A Phase 2, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the Safety and Efficacy of NBI-98854 in Pediatric Subjects With Tourette Syndrome
Phase: PHASE2
Conditions: Tourette Syndrome
Sponsor: Neurocrine Biosciences

 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L 
 
Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n :  0 3 Dece m ber 2 0 1 8 
Pr ot oc ol A me n d me nt N o. 1 Fi n al Versi o n :  0 8 J u ne 2 0 1 8 
Ori gi n al Versi o n D ate:  1 8 Dece m ber 2 0 1 7 
 
A P h ase 2, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, R a n d o mize d Wit h dr a w al 
St u d y t o E v al u ate t he S af et y a n d Effic ac y of N BI -9 8 8 5 4 i n Pe di atri c S u bjects 
wit h T o urette S y n dr o me  
 
 
St u d y N o.:  N BI- 9 8 8 5 4- T S 2 0 0 5 
 
De vel o p me nt P hase:  P hase 2 
 
S p o ns or:   
Ne ur ocri ne Bi oscie nces, I nc.  
 
1 2 7 8 0 El Ca mi n o Real 
 
Sa n Die g o, C A 9 2 1 3 0 
 
Tele p h o ne:  ( 8 5 8) 6 1 7- 7 6 0 0 
 
Facsi mile:   ( 8 5 8) 6 1 7- 7 7 0 5 
 
 
C O N FI D E N TI A L  
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of Ne ur ocri ne Bi oscie nces, I nc.  It is a gree d t hat 
n o  u n p u blis he d  i nf or mati o n  c o ntai ne d  herei n  will  be  p u blis he d  or  discl ose d  wit h o ut  pri or  
a p pr o val  fr o m  t he S p o ns or.    H o we ver,  t his  d oc u me nt  ca n  be  discl ose d  t o  a n  a p pr o priate 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee (I R B/ E C) or a ut h orize d re prese ntati ves of nati o nal 
re g ulat or y a ut h orities u n der t he c o n diti o n t hat t he y res pect its c o nfi de ntial nat ure. 

SI G N A T U R E S:  
I a gree t o c o n d uct t his st u dy i n acc or d a nce wit h t he re q uire me nts of t his cli nic al st u dy pr ot oc ol 
a n d als o i n acc or d a nce wit h t he f oll o wi n g: 
•  Esta blis he d pri nci ples of G o o d Cli nical Practice ( G C P) ( Har m o ni se d) 
•  U nite d States ( U S) C o de of Fe deral Re g ulati o ns ( C F R); U S F o o d a n d Dr u g A d mi nistrati o n 
( F D A) 
 
C LI NI C A L S T U D Y TI T L E : 
A P hase 2, D o u ble- Bli n d, Place b o - C o ntr olle d, Ra n d o mize d Wit h dra wal St u d y t o E val uate t he 
Safet y a n d Efficac y of N BI- 9 8 8 5 4 i n Pe di atric S u bjects wit h T o urette S y n dr o me 
 
P R O T O C O L N o.:  
N BI - 9 8 8 5 4-T S 2 0 0 5 
 
As A gree d:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pri nci pal  I n vesti gat or Si g nat ure 
Date  
 
P RI N CI P A L I N V E S TI G A T O R:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt Pri nci pal I n vesti gat or Na me) 
 
SI T E:   
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
( Pri nt Site Na me) 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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 
LI S T O F T A B L E S  ............................................................................................................ 8 
LI S T O F FI G U R E S .......................................................................................................... 8  
2.  
S Y N O P SI S  .................................................................................................... 9 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S .............. 1 4 
4.  
E T HI C S  ....................................................................................................... 1 6 
5.  
I N T R O D U C TI O N ....................................................................................... 1 6 
5. 1.  
Bac k gr o u n d .................................................................................................. 1 6  
5. 2.  
N BI - 9 8 8 5 4 ................................................................................................... 1 7 
5. 3.  
St u d y a n d D ose Rati o nale  ............................................................................ 1 9 
6.  
S T U D Y O BJ E C TI V E S  ............................................................................... 1 9 
7.  
O V E R VI E W O F S T U D Y D E SI G N  ............................................................ 2 0 
8.  
S T U D Y P O P U L A TI O N  .............................................................................. 2 4 
8. 1.  
I ncl usi o n Criteria ......................................................................................... 2 4 
8. 2.  
E xcl usi o n Criteria ........................................................................................ 2 5  
8. 3.  
S u bject I de ntificati o n a n d Re place me nt  ...................................................... 2 7 
8. 4.  
Ra n d o mizati o n  ............................................................................................. 2 7 
9.  
S T U D Y E V A L U A TI O N S  ........................................................................... 2 7 
9. 1.  
Sc he d ule of Assess me nts  ............................................................................. 2 7 
9. 2.  
Scree ni n g a n d Baseli ne Assess me nts  .......................................................... 3 0 
9. 2. 1.  
Ge n ot y pi n g .................................................................................................. 3 0  
9. 3.  
Efficac y Assess me nts  .................................................................................. 3 0 
9. 3. 1.  
Yale Gl o bal Tic Se verit y Scale  .................................................................... 3 0 
9. 3. 2.  
Pre m o nit or y Ur ge f or Tics Scale  ................................................................. 3 0 
9. 3. 3.  
Cli nical Gl o bal I m pressi o n Scales  ............................................................... 3 1 
9. 3. 4.  
Gilles de la T o urette S y n dr o me - Q ualit y of Life f or C hil dre n a n d 
A d olesce nts  .................................................................................................. 3 1 
9. 4.  
Plas ma Dr u g E x p os ure ................................................................................ 3 1  
9. 5.  
Safet y Assess me nts  ...................................................................................... 3 2 
9. 5. 1.  
Data Safet y M o nit ori n g B oar d ..................................................................... 3 2  
9. 5. 2.  
Vital Si g n Meas ure me nts  ............................................................................. 3 2 
9. 5. 3.  
Me dical Hist or y  ........................................................................................... 3 2 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5

9. 5. 4.  
P h ysical E xa mi nati o n, I ncl u di n g Hei g ht a n d Wei g ht .................................. 3 2 
9. 5. 5.  
Electr ocar di o gra m  ........................................................................................ 3 3 
9. 5. 6.  
Cli nical La b orat or y Assess me nts  ................................................................ 3 3 
9. 5. 7.  
C ol u m bia- S uici de Se verit y Rati n g Scale C hil dre n’s Versi o ns  ................... 3 4 
9. 5. 8.  
C hil dre n’s De pressi o n Rati n g Scale, Re vise d ............................................. 3 5  
9. 5. 9.  
C hil dre n’s Yale- Br o w n O bsessi ve C o m p ulsi ve Scale  ................................ 3 5 
9. 5. 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  . 3 5 
9. 5. 1 1.  
E xtra p yra mi dal S y m pt o m Rati n g Scale -A b bre viate d  ................................. 3 5 
9. 5. 1 2.  
Esti mate d T otal Bl o o d Sa m ple V ol u me Re q uire d b y St u d y  ....................... 3 5 
9. 6.  
S pecific St u d y I nf or mati o n  .......................................................................... 3 6 
9. 6. 1.  
Scree ni n g ( Wee k - 4 t o Da y - 1) .................................................................... 3 6 
9. 6. 2.  
Da y 1 ( Baseli ne Assess me nts a n d Start of D osi n g) ..................................... 3 7  
9. 6. 3.  
O pe n - La bel Treat me nt Peri o d:  Wee ks 2, 4, a n d 6 ( ± 3 da ys f or eac h visit) 3 8 
9. 6. 4.  
Bli n de d Ra n d o mizati o n Peri o d:  Wee ks 8, 1 0, a n d 1 2 ( ± 3 da ys f or eac h 
visit)  ............................................................................................................. 4 0 
9. 6. 5.  
Place b o - C o ntr olle d Wit h dra wal Peri o d:  Wee ks 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 
a n d 3 6 ( ± 3 da ys f or eac h visit)  .................................................................... 4 1 
9. 6. 6.  
F oll o w- u p Peri o d/ Earl y Ter mi nati o n:  We e k 4 0 ( ± 3 da ys) ......................... 4 2  
9. 7.  
St u d y D urati o n ............................................................................................. 4 3  
9. 8.  
Pr o hi biti o ns a n d Restricti o ns  ....................................................................... 4 3 
9. 8. 1.  
Pri or a n d C o nc o mita nt Me dicati o ns ............................................................ 4 3  
9. 8. 2.  
Dietar y Restricti o ns  ..................................................................................... 4 4 
9. 8. 3.  
Ot her Restricti o ns  ........................................................................................ 4 4 
9. 9.  
Wit h dra wal Criteria  ..................................................................................... 4 4 
9. 9. 1.  
Ha n dli n g of Wit h dra wals ............................................................................. 4 5  
9. 9. 2.  
S p o ns or’s Ter mi nati o n of St u d y .................................................................. 4 5  
1 0.  
S T U D Y D R U G  ............................................................................................ 4 5 
1 0. 1.  
St u d y Dr u g S u p plies  .................................................................................... 4 5 
1 0. 2.  
St u d y Dr u g St ora ge...................................................................................... 4 6  
1 0. 3.  
St u d y Dr u g Pac ka gi n g a n d La beli n g  ........................................................... 4 6 
1 0. 4.  
Bli n di n g ....................................................................................................... 4 6  
1 0. 5.  
St u d y Dr u g A d mi nistrati o n .......................................................................... 4 7  
1 0. 6.  
Dr u g C o m plia nce a n d Acc o u nta bilit y  ......................................................... 4 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 6

1 0. 7.  
St u d y Dr u g Ret ur n ....................................................................................... 4 7  
1 1.  
A D V E R S E E V E N T S ................................................................................... 4 7  
1 1. 1.  
Defi niti o n  ..................................................................................................... 4 8 
1 1. 2.  
I nte nsit y of A d verse E ve nts ......................................................................... 4 8 
1 1. 3.  
Relati o ns hi p t o St u d y Dr u g ......................................................................... 4 9  
1 1. 4.  
Rec or di n g A d verse E ve nts .......................................................................... 4 9  
1 1. 5.  
P ost -St u d y F oll o w - U p of A d verse E ve nts ................................................... 5 0 
1 1. 6.  
Seri o us A d verse E ve nts  ............................................................................... 5 0 
1 1. 6. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  ........................................................ 5 0 
1 1. 6. 2.  
Ma na gi n g Seri o us A d verse E ve nts  .............................................................. 5 1 
1 1. 6. 3.  
Re p orti n g Seri o us A d verse E ve nts a n d Ot her I m me diatel y Re p orta ble 
E ve nts  .......................................................................................................... 5 1 
1 1. 6. 4.  
E x pe dite d Safet y Re p orts ............................................................................ 5 1  
1 1. 7.  
Pre g na nc y .................................................................................................... 5 1  
1 2.  
D O C U M E N T A TI O N O F D A T A ................................................................ 5 2  
1 2. 1.  
Case Re p ort F or m ........................................................................................ 5 2  
1 2. 2.  
Data Ca pt ure, Re vie w, a n d Vali dati o n  ........................................................ 5 3 
1 2. 3.  
C o di n g Dicti o naries  ..................................................................................... 5 3 
1 3.  
S T A TI S TI C A L A N D A N A L Y TI C A L P L A N  ............................................ 5 3 
1 3. 1.  
Pri mar y Esti ma n d  ........................................................................................ 5 4 
1 3. 2.  
A nal ysis Sets  ................................................................................................ 5 4 
1 3. 3.  
Sa m ple Size  ................................................................................................. 5 4 
1 3. 4.  
Ha n dli n g of Missi n g Data  ............................................................................ 5 4 
1 3. 5.  
E nr oll me nt a n d Dis p ositi o n of S u bjects ...................................................... 5 4  
1 3. 6.  
De m o gra p hics a n d Baseli ne C haracteristics  ................................................ 5 4 
1 3. 7.  
St u d y Dr u g D osi n g a n d C o m plia nce ........................................................... 5 4  
1 3. 8.  
Efficac y Data  ............................................................................................... 5 5 
1 3. 9.  
Plas ma Dr u g E x p os ure Data  ........................................................................ 5 5 
1 3. 1 0.  
Safet y Data ................................................................................................... 5 5  
1 3. 1 1.  
S oft ware ....................................................................................................... 5 6  
1 3. 1 2.  
I nteri m A nal ysis........................................................................................... 5 6  
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  ................................................ 5 6 
1 4. 1.  
Ge neral Le gal Refere nces  ............................................................................ 5 6 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 7

1 4. 2.  
I nstit uti o nal Re vie w B oar d .......................................................................... 5 6 
1 4. 3.  
Pr ot oc ol A d here nce a n d A me n d me nts  ........................................................ 5 6 
1 4. 4.  
Re q uire d D oc u me nts ................................................................................... 5 7  
1 4. 5.  
I nf or me d C o nse nt ........................................................................................ 5 7 
1 4. 6.  
St u d y M o nit ori n g ......................................................................................... 5 7  
1 4. 7.  
Q ualit y Ass ura nce  ........................................................................................ 5 8 
1 4. 8.  
Rec or d Rete nti o n ......................................................................................... 5 8  
1 4. 9.  
C o nfi de ntialit y ............................................................................................. 5 8  
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 8
1 6. 
R E F E R E N C E S ............................................................................................ 5 9
1 7.
A P P E N DI C E S  ............................................................................................. 6 1
1 7. 1.  
Yale Gl o bal Tic Se verit y Scale  .................................................................... 6 1 
1 7. 2.  
Pre m o nit or y  Ur ge f or Tics  Scale  ................................................................. 6 6  
1 7. 3.  
Cli nical  Gl o bal Im pressi o n  of Tics  - Se verit y  scale  .................................... 6 8  
1 7. 4.  
Cli nical Gl o bal I m pressi o n of T o urette S y n dr o me - Im pr o ve me nt  scale  .... 7 0  
1 7. 5.  
Gilles de la T o urette S y n dr o me - Q ualit y of Life f or C hil dre n a n d 
A d olesce nts  .................................................................................................. 7 2  
1 7. 6.  
C ol u m bia- S uici de Se verit y Rati n g Scale C hil dre n’s Baseli ne/ Scree ni n g 
Versi o n ......................................................................................................... 7 8  
1 7. 7.  
C ol u m bia- S uici de Se verit y Rati n g Scale C hil dre n’s Si nce Last Visit 
Versi o n ......................................................................................................... 8 2  
1 7. 8.  
C hil dre n’s De pressi o n Rati n g Scale,  Re vise d  ............................................. 8 6  
1 7. 9.  
C hil dre n’s Yale- B r o w n Obsessi ve C o m p ulsi ve Scale  ................................ 9 1  
1 7. 1 0.  
Atte nti o n - Deficit  Hy peracti vit y  Dis or der Rati n g  Scale - 5: H o me Versi o n  .. 1 1 3  
1 7. 1 1.  
E xtra p yra mi dal  Sy m pt o m  Rati n g  Scale - Ab bre viate d  ................................. 1 1 8  
LI S T O F T A B L E S  
Ta ble  1: 
Sc he d ule of Assess me nts  ............................................................................. 2 8 
Ta ble  2: 
Esti mate d T otal Bl o o d Sa m ple V ol u me  ...................................................... 3 6 
Ta ble  3: 
I nte nsit y of A d verse E ve nts ......................................................................... 4 9 
Ta ble  4: 
Relati o ns hi p of A d verse E ve nts t o St u d y Dr u g ........................................... 4 9  
LI S T O F FI G U R E S  
Fi g ure 1:  
St u d y Desi g n Sc he matic  .............................................................................. 2 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 5
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 8

