m e ( m L)  
Cli ni c al  c h e mistr y a 
6 b 
5  
3 0  
H e m at ol o g y  
6 b 
6  
3 6  
A p p r o xi m at e  M a xi m u m  T ot al  Bl o o d  S a m pl e  V ol u m e  p e r  S u bj e ct ( m L):  
6 6  
a I n cl u d es s er u m  pr e g n a n c y t est f or f e m al e s u bj e ct s  w h o  ar e  of  c hil d b e ari n g  p ot e nti al  at s cr e e ni n g (if  a p pli c a bl e) 
a n d  o n  D a y  1 ( b a s eli n e).  
b  S u bj e ct s  w h o  d o  n ot r e q uir e s cr e e ni n g  will  o nl y r e q uir e  5 s a m pl e s.  
9. 4.   
S p e cifi c  St u d y I nf o r m ati o n  
9. 4. 1.   
S c r e e ni n g ( D a y s  - 2 8 t o - 1) 
S u bj e cts  w h o  h a v e t h eir fi n al  N BI - 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  visit  > 3 0  d a ys  pri or t o 
a nti ci p at e d  D a y  1 ( b as eli n e)  m ust  u n d er g o s cr e e ni n g.   T h es e s u bj e cts  will  b e s cr e e n e d t o 
d et er mi n e  eli gi bilit y  wit hi n  2 8  d a ys ( D a ys  - 2 8 t o - 1)  b ef or e  D a y  1 ( b as eli n e). 
D uri n g s cr e e ni n g, t h e f oll o wi n g st u d y  e v al u ati o ns  a n d t as ks  will  b e  p erf or m e d  at t h e st u d y 
c e nt er:  
•   O bt ai n i nf or m e d  c o ns e nt/ ass e nt. 
•   Ass ess i n cl usi o n/ e x cl usi o n  crit eri a.  
•   C oll e ct  m e di c al  hist or y.  
•   P erf or m  a  p h ysi c al  e x a mi n ati o n  (i n cl u di n g  h ei g ht  a n d  w ei g ht). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  2 9 
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  1 2- l e a d  E C G i n tri pli c at e ( at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5 mi n ut es). 
•   P erf or m  a s er u m  pr e g n a n c y t est ( β- h C G)  o nl y f or f e m al e s u bj e cts  of  c hil d b e ari n g 
p ot e nti al.  
•   C oll e ct  bl o o d s a m pl e f or  h e m at ol o g y  a n d  cli ni c al  c h e mistr y.  
•   C oll e ct  uri n e s a m pl e f or  uri n al ysis.  
•   A E  m o nit ori n g. 
•   R e c or d  pri or  m e di c ati o ns. 
All s cr e e ni n g  pr o c e d ur es  m ust  b e  c o m pl et e d  a n d r es ults  m ust  b e  e v al u at e d  b y t h e i n v esti g at or 
b ef or e t h e  b as eli n e  pr o c e d ur es  ar e  p erf or m e d  o n  D a y  1. 
T h e f oll o wi n g it e ms  will  als o  b e  c o n d u ct e d  at s cr e e ni n g:  
•   I nstr u ct s u bj e cts  of  c hil d b e ari n g  p ot e nti al  w h o  d o  n ot  pr a cti c e t ot al  a bsti n e n c e t o  c o nti n u e 
usi n g  c o ntr a c e pti o n (s e e  i n cl usi o n  crit eri o n  #6 ). 
•   Eli gi bl e s u bj e cts  will  b e i nstr u ct e d t o r et ur n t o t h e st u d y  c e nt er  o n  D a y   1.   T h e f oll o wi n g 
s h o ul d  b e  c o nsi d er e d f or s c h e d uli n g  p ur p os es:   as  m u c h  as  p ossi bl e,  visits s h o ul d  o c c ur  at 
a p pr o xi m at el y t h e s a m e ti m e  as t h e  D a y  1 ( b as eli n e)  visit t o st a n d ar di z e t h e ti m e  of  d a y f or 
t h e  ass ess m e nt  of  P D  a n d s af et y t hr o u g h o ut t h e st u d y  p eri o d.  
9. 4. 2.   
D a y  1  ( B as eli n e  Ass ess m e nts  a n d  St a rt of  D osi n g)  
F or  s u bj e cts  w h o  h a v e t h eir  fi n al  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4-T S 2 0 0 5  visit  o n t h e s a m e 
d a y  as  D a y  1, t h e  N BI- 9 8 8 5 4- T S 2 0 0 4  or  N BI- 9 8 8 5 4- T S 2 0 0 5  ass ess m e nts f or  p h ysi c al 
e x a mi n ati o n (i n cl u di n g  w ei g ht),  vit al si g n s,  E C G ,  E S R S-A,  C GI -Ti cs - S e v erit y,  a n d 
C & A- G T S -Q O L  s c al e will  b e  us e d f or  D a y  1. 
S u bj e cts  (a n d  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e) will r et ur n t o t h e  st u d y c e nt er  
o n  D a y  1. 
O n  D a y  1, t h e f oll o wi n g  b as eli n e  st u d y  e v al u ati o ns  a n d  t as ks  will  b e  p erf or m e d at t h e st u d y 
c e nt er : 
•   O bt ai n i nf or m e d  c o ns e nt/ ass e nt ( n ot r e q uir e d f or s u bj e cts  w h o  u n d er w e nt s cr e e ni n g). 
•   Ass ess i n cl usi o n/ e x cl usi o n  crit eri a.  
•   C oll e ct  m e di c al  hist or y.  
•   P erf or m  a  p h ysi c al  e x a mi n ati o n (i n cl u di n g  w ei g ht). 
•   M e as ur e  h ei g ht ( n ot r e q uir e d f or s u bj e cts  w h o  u n d er w e nt s cr e e ni n g). 
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  1 2- l e a d  E C G i n tri pli c at e (at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5  mi n ut es ). 
•   P erf or m  a s er u m  pr e g n a n c y t est ( β- h C G)  a n d  a  uri n e  pr e g n a n c y t est  o nl y  f or f e m al e 
s u bj e cts  of  c hil d b e ari n g  p ot e nti al. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 0 
•   C oll e ct  bl o o d s a m pl e f or  h e m at ol o g y  a n d  cli ni c al  c h e mistr y.  
•   C oll e ct  uri n e s a m pl e f or  uri n al ysis.  
•   A d mi nist er t h e  C -S S R S  (C hil dr e n’s  S cr e e ni n g/ B as eli n e  v ersi o n ). 
•   A d mi nist er t h e  E S R S -A.  
•   A d mi nist er t h e  C GI -Ti cs -S e v erit y.  
•   A d mi nist er t h e  C & A -G T S -Q O L.  
•   Dis p e ns e  a  2- w e e k s u p pl y  of  st u d y  dr u g  a n d  pr o vi d e i nstr u cti o ns  o n st or a g e  a n d 
a d mi nistr ati o n  of t h e st u d y  dr u g. 
•   Instr u ct s u bj e cts t o r e c or d t h e  d at e  a n d ti m e  of  e a c h  d os e  o n  t h e l a b els  pr o vi d e d  o n t h e 
st u d y  dr u g  kit  p a c k a gi n g f or m. 
•   I nstr u ct s u bj e cts t o  b e gi n t a ki n g st u d y  dr u g d ail y  at  b e dti m e  ( u n d er s u p er visi o n  of t h eir 
p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e),  b e gi n ni n g  o n  D a y  1.  ( T h e ti mi n g  of 
st u d y dr u g  a d mi nistr ati o n s h o ul d r e m ai n  c o nsist e nt t hr o u g h o ut t h e tr e at m e nt  p eri o d) . 
•   I nstr u ct s u bj e cts (a n d  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e) t o r et ur n t o t h e 
st u d y  c e nt er  at  W e e k   2 (- 7 t o  + 2 d a ys)   a n d t o  bri n g t h eir st u d y  dr u g  kit. 
•   A E  m o nit ori n g. 
•   R e c or d  c o n c o mit a nt  m e di c ati o ns.  
T h e f oll o wi n g  will  als o  b e  c o n d u ct e d  b ef or e s u bj e cts  m a y l e a v e t h e st u d y  c e nt er:  
•   I nstr u ct s u bj e cts  of  c hil d b e ari n g  p ot e nti al  w h o  d o  n ot  pr a cti c e t ot al  a bsti n e n c e t o  c o nti n u e 
usi n g  c o ntr a c e pti o n (s e e  i n cl usi o n  crit eri o n  #6 ). 
•   I nstr u ct s u bj e cts (a n d  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e) t o  n otif y t h e 
i n v esti g at or  b y t el e p h o n e if t h e y  e x p eri e n c e  a n y  A Es  a n d  b ef or e t a ki n g  a n y  n e w 
c o n c o mit a nt  m e di c ati o ns. 
9. 4. 3.   
W e e ks  2  a n d  4 ( ±  3  d a y s)  
S u bj e cts  (a n d  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e) will r et ur n  t o t h e st u d y  c e nt er 
at  W e e k s  2  a n d  4. 
T h e f oll o wi n g st u d y  e v al u ati o ns  a n d t as ks  will  b e  p erf or m e d  at t h e st u d y  c e nt er : 
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  1 2- l e a d  E C G i n tri pli c at e (at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5  mi n ut es ). 
•   P erf or m  a  uri n e  pr e g n a n c y t est  o nl y f or f e m al e  s u bj e cts  of  c hil d b e ari n g  p ot e nti al. 
•   A d mi nist er t h e  C -S S R S ( C hil dr e n’s  Si n c e  La st  Visit  v ersi o n ). 
•   P erf or m  c o m pli a n c e  c h e c k  b y  c o u nti n g t h e  c a ps ul es r et ur n e d.  
•   A E  m o nit ori n g. 
•   R e c or d  c o n c o mit a nt  m e di c ati o ns.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 1 
D os e  Es c al ati o n  Ass ess m e nt  
At t h e  e n d  of  W e e k  2  a n d  W e e k  4  visits,  a  d os e  es c al ati o n  will  o c c ur  b as e d  o n t h e f oll o wi n g 
2  crit eri a:   1) t h e s u bj e ct’s ti cs  ar e  n ot s uffi ci e ntl y  c o ntr oll e d  p er  p h ysi ci a n i n v esti g at or 
ass ess m e nt;  a n d  2)  a n  e v al u ati o n  b y t h e  p h ysi ci a n i n v esti g at or i n di c at es t h at t h e s u bj e ct is 
t ol er ati n g t h e st u d y  dr u g  at t h e  c urr e nt  d os e  a n d  w o ul d li k el y  b e  a bl e t o t ol er at e t h e  n e xt  d os e 
l e v el.   B as e d  o n t h es e  crit eri a, t h e  p h ysi ci a n i n v esti g at or  will  c h o os e  1  of t h e f oll o wi n g  d osi n g 
o pti o ns: 
•   D os e  es c al ati o n,  w hi c h  will  o c c ur i n  2 0  m g i n cr e m e nts:  
−   S u bj e cts  < 5 0  k g  at  b as eli n e:  fr o m  2 0  m g t o  4 0  m g ( W e e k  2); fr o m  4 0  m g t o  6 0  m g 
( W e e k  4). 
−   S u bj e cts  ≥ 5 0  k g  at  b as eli n e:  fr o m  4 0  m g t o  6 0  m g ( W e e k  2); fr o m  6 0  m g t o  8 0  m g 
( W e e k  4). 
