Clinical trial NCT03444038
Conditions: Tourette Syndrome
Sponsor: Neurocrine Biosciences
Start date: 2018-02-08; Completion date: 2019-07-12
Enrollment: 85 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2b, multicenter, open-label study to evaluate the safety and tolerability of optimized doses of NBI-98854 administered once daily for 24 weeks in pediatric subjects with Tourette Syndrome.

Detailed description:

Arms: arm 1: Valbenazine administered once daily for up to 24 weeks
Interventions: intervention 1: Valbenazine
Intervention descriptions: intervention 1: vesicular monoamine transporter 2 (VMAT2) inhibitor

Protocol documents:
Prot_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.  1  Fi n al  V ersi o n  D at e:   0 6  N o v e m b er  2 0 1 7 
Ori gi n al  V ersi o n  D at e:   0 5  S e pt e m b er  2 0 1 7 
 
O p e n -L a b el  S af et y  a n d  T ol e r a bilit y  St u d y  of  O pti mi z e d  D os es  of  N BI -9 8 8 5 4 
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 4 
 
D e v el o p m e nt  P h as e:   P h as e  2 b 
 
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. 


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  als o 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  G o o d  Cli ni c al  Pr a cti c e ( G C P) ( H ar m o ni z e d)
• 
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);  H e alt h  C a n a d a
C LI NI C A L  S T U D Y  TI T L E : 
O p e n -L a b el  S af et y  a n d  T ol er a bilit y  St u d y  of  O pti mi z e d  D os es  of  N BI - 9 8 8 5 4 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 4 
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 nci p al I n v esti g at or  N a m e)  
SI T E: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt  Sit e N a m e)  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 2






T A B L E  O F  C O N T E N T S   
1.  
TI T L E  P A G E  ................................................................................................. 1 
2.  
S Y N O P SI S  .................................................................................................... 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 8 
8.  
S T U D Y  P O P U L A TI O N  .............................................................................. 2 1 
8. 1.  
I n cl usi o n  Crit eri a ......................................................................................... 2 1 
8. 2.  
E x cl usi o n  Crit eri a  ........................................................................................ 2 2 
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 3 
8. 4.  
R a n d o mi z ati o n ............................................................................................. 2 3  
9.  
S T U D Y  E V A L U A TI O N S  ........................................................................... 2 4 
9. 1.  
S c h e d ul e  of  Ass ess m e nts  ............................................................................. 2 4 
9. 2.  
P h ar m a c o d y n a mi c  Ass ess m e nts  .................................................................. 2 7 
9. 2. 1.  
Y al e  Gl o b al  Ti c  S e v erit y  S c al e .................................................................... 2 7  
9. 2. 2.  
Pr e m o nit or y  Ur g e f or  Ti cs  S c al e  ................................................................. 2 7 
9. 2. 3.  
Cli ni c al  Gl o b al I m pr essi o n  S c al es  ............................................................... 2 7 
9. 2. 4.  
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 8 
9. 3.  
Pl as m a  Dr u g  E x p os ur e ................................................................................ 2 8  
9. 4.  
S af et y  Ass ess m e nts  ...................................................................................... 2 8 
9. 4. 1.  
D at a  S af et y  M o nit ori n g  B o ar d  ..................................................................... 2 9 
9. 4. 2.  
Vit al  Si g n  M e as ur e m e nts  ............................................................................. 2 9 
9. 4. 3.  
M e di c al  Hist or y  ........................................................................................... 2 9 
9. 4. 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 9  
9. 4. 5.  
El e ctr o c ar di o gr a m  ........................................................................................ 2 9 
9. 4. 6.  
Cli ni c al  L a b or at or y  Ass ess m e nts  ................................................................ 3 0 
9. 4. 7.  
C ol u m bi a- S ui ci d e  S e v erit y  R ati n g  S c al e  C hil dr e n’s  V ersi o ns  ................... 3 1 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 5


9. 4. 8.  
C hil dr e n’s  D e pr essi o n  R ati n g  S c al e,  R e vis e d  ............................................. 3 1 
9. 4. 9.  
C hil dr e n’s  Y al e- Br o w n  O bs essi v e  C o m p ulsi v e  S c al e ................................ 3 1  
9. 4. 1 0.  
Att e nti o n -D efi cit  H y p er a cti vit y  Dis or d er  R ati n g  S c al e - 5:  H o m e  V ersi o n .. 3 1 
9. 4. 1 1.  
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 ................................. 3 2 
9. 4. 1 2.  
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 ....................... 3 2  
9. 5.  
S p e cifi c  St u d y I nf or m ati o n  .......................................................................... 3 2 
9. 5. 1.  
S cr e e ni n g ( D a ys  - 2 8 t o - 1) ........................................................................... 3 3 
9. 5. 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) ..................................... 3 3 
9. 5. 3.  
D os e  O pti mi z ati o n  P eri o d:   W e e ks  2  a n d  4 (- 2 t o  + 3  d a ys f or  e a c h  visit) .. 3 5  
9. 5. 4.  
D os e  M ai nt e n a n c e  P eri o d:   W e e ks  8,  1 2,  1 6,  2 0,  a n d  2 4 (- 2 t o  + 3  d a ys f or 
e a c h  visit)  ..................................................................................................... 3 6 
9. 5. 5.  
F oll o w- u p  P eri o d/ E arl y  T er mi n ati o n:   W e e k  2 8 (- 2 t o  + 3  d a ys)................. 3 7  
9. 6.  
St u d y  D ur ati o n  ............................................................................................. 3 8 
9. 7.  
Pr o hi biti o ns  a n d  R estri cti o ns ....................................................................... 3 8  
9. 7. 1.  
Pri or  a n d  C o n c o mit a nt  M e di c ati o ns ............................................................ 3 8  
9. 7. 2.  
Di et ar y  R estri cti o ns  ..................................................................................... 3 8 
9. 7. 3.  
Ot h er  R estri cti o ns  ........................................................................................ 3 9 
9. 8.  
Wit h dr a w al  Crit eri a  ..................................................................................... 3 9 
9. 8. 1.  
H a n dli n g  of  Wit h dr a w als ............................................................................. 3 9  
9. 8. 2.  
S p o ns or’s  T er mi n ati o n  of  St u d y .................................................................. 4 0  
1 0.  
S T U D Y  D R U G  ............................................................................................ 4 0 
1 0. 1.  
St u d y  Dr u g  S u p pli es .................................................................................... 4 0  
1 0. 2.  
St u d y  Dr u g  St or a g e  ...................................................................................... 4 0 
1 0. 3.  
St u d y  Dr u g  P a c k a gi n g  a n d  L a b eli n g  ........................................................... 4 0 
1 0. 4.  
Bli n di n g ....................................................................................................... 4 1  
1 0. 5.  
St u d y  Dr u g  A d mi nistr ati o n .......................................................................... 4 1  
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 ......................................................... 4 1  
1 0. 7.  
St u d y  Dr u g  R et ur n  ....................................................................................... 4 1 
1 1.  
A D V E R S E  E V E N T S ................................................................................... 4 2  
1 1. 1.  
D efi niti o n  ..................................................................................................... 4 2 
1 1. 2.  
I nt e nsit y  of  A d v ers e  E v e nts ......................................................................... 4 2 
1 1. 3.  
R el ati o ns hi p t o  St u d y  Dr u g ......................................................................... 4 3  
1 1. 4.  
R e c or di n g  A d v ers e  E v e nts .......................................................................... 4 3  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 6


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  ................................................... 4 4 
1 1. 6.  
S eri o us  A d v ers e  E v e nts ............................................................................... 4 4  
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 4  
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 5  
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 5  
1 1. 6. 4.  
E x p e dit e d  S af et y  R e p orts  ............................................................................ 4 5 
1 1. 7.  
Pr e g n a n c y  .................................................................................................... 4 6 
1 2.  
D O C U M E N T A TI O N  O F  D A T A ................................................................ 4 6  
1 2. 1.  
C as e  R e p ort  F or m  ........................................................................................ 4 6 
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 7  
1 2. 3.  
C o di n g  Di cti o n ari es ..................................................................................... 4 7  
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 7 
1 3. 1.  
A n al ysis  S ets  ................................................................................................ 4 7 
1 3. 2.  
S a m pl e  Si z e  ................................................................................................. 4 7 
1 3. 3.  
H a n dli n g  of  Missi n g  D at a ............................................................................ 4 8  
1 3. 4.  
E nr oll m e nt  a n d  Dis p ositi o n  of  S u bj e cts ...................................................... 4 8  
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 8 
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 8  
1 3. 7.  
P h ar m a c o d y n a mi c  D at a  ............................................................................... 4 8 
1 3. 8.  
Pl as m a  Dr u g  E x p os ur e  D at a  ........................................................................ 4 8 
1 3. 9.  
S af et y  D at a  ................................................................................................... 4 8 
1 3. 1 0.  
S oft w ar e  ....................................................................................................... 4 9 
1 3. 1 1.  
I nt eri m  A n al ysis ........................................................................................... 4 9 
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 9 
1 4. 1.  
G e n er al  L e g al  R ef er e n c es  ............................................................................ 4 9 
1 4. 2.  
I nstit uti o n al  R e vi e w  B o ar d .......................................................................... 4 9 
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 9  
1 4. 4.  
R e q uir e d  D o c u m e nts ................................................................................... 5 0  
1 4. 5.  
I nf or m e d  C o ns e nt ........................................................................................ 5 0 
1 4. 6.  
St u d y  M o nit ori n g ......................................................................................... 5 0  
1 4. 7.  
Q u alit y  Ass ur a n c e ........................................................................................ 5 1  
1 4. 8.  
R e c or d  R et e nti o n  ......................................................................................... 5 1 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
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1 4. 9.  
C o nfi d e nti alit y  ............................................................................................. 5 1 
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  ..................... 5 1
1 6. 
R E F E R E N C E S  ............................................................................................ 5 2
1 7. 
A P P E N DI C E S  ............................................................................................. 5 4
1 7. 1.  
Y al e  Gl o b al  Ti c  S e v erit y  S c al e ( Y G T S S)  ................................................... 5 4 
1 7. 2.  
Pre m o nit or y  Ur ge f or Tics Scale ( P U T S) .................................................... 5 9  
1 7. 3.  
C li nical Gl o bal I m pressi o n of Tics (C GI - Tics) – Se verit y  .......................... 6 1  
1 7. 4.  
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 ( C GI- T S)  – I m pr o v e m e nt 
scale ............................................................................................................. 6 3  
1 7. 5.  
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 olesce nts  .................................................................................................. 6 5  
1 7. 6.  
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 
B aseli ne/ Scree ni n g  Versi o n ......................................................................... 7 1  
1 7. 7.  
C ol u m bi a- S ui ci d e  S e v erit y  R ati n g  S c al e ( C -S S R S)  C hil dr e n’s  Si n c e  L ast 
Visit Versi o n  ................................................................................................ 7 5  
1 7. 8.  
C hil dre n’s De pressi o n Rati n g Scale, Re vise d ( C D R S- R ) ........................... 7 9  
1 7. 9.  
C hil dre n’s Yale- Br o w n O bsessi ve C o m p ulsi ve Scale ( C Y- B O C S)  ........... 8 4  
1 7. 1 0.  
Atte nti o n - Deficit H y peracti vit y  Dis or der Rati n g Scale- 5: H o me Versi o n  1 0 8  
1 7. 1 1.  
E xtra p yra mi dal S y m pt o m Rati n g  Scale- A b bre viate d ............................... 1 1 3  
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 5 
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  ...................................................... 3 2 
T a bl e   3: 
I nt e nsit y  of  A d v ers e  E v e nts ......................................................................... 4 3 
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 ........................................... 4 3  
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  .............................................................................. 2 0 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
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2.   
S Y N O P SI S  
P r ot o c ol  Titl e:  
O p e n -L a b el  S af et y  a n d  T ol er a bilit y  St u d y  of  O pti mi z e d  D os es  of  N BI - 9 8 8 5 4 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  5 5 st u d y  c e nt ers i n  N ort h  A m eri c a. 
O bj e cti v es:  
•  T o  d et er mi n e t h e l o n g- t er m s af et y  a n d t ol er a bilit y  of  u p t o  2 4  w e e ks  of tr e at m e nt  wit h  N BI- 9 8 8 5 4 
i n  p e di atri c s u bj e cts  wit h  T S. 
•  T o  e v al u at e t h e l o n g -t er m p h ar m a c o d y n a mi c ( P D)  eff e cts  of  N BI - 9 8 8 5 4  a d mi nist er e d  o n c e  d ail y 
i n  p e di atri c s u bj e cts  wit h  T S. 
•  T o  e v al u at e  pl as m a  e x p os ur e  of  N BI - 9 8 8 5 4  a n d its  m et a b olit e,  N BI- 9 8 7 8 2, f oll o wi n g r e p e at e d 
d ail y  d os es  of  N BI - 9 8 8 5 4. 
M et h o d ol o g y:   T his is  a  P h as e  2 b,  m ulti c e nt er,  o p e n-l a b el,  d os e- o pti mi z ati o n st u d y  of t h e s af et y, 
t ol er a bilit y,  PD,  a n d  pl as m a  e x p os ur e  of  N BI - 9 8 8 5 4 d os es  i n t h e r a n g e  of  2 0  m g t o  6 0  m g f or s u bj e cts 
< 5 0  k g  a n d  4 0  m g t o  8 0  m g f or s u bj e cts  ≥ 5 0  k g,  a d mi nist er e d  e a c h  ni g ht  at  b e dti m e ( q hs) f or  a t ot a l  of 
2 4  w e e ks  of tr e at m e nt i n  p e di atri c s u bj e cts  wit h  T S.   T his st u d y  will  o nl y i n cl u d e s u bj e cts  w h o 
p arti ci p at e d i n  a n d  c o m pl et e d t h e  pr e vi o us  P h as e  2 b  cli ni c al st u d y  N BI- 9 8 8 5 4- T S 2 0 0 3. 
U p t o  1 2 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,  wi t h  a  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,  4t h  or  5t h  E diti o ns ( D S M- I V  or -V)  di a g n osis  of  T S  will  p arti ci p at 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 t h e  e n d  of t h e tr e at m e nt  p eri o d.   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 f or  a n  a d diti o n al  2 0- w e e k  d os e  m ai nt e n a n c e  p eri o d.   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.   F oll o w- u p  ass ess m e nts  will  b e  c o n d u ct e d  at t h e  e n d  of  W e e k  2 8 ( 4  w e e ks 
aft er t h e l ast  d os e  of t h e st u d y  dr u g).  
Aft er  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  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 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 t h e st art  of 
st u d y  dr u g  d osi n g  o n  D a y  1.   O n  D a y  1 ( b as eli n e),  eli gi bl e s u bj e cts  will r et ur n t o t h e st u d y  c e nt er 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  w h o  c o nti n u e t o  b e  eli gi bl e f or t h e st u d y  will 
t h e n  b e  dis p e ns e d  a  2- w e e k s u p pl y  of st u d y  dr u g,  wit h  assi g n e d  d os e  b as e d  o n  w ei g ht  gr o u p  at  b as eli n e.  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
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B e gi n ni n g  o n  D a y  1, 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  h o m e  at t h e s u bj e ct’s  b e dti 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).   S u bj e cts  will 
c o nti n u e t o s elf -a d mi nist er t h e  st u d y  dr u g  d ail 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  d ur ati o n  of t h e 
2 4- w e e k tr e at m e nt  p eri o d.   S u bj e cts  will r et ur n t o t h e st u d y  c e nt er  at fi x e d i nt er v als ( e n d  of  W e e ks  2,  4, 
8,  1 2,  1 6,  2 0,  2 4,  a n d  2 8) f or st u d y  ass ess m e nts  a n d  dis p e nsi n g  of st u d y  dr u g ( W e e ks  2,  4,  8,  1 2,  1 6,  a n d 
2 0  o nl y).   As  m u c h  as  p ossi bl e, t h es e st u d y  visits  a n d t h e f oll o w- u p  visit s h o ul d  o c c ur  at t h e s a m e ti m e 
as t h e  D a y  1  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 s af et y,  P D,  a n d  pl as m a  e x p os ur e.  
All s u bj e cts  w h o  c o m pl et e t h e  2 4 -w e e k tr e at m e nt  p eri o d  will  e nt er  a  4 -w e e k f oll o w - u p  p eri o d  wit h  a 
f oll o w-u p  visit  at  W e e k  2 8 (s u bj e cts  w h o t er mi n at e  e arl y  will  h a v e  W e e k  2 8  ass ess m e nts  c o n d u ct e d).  
S af et y,  P D,  a n d st u d y  dr u g  e x p os ur e  will  b e  ass ess 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.   T h e 
tr e at m e nt  p eri o d  visits ( W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  a n d  2 4)  a n d t h e f oll o w-u p  visit ( W e e k  2 8)  will  h a v e  a 
visit  wi n d o w  of - 2  or  + 3  d a ys.   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. 
St u d y  P o p ul ati o n:   U p t o  1 2 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)  wit h  a  D S M -I V 
or - V  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  pr e vi o usl y  p arti ci p at e d i n  a n d  c o m pl et e d 
t h e  N BI- 9 8 8 5 4- T S 2 0 0 3 st u d y. 
D u r ati o n  of  T r 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  a p pr o xi m at el y  3 2  w e e ks, i n cl u di n g  u p t o  2 8  d a ys f or s cr e e ni n g,  2 4  w e e ks  of tr e at m e nt, 
a n d  a f oll o w - u p  p eri o d  of  a p pr o xi m at el y  4  w e e ks. 
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  as  c a ps ul es 
c o nt ai ni n g  2 0  m g  or  4 0  m g  of  N BI- 9 8 8 5 4 (fr e e  b as e  e q ui v al e nt).   S u bj e cts  m ust s w all o w t h e  c a ps ul e (s) 
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  T h 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:   
Pl as m a  D r u g  E x p os u r e  
Bl o o d s a m pl es f or  pl as m a st u d y  dr u g  a n d  m et a b olit e  c o n c e ntr ati o n  a n al ys es  will  b e  c oll e ct e d  at  D a y  1 
( pr e d os e)  a n d  at  W e e ks 2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  2 8  (fi n al st u d y  visit  or  e arl y t er mi n ati o n).  
S u bj e cts/ c ar e gi v ers  will  b e  as k e d t o r e c or d  a n d  pr o vi d e  d osi n g ti m es fr o m t h e  e v e ni n g  b ef or e t h e 
tr e at m e nt  p eri o d  visits  wh e n  t h es e  bl o o d s a m pl es  ar e  c oll e ct e d. 
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 nts  will  b e  a d mi nist er e d  at  D a y  1 ( b as eli n e),  a n d  at  W e e ks  2,  4,  8,  1 2,  1 6,  2 0, 
2 4,  a n d  2 8  (fi n al st u d y  visit  or  at  e arl y t er mi n ati o n): 
•   Y al e  Gl o b al  Ti c  S e v erit y  S c al e ( Y G T S S ) 
•   Pr e m o nit or y  Ur g e f or  Ti cs  S c al e ( P U T S ) 
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 )  will  b e  a d mi nist er e d  at  D a y  1 ( b as eli n e)  a n d  W e e ks  1 2  a n d  2 4.   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 ) will  b e  us e d t o r at e t h e  o v er all s e v erit y  of ti cs  b e gi n ni n g  at 
D a y  1 ( b as eli n e),  a n d t h e n  b ot h  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  a d mi nist er e d  at  W e e ks  2,  4,  8,  1 2,  1 6,  2 0, 
2 4,  a n d  2 8  (fi n al st u d y  visit  or  at  e arl y t er mi n ati o n). 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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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 nts:   
•  
A d v ers e  e v e nts ( A Es ) 
•  
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 mistr y,  a n d  uri n al ysis)  
•  
S er u m  pr ol a cti n 
•  
H e m o gl o bi n  A 1 c 
•  
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 e,  ort h ost ati c  p uls e r at e, 
r es pir at or y r at e,  a n d  or al  b o d y t e m p er at ur e) 
•  
P h ysi c al  e x a mi n ati o ns (i n cl u di n g  h ei g ht  a n d  w e i g ht) 
•  
1 2- l e a d  el e ctr o c ar di o gr a ms (E C Gs ) 
•  
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 
•   C hil dr e n’s  D e pr essi o n  R ati n g  S c al e  - R e vis e d  (C D R S - R) 
•  
C hil dr e n’s  Y al e -Br o w n  O bs essi v e  C o m p ulsi v e  S c al e ( C Y -B O C S ) 
•  
Att e nti o n -D efi cit  H y p er a cti vit y  Dis or d er  R ati n g  S c al e- 5:   H o m e  V ersi o n ( A D H D - 5  R ati n g 
S c al 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) 
St atisti c al  M et h o ds : 
S af et y,  P D,  a n d  pl as m a  dr u g  c o n c e ntr ati o n  d at a  will  b e s u m m ari z e d  b y ti m e p oi nt f or t h e  p o ol e d  w ei g ht 
gr o u ps  a n d  e a c h  w ei g ht  gr o u p s e p ar at el y,  usi n g  d es cri pti v e st atisti cs.     
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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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 D H D - 5 R ati n g  S c al e  
Att e nti o n -D efi cit  H y p er a cti vit y  Dis or d er  R ati n g  S c al e - 5:  
H o m e  V ersi o n  
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  
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 0- ∞  
A U C 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 D R S - R 
C hil dr e n’s  D e pr essi o n  R ati n g  S c al e  - R e vis e d  
C D S  
Cli ni c al  Dr u g  S af et y  
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 -B O C S  
C hil dr e n’s  Y al e - Br o w n  O bs essi v e  C o m p ulsi v e  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 - V 
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 ,  4t h 
or  5 t h  E diti o ns 
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 D T A   K2 
Di p ot assi u m  et h yl e n e di a mi n et etr a a c eti c  a ci d  
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  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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I C F 
I nf or m e d  c o ns e nt f or m 
I C H 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o nis ati o n 
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 K  
P h ar m a c o ki n eti c(s)  
P U T S  
Pr e m o nit or y  Ur g e f or  Ti cs  S c al e  
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  
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  
t½   
T er mi n al  h alf -lif e 
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  
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 B C  
W hit e  bl o o d  c ell  
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  
 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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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 nf er e n c e  o n 
H ar m o nis ati o n  [I C H] of  T e c h ni c al  R e q uir e m e nts f or t h e  R e gistr ati o n  of  P h ar m a c e uti c als f or 
H u m a n  Us e  [ 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). 
•   G ui d a n c e f or  Cli ni c al  Tri al  S p o ns ors:   Cli ni c al  Tri al  A p pli c ati o ns,  Eff e cti v e  M a y  2 9,  2 0 1 3, 
H e alt h  C a n a d a  T h er a p e uti c  Pr o d u cts  Dir e ct or at e,  H e alt h  Pr o d u cts  a n d  F o o d  Br a n c h.  
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.   
I N 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  o n e  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 - V,  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;  L e 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 osis.  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 cti 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 ( L e 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  us 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 pt o ms  h a v e si g nifi c a ntl y i m pr o v e d ( L e 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 os o ci al st r 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 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 1 4