2.  
S Y N O P SI S  
P r ot o c ol Title:   A P has e 2, D o u ble -Bli n d, Place b o -C o ntr olle d, Ra n d o mize d Wit h dra wal St u d y t o 
E val u ate t he Saf et y a n d Efficac y of N BI -9 8 8 5 4 i n P e diatric S u bje cts wit h T o urette S y n dr o me  
St u d y Ce nters:   A p pr o xi matel y 5 5 st u d y c e nt ers i n t h e U nit e d Stat es. 
O bjecti ves:  
Pri mar y:  
•  T o e val uate t he mai nte na nc e of efficac y of N BI -9 8 8 5 4 d uri n g a d o u ble -bli n d, place b o -c o ntr olle d 
wit h dra wal p eri o d i n p e diatric s u bje cts wit h T o urett e s y n dr o me ( T S) w h o ha ve res p o n d e d t o 
o p e n -la b el N BI-9 8 8 5 4 treat me nt.  
Sec o n d ar y:  
•  T o e val uate t he eff ect of N BI -9 8 8 5 4 o n meas ures of T S s y m pt o ms d uri n g a place b o -c o ntr olle d 
wit h dra wal p eri o d.  
•  T o e val uate t he s af et y a n d t olera bilit y of N BI -9 8 8 5 4 a d mi nister e d o nce d ail y f or u p t o 3 6 wee ks.  
Met h o d ol o g y:  T his is a P has e 2, d o u ble -bli n d, place b o -c o ntr olle d, ra n d o mize d wit h dra wal st u d y t o 
e val u ate t he s af et y a n d mai nt e n a n ce of efficac y of  a n o pti mize d d ose of N BI-9 8 8 5 4 i n p e diatric s u bje cts 
wit h T S.  T he st u d y i ncl u d es  a n i niti al o p e n-l a b el treat me nt p eri o d f or 6 wee ks, a bli n d e d ra n d o mizati o n 
p eri o d f or 6 wee ks, f oll o we d b y a d o u ble -bli n d, place b o -c o ntr olle d wit h dra wal  p eri o d f or 2 4 wee ks, f or 
a t otal of u p t o 3 6 wee ks of treat me nt.  F oll o w -u p ass ess me nts will b e c o n d ucte d  at t he e n d of Wee k 4 0  
after a 4 -wee k was h o ut of st u d y dr u g, or u p o n earl y ter mi nati o n.  N BI -9 8 8 5 4 will b e titrat e d t o t he 
s u bje ct’s o pti mal d ose i n t he r a n ge of 2 0  m g t o 6 0 m g f or s u bjects < 5 0 k g a n d 4 0  m g t o 8 0  m g f or 
s u bje cts ≥5 0 k g d uri n g t he i nitial o p e n-l a b el tr eat me nt p eri o d. 
A p pr o xi matel y 1 8 0 male a n d f e male p e diatri c s u bjects, 6 t o 1 7 years of a ge, wit h a Dia g n ostic a n d 
Statist ic al Ma n ual of Me ntal Dis or d ers, 4t h or 5t h E diti o ns ( D S M-I V or -5) dia g n osis of T S will b e 
e nr oll e d i nt o t he 6 -we e k o p e n -l a b el, d ose-o pti mizati o n tre at me nt p eri o d.  It is esti mate d  t h at 
a p pr o xi matel y 9 0 of t hese s u bj ects will meet t he criteri o n f or treat me nt r es p o nse after d ose o pti mizati o n, 
a n d will t h e n b e ra n d o mize d i n a 1: 1 rati o t o plac e b o or N BI -9 8 8 5 4  d uri n g t h e 6 -we e k bli n d e d 
ra n d o mizati o n p eri o d, b ef ore e nteri n g  t h e 2 4-we e k, d o u ble -bli n d, place b o -c o ntr olle d  wit h dr a wal  p eri o d.  
Tre at me nt res p o nse will b e b as e d o n t he p h ysi cia n i n vesti gat or’s cli ni cal ass ess me nt of s ufficie nt c o ntr ol 
of tic b e ha vi ors . 
Pri or t o t he c o n d uct of a n y st u d y -rel ate d pr o ce d ures, p are nt al or le gal g u ar dia n i nf or me d c o nse nt wit h 
si g ne d ( or ver b al, if a p plica ble) a n d wit n esse d pe diatric ass e nt m ust b e o btai ne d.  S u bje cts will t h e n b e 
scr ee n e d t o d eter mi n e eli gi bilit y f or u p t o 4 wee ks pri or t o Da y 1 ( b aseli n e).  
O p e n -l a b el Tre at me nt P eri o d ( D ose O pti miz ati o n) 
O n Da y 1 ( b aseli ne), eli gi ble s u bjects will r et ur n t o t h e st u d y ce nter f or c ollecti o n of b aseli ne saf et y a n d 
efficac y assess me nts, a n d t he c olle cti o n of a bl o o d sa m ple f or d eter mi n ati o n of t heir c yt o c hr o me 
P 4 5 0  2 D 6 ( C Y P 2 D 6) meta b olizer st at us.  S u bjects w h o c o nti n ue t o b e eli gi ble will b e pr o vi d e d wit h a 
2- wee k s u p pl y of N BI -9 8 8 5 4, a n d will b e as k e d t o liste n t o a n d si g n a tre at me nt assi g n m e nt scri pt t h at 
e x plai ns t he p ote ntial assi g n me nt t o place b o at s o me p oi nt d uri n g t he treat me nt p eri o d.  St u d y dr u g will 
b e a d mi nist ere d at h o me at t h e s u bje ct’s b e dti me ( q hs) u n d er t h e s u p e r visi o n of t he s u bj ect’s p are nt or 
le g al g uar di a n at a p pr o xi matel y t h e sa m e ti me o nce d ail y f or t he d ur ati o n of t he st u d y. 
F or s u bje cts < 5 0 k g o n Da y 1 ( b aseli n e), t h e starti n g d ose will b e N BI -9 8 8 5 4 2 0 m g a n d f or s u bjects 
≥5 0  k g o n Da y 1 ( b aseli n e), t h e s tarti n g d ose will b e N BI-9 8 8 5 4 4 0 m g.  T hese st arti n g d oses ma y b e 
esc alate d i n i ncr e me nts of 2 0 m g e ver y 2 we e ks t o a ma xi m u m of 6 0 m g f or s u bjects < 5 0 k g a n d a 
ma xi m u m of 8 0  m g f or s u bjects ≥5 0 k g t o ac hie v e a n o pti mal d ose of N BI -9 8 8 5 4 f or eac h s u bject.   D ose 
esc alati o ns will o cc ur at t h e e n d of Wee ks 2 a n d 4 b ase d o n t he f oll o wi n g 2 criteria:  1) t he s u bje ct’s tics 
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are n ot s ufficie ntl y c o ntr oll e d p er p h ysicia n i n vesti g at or assess me nt; a n d 2) a n e v al uati o n b y t he 
p h ysi cia n i n vesti gat or i n dicates t hat t h e  s u bje ct is t olerati n g t h e st u d y dr u g at t he c urre nt d ose a n d w o ul d 
li kel y b e a ble t o t oler ate t he ne xt d ose le v el.  D uri n g t h e o p e n-la b el tre at me nt p eri o d, t he p h ysi cia n 
i n v esti g at or ma y escalat e t h e s u bj ect’s d ose t o t he n e xt d ose le vel, c o nti n ue wit h t he s u bject’s c urre nt 
d ose (ie, o pti mize d d ose has b ee n a c hie v e d), or re d uc e t o t he s u bject’s pri or t olerat e d d ose (i n s u bje cts 
w h o ha ve ha d a d ose esc alati o n).  After W ee k 6, s u bjects will c o nti n u e t o recei v e t h eir o pti mize d d ose of 
N BI -9 8 8 5 4 u ntil t he y are  ra n d o mize d (r es p o n d ers) or t he y disc o nti n ue ( n o nr es p o n d ers).  If a s u bje ct’s 
o pti mal d ose has alr ea d y b ee n esta blis he d at Wee k 2 (ie, 1 or b ot h escalati o n criteria are n ot met) or at 
Wee k 4, n o d ose escal ati o n will b e all o we d at t he s u bse q u e nt visits.  At  a n y ti me d uri n g tre at me nt 
(i n cl u di n g o p e n-l a b el tr eat m e nt, bli n d e d ra n d o mizati o n, a n d d o u ble-bli n d, place b o -c o ntr oll e d  
wit h dra wal  p eri o ds), s u bjects w h o ha d a d ose esc alati o n a n d are u na ble t o t oler ate t heir c urr e nt d ose will 
ha v e t h eir d ose d ecr ease d t o t heir pre vi o us d ose ( d uri n g t he bli n d e d ra n d o mizati o n a n d d o u ble-bli n d, 
place b o -c o ntr oll e d  wit h dra wal  p eri o ds t his will b e d o ne i n a bli n d e d ma n n er; s u bje cts r ecei vi n g pla ce b o 
will c o nti n u e t o rec ei v e place b o).  T h e s u bje ct will c o nti n ue at t h at d ose f or t he re mai n d er of t he st u d y.  
T h e i n vesti g at or ma y r e d uc e t h e s u bje ct’s d ose o nl y 1  ti me d uri n g t he st u d y.  S u bje cts w h o are u na ble t o 
t olerat e t h e st arti n g d ose or res u m pti o n of t he pre vi o usl y t olerat e d d ose will b e disc o nti n ue d fr o m t he 
st u d y. 
S u bje cts wil l ret ur n t o t he st u d y c e nter f or st u d y assess me nts a n d dis p e nsi n g of st u d y dr u g.  As m uc h as 
p ossi ble, t hes e visits s h o ul d o cc ur at t he sa me ti me as t he Da y 1 ( b aseli ne) visit t o sta n d ar diz e t he ti me 
of d a y f or t he assess me nt of efficac y, s af et y, a n d plas m a e x p os ure of st u d y dr u g.  
Bli n d e d R a n d o miz ati o n P eri o d  
At t he e n d of Wee k s 8, 1 0, a n d 1 2, s u bjects w h ose ti cs h a v e res p o n d e d t o N BI -9 8 8 5 4 treat me nt 
(esti mat e d t o b e a p pr o xi matel y 9 0 s u bjects; t h e p h ysi cia n i n vesti gat or will d eter mi ne treat m e nt r es p o nse 
b as e d o n a cli nical assess me nt of s ufficie nt c o ntr ol of tic b e ha vi ors ), a n d w h o are t ol erati n g t heir 
o pti mize d d ose of N BI -9 8 8 5 4 b ase d o n p h ysicia n i n v esti g at or assess me nt, will b e ra n d o mize d ( 1: 1) t o 
rec ei v e plac e b o or c o nti n ue wit h t h eir o pti miz e d d ose of NBI -9 8 8 5 4.  Assess m e nt of treat m e nt r es p o nse 
a n d t olera bilit y will o cc ur at e ac h of t he bli n d e d ra n d o mizati o n  p eri o d visits at Wee ks 8, 1 0, a n d 1 2; 
t heref ore, a s u bje ct w h o di d n ot ac hie ve a treat me nt r es p o nse at Wee k 8 c o ul d ac hi e v e tr eat me nt 
res p o nse at Wee k 1 0 or Wee k 1 2 a n d b e ra n d o mize d.  T he s u bje ct r es p o n d ers, i n vesti gat ors, a n d 
S p o ns or will b e bli n d e d t o t he visit wee k w he n ra n d o mizati o n o cc urs ( pr o gr a m me d o n t he I nteracti v e 
We b Res p o nse S yste m [I W R S]).  Of t he esti mate d 9 0 s u bjects w h o ar e tre at me nt r es p o n d ers, 
a p pr o xi matel y 3 0 will b e ra n d o mize d at e ac h of t he ra n d o mizati o n visits.  
All s u bje cts w h o ac hie ve tre at me nt res p o nse at Wee k 1 2 a n d w h o were n ot pre vi o usl y r a n d o mize d will 
b e ra n d o mize d at Wee k  1 2.  S u bjects r a n d o mize d t o N BI -9 8 8 5 4 will c o nti n u e wit h t heir o pti mize d d ose 
of N BI -9 8 8 5 4.  T he bli n d e d, sta g g ere d ra n d o mizati o n pr o cess was c h ose n t o mi ni mi ze t h e eff ect of 
s u bje cts/i n vesti gat ors k n o wi n g w he n t h e place b o-c o ntr olle d p orti o n of t he st u d y b e gi ns.  
S u bje cts w h o ar e n o nr es p o n d ers at t h e Wee k 1 2 visit a n d w h o wer e n ot pre vi o usl y ra n d o mize d will b e 
disc o nti n u e d  fr o m t he st u d y a n d as ke d t o ret urn 2 t o 4 wee ks after t heir fi nal d ose of st u d y dr u g f or a 
fi nal st u d y visit (t hese s u bje cts will n ot b e i ncl u d e d i n t he efficac y a nal ys es ).  S u bje cts w h o disc o nti n u e 
st u d y p artici p ati o n f or a n y re as o n will b e as k e d t o c o m plete all e arl y ter mi nati o n assess me nts.  
D o u ble -Bli n d, Pl a ce b o -C o ntr olle d  Wit h d r a w al P eri o d  
S u bje cts will c o nti n u e t o self -a d mi nist er t he st u d y dr u g o nc e d ail y at b e dti me ( q hs) u n d er t h e 
s u p er visi o n of t heir p are nt or le g al g uar dia n a n d ret ur n t o t h e st u d y sit e at s c h e d ule d visits 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 ( We e ks 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, a n d 3 6 [ n o 
dis p e nsi n g of st u d y dr u g at Wee k 3 6]).  
F oll o w -u p P eri o d ( o r E a rl y Ter mi n ati o n)  
F oll o w -u p ass ess m e nts f or s u bjects w h o c o m plete t he st u d y will b e c o n d uct e d  at t he e n d of Wee k 4 0  
after a 4 -wee k was h o ut of st u d y dr u g, or at a n earl y ter mi nati o n visit  (s u bj ects w h o are n o nr es p o n d ers at 
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t he We e k 1 2 visit a n d w h o wer e n ot pre vi o usl y ra n d o mize d will b e disc o nti n ue d  fr o m t he st u d y a n d 
as k e d t o ret ur n 2 t o 4 wee ks afte r t heir fi nal d ose of st u d y dr u g f or a fi nal st u d y visit).  All visits will 
ha v e a wi n d o w of ± 3  d a ys.  
A n i n d e p e n d e nt Data Saf et y M o nit ori n g B o ar d ( D S M B) will p eri o dicall y re vie w o n g oi n g cli nic al s af et y 
d ata t o e ns ure t he saf et y a n d well -b ei n g of t he st u d y s u bjects. 
St u d y P o p ul ati o n:   A p pr o xi matel y 1 8 0 male a n d f e male p e diatric s u bjects ( 6 t o 1 7 years of a ge, 
i ncl usi v e) wit h a D S M-I V or -5 dia g n osis of T S  will b e e nr olle d.  T his st u d y will all o w e nr oll me nt of 
p e diatric s u bje cts w h o ha ve pre vi o usl y p artici p ate d i n a n d c o m plete d t h e N BI -9 8 8 5 4 -1 4 0 3, P hase 1 b 
st u d y or N BI-9 8 8 5 4 -1 5 0 1, P hase 2 st u d y.  S u bjects m ust h a v e at le ast m o d erate c urr e nt T S s y m pt o ms, 
as d efi ne d b y a Cli ni cal Gl o b al I m pressi o n of Tics -Se verit y s cale ( C GI -Tics -Se verit y ) sc ore of ≥4 (ie, 
m o d e ratel y ill) at scree ni n g t hat is i n d e p e n d e ntl y v erifie d b y a n e xt er n al vi d e o  re vi e wer.  S u bjects m ust 
ha v e a st a ble ps y c hi atric stat us (s uc h as T S s p ectr u m dia g n oses [ e g, o bsessi v e-c o m p ulsi v e dis or d er, 
A D H D]) as cli nicall y d et er mi ne d b y t he p h ysi cia n i n ves ti gat or. 
D u r ati o n of Tre at me nt a n d St u d y P a rtici p ati o n:   T he e x p ect e d d urati o n of st u d y p arti ci p ati o n f or 
eac h s u bj ect is a p pr o xi matel y 4 4 wee ks, i n cl u di n g u p t o 4 wee ks of scree ni n g, a 3 6 -wee k tr eat me nt 
p eri o d (i ncl u di n g a 6 -we e k N BI -9 8 8 5 4 o p e n -l a b el tre at me nt p eri o d, a 6-wee k bli n d e d ra n d o mizati o n 
p eri o d, a n d a 2 4 -wee k d o u ble -bli n d, place b o -c o ntr olle d wit h dra wal p eri o d), a n d 4 wee ks f or f oll o w -u p 
ass ess m e nts or earl y ter mi n ati o n.  
I n v esti g ati o n al P r o d u ct, D ose, a n d M o d e of A d mi nistr ati o n:  N BI -9 8 8 5 4 w ill b e s u p plie d as ca ps ul es 
c o ntai ni n g 2 0 m g or 4 0 m g of N BI-9 8 8 5 4 (free b ase e q ui vale nt).  Eac h s u bject will r ecei v e 2 ca ps ules 
eac h d a y ( p ossi bl y i ncl u di n g 1 place b o ca ps ul e) t o ac hie ve N BI -9 8 8 5 4 d oses of 2 0  m g, 4 0 m g, 6 0 m g, or 
8 0 m g.  S u bjects will s wall o w t he c a ps ul es at b e dti me wit h at l east 4 o u nces of wat er a n d ma y b e ta ke n 
wit h or wit h o ut f o o d.  
Ref ere n ce T h er a p y, D ose, a n d M o d e of A d mi nistr ati o n:   Matc hi n g plac e b o ca ps ules will b e i d e ntic al 
i n a p p eara nc e t o t he 2 0 m g a n d 4 0 m g N BI-9 8 8 5 4 ca ps ules.  Place b o will b e use d i n t he o p e n -l a b el 
treat me nt, bli n d e d ra n d o mizati o n, a n d d o u ble-bli n d p orti o ns of t he st u d y, e ns uri n g 2 ca ps ules are t a k e n 
f or all d oses.  S u bjects will s wall o w t h e ca ps ules at b e dti me wit h at l east 4 o u nces of water a n d ma y b e 
ta k e n wit h or wit h o ut f o o d. 
Crite ri a f o r E v al u ati o n:   
Effic a c y Assess me nts  
Mai nt e n a n ce of efficac y  d uri n g t h e place b o -c o ntr olle d wit h dra wal p eri o d will b e b ase d o n  a n e val uati o n 
of t he Yale Gl o b al Tic S e verit y S cal e -T otal Ti c Sc ore ( Y G T S S -T T S)  a n d t he C GI -Tics -Se v erit y  sc ale as 
well as s u bje ct disc o nti n uati o ns d ue t o la c k of efficac y  or a tre at me nt -e mer ge nt a d vers e e v e nt ( T E A E) of 
w orse ni n g of tics . 
T h e Y G T S S is d es i g n e d t o rate t h e o ver all s e v erit y of m ot or a n d p h o nic tic s y m pt o ms acr oss a ra n ge of 
di me nsi o ns:  n u m b er, fre q ue nc y, i nt e nsit y, c o m ple xit y, a n d i nt erf ere nc e.  T h e scale als o i ncl u d es a n 
i m p air me nt assess me nt.  T he Y G T S S will b e a d mi nist er e d b y t he i n vestigat or (or q ualifie d d esi g nee) 
usi n g a c o m p uter -b as e d str uct ur e d cli nical i nt er vie w.  At ea c h ti me p oi nt, t h e Y G T S S i nt er vie w will b e 
vi d e o rec or d e d i n its e ntir et y.  T he vi d e o rec or di n g will f oll o w a sta n d ar diz e d set of g ui d eli n es a n d t he 
rec or d e d vi d e o will b e u pl o a d e d t o a sec ur e ce ntr al ser v er.  A n e xter nal vi d e o re vi e wer, n ot affiliate d 
wit h t h e sit e, will ac cess t he c e ntral ser ver t o vie w t h e re c or di n g a n d 1) c o nfir m t he s u bject’s T S s e v erit y 
is at l east m o d erate b as e d o n a C GI-Tics -S e v erit y of ≥4 (a t scre e ni n g o nl y), a n d 2) d eter mi n e if t he 
Y G T S S i nter vie w pr o gra m was a d mi nist ere d pr o p erl y.  T he c o m p uter s oft war e s yste m f or t he Y G T S S 
a d mi nistrati o n, Rater Stati o n ™ ( Bra c k et Gl o b al, L L C; P hila d el p hia, P A), will pr o m pt t he i n vesti g at or 
( or d esi g n ee) t o e nt er a s c ore f or eac h it e m of t he s cal e b ase d o n s u bje ct a n d p are nt res p o ns es d uri n g t h e 
str uct ure d cli ni cal i nt er vie w.  T h e s oft war e will als o g e nerat e i n di vi d ual sc ores f or eac h ite m of t he scale 
(ta n d e m rati n g) a n d will g e n erate t he T T S a n d t he Gl o b al Tic Se verit y Sc ore.  T he Y G T S S will b e 
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a d mi nist er e d at scr ee ni n g, o n Da y 1 ( b aseli ne), a n d at Wee ks 2, 4, 6, 8, 1 0, 1 2,  1 4,  1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 
3 6, a n d 4 0 (fi nal visit or at e arl y ter mi nati o n).  
T h e Cli ni cal Gl o b al I m pressi o n -T o ur ett e S y n dr o me ( C GI -T S) -I m pr o ve me nt sc ale will b e use d t o rate 
t he p h ysi cia n i n vesti gat or’s assess me nt of t he s u bje ct’s o verall i m pr o ve me nt si nc e i niti ati o n of st u d y 
dr u g d osi n g a n d will b e a d mi nister e d at Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d 4 0 
(fi nal visit or at earl y t er mi nati o n).  T h e C GI-Tics -Se verit y, a r ati n g of t he p h ysici a n i n v esti gat or’s 
ass ess m e nt of t he s u bject’s o verall  se verit y of tic b e h a vi ors, will b e ass ess e d at scre e ni n g a n d Da y 1 
( b aseli n e) i n a d diti o n t o t he ti me p oi nts us e d i n t he assess me nt of C GI-T S -I m pr o ve me nt. 
T h e Pre m o nit or y Ur ge f or Tics Scale ( P U T S) a n d t he Gilles d e l a T o ur ett e S y n dr o me -Q ualit y of Lif e 
Scale f or C hil dre n a n d A d olesc e nts ( C & A -G T S -Q O L) will b e a d mi nist er e d at scr ee ni n g, o n Da y 1 
( b aseli n e), a n d at We e ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d 4 0 (fi nal visit or earl y 
ter mi nati o n). 
Pl as m a d r u g e x p os u re t o N BI -9 8 8 5 4 a n d t he a cti v e met a b olite, N BI -9 8 7 8 2  
Bl o o d sa m ples t o e val uat e plas ma c o nce ntrati o ns of N BI -9 8 8 5 4 a n d t he acti ve meta b olite, N BI -9 8 7 8 2 
( ot her meta b olites ma y b e e v al uat e d), will b e c ollecte d at Da y 1 ( b aseli n e) a n d at Wee ks 2, 4, 6, 8, 1 0, 
1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, a n d 4 0 (fi nal st u d y visit or earl y ter mi n ati o n).  S u bje cts/ care gi v ers will b e 
as k e d t o rec or d a n d pr o vi d e d osi n g ti me s of N BI -9 8 8 5 4 f or t he first d ose a n d fr o m t he e ve ni n g b ef ore 
t he treat me nt p eri o d visits w he n t h ese bl o o d sa m ples ar e c olle cte d. 
S af et y Assess me nts  
Saf et y a n d t oler a bilit y will b e m o nit ore d t hr o u g h o ut t he st u d y a n d will i n cl u d e t he f oll o wi n g 
ass ess m e nts:  
•  
A Es.  
•  
Cli nic al l a b orat or y tests ( he m at ol o g y, cli ni cal c he mistr y, a n d uri n al ysis).  
•  
Ser u m pr olacti n.  
•  
Vital si g ns (i ncl u di n g ort h ost ati c s yst olic a n d diast olic bl o o d press ure, ort h ostatic p uls e rate, 
res pir at or y r ate, a n d oral b o d y te m p erat ur e). 
•  
P h ysi cal e x a m i nati o ns (i n cl u di n g h ei g ht a n d wei g ht). 
•  
1 2 -lea d electr o car di o gra ms ( E C Gs). 
•  
C ol u m bia -S uici d e Se v erit y Rati n g Sc al e ( C -S S R S), C hil dr e n’s Versi o n.  
•  
C hil dre n’s De pressi o n Rati n g S cal e - Re vise d ( C D R S -R).  
•  
C hil dre n’s Yal e -Br o w n O bsessi v e  C o m p ulsi v e Sc ale ( C Y -B O C S ). 
•  
Att e nti o n -Deficit H y p era cti vit y Dis or d er Rati n g S cal e -5: H o me Versi o n ( A D H D -5 Rati n g Scale).  
•  
E xtra p yra mi d al S y m pt o m Rati n g Scale - A b bre vi ate d ( E S R S -A).  
St atistic al Met h o ds:  Descri pti ve a n d i nf ere ntial statistics will b e use d t o e v al u ate t he efficac y of 
N BI -9 8 8 5 4 relati ve t o place b o d uri n g t h e wit h dra wal p eri o d.  T he assess me nt of mai nte n a n c e of efficac y 
(ie, s ufficie nt c o ntr ol of tic b e ha vi ors) d uri n g t he plac e b o-c o ntr olle d wit h dra wal p eri o d will b e b ase d o n 
a n e val uati o n of Y G T S S -T T S a n d C GI -Ti cs -S e v erit y as well as s u bje ct disc o nti n uati o n d ue t o lac k of 
efficac y or a T E A E of w orse ni n g of tics .  T he pri mar y efficac y e n d p oi nt will b e ti m e t o l oss of treat me nt 
res p o nse o v er t h e c o urse of t he ra n d o mize d wit h dra wal p eri o d ( t hr o u g h We e k 3 6).  L oss of treat me nt 
res p o nse d uri n g t h e wit h dra wal p eri o d will b e d efi ne d as: 
•  
2 c o nsec uti v e visits wit h 1) a n i ncre ase i n t h e Y G T S S -T T S of greater t ha n 3 5 % or 7  p oi nts fr o m 
t he wit h dra wal p eri o d b aseli n e ( Wee k 8, 1 0, or 1 2, d e p e n di n g o n w h e n t he s u bje ct was 
ra n d o mize d) a n d 2) a n i ncrease i n C GI -Ti cs -S e verit y sc ore of ≥2 p oi nts fr o m t h e wit h dra wal 
p eri o d b aseli ne or  
•  
S u bje ct disc o nti n uati o n d ue t o lac k of efficac y  or a T E A E of w orse ni n g of tics . 
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Statistic al c o m p aris o ns b et wee n N BI -9 8 8 5 4 a n d place b o will b e p erf or me d f or t he efficac y e n d p oi nts f or 
t he c o m bi ne d  wei g ht gr o u ps ( < 5 0 k g, ≥5 0 k g) a n d d ata will als o b e s u m mariz e d d escri pti vel y f or eac h 
wei g ht gr o u p se p arat el y.  T he a nal ys es will i n cl u d e c o m p aris o ns at s p e cifie d ti me p oi nts.   Ti me t o l oss of 
treat me nt resp o nse ( me as ure d i n d a ys fr o m ra n d o mizati o n t o t he first assess me nt visit at w hic h t he 
crit eri a f or l oss of treat me nt res p o nse wer e  met  as meas ur e d b y t he Y G T S S -T T S a n d C GI -Ti cs -Se verit y 
sc ore or d ate of disc o nti n u ati o n d u e t o  eit h er l ac k of efficac y or a T E A E of w orse ni n g of tics ) will b e 
a nal y ze d usi n g a l o g-r a n k test str atifie d b y wei g ht gr o u p.  Ka pla n-Meier esti m ates of l oss of treat m e nt 
res p o nse f or eac h tr eat me nt gr o u p a n d me dia n, u p p er, a n d l o wer q uartiles a n d ass o ciate d c o nfi d e nce 
i nter v als will b e cal c ul at e d w here p ossi ble.  
Saf et y a n d plas ma st u d y dr u g a n d met a b olite c o nce ntr ati o n d at a will b e s u m mariz e d b y ti me p oi nt f or t he 
c o m bi ne d  wei g ht gr o u ps a n d e ac h wei g ht gr o u p se p arat el y, usi n g d es cri pti ve statistics.  
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 5 
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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 - deficit h y p eracti vit y d is or d er 
A D H D - 5 Rati n g S cale  
Att e nti o n -Deficit H y p era cti vit y Dis or d er Rati n g S cal e - 5:  H o me Versi o n 
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsf er as e  
A S T  
As p artat e a mi n otra nsf erase  
A U C  
Are a u n d er t h e plas ma c o n ce ntr ati o n vers us ti me c ur ve  
A U C 0- ∞  
A U C fr o m 0 h o urs e xtra p olate d t o i nfi nit y  
β- h C G  
β- h u ma n c h ori o nic g o na d otr o pi n  
C & A -G T S -Q O L  
Gilles d e la T o ur ett e S y n dr o me -Q ualit y of Life Sc ale f or C hil dre n a n d 
A d olesc e nts  
C BI T  
C o m pre he nsi ve Be ha vi oral I nt er v e nti o n f or Tics 
C D R S - R 
C hil dre n’s De pressi o n Rati n g S cal e - Re vise d  
C F R  
C o d e of Fe d eral Re g ul ati o ns  
C GI -Tics -Se verit y  
Cli nic al Gl o b al I m pressi o n of Tics -Se verit y s cal e  
C GI -T S -I m pr o ve me nt 
Cli n ic al Gl o b al I m pressi o n of T o urette S y n dr o me -I m pr o ve m e nt s cale 
C ma x   
Ma xi m u m plas ma c o nc e ntrati o n  
C R T  
C o ntr olle d r o o m te m p erat ure  
C- S S R S  
C ol u m bia -S uici d e Se v erit y Rati n g Sc al e  
C Y -B O C S  
C hil dre n’s Yal e -Br o w n O bsessi v e  C o m p ulsi v e Sc ale  
C Y P  
C yt o c hr o me  P 4 5 0  
D S M B  
Data S af et y M o nit ori n g B o ar d  
D S M -I V or - 5 
Dia g n ostic a n d Statistic al Ma n u al of Me ntal Dis or d ers , 4t h or 5t h E diti o ns  
D S P V  
Dr u g S af et y a n d P har ma c o vi gila nc e  
E C  
Et hics C o m mitte e  
E C G  
Electr o c ar di o gra m  
e C R F 
Electr o nic c ase r e p ort f or m 
E D C  
Electr o nic d ata ca pt ure  
E D T A K 2 
Di p otassi u m et h yle ne dia mi netetraa cetic a ci d  
E S R S - A 
E xtra p yra mi d al S y m pt o m Rati n g Scale -A b bre viat e d  
F D A  
[ U nit e d Stat es] F o o d a n d Dr u g A d mi nistrati o n 
G C P  
G o o d Cli nical Pra cti ce  
G G T  
Ga m ma -gl uta m yl tr a nsf eras e  
H Bs A g  
He p atitis B s urf ac e a nti g e 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 5 
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H C V -A b  
He p atitis C vir us a nti b o d y  
HI V -A b  
H u ma n i m m u n o d eficie n c y vir us a nti b o d y  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nt er n ati o n al C o nf ere n ce o n Har m o nisati o n 
I R B 
I nstit uti o n al Re vi e w B o ar d 
I W R S 
I nt era cti ve We b Res p o nse S yste m 
M A OI  
M o n o a mi ne o xi d ase i n hi bit or  
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
N BI  
Ne ur o cri ne Bi oscie nces, I n c.  
P C R  
P ol y meras e c h ai n rea cti o n  
P K  
P har mac o ki n eti c(s)  
P T  
Pref erre d ter m  
P U T S  
Pre m o nit or y Ur g e f or Tics S cal e  
Q Tc F  
C orrecte d Q T i nter val usi n g Fri d ericia’s f or m ula  
S A E  
Seri o us a d v ers e e v e nt  
S A P  
Statistic al a nal ysis pla n  
S O C  
S yste m or ga n cl ass  
t½   
A p p are nt t er mi nal half -lif e 
T D  
Tar di ve d ys ki n esia  
T E A E  
Tre at me nt -e mer ge nt a d vers e e v e nt  
tma x   
Ti me t o ma xi m u m plas ma c o nc e ntrati o n  
T S  
T o urette s y n dr o me  
T T S  
T otal Tic S c ore  
U D S  
Uri ne dr u g scree n  
U L N  
U p p er li mit of n or mal  
U S  
U nite d St ates  
V M A T 2  
Vesic ular m o n o a mi ne tr a ns p orter 2  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or g a ni zati o n  
Y G T S S  
Yale Gl o b al Tic Se verit y Sc ale  
 