•   M ai nt e n a n c e  of  c urr e nt  d os e ( wit h  n o f urt h er  d os e i n cr e as es). 
•   D os e r e d u cti o n t o  pr e vi o us  d os e i n s u bj e cts  w h o  h a v e  h a d  a  d os e  es c al ati o n ( o nl y  a si n gl e 
d os e r e d u cti o n is  all o w e d  d uri n g t h e st u d y).   T h e  p h ysi ci a n i n v esti g at or  m a y  d e cr e as e t h e 
d os e t o t h e  pr e vi o us  d os e  at  a n y ti m e  aft er t h e  e n d  of  W e e k  2 (i n cl u di n g  b et w e e n s c h e d ul e d 
st u d y  visits) f or  a n y  s u bj e ct  w h o is  u n a bl e t o t ol er at e  a  gi v e n  d os e i n cr e as e.   S u bj e cts  will 
r e c ei v e t his  d os e f or t h e r e m ai n d er  of t h e tr e at m e nt  p eri o d. 
O n c e  a  d et er mi n ati o n  of  d os e  es c al ati o n,  m ai nt e n a n c e,  or r e d u cti o n is  m a d e, t h e i nt er a cti v e  w e b 
r esp o ns e s yst e m ( I W R S) will  b e  a c c ess e d t o  o bt ai n  a n i d e ntifi c ati o n  n u m b er f or  a  kit  c o nt ai ni n g 
a  2-  or  4- w e e k  s u p pl y  of  st u d y  dr u g t o  b e  dis p e ns e d t o t h e s u bj e ct.  
T h e f oll o wi n g  will  als o  b e  c o n d u ct e d  b ef or e s u bj e cts  m a y l e a v e t h e st u d y  c e nt er:  
•   I nstr u ct s u bje cts  of  c hil d b e ari n g  p ot e nti al  w h o  d o  n ot  pr a cti c e t ot al  a bsti n e n c e t o  c o nti n u e 
usi n g  c o ntr a c e pti o n (s e e  i n cl usi o n  crit eri o n  #6 ). 
•   I nstr u ct s u bj e cts (a n d  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e) t o  n otif y t h e 
i n v esti g at or  b y t el e p h o n e if t h e y  e x p eri e n c e  a n y  A Es  a n d  b ef or e t a ki n g  a n y n e w 
c o n c o mit a nt  m e di c ati o ns.  
•   I nstr u ct s u bj e cts t o r e c or d t h e  d at e  a n d ti m e  of  e a c h  d os e  o n t h e l a b els  pr o vi d e d  o n t h e 
st u d y  dr u g  p a c k a gi n g f or m. 
9. 4. 4.   
W e e ks  8,  1 6,  3 6,  4 8,  a n d  7 2 ( ±  5  d a y s f o r  W e e ks  8  a n d  1 6,  ±  1 4  d a y s f o r 
W e e ks   3 6,  4 8,  a n d  7 2) 
S u bj e cts ( a n d  p ar e nt/l e g al  g u ar di a n f or s u bj e cts  ≤ 1 7  y e ars  of  a g e)  will r et ur n t o t h e st u d y  c e nt er 
at  W e e ks  8,  1 6,  3 6,  a n d  7 2. 
T h e f oll o wi n g st u d y  e v al u ati o ns  a n d t as ks  will  b e  p erf or m e d  at t h e st u d y  c e nt er:  
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  a  uri n e  pr e g n a n c y t e st  o nl y f or f e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al.  
•   A d mi nist er t h e  C - S S R S ( C hil dr e n’s  Si n c e  La st  Visit  v ersi o n). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 2 
•   A d mi nist er t h e  E S R S - A ( W e e ks  8,  1 6,  4 8,  a n d  7 2  o nl y). 
•   A d mi nist er t h e  C GI -Ti cs -S e v erit y.  
•   A d mi nist er t h e  C GI -T S -I m pr o v e m e nt. 
•   A d mi nist er t h e  C & A- G T S -Q O L  ( W e e ks  4 8  a n d  7 2  o nl y). 
•   Dis p e ns e st u d y  dr u g. 
•   P erf or m  c o m pli a n c e  c h e c k  b y  c o u nti n g t h e  c a ps ul es r et ur n e d.  
•   A E  m o nit ori n g. 
•   R e c or d  c o n c o mit a nt  m e di c ati o ns.  
9. 4. 5.   
W e e ks  1 2,  2 0,  2 4,  6 0,  a n d  8 4 ( ±  5  d a y s f o r  W e e ks  1 2,  2 0,  a n d  2 4,  ±  1 4  d a y s f o r 
W e e ks   6 0  a n d  8 4) 
S u bj e cts ( a n d  p ar e nt/l e g al  g u ar di a n f or s u bj e cts  ≤ 1 7  y e ars  of  a g e)  will r et ur n t o t h e st u d y  c e nt er 
at  W e e ks  1 2,  2 0,  2 4,  6 0,  a n d  8 4. 
T h e f oll o wi n g st u d y  e v al u ati o ns  a n d t as ks  will  b e  p erf or m e d  at t h e st u d y  c e nt er:  
•   P erf or m  a  p h ysi c al  e x a mi n ati o n i n cl u di n g  w ei g ht ( W e e ks  1 2,  2 4,  a n d  6 0  o nl y). 
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  1 2- l e a d  E C G i n tri pli c at e ( at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5  mi n ut es) 
( W e e ks  1 2,  2 4,  a n d  6 0  o nl y). 
•   P erf or m  a  uri n e  pr e g n a n c y t est  o nl y f or f e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al.  
•   C oll e ct  bl o o d s a m pl e f or  h e m at ol o g y  a n d  cli ni c al  c h e mistr y ( W e e ks  1 2,  2 4,  a n d  6 0  o nl y). 
•   C oll e ct  uri n e s a m pl e f or  uri n al ysis ( W e e k s  1 2,  2 4,  a n d  6 0  o nl y). 
•   A d mi nist er t h e  C - S S R S ( C hil dr e n’s  Si n c e  La st  Visit  v ersi o n). 
•   A d mi nist er t h e  E S R S - A ( W e e k  2 4  o nl y). 
•   A d mi nist er t h e  C GI -Ti cs - S e v erit y ( W e e k  2 4  o nl y). 
•   A d mi nist er t h e  C GI -T S -I m pr o v e m e nt ( W e e k  2 4  o nl y). 
•   A d mi nist er t h e  C & A -G T S - Q O L ( W e e ks  1 2  a n d  2 4  o nl y). 
•   Dis p e ns e st u d y  dr u g. 
•   P erf or m  c o m pli a n c e  c h e c k  b y  c o u nti n g t h e  c a ps ul es r et ur n e d.  
•   A E  m o nit ori n g. 
•   R e c or d  c o n c o mit a nt  m e di c ati o ns.  
9. 4. 6.   
Fi n al  St u d y  Visit / E a rl y  T e r mi n ati o n:  W e e k  9 6 ( ±  1 4  d a y s ) 
S u bj e cts ( a n d  p ar e nt/l e g al  g u ar di a n f or s u bj e cts  ≤ 1 7  y e ars  of  a g e)  will r et ur n t o t h e st u d y  c e nt er 
at  W e e k  9 6 ( or  u p o n  e arl y t er mi n ati o n)  a n d  t h e f oll o wi n g st u d y  e v al u ati o ns  a n d t as ks  will  b e 
p erf or m e d: 
•   P erf or m  a  p h ysi c al  e x a mi n ati o n i n cl u di n g  w ei g ht.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 3 
•   C oll e ct  vit al si g ns, i n cl u di n g  ort h ost ati c s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur es,  ort h ost ati c 
p uls e r at e, r es pir at or y r at e,  a n d  b o d y t e m p er at ur e.  
•   P erf or m  1 2- l e a d  E C G i n tri pli c at e (at l e ast  1  mi n ut e  a p art  a n d  wit hi n  1 5  mi n ut es ). 
•   P erf or m  a  uri n e  pr e g n a n c y t est  o nl y f or f e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al.  
•   C oll e ct  bl o o d s a m pl e f or  h e m at ol o g y  a n d  cli ni c al  c h e mistr y.  
•   C oll e ct  uri n e s a m pl e f or  uri n al ysis.  
•   A d mi nist er t h e  C - S S R S ( C hil dr e n’s  Si n c e  La st  Visit  v ersi o n). 
•   A d mi nist er t h e  E S R S -A.  
•   A d mi nist er t h e  C GI -Ti cs -S e v erit y.  
•   A d mi nist er t h e  C GI -T S -I m pr o v e m e nt. 
•   A d mi nist er t h e  C & A -G T S -Q O L.  
•   P erf or m  c o m pli a n c e  c h e c k  b y  c o u nti n g t h e  c a ps ul es r et ur n e d.  
•   A E  m o nit ori n g. 
•   R e c or d  c o n c o mit a nt  m e di c ati o ns.  
9. 5.   
St u d y  D u r ati o n  
T h e  e x p e ct e d  d ur ati o n  of st u d y  p arti ci p ati o n f or  e a c h s u bj e ct is  u p t o  1 0 0  w e e ks, i n cl u di n g  u p t o 
4  w e e ks  of s cr e e ni n g  a n d  u p t o  9 6  w e e ks  of st u d y  dr u g tr e at m e nt. 
9. 6.   
P r o hi biti o n s  a n d  R est ri cti o ns  
9. 6. 1.   
P ri o r  a n d  C o n c o mit a nt  M e di c ati o ns  
All  pr es cri pti o n  a n d  o v er t h e  c o u nt er ( O T C)  m e di c ati o ns, i n cl u di n g  di et ar y  a n d  h er b al 
s u p pl e m e nts, t a k e n  b y s u bj e cts  d uri n g t h e  3 0  d a ys  b ef or e  D a y  1 ( b as eli n e)  a n d  d uri n g t h e st u d y 
will  b e  e nt er e d  o n t h e  Pri or  a n d  C o n c o mit a nt  M e di c ati o ns  e C R F.   A n y  a d diti o ns,  d el eti o ns,  or 
c h a n g es i n t h e  d os e  of t h es e  m e di c ati o ns  will  b e  e nt er e d  o n t h e  e C R F  wit h i n di c ati o n,  d os e, 
r o ut e,  a n d  d at es  of  dr u g  a d mi nistr ati o n. 
T h e f oll o wi n g  m e di c ati o ns  ar e  pr o hi bit e d fr o m  1 4  d a ys  b ef or e  D a y  1 ( b as eli n e) ( u nl ess 
ot h er wis e st at e d)  u ntil t h e fi n al st u d y  visit ( or  u p o n  e arl y t er mi n ati o n)  as  d es cri b e d  b el o w:  
•   A nti e m eti cs:   M et o cl o pr a mi d e,  pr o c hl or p er a zi n e,  a n d  pr o m et h a zi n e.  
•   B ot uli n u m t o xi n:   B ot uli n u m t o xi n i nj e cti o ns  ar e  pr o hi bit e d st arti n g  9 0  d a ys  pri or t o 
D a y  1 ( b as eli n e) . 
•   C Y P 3 A 4 i n d u c ers:   Str o n g i n d u c ers  of  C Y P 3 A 4 ( e g,  p h e n yt oi n,  p h e n o b ar bit al, rif a b uti n, 
rif a m pi n,  pri mi d o n e,  St. J o h n's  W ort,  c ar b a m a z e pi n e). 
•   C Y P 3 A 4 i n hi bit ors:   Str o n g i n hi bit ors  of  C Y P 3 A 4 ( e g, itr a c o n a z ol e,  k et o c o n a z ol e, 
cl arit hr o m y ci n).  