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 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 nistr 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 a str 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  part  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 5 4  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 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 ( C m 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.  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 1 5


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, 
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 (P K ),  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 ulti 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 afet 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 os 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 Es) 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 
saf 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 st u d y s u g g est t h at  all  d os es t est e d 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
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( 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 
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 ( 8 0  m g 
s u bj e ct;  m o d erat 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 ( 40  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  
T his is  a  P h as e  2 b,  m ulti c e nt er,  o p e n-l a b el,  d os e- o pti mi z ati o n st u d y  of t h e s af et y, t ol er a bilit y, 
P D,  a n d  pl as m a  e x p os ur e  of  N BI - 9 8 8 5 4 i n t h e r a n g e  of  2 0  m g t o  6 0  m g f or s u bj e cts  < 5 0  k g  a n d 
4 0  m g t o  8 0  m g f or s u bj e cts  ≥ 5 0  k g,  a d mi nist er e d  e a c h  ni g ht  at  b e dti m e ( q hs) f or  a t ot al  of 
2 4  w e e ks  of tr e at m e nt i n  p e di atri c s u bj e cts  wit h  T S.   T his st u d y  will  o nl y i n cl u d e s u bj e cts  w h o 
p arti ci p at e d i n  a n d  c o m pl et e d t h e  pr e vi o us  P h as e  2 b  pl a c e b o - c o ntr oll e d cli ni c al st u d y 
N BI - 9 8 8 5 4- T S 2 0 0 3. 
R ati o n al e f o r  D os e  S el e cti o n  a n d  R e gi m e n 
T h e  c urr e nt st arti n g  d os es  of  N BI- 9 8 8 5 4 (i e,  2 0  m g  or  4 0  m g)  h a v e  b e e n  w ell t ol er at e d i n 
pr e vi o us st u di es i n  p e di atri c s u bj e cts  wit h  T S ( 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).   T h e 
d os e  o pti mi z ati o n  s c h e m e  b ase d  o n  P D , t ol er a bilit y, a n d  s af et y  ass ess m e nts , as  w ell  as  b e dti m e 
d osi n g  will  all o w s u bj e cts t o  p ot e nti all y r e c ei v e  a n  o pti m al  d os e (i e,  o n e t h at is  b ot h  w ell 
t ol er at e d  a n d  effi c a ci o us)  d uri n g t h e tr e at m e nt  p eri o d. 
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  d et er mi n e t h e l o n g- t er m s af et y  a n d t ol er a bilit y of  u p t o  2 4  w e e ks  of tr e at m e nt  wit h 
N BI - 9 8 8 5 4 i n  p e di atri c s u bj e cts  wit h  T S. 
•   T o  e v al u at e t h e l o n g -t er m  P D  eff e cts  of  N BI- 9 8 8 5 4  a d mi nist er e d  o n c e  d ail y i n  p e di atri c 
s u bj e cts  wit h  T S. 
•   T o  e v al u at e  pl as m a  e x p os ur e  of  N BI - 9 8 8 5 4  a n d its  m et a b olit e,  N BI- 9 8 7 8 2, f oll o wi n g 
r e p e at e d  d ail y  d os es  of  N BI- 9 8 8 5 4. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
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7.   
O V E R VI E W  O F  S T U D Y  D E SI G N  
T his is  a  P h as e  2 b,  m ulti c e nt er,  o p e n-l a b el,  d os e- o pti mi z ati o n st u d y  of t h e s af et y, t ol er a bilit y, 
P D,  a n d  pl as m a  e x p os ur e  of  N BI - 9 8 8 5 4  d os es i n t h e r a n g e  of  2 0  m g t o  6 0  m g f or s u bj e cts 
< 5 0   k g  a n d  4 0  m g t o  8 0  m g f or s u bj e cts  ≥ 5 0  k g,  a d mi nist er e d  e a c h  ni g ht  at  b e dti m e ( q hs) f or  a 
t ot al  of  2 4  w e e ks  of tr e at m e nt i n  p e di atri c s u bj e cts  wit h  T S.   T his st u d y  will  o nl y i n cl u d e 
s u bj e cts  w h o  p arti ci p at e d i n  a n d  c o m pl et e d t h e  pr e vi o us  P h as e  2 b  cli ni c al st u d y 
N BI - 9 8 8 5 4- T S 2 0 0 3. 
U p t o  1 2 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,  wit h  a  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,  4t h  or  5t h  E diti o ns  ( D S M-I V  or - V)  di a g n osis  of  T S 
will  p arti ci p at 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 n tr 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).   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 f or  a n  a d diti o n al  2 0-w e e k  d os e  m ai nt e n a n c e  p eri o d.   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.   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.  
F oll o w- u p  ass ess m e nts  will  b e  c o n d u ct e d  at t h e  e n d  of  W e e k  2 8 ( 4  w e e ks  aft er t h e l ast  d os e  of 
t h e st u d y  dr u g). 
Aft er  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  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 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 t h e st art  of st u d y  dr u g  d osi n g  o n  D a y  1.   O n  D a y  1 ( b as elin e),  eli gi bl e s u bj e cts  will 
r et ur n t o t h e st u d y  c e nt er 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  w h o 
c o nti n u e t o  b e  eli gi bl e f or t h e st u d y  will t h e n  b e  dis p e ns e d  a  2- w e e k s u p pl y  of st u d y  dr u g,  wit h 
assi g n e d  d os e  b as e d  o n  w ei g ht  gr o u p  at  b as eli n e.  
B e gi n ni n g  o n  D a y  1, 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  h o m e  at t h e s u bj e ct’s 
b e dti 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 i n s u bj e cts  ≤ 1 7  y e ars  of 
a g e) .   S u bj e cts  will  c o nti n u e t o s elf-a d mi nist er t h e st u d y  d r u g  d ail 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  d ur ati o n  of t h e  2 4-w e e k tr e at m e nt  p eri o d.   S u bj e cts  will r et ur n t o t h e st u d y  c e nt er  at 
fi x e d i nt er v als ( e n d  of  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  2 8) f or st u d y  ass ess m e nts  a n d 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 1 8


dis p e nsi n g  of st u d y  dr u g ( W e e ks  2,  4,  8,  1 2,  1 6,  a n d  2 0  o nl y).   As  m u c h  as  p ossi bl e, t h es e st u d y 
visits  a n d t h e f oll o w- u p  visit s h o ul d  o c c ur  at t h e s a m e ti m e  as t h e  D a y  1  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 s af et y,  P D,  a n d  pl as m a  e x p os ur e.   All s u bj e cts  w h o  c o m pl et e 
t h e  2 4-w e e k tr e at m e nt  p eri o d  will  e nt er  a  4 -w e e k f oll o w - u p  p eri o d  wit h  a f oll o w-u p  visit  at 
W e e k  2 8 (s u bj e cts  w h o t er mi n at e  e arl y  will  h a v e  W e e k  2 8  ass ess m e nts  c o n d u ct e d).   S af et y,  P D, 
a n d st u d y  dr u g  e x p os ur e  will  b e  ass ess 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.   T h e 
tr e at m e nt  p eri o d  visits ( W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  a n d  2 4)  a n d t h e f oll o w- u p  visit ( W e e k  2 8) 
will  h a v e  a  visit  wi n d o w  of - 2  or  + 3  d a ys.   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  ass ess m e nts f or  T S  ar e t h e  Y G T S S, 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),  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  Pr e m o nit or y  Ur g e f or  Ti cs  S c al e ( P U T S),  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 af et y  ass ess m e nts i n cl u di n g  A E  m o nit ori n g,  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 mistr y,  uri n al ysis ,  h e m o gl o bi n  A 1 c,  a n d s er u m pr ol a cti n ),  vit al si g n  m e as ur e m e nts,  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 C G),  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),  C hil dr e n’s  D e pr essi o n  R ati n g  S c al e - R e vis e d ( C D R S - R), t h e 
C hil dr e n’s  Y al e- Br o w n  O bs essi v e  C o m p ulsi v e  S c al e ( C Y - B O C S), t h e  Att e nti o n-D efi cit 
H y p er a cti vit y  Dis or d er  R ati n g  S c al e -5:   H o m e  V ersi o n ( A D H D - 5 R ati n g  S c al e),  a n d 
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)  will  als o  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. 
Bl o o d s a m pl es f or  pl as m a  dr u g  a n d  m et a b olit e  c o n c e ntr ati o n  a n al ys es  will  b e  o bt ai n e d  at  D a y  1 
( b as eli n e)  a n d  at  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  2 8 (fi n al st u d y  visit  or  at  e arl y t er mi n ati o n).  
S u bj e cts/ c ar e gi v ers  will  b e  as k e d t o r e c or d  a n d  pr o vi d e  d osi n g ti m es fr o m t h e  e v e ni n g  b ef or e 
t h e tr e at m e nt  p eri o d  visits  w h e n t h es e  bl o o d s a m pl es  ar e  c oll e ct e d. 
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. 
 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 1 9




