Conditions: Tourette Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
This is a Phase 2, double-blind, placebo-controlled, randomized withdrawal study to evaluate the safety and maintenance of efficacy of an optimized once-daily (qd) dose of NBI-98854 in pediatric subjects with TS.

Detailed description:

Arms:
arm 1: Participants received valbenazine once daily for up to 12 weeks, depending on if and when randomization occured. The starting dose was 20 mg for participants \<50 kg at baseline and 40 mg for participants ≥50 kg at baseline, and could be escalated in increments of 20 mg every 2 weeks to a maximum of 60 mg for participants \<50 kg and 80 mg for participants ≥50 kg to achieve an optimal dose of valbenazine for each participant. arm 2: Participants received placebo (matching valbenazine) once daily from randomization (Week 8, 10, or 12) through Week 36. Randomization into this arm occurred after treatment with valbenazine once daily through randomization. arm 3: Participants received their optimized dose of valbenazine once daily from randomization (Week 8, 10, or 12) through Week 36. Randomization into this arm occurred after treatment with valbenazine once daily through randomization.

Interventions: intervention 1: Valbenazine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: vesicular monoamine transporter 2 (VMAT2) inhibitor intervention 2: non-active dosage form

Protocol document:
Prot_000.pdf: 
 
 
 
 
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
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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
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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
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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 
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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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
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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
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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 par a 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 or at 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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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 
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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 
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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
C o nfi de ntial
Pa ge 3 8


 
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 
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 9


 
•  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
C o nfi de ntial
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
C o nfi de ntial
Pa ge 4 1


 
•  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 
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 4 2


 
•  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. 
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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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). 
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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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.”  
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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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.  
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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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
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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
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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
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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
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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. 
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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. 
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1 7.  
A P P E N DI C E S  
 
 
 
 
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SAP_001.pdf: 
Ne ur ocri ne Bi os cie nces, I n c.  
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
0 2- A u g - 2 0 1 9
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S T A TI S TI C A L A N A L Y SI S  P L A N  
P H A S E 2  
V E R SI O N: Fi n al  
D A T E O F P L A N:  
0 2 -A u g -2 0 1 9
B A S E D O N:  
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 nal 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 
S T U D Y D R U G:  
N BI - 9 8 8 5 4 
P R O T O C O L N U M B E R:  
N BI - 9 8 8 5 4- T S 2 0 0 5 
S T U D Y TI T L E:  
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 dy t o Ev al u ate t he 
S afety a n d Effic acy of N BI- 9 8 8 5 4 i n Pe di atric S u bjects wit h T o urette Sy n dr o me 
S P O N S O R:  
Ne ur ocri ne Bi oscie nces, I nc.  
2 7 8 0 El Ca mi n o Real 
Sa n Die g o, C A 9 2 1 3 0 
8 5 8- 6 1 7- 7 6 0 0
T his st u d y is bei n g c o n d ucte d i n c o m plia nce wit h g o o d cli nical practice, i n cl u di n g t he arc hi vi n g 
of esse ntial d oc u me nts. 