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 5 
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4.  
E T HI C S  
T he st u d y will be c o n d ucte d i n acc or da nce wit h Ne ur ocri ne Bi oscie nces, I nc. ( N BI) sta n dar ds 
t hat meet re g ulati o ns relati n g t o G o o d Cli nical Practice ( G C P).  T hese sta n dar ds res pect t he 
f oll o wi n g g ui deli nes: 
•  G o o d Cli nical Practice:  C o ns oli date d G ui deli ne (I nter nati o nal C o nfere nce o n 
Har m o nis ati o n [I C H] of Tec h nical Re q uire me nts f or t he Re gistrati o n of P har mace uticals f or 
H u ma n Use [c urre nt versi o n]). 
•  U nite d States ( U S) C o de of Fe deral Re g ulati o ns ( C F R) deali n g wit h cli nical st u dies 
( 2 1 C F R parts 5 0, 5 4, 5 6, 3 1 2, a n d 3 1 4). 
T he et hical re q uire me nts of I nstit uti o nal Re vie w B oar ds/ Et hics C o m mittees (I R Bs/ E Cs) a n d t he 
i nf or me d c o nse nt f or ms (I C Fs) a n d asse nt f or ms are disc usse d i n Secti o n  1 4 . 
5.  
I N T R O D U C TI O N 
5. 1.  
B ac k gr o u n d 
T o urette sy n dr o me ( T S) is a m o ve me nt dis or der c haracterize d b y t he prese nce of c hr o nic m ot or 
a n d o ne or m ore v ocal tics t hat ofte n a p pear i n c hil d h o o d or earl y a d olesce nce 
(A P A  D S M -I V, 1 9 9 4; A P A D S M - V, 2 0 1 3).  Tics are defi ne d as ra pi d, n o n- r h yt h mic, 
stere ot y pe d m ot or m o ve me nts or v ocalizatio ns, a n d are t y picall y cate g orize d as si m ple or 
c o m ple x base d o n t heir o vert feat ures.  Si m ple tics are brief, mea ni n gless acti o ns (e g, f orcef ul 
bli n ki n g of t he e yes or gr u nti n g) a n d c o m ple x tics are sl o wer, m ore p ur p osef ul be ha vi ors (e g, 
g yrati n g or utteri n g p hrases; Lec k ma n et al., 1 9 8 9 ; Ca va n na a n d Na ni, 2 0 1 3 ; 
S h prec her a n d K urla n, 2 0 0 9 ).  T he tics f oll o w a wa xi n g a n d wa ni n g c o urse o ver ti me, a n d m ust 
be rec urre nt f or a peri o d of m ore t ha n 1 year t o q ualif y f or dia g n osis.  I n a d diti o n t o tic 
p he n o me na, T S ma y als o prese nt wit h a c o nstellati o n of s y m pt o ms t hat are part of a br oa der 
“ T S s pectr u m,” w hic h ca n i ncl u de o bsessi ve -c o m p ulsi ve be ha vi ors, atte nti o n -deficit  
h y peracti vit y dis or der ( A D H D), a n d i m p ulsi ve or a ntis ocial be ha vi or (C he n et al., 2 0 1 2 ; 
Felli n g  a n d Si n ger, 2 0 1 1). 
It has bee n well esta blis he d t hat T S is pre d o mi na ntl y a dis or der of c hil d h o o d wit h a mea n or 
me dia n a ge of o nset of a p pr o xi matel y 6 years of a ge ( Lec k ma n et al. , 1 9 9 8; R o berts o n, 2 0 1 1 ; 
J a n k o vic a n d K urla n, 2 0 1 1; S wai n et al. , 2 0 0 7).  Tic s y mpt o mat ol o g y  us uall y bec o mes t he m ost 
se vere ar o u n d a ge 1 0 a n d b y t he ti me a d ult h o o d is ac hie ve d at 1 8 years of a ge, m ost  patie nts are 
eit her tic -free or t heir s y m pt oms ha ve si g nifica ntl y i m pr o ve d ( Lec k ma n et al., 1 9 9 8 ; 
K urla n, 2 0 1 0 ).  T S s y m pt o ms ma y als o occ ur i n a d ults a n d t hese tic p he n o me na a p pear t o be a 
re-e mer ge nce or a n e xacer bati o n of c hil d h o o d o nset T S ( C h o ui nar d a n d F or d, 2 0 0 0 ; J a n k o vic 
a n d K urla n, 2 0 1 1). 
P ersiste nt tics ca n ha ve a si g nifica nt i m pact o n patie nt q ualit y of life a n d ofte n lea d t o i m paire d 
ps yc h os ocial f u ncti o ni n g.  S o me of t hese pr o ble ms i ncl u de s ocial is olati o n, b ull yi n g, p h ysical 
disc o mf ort ( wit h pai n or i nj ur y), a n d p o or aca de mic perf or ma nc e (R oess ner et al. , 2 0 1 3).  
Ps yc h os ocial stress ors ca n, i n t ur n, e xacer bate tic s y m pt o mat ol o g y.  It is u n der t hese c o n diti o ns 
t hat p har mac ol o gical i nter ve nti o ns are ofte n c o nsi dere d (C he n et al., 2 0 1 2; S h prec her a n d 
K urla n, 2 0 0 9; R oess ner et al., 2 0 1 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 5 
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Ne ur o pat h ol o gical m o dels ha ve bee n pr o p ose d t o e x plai n t he s y m pt o matic feat ures of T S, a n d 
c o n ver gi n g li nes of e m pirical e vi de nce c o nsiste ntl y i m plicate d o pa mi ner gic d ysf u ncti o n a n d 
d ysre g ulati o n wit hi n prefr o ntal c orte x- basal ga n glia circ uitr y ( Felli n g a n d Si n ger , 2 0 1 1; 
P o urfar et al., 2 0 1 1 ).  F u ncti o nal ne ur oi ma gi n g st u dies ha ve i de ntifie d a patter n of prefr o ntal 
c orte x h y per meta b olis m  a n d re d uce d striatal acti vit y i n T S s u bjects (Ba xter a n d G u ze , 1 9 9 3; 
Bra u n et al., 1 9 9 3 ; P o urfar et al., 2 0 1 1).  P har mac ot h era pe utic a p pr oac hes ai me d at bl oc ki n g 
p osts y na ptic d o pa mi ne- 2 rece pt ors (e g, hal o peri d ol a n d pi m ozi de) ha ve de m o nstrate d efficac y 
i n re d uci n g T S s y m pt o ms.  I n t his re gar d, m o d ulati o n of d o pa mi ner gic t o ne t hr o u g h t he 
a d mi nistrati o n of a vesic ular m o n oa mi ne  tra ns p orter 2 (V M A T 2 ) i n hi bit or, li ke N BI- 9 8 8 5 4, 
ma y als o be a n effecti ve treat me nt o pti o n f or tic s u p pressi o n.  
5. 2.  
N BI - 9 8 8 5 4 
N BI -9 8 8 5 4 ( val be nazi ne t os ylate) is a selecti ve, orall y acti ve V M A T 2 i n hi bit or de vel o pe d b y 
N BI.  N BI- 9 8 8 5 4 is u n der de vel o p me nt f or t he treat me nt of T S.  N BI - 9 8 8 5 4 was a p pr o ve d b y 
t he U S F o o d a n d Dr u g A d mi nistrati o n (F D A ) i n A pril 2 0 1 7 f or t he treat me nt of a d ults wit h 
tar di ve d ys ki nesia ( T D), u n der t he tra de na me I N G R E Z Z A® . 
I n n o ncli nical st u dies, N BI- 9 8 8 5 4 a p pears t o ca use little or n o c yt oc hr o me P 4 5 0 ( C Y P) e nz y me 
i n hi biti o n or i n d ucti o n at p har mac ol o gicall y rele va nt c o nce ntrati o ns.  N BI- 9 8 8 5 4 is a m o derate 
i n hi bit or of P- gl yc o pr otei n ( P-g p), b ut o nl y at c o nce ntrati o ns t hat c o ul d be ac hie ve d i n t he 
ga str oi ntesti nal tract, a n d is n ot a n i n hi bit or of a pa nel of ot her dr u g tra ns p orters.  Meta b olis m 
of N BI- 9 8 8 5 4 is c haracterize 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 - de pe n de nt m o n o-o xi dati o n t o N BI - 1 3 6 1 1 0.  N BI- 9 8 7 8 2 is meta b olize d i n part by 
C Y P 2 D 6.  All 3 e ntities, na mel 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, ca n bi n d t o a n d 
i n hi bit V M A T 2.  H o we ver, N BI- 9 8 7 8 2 is t he m ost p ote nt a n d a p pears t o be res p o nsi ble f or 
m ost  of t he o bser ve d p har mac ol o gical acti vit y of V M A T 2 i n hi biti o n. 
N BI - 9 8 8 5 4 a ppears t o be ra pi dl y a bs or be d wit h a ti me t o ma xi m u m plas ma c o nce ntrati o n (t ma x ) 
t y picall y ra n gi n g fr o m a p pr o xi matel y 0. 5 t o 1. 0 h o urs.  N BI-9 8 8 5 4 reac hes stea d y st ate wit hi n 
1 wee k.  T he acti ve meta b olite N BI - 9 8 7 8 2 gra d uall y f or ms wit h a tma 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 are eli mi nate d wit h a n a p pare nt ter mi nal half-life (t½ ) of 1 5 t o 
2 2 h o urs.  C oa d mi nistrati o n of ket oc o naz ole (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 le d 
t o a 1. 5- a n d 1. 6-f ol d i ncrease i n t he ma xi m u m plas ma c o nce ntrati o n ( Cma x ) of N BI- 9 8 8 5 4 a n d 
N BI - 9 8 7 8 2, res pecti vel y, a n d a 2. 1-f ol d i n crease i n t he area u n der t he plas ma c o nce ntrati o n 
vers us ti me c ur ve ( A U C) fr o m 0 h o urs e xtra p olate 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 oa d mi nistrati o n of N BI- 9 8 8 5 4 a n d rifa m pi n (str o n g C Y P 3 A 4/ 5 i n d u cer) le d t o a n 
a p pr o xi mate 3 0 % a n d 7 0 % decrease i n C ma x  a n d A U C 0 – ∞, res pecti vel y, f or N BI- 9 8 8 5 4, a n d a n 
a p pr o xi mate 5 0 % a n d 8 0 % decrease, res pecti vel y, f or N BI- 9 8 7 8 2 c o m pare d wit h a d mi nistrati o n 
of N BI- 9 8 8 5 4 al o ne.  C oa d mi nistrati 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 res ulte d i n a n 
a p pr o xi mate 1. 9-f ol d i ncrease i n t he C ma x  of di g o xi n.  T he effect of N BI- 9 8 8 5 4 o n di g o xi n 
A U C 0 – ∞ was m o dest ( 1. 4-f ol d i ncrease) a n d t he mea n t½  of di g o xi n was si milar wit h a n d 
wit h o ut N BI- 9 8 8 5 4 a d mi nistrati o n.  Mi daz ola m C ma x  a n d A U C 0 – ∞ were si milar wit h a n d 
wit h o ut N BI- 9 8 8 5 4 a d mi nistrati o n. 
N BI - 9 8 8 5 4 f or t he treat me nt of T S has bee n e val uate d  i n 3 c o m plete d P hase 1 b a n d P hase 2 
st u dies i n s u bjects wit h T S.  T hese i ncl u de 2 st u dies i n pe diatric s u bjects ( 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 he i nitial P hase 1 b, o pe n -la bel, 
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 5 
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m ulti ple -d ose st u d y of t he safet y, t olera bilit y,  p har mac o ki netics  (P K ), a n d p har mac o d y na mics 
( P D) of N BI- 9 8 8 5 4 ( N BI- 9 8 8 5 4- 1 4 0 3) was c o n d ucte d i n c hil dre n ( 6 t o 1 1 years of a ge) a n d 
a d olesce nts ( 1 2 t o 1 8 years of a ge) wit h T S .  D oses of N BI- 9 8 8 5 4 5 m g a n d 1 0 m g were 
a d mi nistere d i n c hil dre n a n d d oses of N BI- 9 8 8 5 4 1 0 m g, 2 5 m g, or 5 0 m g were a d mi nistere d i n 
a d olesce nts dail y o ver a 1 4 -da y treat me nt peri o d f oll o wi n g a m ul ti ple asce n di n g d ose pr ot oc ol.  
St u d y N BI- 9 8 8 5 4- 1 5 0 1 was a P hase 2, m ultice nter, ra n d o mize d, d o u ble- bli n d, 
place b o -c o ntr olle d, parallel gr o u p, d ose-ra n gi n g st u d y t o e val uate t he efficac y, safet y, a n d 
t olera bilit y of 2 d oses of N BI- 9 8 8 5 4 ( 1 0 m g a n d 2 0 m g i n c hil dre n [ 6 t o 1 1 years of a ge], a n d 
2 0 m g a n d 4 0 m g i n a d olesce nts [ 1 2 t o 1 7 years of a ge]) relati ve t o place b o, a d mi nistere d o nce 
dail y f or 6 wee ks i n  9 8 pe diatric s u bjects wit h T S.  S u bjects wit hi n eac h a ge gr o u p were  
ra n d o mize d i n a 1: 1: 1 rati o t o place b o or 1 of t he 2 N BI- 9 8 8 5 4 d oses.  St u d y N BI- 9 8 8 5 4- 1 5 0 5 
was a P hase 2, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, parallel gr o u p st u d y 
t o e val uate t he efficac y, safet y, a n d t olera bilit y of 2 d oses of N BI- 9 8 8 5 4 ( 4 0 m g a n d 8 0 m g) 
relati ve t o place b o, a d mi nistere d o nce dail y f or 8 wee ks i n 1 2 4 a d ult s u bjects wit h T S.  S u bjects 
were  ra n d o mize d i n a 1: 1: 1 rati o t o place b o or 1 of t he 2 N BI- 9 8 8 5 4 d oses.   
Res ults fr o m St u d y N BI- 9 8 8 5 4- 1 4 0 3 re ve ale d re d ucti o ns fr o m baseli ne ( Da y - 1) t o Da y 1 4 i n 
t he Yale Gl o bal Tic Se verit y Scale (Y G T S S ) t otal tic sc ore ( T T S) i n b ot h c hil dre n a n d 
a d olesce nts, a n d t his decrease was o bser ve d irres pecti ve of d ose.  T he mea n p oi nt re d ucti o n i n 
T T S f or all s u bjects acr oss all d oses teste d was - 9. 4 p oi nts at Da y 1 4, w hic h re prese nts a 3 1 % 
decrease fr o m t he mea n  baseli ne sc ore.  Mea n re d ucti o ns fr o m baseli ne were als o o bser ve d i n 
t he Y G T S S i m pair me nt sc ore f or b ot h a ge gr o u ps.  T he P hase 2, N BI- 9 8 8 5 4- 1 5 0 1 st u d y i n 
c hil dre n a n d a d olesce nts di d n ot meet its pri mar y efficac y e n d p oi nt of a si g nifica nt c ha n ge fr o m 
bas eli ne t o Wee k 6 i n t he T T S bet wee n t he place b o a n d acti ve gr o u ps.  A c o m pre he nsi ve 
e x p os ure-res p o nse a nal ysis i n dicate d t hat t he d oses selecte d f or t his st u d y were t o o l o w t o 
pr o vi de a de q uate plas ma e x p os ures f or tic re d ucti o n i n m ost pe diatric s u bjects.  F or t he s u bset 
of s u bjects wit h N BI - 9 8 8 5 4 e x p os ures i n t he rele va nt ra n ge, t here was a re d ucti o n i n tics  
(ra n ge:  - 1 1. 3 t o - 1 3. 7 p oi nts o n t he T T S) c o m pare d wit h  t he s u bset of s u bjects wit h 
s u b-t hera pe utic e x p os ures (ra n ge:  - 4. 7 t o - 8. 3 p oi nts o n t he T T S).  Alt h o u g h t he efficac y res ults 
i n partici pati n g a d ults i n t he N BI- 9 8 8 5 4- 1 5 0 5 st u d y s h o we d a n i m pr o ve me nt i n o verall 
s y m pt o ms of T S as meas ure d b y t he  sec o n dar y e n d p oi nt, Cli nical Gl o bal I m pressi o n of C ha n ge 
( p = 0. 0 1 5 [ n o mi nal]), t he pre-s pecifie d pri mar y e n d p oi nt, t he c ha n ge fr o m baseli ne i n t he 
Y G T S S at Wee k 8 was n ot met ( p = 0. 1 8).   
N BI -9 8 8 5 4 has bee n ge nerall y well t olerate d i n si n gle d oses u p t o 3 0 0 m g a n d i n m ulti ple d oses 
of u p t o 1 0 0 m g i n healt h y v ol u nteers a n d s u bjects wit h T D.  O ver 8 5 0 s u bjects ha ve bee n 
e x p ose d t o N BI- 9 8 8 5 4 i n T D cli nical st u dies.  I n T S s u bjects , safet y res ults fr o m St u d y 
N BI - 9 8 8 5 4- 1 4 0 3 s h o w t hat t he d oses were well t olerate d i n b ot h c hil d a n d a d olesce nt a ge 
gr o u ps.  T here were n o deat hs or seri o us a d verse e ve nts ( S A Es) re p orte d d uri n g t he st u d y a n d 
n o c hil d disc o nti n ue d d ue t o a n a d verse e ve nt ( A E ).  T w o a d olesce nts ( b ot h i n t he N BI- 9 8 8 5 4 
5 0 m g gr o u p) disc o nti n ue d d ue t o A Es.  O ne s u bject disc o nti n ue d o n Da y 2 d ue t o t he A Es of 
a gitati o n, hea dac he, vis ual i m pair me nt, v o miti n g, a n d w orse ni n g of bra d ycar dia a n d t he ot her 
s u bject disc o nti n ue d o n Da y 4 d ue t o t he A Es of i ncrease d a n xiet y a n d i ns o m nia.  Preli mi nar y 
safet y res ults fr o m t he P hase 2, N BI- 9 8 8 5 4- 1 5 0 1 pe diatric st u d y s u g gest t hat all d oses teste d 
( N BI- 9 8 8 5 4 1 0 m g a n d 2 0 m g i n c hil dre 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 olesce nts) 
were well  t olerate d.  T he m ost fre q ue ntl y re p orte d A Es were hea dac he, s o m n ole nce, u p per 
res pirat or y tract i nfecti o n, i ns o m nia, a n d se dati o n.  T here were n o deat hs a n d o nl y o ne S A E i n 
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t he place b o gr o u p (c o n versi o n dis or der).  Preli mi nar y res ults fr o m  St u d y  N BI- 9 8 8 5 4- 1 5 0 5 
s h o we d t hat t he m ost fre q ue ntl y re p orte d A Es were s o m n ole nce ( 2 0. 2 % N BI- 9 8 8 5 4-treate d 
s u bjects a n d 2. 5 % of place b o s u bjects), fati g ue ( 1 4. 3 % N BI- 9 8 8 5 4 a n d 2. 5 % place b o), a n d 
a kat hisia ( 1 3. 1 % N BI- 9 8 8 5 4 a n d 0 % place b o).  Se ve ntee n s u bjects ( 1 3. 7 %) disc o nti n ue d fr o m 
t he st u d y d ue t o A Es, a n d m ost of t hese s u bjects recei ve d N BI- 9 8 8 5 4 8 0 m g ( 1 3/ 1 7 s u bjects) 
a n d t he m ost c o m m o n re as o n f or A E disc o nti n uati o n was a kat hisia (re p orte d i n 5 s u bjects).  
F o ur s u bjects e x perie nce d S A Es d uri n g t he st u d y; t he S A Es i ncl u de d pel vic i nfla m mat or y 
disease ( place b o s u bject; m o derate a n d n ot relate d t o N BI - 9 8 8 5 4), p ne u m ot h ora x ( 80 m g 
s u bject; m o derate a n d u nli kel y relate d t o N BI - 9 8 8 5 4), h y perse nsiti vit y ( 8 0 m g s u bject; 
m o derate a n d p ossi bl y relate d t o N BI - 9 8 8 5 4), a n d p ne u m o nia stre pt oc occal, se ptic s h oc k, re nal 
fail ure ac ute, a n d brac hial ple x us i nj ur y (4 0 m g s u bject; se vere a n d u nli kel y relate d t o 
N BI - 9 8 8 5 4).   
5. 3.  
St u d y a n d D ose R ati o n ale  
T his is a P hase 2, d o u ble- bli n d, place b o- c o ntr olle d, ra n d o mize d wit h dra wal st u d y t o e val uate 
t he safet y a n d mai nte na nce of efficac y of a n o pti mize d d ose of N BI- 9 8 8 5 4 i n pe diatric s u bjects 
wit h T S.  N BI - 9 8 8 5 4 will be titrate d t o t he s u bject’s o pti mal d ose i n t he ra n ge of 2 0 m g t o 
6 0 m g f or s u bjects < 5 0 k g a n d 4 0 m g t o 8 0 m g f or s u bjects ≥5 0 k g d uri n g t he i nitial o pe n- la bel 
treat me nt peri o d. 
R ati o n ale f or D ose Selecti o n a n d Re gi me n  
T he c urre nt starti n g d oses of N BI- 9 8 8 5 4 (ie, 2 0 m g or 4 0 m g) ha ve bee n well t olerate d i n 
pre vi o us st u dies i n pe diatric s u bjects wit h T S (st u dies 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 he d ose o pti mizati o n sc he me base d o n efficac y, t olera bilit y, a n d safet y assess me nts, as well as 
be dti me d osi n g w ill all o w s u bjects t o p ote ntiall y recei ve a n o pti mal d ose (ie, o ne t hat is b ot h 
well t olerate d a n d efficaci o us) d uri n g t he treat me nt peri o d.  F urt her m ore, t he i nter me diate a n d 
hi g h d oses ha ve bee n pre dicte d t o p ote ntiall y pr o vi de a de q uate plas ma le vels of N BI - 9 8 7 8 2 f or 
a greater pr o p orti o n of s u bjects t o ac hie ve cli nicall y mea ni n gf ul tic s u p pressi o n base d o n 
e x p os ure-res p o nse m o deli n g. 
6.  
S T U D Y O B J E C TI V E S  
T he o bjecti ves of t his st u d y are as f oll o ws:  
Pri mar y:  
•  T o e val uate t he mai nte na nce of efficac y of N BI - 9 8 8 5 4 d uri n g a d o u ble- bli n d, 
place b o -c o ntr olle d wit h dra wal peri o d i n pe diatric s u bjects wit h T S w h o ha ve res p o n de d t o 
o pe n- la bel N BI- 9 8 8 5 4 treat me nt. 
Sec o n dar y: 
•  T o e val uate t he effect of N BI - 9 8 8 5 4 o n meas ures of T S s y m pt o ms d uri n g a 
place b o -c o ntr olle d  wit h dra wal peri o d. 
•  T o e val uate t he safet y a n d t olera bilit y of N BI - 9 8 8 5 4 a d mi nistere d o nce dail y f or u p t o 
3 6 wee ks.  
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 5 
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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 hase 2, d o u ble- bli n d, place b o- c o ntr olle d, ra n d o mize d wit h dra wal st u d y t o e val uate 
t he safet y a n d mai nte na nce of efficac y of a n o pti mize d d ose of N BI- 9 8 8 5 4 i n pe diatric s u bjects 
wit h T S.  T he st u d y i ncl u des a n i nitial o pe n -la bel treat me nt peri o d f or 6 wee ks, a bli n de d 
ra n d o mizati o n peri o d f or 6 wee ks, f oll o we d b y a d o u ble- bli n d, place b o-c o ntr olle d wit h dra wal 
peri o d f or 2 4 wee ks, f or a t otal of u p t o 3 6 wee ks of treat me nt.  F oll o w- u p assess me nts will be 
c o n d ucte d at t he e n d of Wee k 4 0 after a 4- wee k was h o ut of st u d y dr u g, or u p o n earl y 
ter mi nati o n.  N BI-9 8 8 5 4 will be titrate d t o t he s u bject’s o pti mal d ose i n t h e ra n ge of 2 0 m g t o 
6 0 m g f or s u bjects < 5 0 k g a n d 4 0 m g t o 8 0 m g f or s u bjects ≥5 0 k g d uri n g t he i nitial o pe n- la bel 
treat me nt peri o d. 
A p pr o xi matel y 1 8 0 male a n d fe male pe diatric s u bjects, 6 t o 1 7 years of a ge, wit h a Dia g n ostic 
a n d Statistical Ma n ual of Me ntal Dis or ders, 4t h or 5t h E diti o ns ( D S M-I V or - 5) dia g n osis of T S 
will be e nr olle d i nt o t he 6 - wee k o pe n-la bel, d ose-o pti mizati o n treat me nt peri o d.  It is esti mate d  
t hat a p pr o xi matel y 9 0 of t hese s u bjects will meet t he criteri o n f or treat me nt res p o nse after d ose 
o pti mizati o n, a n d will t he n be ra n d o mize d i n a 1: 1 rati o t o place b o or N BI - 9 8 8 5 4 d uri n g t he 
6- wee k bli n de d ra n d o mizati o n peri o d, bef ore e nteri n g  t he 2 4- wee k, d o u ble- bli n d, 
place b o -c o ntr olle d  wit h dra wal peri o d.  Treat me nt res p o nse will be base d o n t he  p h ysicia n 
i n vesti gat or’s cli nical assess me nt of s ufficie nt c o ntr ol of tic be ha vi ors. 
Pri or t o t he c o n d uct of a n y st u d y- relate d pr oce d ures, pare ntal or le gal g uar dia n i nf or me d 
c o nse nt wit h si g ne d ( or ver bal, if a p plica ble) a n d wit nesse d pe diatric asse nt m ust be o btai ne d.  
S u bjects will t he n be scree ne d t o deter mi ne eli gi bilit y f or u p t o 4 wee ks pri or t o Da y 1 
( baseli ne). 
O pe n -l a bel Tre at me nt Peri o d ( D ose O pti miz ati o n) 
O n Da y 1 ( baseli ne), eli gi ble s u bjects will ret ur n t o t he st u d y ce nter f or c ollecti o n of baseli ne 
safet y a n d efficac y assess me nts, a n d t he c ollecti o n of a bl o o d sa m ple f or deter mi nati o n of t heir 
C Y P 2 D 6 meta b olizer stat us.  S u bjects w h o c o nti n ue t o be eli gi ble will be pr o vi de d wit h a 
2- wee k s u p pl y of N BI- 9 8 8 5 4, a n d will be as ke d t o liste n t o a n d si g n a treat me nt assi g n me nt 
scri pt t hat e x plai ns t he p ote ntial assi g n me nt t o place b o at s o me p oi nt d uri n g t he treat me nt 
peri o d.  St u d y dr u g will be a d mi nistere d at h o me at t he s u bject’s be dti me ( q hs) u n der t he 
s u per visi o n of t he s u bject’s pare nt or le gal g uar dia n at a p pr o xi matel y t he sa me ti me o nce dail y 
f or t he d urati o n of t he st u d y. 
F or s u bjects < 5 0 k g o n Da y 1 ( baseli ne), t he starti n g d ose will be N BI- 9 8 8 5 4 2 0 m g a n d f or 
s u bjects ≥5 0 k g o n Da y 1 ( baseli ne), t he starti n g d ose will be N BI- 9 8 8 5 4 4 0 m g.  T hese starti n g 
d oses ma y be escalate d i n i ncre me nts of 2 0 m g e ver y 2 wee ks t o a ma xi m u m of 6 0 m g f or 
s u bjects < 5 0 k g a n d a ma xi m u m of 8 0 m g f or s u bjects ≥5 0 k g t o ac hie ve a n o pti mal d ose of 
N BI -9 8 8 5 4 f or eac h s u bject.  D ose escalati o ns will occ ur at t he e n d of Wee ks 2 a n d 4 base d o n 
t he f oll o wi n g 2 criteria:  1) t he s u bject’s tics are n ot s ufficie ntl y c o ntr olle d per p h ysi cia n 
i n vesti gat or assess me nt; a n d 2) a n e val uati o n b y t he p h ysicia n i n vesti gat or i n dicates t hat t he 
s u bject is t olerati n g t he st u d y dr u g at t he c urre nt d ose a n d w o ul d li kel y be a ble t o t olerate  t he 
ne xt d ose le vel.  D uri n g t he o pe n- la bel treat me nt peri o d, t he p h ysicia n i n vesti gat or ma y escalate 
t he s u bject’s d ose t o t he ne xt d ose le vel, c o nti n ue wit h t he s u bject’s c urre nt d ose (ie, o pti mize d 
d ose has bee n ac hie ve d), or re d uce t o t he s u bject’s pr i or t olerate d d ose (i n s u bjects w h o ha ve 
ha d a d ose escalati o n).  After Wee k 6, s u bjects will c o nti n ue t o recei ve t heir o pti mize d d ose of 
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 5 
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N BI - 9 8 8 5 4 u ntil t he y are ra n d o mize d (res p o n ders) or t he y disc o nti n ue ( n o nres p o n ders).  If a 
s u bject’s o pti mal d ose has alrea d y bee n esta blis he d at Wee k 2 (ie, 1 or b ot h escalati o n criteria 
are n ot met) or at Wee k 4, n o d ose escalati o n will be all o we d at t he s u bse q ue nt visits.  At a n y 
ti me d uri n g treat me nt (i ncl u di n g t he o pe n-la bel treat me nt, bli n de d ra n d o mizati o n, a n d 
d o u ble- bli n d, place b o -c o ntr olle d wit h dra wal peri o ds), s u bjects w h o ha d a d ose escalati o n a n d 
are u na ble t o t olerate t heir c urre nt d ose will ha ve t heir d ose decrease d t o t heir pre vi o us d ose 
( d uri n g t he bli n de d ra n d o mizati o n a n d d o u ble- bli n d, place b o -c o ntr olle d wit h dra wal peri o ds t his 
will be d o ne i n a bli n de d ma n ner; s u bjects recei vi n g place b o will c o nti n ue t o recei ve place b o).  
T he s u bject will c o nti n ue at t hat d ose f or t he re mai n der of t he st u d y.  T he i n vesti gat or ma y 
re d uce t he s u bject’s d ose o nl y 1 ti me d uri n g t he st u d y.  S u bjects w h o are u na ble t o t olerate t he 
starti n g d ose or res u m pti o n of t he pre vi o usl y t olerate d d ose will be disc o nti n ue d fr o m t he st u d y.  
S u bjects will ret ur n t o t he st u d y ce nter f or st u d y assess me nts a n d dis pe nsi n g of st u d y dr u g.  As 
m uc h as p ossi ble, t hese visits s h o ul d occ ur at t he sa me ti me as t he Da y 1 ( baseli ne) visit t o 
sta n dar dize t he ti me of da y f or t he assess me nt of efficac y, safet y, a n d plas ma e x p os ure of st u d y 
dr u g. 
Bli n de d R a n d o miz ati o n Peri o d  
At t he e n d of Wee k s 8, 1 0, a n d 1 2, s u bjects w h ose tics ha ve res p o n de d t o N BI- 9 8 8 5 4 treat me nt 
(esti mate d t o be a p pr o xi matel y 9 0 s u bjects; t he p h ysicia n i n vesti gat or  will deter mi ne treat me nt 
res p o nse base d o n a cli nical assess me nt of s ufficie nt c o ntr ol of tic be ha vi ors ), a n d w h o are 
t olerati ng t heir o pti mize d d ose of N BI- 9 8 8 5 4 base d o n p h ysicia n i n vesti gat or assess me nt, will 
be ra n d o mize d ( 1: 1) t o recei ve place b o or c o nti n ue wit h t heir o pti mize d d ose of N BI- 9 8 8 5 4.  
Assess me nt of treat me nt res p o nse a n d t olera bilit y will occ ur at eac h of t he bli n de d 
ra n d o mizati o n peri o d visits at Wee ks 8, 1 0, a n d 1 2; t heref ore, a s u bject w h o di d n ot ac hie ve a 
treat me nt res p o nse at Wee k 8 c o ul d ac hie ve treat me nt res p o nse at Wee k 1 0 or Wee k 1 2 a n d be 
ra n d o mize d.  T he s u bject res p o n ders, i n vesti gat ors, a n d S p o ns or will be bli n de d t o t he visit 
wee k w he n ra n d o mizati o n occ urs ( pr o gra m me d o n t he I nteracti ve We b Res p o nse S yste m 
[I W R S]).  Of t he esti mate d 9 0 s u bjects w h o are treat me nt res p o n ders, a p pr o xi matel y 3 0 will be 
ra n d o mize d at eac h of t he ra n d o mizati o n visits. 
All s u bjects w h o ac hie ve treat me nt res p o nse at Wee k 1 2 a n d w h o were n ot pre vi o usl y 
ra n d o mize d will be ra n d o mize d at Wee k 1 2.  S u bjects ra n d o mize d t o N BI- 9 8 8 5 4 will c o nti n ue 
wit h t heir o pti mize d d ose of N BI- 9 8 8 5 4.  T he bli n de d, sta g gere d ra n d o mizati o n pr ocess w as 
c h ose n t o mi ni mize t he effect of s u bjects/i n vesti gat ors k n o wi n g w he n t he place b o -c o ntr olle d 
p orti o n of t he st u d y be gi ns. 
S u bjects w h o are n o nres p o n ders at t he Wee k 1 2 visit a n d w h o were n ot pre vi o usl y ra n d o mize d 
will be disc o nti n ue d  fr o m t he st u d y a n d as ke d t o ret ur n 2 t o 4 wee ks after t heir fi nal d ose of 
st u d y dr u g f or a fi nal st u d y visit (t hese s u bjects will n ot be i ncl u de d i n t he efficac y a nal yses).  
S u bjects w h o disc o nti n ue st u d y partici pati o n f or a n y reas o n will be as ke d t o c o m plete all earl y 
ter mi nati o n assess me nts.  
D o u ble -Bli n d, Pl ace b o -C o ntr olle d  Wit h dr a w al Peri o d  
S u bjects will c o nti n ue t o self -a d mi nister t he st u d y dr u g o nce dail y at be dti me ( q hs) u n der t he 
s u per visi o n of t heir pare nt or le gal g uar dia n a n d ret ur n t o t he st u d y site at sc he d ule d visits f or 
st u d y assess me nts a n d dis pe nsi n g of st u d y dr u g ( Wee ks 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, a n d 
3 6 [ n o dis pe nsi n g of st u d y dr u g at Wee k 3 6]). 
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 5 
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F oll o w -u p Peri o d ( or E arl y Ter mi n ati o n)  
F oll o w- u p assess me nts f or s u bjects w h o c o m plete t he st u d y will be c o n d ucte d at t he e n d of 
Wee k 4 0 after a 4 - wee k was h o ut of st u d y dr u g, or at a n earl y ter mi nati o n visit (s u bjects w h o are 
n o nres p o n ders at t he Wee k 1 2 visit a n d w h o were n ot pre vi o usl y ra n d o m ize d will be 
disc o nti n ue d fr o m t he st u d y a n d as ke d t o ret ur n 2 t o 4 wee ks after t heir fi nal d ose of st u d y dr u g 
f or a fi nal st u d y visit).  All visits will ha ve a wi n d o w of ± 3 da ys. 
A s c he matic  of t he st u d y desi g n is  s h o w n i n Fi g ure 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 5 
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8.  
S T U D Y P O P U L A TI O N  
T his st u d y will be c o n d ucte d i n a p pr o xi matel y 1 8 0 male a n d fe male pe diatric s u bjects ( 6 t o 
1 7 years of a ge, i ncl usi ve) wit h a D S M -I V or - 5 dia g n osis of T S.  S u bjects m ust meet all  t he 
i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria t o e nter t he st u d y. 
8. 1.  
I ncl usi o n C riteri a 
T o partici pate i n t his st u d y, s u bjects m ust meet t he f oll o wi n g criteria:  
1.  Ha ve d oc u me ntati o n of writte n  ( or ver bal, if a p plica ble) a n d wit nesse d asse nt fr o m t he 
s u bject a n d writte n i nf or me d c o nse nt fr o m t he s u bject's pare nts or le gal g uar dia n. 
2.  Be male or fe male, a ge d 6 t o 1 7 years, i ncl usi ve.  
3.  Be i n g o o d ge neral healt h, as deter mi ne d b y me dical hist or y, p h ysical e xa mi nati o n, cli nical 
la b orat or y assess me nts, a n d 1 2-lea d electr ocar di o gra m (E C G). 
4.  Ha ve a D S M -I V or - 5 dia g n osis of T S. 
5.  Ha ve at least m o derate c urre nt tic se verit y, as defi ne d b y a Cli nical Gl o bal I m pressi o n of 
Tics -Se verit y scale ( C GI -Tics -Se verit y ) s c ore of ≥4 (ie, m o deratel y ill) at scree ni n g.  T his 
deter mi nati o n m ust be i n de pe n de ntl y c o nfir me d b y t he e xter nal vi de o re vie wer usi n g a 
vi de o rec or di n g of t he s u bject's Y G T S S assess me nt a d mi nistere d at t he cli nical site b y a 
trai ne d a n d certifie d rater (ie, t he i n vesti gat or or desi g nee). 
6.  Ha ve T S s y m pt o ms t hat ca use mar ke d distress or si g nifica nt i m pair me nt i n sc h o ol, 
occ u pati o nal, a n d/ or s ocial f u ncti o n. 
7.  S u bjects m ust ha ve a sta ble ps yc hiatric stat us (s uc h as T S s pectr u m dia g n oses [e g, 
o bsessi ve -c o m p ulsi ve dis or der, A D H D]) as cli nicall y deter mi ne d b y t he i n vesti gat or.  
8.  If me dicati o ns are bei n g use d t o treat T S s y m pt o ms a n d/ or T S s pectr u m dia g n oses, s u bjects 
m ust be o n sta ble d oses of t hese me dicati o ns f or a mi ni m u m of 3 0 da ys bef ore Da y 1 
( baseli ne), a n d t he me dicati o n re gi me n is e x pecte d t o re mai n sta ble t hr o u g h o ut t he st u d y 
peri o d.  T he use of c o nc o mita nt d o pa mi ne a nta g o nists (e g, pi m ozi de, hal o peri d ol, 
ari pi praz ole) a n d/ or tetra be nazi ne or de utetra be nazi ne t o treat T S s y m pt o ms is pr o hi bite d.  
Ot her n o n d o pa mi ner gic tic s u p pressi o n t hera p y (e g, cl o ni di ne, g ua nfaci ne) is all o we d 
d uri n g t he st u d y peri o d if t he d ose re gi me n has bee n sta ble f or a mi ni m u m of 3 0 da ys bef ore 
Da y 1 ( baseli ne). 
9.  S u bjects wit h sta ble me dical c o n diti o ns re q uiri n g me dicati o ns t hat are n ot pr o hi bite d per 
pr ot oc ol m ust be o n sta ble d oses of t hese me dicati o ns f or a mi ni m u m of 3 0 da ys bef ore 
Da y  1 ( baseli ne), a n d t he me dicati o n re gi me n is e x pecte d t o re mai n sta ble t hr o u g h o ut t he 
st u d y peri o d. 
1 0.  S u bjects of c hil d beari n g p ote ntial m ust a gree t o use c o ntrace pti o n c o nsiste nt l y fr o m 
scree ni n g u ntil 3 0 da ys (fe males) or 9 0 da ys ( males) after t he last d ose of st u d y dr u g.  A 
fe male s u bject of c hil d beari n g p ote ntial is defi ne d as a fe male ca pa ble of bec o mi n g 
pre g na nt, w hic h i ncl u des s u bjects w h o ha ve ha d t heir first me nstr ual c ycle (ie, me narc he) 
a n d are n ot s ur gicall y sterile (ie, bilateral o o p h orect o m y, h ysterect o m y or bilateral t u bal 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 2 4