•   D o p a mi n e  a g o nists  a n d  pr e c urs ors:   D o p a mi n e  a g o nists ( e g, r o pi nir ol e)  a n d  pr e c urs ors 
( e g,  c ar bi d o p a/l e v o d o p a). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 4 
•   D o p a mi n e  a nt a g o nist:   D o p a mi n e  a nt a g o nists ( e g ,  pi m o zi d e,  h al o p eri d ol,  ari pi pr a z ol e, 
ris p eri d o n e,  cl o z a pi n e,  ol a n z a pi n e,  zi pr asi d o n e).   D e p ot  n e ur ol e pti cs  ar e  pr o hi bit e d 
st arti n g  1 5  w e e ks  pri or t o  D a y  1 ( b as eli n e). 
•   M o n o a mi n e  o xi d as e i n hi bit ors ( M A OIs):   All  M A OIs ( e g, is o c ar b o x a zi d,  p h e n el zi n e, 
s el e gili n e, tr a n yl c y pr o mi n e). 
•   V M A T 2 i n hi bit ors:   V M A T 2 i n hi bit or  m e di c ati o ns ( e g, t etr a b e n a zi n e,  d e ut etr a b e n a zi n e, 
r es er pi n e),  e x c e pt f or st u d y  dr u g. 
•   C a n n a bi n oi ds 
•   As  n e e d e d  us e  of t h e f oll o wi n g  m e di c ati o ns:   a nti c h oli n er gi cs,  b e n z o di a z e pi n es, 
a nti ps y c h oti cs,  ps y c h o sti m ul a nts,  m o o d st a bili z ers,  a nti d e pr ess a nts,  o pi at es,   a n d str o n g 
C Y P 2 D 6 i n hi bit ors. 
9. 6. 2.   
Di et a r y  R est ri cti o ns  
S u bj e cts  ar e  n ot  p er mitt e d t o  c o ns u m e  m or e t h a n  6  c aff ei n e -c o nt ai ni n g  b e v er a g es  a  d a y.  
Al c o h ol is  pr o hi bit e d fr o m  4 8  h o urs  b ef or e  D a y  1  u ntil t h e  fi n al st u d y visit . 
9. 6. 3.   
Ot h e r  R est ri cti o ns  
E x c essi v e  us e  of t o b a c c o  a n d  ot h er  pr o d u cts  c o nt ai ni n g  ni c oti n e (i n cl u di n g  ni c oti n e  g u m  a n d 
p at c h es)  ar e  pr o hi bit e d  d uri n g t h e st u d y (i e, fr o m  3 0  d a ys  b ef or e  D a y  1 [ b as eli n e]  t o t h e fi n al 
st u d y visit   or  u p o n  e arl y t er mi n ati o n).  S u bj e cts  m ust  a gr e e  n ot t o  d o n at e  bl o o d  d uri n g t h e st u d y 
a n d f or  4  w e e ks  aft er  c o m pl eti o n  of t h e st u d y.   M al e s u bj e cts  m ust  a gr e e t o r efr ai n fr o m 
d o n ati n g s p er m  d uri n g t h e st u d y  a n d f or  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
9. 7.   
Wit h d r a w al  C rit e ri a  
S u bj e cts  ar e fr e e t o  dis c o nti n u e t h eir  p arti ci p ati o n i n t h e st u d y  at  a n y ti m e.   T h e i n v esti g at or 
m ust  wit h dr a w  a n y s u bj e ct fr o m t h e st u d y if t h at s u bj e ct r e q u ests t o  b e  wit h dr a w n.  
T h e i n v esti g at or  m ust  wit h dr a w t h e s u bj e ct fr o m t h e st u d y if t h e s u bj e ct  e x p eri e n c es  a n y  of t h e 
f oll o wi n g: 
•   If t h e t y p e, fr e q u e n c y,  or  s e v erit y  of  a n y  A E  b e c o m es u n a c c e pt a bl e/i nt ol er a bl e.  
•   If t h e s u bj e ct is  u n a bl e t o t ol er at e t h e st arti n g  d os e  or r es u m pti o n  of t h e  pr e vi o us  d os e.   
•   Q T c F  v al u e  > 5 0 0  ms e c ( c ar di ol o gist  v erifi e d)   o n a n y  E C G tr a ci n g . 
•   If t h e s u bj e ct  e x hi bits s ui ci d al  b e h a vi or,  or s ui ci d al i d e ati o n  of t y p e  4 ( a cti v e s ui ci d al 
i d e ati o n  wit h s o m e i nt e nt t o  a ct,  wit h o ut s p e cifi c  pl a n)  or t y p e  5 ( a cti v e s ui ci d al i d e ati o n 
wit h s p e cifi c  pl a n  a n d i nt e nt)  b as e d  o n t h e  C -S S R S.  
•   Is l ost t o f oll o w- u p. 
•   S u bj e ct is  c o nfir m e d t o  b e  pr e g n a nt.  




N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 6 
S u bj e cts  < 5 0  k g  at  b as eli n e:  
•   St arti n g  d os e:   2 0  m g  N BI- 9 8 8 5 4 ( o n e  2 0  m g  c a ps ul e) 
•   W e e k  2:   4 0  m g  N BI- 9 8 8 5 4 ( o n e  4 0  m g  c a ps ul e) 
•   W e e k  4:   6 0  m g  N BI- 9 8 8 5 4 ( o n e  6 0  m g  c a ps ul e)  
S u bj e cts  ≥ 5 0  k g  at  b as eli n e:  
•   St arti n g  d os e:   4 0  m g  N BI- 9 8 8 5 4 ( o n e  4 0  m g  c a ps ul e)   
•   W e e k  2:   6 0  m g  N BI- 9 8 8 5 4 ( o n e  6 0  m g  c a ps ul e)  
•   W e e k  4:   8 0  m g  N BI- 9 8 8 5 4 ( o n e  8 0  m g  c a ps ul e)  
If  a s u bj e ct’s  o pti m al  d os e  h as  alr e a d y  b e e n  est a blis h e d  at  W e e k  2,  n o f urt h er  d os e  es c al ati o n 
will  b e  all o w e d  a n d t h e s u bj e ct  will  c o nti n u e  at t h at  d os e   u ntil t h e  e n d  of t h e st u d y.   S u bj e cts 
w h o  h a d  a  d os e  es c al ati o n  m a y  h a v e  a  d os e r e d u cti o n  at  a n y ti m e.  
1 0. 2.   
St u d y  D r u g  St o r a g e  
N BI - 9 8 8 5 4  m ust  b e st or e d  at  c o ntr oll e d r o o m t e m p er at ur e ( C R T) ( 2 0˚ C t o  2 5˚ C  or  6 8˚ F t o 
7 7˚ F)  u n d er t h e  c o n diti o ns s p e cifi e d i n t h e I n v esti g at or’s  Br o c h ur e  a n d i n  a l o c k e d  ar e a 
a c c essi bl e  o nl y t o t h e  p h ar m a cist ( or  d esi g n e e)  u ntil  dis p e nsi n g.   R ef er t o t h e I n v esti g ati o n al 
Pr o d u ct  Pl a n f or  all o w a bl e  e x c ursi o ns  w hil e i n tr a nsit  (if  a p pli c a bl e) a n d i n st or a g e.    
1 0. 3.   
St u d y  D r u g  P a c k a gi n g  a n d  L a b eli n g  
All  p a c k a gi n g  a n d l a b eli n g  o p er ati o ns  will  b e  p erf or m e d  a c c or di n g t o  G o o d  M a n uf a ct uri n g 
Pr a cti c e ( G M P)  a n d  G C P.   S t u d y  dr u g  will  b e s e nt t o  d esi g n at e d st aff  at t h e st u d y  c e nt er  w h o 
m ust  c o m pl et e  a n d r et ur n t h e  Dr u g  S u p pl y  C o nfir m ati o n t o  N BI  or its  d esi g n e e  v eri f yi n g t h e 
r e c ei pt  of t h e  dr u g. 
St u d y  dr u g  will  b e s u p pli e d  as  3 5  c a ps ul es i n 
. 
L a b el t e xt  will i n cl u d e , b ut is  n ot li mit e d t o , t h e  pr ot o c ol  n u m b er,  d os a g e f or m, r o ut e  of 
a d mi nistr ati o n, s p o ns or  n a m e  a n d  a d dr ess, st or a g e  c o n diti o n,  a n d t h e st at e m e nt  “ C a uti o n  –  N e w 
Dr u g:   Li mit e d  b y  F e d er al ( or  U S)  L a w t o I n v esti g ati o n al  Us e. ”  
1 0. 4.   
Bli n di n g  
T his is  a n  o p e n -l a b el st u d y. 
1 0. 5.   
St u d y  D r u g  A d mi nist r ati o n  
St u d y  dr u g  will  b e  a d mi nist er e d  o n c e  d ail y  at  b e dti m e  at  h o m e  ( u n d er t h e s u p er visi o n  of t h e 
s u bj e ct’s  p ar e nt/l e g al  g u ar di a n  f or s u bj e cts  ≤ 1 7  y e ars  of  a g e)  a n d t h e  c a ps ul e m ust  b e 
s w all o w e d  wit h  at l e ast  4  o z.  of  w at er,  wit h  or  wit h o ut f o o d,  e v er y  d a y  at  a p pr o xi m at el y t h e 
s a m e ti m e f or t h e  9 6-w e e k tr e at m e nt  p eri o d.  If  a s u bj e ct f or g ets  or is  u n a bl e t o t a k e t h e st u d y 
dr u g  o n  a  gi v e n  d a y, t h e s u bj e ct s h o ul d s ki p t h at  d os e  a n d r es u m e  n or m al  d osi n g t h e f oll o wi n g 
d a y.   S u bj e cts  or t h eir  p ar e nt/l e g al  g u ar di a n  wil l r e c or d t h e  d at e  a n d ti m e  of t h e first  d os e  aft er  a 
visit  a n d t h e l ast  d os e  pri or t o t h e  n e xt  visit s h o ul d  b e r e c or d e d  o n t h e  pr o vi d e d s u bj e ct r e mi n d er 
c ar ds. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 7 
1 0. 6.   
D r u g  C o m pli a n c e  a n d  A c c o u nt a bilit y  
S u bj e cts  will  bri n g  all  u n us e d st u d y  dr u g   a n d e m pt y st u d y  dr u g  p a c k a gi n g  m at eri al t o t h e  c e nt er 
at  e a c h st u d y  visit f or  dr u g  a c c o u nt a bilit y  a n d r e c o n cili ati o n  b y  st u d y  c e nt er  p ers o n n el.   A 
c o m pli a n c e  c h e c k  will  b e  p erf or m e d  b y  c o u nti n g t h e  c a ps ul es r et ur n e d  at  e a c h st u d y  visit . 
T h e  q u a ntit y  of st u d y  dr u g  dis p e ns e d,  us e d,  a n d r et ur n e d  will  b e r e c or d e d  o n  a  dis p e nsi n g l o g  or 
ot h er wis e  d o c u m e nt e d.   T h e  q u a ntit y  of  st u d y  dr u g l ost  or  d estr o y e d  m ust  als o  b e  a c c o u nt e d f or 
a n d  d o c u m e nt e d.   T h e  d esi g n at e d  p h ar m a cist  or  q u alifi e d  p ers o n n el  will  b e r es p o nsi bl e  f or 
m ai nt ai ni n g  a c c ur at e r e c or ds  of t h e  q u a ntit y  a n d  d at es  of  all st u d y  dr u g s u p pli es r e c ei v e d, 
dis p e ns e d,  a n d r et ur n e d. 