Ne ur ocri ne Bi os cie nces, I n c.  
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
0 2- A u g - 2 0 1 9
3 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................... 1 
T A B L E O F C O N T E N T S  ................................................................................................................. 3 
LI S T O F T A B L E S  ........................................................................................................................... 6 
1.
LI S T O F A B B R E VI A TI O N S ....................................................................................... 7 
2.
I N T R O D U C TI O N ........................................................................................................ 9 
3.
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  .............................................................. 1 0 
3. 1.  
St u d y O bjecti ves  ......................................................................................................... 1 0 
3. 1. 1.  
Pri mar y O bj ecti ve  ....................................................................................................... 1 0 
3. 1. 2.  
S ec o n dar y O bj ecti ve  ................................................................................................... 1 0 
3. 2.  
Pri mar y Esti ma n d  ....................................................................................................... 1 0 
4.
S T U D Y D E SI G N  ....................................................................................................... 1 1 
4. 1.  
S u m mar y of St u d y Desi g n .......................................................................................... 1 1  
4. 2.  
Sa m ple Size C o nsi derati o ns ....................................................................................... 1 1  
4. 3.  
Ra n d o mizati o n ............................................................................................................ 1 1  
4. 4.  
Cli nical Assess me nts  .................................................................................................. 1 1 
5.
P L A N N E D A N A L Y S E S  ............................................................................................ 1 3 
5. 1.  
I nteri m A nal yses ......................................................................................................... 1 3 
5. 2.  
Fi nal A nal yses  ............................................................................................................ 1 3 
6.
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D
H A N D LI N G  ............................................................................................................... 1 4 
6. 1.  
Ge ner al Statistical Pr oce d ures  .................................................................................... 1 4 
6. 2.  
A nal ysis Sets  ............................................................................................................... 1 4 
6. 2. 1.  
Defi niti o n of A nal ysis Sets  ......................................................................................... 1 5 
6. 2. 2.  
S u m mar y of A n al ysis Sets  .......................................................................................... 1 5 
6. 2. 3.  
A p plicati o n of A nal ysis Sets ...................................................................................... 1 5  
6. 3.  
Baseli ne Defi niti o n  ..................................................................................................... 1 6 
6. 4.  
Deri ve d a n d Tra nsf or me d Data .................................................................................. 1 7  
6. 4. 1.  
St u d y Da y  ................................................................................................................... 1 7 
6. 4. 2.  
C ha n ge fr o m Baseli ne  ................................................................................................. 1 7 
6. 4. 3.  
Ha n dli n g of Earl y T er mi nati o n Visit Data  ................................................................. 1 7 
6. 4. 4.  
P ost-ra n d o mizati o n Ti me p oi nts .................................................................................. 1 8  
6. 5.  
Ha n dli n g of Missi n g Dat a ........................................................................................... 1 9  


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
4 
 
 
  
 
6. 5. 1.  
Missi n g Efficac y E n d p oi nts ........................................................................................ 1 9  
6. 5. 2.  
Missi n g Dates  ............................................................................................................. 1 9 
7.  
S T U D Y P O P U L A TI O N  ............................................................................................. 2 2 
7. 1.  
S u bject D is p ositi o n ..................................................................................................... 2 2 
7. 2.  
Pr ot oc ol De viati o ns .................................................................................................... 2 2  
7. 3.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................ 2 3 
7. 4.  
Me dical Hist or y a n d Me dical C o n diti o ns Prese nt at E ntr y ........................................ 2 3  
7. 5.  
St u d y Dr u g D osi n g a n d C o m plia nce .......................................................................... 2 3  
7. 5. 1.  
E x p os ure t o St u d y Dr u g .............................................................................................. 2 3  
7. 5. 2.  
D ose A dj ust me nts a n d D osa ges.................................................................................. 2 5  
7. 5. 3.  
C o m plia nce ................................................................................................................. 2 5  
8.  
P L A S M A C O N C E N T R A TI O N  D A T A  ..................................................................... 2 6 
9.  
E F FI C A C Y  ................................................................................................................. 2 7 
9. 1.  
Ge ner al C o nsi dera ti o ns ............................................................................................... 2 7 
9. 2.  
Statistical M o dels  ........................................................................................................ 2 7 
9. 2. 1.  
Mi x e d -Effect M o del Re p eate d Meas ures ( M M R M)  .................................................. 2 7 
9. 2. 2.  
A nal ysis of C o varia nce ............................................................................................... 2 7  
9. 3.  
A nal ysis of t h e Pri mar y Efficac y E n d p oi nt ................................................................ 2 8  
9. 3. 1.  
Pri mar y Efficac y A nal ysis  .......................................................................................... 2 8 
9. 3. 2.  
Se nsiti vit y A nal ys es of t he Pri mar y Efficac y Res ults  ................................................ 2 8 
9. 4.  
A nal ysis of t h e Sec o n dar y Efficac y E n d p oi nts .......................................................... 2 9  
9. 4. 1.  
Y G T S S T T S ................................................................................................................ 2 9 
9. 4. 2.  
C GI -Tics -Se verit y  ....................................................................................................... 3 0 
9. 5.  
A na l ysis of t h e E x pl orat or y Efficac y E n d p oi nts ........................................................ 3 1 
9. 5. 1.  
Y G T S S  ........................................................................................................................ 3 1 
9. 5. 2.  
C GI -T S -I m pr o ve m e nt ................................................................................................. 3 2 
9. 5. 3.  
Pre m o nit or y Ur ge f or Tics Scale  ................................................................................ 3 3 
9. 5. 4.  
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  ................................................................................................................. 3 4 
1 0.  
S A F E T Y  ..................................................................................................................... 3 6 
1 0. 1.  
Ge ner al C o nsi derati o ns ............................................................................................... 3 6  
1 0. 1. 1.  
B y -visit S u m maries  .................................................................................................... 3 6 
1 0. 1. 2.  
Treat me nt Peri o d D efi niti o ns  ..................................................................................... 3 7 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
5 
 