 
li gati o n f or at least 3 m o nt hs pri or t o scree ni n g).  A male s u bject of c hil d beari n g p ote ntial is 
defi ne d as a s u bject w h o has reac he d s per marc he a n d has n ot bee n vasect o mize d f or at least 
3 m o nt hs pri or t o scree ni n g. 
Acce pta ble met h o ds of c o ntrace pti o n i ncl u de t he f oll o wi n g:  
•  C o n d o m wit h s per mici de (crea m, s pra y, f oa m, gel, s u p p osit or y, or p ol y mer fil m). 
•  Dia p hra g m wit h s per mici de ( wit h or wit h o ut c o n d o m). 
•  Cer vical ca p wit h s per mici de ( wit h or wit h o ut c o n d o m).  
•  Va gi nal s p o n ge i m pre g nate d wit h s per mici de use d wit h a c o n d o m.  
•  I ntra uteri ne de vice (I U D). 
•  H or m o nal c o ntrace pti o n ta ke n f or at least 3 m o nt hs pri or t o scree ni n g.  
S u bjects w h o practice t otal a bsti ne nce fr o m se x ual i nterc o urse as t he preferre d lifest yle are 
n ot re q uire d t o use c o ntrace pti o n ( peri o dic a bsti ne nce is n ot acce pta ble). 
1 1.  Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m β - h u ma n c h ori o nic 
g o na d otr o pi n ( β- h C G) pre g na nc y test at scree ni n g a n d ne gati ve uri ne pre g na nc y test at 
Da y  1 ( baseli ne). 
1 2.  Ha ve a b o d y wei g ht (i n k g) greater t ha n or e q ual t o t he 5t h perce ntile of his/ her a ge - a n d 
ge n der- matc he d wei g ht perce ntile at scree ni n g.  
1 3.  A d olesce nt s u bjects ( 1 2 t o 1 7 years of a ge) m ust ha ve a ne gati ve uri ne dr u g scree n ( U D S; 
ne gati ve f or a m p heta mi nes, bar bit urates, be nz o diaze pi ne, p he nc ycli di ne, c ocai ne, o piates, or 
ca n na bi n oi ds) at scree ni n g ( base d o n res ults fr o m ce ntral la b orat or y) a n d Da y 1 ( bas eli ne; 
base d o n res ults fr o m o n-s ite U D S  kit).  S u bjects w h o are o n sta ble d oses of prescri be d a n d 
s u per vise d ( n ot as nee de d [ pr n]) be nz o diaze pi nes, o piates, or ps yc h osti m ula nts (f or s u bjects 
wit h c o m or bi d A D H D) ca n partici pate i n t he st u d y.  
1 4.  A d olesce nt s u bjects ( 1 2 t o 1 7 years of a ge) m us t ha ve a ne gati ve alc o h ol breat h test at 
scree ni n g a n d Da y 1 ( baseli ne). 
1 5.  Be willi n g a n d a ble t o a d here t o t he st u d y re gi me n a n d st u d y pr oce d ures descri be d i n t he 
pr ot oc ol a n d i nf or me d c o nse nt/asse nt f or ms, i ncl u di n g all re q uire me nts at t he st u d y ce nter 
a n d ret ur n f or t he f oll o w-u p visit.  
8. 2.  
E xcl usi o n Criteri a  
S u bjects will be e xcl u de d fr o m t he st u d y if t he y:  
1.  Are c urre ntl y pre g na nt or lactati n g.  
2.  Ha ve a n u nsta ble me dical c o n diti o n or c hr o nic disease (i ncl u di n g si g nifica nt ne ur ol o gical, 
he patic, re nal, car di o vasc ular, gastr oi ntesti nal, p ul m o nar y, or e n d ocri ne disease), or 
mali g na nc y t hat c o ul d c o nf o u n d i nter pretati o n of st u d y o utc o me. 
3.  Ha d a me dicall y si g nifica nt ill ness wit hi n 3 0 da ys of scree ni n g.  
4.  Ha ve a k n o w n hist or y of ne ur ole ptic mali g na nt s y n dr o me.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 2 5

 
5.  Ha ve a he mat ol o gic mali g na nc y or s oli d t u m or dia g n ose d wit hi n 3 years pri or t o scree ni n g, 
e xce pt f or l ocalize d s ki n ca ncer or carci n o ma i n sit u of t he cer vi x.  
6.  Ha ve a k n o w n hist or y of l o n g Q T s y n dr o me or car diac arr h yt h mia. 
7.  Ha ve a n a vera ge tri plicate E C G c orrecte d Q T i nter val usi n g Fri dericia's f or m ula ( Q Tc F) of 
> 4 5 0 msec at scree ni n g or Da y 1 or t he pr ese nce of a n y cli nicall y si g nifica nt car diac 
a b n or malit y.  
8.  Ha ve ser u m creati ni ne le vels greater t ha n t he u p per li mit of n or mal ( U L N) at scree ni n g, or 
as partate a mi n otra nsferase ( A S T), ala ni ne a mi n otra nsferase ( A L T), ga m ma -gl uta m yl 
tra nsferase ( G G T), or t otal bilir u bi n > 1. 5 ti mes t he U L N at scree ni n g.  S u bjects wit h a 
d oc u me nte d dia g n osis of Gil bert's s y n dr o me are n ot re q uire d t o meet t he bilir u bi n criteria.  
9.  Ha v e a n y of t he f oll o wi n g he mat ol o gic a b n or malities at scree ni n g:  
•  He m o gl o bi n < 1 1. 0 g/ d L. 
•  W hite bl o o d cell ( W B C) c o u nt < 4. 0 × 1 0
3/ m m3. 
•  Platelet c o u nt < 1 0 0, 0 0 0/ m m 3. 
1 0.  Ha ve a cli nical la b orat or y res ult  n ot wit hi n t he refere nce ra n ge a n d dee me d b y t he 
i n vesti gat or t o be cli nicall y si g nifica nt at scree ni n g.  
1 1.  Ha ve a p ositi ve h u ma n i m m u n o deficie nc y vir us a nti b o d y ( HI V -A b) test res ult, he patitis B 
s urface a nti ge n ( H Bs A g) test res ult, or he patitis C vir us a nti b o d y ( H C V- A b) wit h 
c o nfir mat or y p ositi ve p ol y merase c hai n reacti o n ( P C R) refle x test res ult at scree ni n g.  
1 2.  Ha ve recei ve d a n i n vesti gati o nal dr u g ( ot her t ha n N BI- 9 8 8 5 4) wit hi n 3 0 da ys or 5 half-li ves 
(if k n o w n), w hic he ver is l o n ger, bef ore scree ni n g or pla n t o use a n i n vesti gati o nal dr u g 
( ot her t ha n N BI- 9 8 8 5 4) d uri n g t he st u d y. 
1 3.  Ha ve a n aller g y, h y perse nsiti vit y, or i nt olera nce t o V M A T 2 i n hi bit ors (e g, tetra be nazi ne , 
de utetra be nazi ne ). 
1 4.  Ha ve pre vi o us e x perie nce wit h N BI - 9 8 8 5 4 or pre vi o usl y partici pate d i n a n NBI - 9 8 8 5 4 
cli nical st u d y, e xce pt f or s u bjects w h o ha ve pre vi o usl y partici pate d i n a n d c o m plete d t he 
N BI - 9 8 8 5 4- 1 4 0 3, P hase 1 b st u d y or N BI- 9 8 8 5 4- 1 5 0 1, P hase 2 st u d y. 
1 5.  Ha ve recei ve d a n y pr o hi bite d me dicati o n as detaile d i n Secti o n  9. 8. 1 . 
1 6.  E xcessi ve use of t o bacc o a n d/ or nic oti ne-c o ntai ni n g pr o d ucts ( base d o n t he i n vesti gat or’s 
assess me nt) wit hi n 3 0 da ys of scree ni n g.  
1 7.  Ha ve a hist or y of s u bsta nce ( dr u g or alc o h ol) de pe n de nce or a b use wit hi n t he 3 m o nt hs 
bef ore Da y 1 ( baseli ne), as defi ne d i n t he D S M-I V ( S u bsta nce De pe n de nce or A b us e) or 
D S M - 5 ( S u bsta nce Use Dis or der). 
1 8.  Ha ve i nitiate d C o m pre he nsi ve Be ha vi oral I nter ve nti o n f or Tics ( C BI T) d uri n g t he scree ni n g 
peri o d or at Da y 1 ( baseli ne) or pla n t o i nitiate C BI T d uri n g t he st u d y. 
1 9.  Ha ve a bl o o d l oss ≥2 5 0 m L or d o nate d bl o o d wit hi n 5 6 da ys or d o nate d plas ma wit hi n 
7 da ys of Da y 1 ( baseli ne). 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 2 6

 
2 0.  Ha ve a si g nifica nt ris k of s uici dal or vi ole nt be ha vi or.  S u bjects wit h a n y lifeti me hist or y of 
s uici dal be ha vi or, or s uici dal i deati o n of t y pe 4 (acti ve s uici dal i deati o n wit h s o me i nte nt t o 
act, wit h o ut s pecific pla n) or t y pe 5 (acti ve s uici dal i deati o n wit h s pecific pla n a n d i nte nt) i n 
t he 1 year bef ore scree ni n g base d o n t he C ol u m bia- S uici de Se verit y Rati n g Scale ( C- S S R S ) 
C hil dre n’s Versi o n s h o ul d be e xcl u de d. 
2 1.  Ha ve a hist or y of or s us pecte d p o or c o m plia nce i n cli nical researc h st u dies.  
8. 3.  
S u bject I de ntific ati o n a n d Re pl ace me nt 
S u bjects will be i de ntifie d b y t heir u ni q ue s u bject n u m ber a n d i nitials (first, mi d dle, last; a 
h y p he n ma y be use d if t he s u bject has n o mi d dle na me).  T he s u bject i nitials a n d s u bject 
n u m ber will be n ote d o n electr o nic case re p ort f or ms (e C R Fs), all s o urce d oc u me ntati o n, 
la b orat or y d oc u me nts, a n d E C G traci n gs.  S u bjects w h o disc o nti n ue fr o m t he st u d y will n ot be 
re place d. 
8. 4.  
R a n d o miz ati o n 
S u bjects w h ose T S is s ufficie ntl y c o ntr olle d (ie, treat me nt res p o nse base d o n  t he i n vesti gat or’s 
assess me nt) a n d w h o are t olerati n g t heir c urre nt d ose of N BI- 9 8 8 5 4 base d o n t he i n vesti gat or’s 
assess me nt, will be ra n d o mize d ( 1: 1) t o recei ve place b o or N BI - 9 8 8 5 4 at Wee ks 8, 1 0, or 1 2 
(esti mate d t o be a t otal of a p pr o xi matel y 9 0 s u bjects).  T he s u bjects, i n vesti gat ors, a n d S p o ns or 
will be bli n de d t o t he visit wee k w he n ra n d o mizat i o n occ urs ( pr o gra m me d o n t he I W R S).  
A p pr o xi matel y 3 0 s u bjects will be ra n d o mize d at  eac h of t he ra n d o mizati o n visit wee ks, t hat is, 
a p pr o xi matel y 1 5 s u bjects ra n d o mize d t o N BI- 9 8 8 5 4 a n d a p pr o xi matel y 1 5 s u bjects 
ra n d o mize d t o place b o at Wee ks 8, 1 0, a n d 1 2.  S u bjects ra n d o mize d t o N BI-9 8 8 5 4 will 
c o nti n ue wit h t he sa me d ose as t he last d ose t he y were pre vi o usl y recei vi n g  (ie, t heir o pti mize d 
d ose). 
9.  
S T U D Y E V A L U A TI O N S  
9. 1.  
Sc he d ule of Assess me nts  
A sc he d ule of assess me nts t hat s u m marizes t he fre q ue nc y a n d ti mi n g of all assess me nts is 
pr o vi de d i n  Ta ble  1.  S u bject-relate d e ve nts a n d acti vities i ncl u di n g s pecific i nstr ucti o ns, 
pr oce d ures, c o nc o mita nt me dicati o ns,  dis pe nsi n g of st u d y dr u g, a n d descri pti o ns of A Es s h o ul d 
be rec or de d i n t he a p pr o priate s o urce d oc u me 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 2 7

T a ble 1: 
Sc he d ule of Assess me n ts 
P r oce d ure a 
Scree ni n g 
P eri o d  
B as eli ne  
O pe n -L a bel T re at m e nt 
P eri o d  
Bli n de d R a n d o miz ati o n  
P eri o d  
Pl ace b o -C o ntr olle d Wit h dr a w al P eri o d  
F oll o w -
u p/ E T b 
Wee k   
-4 t o D a y -1  
D a y 1 c 
2  
4  
6  
8  
1 0  
1 2  
1 4  
1 6  
1 8  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
Visit d 
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
I nf or m e d c o ns e nt/ass e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tr eat me nt assi g n me nt 
s cri pt/ vi d e oe 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ e xcl usi o n criteria  
X  
u p date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o mizati o n f 
 
 
 
 
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
M e dical hist or y  
X  
u p date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysi cal e xa mi nati o n g 
X  
X  
X  
 
X  
 
 
X  
 
 
 
 
X  
 
 
X  
X  
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -lea d E C Gh 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
Pre g na n c y t est i 
X (s)  
X ( u)  
X ( u)  
X ( u)  
X ( u)  
X ( u)  
X ( u)  
X ( u)  
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X 
( u) 
X ( u)  
Ser ol o g y j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical la b orat or y t ests k 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
He m o gl o bi n A 1 c  
X  
X  
 
 
X  
 
 
X  
 
 
 
 
X  
 
 
X  
X  
Ser u m pr olacti n  
 
X  
X  
 
X  
X  
X  
X  
 
X  
 
 
X  
 
 
X  
X  
Uri ne dr u g s cr ee n l 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol br eat h t est l 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge n ot y p e bl o o d s a m ple m  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P K plas ma s a m ple  
 
X  
X  
X  
X  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
Y G T S S n 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C GI -Ti cs -Se verit y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C GI -T S -I m pr o ve m e nt 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C -S S R S  
X  
X  
X  
X  
X  
X  
X  
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  
X  
X  
X  
X  
X  
X  
X  
X  
A D H D -5 R ati n g S cale  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E S R S -A  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C & A -G T S -Q O L a n d P U T S  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dis pe ns e st u d y dr u g  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
St u d y dr u g d osi n g o 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Dr u g acc o u nta bilit y p  
 
 
X  
X  
X  
X  
X  
X  
X  
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  
X  
X  
X  
X  
X  
X  
Pri or/ c o n c o mita nt 
me di cati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C all t o s u bject q  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Defi niti o ns a n d f o ot n ot es o n t he f oll o wi n g pa ge . 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 2 8

A D H D - 5 Rati n g  Scale = Att e nti o n-Deficit H y per acti vit y Dis or der Rati n g Scale -5:  H o me Versi o n; A E =a d verse e ve nt; C & A -G T S -Q O L = Gilles de la T o ur ett e 
S y n dr o me -Q ualit y of Life f or C hil dr e n a n d A d oles ce nts; C D R S -R = C hil dr e n’s De pr essi o n R ati n g Scale - Re vis e d; C GI -Tics - Se verit y = Cli nical Gl o bal 
I m pr essi o n of Tics-Se verit y sc ale; C GI -T S -I m pr o ve me nt = Cli nical Gl o bal I m pr essi o n of T o ur ett e S y n dr o me-I m pr o ve me nt scale; C-S S R S = C ol u m bia -S uici de 
Se verit y R ati n g Scale; C Y -B O C S = C hil dr e n’s Yale -Br o w n O bsessi ve C o m p ulsi ve Scale; C Y P =c yt o c hr o me P 4 5 0; E C G =electr o car 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 Rati n g Scale -A b br e viat e d; E T =earl y t er mi nati o n; Q T c F =c orr ecte d Q T i nt er val usi n g Fri dericia’s f or m ula; 
P K = p har mac o ki netics; P U T S = Pr e m o nit or y Ur ge f or Tics Scale; s =ser u m; u = uri ne; Y G T S S = Yale Gl o bal Tic Se verit y Scale.  
 
a As m uc h as p ossi ble, st u d y visits s h o ul d o cc ur at a p pr o xi mat el y t he sa me ti me as t he Da y 1 visit t o sta n dar dize t he ti me of d a y f or t he assess me nt of efficac y, 
safet y, a n d plas ma e x p os ur e t hr o u g h o ut t he st u d y peri o d. 
b  Fi nal st u d y visit f or s u bjects w h o c o m plet e t he st u d y ( or earl y t er mi nati o n).  S u bjects w h o ar e n o nr es p o n ders at t he We e k 1 2 visit a n d w h o wer e n ot pr e vi o usl y 
r a n d o mize d will be disc o nti n ue d fr o m t he st u d y a n d as ke d t o r et ur n 2 t o 4 wee ks aft er t heir fi nal d ose of st u d y dr u g f or a fi nal st u d y visit.  
c Da y 1 is t he da y of baseli ne  assess me nts.  Da y 1 is als o t he first da y of d osi n g; st u d y dr u g will be a d mi nist er e d at h o me at be dti me.  
d  Visits ( ot her t ha n scr ee ni n g a n d Da y 1) will ha ve a wi n d o w of ± 3 da ys.  
e S u bjects will be s h o w n t he vi d e o title d “ Y o ur R ole i n a Cli nical Trial, S o me I nf or mati o n a b o ut Resear c h St u dies” ( at scr ee ni n g o nl y) a n d i nf or me d a b o ut t he 
place b o -c o ntr olle d desi g n of t he st u d y usi n g t he treat me nt assi g n me nt scri pt pr o vi d e d b y t he S p o ns or ( o n Da y 1 [ baseli ne] o nl y).  
f S u bjects w h ose tics ha ve r es p o n de d t o N BI -9 8 8 5 4 tr eat me nt (t he p h ysicia n i n vesti gat or will d et er mi n e tr eat me nt r es p o nse base d o n a cli nical assess me nt of 
s ufficie nt c o ntr ol of tic be ha vi ors), a n d w h o ar e t oler ati n g t heir o pti mize d d ose of N BI -9 8 8 5 4 base d o n p h ysicia n i n vesti gat or assess me nt, will be r a n d o mize d 
( 1: 1) t o r ecei ve place b o or c o nti n ue wit h t heir o pti mize d d ose of N BI-9 8 8 5 4.  T he s u bject r es p o n ders, i n vesti g at ors, a n d S p o ns or will be bli n d e d t o t he visit 
wee k w he n r a n d o mizati o n o cc urs ( pr o gr a m me d o n t he I nt er acti ve We b Res p o nse S yst e m [I W R S]).  
g  T he p h ysical e xa mi nati o n will i ncl u de hei g ht (scr ee ni n g o nl y) a n d wei g ht, me as ur e d wit h s u bje cts n ot weari n g s h o es.  
h  A st a n dar d 1 2 -lea d E C G will be c o n d uct e d i n tri plicat e ( at least 1 mi n ut e a part an d wit hi n 1 5 mi n ut es) aft er t he s u bje ct has r est e d s u pi ne f or at le ast 5 mi n ut es.  
T he E C G para met ers will be base d o n t he E C G ma c hi ne r ea di n gs ( Q T c F ma y be calc ulat e d).  
i A ser u m pr e g na nc y t est will be c o n d uct e d at scr ee ni n g, a uri ne pr e g na nc y t est will be c o n d uct e d o n Da y 1 (r es ults will be us e d t o c o nfir m eli gi bilit y), a n d at all 
ot her st u d y visits o nl y f or fe male s u bje cts of c hil d beari n g p ot e ntial.  
j Bl o o d will be c ollect e d f or he patitis B s urfac e a nti ge n, he p atitis C vir us a nti b o d y, a n d h u ma n i m m u n o deficie nc y vir us a nti b o d y a n d r efle x P C R t esti n g.  
k  Cli nical la b orat or y t ests i ncl u de he mat ol o g y, cli nic al c he mistr y, a n d uri nal ysis.  T her e ar e n o fasti n g r e q uir e me nts f or cli nical la b or at or y t ests.  
l Assesse d i n a d olesce nt s u bjects o nl y ( 1 2 t o 1 7 years of a ge).  Uri ne dr u g scr ee n will be a nal yz e d at scr ee ni n g a n d Da y 1 b y t he ce ntr al la b.  I n a d diti o n, a uri ne 
dr u g scr ee n kit pr o vi de d b y t he ce ntr al la b will be use d at t he sit e t o c o nfir m eli gi bilit y o n Da y 1.  
m  Ge n ot y pi n g  bl o o d sa m ple  f or C Y P 2 D 6 met a b olizer st at us. 
n  I ncl u di n g vi de o r ec or di n g. 
o  St u d y dr u g will be a d mi nist er e d o nce dail y at  t he s u bject’s be dti me at h o me u n der t he s u per visi o n of t heir par e nt/ g uar dia n.  T he dat e a n d ti me of eac h d osi n g of 
st u d y dr u g will be r ec or de d.  S u bjects/car e gi vers will be as ke d t o r ec or d a n d pr o vi de d osi n g ti mes of N BI -9 8 8 5 4 f or t he first d ose a n d fr o m t he e ve ni n g bef or e 
t he tr eat me nt peri o d visits w he n P K bl o o d sa m ples ar e c ollect e d. 
p  S u bjects will bri n g all u n use d st u d y dr u g a n d e m pt y st u d y dr u g pac ka gi n g mat erial, a n d a c o m plia nce c hec k wil l be perf or me d b y c o u nti n g t he ca ps ules 
r et ur ne d at eac h st u d y visit. 
q  Sit es ar e t o call s u bjects wit hi n 3 t o 7 da ys aft er t he Da y 1 visit t o i n q uir e a b o ut c o m plia nce or t oler a bilit y iss ues.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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Pa ge 2 9