8.   
S T U D Y  P O P U L A TI O N  
T his st u d y  will  b e  c o n d u ct e d i n  u p t o  1 2 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)  wit h  a  D S M -I V  or - V  di a g n osis  of  T S.   S u bj e cts  m ust  m e et all  t h e i n cl usi o n  crit eri a  a n d 
n o n e  of t h e  e x cl usi o n  crit eri a t o  e nt er t h e st u d y. 
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  p arti ci p at e d i n  a n d   c o m pl et e d t h e  P h as e  2 b N BI - 9 8 8 5 4- T S 2 0 0 3 st u d y. 
2.   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 nts  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;  writt e n 
i nf or m e d  c o ns e nt fr o m s u bj ects  1 8  y e ars  of  a g e.  
3.   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. 
4.   B e i n  g o o d  g e n er al  h e alt h  as  d et er mi n e d  b y  m e di c al  hist or y,  p h ysi c al  e x a mi n ati o n,  cli ni c al 
l a b or at or y  ass ess m e nts,  a n d  1 2-l e a d  E C G. 
5.   H a v e  a  D S M -I V  or - V  di a g n osis  of  T S. 
6.   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.  
7.   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 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). 
8.   S u bj e cts  wit h st a bl e  m e di c al  c o n diti o ns r e q uiri n g  m e di c ati o ns t h at  ar e  n ot  pr o hi bit e d  p er 
pr ot o c ol  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. 
9.   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 
s cr e e ni n g  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 s cr e e nin g).   A  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 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 s cr e e ni n g.   
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). 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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•   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  b ei n g t a k e n f or  at l e ast  3  m o nt hs  pri or t o s cr e e ni n g.  
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). 
1 0.  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  a n d  n e g ati v e  uri n e  pr e g n a n c y t est  at 
D a y  1 ( b as eli n e).   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  pr e m e n o p a us al 
f e mal 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 erili z e d . 
1 1.  A d ol es c e nt s u bj e cts ( 1 2 t o  1 8  y e ars  of  a g e)  m ust  h a v e  a  n e g ati v e  uri n e  dr u g s cr e e n ( n e g ati v e 
f or  a m p h et a mi nes,  b ar bit ur at es,  b e n z o di a z e pi n e,  p h e n c y cli di n e,  c o c ai n e,  o pi at es,  or 
c a n n a bi n oi ds)  at s cr e e ni n g ( b as e d  o n r es ults fr o m  c e ntr al l a b or at or y)  a n d  b as eli n e ( D a y  1; 
b as e d  o n r es ults fr o m  o n-sit e  uri n e  dr u g s cr e e n  kit).   S u bj e cts  w h o  ar e  o n st a bl e  d os es  of 
pr es cri b e d  a n d s u p er vis e d ( n ot  as  n e e d e d [ pr n])  b e n z o di a z e pi n es,  o pi at es,  or 
ps y c h osti m ul a nts (f or s u bj e cts  wit h  c o m or bi d  A D H D)  c a n  p arti ci p at e i n t h e st u d y. 
1 2.  A d ol es c e nt s u bj e cts ( 1 2 t o  1 8  y e ars  of  a g e)  m ust  h a v e  a  n e g ati v e  al c o h ol  br e at h t est  at 
s cr e e ni n g  a n d D a y  1 ( b as eli n e) .  
1 3.  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 f oll o w- u p  visit. 
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  or  ps y c hi atri c  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  of 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 s cr e e ni n g. 
3.   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 s cr e e ni n g. 
4.   H a v e  a  hist or y  of s u bst 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  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 -V ( S u bst a n c e  Us e  Dis or d er).  
5.   Ar e  c urr e ntl y  pr e g n a nt  or l a ct ati n g.  
6.   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. 
7.   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. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
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8.   H a v e  a s cr e e ni n g  or  D a y  1  a v er a g e tri pli c at e  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 ca nt  c ar di a c 
a b n or m alit y. 
9.   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 p p er li mit  of  n or m al ( 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. 
1 0.  H a v e  a n y  of t h e f oll o wi n g  h e m at ol o gi c  a b n or m aliti es  at s cr e e ni n g:  
•   H e m o gl o bi n  < 1 1. 0  g/ d L. 
•   W hit e   bl o o d  c ell ( W B C)  c o u nt  < 4. 0  ×  1 03/ m m3. 
•   Pl at el et  c o u nt  < 1 0 0, 0 0 0/ m m 3. 
1 1.  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 s cr e e ni n g, 
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 2.  H a v e  a  cli ni c al  c h e mistr y,  h e m at ol o g y,  or  uri n al ysis r es ult  n ot  wit hi n t h e l a b or at or y’s 
r ef er e n c e r a n g e  a n d  d e e m e d  b y t h e i n v esti g at or t o  b e  cli ni c all y si g nifi c a nt  at s cr e e ni n g.  
1 3.  H a v e r e c ei v e d  a n y  i n v esti g ati o n al pr o d u ct ( ot h er t h a n  N BI- 9 8 8 5 4)  wit hi n  a ti m e  p eri o d 
e q u al t o  5  h alf- li v es  of t h e  pr o d u ct, if  k n o w n,  or  a  mi ni m u m  of  3 0  d a ys  b ef or e s cr e e ni n g, 
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 4.  H a v e r e c ei v e d  a n y  pr o hi bit 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. 7. 1 . 
1 5.  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 6.  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  hist or y  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) i n 
t h e  p ast  y e ar  b ef or e s cr e e ni n g  b as e d  o n t h e  C- S S R S  C hil dr e n’s  V ersi o n s h o ul d  b e  e x cl u d e d. 
1 7.  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). 
1 8.  H a v e  a  hist or y  of  or s us 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.  
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 (first,  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. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
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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.   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 cific 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. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
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T a bl e  1:  
S c h e d ul e  of  Ass ess m e nts  
P r o c e d u r e a 
S c r e e ni n g 
P e ri o d  
T r e at m e nt  P e ri o d  
F oll o w -u p  P e ri o d/ 
E T  
D a y  1 b 
D os e 
O pti mi z ati o n    
D os e  M ai nt e n a n c e  
W e e k        D a y  -2 8  t o -1   
B as eli n e    D osi n g   
2   
4   
8   
1 2   
1 6   
2 0   
2 4  
2 8 c 
Visit d 
1  
2   
--  
3   
4   
5   
6   
7   
8   
9  
1 0  
I nf or m e d c o ns e nt/ ass e nt  
X  
 
  
  
  
  
  
  
  
 
 
I n cl usi o n/ e x cl usi o n  crit eri a 
X   
u p d at e   
  
  
  
  
  
  
  
 
 
M e di c al  hist or y  
X   
u p d at e   
  
  
  
  
  
  
  
 
 
P E (i n cl u di n g  w ei g ht)  
X  
X  
  
X   
  
  
  
X   
  
X  
X  
H ei g ht  
X  
  
  
  
  
  
  
  
  
 
 
Vit al si g ns  
X  
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
1 2 -l e a d E C G e 
X  
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
Pr e g n a n c y  t estf 
X (s)   
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 e stsg 
X  
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
Uri n e  dr u g  s cr e e n ( a d ol es c e nts) h 
X  
X  
  
  
  
  
  
  
  
 
 
Al c o h ol  br e at h t est ( a d ol es c e nts)   
X  
X  
  
  
  
  
  
  
  
 
 
H e m o gl o bi n  A 1 c  
X  
X   
  
  
  
  
X   
  
  
X  
 
Bl o o d  s a m pl e f or  pr ol a cti n  
 
X  
  
  
  
  
X   
  
  
X  
X  
P K  bl o o d s a m pl e  
 
X   
  
X   
X   
X   
X   
X   
X   
X  
X  
Y G T S S (i n cl u di n g  vi d e o 
r e c or di n g) 
 
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
P U T S  
 
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
C GI -Ti cs -S e v erit y   
 
X  
  
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  
X  
C -S S R S  
X  
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
C Y -B O C S  a n d  C D R S -R  
 
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
A D H D -5  R ati n g  S c al e  
 
X   
  
  
  
  
X   
  
  
X  
X  
E S R S -A  
 
X  
  
X   
X   
X   
X   
X   
X   
X  
X  
C & A -G T S -Q O L  
 
X   
 
  
 
  
X   
  
  
X  
 
St u d y  dr u g  d osi n g  at  h o m e i 
 
 
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   
 
 
St u d y  dr u g  a c c o u nt a bilit y j 
 
  
  
X   
X   
X   
X   
X   
X   
X  
 
A E  m o nit ori n g  
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  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
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C o nfi de ntial
Pa ge 2 5


A D H D = a tt e nti o n d e fi cit- hy p er a cti vit y  d is or d er; A E = a d v ers e  e v e nt;  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 D R S - R =C hil dr e n’s  D e pr essi o n  R ati n g  S c al e  - R e vis e d;  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;  C Y -B O C S = C hil dr e n’s 
Y al e -Br o w n  O bs essi v e -C o m p ulsi v e  S c al e;  E C G = el e ctr o c ar di o gr a m;  E S R S - A =E xtr a p yr a mi d al  S y m pt o ms  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;  P E = p h ysi c al  e x a mi n ati o n;  P K = p h ar m a c o ki n eti cs;  P U T S = Pr e m o nit or y  Ur g e f or  Ti cs  S c al e; s = s er u m;  u 
= uri n e;  Y G T S S = Y al e  Gl o b al  Ti c  S e v erit y  S c al e.  
a  As  m u c h  as  p ossi bl e, st u d y  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  a s t h e  D a y  1  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 e ss m e nt  of 
p h ar m c o d y n a mi cs, s af et y,  a n d  pl as m a  e x p os ur e t hr o u g h o ut t h e st u d y  p eri o d.  
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.    
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 Visits  ( ot h er t h a n s cr e e ni n g  a n d  D a y  1) will  h a v e  a  wi n d o w  of  -2 t o  + 3  d a ys.  
e  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 e s )  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 e s.  
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 a l c ul at e d). 
f  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  a n d  uri n e  pr e g n a n c y t e sts  will  b e  c o n d u ct e d  at  all  ot h er st u d y  visits  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.  
g Cli ni c al l a b or at or y t e sts i n cl u d e  h e m at ol o g y,  cli ni c al  c h e mistr y , a n d  uri n al ysis.   All  bl o o d s a m pl es  will  b e  o bt ai n e d  u n d er  n o nf a st e d  c o n diti o ns.  
h A n  o n -sit e  uri n e  dr u g s cr e e n s h o ul d  b e  p erf or m e d  pri or t o  dis p e nsi n g st u d y  dr u g.  
i  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  e a c h  d osi n g  of st u d y  dr u g  will  b e r e c or d e d.  
j  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 e s r et ur n e d  at  e a c h st u d y  visit.  
 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 2 6


9. 2.   
P h a r m a c o d y n a mi c  Ass ess m e nts  
9. 2. 1.   
Y al e  Gl o b al  Ti c  S e v e rit y  S c al e  
T h e  Y G T S S  will  b e  us e d t o  ass ess ti c  b e h a vi ors  ass o ci at e d  wit h  T S ( L e c k m a n  et  a l.,  1 9 8 9).  T h e 
Y G T S S is  d esi g n e d t o r at e t h e  o v er all s e v erit y  of  m ot or  a n d  p h o ni c ti c s y m pt o ms  a cr oss  a r a n g e 
of  di m e nsi o ns:   n u m b er, fr e q u e n c y, i nt e nsit y,  c o m pl e xit y,  a n d i nt erf er e n c e .  T h e s c al e  als o 
i n cl u d es  a n i m p air m e nt  ass ess m e nt.  T h e  Y G T S S  will  b e  a d mi nist er e d  b y t h e i n v esti g at or ( or 
q u alifi e d  d esi g n e e)  usi n g  a  c o m p ut er- b as e d str u ct ur e d  cli ni c al i nt er vi e w.   At  e a c h ti m e p oi nt, t h e 
Y G T S S i nt er vi e w  will  b e  vi d e o r e c or d e d.   T h e  vi d e o r e c or di n g  will f oll o w  a st a n d ar di z e d s et  of 
g ui d eli n es  a n d t h e r e c or d e d  vi d e o  will  b e  u pl o a d e d t o  a s e c ur e  c e ntr al s er v er.   A  bli n d e d, 
e xt er n al  vi d e o r e vi e w er ,  n ot  affili at e d  wit h t h e sit e, will  a c c ess t h e  c e ntr al s er v er t o  vi e w t h e 
r e c or di n g  a n d  d et er mi n e if t h e  Y G T S S i nt er vi e w  pr o gr a m  w as  a d mi nist er e d  pr o p erl y.   T h e 
c o m p ut er s oft w ar e s yst e m f or t h e  Y G T S S  a d mi nistr ati o n,  R at er  St ati o n ™ ( Br a c k et  Gl o b al, L L C ; 
P hil a d el p hi a,  P A),  will  pr o m pt  t h e i n v esti g at or ( or  a  q u alifi e d  d esi g n e e), a tr ai n e d  a n d  c ertifi e d 
r at er, t o  e nt er  a s c or e f or  e a c h it e m  of t h e s c al e b a s e d  o n s u bj e ct  a n d  p ar e nt r es p o ns es  d uri n g t h e 
str u ct ur e d  cli ni c al i nt er vi e w .   As  m u c h  as  p ossi bl e,  a  gi v e n s u bj e ct s h o ul d  h a v e t h e s a m e r at er 
t hr o u g h o ut t h e st u d y.  T h e s oft w ar e  will  als o  g e n er at e  i n di vi d u al s c or es f or  e a c h it e m  of t h e 
s c al e (t a n d e m r ati n g)  a n d  will  g e n e r at e t h e T T S  a n d t h e  Gl o b al  Ti c  S e v erit y  S c or e.  
T h e  Y G T S S  will  b e  a d mi nist er e d  at  D a y  1 ( b as eli n e) ,  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4, a n d  at t h e 
f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e  Y G T S S is  pr o vi d e d i n 
A p p e n di x  1 7. 1 .  
9. 2. 2.   
P r e m o nit o r y  U r g e f o r  Ti cs  S c al e  
T h e  P U T S is  a  v ali d  a n d r eli a bl e i nstr u m e nt f or  q u a ntif yi n g t h e  pr e m o nit or y  ur g e  p h e n o m e n a 
ass o ci at e d  w it h tics ( W o o ds  et  al.,  2 0 0 5 ).  E a c h  of t h e  9 it e ms i n t h e  P U T S is r at e d  o n  a  4- p oi nt 
s c al e ( 1 = n ot  at  al l tr u e,  2 = a littl e tr u e,  3 = pr ett y  m u c h tr u e,  4 = v er y  m u c h tr u e)  a n d s u m m e d t o 
yi el d  a t ot al s c or e r efl e cti n g t h e  pr es e n c e  a n d fr e q u e n c y  of  pr e -ti c (i e,  pr e m o nit or y)  ur g es  al o n g 
wit h r eli ef t h at  m a y  b e  e x p eri e n c e d  aft er ti cs  h a v e  b e e n  c o m pl et e d.    
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  P U T S  at D a y  1 ( b as eli n e),  W e e ks  2,  4,  8,  1 2, 
1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e  P U T S is 
pr o vi d e d i n  A p p e n di x  1 7. 2 . 
9. 2. 3.   
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  C GI -T S – I m pr o v e m e nt s c al es  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 c s- Se v erit y s c al e  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  at  D a y  1 ( b as eli n e) ,  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e 
f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e  C GI-Ti cs -S e v erit y s c al e is 
pr o vi d e d i n  A p p e n di x  1 7. 3 . 
T h e  C GI -T S – I m pr o v e m e nt s c al e 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 s c al es  will  b e  ass ess e d  b y t h e i n v esti g at or  at W e e ks  2,  4,  8,  1 2,  1 6,  2 0, 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 2 7