 
  
 
1 0. 2.  
A d verse E v e nts  ........................................................................................................... 3 9 
1 0. 2. 1.  
A d verse E v e nts Res ulti n g i n Pre mat ure Disc o nti n uati o n fr o m St u d y........................ 3 9  
1 0. 2. 2.  
A d verse E v e nts Res ulti n g i n St u d y Dr u g D ose Re d ucti o ns ....................................... 4 0  
1 0. 2. 3.  
Deat hs a n d Ot h er Seri o us A d verse E v e nts  ................................................................. 4 0 
1 0. 2. 4.  
S u m maries b y N BI - 9 8 8 5 4 D ose ................................................................................. 4 0 
1 0. 3.  
Cli nical La b or at or y D ata  ............................................................................................ 4 0 
1 0. 4.  
Vital Si g ns  .................................................................................................................. 4 3 
1 0. 5.  
B o d y Wei g ht ............................................................................................................... 4 3  
1 0. 6.  
Electr ocar di o gra m  ....................................................................................................... 4 4 
1 0. 7.  
C ol u m bia -S uici de Se verit y Rati n g Scale C hil dre n’s Versi o ns  .................................. 4 4 
1 0. 8.  
E xtra p yra mi dal  S y m pt o m  Rati n g  Scale - A b bre viate d ................................................ 4 6 
1 0. 9.  
C hil dre n’s Yale- Br o w n O bsessi ve - C o m p ulsi ve Scale ............................................... 4 6 
1 0. 1 0.  
C hil dre n’s De pr essi o n Rati n g Scal e, Re vise d  ............................................................ 4 6 
1 0. 1 1.  
Atte nti o n -Deficit H y peracti vit y Dis or der R ati n g S cale - 5: H o me Versi o n ................. 4 7 
1 0. 1 2.  
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 4 7  
1 1.  
A P P E N DI C E S  ............................................................................................................ 4 9 
1 1. 1.  
Sa m ple  
 C o de....................................................................................................... 4 9  
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
6 
 
 
  
 
LI S T O F T A B L E S  
Ta ble  1: 
List of A b br e viati o ns .................................................................................................... 7 
Ta ble  2: 
Data S u m maries b y A nal ysis Set  ................................................................................ 1 6 
Ta ble  3: 
All o wa ble St u d y D a y Ra n ge f or Earl y Ter mi nati o n Visit Ma p pi n g i n N o n -
Ra n d o mize d S u bjects .................................................................................................. 1 8  
Ta ble 4:  
All o wa ble St u d y D a y Ra n ge f or Earl y Ter mi nati o n Visit Ma p pi n g i n 
Ra n d o mize d S u bjects .................................................................................................. 1 8  
Ta ble  5: 
Ti me p oi nt Defi niti o ns f or P ost- Ra n d o mizati o n S u m maries  ...................................... 1 9 
Ta ble  6: 
Descri pti o n of Tr eat me nt Peri o ds f or E ve nt D ata ...................................................... 3 8  
Ta ble  7: 
P ote ntiall y Cli nicall y Si g nifica nt Criteria f or Cli nical La b orat or y Varia bles  ............ 4 2 
Ta ble  8: 
P ote ntiall y Cli nicall y Si g nifica nt Criteria f or Vital Si g ns Varia bl es i n 
C hil dre n ( 6 t o 1 1 years of a ge) ................................................................................... 4 3  
Ta ble  9: 
P ote ntiall y Cli nicall y Si g nifica nt Criteria f or Vital Si g ns Varia bl es i n 
A d olesce nts ( 1 2 t o 1 7 years of a ge) ............................................................................ 4 3  
 