 
9. 2.  
Scree ni n g a n d B aseli ne Assess me nts  
9. 2. 1.  
Ge n ot y pi n g  
O n Da y 1 ( baseli ne), a bl o o d sa m ple will be c ollecte d fr o m e nr olle d s u bjects f or t he a nal ysis of 
C Y P 2 D 6 stat us (ie, e xte nsi ve, i nter me diate, p o or, or ultrara pi d meta b olizers).  A p pr o xi matel y 
4 m L of bl o o d will be c ollecte d i n t u bes c o ntai ni n g di p otassi u m et h yle ne dia mi netetraacetic aci d 
( E D T A K2).  After t he sa m ple is o btai ne d, it s h o ul d be t h or o u g hl y mi xe d.  T he vials will be 
st o p pere d a n d la bele d wit h t he st u d y barc o de a n d s u bject n u m ber.  T he sa m ples will be st ore d at 
a p pr o xi matel y - 2 0° C wit hi n a p pr o xi matel y 1 5 mi n utes of c ollecti o n.  T he c ollecti o n a n d 
s u b missi o n of me dical i nf or mati o n will be acc o m plis he d wit h strict a d here nce t o pr ofessi o nal 
sta n dar ds of c o nfi dentialit y.  Ge n ot y pi n g bl o o d sa m ples c ollecte d fr o m s u bjects will be s hi p pe d 
t o a ce ntral la b orat or y f or a nal ysis. 
9. 3.  
Effic ac y  Assess me nts  
9. 3. 1.  
Y ale Gl o b al Tic Se verit y Sc ale  
T he Y G T S S will be use d t o assess tic be ha vi ors ass ociate d wit h T S ( Lec k ma n et al., 1 9 8 9 ).  T he 
Y G T S S is desi g ne d t o rate t he o verall se verit y of m ot or a n d p h o nic tic s y m pt o ms acr oss a ra n ge 
of di me nsi o ns:  n u m ber, fre q ue nc y, i nte nsit y, c o m ple xit y, a n d i nterfere nce.  T he scale als o 
i ncl u des a n i m pair me nt assess me nt.  T he Y G T S S will be a d mi nistere d b y t he i n vesti gat or ( or 
q ualifie d desi g nee) usi n g a c o m p uter- base d str uct ure d cli nical i nter vie w.  At eac h ti me p oi nt, t he 
Y G T S S i nter vie w will be vi de o rec or de d.  T he vi de o rec or di n g will f oll o w a sta n dar dize d set of 
g ui deli nes a n d t he rec or de d vi de o will be u pl oa de d t o a sec ure ce ntral ser ver.  A n e xter nal vi de o 
re vie wer, n ot affiliate d wit h t he site, will access t he ce ntral ser ver t o vie w t he rec or di n g a n d 
1) c o nfir m t he s u bject’s T S se verit y is at least m o derate base d o n a C GI -Tics -Se verit y of ≥4 (at 
scree ni n g o nl y), a n d 2) deter mi ne if t he Y G T S S i nter vie w pr o gra m was a d mi nistere d pr o perl y.  
T he c o m p uter s oft ware s yste m f or t he Y G T S S a d mi nistrati o n, Rater Stati o n ™ ( Brac ket Gl o bal, 
L L C; P hila del p hia, P A), will pr o m pt t he trai ne d a n d certifie d rater  (ie, t he i n vesti gat or or 
q ualifie d desi g nee)  t o e nter a sc ore f or eac h ite m of t he scale base d o n s u bject a n d pare nt 
res p o nses d uri n g t he str uct ure d cli nical i nter vie w.  T he s oft ware will als o ge nerate i n di vi d ual 
sc ores f or eac h ite m of t he scale (ta n de m rati n g) a n d will gene rate t he T T S a n d t he Gl o bal Tic 
Se verit y Sc ore.  
T he Y G T S S will be a d mi n istere d b y t he i n vesti gat or ( or q ualifie d desi g nee)  at scree ni n g, Da y 1 
( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w-u p visit 
( Wee k 4 0), or earl y ter mi nati o n.  As m uc h as p ossi ble, a gi ve n s u bject s h o ul d ha ve t he sa me 
rater t hr o u g h o ut t he st u d y.  A c o p y of t he Y G T S S is pr o vi de d i n A p pe n di x 1 7. 1 .  
9. 3. 2.  
Pre m o nit or y Ur ge f or Tics Sc ale  
T he Pre m o nit or y Ur ge f or Tics Scale  (P U T S ) is a vali d a n d relia ble i nstr u me nt f or q ua ntif yi n g 
t he pre m o nit or y ur ge p he n o me na ass ociate d wit h tics (W o o ds et al., 2 0 0 5 ).  Eac h of t he 9 ite ms 
i n t he P U T S is rate d o n a 4-p oi nt scale ( 1 = n ot at all tr ue, 2 =a little tr ue, 3 = prett y m uc h tr ue, 
4 = ver y m uc h tr ue) a n d s u m me d t o yiel d a t otal sc ore reflecti n g t he prese nce a n d fre q ue nc y of 
pre- tic (ie, pre m o nit or y) ur ges al o n g wit h relief t hat ma y be e x perie nce d after tics ha ve bee n 
c o m plete 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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T he s u bject will c o m plete t he P U T S at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 
1 6, 1 8, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n.  T he 
s u bject ca n recei ve assista nce filli n g o ut q uesti o n naire if nee de d.  A c o p y of t he P U T S is 
pr o vi de d i n A p pe n di x 1 7. 2 . 
9. 3. 3.  
Cli nic al Gl o b al I m pressi o n Sc a les 
T he C GI- Tics -Se verit y  scale a n d C GI -T S -I m pr o ve me nt scale will be use d t o rate t he s u bject’s 
o verall se verit y of tics a n d o verall i m pr o ve me nt of T S.   
T he C GI -Tics - Se verit y scale will be use d t o assess o verall se verit y o n a 7- p oi nt scale (ra n ge; 
1 = n or ma l, n ot at all ill t o 7 =a m o n g t he m ost e xtre mel y ill s u bjects).  T he C GI -Tics -S e verit y 
scale will be assesse d b y t he i n vesti gat or ( or desi g nee) at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 
4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y 
ter mi nati o n.  A c o p y of t he C GI-Tics -Se verit y scale is pr o vi de d i n A p pe n di x 1 7. 3 . 
T he C GI -T S -I m pr o ve me nt scale will be use d t o assess o verall i m pr o ve me nt si nce t he i nitiati o n 
of st u d y dr u g d osi n g o n a 7 -p oi nt scale (ra n ge; 1 = ver y m uc h i m pr o ve d t o 7 = ver y m u c h w orse) .  
T he C GI -T S -I m pr o ve me nt scale will be assesse d b y t he i n vesti gat or ( or desi g nee) at Wee ks 2, 
4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y 
ter mi nati o n.  A c o p y of t he C GI -T S -I m pr o ve me nt scale is pr o vi de d i n A p pe n di x 1 7. 4 . 
9. 3. 4.  
Gilles de l a T o urette S y n dr o me -Q u alit y of Life f or C hil dre n a n d A d olesce nts  
T he Gilles de la T o urette S y n dr o me - Q ualit y of Life f or C hil dre n a n d A d olesce nts 
( C & A-G T S -Q O L ) is a vali d a n d relia ble i nstr u me nt t o assess t he q ualit y of life i n c hil dre n a n d 
a d olesce nts wit h T S ( Ca va n na 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 bscales ( ps yc h ol o gical, ph ysical, o bsessi ve -c o m p ulsi ve, a n d c o g niti ve).  Eac h ite m is rate d 
acr oss 5  res p o nse o pti o ns:  “ Ne ver,” “ Rarel y,” “ S o meti mes,” “ Ofte n,” a n d “ Al wa ys.”  T here are 
2 versi o ns of t his i nstr u me nt:  1 versi o n f or c hil dre n a ge d 6 t o 1 2 years a n d 1 versi o n f or 
a d olesce nts a ge d 1 3 t o 1 7 years.  T he C & A -G T S -Q O L als o i ncl u des a vis ual a nal o g  scale, 
assessi n g h o w satisfie d t he s u bject feels wit h his/ her life (ra n ge of 0  t o 1 0 0, wit h 1 0 0 
re prese nti n g t he greatest satisfacti o n). 
T he s u bject will c o m plete t he C & A -G T S -Q O L at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 
1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y t er mi nati o n.  
T he s u bject ca n recei ve assista nce filli n g o ut q uesti o n naire if nee de d.   C o pies of b ot h versi ons 
of t he C & A- G T S -Q O L are  pr o vi de d i n A p pe n di x 1 7. 5 . 
9. 4.  
Pl as m a D r u g E x p os ure  
Bl o o d sa m ples t o e val uate plas ma c o nce ntrati o ns of N BI - 9 8 8 5 4 a n d t he acti ve meta b olite 
N BI - 9 8 7 8 2 will be c ollecte d  at Da y 1 ( bas eli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 
a n d at t he f oll o w - u p visit ( Wee k 4 0), or earl y ter mi nati o n.  T he e xact ti me of c ollecti o n will be 
rec or de d o n t he e C R F.  S u bjects/care gi vers will be as ke d t o rec or d a n d pr o vi de d osi n g ti me s of 
N BI - 9 8 8 5 4 f or t he first d ose a n d fr o m t he e ve ni n g bef ore t he treat me nt peri o d visits w he n P K 
bl o o d sa m ples are c ollecte d.  
F or eac h  plas ma sa m ple, a p pr o xi matel y 2  m L of bl o o d will be c ollecte d i n t u bes c o ntai ni n g 
E D T A K 2.  T he bl o o d sa m ples will be pr ocesse d a n d st ore d acc or di n g t o t he pr oce d ure as 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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s pecifie d i n t he la b orat or y ma n ual.  S a m ples will be s hi p pe d o n dr y ice t o t he ce ntral la b orat or y 
f or a nal ysis. 
9. 5.  
S af et y Assess me nts  
C o nc o mita nt me dicati o n use a n d A Es will be m o nit ore d t hr o u g h o ut t he st u d y as des cri be d i n 
Secti o n  9. 8. 1  a n d Secti o n  1 1 , res pecti vel y.  A d diti o nal safet y assess me nts are descri be d i n t he 
f oll o wi n g secti o ns. 
F or a n y a b n or mal vital si g n meas ure me nt, p h ysical e xa mi nati o n fi n di n g, cli nical la b orat or y test, 
or E C G para meter dee me d cli nicall y si g nifica nt , t he i n vesti gat or will perf or m a p pr o priate 
f oll o w-u p assess me nts (e g, re peat a nal ysis), u ntil t he ca use of t he a b n or malit y is deter mi ne d 
a n d/ or u ntil t he val ue ret ur ns t o baseli ne ( or wit hi n n or mal li mits), or t he i n vesti gat or dee ms t he 
a b n or malit y t o be of n o cli nical si g nifica nce.   If t he i n vesti gat or deter mi nes t hat a s u bject has a 
cli nicall y si g nifica nt fi n di n g of treat me nt -e mer ge nt de pressi o n, s uici dal i deati o n, ps yc hiatric 
s y m pt o ms ( base d u p o n t he C-S S R S, C hil dre n’s De pressi o n Rati n g Scale- Re vise d [ C D R S- R], 
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 ], or cli nical assess me nt), t he 
fi n di n g will be d oc u me nte d as a n A E, a n d a p pr o priate ps yc hiatric e val uati o n a n d i nter ve nti o n 
will be pr o vi de d. 
9. 5. 1.  
D at a S afet y M o nit ori n g B o ar d 
A n i n de pe n de nt Data Safet y M o nit ori n g B oar d ( D S M B) will peri o dicall y re vie w o n g oi n g 
cli nical safet y data t o e ns ure t he safet y a n d well -bei n g of t he st u d y s u bjects.  T he safet y data 
re vie w ma y res ult i n rec o m me n dati o n f or earl y ter mi nati o n of t he st u d y or c ha n ges t o t he 
pr ot oc ol a n d i nf or me d c o nse nt.  A D S M B c harter will descri be t he res p o nsi bilities, ti mi n g of 
meeti n gs, a n d data re vie w pr oce d ures f or t he me m bers t o f oll o w.  
9. 5. 2.  
Vit al Si g n Me as ure me nts  
Vital si g ns will i ncl u de ort h ostatic s yst olic a n d diast olic bl o o d press ure, ort h ostatic p ulse rate, 
res pirat or y rate (rec or de d o nl y s u pi ne), a n d oral b o d y te m perat ure.  Bl o o d press ure will be 
meas ure d usi n g a cali brate d a ut o matic bl o o d press ure c uff after t he s u bject has bee n s u pi ne f or 
at least 5 mi n utes a n d after a p pr o xi matel y 2 mi n utes of sta n di n g.  
Vital si g n meas ure me nts will be c ollecte d at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 
1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n.  
Vital si g n meas ure me nts will be o btai ne d bef ore a n y sc he d ule d bl o o d sa m ple c ollecti o n . 
9. 5. 3.  
Me dic al Hist or y  
A me dical hist or y will be ta ke n at t he scree ni n g visit a n d u p date d o n Da y  1 ( baseli ne) a n d as 
nee de d t hr o u g h o ut t he st u d y .  T he a ge at T S dia g n osis will be d oc u me nte d f or all s u bjects; if 
necessar y, s u bject  a ge at T S o nset ca n be esti mate d b y t he i n vesti gat or base d u p o n a vaila ble 
cli nical i nf or mati o n. 
9. 5. 4.  
P h ysic al E x a mi n ati o n, I ncl u di n g Hei g ht a n d Wei g ht  
T he c o m plete p h ysical e xa mi nati o n will c o nsist of a n assess me nt of ge neral a p peara nce, s ki n 
a n d m uc osae, hea d, e yes, ears, n ose, t hr oat, nec k (i ncl u di n g t h yr oi d), l y m p h n o des, c hest/l u n gs, 
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 5 
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car di o vasc ular, a b d o me n, e xtre mities, m usc ul os keletal, a n d ne ur ol o gical s yste m.  A c o m plete 
p h ysical e xa mi nati o n i ncl u di n g wei g ht will be perf or me d at scree ni n g, Da y 1 ( baseli ne) , a n d at 
Wee ks 2, 6, 1 2, 2 4, 3 6, a n d at t he f oll o w-u p visit ( Wee k 4 0 ), or earl y ter mi nati o n.  Hei g ht will 
be meas ure d at scree ni n g o nl y.  Hei g ht a n d wei g ht will be meas ure d wit h s u bjects n ot weari n g 
s h oes. 
9. 5. 5.  
Electr oc ar di o gr a m  
A sta n dar d 1 2- lea d E C G will be rec or de d i n tri plicate (at least 1 mi n ute a part a n d wit hi n 
1 5 mi n utes) after t he s u bject has reste d s u pi ne f or at least 5 mi n utes.  T he E C G para meters t hat 
will be assesse d i ncl u de heart rate ( H R), P R i nter val, Q R S d urati o n, Q T  i nter val, a n d Q Tc F 
( mac hi ne rea di n gs or calc ulate d).  A d diti o nall y, t he occ urre nce of de- a n d re- p olarizati o n a n d 
r h yt h m dis or ders or ot her a b n or malities will be assesse d.  Base d o n t he re vie w of t hese 
para meters, t he i n vesti gat or or desi g nee will n ote if t he E C G is N or mal, A b n or mal n ot 
Cli nicall y Si g nifica nt, or A b n or mal Cli nicall y Si g nifica nt.  If t he E C G is A b n or mal Cli nicall y 
Si g nifica nt, t he i n vesti gat or or desi g nee will pr o vi de a descri pti o n of t he a b n or malit y rec or de d 
o n t he A E e C R F. 
T he 1 2- lea d E C G rec or di n gs will be c o n d ucte d at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 
1 0, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n. 
9. 5. 6.  
Cli nic al L a b or at or y Assess me nts  
All cli nical la b orat or y assess me nts will be perf or me d b y a ce ntral la b orat or y, w hic h will 
pr o vi de i nstr ucti o ns a n d s u p plies t o t he st u d y staff bef ore st u d y i nitiati o n.  T he i nstr ucti o ns will 
be i ncl u de d i n a la b orat or y ma n ual.  T he la b orat or y test batter y will i ncl u de r o uti ne a n d 
scree ni n g la b orat or y tests. 
Cli nical safet y la b orat or y assess me nts will be perf or me d at scree ni n g, Da y 1 ( baseli ne), 
Wee ks  2, 4, 6, 8, 1 0, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y 
ter mi nati o n.  T here are n o fasti n g re q uire me nts f or la b orat or y assess me nts.  
T he f oll o wi n g cli nical safet y la b orat or y assa ys will be perf or me d:  
He mat ol o g y :  c o m plete bl o o d c o u nt i ncl u di n g W B C c o u nt wit h differe ntial, re d bl o o d cell 
c o u nt, he m o gl o bi n, he mat ocrit, platelet c o u nt, mea n c or p usc ular he m o gl o bi n ( M C H), mea n 
c or p usc ular he m o gl o bi n c o nce ntrati o n ( M C H C), mea n c or p usc ular v ol u me ( M C V), re d cell 
distri b uti o n wi dt h ( R D W), a n d mea n platelet v ol u me ( M P V). 
Cli nical C he mistr y :  s o di u m, p otassi u m, calci u m, ma g nesi u m, c hl ori de, bl o o d urea nitr o ge n, 
bicar b o nate, creati ni ne, uric aci d, al b u mi n, al kali ne p h os p hatase, lactate de h y dr o ge n ase, A L T, 
A S T, G G T, creati ne ki nase, t otal bilir u bi n, t otal c h olester ol, tri gl yceri des, t otal pr otei n , a n d 
gl uc ose.  
Uri nal ysis :  s pecific gra vit y, nitrites, ket o nes, pr otei n, ur o bili n o ge n, gl uc ose, bilir u bi n, 
le u k oc yte esterase, occ ult bl o o d, a n d p H; micr osc o pic e xa mi nati o n of se di me nt will be 
perf or me d o nl y if t he res ul ts of t he uri nal ysis di pstic k e val uati o n are p ositi ve f or nitrites, 
pr otei n, le u k oc yte esterase, or bl o o d. 
T he f oll o wi n g a d diti o nal la b orat or y tests will be perf or me 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 3 3

 
Ser ol o g y :  Bl o o d will be c ollecte d f or HI V-A b, H Bs A g, a n d H C V - A b a n d refle x P C R testi n g at 
scree ni n g.  T he f oll o wi n g a p pr o xi mate a m o u nts will be c ollecte d:  9 m L (c hil dre n, 6 t o 1 1 years 
of a ge) or 1 0 m L (a d olesce nts, 1 2 t o 1 7 years of a ge). 
He m o gl o bi n A 1c :  Bl o o d sa m ples f or he m o gl o bi n A 1c will be c ollecte d at scree ni n g, Da y 1 
( baseli ne), a n d at wee ks 6, 1 2, 2 4, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y t er mi nati o n.  
A p pr o xi matel y 2 m L i n E D T A K 2 will be c ollecte d i n all s u bjects.  
Ser u m Pr olacti n :  Bl o o d sa m ples t o deter mi ne ser u m pr olacti n c o nce ntrati o n will be c ollecte d at 
Da y 1 ( baseli ne), Wee ks 2, 6, 8, 1 0, 1 2, 1 6, 2 4, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or 
earl y ter mi nati o n.   A p pr o xi matel y 2. 5 m L (c hil dre n, 6 t o 1 1 years of a ge) or 5 m L (a d olesce nts, 
1 2 t o 1 7 years of a ge) of bl o o d will be c ollecte d i nt o a ser u m se parat or t u be.  Ser u m pr olacti n 
sa m ples will be s hi p pe d t o a ce ntral la b orat or y f or a nal ysis.  Pr olacti n res ults will re mai n 
bli n de d t o t he i n vesti gat or  a n d t he S p o ns or. 
U D S  a n d Alc o h ol Breat h  Test :  T he U D S  will test f or a m p heta mi nes , bar bit urates, 
p he nc ycli di ne, be nz o diaze pi nes, ca n na bi n oi ds, c ocai ne, a n d o piates.  U D S will be a nal yze d at 
scree ni n g a n d Da y 1 b y t he ce ntral la b.  I n a d diti o n, a U D S kit pr o vi de d b y t he ce ntral la b will 
be use d at t he site t o c o nfir m eli gi bilit y o n Da y 1.  A n alc o h ol breat hal yzer test will be 
perf or me d at scree ni n g a n d o n Da y 1.  T he U D S  a n d alc o h ol breat hal yzer test will be perf or me d 
o nl y i n a d olesce nt s u bjects ( 1 2 t o 1 7 years  of a ge).  A U D S  usi n g a kit pr o vi de d b y t he ce ntral 
la b orat or y ma y be c o n d ucte d at t he cli nical site at a n y ti me d uri n g t he st u d y if t he s u bject 
(a d olesce nt s u bjects o nl y) is s us pecte d of s u bsta nce or dr u g a b use. 
Pre g na nc y Tests :  Pre g na nc y tests will be c o n d ucte d o nl y for fe male s u bjects of c hil d beari n g 
p ote ntial.  A ser u m pre g na nc y test will be c o n d ucte d at scree ni n g , a n d a uri ne pre g na ncy test 
will be c o n d ucte d o n Da y 1 a n d at Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at 
t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n usi n g a uri ne pre g na nc y kit pr o vi de d b y t he 
ce ntral la b orat or y.  
9. 5. 7.  
C ol u m bi a -S uici de Se verit y R ati n g Sc ale C hil dre n’s Versi o ns  
T he C -S S R S is a vali date d i nstr u me nt t o pr os pecti vel y assess s uici dal i deati o n a n d be ha vi or 
( htt p:// w w w.cssrs.c ol u m bia.e d u).  T here are versi o ns of t he q uesti o n naire desi g ne d f or use at 
scree ni n g (C hil dre n’s Baseli ne/ Scree ni n g versi o n) a n d at baseli ne a n d visits t hr o u g h o ut t he 
st u d y (C hil dre n’s Si nce Last Visit versi o n).  All versi o ns of t he C - S S R S i ncl u de a series of 
scree ni n g q uesti o ns relate d t o s uici dal i deati o n a n d s uici dal be ha vi or.  S u bject res p o nses of 
“ yes ” t o o ne or m ore scree ni n g q uesti o ns will pr o m pt a d diti o nal q uesti o ns t hat e val uate 
fre q ue nc y a n d i nte nsit y of s uici dal i deati o n a n d/ or be ha vi or.  S u bjects wit h a n y lifeti me s uici dal 
be ha vi or or s uici dal i deati o n of t y pe 4 (acti ve s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut 
s pecific pla n) or t y pe  5 (acti ve s uici dal i deati o n wit h s pecific pla n a n d i nte nt) i n t he 1 year  
bef ore scree ni n g base d o n t he C- S S R S C hil dre n’s versi o n s h o ul d be e xcl u de d (see 
e xcl usi o n  criteri o n # 2 0  i n Secti o n 8. 2). 
T he C -S S R S will be a d mi nistere d a n d sc ore d b y t he i n vesti gat or or q ualifie d st u d y c e nter 
pers o n nel at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, 
a n d at t he f oll o w - u p visit ( Wee k 4 0), or earl y ter mi nati o n.  A c o p y  of eac h C hil dre n’s versi o n of 
t he C- S S R S is pr o vi de d i n A p pe n di x 1 7. 6  a n d A p pe n di x 1 7. 7 , res pecti vel 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 3 4

 
9. 5. 8.  
C hil dre n’s De pressi o n R ati n g Sc ale, Re vise d  
T he C D R S- R is a 1 7- ite m, se mi-str uct ure d i nter vie w t o deter mi ne t he se verit y of de pressi o n i n 
c hil dre n.  T he i n vesti gat or ( or desi g nee) will a d mi nister t he C D R S - R at scree ni n g, Da y 1 
( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w-u p visit 
( Wee k 4 0), or earl y ter mi nati o n.  A c o p y  of t he C D R S- R is pr o vi de d i n A p pe n di x 1 7. 8 . 
9. 5. 9.  
C hil dre n’s Y ale -Br o w n O bsessi ve  C o m p ulsi ve Sc ale  
T he C Y- B O C S is a se mi -str uct ure d i nter vie w desi g ne d t o rate t he se verit y of o bsessi ve a n d 
c o m p ulsi ve s y m pt o ms i n c hil dre n.  T he i n vesti gat or ( or desi g nee) will a d mi nister t he 
C Y- B O C S at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 
3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n.   A c o p y of t he C Y-B O C S is 
pr o vi de d i n A p pe n di x 1 7. 9 . 
9. 5. 1 0.  
Atte nti o n- Deficit H y per acti vit y Dis or der R ati n g Sc ale - 5:  H o me Versi o n  
T he Atte nti o n -Deficit H y peracti vit y Dis or der Rati n g Scale - 5:  H o me Versi o n (A D H D - 5 Rati n g 
Scale ) will be use d t o deter mi ne t he fre q ue nc y a n d se verit y of A D H D s y m pt o ms a n d 
i m pair me nts.  T he  scale c o mes i n 2 versi o ns:  c hil d (a ges 5 - 1 0 years) a n d a d olesce nt (a ges 
1 1- 1 7 years).  B ot h  versi o ns c o nsist of 2 s y m pt o m s u bscales, I natte nti o n ( 9 ite ms) , a n d 
H y peracti vit y – I m p ulsi vit y ( 9 ite ms), as well as a T otal Scale ( 1 8 ite ms).  I n a d diti o n, 6 d o mai ns 
of i m pair me nt t hat are c o m m o n a m o n g c hil dre n wit h A D H D are assesse d:   relati o ns hi ps wit h 
si g nifica nt ot hers (fa mil y me m bers f or t he h o me versi o n a n d teac hers f or t he sc h o ol versi o n), 
peer relati o ns hi ps, aca de mic f u ncti o ni n g, be ha vi oral f u ncti o ni n g, h o me w or k perf or ma nce, a n d 
self-estee m. 
T he A D H D -5 Rati n g Scale  will be c o m pl ete d i n de pe n de ntl y b y t he s u bject’s pare nt or g uar dia n 
at scree ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, 3 6, a n d at t he 
f oll o w-u p visit ( Wee k 4 0), or earl y ter mi nati o n.   A c o p y of b ot h versi o ns of t he A D H D- 5 
Rati n g Scale  is pr o vi de d i n A p pe n di x 1 7. 1 0 . 
9. 5. 1 1.  
E xtr a p y r a mi d al S y m pt o m R ati n g Sc ale- A b bre vi ate d  
T he E xtra p yra mi dal S y m pt o m Rati n g Scale - A b bre viate d (E S R S - A) is a ps yc h o metricall y 
vali date d i nstr u me nt t hat assesses 4  t y pes of m o ve me nt dis or ders:  par ki ns o nis m, a kat hisia, 
d yst o nia, a n d d ys ki nesia  (C h o ui nar d a n d Mar g olese, 2 0 0 5 ).  T he i n ves ti gat or ( or desi g nee) will 
a d mi nister t he E S R S -A at scre e ni n g, Da y 1 ( baseli ne), Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 
2 4, 2 8, 3 2, 3 6, a n d at t he f oll o w- u p visit ( Wee k 4 0), or earl y ter mi nati o n.  A c o p y of t he 
E S R S - A is pr o vi de d i n A p pe n di x 1 7. 1 1 . 
9. 5. 1 2.  
Esti m ate d T ot al Bl o o d S a m ple V ol u me Re q uire d b y St u d y 
T he esti mate d t otal bl o o d sa m ple v ol u me f or eac h s u bject is prese nte d i n  Ta ble  2.  T hese 
esti mates i ncl u de sa m ples t o be c ollecte d d uri n g scree ni n g, t he treat me nt peri o d, a n d t he fi nal 
visit ( Wee k 4 0 or u p o n earl y ter mi nati 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 3 5

 
T a ble 2:  
Esti m ate d T ot al Bl o o d S a m ple V ol u me 
P a r a meter  
N u m be r of S a m ples 
Re q uire d  
A p pr o xi m at e  
V ol u m e ( m L)  
A p pr o xi m at e T ot al 
V ol u m e ( m L)  
C hil d re n ( 6 t o 1 1 ye ars of a ge)  
Cli nical c he mistr y a 
1 5 
2. 5 
3 7. 5 
He mat ol o g y  
1 5 
3 
4 5 
Ge n ot y pi n g  
1 
4 
4 
He m o gl o bi n A 1c  
7 
2 
1 4 
Ser u m pr olacti n  
1 0 
2. 5 
2 5 
Ser ol o g y  
1 
9 
9 
P har mac o ki netics  
1 4 
2 
2 8 
A p pr o xi m at e M a xi m u m T ot al Bl o o d S a m ple V ol u m e per S u bj ect ( m L):  
1 6 2 . 5 
A d oles ce nts ( 1 2 t o 1 7 ye ars of a ge)  
Cli nical c he mistr y a 
1 5 
5 
7 5 
He mat ol o g y  
1 5 
4 
6 0 
Ge n ot y pi n g  
1 
4 
4 
He m o gl o bi n A 1c  
7 
2 
1 4 
Ser u m pr olacti n  
1 0 
5 
5 0 
Ser ol o g y  
1 
1 0 
1 0 
P har mac o ki netics  
1 4 
2 
2 8 
A p pr o xi m at e M a xi m u m T ot al Bl o o d S a m ple V ol u m e per S u bj ect ( m L):  
2 4 1 
a  I n cl u d es pre g na n c y t est f or f e mal e s u bj ects w h o ar e of c hil d b eari n g p ot e ntial at s cr ee ni n g. 
9. 6.  
S pecific St u d y I nf or m ati o n  
After pr o vi di n g pare ntal or le gal g uar dia n i nf or me d c o nse nt wit h si g ne d  ( or ver bal, if 
a p plica ble)  a n d wit nesse d pe diatric asse nt , s u bjects will u n der g o scree ni n g pr oce d ures wit hi n 
4 wee ks  of Da y 1. 
9. 6. 1.  
Scree ni n g  (Wee k - 4 t o D a y  - 1) 
D uri n g scree ni n g, t he f oll o wi n g st u d y e val uati o ns a n d tas ks will be perf or me d at t he st u d y 
ce nter: 
•  O btai n i nf or me d c o nse nt/asse nt. 
•  S u bjects will be s h o w n t he vi de o title d “ Y o ur R ole i n a Cli nical Trial, S o me I nf or mati o n 
A b o ut Researc h St u dies.” 
•  Assess i ncl usi o n/e xcl usi o n criteria.  
•  C ollect me dical hist or y. 
•  Perf or m a p h ysical e xa mi nati o n (i ncl u di n g hei g ht a n d wei g ht).  
•  C ollect vital si g ns, i ncl u di n g ort h ostatic s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 3 6