1 0. 7.   
St u d y  D r u g  R et u r n  
Writt e n  d o c u m e nt ati o n t o  a c c o u nt f or st u d y  dr u g  a n d st u d y  dr u g  m at eri als is  m a n d at or y;  all 
u n us e d st u d y  dr u g  a n d st u d y  dr u g  m at eri als  m ust  b e  k e pt i n  a s e c ur e l o c ati o n f or fi n al 
a c c o u nt a bilit y  a n d r e c o n cili ati o n.   R et ur n e d st u d y  dr u g  a n d st u d y  dr u g  m at eri al  m ust  b e 
a c c o u nt e d f or  o n  a st u d y  dr u g r et ur n f or m  pr o vi d e d  b y  N BI  or  d esi g n e e.   T h e i n v esti g at or  m ust 
pr o vi d e  a  wri tt e n  e x pl a n ati o n f or  a n y  d estr o y e d  or  missi n g  st u d y  dr u g  or  st u d y  dr u g  m at eri als. 
R et ur ns  will  b e s hi p p e d t o  N BI  or its  d esi g n e e  at t h e  c o m pl eti o n  of t h e st u d y  a c c or di n g t o 
i nstr u cti o ns  pr o vi d e d  b y  N BI  or its  d esi g n e e.   St u d y  dr u g r et ur n f or ms  m ust  b e  c o m pl et e d f or 
t h e s hi p m e nt  of r et ur ns  a n d s e nt  wit h t h e st u d y  dr u g  a n d st u d y  dr u g  m at eri als.   O n e  c o p y  of t h e 
st u d y  dr u g r et ur n f or m  will  b e r et ai n e d i n t h e i n v esti g at or’s st u d y fil e.  
All r et ur n e d st u d y  dr u g  a n d st u d y  dr u g  m at eri als s h o ul d  b e st or e d, i n v e nt ori e d, r e c o n cil e d,  a n d 
r et ur n e d  a c c or di n g t o  a p pli c a bl e st at e  a n d f e d er al r e g ul ati o ns  a n d st u d y  pr o c e d ur es.  
1 1.   
A D V E R S E  E V E N T S  
All  A Es,  w h et h er  o bs er v e d  b y t h e i n v esti g at or, r e p ort e d  b y t h e s u bj e ct,  n ot e d fr o m l a b or at or y 
fi n di n gs,  or i d e ntifi e d  b y  ot h er  m e a ns,  will  b e r e c or d e d fr o m t h e ti m e t h e s u bj e ct si g n e d t h e I C F 
u ntil t h e s u bj e ct’s fi n al st u d y  visit  ( W e e k  9 6  or u p o n  e arl y t er mi n ati o n ). 
1 1. 1.   
D efi niti o n  
A n  A E is  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a  p ati e nt  or  cli ni c al i n v esti g ati o n s u bj e ct 
a d mi nist er e d  a  p h ar m a c e uti c al  pr o d u ct  a n d  w hi c h  d o es  n ot  n e c ess aril y  h a v e t o  h a v e  a  c a us al 
r el ati o ns hi p  wit h t his tr e at m e nt.   A n  A E  c a n t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n 
(i n cl u di n g  a n  a b n or m al l a b or at or y fi n di n g, f or  e x a m pl e), s y m pt o m,  or  dis e as e t e m p or all y 
ass o ci at e d  wit h t h e  us e  of  a  m e di ci n al  pr o d u ct,  w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e 
m e di ci n al  pr o d u ct.  
A d v ers e  e v e nts i n cl u d e,  b ut  ar e  n ot li mit e d t o:  ( 1)  a  w or s e ni n g  or  c h a n g e i n  n at ur e, s e v erit y,  or 
fr e q u e n c y  of  c o n diti o ns  pr es e nt  at t h e st art  of t h e st u d y; ( 2) s u bj e ct  d et eri or ati o n  d u e t o  pri m ar y 
ill n ess; ( 3) i nt er c urr e nt ill n ess;  a n d ( 4)  dr u g i nt er a cti o n. 
If  at  a n y ti m e  aft er t h e  b as eli n e  visit ( D a y  1), t h e s u bj e ct’s r es p o ns e t o t h e s ui ci d al i d e ati o n 
s e cti o n  of t h e  C-S S R S is  w ors e t h a n t h e  b as eli n e  ass ess m e nt it  will  b e  d o c u m e nt e d  as  a n  A E.  
All s ui ci d al  b e h a vi ors  will  b e  d o c u m e nt e d  as  a n  A E.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 8 
S u bj e cts s h o ul d  b e  q u esti o n e d i n  a  g e n er al  w a y,  wit h o ut  as ki n g  a b o ut t h e  o c c urr e n c e  of  a n y 
s p e cifi c s y m pt o m.   T h e i n v esti g at or s h o ul d  att e m pt t o  est a blis h  a  di a g n osis  of t h e  e v e nt  b as e d 
o n si g ns,  s y m pt o ms,  a n d/ or  ot h er  cli ni c al i nf or m ati o n.  I n s u c h  c as es, t h e  di a g n osis s h o ul d  b e 
d o c u m e nt e d  as t h e  A E  a n d  n ot t h e i n di vi d u al si g ns/s y m pt o ms.   F oll o wi n g  q u esti o ni n g  a n d 
e v al u ati o n,  all  A Es,  w h et h er  b eli e v e d  b y t h e i n v esti g at or t o  b e r el at e d  or  u nr el at e d t o t h e st u d y 
dr u g,  m ust  b e  d o c u m e nt e d i n t h e s u bj e ct’s  m e di c al r e c or ds, i n  a c c or d a n c e  wit h t h e 
i n v esti g at or’s  n or m al  cli ni c al  pr a cti c e  a n d  o n t h e  A E  e C R F.   E a c h  A E is t o  b e  e v al u at e d f or 
d ur ati o n, i nt e nsit y, fr e q u e n c y,  s eri o us n ess,  o ut c o m e,  ot h er  a cti o ns t a k e n,  a n d r el ati o ns hi p t o t h e 
st u d y  dr u g.  
T h e f oll o wi n g  ar e  n ot  c o nsi d er e d  A Es:  
•   C o nti n u o us  p ersist e nt  dis e as e/s y m pt o m  pr es e nt  b ef or e  dr u g  a d mi nistr ati o n,  u nl ess it 
u n e x p e ct e dl y  pr o gr ess es,  or i n cr e as es i n s e v erit y f oll o wi n g  d r u g  a d mi nistr ati o n. 
•   R e c urr e n c e  of  T S s y m pt o ms,  u nl ess  w or s e n e d fr o m  b as eli n e. 
•   Pr e g n a n c y. 
1 1. 2.   
I nt e nsit y  of  A d v e rs e  E v e nts 
A d v ers e  e v e nts  m ust  b e  gr a d e d f or i nt e nsit y.   A n i nt e nsit y  c at e g or y  of  mil d,  m o d er at e,  or 
s e v er e,  as  d efi n e d i n T a bl e   3,  m ust  b e  e nt er e d  o n t h e  A E  e C R F.  It s h o ul d  b e  n ot e d t h at t h e t er m 
“s e v er e ”  us e d t o  gr a d e i nt e nsit y is  n ot s y n o n y m o us  wit h t h e t er m  “s eri o us. ”  
T a bl e  3:   
I nt e nsit y  of  A d v e rs e  E v e nts 
G r a d e    
I nt e nsit y 
Mil d  
A n  A E t h at is  us u all y tr a nsi e nt  a n d  m a y r e q uir e  o nl y  mi ni m al tr e at m e nt  or t h er a p e uti c 
i nt er v e nti o n.   T h e  e v e nt  d o es  n ot  g e n er all y i nt erf er e  wit h  us u al  a cti viti e s  of  d ail y li vi n g. 
M o d e r at e  
A n  A E t h at is  us u all y  all e vi at e d  wit h  a d diti o n al s p e cifi c t h er a p e uti c i nt er v e nti o n.   T h e 
e v e nt i nt erf er e s  wit h  us u al  a cti viti es  of  d ail y li vi n g,  c a usi n g  dis c o mf ort  b ut  p o s es  n o 
si g nifi c a nt  or  p er m a n e nt ris k  of  h ar m t o t h e  r es e ar c h  p arti ci p a nt. 
S e v e r e  
A n  A E t h at i nt err u pt s  us u al  a cti viti e s  of  d ail y li vi n g,  or si g nifi c a ntl y  aff e ct s  cli ni c al st at us, 
or  m a y r e q uir e i nt e nsi v e t h er a p e uti c i nt er v e nti o n.  
1 1. 3.   
R el ati o ns hi p t o  St u d y  D r u g  
T h e i n v esti g at or  will  d o c u m e nt  his/ h er  o pi ni o n  of  t h e r el ati o ns hi p  of t h e  A E t o tr e at m e nt  wit h 
st u d y  dr u g  usi n g t h e  crit eri a  o utli n e d i n  T a bl e   4.   A n  A E is  d e e m e d  ass o ci at e d  wit h t h e  us e  of 
t h e st u d y dr u g  “if t h er e is  a r e as o n a bl e  p ossi bilit y t h at t h e  dr u g  c a us e d t h e  A E ” ( ot h er wis e 
r ef err e d t o  as  a s us p e ct e d  a d v ers e r e a cti o n).   R e as o n a bl e  p ossi bilit y  m e a ns t h er e is  e vi d e n c e t o 
s u g g est  a  c a us al r el ati o ns hi p  b et w e e n t h e  dr u g  a n d t h e  A E  ( Titl e  2 1  C F R  3 1 2. 3 2 [ a]). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  3 9 
T a bl e  4:  
R el ati o ns hi p  of  A d v e rs e  E v e nts t o  St u d y  D r u g  
R el ati o ns hi p   D es c ri pti o n  
D efi nit e  
A r e a cti o n t h at f oll o w s  a r e as o n a bl e t e m p or al s e q u e n c e fr o m  a d mi nistr ati o n  of t h e  dr u g  or i n 
w hi c h t h e  dr u g l e v el  h a s  b e e n  est a blis h e d i n  b o d y fl ui ds  or tiss u e; t h at f oll o w s  a  k n o w n  or 
e x p e ct e d r es p o ns e  p att er n t o t h e s us p e ct e d  dr u g;  a n d t h at is  c o nfir m e d  b y i m pr o v e m e nt  o n 
st o p pi n g  or r e d u ci n g t h e  d o s a g e  of t h e  dr u g,  a n d r e a p p e ar a n c e  of t h e r e a cti o n  o n r e p e at e d 
e x p o s ur e.  
P ossi bl e  
A n  a d v ers e  e v e nt i n  w hi c h t h er e is r e as o n a bl e  p o ssi bilit y t h at t h e  dr u g  c a us e d t h e  e v e nt.  
R e as o n a bl e  p o ssi bilit y  m e a ns t h er e is  e vi d e n c e t o s u g g est  a  c a us al r el ati o ns hi p  b et w e e n t h e 
dr u g  a n d t h e  a d v ers e  e v e nt.  