2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e 
C GI -T S – I m pr o v e m e nt s c al e is  pr o vi d e d i n  A p p e n di x  1 7. 4 . 
9. 2. 4.   
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 r e 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 ite 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 - 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 p l et e t h e  C & A-G T S -Q O L  at  D a y  1 ( b as eli n e) , a n d  W e e ks   1 2  a n d  2 4.  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 ut t h e q u esti o n n air e if  n e e d e d.   C o pi es  of  b ot h  v ersi o ns  of 
t h e  C & A-G T S -Q O L  ar e   pr o vi d e d i n  A p p e n di x 1 7. 5 . 
9. 3.   
Pl as m a  D r u g  E x p os u r e  
Bl o o d s a m pl es t o  e v al u at e  pl as m a  c o n c e ntr ati o ns  of  N BI- 9 8 8 5 4  a n d  t h e  m et a b olit e  N BI- 9 8 7 8 2 
will  b e  c oll e ct e d  at  D a y  1 ( pr e d os e)  a n d  at  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p 
visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   T h e  e x a ct ti m e  of  c ol l e cti o n  will  b e r e c or d e d  o n t h e 
e C R F.  
F or  e a c h  pl as m a s a m pl e,  a p pr o xi m at el y  2   m L  of  bl o o d  will  b e  c oll e ct e d i n t u b es  c o nt ai ni n g 
di p ot assi u m  et h yl e n e di a mi n et etr a a c eti c  a ci d ( E D T A  K 2).   T h e  bl o o d s a m pl es  will  b e  pr o c ess e d 
a n d st or e d  a c c or di n g t o t h e  pr o c e d ur e  as s p e cifi e d i n t h e l a b or at or y  m a n u al.   T h es e s a m pl es  will 
b e s hi p p e d  o n  dr y i c e t o t h e  c e ntr al l a b or at or y f or  a n al ysis.   R ef er t o t h e l a b or at or y  m a n u al f or 
a d diti o n al  d et ails.  
9. 4.   
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. 7. 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. 
A n y  a b n or m al  vit al si g n  m e as ur e m e nt,  p h ysi c al  e x a mi n ati o n fi n di n g,  cli ni c al l a b or at or y t est,  or 
E C G  p ar a m et er  d e e m e d  cli ni c all y si g nifi c a nt  b y t h e i n v esti g at or  will  b e r e p e at e d, i n cl u di n g t est 
r es ults  o bt ai n e d at 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,  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.  If t h e i n v esti g at or  d et er mi n es t h at  a s u bj e ct  h as  a  cli ni c all y si g nifi c a nt fi n di n g  of 
tr e at m e nt- e m er g e nt  d e pr essi o n, s ui ci d al i d e ati o n,  ps y c hi atri c s y m pt o ms ( b as e d  u p o n t h e 
C- S S R S,  C D R S -R,  C Y -B O C S,  A D H D- 5  R ati n g  S c al e , or  cli ni c al  ass ess m e nt), t h e fi n di n g  will 
b e  d o c u m e nt e d  as  a n  A E,  a n d  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. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 2 8


9. 4. 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 m i 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. 4. 2.   
Vit al  Si g n  M e as u r e m e nts  
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 ut es  a n d  aft er  a p pr o x i 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,  D a y  1 ( b as eli n e) ,  W e e ks  2,  4,  8,  1 2,  1 6, 
2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  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. 4. 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 t h e s cr e e ni n g  visit  a n d  u p d at e 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. 4. 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 
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,  D a y  1 ( b as eli n e) ,  a n d at 
W e e ks  2,  1 6,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8 ),  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  o nl y.   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. 4. 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 alit y r e c or d e d 
o n t h e  A E  e C R F. 
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,  D a y  1 ( b as eli n e),  a n d at  W e e ks  2, 
4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 2 9


9. 4. 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,  D a y  1 ( b as eli n e) ,  a n d at 
W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  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 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).  
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 ati 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 es,  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  nitri t 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:  
H e m o gl o bi n  A 1 c:   Bl o o d s a m pl es f or  h e m o gl o bi n  A 1 c  will  b e  c oll e ct e d  at s cr e e ni n g,  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  a n d  2 4.   A p pr o xi m at el y  2 m L i n  E D T A  K 2 will  b e 
c oll e ct e d i n  all s u bj e cts.  
S er u m  Pr ol a cti n:   Bl o o d s a m pl es t o  d et er mi n e s er u m  pr ol a cti n  c o n c e ntr ati o n  will  b e  c oll e ct e d  at 
D a y  1 ( b as eli n e),  at  W e e ks  1 2  a n d   2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y 
t er mi n ati o n.   S er u m  pr ol acti n s a m pl es  will  b e s hi p p e d t o  a  c e ntr al l a b or at or y f or  a n al ysis.  
Uri n e  Dr u g  S cr e e n  a n d  Al c o h ol  Br e at h  T est :   T h e  uri n e  dr u g s cr e e n  will t est f or  a m p h et a mi n es, 
b ar bit ur at es,  p h e n c y cli di n e,  b e n z o di a z e pi n es,  c a n n a bi n oi ds,  c o c ai n e,  a n d  o pi at es.   Uri n e t esti n g 
kits  will  b e  pr o vi d e d  b y t h e  c e ntr al l a b or at or y f or  pr eli mi n ar y  c o nfir m ati o n  of  n e g ati v e  dr u g 
s cr e e n at t h e sit e   pri or t o  d osi n g.   A s e p ar at e  uri n e s a m pl e  will  als o  b e s e nt t o t h e  c e ntr al 
l a b or at or y f or  a n al ysis.   A  uri n e  dr u g s cr e e n  a n d  al c o h ol  br e at h al y z er t est  will  b e  p erf or m e d  at 
s cr e e ni n g  a n d  o n  D a y  1.   T h e  uri n e  dr u g s cr e e n  a n d  al c o h ol  br e at h al y z er t est  will  b e  p erf or m e d 
o nl y i n  a d ol es c e nt s u bj e cts ( 1 2  t o  1 8 y e ars  of  a g e).    A  uri n e  dr u g s cr e e n  usi n g  a  kit  pr o vi d e d  b y 
t h e  c e ntr al l a b or at or y  m a y  b e  c o n d u ct e d  at t h e  cli ni c al sit e  at  a n y ti m e  d uri n g t h e st u d y if t h e 
s u bj e ct ( a d ol es c e nt s u bj e cts  o nl y) is s us p e ct e d  of s u bst a n c e  or  dr u g  a b us e. 
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  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,  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8), 
or  e arl y t er mi n ati o n.  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 0


9. 4. 7.   
C ol u m bi a -S ui ci d e  S e v e rit y  R ati n g  S c al e  C 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  b as eli n e  a n d  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  L ast  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 lifeti 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  1  y e ar  
b ef or e s cr e e ni n g  b as e d  o n t h e  C -S S R S  C hil dr e n’s  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  # 1 6 ). 
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  at s cr e e ni n g,  D a y  1 ( b as eli n e),  a n d  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p 
visit ( W e e k   2 8),  or  e arl y t er mi n ati o n.  A  c o p y  of  e a c h  C hil dr e n’s  v ersi o n  of t h e  C- S S R S  is 
pr o vi d e d i n  A p p e n di x  1 7. 6  a n d  A p p e n di x  1 7. 7 , r es p e cti v el y. 
9. 4. 8.   
C hil d r e n’s  D e p r essi o n  R ati n g  S c al e,  R e vis e d  
T h e  C D R S -R is  a  1 7 -it e m, s e mi-str u ct ur e d i nt er vi e w t o  d et er mi n e t h e s e v erit y  of  d e pr essi o n i n 
c hil dr e n.   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  C D R S- R  o n D a y  1  ( b as eli n e)  a n d at 
W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A 
c o p y  of t h e  C D R S - R is  pr o vi d e d i n A p p e n di x  1 7. 8 . 
9. 4. 9.   
C hil d r e n’s  Y al e -B r o w n  O bs essi v e   C o m p ulsi v e  S c al e 
T h e  C Y -B O C S is  a s e mi -str u ct ur e d i nt er vi e w  d esi g n e d t o r at e t h e s e v erit y  of  o bs essi v e  a n d 
c o m p ulsi v e s y m pt o ms i n  c hil dr e n.   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 
C Y -B O C S  at  D a y  1 ( b a s eli n e),  W e e ks  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit 
( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e  C Y- B O C S is  pr o vi d e d i n A p p e n di x  1 7. 9 . 
9. 4. 1 0.   
Att e nti o n -D efi cit  H y p e r a cti vit y  Dis o r d e r  R ati n g  S c al e - 5:  H o m e  V e rsi o n 
T h e  A D H D  R ati n g  S c al e - 5:   H o m e  V ersi o n  will  b e  us e d t o  d et er mi n e t h e fr e q u e n c y  a n d 
s e v erit y  of  A D H D s y m pt o ms  a n d i m p air m e nts  o v er t h e  p ast  2  w e e ks.   T h e  s c al e  c o m es i n 
2  v ersi o ns:   c hil d ( a g es  5 - 1 0  y e ars)  a n d  a d ol es c e nt ( a g es  1 1-1 7  y e ars ; s u bj e cts  1 8  y e ars  of  a g e 
will  als o  us e t his  v ersi o n ).  B ot h   v ersi o ns  c o nsist  of  2 s y m pt o m s u bs c al es, I n att e nti o n ( 9 it e ms), 
a n d  H y p er a cti vit y – I m p ulsi vit y ( 9 it e ms),  as  w ell  as  a  T ot al  S c al e ( 1 8 it e ms).   I n  a d diti o n, 
6  d o m ai ns  of i m p air m e nt t h at  ar e  c o m m o n  a m o n g  c hil dr e n  wit h  A D H D  ar e  ass ess e d:  
r el ati o ns hi ps  wit h si g nifi c a nt  ot h ers (f a mil y  m e m b ers f or t h e  h o m e  v ersi o n  a n d t e a c h ers f or t h e 
s c h o ol  v ersi o n),  p e er r el ati o ns hi ps,  a c a d e mi c f u n cti o ni n g,  b e h a vi or al f u n cti o ni n g,  h o m e w or k 
p erf or m a n c e,  a n d s elf -est e e m.  
It  will  b e  c o m pl et e d i n d e p e n d e ntl y  b y t h e s u bj e ct’s  p ar e nt  or  g u ar di a n  at  D a y  1 ( b as eli n e), 
W e e ks  1 2  a n d  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8 ),  or  e arl y t er mi n ati o n.   A  c o p y  of  b ot h 
v ersi o ns  of  t h e  A D H D  R ati n g S c al e - 5:  H o m e  V ersi o n is  pr o vi d e d i n A p p e n di x  1 7. 1 0 . 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 1


9. 4. 1 1.   
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 a r 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) , W e e ks  2 ,  4,  8, 
1 2,  1 6,  2 0,  2 4,  a n d  at t h e f oll o w- u p  visit ( W e e k  2 8),  or  e arl y t er mi n ati o n.   A  c o p y  of t h e 
E S R S - A is  pr o vi d e d i n  A p p e n di x 1 7. 1 1 . 
9. 4. 1 2.   
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 s cr e e ni n g, t h e tr e at m e nt  p eri o d,  a n d t h e fi n al 
visit ( W e e k  2 8  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 o t 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 e s 
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)  
C hil d r e n ( 6 t o  1 1  y e a rs  of  a g e)  
Cli ni c al  c h e mistr y a 
1 0  
2. 5  
2 5  
H e m at ol o g y  
1 0  
3 
3 0  
H e m o gl o bi n  A 1 c  
4 
2 
8 
S er u m  pr ol a cti n  
4 
2. 5  
1 0  
P h ar m a c o ki n eti cs  
9 
2 
1 8 
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):  
9 1  
A d ol es c e nts ( 1 2 t o  1 8  y e a rs  of  a g e)  
Cli ni c al  c h e mistr y a 
1 0  
5 
5 0  
H e m at ol o g y  
1 0  
4 
4 0  
H e m o gl o bi n  A 1 c  
4 
2 
8 
S er u m  pr ol a cti n  
4 
5 
2 0  
P h ar m a c o ki n eti cs  
9 
2 
1 8  
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):  
1 3 6  
a .   I n cl u d es  pr e g n a n c y t est f or f e m al e s u bj e cts  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. 
9. 5.   
S p e cifi c  St u d y I nf o r m ati o n  
Aft er  pr o vi di n g  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 ( as 
r e q uir e d  b y t h e  g o v er ni n g I R B), s u bj e cts  will  u n d er g o s cr e e ni n g  pr o c e d ur es  wit hi n  2 8  d a ys  of 
D a y  - 1. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 2


9. 5. 1.   
S c r e e ni n g  ( D a ys - 2 8 t o - 1) 
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). 
•   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.  
•   P erf or m  al c o h ol  br e at h al y z er t est  a n d  uri n e  dr u g s cr e e n ( b ot h  o nl y i n  a d ol es c e nt s u bj e cts). 
•   C oll e ct  bl o o d s a m pl e f or  h e m o gl o bi n  A 1 c. 
•   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 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  # 9 i n S e cti o n  8. 1 ). 
•   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 ch  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 , s af et y,  a n d  pl as m a  e x p os ur e t hr o u g h o ut t h e st u d y  p eri o d.  
9. 5. 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) 
S u bj e cts  (a n d  p ar e nts/l e g al  g u ar di a ns  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 : 
•   U p d at e  i n cl usi o n  a n d  e x cl usi o n crit er i a. 
•   U p d at e  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.  
•   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.  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 3


•   P erf or m  1 2 -l e a d  E C G i n tri pli c ate ( 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.  
•   P erf or m  al c o h ol  br e at h al y z er t est  a n d  uri n e  dr u g s cr e e n ( b ot h  o nl y i n  a d ol es c e nt s u bj e cts). 
•   C oll e ct  bl o o d s a m pl e f or  h e m o gl o bi n  A 1 c. 
•   C oll e ct  bl o o d s a m pl e f or  s er u m pr ol a cti n. 
•   C oll e ct  P K  bl o o d s a m pl e f or  N BI- 9 8 8 5 4  a n d  m et a b olit e  c o n c e ntr ati o ns. 
•   A d mi nist er t h e  Y G T S S , i n cl u di n g  vi d e o r e c or di n g. 
•   A d mi nist er t h e  P U T S.  
•   A d mi nist er t h e  C GI -Ti cs -S e v erit y s c al e . 
•   A d mi nist er t h e  C -S S R S ( C hil dr e n’s  Si n c e  L ast  Visit  v ersi o n ). 
•   A d mi nist er  t h e  C Y-B O C S  a n d  C D R S -R.  
•   A d mi nist er t h e  A D H D - 5 R ati n g  S c al e . 
•   A d mi nist er t h e  E S R S -A.  
•   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. 
•   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  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 nts/l e g al  g u ar di a ns  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 nts/l e g al  g u ar di a ns  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 ( - 2 t o  + 3 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  # 9 i n S e cti o n  8. 1 ). 
•   I nstr u ct s u bj e cts (a n d  p ar e nts/l e g al  g u ar di a ns  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.  
N ot e, s u bs e q u e nt st u d y  visits  d uri n g t h e  d os e  o pti mi z ati o n  p eri o d  will  b e  1 4  d a ys fr o m t h e 
pr e vi o us  visit ( 2 8  d a ys fr o m t h e  pr e vi o us  visit  d uri n g t h e  d os e  m ai nt e n a n c e  p eri o d  a n d 
f oll o w- u p  p eri o d); f or  e x a m pl e, t h e  W e e k  2  visit  will  b e  o n  D a y  1 5 (- 2 t o  + 3  d a ys)  a n d t h e 
W e e k  4  visit  will  b e  o n  D a y  2 9 (- 2 t o  + 3  d a ys). 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 4