 
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes). 
•  Perf or m a ser u m pre g na nc y test ( β- h C G) o nl y f or fe male s u bjects of c hil d beari n g p ote ntial. 
•  C ollect bl o o d sa m ple f or ser ol o g y testi n g ( HI V- A b, H Bs A g, a n d H C V - A b). 
•  C ollect bl o o d sa m ple f or he mat ol o g y a n d cli nical c he mistr y . 
•  C ollect uri ne sa m ple f or uri nal ysis.  
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c. 
•  Perf or m alc o h ol breat hal yzer test a n d U D S  ( b ot h o nl y i n a d olesce nt s u bjects). 
•  A d mi nister t he Y G T S S, i ncl u di n g vi de o rec or di n g.  
•  A d mi nister t he C GI -Tics -Se verit y scale.  
•  A d mi nister t he C - S S R S ( C hil dre n’s Baseli ne/ Scree ni n g versi o n). 
•  A d mi nister t he C Y - B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D -5 Rati n g Scale.  
•  A d mi nister t he E S R S -A.  
•  A d mi nister t he P U T S.  
•  A d mi nister t he C & A -G T S -Q O L.  
•  A E m o nit ori n g. 
•  Rec or d pri or me dicati o ns. 
All scree ni n g pr oce d ures m ust be c o m plete d a n d res ults m ust be e val uate d b y t he i n vesti gat or 
bef ore t he baseli ne pr oce d ures are perf or me d o n Da y 1. 
T he f oll o wi n g ite ms will als o be c o n d ucte d at scree ni n g:  
•  I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice  t otal a bsti ne nce t o c o nti n ue 
usi n g c o ntrace pti o n (see i ncl usi o n criteri o n #1 0 i n Secti o n  8. 1 ). 
•  Eli gi ble s u bjects will be i nstr ucte d t o ret ur n t o t he st u d y ce nter o n Da y 1.  T he f oll o wi n g 
s h o ul d be c o nsi dere d f or sc he d uli n g p ur p oses:  as m uc h as p ossi ble, visits s h o ul d occ ur at 
a p pr o xi matel y t he sa me ti me as t he Da y 1 ( baseli ne)  visit t o  sta n dar dize t he ti me of da y f or 
t he assess me nt of efficac y, safet y, a n d plas ma e x p os ure t hr o u g h o ut t he st u d y peri o d.  
9. 6. 2.  
D a y 1  ( B aseli ne Assess me nts a n d St art of D osi n g)  
S u bjects  a n d pare nts/le gal g uar dia ns  will ret ur n t o t he st u d y ce nter o n Da y 1. 
O n Da y 1, t he f oll o wi n g baseli ne st u d y e val uati o ns a n d tas ks will be perf or me d at t he st u d y 
ce nter: 
•  S u bjects will be i nf or me d a b o ut t he place b o -c o ntr olle d desi g n of t he st u d y usi n g t h e 
treat me nt assi g n me nt scri pt pr o vi de d b y t he S p o ns or. 
•  U p date i ncl usi o n/e xcl usi o n  criteria . 
•  U p date me dical hist or y.  
•  Perf or m a p h ysical e xa mi nati o n i ncl u di n g  wei g ht.  
•  C ollect vital si g ns, i ncl u di n g ort h ostatic s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 3 7

 
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes). 
•  Perf or m a uri ne pre g na nc y test o nl y f or fe male s u bjects of c hil d beari n g p ote ntial. 
•  C ollect bl o o d sa m ple f or he mat ol o g y a n d cli nical c he mistr y.  
•  C ollect uri ne sa m ple f or uri nal ysis.  
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c. 
•  C ollect bl o o d sa m ple f or ser u m pr olacti n.  
•  Perf or m alc o h ol breat hal yzer test a n d U D S  ( b ot h o nl y i n a d olesce nt s u bjects). 
•  C ollect bl o o d sa m ple f or C Y P 2 D 6 ge n ot y pe stat us. 
•  C ollect P K bl o o d sa m ple f or N BI- 9 8 8 5 4 a n d meta b olite c o nce ntrati o ns. 
•  A d mi nister t he Y G T S S , i ncl u di n g vi de o rec or di n g. 
•  A d mi nister t he C GI -Tics -Se verit y scale . 
•  A d mi nister t he C -S S R S ( C hil dre n’s Si nce Last Visit versi o n ). 
•  A d mi nister  t he C Y- B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D - 5 Rati n g Scale . 
•  A d mi nister t he E S R S -A.  
•  A d mi nister t he P U T S.  
•  A d mi nister t he C & A -G T S -Q O L.  
•  Dis pe nse a 2 - wee k s u p pl y of st u d y dr u g a n d pr o vi de i nstr ucti o ns o n st ora ge a n d 
a d mi nistrati o n of t he st u d y dr u g (see Secti o n  1 0. 5 ). 
•  Instr uct s u bjects t o rec or d t he date a n d ti me of eac h d ose o n t he la bels pr o vi de d o n t he st u d y 
dr u g kit pac ka gi n g f or m. 
•  I nstr uct s u bjects t o ta ke t he st u d y dr u g dail y  at be dti me  ( u n der s u per visi o n of t heir 
pare nts/le gal g uar dia ns ) be gi n ni n g o n Da y 1.  ( T he ti mi n g of st u d y dr u g a d mi nistrati o n 
s h o ul d re mai n c o nsiste nt t hr o u g h o ut t he treat me nt peri o d). 
•  I nstr uct s u bjects a n d pare nts/le gal g uar dia ns t o ret ur n t o t he st u d y ce nter at Wee k 2 
( ± 3 da ys)  a n d t o bri n g t heir st u d y dr u g kit. 
•  A E m o nit ori n g. 
•  Rec or d c o nc o mita nt me dicati o ns.  
T he f oll o wi n g will als o be c o n d ucte d bef ore s u bjects ma y lea ve t he st u d y ce nter:  
•  I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice t otal a bsti ne nce t o c o nti n ue 
usi n g c o ntrace pti o n (see  i ncl usi o n criteri o n #1 0 i n Secti o n 8. 1 ). 
•  I nstr uct s u bjects a n d pare nts/le gal g uar dia ns t o n otif y t he i n vesti gat or b y tele p h o ne if t he y 
e x perie nce a n y A Es a n d bef ore ta ki n g a n y  ne w c o nc o mita nt me dicati o ns. 
Sites are t o call s u bjects wit hi n 3 t o 7 da ys after t he Da y 1 visit t o i n q uire a b o ut c o m plia nce or 
t olera bilit y iss ues. 
9. 6. 3.  
O pe n -L a bel Tre at me nt Peri o d :  Wee ks 2,  4, a n d 6 ( ±3 d a ys  f or e ac h visit) 
S u bjects a n d pare nts/le gal g uar dia ns will r et ur n t o t he st u d y ce nter at Wee ks 2, 4, a n d 6. 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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At Wee ks 2, 4, a n d 6, t he f oll o wi n g st u d y e val uati o ns a n d tas ks will be perf or me d  at t he st u d y 
ce nter: 
•  Perf or m a p h ysical e xa mi nati o n i ncl u di n g  wei g ht  ( Wee ks 2 a n d 6 o nl y). 
•  C ollect vital si g ns, i ncl u di n g ort h ostatic s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes ). 
•  Perf or m a uri ne pre g na nc y test o nl y f or fe male s u bjects of c hil d beari n g p ote ntial. 
•  C ollect bl o o d sa m ple f or he mat ol o g y a n d cli nical c he mistr y .  
•  C ollect uri ne sa m ple f or uri nal ysis.  
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c ( Wee k 6 o nl y). 
•  C ollect bl o o d sa m ple f or ser u m pr olacti n ( Wee ks 2 a n d 6 o nl y). 
•  C ollect P K bl o o d sa m ple f or N BI- 9 8 8 5 4 a n d meta b olite c o nce ntrati o ns. 
•  A d mi nister t he Y G T S S , i ncl u di n g vi de o rec or di n g. 
•  A d mi nister t he C GI -Tics -Se verit y scale . 
•  A d mi nister t he C GI -T S -I m pr o ve me nt scale. 
•  A d mi nister t he C -S S R S ( C hil dre n’s Si nce Last Visit versi o n). 
•  A d mi nister  t he C Y- B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D -5 Rati n g Scale.  
•  A d mi nister t he E S R S -A.  
•  A d mi nister t he P U T S.  
•  A d mi nister t he C & A -G T S -Q O L.  
•  Dis pe nse a 2 - wee k s u p pl y of st u d y dr u g. 
•  Perf or m c o m plia nce c hec k b y c o u nti n g t h e ca ps ules ret ur ne d.  
•  A E m o nit ori n g. 
•  Rec or d c o nc o mita nt me dicati o ns.  
D ose Esc al ati o n Assess me nt  
At t he e n d of Wee k 2 a n d Wee k 4 visits, a d ose escalati o n will occ ur  base d o n t he f oll o wi n g 
2 criteria:  1) t he s u bject ’s tics are n ot s ufficie ntl y c o ntr olle d per p h ysicia n i n vesti gat or 
assess me nt; a n d 2) a n e val uati o n b y t he p h ysicia n i n vesti gat or i n dicates t hat t he s u bject is 
t olerati n g t he st u d y dr u g at t he c urre nt d ose a n d w o ul d li kel y be a ble t o t olerate t he ne xt d ose 
le vel.  Base d o n t hese criteria, t he p h ysicia n i n vesti gat or will c h o ose 1 of t he f oll o wi n g d osi n g 
o pti o ns: 
•  D ose escalati o n, w hic h will occ ur i n 2 0 m g i ncre me nts:  
− S u bjects < 5 0 k g at baseli ne :  fr o m 2 0 m g t o 4 0 m g ( Wee k 2); fr o m 4 0 m g t o 6 0 m g 
( Wee k 4). 
− S u bjects ≥5 0 k g at baseli ne :  fr o m 4 0 m g t o 6 0 m g ( Wee k 2); fr o m 6 0 m g t o 8 0 m g 
( Wee k 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 5 
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•  Mai nte na nce of c urre nt d ose ( wit h n o f urt her d ose i ncreases). 
•  D ose re d ucti o n t o pre vi o us d ose i n s u bjects w h o ha ve ha d a d ose escalati o n  ( o nl y a si n gle 
d ose re d ucti o n is all o we d d uri n g t he st u d y) .  T he p h ysicia n i n vesti gat or ma y decrease t he 
d ose t o t he pre vi o us d ose at a n y ti me after t he e n d of Wee k 2 (i ncl u di n g bet wee n sc he d ule d 
st u d y visits) f or a n y s u bject w h o is u na ble t o t olerate a gi ve n d ose i ncrease.  S u bjects will 
recei ve t his d ose f or t he re mai n der of t he treat me nt peri o d. 
O nce a deter mi nati o n of d ose escalati o n, mai nte na nce, or re d ucti o n is ma de, t he I W R S will be 
accesse d t o o btai n a n i de ntificati o n n u m ber f or a kit c o ntai ni n g a 2 -wee k  s u p pl y of st u d y dr u g 
t o be dis pe nse d t o t he s u bject.  
T he f oll o wi n g will als o be  c o n d ucte d bef ore s u bjects ma y lea ve t he st u d y ce nter:  
•  I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice t otal a bsti ne nce t o c o nti n ue 
usi n g c o ntrace pti o n (see i ncl usi o n criteri o n #1 0 i n Secti o n  8. 1 ). 
•  I nstr uct s u bjects a n d pare nts/le gal g uar dia ns t o n otif y t he i n vesti gat or b y tele p h o ne if t he y 
e x perie nce a n y A Es a n d bef ore ta ki n g a n y ne w c o nc o mita nt me dicati o ns. 
•  I nstr uct s u bjects t o rec or d t he date a n d ti me of eac h d ose o n t he la bels pr o vi de d o n t he st u d y 
dr u g pac ka gi n g f or m. 
9. 6. 4.  
Bli n de d R a n d o miz ati o n Peri o d :  Wee ks 8, 1 0, a n d 1 2 ( ± 3 d a ys f or e ac h visit) 
S u bjects a n d pare nts/le gal g uar dia ns will ret ur n t o t he st u d y ce nter at Wee ks  8, 1 0, a n d 1 2. 
At Wee ks 8, 1 0, a n d 1 2, t he f oll o wi n g st u d y e val uati o ns a n d tas ks will be perf or me d at t he 
st u d y ce nter: 
•  Perf or m ra n d o mizati o n of s u bjects w h ose tic be ha vi ors are s ufficie ntl y c o ntr olle d a n d are 
t olerati n g t heir o pti mize d d ose of N BI- 9 8 8 5 4 (at Wee ks 8, 1 0, or 1 2; visit w he n 
ra n d o mizati o n occ urs will be bli n de d). 
•  Perf or m a p h ysical e xa mi nati o n i ncl u di n g wei g ht ( Wee k  1 2 o nl y). 
•  C ollect vital si g ns, i ncl u di n g ort h ostatic s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes ). 
•  Perf or m a uri ne pre g na nc y test o nl y f or fe male s u bjects of c hil d beari n g p ote ntial. 
•  C ollect bl o o d sa m ple f or he mat ol o g y a n d cli nical c he mistr y.  
•  C ollect uri ne sa m ple f or uri nal ysis.  
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c ( Wee k 1 2 o nl y). 
•  C ollect bl o o d sa m ple f or ser u m pr olacti n.  
•  C ollect P K bl o o d sa m ple f or N BI- 9 8 8 5 4 a n d m eta b olite c o nce ntrati o ns. 
•  A d mi nister t he Y G T S S, i ncl u di n g vi de o rec or di n g.  
•  A d mi nister t he C GI -Tics -Se verit y scale . 
•  A d mi nister t he C GI -T S -I m pr o ve me nt scale. 
•  A d mi nister t he C - S S R S ( C hil dre n’s Si nce Last Visit versi 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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Pa ge 4 0