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
7 
 
 
  
 
1.  
LI S T O F A B B R E VI A TI O N S 
T a ble 1:  
List of A b bre vi ati o ns 
A b bre vi ati o n  
Ter m  
A D H D  
Atte nti o n -Deficit H y peracti vit y Dis or der  
A D H D Rati n g Scale - 5 
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 E  
A d verse e ve nt  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne tra nsa mi nase  
A N C O V A  
A nal ysis of c o varia nce  
A S T  
As partate tra nsa mi nase  
A T C  
A nat o mical T hera pe utic C he mical Classificati o n  
B L Q  
Bel o w t he l o wer li mit of q ua ntificati o n  
B MI  
B o d y mass i n de x 
B U N  
Bl o o d urea nitr o ge n 
C & A -G T S -Q O L  
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 D R S - R 
C hil dre n’s De pressi o n Rati n g Scale - Re vise d  
C GI - S 
Cli nical Gl o bal I m pressi o n of M o ve me nt Se verit y  
C GI -Tics -Se verit y  
Cli nical Gl o bal I m pressi o n of Tics -Se verit y scale  
C GI -T S -I m pr o ve me nt 
Cli nical Gl o bal I m pressi o n of T o urette S y n dr o me- I m pr o ve me nt scale  
C M H  
C oc hra n- Ma ntel -Hae nszel  
C- S S R S  
C ol u m bia- S uici de Se verit y Rati n g Scale  
C Y -B O C S  
C hil dre n’s Yale -Br o w n O bsessi ve C o m p ulsi ve Scale  
D S M -I V or - 5 
Dia g n ostic a n d Statistical Ma n ual of Me n tal Dis or ders, 4t h or 5t h E diti o ns 
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E S R S - A 
E xtra p yra mi dal S y m pt o m Rati n g Scale -A b bre viate d  
E T  
Earl y ter mi nati o n  
F A S  
F ull a nal ysis set  
G G T  
Ga m ma -gl uta m yl tra nsferase  
I P D 
I m p orta nt pr ot oc ol de viati o n  
I W R S 
I nteracti ve We b Res p o nse S yste m 
K M  
Ka pla n -Meier  


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
8 
 
 
  
 
L O C F  
Last o bser vati o n carrie d f or war d  
L S  
Least -s q uares 
M e d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
Mi xe d -effect m o del re peate d meas ures  
N RI  
N o nres p o n der i m p utati o n 
P C S  
P ote ntiall y cli nicall y si g nifica nt  
P T  
Preferre d ter m  
P U T S  
Pre m o nit or y Ur ge f or Tics Scale  
Q T c F  
Fri dericia’s c orrecti o n of Q T i nter val  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S D  
Sta n dar d de viati o n  
S E M  
Sta n dar d err or of t he mea n 
S O C  
S yste m or ga n class  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T S  
T o urette S y n dr o me 
T T S  
T otal Tic Sc ore  
U L N  
U p per li mit of n or mal 
V A S  
Vis ual a nal o g scale  
W H O  
W orl d Healt h Or ga nizati o n 
Y G T S S  
Yale Gl o bal Tic Se verit y Scale  
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
9 
 
 
  
 
2.  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pla n ne d a nal ys es a n d d ata 
dis pla ys t hat will be pre p are d t o s u m marize t he data fr o m t he P hase 2 st u d y descri be d i n 
Ne ur ocri ne Bi os cie nces, I n c. ( N BI) Pr ot o c ol N BI- 9 8 8 5 4- T S 2 0 0 5. 
T his S A P was de vel o pe d i n acc or d a nce wit h I C H E 9 g ui da n ce. All decisi o ns re gar di n g t he fi nal 
a nal ysis, as defi ne d i n t his S A P d oc u me nt, will be ma de pri or t o data b ase l o c k a n d u n bli n di n g of 
t he st u d y tea m t o t he st u d y dat a. F urt her i nf or m ati o n relate d t o st u d y d esi g n a n d met h o d ol o g y 
ca n be f o u n d i n t he pr ot o c ol. 
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
1 0 
 