U nli k el y  
A r e a cti o n t h at f oll o w s  a  r e as o n a bl e t e m p or al s e q u e n c e fr o m  a d mi nistr ati o n  of t h e  dr u g; t h at 
f oll o ws  a  k n o w n  or s us p e ct e d r es p o ns e  p att er n t o t h e s u s p e ct e d  dr u g;  b ut t h at  c o ul d r e as o n a bl y 
b e  e x pl ai n e d  b y  k n o w n  c h ar a ct eristi c s  of t h e s u bj e ct’s  cli ni c al  st at e.  
N ot  R el at e d   
A n y  e v e nt  t h at  d o es  n ot  m e et t h e  a b o v e  crit eri a. 
1 1. 4.   
R e c o r di n g  A d v e rs e  E v e nts  
F or  e nr oll e d  s u bj e cts,  e a c h  A E  will  b e list e d  as  a s e p ar at e  e ntr y  o n  a n  A E  e C R F.   S cr e e n f ail ur e 
s u bj e cts  will  h a v e  A E i nf or m ati o n  n ot e d i n t h e s o ur c e  d o c u m e nt ati o n.   T h e i n v esti g at or ( or 
d esi g n e e)  will  pr o vi d e i nf or m ati o n  o n  d at es  a n d ti m es  of  o ns et  a n d r es ol uti o n, i nt e nsit y, 
s eri o us n ess, fr e q u e n c y,  a cti o n(s) t a k e n,  c h a n g es i n st u d y  dr u g  u s a g e, r el ati o ns hi p t o st u d y  dr u g, 
a n d  o ut c o m e. 
T h e f oll o wi n g  c at e g ori es  of  m e di c al  e v e nts t h at  c o ul d  o c c ur  d uri n g  p arti ci p ati o n i n  a  cli ni c al 
st u d y  m ust  b e r e p ort e d  wit hi n  2 4  h o urs t o  N BI  or its  d esi g n e e: 
•   S eri o us  a d v ers e  e v e nt, i n cl u di n g  d e at h ( R ef er t o  S e cti o n  1 1. 6 ). 
•   Pr e g n a n c y (r ef er t o  S e cti o n  1 1. 7 ). 
•   E v e nts  of s ui ci d al  b e h a vi or  or s ui ci d al i d e ati o n  of t y p e  4 ( a cti v e s ui ci d al i d e ati o n  wit h 
s o m e i nt e nt t o  a ct,  wit h o ut s p e cifi c  pl a n)  or t y p e  5 ( a cti v e s ui ci d al i d e ati o n  wit h s p e cifi c 
pl a n  a n d i nt e nt)  b as e d  o n t h e  C -S S R S.  
1 1. 5.   
P ost -St u d y  F oll o w -U p  of  A d v e rs e  E v e nts  
All  A Es, i n cl u di n g  cli ni c all y si g nifi c a nt  c h a n g es i n  E C Gs,  p h ysi c al  e x a mi n ati o n fi n di n gs,  or 
is ol at e d  cli ni c all y si g nifi c a nt l a b or at or y fi n di n gs  m ust  b e f oll o w e d  u ntil t h e  e v e nt r es ol v es, t h e 
c o n diti o n st a bili z es, t h e  e v e nt is  ot h er wis e  e x pl ai n e d,  or t h e s u bj e ct is l ost t o f oll o w - u p.  If 
r es ol v e d,  a r es ol uti o n  d at e s h o ul d  b e  d o c u m e nt e d  o n t h e  e C R F.   
A d v ers e  e v e nts  o n g oi n g  at t h e fi n al  visit  or  u p o n  e arl y t er mi n ati o n   will  b e f oll o w e d f or  as l o n g 
as  n e c ess ar y t o  a d e q u at el y  e v al u at e t h e s u bj e ct’s s af et y  or  u ntil t h e  e v e nt st a bili z es  or r es ol v es 
or  u nti l t h e s u bj e ct is l ost t o f oll o w- u p.   T h e i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at f oll o w 
u p i n cl u d es  a n y s u p pl e m e nt al i n v esti g ati o ns  as  m a y  b e i n di c at e d t o  el u ci d at e t h e  n at ur e  a n d/ or 
c a us alit y  of t h e  A E.   T his  m a y i n cl u d e  a d diti o n al l a b or at or y t ests   or i n v esti g ati o ns, 
hist o p at h ol o gi c al  e x a mi n ati o ns,  or  c o ns ult ati o n  wit h  ot h er  h e alt h  c ar e  pr of essi o n als,  as is 
pr a cti c al.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 0 
1 1. 6.   
S e ri o us  A d v e rs e  E v e nts  
All  S A Es  will  b e r e c or d e d fr o m t h e ti m e t h e s u bj e ct  h as si g n e d t h e I C F  u ntil  3 0  d a ys  aft er t h e 
l ast  d os e  of st u d y  dr u g. 
1 1. 6. 1.   
D efi niti o n  of  a  S e ri o us  A d v e rs e  E v e nt  
A n  S A E is  a n y  A E t h at r es ults i n  a n y  of t h e f oll o wi n g  o ut c o m es:  
•   D e at h.  
•   A  lif e-t hr e at e ni n g A E .   Lif e t hr e at e ni n g  m e a ns t h at t h e s u bj e ct  w as, i n t h e  vi e w  of t h e 
i n v esti g at or  or s p o ns or,  at i m m e di at e ris k  of  d e at h fr o m t h e r e a cti o n  as it  o c c urr e d.  It  d o es 
n ot  m e a n t h at  h y p ot h eti c all y t h e  e v e nt  mi g ht  h a v e  c a us e d  d e at h if it  o c c urr e d i n  a  m or e 
s eri o us f or m. 
•   I n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n.   H os pit ali z ati o n f or 
el e cti v e tr e at m e nt  or  a  pr e e xisti n g  c o n diti o n t h at  di d  n ot  w ors e n  d uri n g t h e  cli ni c al 
i n v esti g ati o n is  n ot  c o nsi d er e d  a n  A E.   H o s pit ali z ati o n  or  n ursi n g  h o m e  a d missi o n f or t h e 
p ur p os e  of  c ar e gi v er r es pit e is  n ot  c o nsi d er e d  a n  A E.   C o m pli c ati o ns t h at  o c c ur  d uri n g 
h os pit ali z ati o n  ar e  A Es,  a n d if  a  c o m pli c ati o n  pr ol o n gs  h os pit ali z ati o n, t h e  e v e nt is 
c o nsi d er e d s eri o us.   Tr e at m e nt i n  a  h os pit al  e m er g e n c y r o o m is  n ot  a  h os pit ali z ati o n.  
•   A  p ersist e nt  or si g nifi c a nt i n c a p a cit y  or s u bst a nti al  disr u pti o n  of  a  p ers o n’s  a bilit y t o 
c o n d u ct  n or m al lif e f u n cti o ns. 
•   A  c o n g e nit al  a n o m al y/ birt h  d ef e ct.  
•   I m p ort a nt  m e di c al  e v e nts t h at  m a y  n ot r es ult i n  d e at h,  b e lif e t hr e at e ni n g,  or r e q uir e 
h os pit ali z ati o n.   T h es e  e v e nts  m a y  b e  c o nsi d er e d s eri o us  w h e n,  b as e d  o n  a p pr o pri at e 
m e di c al j u d g m e nt, t h e y  m a y j e o p ar di z e t h e  h e alt h  of t h e s u bj e ct  a n d  m a y r e q uir e  m e di c al 
or s ur gi c al i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  o ut c o m es list e d.   A n y  ot h er  e v e nt t h o u g ht  b y 
t h e i n v esti g at or t o  b e s eri o us s h o ul d  als o  b e r e p ort e d, f oll o wi n g t h e r e p orti n g r e q uir e m e nts 
d et ail e d i n t his s e cti o n.   E x a m pl es  of s u c h  m e di c al  e v e nts i n cl u d e  all er gi c  br o n c h os p as m 
r e q uiri n g i nt e nsi v e tr e at m e nt i n  a n  e m er g e n c y r o o m  or  at  h o m e,  bl o o d  d ys cr asi as, 
c o n v ulsi o ns t h at  d o  n ot r es ult i n i n p ati e nt  h os pit ali z ati o n,  or t h e  d e v el o p m e nt  of  dr u g 
d e p e n d e n c y  or  dr u g  a b us e. 
1 1. 6. 2.   
M a n a gi n g  S e ri o us  A d v e rs e  E v e nts  
S u bj e cts  e x p eri e n ci n g  a n  S A E  or  a n  e m er g e n c y  sit u ati o n  will  b e  e x a mi n e d  b y  a  p h ysi ci a n  as 
s o o n  as  p ossi bl e.   T h e  p h ysi ci a n i n  att e n d a n c e  will  d o  w h at e v er is  m e di c all y  n e e d e d f or t h e 
s af et y  a n d  w ell - b ei n g  of t h e s u bj e ct.   T h e s u bj e ct  will r e m ai n  u n d er  o bs er v ati o n  as l o n g  as 
m e di c all y i n di c at e d.   A p pr o pri at e l a b or at or y st u di es  will  b e  c o n d u ct e d  u ntil  all  p ar a m et ers 
r et ur n t o  n or m al  or  ar e  ot h er wis e  e x pl ai n e d  or st a bl e.   T h e s u bj e ct  will  b e f oll o w e d  u ntil t h e 
S A E r es ol v es  or  u ntil t h e s u bj e ct is  m e di c all y st a bili z e d.   T h e i n v esti g at or ( or  d esi g n e e)  will 
n otif y t h e  N BI  M e di c al  M o nit or ( a n d t h e I R B, if  n e c ess ar y) i m m e di at el y ( wit hi n  2 4  h o urs)  of 
t h e  S A E  a n d t h e  o ut c o m e  of t h e  S A E. 
If  wit hi n t h e ti m e  of i nf or m e d  c o ns e nt  u ntil  3 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g,  a n 
i n v esti g at or  b e c o m es  a w ar e  of  a n  S A E, t h e n t h e  e v e nt  m ust  b e  d o c u m e nt e d  a n d r e p ort e d  as 
d es cri b e d i n  S e cti o n  1 1. 6. 3 . 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 1 
1 1. 6. 3.   
R e p o rti n g  S e ri o us  A d v e rs e  E v e nts  a n d  Ot h e r I m m e di at el y  R e p o rt a bl e  E v e nts  
S eri o us  A Es  a n d  ot h er i m m e di at el y r e p ort a bl e  e v e nts ( d efi n e d i n  S e cti o n  1 1. 4 )  m ust  b e r e p ort e d 
wit hi n  2 4  h o urs  of first  k n o wl e d g e  of t h e  e v e nt  b y st u d y  p ers o n n el t o t h e  N BI  M e di c al  M o nit or 
or  N BI  Dr u g  S af et y  a n d  P h ar m a c o vi gil a n c e  (D S P V )  D e p art m e nt.   R e p orts  of  S A Es  or 
pr e g n a n ci es s h o ul d  b e f oll o w e d  b y  a f a x  or  e m ail  of t h e  S A E  or  Pr e g n a n c y  F or m.  It is 
i m p ort a nt t h at t h e i n v esti g at or  pr o vi d es  his  or  h er  ass ess m e nt  of r el ati o ns hi p t o st u d y  dr u g  at t h e 
ti m e  of t h e i niti al  S A E r e p ort.  
F or  S A Es  or  Ot h er I m m e di at el y  R e p ort a bl e  E v e nts,  c o nt a ct  D S P V : 
  
D S P V  t el e p h o n e: ( 8 6 6)  6 2 6- 7 7 9 2  o r ( 8 5 8)  6 1 7- 7 7 9 2 
  
D S P V  f a csi mil e:  ( 8 8 8)  6 1 7- 7 5 5 1 
  
D S P V   e-m ail:    
c ds @ n e u r o c ri n e. c o m  
  
N BI  M e di c al  M o nit o r:      
T el e p h o n e:  
 
                          
C ell  p h o n e:  
 
1 1. 6. 4.   