9. 5. 3.   
D os e  O pti mi z ati o n  P e ri o d:   W e e ks  2  a n d  4 (- 2 t o  + 3  d a ys  f o r  e a c h  visit) 
S u bj e cts  (a n d  p ar e nts/l e g al  g u ar di a ns  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   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 : 
•   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 k  2  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). 
•   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.  
•   C oll e ct  P K  bl o o d s a m pl e  f or  N BI- 9 8 8 5 4  a n d  m et a b olit e  c o n c e ntr ati o ns. 
•   A d mi nist er t h e  Y G T S S , i n cl u di n g  vi d e o r e c or di n g. 
•   A d mi nist er t h e  P U T S.  
•   A d mi nist er t h e  C GI -Ti cs -S e v erit y s c al e . 
•   A d mi nist er t h e  C GI -T S -I m pr o v e m e nt s c al e. 
•   A d mi nist er t h e  C -S S R S ( C hil dr e n’s  Si n c e  L ast  Visit  v ersi o n ). 
•   A d mi nist er  t h e  C Y-B O C S  a n d  C D R S -R.  
•   A d mi nist er t h e  E S R S -A.  
•   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.  
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 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 5


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 es p 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 -w e e k  ( W e e k  2)  or  4-w e e k ( W e e k  4)  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 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  # 9 i n S e cti o n  8. 1 ). 
•   I nstr u ct s u bj e cts (a n d  p ar e nts/l e g al  g u ar di a ns  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 a ti 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. 5. 4.   
D os e  M ai nt e n a n c e  P e ri o d:   W e e ks  8,  1 2,  1 6,  2 0,  a n d  2 4 (- 2 t o  + 3  d a ys f o r  e a c h 
visit)  
At  W e e ks  8,  1 2,  1 6,  2 0,  a n d  2 4 t h e f oll o wi n g  st ud 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 k s  1 6  a n d  2 4  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). 
•   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 o ll e ct  uri n e s a m pl e f or  uri n al ysis. 
•   C oll e ct  bl o o d s a m pl e f or  h e m o gl o bi n  A 1 c ( W e e ks  1 2  a n d  2 4  o nl y). 
•   C oll e ct  bl o o d s a m pl e f or s er u m  pr ol a cti n ( W e e ks  1 2  a n d  2 4  o nl y). 
•   C oll e ct  P K  bl o o d s a m pl e f or  N BI- 9 8 8 5 4  a n d  m et a b olit e  c o n c e ntr ati o ns. 
•   A d mi nist er t h e  Y G T S S,  i n cl u di n g  vi d e o r e c or di n g. 
•   A d mi nist er t h e  P U T S.  
•   A d mi nist er t h e  C GI -Ti cs – S e v erit y s c al e  
•   A d mi nist er t h e  C GI -T S – I m pr o v e m e nt s c al e. 
•   A d mi nist er t h e  C - S S R S ( C hil dr e n’s  Si n c e  L ast  Visit  v ersi o n). 
•   A d mi nist er t h e  C Y -B O C S  a n d  C D R S -R.  
•   A d mi nist er t h e  A D H D - 5 R ati n g  S c a l e ( W e e ks  1 2  a n d  2 4  o nl y). 
•   A d mi nist er t h e  E S R S -A.  
•   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  a  4- w e e k s u p pl y  of st u d y  dr u g ( W e e ks  8,  1 2,  1 6,  a n d  2 0  o nl y ). 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 6


•   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.  
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  # 9 i n S e cti o n  8. 1 ). 
•   I nstr u ct s u bj e cts (a n d  p ar e nts/l e g al  g u ar di a ns  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. 5. 5.   
F oll o w- u p  P e ri o d / E a rl y  T e r mi n ati o n:  W e e k  2 8 (- 2 t o  + 3  d a ys) 
At  W e e k  2 8 ( or  u p o n  e arl y t er mi n ati o n) 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.  
•   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.  
•   C oll e ct  bl o o d s a m pl e f or  s er u m pr ol a cti n. 
•   C oll e ct  P K  bl o o d s a m pl e f or  N BI- 9 8 8 5 4  a n d  m et a b olit e  c o n c e ntr ati o ns. 
•   A d mi nist er t h e  Y G T S S , i n cl u di n g  vi d e o r e c or di n g. 
•   A d mi nist er t h e  P U T S.  
•   A d mi nist er t h e  C GI -Ti cs – S e v erit y s c al e . 
•   A d mi nist er t h e  C GI -T S – I m pr o v e m e nt s c al e. 
•   A d mi nist er t h e  C -S S R S ( C hil dr e n’s  Si n c e  L ast  Visit  v ersi o n ). 
•   A d mi nist er  t h e  C Y-B O C S  a n d  C D R S -R.  
•   A d mi nist er t h e  A D H D - 5 R ati n g  S c al e . 
•   A d mi nist er t h e  E S R S -A.  
•   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.  
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 7


9. 6.   
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  a p pr o xi m at el y  3 2  w e e ks, 
i n cl u di n g  u p t o  2 8  d a ys f or s cr e e ni n g,  2 4  w e e ks  of tr e at m e nt,  a n d  a f oll o w- u p  p eri o d  of 
a p pr o xi m at el y  4  w e e ks. 
9. 7.   
P r o hi biti o ns  a n d  R est ri cti o ns  
9. 7. 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  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  b as eli n e ( D a y  1)  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 
o t 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  f or tr e at m e nt  of  T S 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 a rit 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). 
•   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 z i n e, r es er pi n e)  ar e 
pr o hi bit e d,  e x c e pt f or st u d y  dr u g. 
•   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 osti 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,  c a n n a bi n oi ds, 
a n d str o n g  C Y P 2 D 6 i n hi bit ors.   
9. 7. 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.  
Gr a p efr uit j ui c e  or  gr a p efr uit  pr o d u cts  ar e  pr o hi bit e d fr o m  7  d a ys  b ef or e  D a y   1  u ntil t h e 
f oll o w- u p  visit.   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 f oll o w- u p  visit. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 3 8


9. 7. 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 s cr e e ni n g t o t h e f oll o w- u p  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, i n cl u di n g 
t h e s cr e e ni n g  p eri o d,  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 th e l ast  d os e  of st u d y 
dr u g. 
9. 8.   
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. 
T h e i n v esti g at or  or  N BI  m a y  wit h dr a w t h e s u bj e ct fr o m t h e st u d y f or  ot h er r e as o ns  as  d es cri b e d 
b el o w.   T h es e s h o ul d  b e  dis c uss e d  o n  a  c as e- b y -c as e  b as is  wit h t h e  N BI  m e di c al  m o nit or ( or 
d esi g n e e)  pri or t o  wit h dr a wi n g t h e s u bj e ct fr o m t h e st u d y.  
•   D e v el o ps  a  cli ni c all y si g nifi c a nt l a b or at or y ( e g,  A L T  or  A S T  ≥ 2. 5 ti m es  U L N)  or  E C G 
a b n or m alit y. 
•   R e q uir es  a  m e di c ati o n t h at is  pr o hi bit e d  b y t h e  pr ot o c ol (r ef er t o  S e cti o n  9. 7. 1 ). 
•   Is  n o n- c o m pli a nt  wit h t h e  d osi n g r e gi m e n ( < 8 0 %  d osi n g  c o m pli a n c e)  as  v erifi e d  b y  dr u g 
a c c o u nt a bilit y ( R ef er t o  S e cti o n  1 0. 6 ). 
All s u bj e cts  pr e m at ur el y  dis c o nti n ui n g t h e st u d y, r e g ar dl ess  of  c a us e, s h o ul d  h a v e  all  e arl y 
t er mi n ati o n  ass ess m e nts  p erf or m e d (s e e S e cti o n  9. 5. 5 ). 
9. 8. 1.   
H a n dli n g  of  Wit h d r a w als  
If  a s u bj e ct  pr e m at ur el y  wit h dr a ws fr o m t h e st u d y,  eit h er  at  his/ h er r e q u est,  at t h e r e q u est  of t h e 
p ar e nt  or l e g al  g u ar di a n,  or  at t h e i n v esti g at or’s  dis cr eti o n, t h e i n v esti g at or  will r e c or d t h e 
r e as o n f or  wit h dr a w al  o n t h e r el e v a nt  e C R F.   All s u bj e cts  w h o  wit h dr a w fr o m t h e st u d y 
pr e m at ur el y  s h o ul d h a v e  all  e arl y t er mi n ati o n  ass ess m e nts  p erf or m e d.  
It is  cr u ci al t o  o bt ai n f oll o w- u p  d at a f or  a n y s u bj e ct  wit h dr a w n  b e c a us e  of  a n  A E,  a b n or m al 
l a b or at or y t est,  vit al si g n  m e as ur e m e nt,  p h ysi c al  e x a mi n ati o n,  or  E C G fi n di n g.  I n  a n y  c as e, 
e v er y  eff ort  m ust  b e  m a d e t o  u n d ert a k e s af et y f oll o w- u p  pr o c e d ur es. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
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Pa ge 3 9






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 2 8  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  ass o ci at e d  wit h t h e  us e  of  a  dr u g i n  h u m a ns, 
w h et h er  or  n ot  c o nsi d er e d  dr u g r el at e d.   D uri n g t h e st u d y,  cli ni c all y si g nifi c a nt  a d v ers e  c h a n g es 
i n  cli ni c al st at us,  E C Gs, l a b or at or y  v al u es ( n ot  ass o ci at e d  wit h  a n  A E  or  c o n c urr e nt  m e di c al 
c o n diti o n),  or  p h ysi c al  e x a mi n ati o ns  ar e  c o nsi d er e d  A Es.   A n y s u bj e ct  c o m pl ai nt  ass o ci at e d 
wit h s u c h  a n  a b n or m al fi n di n g  will  als o  b e r e p ort e d  as  a n  A E. 
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 ors 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  prim 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. 
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  dr 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 ors 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. ” 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
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Pa ge 4 2


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 es 
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 es  wit h  us u al  a cti viti e s  of  d ail y li vi n g,  c a usi n g  dis c o mf ort  b ut 
p os 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 pts  us u a l  a cti viti e s  of  d ail y li vi n g,  or si g nifi c a ntl y  aff e cts  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]). 
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 ws  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 ws  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 os 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 os 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 ossi 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 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 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 ws  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 us 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 eristics  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  us 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 ). 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 4 3


•   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.  
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 os 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 
Pa ge 4 4


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 u s 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 . 
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  Cli ni c al  Dr u g  S af et y ( C D S)  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  C D S:  
  
C D S 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 
  
C D S f a csi mil e:    ( 8 8 8)  6 1 7- 7 5 5 1 
  
C D S  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 e ur o cri n e  Bi os ci e n c es, I n c.  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  vi a t el e p h o n e  or f a csi mil e;  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 e ur o cri n e  Bi os ci e n c es, I n c.  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 s af 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. 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 4 5


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  # 9  i n S e cti o n  8. 1 )  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 nstr 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  C D S.   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). 
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 ecifi 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 nt 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  v i 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 ert i 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 
Ne ur ocri ne Bi oscie nces, I nc., St u d y N o. N BI- 9 8 8 5 4- T S 2 0 0 4 
Cli nical St u d y Pr ot oc ol A me n d me nt 1 Fi nal Versi o n
0 6 N o ve m ber 2 0 1 7
C o nfi de ntial
Pa ge 4 6


will  b e  ar c hi v e d  o n  a p pr o pri 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 
e l 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. 
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 cr i 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 ( 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  s e v er al   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 ysis  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.  
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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 i n cl u d e d  i n e a c h  w ei g ht   gr o u p,  w h o  c o m pl et e d t h e  d os e  o pti mi z ati o n  p eri o d (i e,  u p t o 
W e e k  4),  w h o  c o m pl et e d t h e  d os e  m ai nt e n a n c e  p eri o d (i e,  u p t o  W e e k  2 4),  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  als o  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 cs  a n d  B as eli n e  C h a r a c t 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 ],  C Y P 2 D 6  g e n ot y p e st at us [c arri e d  o v er fr o m 
N BI - 9 8 8 5 4- T S 2 0 0 3 st u d y],  a g e  at  T S  di a g n osis,  a n d  b as eli n e  v al u es f or t h e Y G T S S  T T S)  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).  
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 ( W e e ks  2,  4,  8, 
1 2,  1 6,  2 0,  a n d  2 4)  a n d f or t h e f ull tr e at m e nt  p eri o d.   
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  Y G T S S,  P U T S,  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.   S e v er al  d eri v e d  v ari a bl es  b as e d  o n t h es e 
m e as ur es ( e g, t h e  Y G T S S  T T S)  will  b e s u m m ari z e d  wit h  d es cri pti v e st atisti cs.   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. 
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.   
Pl as m a  D r u g  E x p os u r e  D at a  
T h e  pl as m a  c o n c e ntr ati o ns  of  N BI - 9 8 8 5 4  a n d t h e  m et a b olit e  N BI- 9 8 7 8 2  will  b e su m m ari z e d 
wit h  d es cri pti v e st atisti cs  b y  visit ( D a y  1  a n d  W e e ks   2,  4,  8,  1 2,  1 6,  2 0,  2 4,  a n d  2 8)  a n d  d os e 
(l ast  d os e r e c ei v e d  pri or t o  bl o o d s a m pl e  b ei n g  dr a w n).   C o n c e ntr ati o ns  b el o w t h e l o w er li mit  of 
q u a ntifi c ati o n  will  b e s et  e q u al t o  z er o f or  all  pl as m a  c o n c e ntr ati o n s u m m ari es.   T h es e  d at a  will 
b e s u m m ari z e d f or  e a c h  w ei g ht  gr o u p s e p ar at el y. 
1 3. 9.   
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 e d 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  of  e v e nts, 
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n u m b er  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,  a n d  p er c e nt a g e  of 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 i n cl u di n g  all  T E A Es,  o nl y  T E A Es t h at  ar e  c o nsi d er e d t o  b e 
p ossi bl y  or  d efi nit el y r el at e d t o st u d y  dr u g,  a n d  T E A Es  a c c or di n g t o  m a xi m u m i nt e nsit y.   
A d diti o n al s u m m ari es  will  b e  pr es e nt e d f or  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 ns, 
pr e m at ur e  dis c o nti n u ati o ns fr o m t h e st u d y,  S A Es,  a n d  d e at hs. 
Cli ni c al l a b or at or y,  vit al si g ns,  E C G,  C -S S R S,  E S R S -A,  C Y -B O C S,  C D R S -R,  a n d  A D H D - 5 
R ati n g  S c al e  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.   Cli ni c all y si g nifi c a nt  p h ysi c al  e x a mi n ati o n fi n di n gs  will  b e  dis pl a y e d i n  a  d at a 
listi n g.   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. 1 0.   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 1.   I nt e ri m  A n al ysis 
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. 
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  FD A,  H e alt h 
C a n a 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 ul es.   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,  as  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 
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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 esti 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  a n d/ or  Cli ni c al  Tri al  Sit e 
I nf or m ati o n  F or m –  as  a p pli c a bl e ). 
•   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 n f 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 
All  p ar e nts  or l e g al  g u ar di a ns  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  y e ars 
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  ce 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 v i 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 
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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  an d  F D A  G ui d eli n es,  H e alt h  C a n a 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 
in 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.  If 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. 
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 u rr 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 sit e.   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.  
Pa ge 5 1