 
  
 
3.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  
3. 1.  
St u d y O bjecti ves  
3. 1. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his cli nical st u d y is:  
•  T o e val uate t he m ai 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 w al peri o d i n pe diatric s u bjects wit h T o urette S y n dr o m e ( T S) w h o 
ha ve res p o n d e d t o o pe n l a bel N BI- 9 8 8 5 4 treat me nt. 
3. 1. 2.  
Sec o n d ar y O bjecti ve  
T he sec o n d ar y o bjecti ves of t his st u d y are:  
•  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 peri o d. 
•  T o e val uate t he s afet y a n d t olera bilit y of N BI - 9 8 8 5 4 a d mi nistere d o nce d ail y f or u p t o 
3 6 wee ks.  
3. 2.  
Pri m ar y Esti m a n d  
T he pri mar y esti ma n d is t he differ e nce b et 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 -Mei er Pr o d uct li mit esti mates of ti mes t o l oss of treat me nt res p o ns e d uri n g t h e 
wit h dra wal p orti o n of t his st u d y i n pe diatric s u bj ects 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 v e 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 nt ere 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 str ate 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 
reas o ns ot her t h a 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 uatio n will 
be ce ns or e 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 d efi 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 9. 3. 1 .  
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
1 1 
 
 
  
 
4.  
S T U D Y D E SI G N  
4. 1.  
S u m m ar y of St u d y Desi 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 h e 
safet y a n d mai nte n a 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 w ee 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 w ee 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- w ee 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 he ra n ge of 2 0 m g t o 6 0 
m g f or s u bj ects < 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 m ale a n d fe male p e 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 p e n -la b el, 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 h e 6-
wee k bli n de d r a 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 w al 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 h a vi ors. 
4. 2.  
S a m ple Size C o nsi der ati o ns  
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 cal c ulati o n. 
4. 3.  
R a n d o miz ati o n  
At t he e n d of Wee ks 8, 1 0, a n d 1 2, s u bjects w h ose tics ha ve res p o n d e d t o N BI- 9 8 8 5 4 treat me nt 
(t he p h ysi cia 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 b e ha vi ors), a n d w h o are t olerati n g t h eir 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 ass ess me nt, will be ra n d o mize d i n a 1: 1 rati o 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 h e bli n de d ra n d o mizati o n peri od visits at Wee ks 8, 1 0, a n d 1 2; 
t heref or e, 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 d ers, 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 a ntici p ate d t o 
be treat me nt r es 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 h e ra n d o mizati o n 
visits. Ra n d o mizati o n will be stratifie d base d o n s u bject’s wei g ht gr o u p at baseli ne ( < 5 0 k g vs. 
≥5 0 k g).  
4. 4.  
Cli nic al Assess me nts  
Efficac y assess me nts f or T S i ncl u de:  
•  Yale Gl o bal Tic Se v erit y Scale ( Y G T S S),  


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
1 2 
 
 
  
 
•  Cli nical Gl o bal I m pr essi o n of Tics -Se verit y scale ( C GI -Tics -Se v erit y) ,  
•  Cli nical Gl o bal I m pr essi o n of T o urette S y n dr o me- I m pr o ve me nt scale ( C GI-T S -
I m pr o v e me nt),  
•  Pre m o nit or y Ur ge f or Tics Scale ( P U T S), a n d  
•  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).  
Safet y assess me nts i ncl u de: 
•  a d verse e ve nt ( A E) m o nit ori n g,  
•  cli nical la b orat or y tests ( he mat ol o g y, cli nical c he mistr y, a n d uri nal ysis),  
•  ser u m pr olacti n, 
•  he m o gl o bi n A 1c, 
•  vital si g n meas ur e me nts,  
•  p h ysical e x a mi nati o ns, i ncl u di n g w ei g ht,  
•  1 2- lea d electr ocar di o gra m ( E C G),  
•  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), 
•  C hil dre n’s De pr essi o n Rati n g Scal e - 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),  
•  Atte nti o n -Deficit H y peracti vit y Dis or der R ati n g S cale -5: H o me Versi o n ( A D H D Rati n g 
Scale -5), a n d  
•  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).  
Bl o o d sa m ples f or plas m a dr u g a n d meta b olite c o nce ntrati o n a n al ys es are als o c ollecte d. 
S u bjects/care 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 fr o m t he e ve ni n g bef ore t he 
treat me nt peri o d visits w he n t hese sa m ples are c ollecte d. 
T he sc he d ule of assess m e nts ca n be f o u n d i n t he pr ot oc ol. 
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
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5.  
P L A N N E D A N A L Y S E S  
5. 1.  
I nteri m A n al yses 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y. 
5. 2.  
Fi n al A n al yses  
Fi nal a nal yses, as s pecifi e d i n t he pr ot oc ol a n d i n t his S A P, will be perf or me d after t h e st u d y 
data base h as bee n l o c ke d a n d treat me nt c o d e has b ee n u n bli n de d.  