 
•  A d mi nister t he C Y - B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D - 5 Rati n g Scale.  
•  A d mi nister t he E S R S -A.  
•  A d mi nister t he P U T S.  
•  A d mi nister t he C & A -G T S -Q O L.  
•  Dis pe nse a  2- wee k ( Wee ks 8 a n d 1 0 o nl y) or a 4- wee k s u p pl y of st u d y dr u g ( Wee k 1 2 
o n l y). 
•  Perf or m c o m plia nce c hec k b y c o u nti n g t h e ca ps ules ret ur ne d.  
•  A E m o nit ori n g. 
•  Rec or d c o nc o mita nt me dicati o ns.  
T he f oll o wi n g will als o be c o n d ucte d bef ore s u bjects ma y lea ve t he st u d y ce nter:  
•  I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice t otal a bsti ne nce t o c o nti n ue 
usi n g c o ntrace pti o n (see i ncl usi o n criteri o n #1 0 i n Secti o n  8. 1 ). 
•  I nstr uct s u bjects a n d pare nts/le gal g uar dia ns t o n otif y t he i n vesti gat or b y tele p h o ne if t he y 
e x perie nce a n y A Es a n d bef ore ta ki n g a n y ne w c o nc o mita nt me dicati o ns.  
•  I nstr uct s u bjects t o rec or d t he date a n d ti me of eac h d ose o n t he la bels pr o vi de d o n t he st u d y 
dr u g pac ka gi n g f or m. 
S u bjects w h ose T S is n ot s ufficie ntl y c o ntr olle d at Wee k 1 2, a n d w h o were n ot pre vi o usl y 
ra n d o mize d, will be disc o nti n ue d fr o m t he st u d y (t he n otice t o disc o nti n ue t he s u bject will be 
ge nerate d b y t he I W R S) a n d as ke d t o ret ur n 2 t o 4 wee ks after t heir fi nal d ose of st u d y dr u g 
(see Secti o n  9. 6. 6 ). 
9. 6. 5.  
Pl ace b o -C o ntr olle d  Wit h dr a w al Peri o d:  Wee ks 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, a n d 3 6 
( ± 3 d a ys f or e ac h visit)  
S u bjects a n d pare nts/le gal g uar dia ns will ret ur n t o t he st u d y ce nter at Wee ks  1 4, 1 6, 1 8, 2 0, 2 4, 
2 8, 3 2, a n d 3 6. 
At Wee ks 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, a n d 3 6, t he f oll o wi n g st u d y e val uati o ns a n d tas ks will be 
perf or me d at t he st u d y ce nter:  
•  Perf or m a p h ysical e xa mi nati o n i ncl u di n g wei g ht ( Wee ks 2 4 a n d 3 6 o nl y).  
•  C ollect vital si g ns, i ncl u di n g ort h ostatic  s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes) 
( Wee ks 1 6, 2 0, 2 4, 2 8, 3 2, a n d 3 6 o nl y). 
•  Perf or m a uri ne pre g na nc y te st o nl y f or fe male s u bjects of c hil d beari n g p ote ntial. 
•  C ollect bl o o d sa m ple f or he mat ol o g y a n d cli nical c he mistr y  ( Wee ks 1 6, 2 0, 2 4, 2 8, 3 2, a n d 
3 6 o nl y).  
•  C ollect uri ne sa m ple f or uri nal ysis  ( Wee ks 1 6, 2 0, 2 4, 2 8, 3 2, a n d 3 6 o nl y). 
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c ( Wee ks 2 4 a n d 3 6 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
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•  C ollect bl o o d sa m ple f or ser u m pr olacti n ( Wee ks 1 6, 2 4, a n d 3 6 o nl y). 
•  C ollect P K bl o o d sa m ple f or N BI- 9 8 8 5 4 a n d meta b olite c o nce ntrati o ns ( Wee ks 1 6, 2 0, 2 4, 
2 8, 3 2, a n d 3 6 o nl y). 
•  A d mi nister t he Y G T S S, i ncl u di n g vi de o rec or di n g. 
•  A d mi nister t he C GI -Tics -Se verit y scale . 
•  A d mi nister t he C GI -T S -I m pr o ve me nt scale. 
•  A d mi nister t he C - S S R S ( C hil dre n’s Si nce Last Visit versi o n). 
•  A d mi nister t he C Y - B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D -5 Rati n g Scale.  
•  A d mi nister t he E S R S -A.  
•  A d mi nister t he P U T S.  
•  A d mi nister t he C & A -G T S -Q O L.  
•  Dis pe nse a 2- or 4- wee k s u p pl y of st u d y dr u g ( Wee ks 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, a n d 3 2 o nl y). 
•  Perf or m c o m plia nce c hec k b y c o u nti n g t h e ca ps ules ret ur ne d.  
•  A E m o nit ori n g. 
•  Rec or d c o nc o mita nt me dicati o ns.  
T he f oll o wi n g w ill als o be c o n d ucte d bef ore s u bjects ma y lea ve t he st u d y ce nter: 
•  I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice t otal a bsti ne nce t o c o nti n ue 
usi n g c o ntrace pti o n (see i ncl usi o n criteri o n # 1 0 i n Secti o n  8. 1 ). 
•  I nstr uct s u bjects a n d pare nts/le gal g uar dia ns t o n otif y t he i n vesti gat or b y tele p h o ne if t he y 
e x perie nce a n y A Es a n d bef ore ta ki n g a n y ne w c o nc o mita nt me dicati o ns.  
•  I nstr uct s u bjects t o rec or d t he date a n d ti me of eac h d ose o n t he la bels pr o vi de d o n t he st u d y 
dr u g pac ka gi n g f or m. 
9. 6. 6.  
F oll o w -u p  Peri o d / E arl y Ter mi n ati o n:  Wee k 4 0 ( ± 3 d a ys ) 
S u bjects a n d pare nts/le gal g uar dia ns will ret ur n t o t he st u d y ce nter at Wee k 4 0 ( or u p o n earl y 
ter mi nati o n). 
A t Wee k 4 0 ( or u p o n earl y ter mi nati o n), t he f oll o wi n g st u d y e val uati o ns a n d tas ks will be 
perf or me d at t he st u d y ce nter:  
•  Perf or m a p h ysical e xa mi nati o n i ncl u di n g wei g ht.  
•  C ollect vital si g ns, i ncl u di n g ort h ostatic s yst olic a n d diast olic bl o o d press ures, ort h ostatic 
p ulse rate, res pirat or y rate, a n d b o d y te m perat ure.  
•  Perf or m 1 2- lea d E C G i n tri plicate (at least 1 mi n ute a part a n d wit hi n 1 5 mi n utes). 
•  Perf or m a uri ne pre g na nc y test o nl y f or fe male s u bjects of c hil d beari n g p ote ntial.  
•  C ollect bl o o d sa m ple f or h e mat ol o g y a n d cli nical c he mistr y.  
•  C ollect uri ne sa m ple f or uri nal ysis.  
•  C ollect bl o o d sa m ple f or he m o gl o bi n A 1c. 
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 5 
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•  C ollect bl o o d sa m ple f or ser u m pr olacti n.  
•  C ollect P K bl o o d sa m ple f or N BI- 9 8 8 5 4 a n d meta b olite c o nce ntrati o ns. 
•  A d mi nister t he Y G T S S, i ncl u di n g vi de o rec or di n g. 
•  A d mi nister t he C GI -Tics -Se verit y scale . 
•  A d mi nister t he C GI -T S -I m pr o ve me nt scale. 
•  A d mi nister t he C - S S R S ( C hil dre n’s Si nce Last Visit versi o n). 
•  A d mi nister t he C Y - B O C S a n d C D R S- R. 
•  A d mi nister t he A D H D -5 Rati n g Scale.  
•  A d mi nister t he E S R S -A.  
•  A d m i nister t he P U T S. 
•  A d mi nister t he C & A -G T S -Q O L.  
•  A E m o nit ori n g. 
•  Rec or d c o nc o mita nt me dicati o ns.  
I nstr uct s u bjects of c hil d beari n g p ote ntial w h o d o n ot practice t otal a bsti ne nce t o c o nti n ue usi n g 
c o ntrace pti o n f or 3 0 da ys (fe males) or 9 0 da ys ( males) after last d ose of st u d y dr u g (see 
i ncl usi o n criteri o n # 1 0 i n Secti o n  8. 1 ). 
9. 7.  
St u d y D ur ati o n  
T he e x pecte d d urati o n of st u d y partici pati o n f or eac h s u bject is a p pr o xi matel y 4 4 w ee ks, 
i ncl u di n g u p t o 4 wee ks of scree ni n g, a 3 6-wee k treat me nt peri o d (i ncl u di n g a 6 -wee k 
N BI - 9 8 8 5 4 o pe n-la bel treat me nt peri o d, a 6- wee k bli n de d ra n d o mizati o n peri o d, a n d a 2 4-wee k 
d o u ble- bli n d, place b o-c o ntr olle d wit h dra wal peri o d), a n d 4 wee ks f or f oll o w- u p assess me nts or 
earl y ter mi nati o n. 
9. 8.  
Pr o hi biti o ns a n d R estricti o ns  
9. 8. 1.  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
All prescri pti o n a n d o ver t he c o u nter me dicati o ns, i ncl u di n g dietar y a n d her bal s u p ple me nts, 
ta ke n b y s u bjects d uri n g t he 3 0 da ys bef or e baseli ne ( Da y 1) a n d d uri n g t he st u d y will be 
e ntere d o n t he Pri or a n d C o nc o mita nt Me dicati o ns e C R F.  A n y a d diti o ns, deleti o ns, or c ha n ges 
i n t he d ose of t hese me dicati o ns will be e ntere d o n t he e C R F wit h i n dicati o n, d ose, r o ute, an d 
dates of dr u g a d mi nistrati o n.  
T he f oll o wi n g me dicati o ns are pr o hi bite d fr o m 1 4 da ys bef ore Da y 1 ( baseli ne) ( u nless 
ot her wise state d) u ntil t he fi nal st u d y visit ( or u p o n earl y ter mi nati o n) as descri be d bel o w:  
•  A ntie metics:  Met ocl o pra mi de, pr oc hl or perazi ne, a n d pr o met hazi ne.  
•  B ot uli n u m t o xi n:  B ot uli n u m t o xi n i njecti o ns f or treat me nt of T S are pr o hi bite d starti n g 
9 0 da ys pri or t o Da y 1 ( baseli ne) . 
•  C Y P 3 A 4 i n d ucers:  Str o n g i n d ucers of C Y P 3 A 4 (e g, p he n yt oi n, p he n o bar bital, rifa b uti n, 
rifa m pi n, pri mi d o ne, St. J o h n's W ort, carba maze pi ne).  
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 5 
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•  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, itrac o naz ole, ket oc o naz ole, 
clarit hr o m yci n).  
•  D o pa mi ne a g o nists a n d prec urs ors:  D o pa mi ne a g o nists (e g, r o pi nir ole) a n d prec urs ors (e g, 
car bi d o pa/le v o d o pa). 
•  D o pa mi ne a nta g o nist: D o pa mi ne a nta g o nists (e g, pi m ozi de, hal o peri d ol, ari pi praz ole, 
ris peri d o ne, cl oza pi ne, ola nza pi ne, zi prasi d o ne).  De p ot ne ur ole ptics are pr o hi bite d starti n g 
1 5 wee ks pri or t o Da y 1 ( baseli ne). 
•  M o n oa mi ne o xi dase i n hi bit ors ( M A OIs):  All M A OIs (e g, is ocar b o xazi d, p he nelzi ne, 
sele gili ne, tra n ylc y pr o mi ne). 
•  V M A T 2 i n hi bit ors:  V M A T 2 i n hi bit or me dicati o ns (e g, tetra be nazi ne, de utetra be nazi ne, 
reser pi ne) are pr o hi bite d, e xce pt f or st u d y dr u g. 
•  Ca n na bi n oi ds 
•  As nee de d use of t he f oll o wi n g me dicati o ns:  a ntic h oli ner gics, be nz o diaze pi nes, 
a nti ps yc h otics, ps yc h osti m ula nts, m o o d sta bilizers, a nti de pressa nts, o piates,  a n d str o n g 
C Y P 2 D 6 i n hi bit ors.   
9. 8. 2.  
Diet ar y Restricti o ns  
Alc o h ol is pr o hi bite d fr o m 4 8 h o urs bef ore Da y 1 u ntil t he f oll o w- u p visit .  S u bjects are n ot 
per mitte d t o c o ns u me m ore t ha n 6 caffei ne -c o ntai ni n g be vera ges a da y.  Gra pefr uit j uice or 
gra pefr uit pr o d ucts are pr o hi bite d fr o m 7 da ys bef ore Da y 1 u ntil t he f oll o w- u p visit.  
9. 8. 3.  
Ot her Restricti o ns  
E xcessi ve use of t o bacc o a n d ot her pr o d ucts c o ntai ni n g nic oti ne (i ncl u di n g nic oti ne  g u m a n d 
patc hes) are pr o hi bite d d uri n g t he st u d y (ie, fr o m 3 0 da ys bef ore scree ni n g t o t he f oll o w- u p visit  
or u p o n earl y ter mi nati o n ).  S u bjects m ust a gree n ot t o d o nate bl o o d d uri n g t he st u d y, i ncl u di n g 
t he scree ni n g peri o d, a n d f or 4 wee ks after c o m pleti o n of t he st u d y.  Male s u bjects m ust a gree 
t o refrai n fr o m d o nati n g s per m d uri n g t he st u d y a n d f or 9 0 da ys after t he last d ose of st u d y 
dr u g. 
9. 9.  
Wit h dr a w al C riteri a  
S u bjects are free t o disc o nti n ue t heir partici pati o n i n t he st u d y at a n y ti me.  T he i n vesti gat or 
m ust wit h dra w a n y s u bject fr o m t he st u d y if t hat s u bject re q uests t o be wit h dra w n.  
T he i n vesti gat or m ust wit h dra w t he s u bject fr o m t he st u d y if t he s u bject e x perie nces a n y of t he 
f oll o wi n g: 
•  If t he t y pe, fre q ue nc y, or se verit y of a n y A E bec o mes u nacce pta ble/i nt olera ble.  
•  If t he s u bject is u na ble t o t olerate t he starti n g d ose or res u m pti o n of t he pre vi o us d ose.   
•  Q Tc F val ue > 5 0 0 msec (car di ol o gist verifie d)  o n a n y E C G traci n g .  
•  If t he s u bject e x hi bits s uici dal be ha vi or, or s uici dal i deati o n of t y pe 4 (acti ve s uici dal 
i deati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n) or t y pe 5 (acti ve s uici dal i deati o n 
wit h s pecific pla n a n d i nte nt) base d o n t he C -S S R S.  
•  Is l ost t o f oll o w- u p. 
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i de ntit y of t he s u bject’s treat me nt assi g n me nt, or f or re g ulat or y re p orti n g re q uire me nts.  All 
atte m pts t o c o ntact t he N BI Me dical M o nit or (refer t o Secti o n  1 1. 6. 3  f or c o ntact i nf or mati o n) 
m ust be ma de bef ore u n bli n di n g a  s u bject.  T he u n bli n di n g f or m t hat c o ntai ns t he date, ti me, t he 
reas o n t he bli n d was br o ke n, a n d na me of N BI re prese ntati ve c o ntacte d m ust be c o m plete d. 
1 0. 5.  
St u d y D r u g A d mi nistr ati o n  
St u d y dr u g will be a d mi nistere d o nce dail y at be dti me  at h o me u n der t he s u per visi o n of t he 
s u bject’s pare nt/le gal g uar dia n, a n d t he ca ps ules m ust be s wall o we d wit h at least 4 o u nces of 
water , wit h or wit h o ut f o o d, e ver y da y at a p pr o xi matel y t he sa me ti me f or t he d urati o n of t he 
treat me nt peri o d.  If a s u bject f or gets or is u na ble t o ta ke t he st u d y dr u g o n a gi ve n d a y, t he 
s u bject s h o ul d s ki p t hat d ose a n d res u me n or mal d osi n g t he f oll o wi n g da y.  S u bjects or t heir 
pare nts/le gal g uar dia ns  will rec or d t he date a n d ti me of st u d y dr u g d osi n g eac h da y  o n t he la bels 
pr o vi de d o n t he st u d y dr u g pac ka gi n g f or m. 
1 0. 6.  
D r u g C o m pli a nce a n d Acc o u nt a bilit y  
S u bjects will bri n g all u n use d st u d y dr u g  a n d e m pt y st u d y dr u g pac ka gi n g material t o t he ce nter 
at eac h st u d y visit f or dr u g acc o u nta bilit y a n d rec o nciliati o n b y s t u d y ce nter pers o n nel.  A 
c o m plia nce c hec k will be perf or me d b y c o u nti n g t he ca ps ules ret ur ne d at eac h st u d y visit . 
T he q ua ntit y of st u d y dr u g dis pe nse d, use d, a n d ret ur ne d will be rec or de d o n a dis pe nsi n g l o g or 
ot her wise d oc u me nte d.  T he q ua ntit y of st u d y dr u g l ost or destr o ye d m ust als o be acc o u nte d f or 
a n d d oc u me nte d.  T he desi g nate d p har macist or q ualifie d pers o n nel will be res p o nsi ble f or 
mai ntai ni n g acc urate rec or ds of t he q ua ntit y a n d dates of all st u d y dr u g s u p plies recei ve d, 
dis pe nse d, a n d ret ur ne d. 
1 0. 7.  
St u d y D r u g R et ur n  
Writte n d oc u me ntati o n t o acc o u nt f or st u d y dr u g a n d st u d y dr u g materials is ma n dat or y; all 
u n use d st u d y dr u g a n d st u d y dr u g materials m ust be ke pt i n a sec ure l ocati o n f or fi nal 
acc o u nta bilit y a n d rec o nciliati o n.  Ret ur ne d st u d y dr u g a n d st u d y dr u g material m ust be 
acc o u nte d f or o n a st u d y dr u g ret ur n f or m pr o vi de d b y N BI or desi g nee.  T he i n vesti gat or m ust 
pr o vi de a writte n e x pla nati o n f or a n y destr o ye d or missi n g st u d y dr u g or st u d y dr u g materials.  
Ret ur ns will be s hi p pe d t o N BI o r its desi g nee at t he c o m pleti o n of t he st u d y acc or di n g t o 
i nstr ucti o ns pr o vi de d b y N BI or its desi g n ee.  St u d y dr u g ret ur n f or ms m ust be c o m plete d f or 
t he s hi p me nt of ret ur ns a n d se nt wit h t he st u d y dr u g a n d st u d y dr u g materials.  O ne c o p y of t he 
st u d y dru g ret ur n f or m will be retai ne d i n t he i n vesti gat or’s st u d y file.  
All ret ur ne d st u d y dr u g a n d st u d y dr u g materials s h o ul d be st ore d, i n ve nt orie d, rec o ncile d, a n d 
ret ur ne d acc or di n g t o a p plica ble state a n d fe deral re g ulati o ns a n d st u d y pr oce d ures. 
1 1.  
A D V E R S E E V E N T S  
All A Es, w het her o bser ve d b y t he i n vesti gat or, re p orte d b y t he s u bject, n ote d fr o m la b orat or y 
fi n di n gs, or i de ntifie d b y ot her mea ns, will be rec or de d fr o m t he ti me t he s u bject si g ne d t he I C F 
u ntil t he s u bject’s fi nal st u d y visit  ( Wee k 4 0 or u p o n earl y ter mi nati o n). 
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1 1. 1.  
D efi niti o n  
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve t o ha ve a ca usal 
relati o ns hi p wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he 
me dici nal pr o d uct.  
A d verse e ve nts i ncl u de, b ut are n ot li mite d t o:  ( 1) a w orse ni n g or c ha n ge i n nat ure, se verit y, or 
fre q ue nc y of c o n diti o ns prese nt at t he start of t he st u d y; ( 2) s u bject deteri orati o n d ue t o pri mar y 
ill ness; ( 3) i nterc urre nt ill ness; a n d ( 4) dr u g i nteracti o n. 
If at a n y ti me after t he baseli ne visit ( Da y 1), t he s u bject’s res p o nse t o t he s uici dal i deati o n 
secti o n of t he C-S S R S is w orse t ha n t he baseli ne assess me nt it will be d oc u me nte d as a n A E.  
All s uici dal be ha vi ors will be d oc u me nte d as a n A E.  
S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g a b o ut t he occ urre nce of a n y 
s pecific s y m pt o m.  T he i n vesti gat or s h o ul d atte m pt t o esta blis h a dia g n osis of t he e ve nt base d 
o n si g ns, s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n.  I n s uc h cases, t he dia g n osis s h o ul d be 
d oc u me nte d as t he A E a n d n ot t he i n di vi d ual si g ns/s y m pt o ms.  F oll o wi n g q uesti o ni n g a n d 
e val uati o n, all A Es, w het her belie ve d b y t he i n vesti gat or t o be relate d or u nrelate d t o t he st u d y 
dr u g, m ust be d oc u me nte d i n t he s u bject’s me dical rec or ds, i n acc or da nc e wit h t he 
i n vesti gat or’s n or mal cli nical practice a n d o n t he A E e C R F.  Eac h A E is t o be e val uate d f or 
d urati o n, i nte nsit y, fre q ue nc y, seri o us ness, o utc o me, ot her acti o ns ta ke n, a n d relati o ns hi p t o t he 
st u d y dr u g.  
T he f oll o wi n g are n ot c o nsi dere d A Es:  
•  C o n ti n u o us persiste nt disease/s y m pt o m prese nt bef ore dr u g a d mi nistrati o n, u nless it 
u ne x pecte dl y pr o gresses, or i ncreases i n se verit y f oll o wi n g dr u g a d mi nistrati o n . 
•  Rec urre nce of T S s y m pt o ms, u nless w orse ne d fr o m baseli ne. 
•  Pre g na nc y. 
1 1. 2.  
I nte nsit y of A d verse E ve nts 
A d verse e ve nts m ust be gra de d f or i nte nsit y.  A n i nte nsit y cate g or y of mil d, m o derate, or 
se vere, as defi ne d i n Ta ble  3, m ust be e ntere d o n t he A E e C R F.  It s h o ul d be n ote d t hat t he ter m 
“se vere” use d t o gra de i nte nsit y is n ot s y n o n y m o us wit h t he ter m “seri o us.”  
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T a ble 3:  
I nte nsit y of A d verse E ve nts 
Gr a de  
I nt e nsit y 
Mil d  
A n A E t hat is us uall y tr a nsie nt a n d ma y r e q uir e o nl y mi ni mal tr eat me nt or 
t her a pe utic i nt er ve nti o n.  T he e ve nt d o es n ot ge ner all y i nt erfer e wit h us ual acti vities 
of dail y li vi n g.  
M o der at e  
A n A E t hat is us uall y alle viat e d wit h a d diti o nal s p ecific t her a pe utic i nt er ve nti o n.  
T he e ve nt i nt erfer es wit h us ual acti vities of dail y li vi n g, ca usi n g dis c o mf ort b ut 
p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he r esear c h partici p a nt.  
Se vere  
A n A E t hat i nt err u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y affects cli nic al 
st at us, or ma y r e q uir e i nt e nsi ve t her a pe utic i nt er ve nti o n. 
1 1. 3.  
R el ati o ns hi p t o St u d y Dr u g  
T he i n vesti gat or will d oc u me nt his/ her o pi ni o n of t he relati o ns hi p of t he A E t o treat me nt wit h 
st u d y dr u g usi n g t he criteria o utli ne d i n Ta ble  4.  A n A E is dee me d ass ociate d wit h t he use of 
t he st u d y dr u g “if t here is a reas o na ble p ossi bilit y t hat t he dr u g ca use d t he A E” ( ot her wise 
referre d t o as a s us pecte d a d verse reacti o n).  Reas o na ble p ossi bilit y mea ns t here is e vi de nce t o 
s u g gest a ca usal relati o ns hip bet wee n t he dr u g a n d t he A E ( Title 2 1 C F R 3 1 2. 3 2 [a]). 
T a ble 4: 
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g  
Rel ati o ns hi p  
Desc ri pti o n  
Defi nit e  
A r eacti o n t hat f oll o ws a r eas o na ble t e m p or al se q u e nc e fr o m a d mi nistr ati o n of t he dr u g or i n 
w hic h t he dr u g le vel has be e n est a blis he d i n b o d y fl ui ds or tiss ue; t hat f oll o ws a k n o w n or 
e x pe ct e d r es p o nse patt er n t o t he s us pect e d dr u g; a n d t hat is c o nfir me d b y i m pr o ve me nt o n 
st o p pi n g or r e d uci n g t he d osa ge of t he dr ug, a n d r ea p pear a nce of t he r eacti o n o n r e peat e d 
e x p os ur e.  
P ossi ble  
A n a d verse e ve nt i n w hic h t her e is r eas o na ble p ossi bilit y t hat t he dr u g ca use d t he e ve nt.  
Reas o na ble p ossi bilit y mea ns t her e is e vi d e nce t o s u g gest a ca usal r elati o ns hi p bet wee n t he 
dr u g a n d t he a d verse e ve nt. 
U nli kel y  
A r eacti o n t hat f oll o ws a r eas o na ble t e m p or al se q u e nc e fr o m a d mi nistr ati o n of t he dr u g; t hat 
f oll o ws a k n o w n or s us pect e d r es p o nse patt er n t o t he s us pect e d dr u g; b ut t hat c o ul d 
r eas o na bl y be e x plai ne d b y k n o w n c har act eristics of t he s u bject’s cli nical st at e.  
N ot Rel at e d  
A n y e ve nt t hat d o es n ot me et t he a b o ve crit eria.  
1 1. 4.  
R ec o rdi n g A d verse E ve nts  
F or e nr olle d  s u bjects, eac h A E will be liste d as a se parate e ntr y o n a n A E e C R F.  Scree n fail ure 
s u bjects will ha ve A E i nf or mati o n n ote d i n t he s o urce d oc u me ntati o n.  T he i n vesti gat or ( or 
desi g nee) will pr o vi de i nf or mati o n o n dates a n d ti mes of o nset a n d res ol uti o n, i nte nsit y, 
seri o us ness, fre q ue nc y, acti o n(s) ta ke n, c ha n ges i n st u d y dr u g usa ge, relati o ns hi p t o st u d y dr u g, 
a n d o utc o me. 
T he f oll o wi n g cate g ories of me dical e ve nts t hat c o ul d occ ur d uri n g partici pati o n i n a cli nical 
st u d y m ust be re p orte d wit hi n 2 4 h o urs t o N BI or its desi g nee: 
•  Seri o us a d verse e ve nt, i ncl u di n g deat h ( Refer t o Secti o n  1 1. 6 ). 
•  Pre g na nc y (refer t o Secti o n  1 1. 7 ). 
•  E ve nts of s uici dal be ha vi or or s uici dal i deati o n of t y pe 4 (acti ve s uici dal i deati o n wit h 
s o me i nte nt t o act, wit h o ut s pecific pla n) or t y pe 5 (acti ve s uici dal i deati o n wit h s pecific 
pla n a n d i nte nt) base d o n t he C -S S R S.  
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1 1. 5.  
P ost -St u d y F oll o w -U p of A d verse E ve nts  
All A Es, i ncl u di n g cli nicall y si g nifica nt c ha n ges i n E C Gs, p h ysical e xa mi nati o n fi n di n gs, or 
is olate d cli nicall y si g nifica nt la b orat or y fi n di n gs m ust be f oll o we d u ntil t he e ve nt res ol ves, t he 
c o n diti o n sta bilizes, t he e ve nt is ot her wise e x plai ne d, or t he s u bject is l ost t o f oll o w - u p.  If 
res ol ve d, a res ol uti o n date s h o ul d be d oc u me nte d o n t he e C R F.   
A d verse e ve nts o n g oi n g at t he fi nal visit or u p o n earl y ter mi nati o n  will b e f oll o we d f or as l o n g 
as necessar y t o a de q uatel y e val uate t he s u bject’s safet y or u ntil t he e ve nt sta bilizes or res ol ves 
or u nti l t he s u bject is l ost t o f oll o w- u p.  T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w 
u p i ncl u des a n y s u p ple me ntal i n vesti gati o ns as ma y be i n dicate d t o el uci date t he nat ure a n d/ or 
ca usalit y of t he A E.  T his ma y i ncl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals, as is 
practical.  
1 1. 6.  
Seri o us A d verse E ve nts  
All S A Es will be rec or de d fr o m t he ti me t he s u bject has si g ne d t he I C F u ntil 3 0 da ys after t he 
last d ose of st u d y dr u g or t he fi nal st u d y visit, w hic he ver is l o n ger i n d urati o n. 
1 1. 6. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  
A n S A E is a n y A E t hat res ults i n a n y of t h e f oll o wi n g o utc o mes:  
•  Deat h.  
•  A life-t hreate ni n g A E .  Life t hreate ni n g mea ns t hat t he s u bject was, i n t he vie w of t he 
i n vesti gat or or S p o ns or, at i m me diate ris k of deat h fr o m t he reacti o n as it occ urre d.  It d oes 
n ot mea n t hat h y p ot heticall y t he e ve nt mi g ht ha ve ca use d deat h if it occ urre d i n a m ore 
seri o us f or m. 
•  I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.  H os pitalizati o n f or 
electi ve treat me nt or a pree xisti n g  c o n diti o n t hat di d n ot w orse n d uri n g t he cli nical 
i n vesti gati o n is n ot c o nsi dere d a n A E.  H os pitalizati o n or n ursi n g h o me a d missi o n f or t he 
p ur p ose of care gi ver res pite is n ot c o nsi dere d a n A E.  C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n are A Es, a n d  if a c o m plicati o n pr ol o n gs h os pitalizati o n, t he e ve nt is 
c o nsi dere d seri o us.  Treat me nt i n a h os pital e mer ge nc y r o o m is n ot a h os pitalizati o n.  
•  A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o 
c o n d uct n or mal life f u ncti o ns.  
•  A c o n ge nital a n o mal y/ birt h defect.  
•  I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life t hreate ni n g, or re q uire 
h os pitalizati o n.  T hese e ve nts ma y be c o nsi dere d seri o us w he n, base d o n a p pr o priate 
me dical j u d g me nt, t he y ma y je o par dize t he  healt h of t he s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d.  A n y ot her e ve nt t h o u g ht b y t he 
i n vesti gat or t o be seri o us s h o ul d als o be re p orte d, f oll o wi n g t he re p orti n g re q uire me nts 
detaile d i n t his secti o n.  E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias, 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de nc y or dr u g a b u se. 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 0

 
1 1. 6. 2.  
M a n a gi n g Seri o us A d verse E ve nts  
S u bjects e x perie nci n g a n S A E or a n e mer ge nc y sit uati o n will be e xa mi ne d b y a p h ysicia n as 
s o o n as p ossi ble.  T he p h ysicia n i n atte n da nce will d o w hate ver is me dicall y nee de d f or t he 
safet y a n d well- bei n g of t he s u bject.  T he s u bject will re mai n u n der o bser vati o n as l o n g as 
me dicall y i n dicate d.  A p pr o priate la b orat or y st u dies will be c o n d ucte d u ntil all para meters 
ret ur n t o n or mal or are ot her wise e x plai ne d or sta ble.  T he s u bject will be f oll o we d u ntil t he 
S A E res ol ves or  u ntil t he s u bject is me dicall y sta bilize d.  T he i n vesti gat or ( or desi g nee) will 
n otif y t he N BI Me dical M o nit or (a n d t he I R B, if necessar y) i m me diatel y ( wit hi n 2 4 h o urs) of 
t he S A E a n d t he o utc o me of t he S A E. 
If wit hi n t he ti me of i nf or me d c o nse nt u ntil 3 0 da ys after t he last d ose of st u d y dr u g or fi nal 
st u d y visit ( w hic he ver is l o n ger i n d urati o n), a n i n vesti gat or bec o mes a ware of a n S A E, t he n t he 
e ve nt m ust be d oc u me nte d a n d re p orte d as descri be d i n Secti o n  1 1. 6. 3 . 
1 1. 6. 3.  
Re p orti n g Seri o us A d verse E ve nts a n d Ot her I m me di atel y Re p ort a ble E ve nts  
Seri o us A Es a n d ot her i m me diatel y re p orta ble e ve nts ( defi ne d i n Secti o n  1 1. 4 ) m ust be re p orte d 
wit hi n 2 4 h o urs of first k n o wle d ge of t he e ve nt b y st u d y pers o n nel t o t he N BI Me dical M o nit or 
or N BI Dr u g Safet y a n d P har mac o vi gila nce ( D S P V)  De part me nt.  Re p orts of S A Es or 
pre g na ncies s h o ul d be f oll o we d b y a fa x or e mail of t he S A E or Pre g na nc y F or m.  It is 
i m p orta nt t hat t he i n vesti gat or pr o vi des his or her assess me nt of relati o ns hi p t o st u d y dr u g at t he 
ti me of t he i nitial S A E re p ort.  
F or S A Es or Ot her I m me diatel y Re p orta ble E ve nts, c o ntact C D S:  
 
D S P V  tele p h o ne: ( 8 6 6) 6 2 6- 7 7 9 2 or ( 8 5 8) 6 1 7- 7 7 9 2 
 
D S P V  f acsi mile:  ( 8 8 8) 6 1 7- 7 5 5 1 
 
D S P V  e-m ail:   
c ds @ ne ur ocri ne.c o m  
 
N BI Me dic al M o nit or:    
Tele p h o ne:  
 
  
  
  
  
  
  
  
  
 
Cell p h o ne:  
 
1 1. 6. 4.  
E x pe dite d S afet y Re p orts 
Ne ur ocri ne Bi oscie nces, I nc. or its re prese ntati ves will s u b mit a n E x pe dite d Safet y Re p ort f or 
a n y s us pecte d a d verse reacti o n (as defi ne d i n Secti o n  1 1. 3 ) t hat is c o nsi dere d b ot h seri o us a n d 
u ne x pecte d wit hi n 1 5 cale n dar da ys a n d f or a n y u ne x pecte d fatal or life- t hreate ni n g e x perie nce 
wit hi n 7 cale n dar da ys t o t he a p plica ble re g ulat or y a ut h orit y(ies) ; or acc or di n g t o c o u ntr y 
s pecific re g ulati o ns. 
Ne ur o cri ne Bi oscie nces, I nc. or its re prese ntati ves will se n d c o pies of eac h safet y re p ort 
s u b mitte d t o re g ulat or y a ut h orities t o t he i n vesti gat ors.  T he safet y re p ort m ust be s u b mitte d t o 
t he a p pr o priate I R B as s o o n as p ossi ble.  D oc u me ntati o n of t he s u b missi o n t o t he I R B a n d 
recei pt b y t he I R B (if a p plica ble) m ust be retai ne d f or eac h safet y re p ort. 
1 1. 7.  
Pre g n a nc y  
Pre g na nc y is neit her a n A E n or a n S A E u nless t he criteria f or a n S A E are met.  H o we ver, all 
pre g na ncies i n fe male s u bjects w h o recei ve d N BI - 9 8 8 5 4 will be f oll o we d t o assess f or 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 1

 
c o n ge nital a n o mal y.  S u bjects m ust be c o u nsele d at all visits t o c o nti n ue usi n g c o ntrace pti o n 
(see i ncl usi o n criteri o n # 1 0 i n Secti o n  8. 1 ) u ntil 3 0 da ys (fe males) or 9 0 da ys ( males) after t he 
last d ose of st u d y dr u g.  If at a n y ti me bet wee n t he ti me t he s u bject si g ns t he I C F a n d t he last 
st u d y visit a s u bject belie ves s he is pre g na nt, t he s u bject will be i nstr ucte d t o st o p ta ki n g t he 
st u d y me dicati o n a n d ret ur n t o t he st u d y c e nter wit hi n 2 4 h o urs a n d u n der g o a ser u m pre g na nc y 
test t o c o nfir m pre g na nc y. 
All c o nfir me d pre g na ncies, i n s u bjects w h o recei ve d st u d y dr u g, m ust be i m me d iatel y re p orte d 
t o N BI (refer t o Secti o n  1 1. 6. 3  f or c o ntact i nf or mati o n), f oll o we d b y fa x or e mail of t he 
pre g na nc y f or m t o N BI D S P V .  A first tri mester ultras o u n d will be re q uire d f or all c o nfir me d 
pre g na ncies.  Pre g na ncies i n s u bjects w h o recei ve d N BI - 9 8 8 5 4 will be f oll o we d u ntil res ol uti o n 
(ie, ter mi nati o n [ v ol u ntar y or s p o nta ne 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 ase R e p ort F or m  
T he C R F data f or t his st u d y are bei n g c ollecte d wit h a n electr o nic data ca pt ure ( E D C) s yste m 
.  T he E D C s yste m a n d t he 
st u d y-s pecific e C R Fs will c o m pl y wit h Title 2 1 C F R Part 1 1.  T he d oc u me ntati o n relate d t o t he 
vali dati o n of t he E D C s yste m is a vaila ble t hr o u g h t he ve n d or,  
, w hile t he vali dati o n of 
t he st u d y s pecific e C R Fs will be c o n d ucte d b y N BI a n d t he re q uire d d oc u me ntati o n will be 
mai ntai ne d i n t he Trial Master File.  
T he i n vesti gat or will d oc u me nt s u bject data i n his/ her o w n s u bject files.  T hese s u bject files will 
ser ve as s o urce data f or t he st u d y.  All e C R F data re q uire d b y t his pr ot oc ol will be rec or de d b y 
a ut h orize d st u d y pers o n nel i n t he E D C s yste m, wit h t he e xce pti o n of data ca pt ure d i n a n 
electr o nic f or mat, w hic h will be l oa de d electr o nicall y i nt o t he a p pr o priate e C R Fs.  All data 
e ntere d i nt o t he e C R F will be s u p p orte d b y s o urce d oc u me ntati o n.  T he e C R F f or ea c h s u bject 
m ust be re vie we d b y t he i n vesti gat or a n d si g ne d o n t he a p pr o priate e C R F pa ge(s).  T his s h o ul d 
be d o ne as s o o n as p ossi ble after t he s u bject c o m pletes t he st u d y.   
T he i n vesti gat or or a n a ut h orize d me m ber of t he i n vesti gat or's staff will ma ke a n y ne cessar y 
a d diti o ns/c orrecti o ns t o t he e C R F.  All c h a n ge i nf or mati o n, i ncl u di n g t he da te, pers o n 
perf or mi n g t he c orrecti o ns, a n d reas o n f or t he c ha n ge will be a vaila ble via t he electr o nic a u dit 
trail, w hic h is part of t he E D C s yste m.  T he e C R Fs will be re vie we d peri o dicall y f or 
c o m plete ness, le gi bilit y, a n d acce pta bilit y b y N BI ( or desi g nee).  N BI will als o be all o we d 
access t o all s o urce d oc u me nts a n d me dical rec or ds perti ne nt t o t he st u d y i n or der t o verif y 
e C R F e ntries.  T he Pri nci pal I n vesti gat or will re vie w t he e C R Fs f or c o m plete ness a n d acc urac y 
a n d e nter his or her electr o nic si g nat ure o n t he e C R Fs as e vi de nce t here of.  
 will pr o vi de access t o t he N BI  p ortal of t he E D C s yste m f or t he d urati o n of t he st u d y 
t hr o u g h a pass w or d-pr otecte d met h o d of i nter net access.  S uc h access will be re m o ve d fr o m 
i n vesti gat or sites at t he e n d of t he site's partici pati o n i n t he st u d y.  Data fr o m t he E D C s yste m 
will be arc hi ve d o n a p pr o priate data me dia ( C D R O M, etc.) a n d pr o vi de d t o t he i n vesti gat or at 
t hat ti me as a d ura ble rec or d of t he site's e C R F data.  Alt h o u g h n ot re q uire d, t he i n vesti gat or 
ma y  ma ke pa per pri nt o uts fr o m t hat me dia.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 2

 
All cli nical w or k c o n d ucte d u n der t his pr ot oc ol is s u bject t o G C P re g ulati o ns.  T his i ncl u des a n 
i ns pecti o n b y N BI a n d/ or healt h a ut h orit y re prese ntati ves at a n y ti me.  T he Pri nci pal 
I n vesti gat or will a gree t o t he i nspecti o n of st u d y- relate d rec or ds b y healt h a ut h orit y 
re prese ntati ves a n d/ or N BI. 
1 2. 2.  
D at a C a pt ure, R e vie w, a n d V ali d ati o n  
Data e ntere d i n t he E D C s yste m will be verifie d a gai nst t he s o urce data b y N BI ( or d esi g nee).  
A n y discre pa ncies will be c orrecte d o n -li ne b y a ut h orize d site pers o n nel.  After c o m pleti o n of 
t he e ntr y pr ocess, a ut o mate d (c o m p uter-ge nerate d) l o gic c hec ks will r u n i n or der t o i de ntif y 
ite ms s uc h as i nc o nsiste nt st u d y dates.  I n a d diti o n, ma n ual re vie w/c hec ks ma y be perf or me d b y 
N BI o n t he data.  A n y i nc o nsiste ncies/err ors/ o missi o ns i de ntifie d will be se nt t o t he site ( via a n 
electr o nic q uer y) f or t he necessar y c orrecti o ns t o be ma de t o t he e C R F.  O nce e ntere d a n d sa ve d 
i n a n e C R F, data i m me diatel y bec o me part of t he st u d y data base a n d are a vaila ble t o N BI. 
1 2. 3.  
C o di n g Dicti o n aries  
A d verse e ve nts a n d me dical hist or y will be c o de d usi n g t he c h ose n versi o n of t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A).  Pri or a n d c o nc o mita nt me dicati o ns will be 
c o de d usi n g t he c h ose n versi o n of t he W orl d H ealt h Or ga nizati o n Dr u g ( W H O Dr u g) 
Dicti o nar y.  
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  
Descri pti ve a n d i nfere ntial statistics will be use d t o e val uate a n d s u m marize t he data fr o m t his 
st u d y.  T he ter m “ descri pti ve statistics” refers t o t he n u m ber of s u bjects ( n), mea n, me dia n, 
sta n dar d de viati o n ( S D), sta n dar d err or of t he mea n ( S E M), mi ni m u m, a n d ma xi m u m f or 
c o nti n u o u s a n d or di nal cate g orical varia bles; a n d refers t o t he n u m ber a n d perce nta ge of 
s u bjects f or cate g orical varia bles.  T he ter m “i nfere ntial statistics” refers t o h y p ot hesis tests 
w hic h will be perf or me d t o assess differe nces bet wee n t he N BI - 9 8 8 5 4 treat me nt gr o u p a n d t he 
place b o treat me nt gr o u p f or selecte d efficac y varia bles usi n g data f or t he c o m bi ne d wei g ht 
gr o u ps ( < 5 0 k g a n d ≥5 0 k g).  N ote t hat descri pti ve statistics will be prese nte d f or t he c o m bi ne d  
wei g ht gr o u ps a n d f or eac h wei g ht gr o u p se paratel y, u n less s pecifie d ot her wise.  O nl y 
c o m bi ne d  wei g ht gr o u ps will be use d f or i nfere ntial statistics.  
P val ues re p orte d f or h y p ot hesis tests will be t w o -si de d, wit h p val ues < 0. 0 5 bei n g c o nsi dere d t o 
re prese nt a statisticall y si g nifica nt res ult.  P val ues will b e re p orte d wit h o ut a dj ust me nts f or 
m ulti plicit y.  
T he a nal ysis pla n pr o vi de d i n t his pr ot oc ol re prese nts a brief descri pti o n of t he pla n ne d 
a nal yses.  T he c o m pre he nsi ve statistical a nal ysis pla n ( S A P ) will be ge nerate d pri or t o fi nal 
st u d y data base l oc k a n d treat me nt u n bli n di n g.  T he S A P ma y i ncl u de a d diti o nal a nal yses a n d 
data s u m maries n ot descri be d i n t his pr ot oc ol as well as m o dificati o ns t o t he met h o ds of 
a nal ysis descri be d i n t his pr ot oc ol. 
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 3