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 
gl u c os e  m et a b olis m  diff er e nti ati n g  p ati e nts  a n d  c o ntr ols.  N e ur o ps y c h o p h ar m a c ol o g y.  1 9 9 3 
D e c; 9( 4): 2 7 7- 9 1. 
C a v a n n a  A E ,  N a ni  A.  T o ur ett e s y n dr o m e  a n d  c o ns ci o us n ess  of  a cti o n.  Tr e m or  Ot h er 
H y p er ki n et  M o v ( N Y).  2 0 1 3  S e p  2 3; 3. 
C a v a n n a  A E,  L u o ni  C,  S el vi ni  C,  Bl a n gi ar d o  R,  E d d y  C M,  Sil v estri  P R,  et  al.  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): 
d e v el o p m e nt  a n d  v ali d ati o n  of t h e It ali a n  v ersi o n.  B e h a v  N e ur ol.  2 0 1 3; 2 7( 1): 9 5- 1 0 3. 
C h e n JJ,  O n d o  W G,  D as hti p o ur  K,  S w o p e  D M.  T etr a b e n a zi n e f or t h e tr e at m e nt  of  h y p er ki n eti c 
m o v e m e nt  dis or d ers:  a r e vi e w  of t h e lit er at ur e.  Cli n  T h er.  2 0 1 2 J ul; 3 4 ( 7): 1 4 8 7- 5 0 4. 
C h o ui n ar d  S,  F or d  B.  A d ult  o ns et ti c  dis or d ers. J  N e ur ol  N e ur os ur g  Ps y c hi atr y.  2 0 0 0 
J u n; 6 8( 6): 7 3 8- 4 3. 
C h o ui n ar d  G,  M ar g ol es e  H C.  M a n u al f or 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 ( E S R S).  
S c hi z o p hr  R es.  2 0 0 5 J ul  1 5; 7 6( 2 - 3): 2 4 7- 6 5. 
F elli n g  RJ ,  Si n g er  H S.  N e ur o bi ol o g y  of t o ur ett e s y n dr o m e:  c urr e nt st at us  a n d  n e e d f or f urt h er 
i n v esti g ati o n. J  N e ur os ci.  2 0 1 1  A u g  3 1; 3 1( 3 5): 1 2 3 8 7- 9 5. 
Ja n k o vi c J ,  K url a n  R.  T o ur ett e s y n dr o m e:  e v ol vi n g  c o n c e pts.  M o v  Dis or d.  2 0 1 1 
M a y; 2 6( 6): 1 1 4 9- 5 6. 
K url a n  R.  Cli ni c al  pr a cti c e.  T o ur ett e's  S y n dr o m e.  N  E n gl J  M e d.  2 0 1 0  D e c  9; 3 6 3( 2 4): 2 3 3 2- 8. 
L e c k m a n J F,  Ri d dl e  M A,  H ar di n  M T,  Ort  SI,  S w art z  K L,  St e v e ns o n J,  et  al.  T h e  Y al e  Gl o b al 
Ti c  S e v erit y  S c al e: i niti al t esti n g  of  a  cli ni ci a n -r at e d s c al e  of ti c s e v erit y. J  A m  A c a d  C hil d 
A d ol es c  Ps y c hi atr y.  1 9 8 9 J ul; 2 8( 4): 5 6 6- 7 3. 
L e c k m a n J F,  Z h a n g  H,  Vit al e  A,  L a h ni n  F,  L y n c h  K,  B o n di  C,  et  al.  C o urs e  of ti c s e v erit y i n 
T o ur ett e s y n dr o m e: t h e first t w o  d e c a d es.  P e di atri cs.  1 9 9 8 J ul; 1 0 2( 1  Pt  1): 1 4- 9. 
P o urf ar  M,  F ei gi n  A,  T a n g  C C,  C ar b o n- C orr ell  M,  B uss a  M,  B u d m a n  C,  et  al.  A b n or m al 
m et a b oli c  br ai n  n et w or ks i n  T o ur ett e s y n dr o m e.  N e ur ol o g y.  2 0 1 1  M ar  1 5; 7 6( 1 1): 9 4 4- 5 2. 
R o b erts o n  M M.  Gill es  d e l a  T o ur ett e s y n dr o m e: t h e  c o m pl e xiti es  of  p h e n ot y p e  a n d tr e at m e nt. 
Br J  H os p  M e d ( L o n d).  2 0 1 1  F e b; 7 2( 2): 1 0 0 – 7. 
R o ess n er  V,  S c h o e n ef el d  K,  B us e J,  B e n d er  S,  E hrli c h  S,  M ü n c h a u  A.  P h ar m a c ol o gi c al 
tr e at m e nt  of ti c  dis or d ers  a n d  T o ur ett e  S y n dr o m e.  N e ur o p h ar m a c ol o g y.  2 0 1 3  M a y; 6 8: 1 4 3- 9. 
Pa ge 5 2


S h pr e c h er  D ,  K url a n  R.  T h e  m a n a g e m e nt  of ti cs.  M o v  Dis or d.  2 0 0 9 J a n  1 5; 2 4( 1): 1 5- 2 4. 
S u  M T,  M c F arl a n e  F,  C a v a n n a  A E,  T er mi n e  C,  M urr a y I,  H ei d e m e y er  L,  et  al.  T h e  E n glis h 
v ersi o n  of 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). J  C hil d  N e ur ol.  2 0 1 7 J a n; 3 2( 1): 7 6- 8 3. 
S w ai n J E,  S c a hill  L,  L o m br os o  PJ,  Ki n g  R A,  L e c k m a n J F.  T o ur ett e s y n dr o m e  a n d ti c  dis or d ers: 
a  d e c a d e  of  pr o gr ess. J  A m  A c a d  C hil d  A d ol es c  Ps y c hi atr y.  2 0 0 7  A u g; 4 6( 8): 9 4 7 – 6 8. 
W o o ds  D W,  Pi a c e nti ni J,  Hi ml e  M B,  C h a n g  S.  Pr e m o nit or y  Ur g e f or  Ti cs  S c al e ( P U T S): i niti al 
ps y c h o m etri c r es ults  a n d  e x a mi n at i o n  of t h e  pr e m o nit or y  ur g e  p h e n o m e n o n i n  y o ut hs  wit h  Ti c 
dis or d ers. J  D e v  B e h a v  P e di atr.  2 0 0 5  D e c; 2 6( 6): 3 9 7- 4 0 3. 
Pa ge 5 3


1 7.   
A P P E N DI C E S  
1 7. 1.   
Y al e  Gl o b al  Ti c  S e v e rit y  S c al e ( Y G T S S)  
 
 
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SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
19-FEB-2020 
 
1 
 
 
  
 
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 2B 
 
VERSION: Final 
DATE OF PLAN: 
19-FEB-2020 
 
BASED ON: 
Protocol Amendment No. 1 Final Version Date: 06 November 2017 
Original Version Date: 05 September 2017 
 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI-98854-TS2004 
STUDY TITLE: 
Open-Label Safety and Tolerability Study of Optimized Doses of NBI-98854 for the Treatment 
of Pediatric Subjects with Tourette Syndrome 
 
SPONSOR: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
858-617-7600 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 




Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
19-FEB-2020 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................8 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
4. 
STUDY DESIGN .........................................................................................................8 
4.1. 
Summary of Study Design ............................................................................................8 
4.2. 
Sample Size Considerations .......................................................................................10 
4.3. 
Randomization ............................................................................................................10 
4.4. 
Clinical Assessments ..................................................................................................10 
5. 
PLANNED ANALYSES ............................................................................................11 
5.1. 
Interim Analyses .........................................................................................................11 
5.2. 
Final Analyses ............................................................................................................11 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................11 
6.1. 
General Statistical Procedures ....................................................................................11 
6.2. 
Analysis Populations ..................................................................................................11 
6.3. 
Baseline Definition .....................................................................................................12 
6.4. 
Derived and Transformed Data ..................................................................................12 
6.4.1. 
Study Day ...................................................................................................................12 
6.4.2. 
Change from Baseline .................................................................................................12 
6.4.3. 
Handling of Early Termination Visit Data .................................................................12 
6.5. 
Handling of Missing Data ...........................................................................................13 
6.5.1. 
Missing Outcome Data ...............................................................................................13 
6.5.2. 
Missing Dates .............................................................................................................13 
6.5.2.1. 
First and Last Dose Dates ...........................................................................................13 
6.5.2.2. 
Missing Start Dates for Adverse Events and Prior and Concomitant 
Medications .................................................................................................................14 
7. 
STUDY POPULATION .............................................................................................14 
7.1. 
Subject Disposition .....................................................................................................14 
7.2. 
Protocol Deviations ....................................................................................................15 
7.3. 
Demographic and Baseline Characteristics ................................................................15 
7.4. 
Medical History and Medical Conditions Present at Entry ........................................15 


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NBI-98854-TS2004 
Statistical Analysis Plan 
 
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7.5. 
Study Drug Dosing and Compliance ..........................................................................16 
7.5.1. 
Exposure to Study Drug ..............................................................................................16 
7.5.2. 
Dose Adjustments and Dosages..................................................................................16 
7.5.3. 
Compliance .................................................................................................................16 
8. 
PLASMA CONCENTRATION DATA .....................................................................16 
9. 
PHARMACODYNAMIC ASSESSMENTS ..............................................................17 
9.1. 
Yale Global Tic Severity Scale...................................................................................17 
9.2. 
CGI-Tics-Severity .......................................................................................................17 
9.3. 
CGI-TS-Improvement .................................................................................................18 
9.4. 
Premonitory Urge for Tics Scale ................................................................................18 
9.5. 
Gilles de la Tourette Syndrome-Quality of Life Scale for Children and 
Adolescents .................................................................................................................18 
10. 
SAFETY .....................................................................................................................19 
10.1. 
Adverse Events ...........................................................................................................19 
10.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study........................20 
10.1.2. 
Adverse Events Resulting in Study Drug Dose Reductions .......................................20 
10.1.3. 
Deaths and Other Serious Adverse Events .................................................................20 
10.2. 
Clinical Laboratory Data ............................................................................................21 
10.3. 
Vital Signs ..................................................................................................................22 
10.4. 
Body Weight ...............................................................................................................23 
10.5. 
Electrocardiogram .......................................................................................................23 
10.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions ..................................24 
10.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................................25 
10.8. 
Children’s Yale-Brown Obsessive-Compulsive Scale ...............................................26 
10.9. 
Children’s Depression Rating Scale, Revised ............................................................26 
10.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale-5: Home Version .................26 
10.11. 
Prior and Concomitant Medications ...........................................................................27 
 
 


Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping ..........................13 
Table 3: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables ............22 
Table 4: 
Potentially Clinically Significant Criteria for Vital Signs Variables in 
Children ......................................................................................................................23 
Table 5: 
Potentially Clinically Significant Criteria for Vital Signs Variables in 
Adolescents .................................................................................................................23 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................9 
 
 


Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
19-FEB-2020 
 
6 
 
 
  
 
1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
ADHD 
Attention-Deficit Hyperactivity Disorder 
ADHD Rating 
Scale-5 
Attention-Deficit Hyperactivity Disorder Rating Scale-5: Home Version  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical Classification  
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
C&A-GTS-QOL 
Gilles de la Tourette Syndrome – Quality of Life Scale for Children and 
Adolescents  
CDRS-R 
Children’s Depression Rating Scale - Revised  
CGI-S 
Clinical Global Impression of Movement Severity  
CGI-Tics-
Severity 
Clinical Global Impression of Tics-Severity scale  
CGI-TS-
Improvement 
Clinical Global Impression of Tourette Syndrome-Improvement scale  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CY-BOCS 
Children’s Yale-Brown Obsessive Compulsive Scale  
DSM-IV or -V 
Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Editions  
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated  
ET 
Early Termination 
GGT 
Gamma-Glutamyl Transferase 
IPD 
Important Protocol Deviation  
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
NBI 
Neurocrine Biosciences, Inc. 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic 


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NBI-98854-TS2004 
Statistical Analysis Plan 
 
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PT 
Preferred Term 
PUTS 
Premonitory Urge for Tics Scale  
QTcF 
Fridericia’s Correction of QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TS 
Tourette Syndrome 
TTS 
Total Tic Score  
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization  
YGTSS 
Yale Global Tic Severity Scale  
 


Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
19-FEB-2020 
 
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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays that will be prepared to summarize the data from the Phase 2b study described in 
Neurocrine Biosciences, Inc. (NBI) Protocol NBI-98854-TS2004. 
This SAP was developed in accordance with ICH E9 guidance. Further information related to 
study design and methodology can be found in the protocol. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this clinical study are as follows: 
• To determine the long-term safety and tolerability of up to 24 weeks of treatment with 
NBI-98854 in pediatric subjects with Tourette Syndrome (TS). 
• To evaluate the long-term pharmacodynamic (PD) effects of NBI-98854 administered once 
daily in pediatric subjects with TS. 
• To evaluate plasma exposure of NBI-98854 and its metabolite, NBI-98782, following 
repeated daily doses of NBI-98854. 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 2b, multicenter, open-label, dose-optimization study of the safety, tolerability, 
PD, and plasma exposure of NBI-98854 doses in the range of 20 mg to 60 mg for subjects 
<50 kg and 40 mg to 80 mg for subjects ≥50 kg, administered each night at bedtime for a total of 
24 weeks of treatment in pediatric subjects with TS. This study will only include subjects who 
participated in and completed the previous Phase 2b clinical study NBI-98854-TS2003. 
Up to 120 male and female pediatric subjects, 6 to 18 years of age, with a Diagnostic and 
Statistical Manual of Mental Disorders, 4th or 5th Editions (DSM-IV or -V) diagnosis of TS will 
participate.   
The starting dose will be NBI-98854 20 mg for subjects <50 kg at baseline and NBI-98854 
40 mg for subjects ≥50 kg at baseline. The dose may be escalated in increments of 20 mg every 2 
weeks to a maximum of 60 mg for subjects <50 kg and 80 mg for subjects ≥50 kg to achieve an 
optimal dose of NBI-98854 for each subject. Dose escalations may occur at the end of Weeks 2 
and 4. After Week 4, subjects will continue to receive their optimized dose of NBI-98854 for an 
additional 20-week dose maintenance period. At any time after Week 2, the physician 
investigator may decrease the dose to the previous dose for any subject who had a dose 
escalation and who is unable to tolerate a given dose increase. The subject will continue at that 
dose until the end of the treatment period. Subjects who are unable to tolerate the starting dose or 
resumption of the previous dose will be discontinued from the study.  Follow-up assessments 
will be conducted at the end of Week 28 (4 weeks after the last dose of the study drug). Full 
details of the dose optimization and maintenance are provided in the Protocol. 
A schematic of the study design is shown in Figure 1. 




Neurocrine Biosciences, Inc. 
 
NBI-98854-TS2004 
Statistical Analysis Plan 
 
19-FEB-2020 
 
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4.2. 
Sample Size Considerations 
The sample size for this open-label safety study is based on practical considerations and not on a 
statistical power calculation. 
4.3. 
Randomization 
This is an open-label study. Subjects are not randomized to treatment in this study. 
4.4. 
Clinical Assessments 
Safety assessments include: 
• adverse event (AE) monitoring,  
• clinical laboratory tests (hematology, clinical chemistry, and urinalysis),  
• serum prolactin 
• hemoglobin A1c 
• vital sign measurements,  
• physical examinations, including weight,  
• 12-lead electrocardiogram (ECG),  
• Columbia-Suicide Severity Rating Scale (C-SSRS), Children’s Version, 
• Children’s Depression Rating Scale - Revised (CDRS-R),  
• Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS),  
• Attention-Deficit Hyperactivity Disorder Rating Scale-5: Home Version (ADHD Rating 
Scale-5), and 
• Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A). 
PD assessments for TS include:  
• Yale Global Tic Severity Scale (YGTSS),  
• Clinical Global Impression of Tics-Severity scale (CGI-Tics-Severity),  
• Clinical Global Impression of Tourette Syndrome-Improvement scale (CGI-TS-
Improvement),  
• Premonitory Urge for Tics Scale (PUTS), and  
• Gilles de la Tourette Syndrome – Quality of Life Scale for Children and Adolescents 
(C&A-GTS-QOL).  
Blood samples for plasma drug and metabolite concentration analyses are also collected. 
Subjects/caregivers will be asked to record and provide dosing times from the evening before the 
treatment period visits when these samples are collected. 
The schedule of assessments can be found in the protocol. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
An interim analysis is not planned for this study. 
5.2. 
Final Analyses 
A single, final analysis will be performed after the study database has been locked. 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
General Statistical Procedures 
Descriptive statistics will be used to summarize the data from this study. The term “descriptive 
statistics” refers to the number of subjects, mean, median, standard deviation (SD), standard 
error of the mean (SEM), minimum, and maximum for numerical variables; and refers to the 
number and/or percentage of subjects for categorical variables. Additional descriptive statistics 
may be presented for selected variables.  
A single treatment group (NBI-98854) will be used for all analyses. Descriptive statistics will 
generally be presented separately for each baseline weight group (<50 kg vs. ≥50 kg) and for the 
pooled weight groups. Each table will therefore have 3 columns:  
• NBI-98854 (<50 kg baseline weight group) 
• NBI-98854 (≥50 kg baseline weight group) 
• NBI-98854 (All Subjects) 
Select tables will display results by NBI-98854 dose level. 
Summary statistics will be displayed using the following decimal precision rules: the minimum 
and maximum will have the same number of decimal places as the data; the mean, median, SD, 
and SEM will have one more decimal place than the data being summarized. Percentages will be 
displayed using one decimal place; percentages for 0 counts will be omitted. These rules may be 
modified if warranted, based on practical considerations.  
6.2. 
Analysis Populations  
For purposes of defining analysis sets, “enrolled subjects” refers to subjects enrolled into the 
study at the Day 1 visit (i.e., are not screen failures) as specified by the subject enrollment 
electronic case report form (eCRF). 
Unless otherwise specified, the safety analysis set will be used for all analyses in this study. The 
safety analysis set will include all enrolled subjects who take at least one dose of study drug and 
have any data collected after the initial dose of study drug. If it is unknown whether or not the 
subject took at least one dose of study drug but the subject was dispensed study drug and has 
postbaseline data in the study database, the subject will be included in the safety analysis set. 