E x p e dit e d  S af et y  R e p o rts 
N BI  or its r e pr es e nt ati v es  will s u b mit  a n  E x p e dit e d  S af et y  R e p ort f or  a n y  s us p e ct e d  a d v ers e 
r e a cti o n ( as  d efi n e d i n S e cti o n  1 1. 3 ) t h at is  c o nsi d er e d  b ot h s eri o us  a n d  u n e x p e ct e d  wit hi n  1 5 
c al e n d ar  d a ys  a n d f or  a n y  u n e x p e ct e d f at al  or lif e t hr e at e ni n g  e x p eri e n c e  wit hi n  7  c al e n d ar  d a ys 
t o t h e  a p pli c a bl e r e g ul at or y  a ut h orit y(i es);  or  a c c or di n g t o  c o u ntr y  s p e cifi c r e g ul ati o ns. 
N BI  or its r e pr es e nt ati v es  will s e n d  c o pi es  of  e a c h  saf et y  re p ort s u b mitt e d t o r e g ul at or y 
a ut h oriti es t o t h e i n v esti g at ors.   T h e s af et y r e p ort  m ust  b e s u b mitt e d t o t h e  a p pr o pri at e I R B  as 
s o o n  as  p ossi bl e.   D o c u m e nt ati o n  of t h e s u b missi o n t o t h e I R B  a n d r e c ei pt  b y t h e I R B (if 
a p pli c a bl e)  m ust  b e r et ai n e d f or  e a c h s af et y r e p ort.  
1 1. 7.   
P r e g n a n c y  
Pr e g n a n c y is  n eit h er  a n  A E  n or  a n  S A E  u nl ess t h e  crit eri a f or  a n  S A E  ar e  m et.   H o w e v er,  all 
pr e g n a n ci es i n f e m al e s u bj e cts  w h o r e c ei v e d  N BI - 9 8 8 5 4  will  b e f oll o w e d t o  ass ess f or 
c o n g e nit al  a n o m al y.   S u bj e cts  m ust  b e  c o u ns el e d  at  all  visits t o  c o nti n u e  usi n g  c o ntr a c e pti o n 
(s e e i n cl usi o n  crit eri o n  #6 )  u ntil 3 0  d a ys  (f e m al es)  or  9 0  d a ys ( m al es) aft er t h e l ast  d os e  of 
st u d y  dr u g.  If  at  a n y ti m e  b et w e e n t h e ti m e t h e s u bj e ct si g ns t h e I C F  a n d t h e l ast st u d y  visit  a 
s u bj e ct  b eli e v es s h e is  pr e g n a nt, t h e s u bj e ct  will  b e i nst r u ct e d t o st o p t a ki n g t h e st u d y 
m e di c ati o n  a n d r et ur n t o t h e st u d y  c e nt er  wit hi n  2 4  h o urs  a n d  u n d er g o  a s er u m  pr e g n a n c y t est t o 
c o nfir m  pr e g n a n c y. 
All  c o nfir m e d  pr e g n a n ci es, i n s u bj e cts  w h o r e c ei v e d st u d y  dr u g,  m ust  b e i m m e di at el y r e p ort e d 
t o  N BI (r ef er t o S e cti o n  1 1. 6. 3  f or  c o nt a ct i nf or m ati o n), f oll o w e d  b y f a x  or  e m ail  of t h e 
pr e g n a n c y f or m t o  N BI  D S P V .   A first tri m est er  ultr as o u n d  will  b e r e q uir e d f or  all  c o nfir m e d 
pr e g n a n ci es.   Pr e g n a n ci es i n s u bj e cts  w h o r e c ei v e d  N BI - 9 8 8 5 4  will  b e f oll o w e d  u ntil r es ol uti o n 
(i e, t er mi n ati o n [ v ol u nt ar y  or s p o nt a n e o us]  or  birt h). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 2 
1 2.   
D O C U M E N T A TI O N  O F  D A T A 
1 2. 1.   
C as e  R e p o rt  F o r m  
T h e  C R F  d at a f or t his st u d y  ar e  b ei n g  c oll e ct e d  wit h  a n  el e ctr o ni c  d at a  c a pt ur e ( E D C) s yst e m 
.   T h e  E D C s yst e m  a n d t h e 
st u d y-s p e cifi c  e C R Fs  will  c o m pl y  wit h  Titl e  2 1  C F R  P art  1 1.   T h e  d o c u m e nt ati o n r el at e d t o t h e 
v ali d ati o n  of t h e  E D C s yst e m is  a v ail a bl e t hr o u g h t h e  v e n d or,   
,  w hil e t h e  v ali d ati o n  of 
t h e st u d y  s p e cifi c  e C R Fs  will  b e  c o n d u ct e d  b y  N BI  a n d t h e r e q uir e d  d o c u m e nt ati o n  will  b e 
m ai nt ai n e d i n t h e  Tri al  M ast er  Fil e.  
T h e i n v esti g at or  will  d o c u m e nt s u bj e ct  d at a i n  his/ h er  o w n s u bj e ct fil es.   T h es e s u bj e ct fil es  will 
s er v e  as s o ur c e  d at a f or  t h e st u d y.   All  e C R F  d at a r e q uir e d  b y t his  pr ot o c ol  will  b e r e c or d e d  b y 
a ut h ori z e d st u d y  p ers o n n el i n t h e  E D C s yst e m,  wit h t h e  e x c e pti o n  of  d at a  c a pt ur e d i n  a n 
el e ctr o ni c f or m at,  w hi c h  will  b e l o a d e d  el e ctr o ni c all y i nt o t h e  a p pr o pri at e  e C R Fs.   All  d at a 
e n t er e d i nt o t h e  e C R F  will  b e s u p p ort e d  b y s o ur c e  d o c u m e nt ati o n.   T h e  e C R F f or  e a c h s u bj e ct 
m ust  b e r e vi e w e d  b y t h e i n v esti g at or  a n d si g n e d  o n t h e  a p pr o pri at e  e C R F  p a g e(s).   T his s h o ul d 
b e  d o n e  as s o o n  as  p ossi bl e  aft er t h e s u bj e ct  c o m pl et es t h e st u d y.    
T h e  i n v esti g at or  or  a n  a ut h ori z e d  m e m b er  of t h e i n v esti g at or's st aff  will  m a k e  a n y  n e c ess ar y 
a d diti o ns/ c orr e cti o ns t o t h e  e C R F.   All  c h a n g e i nf or m ati o n, i n cl u di n g t h e  d at e,  p ers o n 
p erf or mi n g t h e  c orr e cti o ns,  a n d r e as o n f or t h e  c h a n g e  will  b e  a v ail a bl e  vi a t h e  el e ctr o ni c  a u dit 
tr ail,  w hi c h is  p art  of t h e  E D C s yst e m.   T h e  e C R Fs  will  b e r e vi e w e d  p eri o di c all y f or 
c o m pl et e n ess, l e gi bilit y,  a n d  a c c e pt a bilit y  b y  N BI ( or  d esi g n e e).   N BI  will  als o  b e  all o w e d 
a c c ess t o  all s o ur c e  d o c u m e nts  a n d  m e di c al r e c or ds  p erti n e nt  t o t h e st u d y i n  or d er t o  v erif y 
e C R F  e ntri es.   T h e  Pri n ci p al I n v esti g at or  will r e vi e w t h e  e C R Fs f or  c o m pl et e n ess  a n d  a c c ur a c y 
a n d  e nt er  his  or  h er  el e ctr o ni c si g n at ur e  o n t h e  e C R Fs  as  e vi d e n c e t h er e of.  
  will  pr o vi d e  a c c ess t o t h e N BI  p ort al  of t h e  E D C s yst e m f or t h e  d ur ati o n  of t h e st u d y 
t hr o u g h  a  p ass w or d-pr ot e ct e d  m et h o d  of i nt er n et  a c c ess.   S u c h  a c c ess  will  b e r e m o v e d fr o m 
i n v esti g at or sit es  at t h e  e n d  of t h e sit e's  p arti ci p ati o n i n t h e st u d y.   D at a fr o m t h e  E D C s yst e m 
will  b e  ar c hi v e d  o n  a p pr o pr i at e  d at a  m e di a ( C D  R O M,  et c.)  a n d  pr o vi d e d t o t h e i n v esti g at or  at 
t h at ti m e  as  a  d ur a bl e r e c or d  of t h e sit e's  e C R F  d at a.   Alt h o u g h  n ot r e q uir e d, t h e i n v esti g at or 
m a y  m a k e  p a p er  pri nt o uts fr o m t h at  m e di a.  
All  cli ni c al  w or k  c o n d u ct e d  u n d er t his  pr ot o c ol is  s u bj e ct t o  G C P r e g ul ati o ns.   T his i n cl u d es  a n 
i ns p e cti o n  b y  N BI  a n d/ or  h e alt h  a ut h orit y r e pr es e nt ati v es  at  a n y ti m e.   T h e  Pri n ci p al 
I n v esti g at or  will  a gr e e t o t h e i ns p e cti o n  of st u d y-r el at e d r e c or ds  b y  h e alt h  a ut h orit y 
r e pr es e nt ati v es  a n d/ or  N BI. 
1 2. 2.   
D at a  C a pt u r e,  R e vi e w,  a n d  V ali d ati o n  
D at a  e nt er e d i n t h e  E D C s yst e m  will  b e  v erifi e d  a g ai nst t h e s o ur c e  d at a  b y  N BI ( or  d esi g n e e).  
A n y  dis cr e p a n ci es  will  b e  c orr e ct e d  o n -li n e  b y  a ut h ori z e d sit e  p ers o n n el.   Aft er  c o m pl eti o n  of 
t h e  e ntr y  pr o c ess,  a ut o m at e d ( c o m p ut er-g e n er at e d) l o gi c  c h e c ks  will r u n i n  or d er t o i d e ntif y 
it e ms s u c h  as i n c o nsist e nt st u d y  d at es.  I n  a d diti o n,  m a n u al r e vi e w/ c h e c ks  m a y  b e  p erf or m e d  b y 
N BI  o n t h e  d at a.   A n y i n c o nsist e n ci es/ err ors/ o missi o ns i d e ntifi e d  will  b e s e nt t o t h e sit e ( vi a  a n 
el e ctr o ni c  q u er y) f or t h e  n e c ess ar y  c orr e cti o ns t o  b e  m a d e t o t h e  e C R F.   O n c e  e nt er e d  a n d s a v e d 
i n  a n  e C R F,  d at a i m m e di at el y  b e c o m e  p art  of t h e st u d y  d at a b as e  a n d  ar e  a v ail a bl e t o  N BI. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 3 
1 2. 3.   
C o di n g  Di cti o n a ri es  
A d v ers e  e v e nts  a n d  m e di c al  hist or y  will  b e  c o d e d  usi n g t h e   c h os e n  v ersi o n  of t h e  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 e d D R A).   Pri or  a n d  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 t h e  c h os e n  v ersi o n  of t h e  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 
Dr u g). 
1 3.   
S T A TI S TI C A L  A N D  A N A L Y TI C A L  P L A N  
D es cri pti v e  st atisti c al  m et h o ds  will  b e  us e d t o  e v al u at e  a n d s u m m ari z e t h e  d at a fr o m t his st u d y.  