 
1 3. 1.  
Pri m ar y Esti m a n d  
T he pri mar y esti ma n d is t he differe nce bet wee n N BI- 9 8 8 5 4 a n d place b o i n t he distri b uti o n of 
Ka pla n -Meier Pr o d uct li mit esti mates of ti mes t o l oss of treat me nt res p o nse d uri n g t he 
wit h dra wal p orti o n of t his st u d y i n pe diatric s u bjects wit h T S w h ose tic be ha vi ors are 
s ufficie ntl y c o ntr olle d a n d w h o ha ve t olerate d  N BI - 9 8 8 5 4 d uri n g u p t o 1 2 wee ks of o pe n-la bel 
d ose o pti mizati o n treat me nt a n d w h o ha ve e ntere d t he ra n d o mize d wit h dra wal p orti o n of t his 
st u d y.  A n o n-treat me nt strate g y will be use d f or t he i nterc urre nt e ve nts of st u d y disc o nti n uati o n 
f or reaso ns ot her t ha n t he lac k of efficac y  or a T E A E of w orse ni n g of tics:  ti me t o l oss of 
treat me nt res p o nse f or s u bjects w h o d o n ot ha ve a l oss of treat me nt res p o nse pri or t o 
disc o nti n uati o n will be ce ns ore d at t he ti me of disc o nti n uati o n.   
A d diti o nal details  re gar di n g t he defi niti o n of l oss of treat me nt res p o nse a n d a nal ysis met h o ds 
are pr o vi de d i n Secti o n  1 3. 8 . 
1 3. 2.  
A n al ysis Sets  
A nal ysis sets will be descri be d i n detail  i n t he S A P.  T hese will i ncl u de t he safet y a n al ysis set 
a n d t he f ull a nal ysis set  ( F A S). 
1 3. 3.  
S a m ple Size  
T he sa m ple size f or t his st u d y is base d o n t he pr ojecte d n u m ber of s u bjects e x pecte d t o res p o n d 
t o treat me nt wit h N BI- 9 8 8 5 4 a n d n ot o n a f or mal statistical p o wer calc ulati o n.  
1 3. 4.  
H a n dli n g of Missi n g D at a  
C o n ve nti o ns f or t he ha n dli n g of missi n g data will be descri be d i n t he S A P. 
1 3. 5.  
E nr oll me nt a n d Dis p ositi o n of S u bjects  
A s u m mar y of s u bject dis p ositi o n will be pre pare d t hat dis pla ys t he n u m ber of  s u bjects w h o 
were e nr olle d, w h o were ra n d o mize d, w h o were ra n d o mize d a n d c o m plete d t he 
place b o -c o ntr olle d  wit h dra wal peri o d, w h o were ra n d o mize d a n d c o m plete d t he f oll o w- u p 
peri o d, a n d w h o were n ot ra n d o mize d a n d e n de d st u d y partici pati o n.  T he n u m ber of s u bjects 
w h o disc o nti n ue d fr o m t he st u d y will als o be dis pla ye d b y reas o n f or disc o nti n uati o n. 
1 3. 6.  
D e m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hic data (a ge, ge n der, race, a n d et h nicit y) a n d baseli ne c haracteristics (i ncl u di n g 
hei g ht, wei g ht, b o d y mass i n de x [ B MI ], C Y P 2 D 6 ge n ot y pe stat us, a ge at T S dia g n osis, a n d 
baseli ne val ues f or t he Y G T S S T T S) will be s u m marize d wit h descri pti ve stati stics.  Me dical 
hist or y will be s u m marize d acc or di n g t o Me d D R A S yste m Or ga n Class ( S O C) a n d Preferre d 
Ter m ( P T).  
1 3. 7.  
St u d y D r u g D osi n g a n d C o m pli a n ce  
T he n u m ber a n d perce nta ge of s u bjects w h o are d ose c o m plia nt (at least 8 0 % of e x pecte d 
n u m ber of d oses ta ke n) will be s u m marize d wit h descri pti ve statistics b y visit ( Wee ks 2, 4, 6, 8, 
1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 4, 2 8, 3 2, a n d 3 6).   
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 4

 
T he n u m ber a n d perce nta ge of s u bjects wit h d ose a dj ust me nts will be s u m marize d.  
1 3. 8.  
Effic ac y  D at a  
Descri pti ve a n d i nfere ntial statistics will be use d t o e val uate t he efficac y of N BI - 9 8 8 5 4 relati ve 
t o place b o d uri n g t he wit h dra wal peri o d.  T he pri mar y efficac y e n d p oi nt will be ti me t o l oss of 
treat me nt res p o nse o ver t he c o urse of t he wit h dra wal peri o d (t hr o u g h Wee k 3 6).  L oss of 
treat me nt res p o nse d uri n g t he wit h dra wal peri o d will be defi ne d as : 
•  2 c o nsec uti ve visits wit h 1) a n i ncrease i n t he Y G T S S - T T S of greater t ha n 3 5 % or 7 p oi nts 
fr o m t he wit h dra wal peri o d baseli ne ( Wee k 8, 1 0, or 1 2, de pe n di n g o n w he n t he s u bject was 
ra n d o mize d) a n d 2) a n i ncrease i n C GI -Tics - Se verit y sc ore of ≥2 p oi nts fr o m t he wit h dra wal 
peri o d baseli ne; or, 
•  S u bject disc o nti n uati o n d ue t o lac k of efficac y  or a T E A E of w orse ni n g of tics. 
T he pri mar y efficac y e n d p oi nt (ti me t o l oss of treat me nt res p o nse) will be meas ure d i n da ys 
fr o m ra n d o mizati o n t o t he first assess me nt visit at w hic h t he criteria f or l oss of treat me nt 
res p o nse were  met as meas ure d b y t he Y G T S S -T T S a n d C GI -Tics -Se verit y sc ore or date of 
disc o nti n uati o n d ue t o eit her lac k of efficac y or a T E A E of w orse ni n g of tics a n d will be 
a nal yze d usi n g a l o g-ra n k test stratifie d b y wei g ht gr o u p.  Ka pla n-Meier esti mates of l oss of 
treat me nt res p o nse f or eac h treat me nt gr o u p a n d me dia n, u p per, a n d l o wer q uartiles a n d 
ass ociate d c o nfi de nce i nter vals  will be calc ulate d w here p ossi ble.  
A d diti o nal efficac y e n d p oi nts base d o n t he Y G T S S, P U T S, C GI- Tics - Se verit y, 
C GI -T S -I m pr o ve me nt, a n d C & A-G T S -Q O L data meas ure d at eac h visit will als o be a nal yze d 
f or t his st u d y.  Se veral deri ve d varia bles base d o n t hese meas ures (e g, t he Y G T S S-T T S mea n 
c ha n ge fr o m baseli ne [ Da y 1]) will be s u m marize d wit h descri pti ve statistics a n d a nal yze d 
usi n g mi xe d m o del re peate d meas ures a n d a nal ysis of varia nce or c o varia nce m o dels.  T he S A P 
will pr o vi de a detaile d descri pti o n of t he  deri ve d varia bles a n d met h o ds of a nal ysis f or t hese 
a d diti o nal  efficac y e n d p oi nts.  
1 3. 9.  
Pl as m a D r u g E x p os ure  D at a  
T he plas ma c o nce ntrati o ns of N BI - 9 8 8 5 4 a n d t he acti ve meta b olite N BI - 9 8 7 8 2 will be 
s u m marize d wit h descri pti ve statistics b y visit ( Da y 1 a n d Wee ks 2, 4, 6, 8, 1 0, 1 2, 1 6, 2 0, 2 4, 
2 8, 3 2, 3 6, a n d 4 0 [ or earl y ter mi nati o n]) a n d d ose (last d ose recei ve d pri or t o bl o o d sa m ple 
bei n g dra w n).  C o nce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n will be set e q ual t o zer o 
f or all plas ma c o nce ntrati o n s u m maries.  T hese data will be s u m marize d f or eac h wei g ht gr o u p 
se paratel y. 
1 3. 1 0.  
S af et y D at a  
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es ), cate g orize d b y Me d D R A S O C a n d/ or P T will be 
s u m marize d i n fre q ue nc y ta bles.  T he T E A E s u m mar y ta bles will i ncl u de t he n u m ber a n d 
perce nta ge of u ni q ue s u bjects e x perie nci n g eac h e ve nt .  S u m mar y ta bles will be prese nte d f or 
all T E A Es, se vere T E A Es, T E A Es lea di n g t o st u d y dr u g d ose re d ucti o n, T E A Es lea di n g t o 
earl y disc o nti n uati o n fr o m t he st u d y, a n d S A 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 5

 
A n A E o ver vie w s u m mar y ta ble will be pr o vi de d w hic h s u m marizes t he n u m ber a n d perce nta ge 
of s u bjects wit h a n y T E A E, a n y T E A E lea di n g t o st u d y dr u g d ose re d ucti o n, a n y T E A E lea di n g 
t o st u d y disc o nti n uati o n, a n y S A E, a n d a n y T E A E res ulti n g i n deat h.  T he s u m mar y ta ble will 
als o i ncl u de t he ma xi m u m T E A E i nte nsit y ( mil d, m o derate, se vere) re p orte d f or eac h s u bject.  
Cli nical la b orat or y, vital 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 
Rati n g Scale data will be s u m marize d wit h descri pti ve statistics.  P ote ntiall y cli nicall y 
sig nifica nt ( P C S) val ues f or selecte d cli nical la b orat or y a n d vital si g ns varia bles will be 
s u m marize d.  Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d acc or di n g t o W H O Dr u g 
A nat o mical T hera pe utic C he mical Classificati o n ( A T C) cate g ories.  
1 3. 1 1.  
S oft w are 
Statistical calc ulati o ns a n d s u m maries will be ge nerate d usi n g 
 
. 
1 3. 1 2.  
I nteri m A n al ysis 
A n i nteri m a nal ysis is n ot pla n ne 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.  
Ge ner al Le g al R ef ere nces  
T he st u d y will be carrie d o ut acc or di n g t o t he pr o visi o n of t he U S  C F R, t he U S F D A, a n d t he 
I C H G ui deli nes f or G C P.  All cli nical w or k c o n d ucte d u n der t his pr ot oc ol is s u bject t o G C P 
r ules.  T his i ncl u des a n i ns pecti o n b y N BI or its re prese ntati ve, healt h a ut h orit y, or I R B 
re prese ntati ves at a n y ti me.  T he i n vesti gat or m ust a gree t o t he i ns pecti o n of st u d y-r elate d 
rec or ds b y healt h a ut h orit y re prese ntati ves a n d/ or N BI or its desi g nee. 
1 4. 2.  
I nstit uti o n al R e vie w B o ar d 
T he fi nal a p pr o ve d pr ot oc ol, t he I C F, a n d asse nt d oc u me nt  will be re vie we d b y t he I R B f or t he 
cli nical site.  T he c o m mittee’s decisi o n c o ncer ni n g c o n d uct of t he st u d y will be se nt i n writi n g 
t o t he i n vesti gat or a n d a c o p y will be f or war de d t o N BI.  T he i n vesti gat or m ust a gree t o ma ke 
a n y re q uire d pr o gress re p orts t o t he I R B, as well as re p orts of S A Es, life-t hreate ni n g pr o ble ms, 
or deat h.  
1 4. 3.  
Pr ot oc ol A d here nce a n d A me n d me nts  
T he pr ot oc ol m ust be rea d t h or o u g hl y a n d t he i nstr ucti o ns m ust be f oll o we d e xactl y .  A n y 
c ha n ges i n t he pr ot oc ol will re q uire a  f or mal a me n d me nt.  S uc h a me n d me nts will be a gree d 
u p o n a n d a p pr o ve d i n writi n g b y t he i n vesti gat or a n d N BI.  T he I R B will be n otifie d of all 
a me n d me nts t o t he pr ot oc ol.  A me n d me nts t o t he pr ot oc ol will n ot be i m ple me nte d u ntil writte n 
I R B a p pr o val has bee n recei ve 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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 6

 
1 4. 4.  
R e q uire d D oc u me nts  
T he i n vesti gat or m ust pr o vi de t o N BI or its re prese ntati ves t he f oll o wi n g d oc u me nts bef ore t he 
e nr oll me nt of a n y s u bject ( ori gi nals  s h o ul d be ke pt b y t he i n vesti gat or i n t he i n vesti gat or’s 
re g ulat or y d oc u me nt bi n der): 
•  Si g ne d  c o p y of t he a p pr o ve d pr ot oc ol. 
•  I n vesti gat or’s Br oc h ure ac k n o wle d ge me nt pa ge. 
•  C o m plete d a n d si g ne d state me nt of i n vesti gat or ( F or m F D A 1 5 7 2). 
•  C urric ul u m vitae a n d c urre nt me dical lice nse of t he i n vesti gat or a n d s u bi n vesti gat ors.  
•  Fi na ncial discl os ure i nf or mati o n as re q uire d.  
•  Letter of a p pr o val fr o m t he I R B f or t he pr ot oc ol, c o nse nt f or m, a n d asse nt f or m. 
•  C o p y of t he I R B a p pr o ve d writte n I C F a n d asse nt t o be use d. 
•  La b orat or y d oc u me nts (certificati o ns/accre ditati o ns, n or mal ra n ges) if n ot pr o vi de d b y a 
ce ntral  la b orat or y. 
1 4. 5.  
I nf or me d C o nse nt 
All pare nts or le gal g uar dia ns will pr o vi de i nf or me d c o nse nt wit h si g ne d ( or ver bal, if 
a p plica ble) a n d wit nesse d pe diatric asse nt bef ore t he perf or ma nce of a n y st u d y- relate d 
pr oce d ures. 
Eac h s u bject’s c hart will i ncl u de t he s i g ne d I C F wit h si g ne d a n d wit nesse d pe diatric asse nt  
( u nless asse nt was ver bal) f or st u d y partici pati o n.  W he n t he st u d y treat me nt is c o m plete d a n d 
t he e C R F has bee n m o nit ore d, t he I C F a n d si g ne d a n d wit nesse d pe diatric asse nt will be ke pt i n 
t he i n vesti gat or’s ce ntral st u d y file.  Re g ulat or y a ut h orities ma y c hec k t he e xiste nce of t he 
si g ne d I C F a n d t he si g ne d a n d wit nesse d pe diatric asse nt i n t his ce ntral st u d y f ol der.  
1 4. 6.  
St u d y M o nit ori n g  
T hr o u g h o ut t he c o urse of t he st u d y, t he st u d y m o nit or will m a ke fre q ue nt c o ntacts wit h t he 
in vesti gat or.  T his will i ncl u de e mails, tele p h o ne calls,  a n d o n-site visits .  D uri n g t he o n-site 
visits, t he e C R Fs will be re vie we d f or c o m plete ness a n d a d here nce t o t he pr ot oc ol.  As part of 
t he data a u dit, s o urce d oc u me nts will be ma de a vaila ble f or re vie w b y t he st u d y m o nit or.  T he 
st u d y m o nit or will als o perf or m dr u g acc o u nta bilit y c hec ks a n d ma y peri o dicall y re q uest re vie w 
of t he i n vesti gat or st u d y file t o e ns ure c o m plete ness of d oc u me ntati o n i n all res pects of cli nical 
st u d y c o n d uct. 
U p o n c o m pleti o n of t he st u d y, t he st u d y m o nit or will arra n ge f or a fi nal re vie w of t he st u d y 
files after w hic h t he files s h o ul d be sec ure d f or t he a p pr o priate ti me peri o d.  T he i n vesti gat or or 
a p p oi nte d dele gate will recei ve t he st u d y m o nit or d uri n g t hese o n- site visits, will c o o perate i n 
pr o vi di n g t he d oc u me nts f or i ns pecti o n, a n d res p o n d t o i n q uiries.  I n a d diti o n, t he i n vesti gat or 
will per mit i ns pecti o n of t he st u d y files b y a ut h orize d re prese ntati ves of t he re g ulat or y a ge ncies.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
0 3 Dece m ber 2 0 1 8
C o nfi de ntial
Pa ge 5 7

 
1 4. 7.  
Q u alit y Ass ur a nce  
T he st u d y will be c o n d ucte d i n acc or da nce wit h N BI’s sta n dar d o perati n g pr oce d ures desi g ne d 
t o e ns ure t hat all pr oce d ures are i n c o m plia nce wit h G C P a n d F D A G ui deli nes, a n d acc or di n g t o 
nati o nal la w.  Q ualit y ass ura nce a u dits ma y be perf or me d at t he discreti o n of N BI. 
1 4. 8.  
R ec or d R ete nti o n  
Fe deral re g ulati o ns re q uire t hat rec or ds of dr u g dis p ositi o n, e C R Fs, a n d all re p orts of t his 
i n vesti gati o n s hall be retai ne d b y t he i n vesti gat or f or a mi ni m u m of 2 years after n otificati o n b y 
N BI t hat t he re g ulat or y a ut h orities ha ve bee n n otifie d of t he st u d y's ter mi nati o n, or 2 years after 
a p pr o val of t he mar keti n g a p plicati o n.  If t he i n vesti gat or is u na ble t o retai n t he st u d y 
d oc u me nts f or t he re q uire d a m o u nt of ti me, N BI m ust be i nf or me d of t he i n di vi d ual w h o will be 
ass u mi n g t his res p o nsi bilit y. 
1 4. 9.  
C o nfi de nti alit y  
N BI a n d t he cli nical site affir m a n d u p h ol d t he pri nci ple of t he s u bject’s ri g ht t o pr otecti o n 
a gai nst i n vasi o n of pri vac y.  T hr o u g h o ut t his st u d y, all data will be i de ntifie d o nl y b y a n 
i de ntificati o n n u m ber a n d, w here a p plica ble, s u bject’s i nitials a n d birt h date. 
All i nf or mati o n c o ncer ni n g t his st u d y a n d w hic h was n ot pre vi o usl y p u blis he d is c o nsi dere d 
c o nfi de ntial i nf or mati o n.  T his c o nfi de ntial i nf or mati o n s hall re mai n t he s ole pr o pert y of N BI; it 
s hall n ot be discl ose d t o ot hers wit h o ut writte n c o nse nt of N BI; a n d s hall n ot be use d e xce pt i n 
t he perf or ma nce of t his st u d y. 
T he i nf or mati o n c o m pile d d uri n g t he c o n d uct of t his cli nical st u d y is als o c o nsi dere d 
c o nfi de ntial a n d ma y be discl ose d a n d/ or use d o nl y b y N BI a s dee me d necessar y.  T o all o w t he 
use of t he i nf or mati o n deri ve d fr o m t his cli nical st u d y a n d t o e ns ure c o m plia nce wit h c urre nt 
fe deral re g ulati o ns, t he i n vesti gat or is o bli ge d t o f ur nis h N BI wit h t he c o m plete test res ults a n d 
all data c o m pile 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 satisfact or y recei pt of all re q uire d re g ulat or y d oc u me nts, N BI ( or desi g nee) will arra n ge 
t hat all st u d y material be deli vere d t o t he st u d y site.  S u bject e ntr y s h o ul d n ot be gi n u ntil after 
t he re q uire d re g ulat or y d oc u me nts are c o nfir me d as recei ve d a n d t he I n vesti gat or 
Meeti n g/I nitiati o n Meeti n g has occ urre d.  All pers o n nel e x pecte d t o be i n v ol ve d i n t he c o n d uct 
of t he st u d y will u n der g o orie ntati o n t o i ncl u de re vie w of st u d y pr ot oc ol, i nstr ucti o ns f or e C R F 
c o m pleti o n, A E re p orti n g, a n d o verall res p o nsi bilities i ncl u di n g t h ose f or dr u g acc o u nta bilit y 
a n d st u d y file mai nte na nce. 
If t he st u d y is disc o nti n ue d, all s u bjects s h o ul d u n der g o a c o m plete f oll o w- u p e xa mi nati o n.  
A n y cli nicall y rele va nt fi n di n g, i ncl u di n g la b orat or y val ues of p ote ntial cli nical c o ncer n, a n d 
a d verse e x perie nces will be f oll o we d u ntil t he y res ol ve or ret ur n t o a cli nicall y acce pta ble le vel.  
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 5 
Cli nical St u d y Pr ot oc ol A me n d me nt N o. 2 Fi nal Versi o n
Pa ge 5 8

 
1 6.  
R E F E R E N C E S  
A merica n Ps yc hiatric Ass ociati o n. Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, 
F o urt h E diti o n. 1 9 9 4. 
A merica n Ps yc hiatric Ass ociati o n. Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders, Fift h 
E diti o n. 2 0 1 3. 
Ba xter L R , G u ze B H. Ne ur oi ma gi n g.  I n: K urla n, R. ( E d), Ha n d b o o k of T o urette s y n dr o me a n d 
relate d tic a n d be ha vi oral dis or ders.  R oc hester: Marcel Dec ker I nc.; 1 9 9 3. 
Bra u n A R, St oetter B, Ra n d ol p h C, Hsia o J K, Vla dar K, Ger nert J, et al. T he f u ncti o nal 
ne ur oa nat o m y of T o urette's s y n dr o me: a n F D G- P E T st u d y. I. Re gi o nal c ha n ges i n cere bral 
gl uc ose meta b olis m differe ntiati n g patie nts a n d c o ntr ols. Ne ur o ps yc h o p har mac ol o g y. 1 9 9 3 
Dec; 9( 4): 2 7 7- 9 1. 
Ca va n na A E, Na ni A. T o urette s y n dr o me a n d c o nsci o us ness of acti o n. Tre m or Ot her 
H y per ki net M o v ( N Y). 2 0 1 3 Se p 2 3; 3. 
Ca va n na A E, L u o ni C, Sel vi ni C, Bla n giar d o R, E d d y C M, Sil vestri P R, et al. T he Gilles de la 
T o urette S y n dr o me- Q ualit y of Life Scale f or c hil dre n a n d a d olesce nts ( C & A -G T S -Q O L): 
de vel o p me nt a n d vali dati o n of t he Italia n versi o n. Be ha v Ne ur ol. 2 0 1 3; 2 7( 1): 9 5- 1 0 3. 
C he n JJ, O n d o W G, Das hti p o ur K, S w o pe D M. Tetra be nazi ne f or t he treat m e nt of h y per ki netic 
m o ve me nt dis or ders: a re vie w of t he liter at ure. Cli n T her. 2 0 1 2 J ul; 3 4( 7): 1 4 8 7- 5 0 4. 
C h o ui nar d S, F or d B. A d ult o nset tic dis or ders. J Ne ur ol Ne ur os ur g Ps yc hiatr y. 2 0 0 0 
J u n; 6 8( 6): 7 3 8- 4 3. 
C h o ui nar d G, Mar g olese H C. Ma n ual f or t he E xtra p yr a mi dal S y m pt o m Rati n g Scale ( E S R S).  
Sc hiz o p hr Res. 2 0 0 5 J ul 1 5; 7 6( 2- 3): 2 4 7- 6 5. 
Felli n g RJ , Si n ger H S. Ne ur o bi ol o g y of t o urette s y n dr o me: c urre nt stat us a n d nee d f or f urt her 
i n vesti gati o n. J Ne ur osci. 2 0 1 1 A u g 3 1; 3 1( 3 5): 1 2 3 8 7- 9 5. 
J a n k o vic J, K urla n R. T o urette s y n dr o me: e v ol vi n g c o nce pts. M o v Dis or d. 2 0 1 1 
Ma y; 2 6( 6): 1 1 4 9- 5 6. 
K urla n R. Cli nical practice. T o urette's S y n dr o me. N E n gl J Me d. 2 0 1 0 Dec 9; 3 6 3( 2 4): 2 3 3 2- 8. 
Lec k ma n J F, Ri d dle M A, Har di n M T, Ort SI, S wartz K L, Ste ve ns o n J, et al. T he Yale Gl o bal 
Tic Se verit y Scale: i nitial testi n g of a cli nicia n -rate d scale of tic se verit y. J A m Aca d C hil d 
A d olesc Ps yc hiatr y. 1 9 8 9 J ul; 2 8( 4): 5 6 6- 7 3. 
Lec k ma n J F, Z ha n g H, Vitale A, La h ni n F, L y nc h K, B o n di C, et al. C o urse of tic se verit y i n 
T o urette s y n dr o me: t he first t w o deca des. Pe diatrics. 1 9 9 8 J ul; 1 0 2( 1 Pt 1): 1 4- 9. 
P o urfar M, Fei gi n A, Ta n g C C, Car b o n- C orrell M, B ussa M, B u d ma n C, et al. A b n or mal 
meta b olic brai n net w or ks i n T o urette s y n dr o me. Ne ur ol o g y. 2 0 1 1 Mar 1 5; 7 6( 1 1): 9 4 4- 5 2. 
R o berts o n M M. Gilles de la T o urette s y n dr o me: t he c o m ple xities of p he n ot y pe a n d treat me nt. 
Br J H os p Me d ( L o n d). 2 0 1 1 Fe b; 7 2( 2): 1 0 0 – 7. 
R oess ner V, Sc h oe nefel d K, B use J, Be n der S, E hrlic h S, M ü nc ha u A. P har mac ol o gical 
treat me nt of tic dis or ders a n d T o urette S y n dr o me. Ne ur o p har mac ol o g y. 2 0 1 3 Ma y; 6 8: 1 4 3- 9. 
Pa ge 5 9

 
S h prec her D, K urla n R. T he ma na ge me nt of tics. 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, Mc Farla ne F, Ca va n na A E, Ter mi ne C, M urra y I, Hei de me yer L, et al. T he E n glis h 
versi o n of t he Gilles de la T o urette S y n dr o me -Q ualit y of Life Scale f or C hil dre n a n d 
A d olesce nts ( C & A -G T S - Q O L). J C hil d Ne ur ol. 2 0 1 7 Ja n; 3 2( 1): 7 6- 8 3. 
S wai n J E, Sca hill L, L o m br os o PJ, Ki n g R A, Lec k ma n J F. T o urette s y n dr o me a n d tic dis or ders: 
a deca de of pr o gress. J A m Aca d C hil d A d olesc Ps yc hiatr y. 2 0 0 7 A u g; 4 6( 8): 9 4 7 – 6 8. 
W o o ds D W, Piace nti ni J, Hi mle M B, C ha n g S. Pre m o nit or y Ur ge f or Tics Scale ( P U T S): i nitial 
ps yc h o metric res ults a n d e xa mi nati o n of t he pre m o nit or y ur ge p he n o me n o n i n y o ut hs wit h Tic 
dis or ders. J De v Be ha v Pe diatr. 2 0 0 5 Dec; 2 6( 6): 3 9 7- 4 0 3. 
Pa ge 6 0

 
1 7.  
A P P E N DI C E S  
 
 
 
 
Pa ge 6 1