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Summaries of subject disposition, analysis set inclusion/exclusion status, and important protocol 
deviations (IPDs) will include all enrolled subjects.  
6.3. 
Baseline Definition 
The assessments collected at the Day 1 study visit will serve as the baseline value for all 
assessments, excluding any assessments that occur after the first dose of study drug. If a Day 1 
visit value is not available, then the last measurement collected on or prior to the date of the first 
dose of study drug will serve as baseline. 
6.4. 
Derived and Transformed Data 
6.4.1. 
Study Day 
Study day is calculated relative to the date of the Day 1 visit. If the date of interest occurs on or 
after the Day 1 visit, then the study day will be calculated as: date of interest – date of Day 1 visit 
+ 1. If the date of interest occurs prior to the Day 1 visit, then the study day will be calculated as: 
date of interest – date of Day 1 visit. 
6.4.2. 
Change from Baseline 
Change from baseline is calculated as (postbaseline value – baseline value). 
6.4.3. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject discontinues from the study prior to 
completing the scheduled Week 28 visit. The data collected at ET visits will be included in 
summary tables and figures in accordance with the ET visit mapping scheme described in this 
section.  
An ET visit will be mapped to the next scheduled study visit if it occurs within 7 days prior to 
and 6 days after the expected study day of the next scheduled visit (with the requirement that the 
scheduled visit prior to the ET visit was actually completed by the subject) for visits that are 
expected to occur every 2 weeks and within 14 days prior to and 13 days after for visits that are 
expected to occur every 4 weeks. ET visits occurring after the Week 24 visit will be mapped to 
the Week 28 follow-up visit if it occurs after day 181. 
Early termination visit data which are not mapped to a scheduled visit will not be included in by-
visit analyses and summaries. They will be included in any analyses that look across all available 
assessments during the treatment period, including unscheduled visits. They will also be included 
in any applicable by-subject data listings. 
Table 2 displays the allowable study day range for each scheduled visit for ET visit mapping 
purposes. 


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Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping 
Scheduled Visit 
Target Study Day 
Visit Window  
(Study Day Range) 
Week 2 
14 
7-20 
Week 4 
28 
21-34 
Week 8 
56 
42-69 
Week 12 
84 
70-97 
Week 16 
112 
98-125 
Week 20 
140 
126-153 
Week 24 
168 
154-181 
Week 28 
196 
>181 
 
6.5. 
Handling of Missing Data 
6.5.1. 
Missing Outcome Data 
Missing values for outcome measures will generally not be replaced with imputed values except 
as noted in Section 6.4.3 for the ET visit data mapped to scheduled visits for data summary 
purposes. 
6.5.2. 
Missing Dates 
6.5.2.1. 
First and Last Dose Dates  
Missing and incomplete (“partial”) dates for first and last dose dates will be imputed for the 
purpose of estimating exposure and defining treatment periods. Missing dates will not be 
imputed for subjects when the subject is known to have not taken at least one dose of study drug, 
as documented by the site in the dosing eCRF.  
The imputation rules for first dose date are as follows: 
• If the date is completely missing or if both the day and month are missing, the date will 
be imputed as the date when the first study drug kit was assigned; 
• If only the day is missing, the date will be imputed as the date when the first study drug 
kit was assigned if the month and year match the kit assignment date; if the month and 
year occur after the kit assignment date, the missing day will be imputed as the first day 
of the month. 
If the date of the last dose of study drug is missing, then the last dose date will be imputed as the 
earliest of:  
• the Week 24 visit date,  
• study discontinuation date for subjects who discontinue before Week 24,  
• the date when the last study drug kit(s) was assigned + the number of doses dispensed 
with the kit(s).  


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6.5.2.2. 
Missing Start Dates for Adverse Events and Prior and Concomitant Medications 
Missing and incomplete dates for AEs and concomitant medications will be imputed for the 
purpose of estimating the time of the event or medication usage in relationship to study 
treatment. Any data listings will display the original dates as reported in the database.   
The imputation rules for AE start dates are as follows: 
• If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug; 
• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the month and year of the AE start date match the date of the first dose of study 
drug; otherwise, the missing day will be imputed as the first day of the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the AE start date is in the same year as the date of the first dose of 
study drug; otherwise, the missing day and month will be imputed as 01 January; 
• If any of the above imputations result in a start date that is later than an existing (not 
imputed) end date for the event, the start date will be imputed as the end date. 
The imputation rules for concomitant medication start dates are as follows: 
• If the date is completely missing, the date will be imputed as 01 January in the year of the 
subject’s screening vital signs assessment; 
• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the concomitant medication start date is in the same month and year as the date of 
the first dose of study drug; otherwise, the missing day will be imputed as the first day of 
the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the concomitant medication start date is in the same year as the date 
of the first dose of study drug; otherwise, the missing day and month will be imputed as 
01 January; 
• If any of the above imputations result in a start date which is later than an existing (not 
imputed) medication stop date, the start date will be imputed as the stop date. 
7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
The summary of subject disposition will display the number of subjects who were enrolled, who 
received at least one dose of study drug, who completed the dose optimization period (i.e., up to 
Week 4, excluding ET visits mapped to Week 4), who completed the dose maintenance period 
(i.e., up to Week 24, excluding ET visits mapped to Week 24), and who completed the study. 
The number of subjects who did not complete the study will also be summarized, both overall 
and according to the reason for early discontinuation. 


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7.2. 
Protocol Deviations 
Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into 
the study database and used to identify IPDs. IPDs are protocol deviations that might 
significantly affect the completeness, accuracy and/or reliability of the study data or that might 
significantly affect a subject’s rights, safety, or well-being. An assessment of IPDs will be 
performed by a committee composed of NBI Clinical Development project team members prior 
to database lock. This committee will review a listing of all protocol deviations reported in the 
study database and determine which deviations are IPDs.  
A summary of the number and percentage of subjects with IPDs by deviation category will be 
provided using all enrolled subjects.  
All protocol deviations entered into the study database will be presented in a data listing. Any 
IPDs will be flagged in the listing. 
7.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized using descriptive statistics for 
continuous variables, and frequency counts and percentages for categorical variables. 
Demographics include: 
• Age (years) 
• Age category (child [ages 6-11], adolescent [ages 12-18])  
• Sex 
• Ethnicity 
• Race 
Study baseline subject characteristics include: 
• Age at TS diagnosis (years) 
• Baseline value of TTS 
• Height (measured at screening; cm) 
• Weight (presented in both pounds and kilograms) 
• Body mass index (BMI; measured at screening; kg/m2) 
• CYP2D6 genotype status (measured at baseline in clinical study NBI-98854-TS2003) 
7.4. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized in frequency tables (number and percentage of subjects) by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT), with SOCs and PTs within each SOC sorted alphabetically 


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7.5. 
Study Drug Dosing and Compliance 
7.5.1. 
Exposure to Study Drug 
The duration of exposure to study drug will be calculated as: last dose date – first dose date +1. 
Duration of exposure will be summarized with descriptive statistics. The number and percentage 
of subjects with the following exposure categories will also be presented: 
• >0 to <2 weeks 
• ≥2 to <4 weeks 
• ≥4 to <8 weeks 
• ≥8 to <12 weeks 
• ≥12 to <16 weeks 
• ≥16 to <20 weeks 
• ≥20 to <24 weeks 
• ≥24 weeks 
7.5.2. 
Dose Adjustments and Dosages 
The number and percentage of subjects with a dose reduction at any time will be presented. 
Percentages will be based on the number of subjects with at least one dose escalation.  
Descriptive statistics of study drug dosages for the last dose received in the study will also be 
presented.  
7.5.3. 
Compliance 
Subjects will bring all unused study drug and empty study drug packaging material to the center 
at each study visit for drug accountability and reconciliation by study center personnel. A 
compliance check will be performed by counting the capsules returned at each study visit. The 
site will then enter whether the subject’s dosing compliance since the previous visit was ≥80% 
into the eCRF. 
The number and percentage of subjects who are dosing compliant at each visit during the 
treatment period will be provided. 
8. 
PLASMA CONCENTRATION DATA 
The plasma concentrations of NBI-98854 and its active metabolite NBI-98782 will be 
summarized with descriptive statistics by visit and by the last dose level received prior to the 
blood sample being drawn (20, 40, 60, or 80 mg). The dose at the Week 28 visit will reflect the 
last dose the subject received during the study treatment period (i.e., the dose level at the 
subject’s Week 24 visit). These summary tables will be presented separately for each baseline 
weight group (<50 kg vs. ≥50 kg). There will not be a pooled weight groups summary.  


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Concentrations below the lower limit of quantification (BLQ) will be set equal to zero for all 
plasma concentration summaries. The lower limits of quantification are as follows: (a) NBI-
98854: 1.00 ng/mL and (b) NBI-98782: 0.100 ng/mL. 
The following additional descriptive statistics will be included in the plasma concentration 
summary tables: (a) the number of plasma concentration values greater than or equal to the lower 
limit of quantification, (b) the geometric mean, and (c) the geometric coefficient of variation 
(%). 
9. 
PHARMACODYNAMIC ASSESSMENTS 
9.1. 
Yale Global Tic Severity Scale 
The following three analysis variables are based on the YGTSS: (a) the Total Tic Score (TTS), 
(b) the Impairment score, and (c) the Global Tic Severity score. 
The TTS is defined as the sum of the YGTSS motor tic severity score and phonic (vocal) tic 
severity score. The motor tic severity score is calculated as the sum of the scores for the 5 motor 
tic items (number, frequency, intensity, complexity, and interference). The score for each item 
can range from 0 to 5, for a maximum total score of 25. The vocal (phonic) tic severity score is 
calculated similarly. If any one of the 5 items for the motor or vocal tic severity score is not 
scored (i.e., has a missing value), the associated severity score will be set equal to missing. If any 
of these items has a missing value at a given subject visit, the TTS value for the subject visit will 
also be set equal to missing.  The TTS value can range from 0 to 50, with higher scores 
representing greater severity. 
The YGTSS Impairment score is captured directly in the eCRF.  This score can range in value 
from 0 to 50, with higher scores representing more severe impairment.   
The YGTSS Global Tic Severity score is the sum of the TTS and the Impairment score.  The 
YGTSS Global Tic Severity score at a given subject visit will be set equal to missing if either of 
the TTS or Impairment scores are missing.  The YGTSS Global Tic Severity score value can 
range from 0 to 100. 
For each of these variables, descriptive statistics will be presented for the observed and change 
from baseline values at baseline and at each postbaseline visit. 
9.2. 
CGI-Tics-Severity 
Each of the CGI-Tics-Severity response categories will be assigned a numerical score as follows: 
• Normal, not at all ill = 1 
• Borderline ill = 2 
• Mildly ill = 3 
• Moderately ill = 4 
• Markedly ill = 5 
• Severely ill = 6 
• Among the most extremely ill patient = 7 


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For the numerical scores, descriptive statistics will be presented for the observed and change 
from baseline values at baseline and at each postbaseline visit. Frequency counts using the 
response categories will also be presented. 
9.3. 
CGI-TS-Improvement  
Each of the CGI-TS-Improvement response categories will be assigned a numerical score as 
follows: 
• Very much improved = 1 
• Much improved = 2 
• Minimally improved = 3 
• Not changed = 4 
• Minimally worse = 5 
• Much worse = 6 
• Very much worse = 7 
For the numerical scores, descriptive statistics will be presented for the observed values at each 
postbaseline visit. Frequency counts using the response categories will also be presented. 
9.4. 
Premonitory Urge for Tics Scale 
The PUTS is an instrument for quantifying the premonitory urge phenomena associated with tics. 
It consists of 9 items, each of which is scored on a 4-point scale: 
• 1 = not at all true 
• 2 = a little true 
• 3 = pretty much true 
• 4 = very much true 
The PUTS total score is calculated as the sum of the scores for the 9 items. The PUTS total score 
value can range from 9 to 36. If any one of the 9 items is not scored (i.e., has a missing value), 
the PUTS total score will be set equal to missing.  
Descriptive statistics will be presented for the observed and change from baseline values at 
baseline and at each postbaseline visit. 
9.5. 
Gilles de la Tourette Syndrome-Quality of Life Scale for Children 
and Adolescents 
The C&A-GTS-QOL has two parts:  
(1) a 27-item scale which includes 4 factors (subscales), with each of the 27 items scored on 
a 5-point scale (1=never, 2=rarely, 3=sometimes, 4=often, 5=always); and 
(2) a visual analog scale (VAS) which ranges in value from 0 to 100, with 0 representing 
extremely unhappy/dissatisfied with life, and 100 representing extremely happy/satisfied 
with life.   