T h e t er m  “ d es cri pti v e st atisti cs ” r ef ers t o t h e  n u m b er  of s u bj e cts ( n),  m e a n,  m e di a n, st a n d ar d 
d e vi ati o n ( S D), st a n d ar d  err or  of t h e  m e a n ( S E M),  mi ni m u m,  a n d  m a xi m u m f or  c o nti n u o us  a n d 
or di n al  c at e g ori c al  v ari a bl es;  a n d r ef ers t o 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 f or  c at e g ori c al 
v ari a bl es.   D es cri pti v e st atisti cs  will  b e  pr es e nt e d f or  e a c h   w ei g ht  gr o u p ( < 5 0  k g  a n d  ≥ 5 0 k g)  
( n ot e t h at  a d diti o n al s u m m ari es  m a y  b e s p e cifi e d i n t h e  d et ail e d st atisti c al  a n al ysis  pl a n [ S A P]).  
T h e  a n al ysis  pl a n  pr o vi d e d i n t his  pr ot o c ol r e pr es e nts  a  bri ef  d es cri pti o n  of t h e  pl a n n e d 
a n al ys es.   T h e  c o m pr e h e nsi v e  S A P  will  b e  g e n er at e d  pri or t o fi n al st u d y  d at a b as e l o c k.   T h e 
S A P  m a y i n cl u d e  a d diti o n al  a n al ys es  a n d  d at a s u m m ari es  n ot  d es cri b e d i n t his  pr ot o c ol.  
1 3. 1.   
A n al y sis  S ets  
A  si n gl e  a n al ysis s et, t h e s af et y  a n al ysis  s et,  will  b e  d efi n e d f or t his st u d y.  T h e s af et y  a n al ysis 
s et  will i n cl u d e  all s u bj e cts  w h o t a k e  at l e ast  1  d os e  of st u d y  dr u g  a n d  h a v e  a n y  p ost d osi n g 
s af et y  d at a. 
1 3. 2.   
S a m pl e  Si z e  
T h e s a m pl e si z e f or t his  o p e n -l a b el s af et y  st u d y is  b as e d  o n  pr a cti c al  c o nsi d er ati o ns  a n d  n ot  o n 
a st atisti c al  p o w er  c al c ul ati o n.  
1 3. 3.   
H a n dli n g  of  Missi n g  D at a  
C o n v e nti o ns f or t h e  h a n dli n g  of  missi n g  d at a  will  b e  d es cri b e d i n t h e  S A P.  
1 3. 4.   
E n r oll m e nt  a n d  Dis p ositi o n  of  S u bj e cts  
T h e s u m m ar y  of s u bj e ct  e nr oll m e nt  a n d  dis p ositi o n  will  dis pl a y t h e  n u m b er  of s u bj e cts  w h o 
w er e  e nr oll e d  a n d  w h o  c o m pl et e d t h e st u d y.   T h e  n u m b er  of s u bj e cts  w h o  di d  n ot  c o m pl et e t h e 
st u d y  will  also  b e s u m m ari z e d,  b ot h  o v er all  a n d  a c c or di n g t o t h e r e as o n f or  e arl y 
dis c o nti n u ati o n. 
1 3. 5.   
D e m o g r a p hi c s  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 c  d at a ( a g e,  g e n d er, 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 (i n cl u di n g 
h ei g ht,  w ei g ht,  b o d y  m ass i n d e x [ B MI ], a n d  a g e  at  T S  di a g n osis)  will  b e s u m m ari z e d  wit h 
d es cri pti v e st atisti cs.   M e di c al  hist or y  will  b e s u m m ari z e d  a c c or di n g t o  M e d D R A  S yst e m 
Or g a n  Cl ass ( S O C)  a n d  Pr ef err e d  T er m ( P T). 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 4 
1 3. 6.   
St u d y  D r u g  D osi n g  a n d  C o m pli a n c e  
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  w h o  ar e  d os e  c o m pli a nt ( at l e ast  8 0 %  of  e x p e ct e d 
n u m b er  of  d os es t a k e n)  will  b e s u m m ari z e d  wit h  d es cri pti v e st atisti cs  b y  visit.    
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  wit h  d os e  a dj ust m e nts  will  b e s u m m ari z e d.   
1 3. 7.   
P h a r m a c o d y n a mi c  D at a  
T h e  P D  m e as ur es i n t his st u d y i n cl u d e t h e  C GI -Ti cs - S e v erit y,  C GI-T S -I m pr o v e m e nt,  a n d 
C & A- G T S -Q O L.   F or  e a c h  P D  m e as ur e,  d es cri pti v e st atisti cs  will  b e  pr es e nt e d f or  e a c h  visit 
a n d f or t h e  c h a n g es fr o m  D a y  1 ( b as eli n e)  t o  e a c h  p ost b as eli n e  visit ( ot h er t h a n 
C GI -T S -I m pr o v e m e nt,  w hi c h is  n ot  m e as ur e d  at  b as eli n e). 
T h e  S A P  will  pr o vi d e  a f ull  d es cri pti o n  of t h e  d eri v e d  v ari a bl es t h at  will  b e s u m m ari z e d f or 
t h es e  P D  m e as ur es. 
1 3. 8.   
S af et y  D at a  
Tr e at m e nt -e m er g e nt  a d v ers e  e v e nts ( T E A Es ),  c at e g ori z e d  b y  M ed D R A  S O C  a n d/ or  P T  will  b e 
s u m m ari z e d i n fr e q u e n c y t a bl es.   T h e  T E A E s u m m ar y t a bl es  will i n cl u d e t h e  n u m b er  a n d 
p er c e nt a g e  of  u ni q u e s u bj e cts  e x p eri e n ci n g  e a c h  e v e nt .  S u m m ar y t a bl es  will  b e  pr es e nt e d f or 
all  T E A Es, s e v er e  T E A Es,  T E A Es l e a di n g t o st u d y  dr u g  d os e r e d u cti o n,  T E A Es l e a di n g t o 
e arl y  dis c o nti n u ati o n fr o m t h e st u d y,  a n d  S A Es.  
A n  A E  o v er vi e w s u m m ar y t a bl e  will  b e  pr o vi d e d  w hi c h s u m m ari z es 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  wit h  a n y  T E A E,  a n y  T E A E l e a di n g t o st u d y  dr u g  d o s e r e d u cti o n,  a n y  T E A E l e a di n g 
t o st u d y  dis c o nti n u ati o n,  a n y  S A E,  a n d  a n y  T E A E r es ulti n g i n  d e at h.   T h e s u m m ar y t a bl e  will 
als o i n cl u d e t h e  m a xi m u m  T E A E i nt e nsit y ( mil d,  m o d er at e, s e v er e) r e p ort e d f or  e a c h s u bj e ct.  
Cli ni c al l a b or at or y,  vit al si g ns,  E C G,  C -S S R S,  a n d  E S R S -A  d at a  will  b e s u m m ari z e d  wit h 
d es cri pti v e st atisti cs.   P ot e nti all y  cli ni c all y si g nifi c a nt ( P C S)  v al u es f or s el e ct e d  cli ni c al 
l a b or at or y  a n d  vit al si g ns  v ari a bl es  will  b e s u m m ari z e d.   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  a c c or di n g t o  W H O  Dr u g  A n at o mi c al  T h er a p e uti c  C h e mi c al  Cl assifi c ati o n 
( A T C)  c at e g ori es. 
1 3. 9.   
S oft w a r e 
St atisti c al  c al c ul ati o ns  a n d s u m m ari es  will  b e  g e n er at e d  usi n g 
 
. 
1 3. 1 0.   
I nt e ri m  A n al y sis  
A n i nt eri m  a n al ysis is  n ot  pl a n n e d f or t his st u d y.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 5 
1 4.   
R E G U L A T O R Y  A N D  E T HI C A L I S S U E S  
1 4. 1.   
G e n e r al  L e g al  R ef e r e n c es  
T h e st u d y  will  b e  c arri e d  o ut  a c c or di n g t o t h e  pr o visi o n  of t h e  U S   C F R, t h e  U S  F D A,  a n d t h e 
I C H G ui d eli n es f or  G C P.   All  cli ni c al  w or k  c o n d u ct e d  u n d er t his  pr ot o c ol is s u bj e ct t o  G C P 
r e g ul ati o ns.   T his i n cl u d es  a n i ns p e cti o n  b y  N BI  or its r e pr es e nt ati v e,  h e alt h  a ut h orit y, or I R B 
r e pr es e nt ati v es  at  a n y ti m e.   T h e i n v esti g at or  m ust  a gr e e t o t h e i ns p e cti o n  of st u d y-r el at e d 
r e c or ds  b y  h e alt h  a ut h orit y r e pr es e nt ati v es  a n d/ or  N BI  or its  d esi g n e e. 
1 4. 2.   
I nstit uti o n al  R e vi e w  B o a r d 
T h e fi n al  a p pr o v e d  pr ot o c ol,  t h e I C F,  a n d  ass e nt  d o c u m e nt will  b e r e vi e w e d  b y t h e I R B f or t h e 
cli ni c al sit e.   T h e  c o m mitt e e’s  d e cisi o n  c o n c er ni n g  c o n d u ct  of t h e st u d y  will  b e s e nt i n  writi n g 
t o t h e i n v esti g at or  a n d  a  c o p y  will  b e f or w ar d e d t o  N BI.   T h e i n v esti g at or  m ust  a gr e e t o  m a k e 
a n y r e q uir e d  pr o gr ess r e p orts t o t h e I R B,  a s  w ell  as r e p orts  of  S A Es, lif e-t hr e at e ni n g  pr o bl e ms, 
or  d e at h.  
1 4. 3.   
P r ot o c ol  A d h e r e n c e  a n d  A m e n d m e nts  
T h e  pr ot o c ol  m ust  b e r e a d t h or o u g hl y  a n d t h e i nstr u cti o ns  m ust  b e f oll o w e d  e x a ctl y .  A n y 
c h a n g es i n t h e  pr ot o c ol  will r e q uir e  a f or m al  a m e n d m e nt.   S u c h  a m e n d m e nts  will  b e  a gr e e d 
u p o n  a n d  a p pr o v e d i n  writi n g  b y t h e i n v esti g at or  a n d  N BI.   T h e I R B  will  b e  n otifi e d  of  all 
a m e n d m e nts t o t h e  pr ot o c ol.   A m e n d m e nts t o t h e  pr ot o c ol  will  n ot  b e i m pl e m e nt e d  u ntil  writt e n 
I R B  a p pr o v al  h as  b e e n r e c ei v e d.  
1 4. 4.   
R e q ui r e d  D o c u m e nts  
T h e i n v esti g at or  m ust  pr o vi d e t o  N BI  or its r e pr es e nt ati v es t h e f oll o wi n g  d o c u m e nts  b ef or e t h e 
e nr oll m e nt  of  a n y s u bj e ct ( ori gi n als  s h o ul d  b e  k e pt  b y t h e i n v esti g at or i n t h e i n v est i g at or’s 
r e g ul at or y  d o c u m e nt  bi n d er): 
•   Si g n e d  c o p y  of t h e  a p pr o v e d  pr ot o c ol. 
•   I n v esti g at or’s  Br o c h ur e  a c k n o wl e d g e m e nt  p a g e. 
•   C o m pl et e d  a n d si g n e d st at e m e nt  of i n v esti g at or ( F or m  F D A  1 5 7 2). 