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The C&A-GTS-QOL total score is calculated as the sum of the scores for the 27 items. If any 
one of the 27 items is not scored (i.e., has a missing value), the total score will be set equal to 
missing.  
Scores will be calculated for each of the 4 C&A-GTS-QOL factors in a similar fashion. These 
factors and the corresponding item numbers are as follows:  
• Psychological (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27) 
• Physical and activities of daily living (1, 2, 3, 4, 5, 6, 26) 
• Obsessive-compulsive (7, 8, 9, 10, 15) 
• Cognitive (11, 12, 13, 14) 
The total score and each factor will be normalized to a value that can range from 0 to 100 by 
using the following formula: 
100 ×
𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠−𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠−𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑒𝑒 
Two versions of this instrument are used in this trial: 1 version for children aged 6 to 12 years 
and 1 version for adolescents aged 13 to 18 years. Scoring is identical for both versions and all 
results will be combined for analyses. 
Descriptive statistics will be presented for the observed and change from baseline C&A-GTS-
QOL normalized total scores, the 4 normalized factor scores, and the VAS scores at baseline and 
at each postbaseline visit. 
10. 
SAFETY 
10.1. 
Adverse Events 
Adverse events are recorded in the eCRF. Each AE will be coded to SOC and PT using 
MedDRA 
.   
A treatment-emergent adverse event (TEAE) is an AE not present prior to the initiation of study 
drug dosing, or is an already present event that worsens either in intensity or frequency following 
the initiation of study drug dosing. The determination of whether an AE is treatment-emergent is 
based on the AE onset date relative to the date of the subject’s first dose of study drug. If the AE 
onset date and date of the first dose of study drug are the same, or if the AE onset date is 
unknown, it will be assumed that the AE is a TEAE. 
The frequency tables will include the number and percentage of unique subjects experiencing 
each event at least once during the study. Unless otherwise specified, summary tables will 
include events with a start date on or after the date of the first dose of study drug and on or 
before the date of the last dose of study drug + 30 days. Missing or incomplete AE onset dates or 
study drug dosing dates will be imputed as described in Section 6.5.2. 
Two versions of the primary TEAE frequency tables will be presented: 
• Frequency of TEAEs by SOC and PT, with SOCs and PTs within each SOC sorted by 
decreasing frequency (number of unique subjects) 


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• Frequency of TEAEs by PT, with PT sorted by decreasing frequency (number of unique 
subjects)  
Summary tables of severe TEAEs will also be presented. The number and percentage of subjects 
with a severe TEAE will be presented by PT within SOC (presented in the same method as the 
primary TEAE table). The first line of the table will display the number and percentage of 
subjects with at least one severe TEAE. 
An AE overview summary table will be provided which summarizes the number and percentage 
of subjects with any TEAE, any TEAE leading to dose reduction, any TEAE leading to study 
discontinuation, any serious TEAE, and any TEAE resulting in death. The summary table will 
also include the maximum TEAE intensity (mild, moderate, severe) reported for each subject. 
10.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study 
Summary tables of TEAEs resulting in early discontinuation from study will be presented. The 
number and percentage of subjects with a TEAE resulting in study discontinuation will be 
presented by PT within SOC (presented in the same method as the primary TEAE table). More 
than one AE can contribute to study discontinuation per subject. The first line of the table will 
display the number and percentage of subjects with at least one TEAE leading to study 
discontinuation. 
A listing of TEAEs resulting in premature study discontinuation will be provided which includes 
weight group, subject ID, last study drug dose level received prior to the onset date of the 
TEAE(s) leading to discontinuation, study day of the discontinuation, and other relevant 
information from the AE eCRF.  
10.1.2. 
Adverse Events Resulting in Study Drug Dose Reductions 
Summary tables of TEAEs resulting in study drug dose reductions will be presented. The number 
and percentage of subjects with a TEAE resulting in a dose reduction will be presented by PT 
within SOC (presented in the same method as the primary TEAE table). More than one AE can 
contribute to a dose reduction per subject. The first line of the table will display the number and 
percentage of subjects with at least one TEAE leading to dose reduction.  
10.1.3. 
Deaths and Other Serious Adverse Events 
Summary tables of serious adverse events (SAEs) will be presented. The tables will include the 
frequency of SAEs presented by PT within SOC (presented in the same method as the primary 
TEAE table). 
Separate listings of SAEs and fatal TEAEs will also be provided. Each listing will include weight 
group, subject ID, last study drug dose level received prior to the onset date of the SAE or fatal 
TEAE, study day of the SAE or fatal TEAE, and any additional relevant information from the 
AE eCRF. 


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10.2. 
Clinical Laboratory Data 
By visit summaries 
The clinical chemistry, hematology, hemoglobin A1c, and prolactin data will be summarized 
with descriptive statistics at baseline and at each postbaseline visit. Both observed values and 
changes from baseline will be summarized.  
In addition to the summaries described above, the prolactin data will also be summarized for 
each sex separately. 
Shift tables 
Shift tables will be presented for selected clinical laboratory variables based on the reference 
range-based categories of “Low,” “Normal,” or “High.” A clinical laboratory variable value will 
be assigned to one of these three categories according to the reference ranges provided by the 
central clinical laboratory.  
Each shift table will have three rows and three columns, with rows reflecting the reference range 
category at baseline, and columns reflecting the reference range category at the subject’s last 
study visit during the treatment period of the study. A “Total” row and “Total” column will also 
be included. Subjects with a missing baseline value or who do not have postbaseline data will not 
be included in the tables for that variable. The number and percentage of subjects in each shift 
category will be displayed in the table; percentages will be based on the number of subjects  
included in the table. 
Shift tables will be presented for the following clinical laboratory variables: aspartate 
transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl 
transferase (GGT), total bilirubin, creatine kinase, creatinine, blood urea nitrogen, white blood 
cell count, absolute neutrophil count, hemoglobin, and platelet count. 
Potentially clinically significant (PCS) values 
Summaries of sponsor-defined PCS values will be presented for the following clinical laboratory 
variables: ALT, AST, ALP, creatine kinase, GGT, total bilirubin, white blood cell count, 
absolute neutrophil count, creatinine, and BUN. The number and percentage of subjects with 
PCS values that are reported at any postbaseline visit (scheduled or unscheduled, including 
repeat values) will be summarized by treatment. The criteria for identifying PCS clinical 
laboratory values are provided in Table 3. 


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Table 3: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 
AST 
>3 x ULN 
ALP 
>2.5 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
Absolute neutrophil count 
<1.5 x 1000/µL 
Creatinine 
>1.5 x baseline value or >1.5 x ULN 
BUN 
>30 mg/dL (>10.71 mmol/L) 
10.3. 
Vital Signs 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics at baseline and at each 
postbaseline visit. Both observed values and changes from baseline will be summarized.  
Summaries of sponsor-defined PCS values will be presented for systolic blood pressure, diastolic 
blood pressure, and heart rate. The number and percentage of subjects with PCS values that are 
reported at any postbaseline visit (scheduled or unscheduled) will be summarized. The criteria 
for identifying PCS vital signs values for children (6 to 11 years of age at baseline) and 
adolescents (12 to 18 years of age at baseline) are provided in Table 4 and Table 5, respectively. 
Both supine and standing values will be included in the identification and summary of PCS 
values. 
  


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Table 4: 
Potentially Clinically Significant Criteria for Vital Signs Variables in 
Children 
Variable Name 
PCS – Low if: 
PCS – High if: 
Decrease from Baseline is: 
Observed 
Value is: 
AND 
Increase from 
Baseline is: 
Systolic Blood Pressure 
≥20 mmHg 
>130 mmHg 
 
≥20 mmHg 
Diastolic Blood Pressure 
≥10 mmHg 
>85 mmHg 
 
≥10 mmHg 
Heart Rate 
≥15 bpm 
>130 bpm 
 
≥10 bpm 
 
Table 5: 
Potentially Clinically Significant Criteria for Vital Signs Variables in 
Adolescents 
Variable Name 
PCS – Low if: 
PCS – High if: 
Decrease from Baseline is: 
Observed 
Value is: 
AND 
Increase from 
Baseline is: 
Systolic Blood Pressure 
≥20 mmHg 
>145 mmHg 
 
≥20 mmHg 
Diastolic Blood Pressure 
≥10 mmHg 
>90 mmHg 
 
≥10 mmHg 
Heart Rate 
≥15 bpm 
>110 bpm 
 
≥10 bpm 
10.4. 
Body Weight  
The body weight data (in units of kilograms) will be summarized with descriptive statistics at 
baseline and at each scheduled postbaseline visit. Both observed values and changes from 
baseline will be summarized.  
10.5. 
Electrocardiogram 
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and Fridericia’s correction of QT interval [QTcF]) measured at each visit will be 
averaged for the purpose of analysis. For the categorical ECG interpretation variable (the 
investigator’s assessment of the ECG as “Normal”, “Abnormal, not Clinically Significant”, or 
“Abnormal, Clinically Significant”), which is also reported for each replicate, the value that 
represents the greatest degree of abnormality will be used in all summary tables. If less than 3 
values are recorded at an assessment, then the average of the available value(s) for the 
quantitative variables and the greatest degree of abnormality values(s) for the interpretation 
variable will be used. 
The quantitative ECG variables will be summarized with descriptive statistics at baseline and at 
each scheduled postbaseline visit. Both observed values and changes from baseline will be 
summarized. Frequency counts and percentages for the ECG interpretation variable categories 
will also be presented at baseline and at each scheduled postbaseline visit. 
Categorical summaries will be presented for the QT and QTcF interval data. For these 
summaries, a subject’s highest reported postbaseline value (including values reported at 


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unscheduled visits) will be used to determine in which category(s) the subject will be counted. 
The averaged triplicate values will be used when determining each subject’s highest reported 
values. 
Two categorical summaries will be presented for the QT and QTcF intervals (each interval will 
be summarized separately). For the first summary, the number and percentage of subjects whose 
highest reported QT or QTcF postbaseline value meets the following thresholds will be 
summarized: 
• Greater than 450 msec 
• Greater than 480 msec 
• Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects whose 
largest QT or QTcF increase from their baseline value meets the following thresholds:  
• Greater than 30 msec 
• Greater than 60 msec 
10.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions 
The C-SSRS data will be presented in the following summaries: 
• Screening/lifetime assessment  
• Screening/past 1 year assessment 
• Baseline (Day 1) assessment 
• All postbaseline assessments (through Week 28, including unscheduled visit assessments)  
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category). These C-SSRS items and categories are as follows: 
• Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
• Suicidal Ideation Category: Any of items (1) through (5) 
• Suicidal Behavior Items (not reported for the Screening/past 1 year assessment) 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(10) 
Completed suicide 


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• Suicidal Behavior Category: Any of items (6) through (10) 
• Suicidal Ideation or Behavior Category: Any of items (1) through (10) 
For the “all postbaseline assessments” summary, each subject’s C-SSRS responses for all 
postbaseline assessments during the study will be evaluated, and a “Yes” response at any 
postbaseline assessment for a particular item or category will be considered as a “Yes” for that 
item or category for the subject. 
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline scores will be presented. The shift table scores are defined as the 
following: 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Active suicidal ideation with any methods (not plan) without intent to act 
4 = Active suicidal ideation with some intent to act, without specific plan 
5 = Active suicidal ideation with specific plan and intent 
The shift tables will display the number and percentage of subjects within each cell of a 6 x 6 
table, with the rows representing the baseline score and the columns representing the maximum 
score recorded across all postbaseline assessments (including both scheduled and unscheduled 
visits). Subjects missing either a baseline score or all postbaseline scores will not appear in the 
table.  
10.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated 
The ESRS-A assesses 4 types of movement disorders: parkinsonism, dystonia, akathisia, and 
dyskinesia. The ESRS-A consists of four subscales, one for each type of movement disorder. The 
ESRS-A contains 10 items to evaluate parkinsonism, 6 items to evaluate dystonia, 6 items to 
evaluate dyskinesia, and 2 items to evaluate akathisia. Each item score can range from 0 to 5, for 
a maximum possible parkinsonism score of 50, maximum possible dystonia score of 30, 
maximum possible dyskinesia score of 30, and maximum possible akathisia score of 10. A 
Clinical Global Impression of Movement Severity (CGI-S) is also completed for each type of 
movement disorder and is also is scored on a 0 to 5 scale. 
The subscale scores for each type of movement disorder (parkinsonism, akathisia, dystonia, and 
dyskinesia) will be calculated as the sum of the scores of the individual items comprising each 
subscale. The overall total score will be calculated as the sum of each of the subscale scores. If 
any one of the items is not scored (i.e., has a missing value), the associated subscale score and 
total score will be set equal to missing. The CGI-S scores will be summarized separately from 
the subscale scores. 
Each of the subscale scores for parkinsonism, akathisia, dystonia, and dyskinesia, and the overall 
total score will be summarized with descriptive statistics at baseline and at each scheduled 
postbaseline visit. Both observed values and changes from baseline will be summarized.  
The CGI-S scores for each subscale will be summarized with descriptive statistics at baseline and 
at each scheduled postbaseline visit. Both observed values and changes from baseline will be 
summarized.  


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10.8. 
Children’s Yale-Brown Obsessive-Compulsive Scale 
The CY-BOCS is a semi-structured interview designed to rate the severity of obsessive and 
compulsive symptoms in children.  
The CY-BOCS obsession subtotal score is calculated as the sum of the scores for items 1 through 
5 of the CY-BOCS scale (excluding item 1b), and the CY-BOCS compulsion subtotal score is 
calculated as the sum of the scores for items 6 through 10 of the CY-BOCS scale (excluding item 
6b). The CY-BOCS total score is the sum of the obsession and compulsion subtotal scores. Each 
item score ranges from 0 to 4, with a maximum possible obsession subtotal score of 20, a 
maximum possible compulsion subtotal score of 20, and a maximum possible total score of 40. If 
any one of these 10 items is not scored (i.e., has a missing value), the associated subtotal score 
and total score will be set equal to missing. 
The obsession subtotal, compulsion subtotal and total scores will be summarized with descriptive 
statistics at baseline and at each scheduled postbaseline visit. Both observed values and changes 
from baseline will be summarized.  
10.9. 
Children’s Depression Rating Scale, Revised 
The CDRS-R is a 17-item, semi-structured interview to determine the severity of depression in 
children.  
The CDRS-R total score is calculated as the sum of the 17 items making up the CDRS-R. Each 
item score ranges from 1 to 7 with the exception of items 4, 5, and 16, which range from 1 to 5. 
The maximum possible total score is 113. If any one of the 17 items is not scored (i.e., has a 
missing value), the total score will be set equal to missing. 
The total score will be summarized with descriptive statistics at baseline and at each scheduled 
postbaseline visit. Both observed values and changes from baseline will be summarized.  
10.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale-5: Home 
Version 
The ADHD Rating Scale-5: Home Version will be used to determine the frequency and severity 
of ADHD symptoms and impairments over the 2 weeks prior to each visit.  
The scale consists of 2 symptom subscales: Inattention (9 items) and Hyperactivity-Impulsivity 
(9 items). The Inattention subscale and Hyperactivity-Impulsivity subscale scores are each 
derived by summing up the 9 relevant item scores. Each item score ranges from 0 to 3, therefore 
each subscale score has a range of 0 to 27. The Total Scale raw score is defined as the sum of the 
Inattention and Hyperactivity-Impulsivity subscale scores, and has a range of 0 to 54. If any one 
of the 18 items is not scored (i.e., has a missing value), the affected subscale score(s) and Total 
Scale raw score will be set equal to missing. 
The scale also assesses 6 domains of impairment that are common among children and 
adolescents with ADHD: relationships with family members, peer relationships, academic 
functioning, behavioral functioning, homework performance, and self-esteem. Each domain 
impairment item ranges from 0-3 and is assessed after completing each of the 2 subscales (i.e., 
each impairment item is assessed twice). The score for each domain is defined as the higher 
(worst) of the two scores. A total impairment score is defined as the sum of the 6 impairment 


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items (using the higher of the two scores) and has a range of 0 to 18. If any one of the 12 
individual items is not scored (i.e., has a missing value), the total impairment score will be set 
equal to missing. 
Two versions of this instrument are used in this trial: 1 version is for children aged 5 to 10 years 
and 1 version is for adolescents aged 11 to 17 years. Scoring is identical for both versions and all 
results will be combined for analyses. 
The Inattention and Hyperactivity-Impulsivity subscale scores, the Total Scale raw score, and the 
Total Impairment score will be summarized with descriptive statistics at baseline and at each 
scheduled postbaseline visit. Both observed values and changes from baseline will be 
summarized.  
10.11. 
Prior and Concomitant Medications 
Prior medications and concomitant medications will be summarized by World Health 
Organization (WHO) Drug Anatomical Therapeutic Chemical Classification (ATC) Level 3 
category (or Level 2 if there is not an applicable Level 3 category) and preferred name. 
Medications will be assigned to one or two study periods (pre-study or during screening vs. 
during the treatment or posttreatment follow-up periods) based on the medication start and stop 
dates relative to study drug dosing. Medications that were started and stopped prior to the date of 
the first dose of study drug will be assigned to the prestudy/screening period only, while 
medications started prior to the first dose of study drug and either stopped during the study or 
indicated as “ongoing” will be assigned to both the prestudy/screening and 
treatment/posttreatment period. A given medication can therefore be assigned to one or two 
study periods in the tabular summaries, depending on its start and end dates. 
The number and percentage of subjects using medications in each WHO Drug ATC category 
(Level 3/preferred name) will be summarized by the study periods defined in the previous 
paragraph. A subject may take the same medication more than once or multiple medications for a 
subject may be classified under the same ATC level or preferred name. A subject is counted only 
once for each level of medication classification within a summary.