•   C urri c ul u m  vit a e  a n d  c urr e nt  m e di c al li c e ns e  of t h e i n v esti g at or  a n d s u bi n v esti g at ors.  
•   Fi n a n ci al  dis cl os ur e i nf or m ati o n  as r e q uir e d.  
•   L ett er  of  a p pr o v al fr o m t h e I R B f or  t h e pr ot o c ol,  c o ns e nt f or m,  a n d  ass e nt f or m. 
•   C o p y  of t h e I R B  a p pr o v e d  writt e n I C F  a n d  ass e nt  t o  b e  us e d. 
•   L a b or at or y  d o c u m e nts ( c ertifi c ati o ns/ a c cr e dit ati o ns ,  n or m al r a n g es) if  n ot  pr o vi d e d  b y  a 
c e ntr al l a b or at or y.  
1 4. 5.   
I nf o r m e d  C o ns e nt 
S u bj e cts’  p ar e nt  or l e g al  g u ar di a n  will  pr o vi d e i nf or m e d  c o ns e nt  wit h si g n e d  a n d  wit n ess e d 
p e di atri c  ass e nt  b ef or e t h e  p erf or m a n c e  of  a n y st u d y- r el at e d  pr o c e d ur es f or s u bj e cts  ≤ 1 7  ye ars 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 6 
of  a g e.   S u bj e cts  1 8  y e ars  of  a g e  will  pr o vi d e t h eir  writt e n i nf or m e d  c o ns e nt  b ef or e t h e 
p erf or m a n c e  of  a n y st u d y-r el at e d  pr o c e d ur es. 
E a c h s u bj e ct’s  c h art  will i n cl u d e t h e si g n e d I C F  wit h si g n e d  a n d  wit n ess e d  p e di atri c  ass e nt  f or 
st u d y  p arti ci p ati o n.   W h e n t h e st u d y tr e at m e nt is  c o m pl et e d  a n d t h e  e C R F  h as  b e e n  m o nit or e d, 
t h e I C F  a n d si g n e d  a n d  wit n ess e d  p e di atri c  ass e nt  will  b e  k e pt i n t h e i n v esti g at or’s  c e ntr al st u d y 
fil e.   R e g ul at or y  a ut h oriti es  m a y  c h e c k t h e  e xist e n c e  of t h e si g n e d I C F a n d t h e si g n e d  a n d 
wit n ess e d  p e di atri c  ass e nt  i n t his  c e ntr al st u d y f ol d er. 
1 4. 6.   
St u d y  M o nit o ri n g  
T hr o u g h o ut t h e  c o urs e  of t h e st u d y, t h e st u d y  m o nit or  will  m a k e fr e q u e nt  c o nt a cts  wit h t h e 
in v esti g at or.   T his  will i n cl u d e  e m ails, t el e p h o n e  c alls,   a n d  o n-sit e visits .   D uri n g t h e  o n-sit e 
visits, t h e  e C R Fs  will  b e r e vi e w e d f or  c o m pl et e n ess  a n d  a d h er e n c e t o t h e  pr ot o c ol.   As  p art  of 
t h e  d at a  a u dit, s o ur c e  d o c u m e nts  will  b e  m a d e  a v ail a bl e f or r e vi e w  b y t h e st u d y  m o nit or.   T h e 
st u d y  m o nit or  will  als o  p erf or m  dr u g  a c c o u nt a bilit y  c h e c ks  a n d  m a y  p eri o di c all y r e q u est r e vi e w 
of t h e i n v esti g at or st u d y fil e t o  e ns ur e  c o m pl et e n ess  of  d o c u m e nt ati o n i n  all r es p e cts  of  cli ni c al 
st u d y  c o n d u ct. 
U p o n  c o m pl eti o n  of t h e st u d y, t h e st u d y  m o nit or  will  arr a n g e f or  a fi n al r e vi e w  of t h e st u d y 
fil es  aft er  w hi c h t h e fil es s h o ul d  b e s e c ur e d f or t h e  a p pr o pri at e ti m e  p eri o d.   T h e i n v esti g at or  or 
a p p oi nt e d  d el e g at e  will r e c ei v e t h e st u d y  m o nit or  d uri n g t h es e  o n- sit e visits,  will  c o o p er at e i n 
pr o vi di n g t h e  d o c u m e nts f or i ns p e cti o n,  a n d r es p o n d t o i n q uiri es.   I n  a d diti o n, t h e i n v esti g at or 
will  p er mit i ns p e cti o n  of t h e st u d y fil es  b y  a ut h ori z e d r e pr es e nt ati v es  of t h e r e g ul at or y  a g e n ci es.  
1 4. 7.   
Q u alit y  Ass u r a n c e  
T h e st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h  N BI’s st a n d ar d  o p er ati n g  pr o c e d ur es  d esi g n e d 
t o  e ns ur e t h at  all  pr o c e d ur es  ar e i n  c o m pli a n c e  wit h  G C P  a n d  F D A  G ui d eli n es,  a n d  a c c or di n g t o 
n ati o n al l a w.   Q u alit y  ass ur a n c e  a u dits  m a y  b e  p erf or m e d  at t h e  dis cr eti o n  of  N BI.  
1 4. 8.   
R e c o r d  R et e nti o n  
F e d er al r e g ul ati o ns r e q uir e t h at r e c or ds  of  dr u g  dis p ositi o n,  e C R Fs,  a n d  all r e p orts  of t his 
i n v esti g ati o n s h all  b e r et ai n e d  b y t h e i n v esti g at or f or  a  mi ni m u m  of  2  y e ars  aft er  n otifi c ati o n  b y 
N BI t h at t h e r e g ul at or y  a ut h oriti es  h a v e  b e e n  n otifi e d  of t h e st u d y's t er mi n ati o n,  or  2  y e ars  aft er 
a p pr o v al  of t h e  m ar k eti n g  a p pli c ati o n.  I f t h e i n v esti g at or is  u n a bl e t o r et ai n t h e st u d y 
d o c u m e nts f or t h e r e q uir e d  a m o u nt  of ti m e,  N BI  m ust  b e i nf or m e d  of t h e i n di vi d u al  w h o  will  b e 
ass u mi n g t his r es p o nsi bilit y.  
1 4. 9.   
C o nfi d e nti alit y  
N BI  a n d t h e  cli ni c al sit e  affir m  a n d  u p h ol d t h e  pri n ci pl e  of t h e s u bj e ct’s ri g ht t o  pr ot e cti o n 
a g ai nst i n v asi o n  of  pri v a c y.   T hr o u g h o ut t his st u d y,  all  d at a  will  b e i d e ntifi e d  o nl y  b y  a n 
i d e ntifi c ati o n  n u m b er  a n d,  w h er e  a p pli c a bl e, s u bj e ct’s i niti als  a n d  birt h  d at e. 
All i nf or m ati o n  c o n c er ni n g t his st u d y  a n d  w hi c h  w as  n ot  pr e vi o usl y  p u blis h e d is  c o nsi d er e d 
c o nfi d e nti al i nf or m ati o n.   T his  c o nfi d e nti al i nf or m ati o n s h all r e m ai n t h e s ol e  pr o p ert y  of  N BI; it 
s h all  n ot  b e  dis cl os e d t o  ot h ers  wit h o ut  writt e n  c o ns e nt  of  N BI;  a n d s h all  n ot  b e  us e d  e x c e pt i n 
t h e  p erf or m a n c e  of t his st u d y. 


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 7 
T h e i nf or m ati o n  c o m pil e d  d uri n g t h e  c o n d u ct  of t his  cli ni c al st u d y is  als o  c o nsi d er e d 
c o nfi d e nti al  a n d  m a y  b e  dis cl os e d  a n d/ or  us e d  o nl y  b y  N BI  as  d e e m e d  n e c ess ar y.   T o  all o w t h e 
us e  of t h e i nf or m ati o n  d eri v e d fr o m t his  cli ni c al st u d y  a n d t o  e ns ur e  c o m pli a n c e  wit h  c urr e nt 
f e d er al r e g ul ati o ns, t h e i n v esti g at or is  o bli g e d t o f ur nis h  N BI  wit h t h e  c o m pl et e t est r es ults  a n d 
all  d at a  c o m pil e d i n t his st u d y.  
1 5.   
S T U D Y  C O M M E N C E M E N T  A N D  DI S C O N TI N U A TI O N  
U p o n s atisf a ct or y r e c ei pt  of  all r e q uir e d r e g ul at or y  d o c u m e nts ,  N BI ( or  d esi g n e e)  will  arr a n g e 
t h at  all st u d y  m at eri al  b e  d eli v er e d t o t h e st u d y  c e nt er.   S u bj e ct  e ntr y  s h o ul d  n ot  b e gi n  u ntil  aft er 
t h e r e q uir e d r e g ul at or y  d o c u m e nts  ar e  c o nfir m e d  as r e c ei v e d  a n d t h e I n v esti g at or 
M e eti n g/I niti ati o n  M e eti n g  h as  o c c urr e d.   All  p ers o n n el  e x p e ct e d t o  b e i n v ol v e d i n t h e  c o n d u ct 
of t h e st u d y  will  u n d er g o  ori e nt ati o n t o i n cl u d e r e vi e w  of st u d y  pr ot o c ol, i nstr u cti o ns f or  e C R F 
c o m pl eti o n,  A E r e p orti n g,  a n d  o v er all r es p o nsi biliti es i n cl u di n g t h os e f or  dr u g  a c c o u nt a bilit y 
a n d st u d y  fil e  m ai nt e n a n c e. 
If t h e st u d y is  dis c o nti n u e d,  all s u bj e cts s h o ul d  u n d er g o  a  c o m pl et e f oll o w- u p  e x a mi n ati o n.  
A n y  cli ni c all y r el e v a nt fi n di n g, i n cl u di n g l a b or at or y  v al u es  of  p ot e nti al  cli ni c al  c o n c er n,  a n d 
a d v ers e  e x p eri e n c es  will  b e f oll o w e d  u ntil t h e y r es ol v e  or r et ur n t o  a  cli ni c all y  a c c e pt a bl e l e v el.  


N e ur o cri n e  Bi o s ci e n c es, I n c.,  St u d y  N o.  N BI - 9 8 8 5 4- T S 2 0 0 7 
Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  2  Fi n al  V ersi o n  
0 3  D e c e m b er  2 0 1 8  
C o nfi d e nti al 
P a g e  4 8 
1 6.   
R E F E R E N C E S  
A m eri c a n  Ps y c hi atri c  Ass o ci ati o n.  Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers, 
F o urt h  E diti o n.  1 9 9 4. 
A m eri c a n  Ps y c hi atri c  Ass o ci ati o n.  Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers,  Fift h 
E diti o n.  2 0 1 3. 
B a xt er  L R ,  G u z e  B H.  N e ur oi m a gi n g.  I n:  K url a n,  R. ( E d),  H a n d b o o k  of  T o ur ett e s y n dr o m e  a n d 
r el at e d ti c  a n d  b e h a vi or al  dis or d ers.   R o c h est er:  M ar c el D e c k er I n c. ;  1 9 9 3. 
Br a u n  A R,  St o ett er  B,  R a n d ol p h  C,  Hsi a o J K,  Vl a d ar  K,  G er n ert J,  et  al.  T h e f u n cti o n al 
n e ur o a n at o m y  of  T o ur ett e's s y n dr o m e:  a n  F D G- P E T st u d y. I.  R e gi o n al  c h a n g es i n  c er e br al 
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