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
1 4 
 
 
  
 
6.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A  A N A L Y S E S A N D 
H A N D LI N G  
All a nal ys es descri be d i n t his pla n are c o nsi dere d a pri ori  a nal yses i n t hat t he y h a ve b ee n defi ne d 
pri or t o l oc ki n g t he st u d y data base a n d u n bli n di n g t he treat me nt gr o u p assi g n me nts. A nal ys es 
defi ne d s u bse q u e nt t o l oc ki n g t he dat a base a n d u n bli n di n g will be c o nsi dere d p ost h oc  a nal yses 
a n d will be a p plie d as e x pl orat or y met h o d ol o g y. A n y p ost h oc  a nal yses will be clearl y i de ntifie d 
i n t he cli nical st u d y r e p ort. 
“ Wit h dra wal Peri o d” f or p ur p oses of a n al ys es i ncl u des t he place b o -c o ntr oll e d wit h dra wal p eri o d 
a n d a n y p ost-r a n d o mizati o n data c ollecte d i n t he bli n de d ra n d o mizati o n peri o d. 
6. 1.  
Ge ner al St atistic al Pr oce d ures  
Descri pti ve a n d i nf er e ntial statistical met h o ds will be use d t o s u m marize t he data fr o m t his 
st u d y. T he ter m “ des cri pti ve statistics” refers t o t he n u m ber of s u bjects, 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 n u merical 
varia bles; a n d r ef ers t o t he n u m ber a n d/ or p erce nta ge of s u bjects f or cate g orical varia bles. 
A d diti o nal d escri pti ve statistics ma y be prese nt e d f or select e d vari a 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 b et 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 gr o u p f or select e d efficac y vari a bles d uri n g t he 
wit h dra wal peri o d. All h y p ot hesis tests will be tests of t he n ull h y p ot hesis of n o differe nce 
bet wee n t he tr eat me nt gr o u ps bei n g c o m pare d v ers us t he t w o-si de d alter nati ve h y p ot hesis t hat 
t here is a diff ere n ce. T h e le vel of si g nifi ca nce ( T y pe I err or) f or declari n g statistical si g nifica n ce 
will be 0. 0 5. 
Descri pti ve statistics will ge n erall y be prese nt e d s e parat el y f or eac h b aseli ne wei g ht gr o u p ( < 5 0 
k g vs. ≥5 0 k g) a n d f or t h e p o ole d wei g ht gr o u ps. T he treat me nt gr o u ps f or all 3 wei g ht gr o u p 
cate g ories are N BI- 9 8 8 5 4 a n d Place b o. T he N BI- 9 8 8 5 4 treat me nt gr o u p i n cl u des all p ossi ble 
st u d y dr u g d oses (ra n gi n g fr o m 2 0 m g t o 8 0 m g). Select ta bles will i ncl u de a n “ All S u bjects” 
treat me nt gr o u p, w hic h c o m bi nes t he N BI- 9 8 8 5 4 a n d Place b o treat me nt gr o u ps. Select ta bles 
will se parate t he N BI - 9 8 8 5 4 treat me nt gr o u p b y dis pe nse d d ose. A si n gle treat me nt gr o u p ( N BI-
9 8 8 5 4) will ge n erall y be use d f or s u m maries t hat i ncl u de pre-ra n d o mizati o n data. 
Se parate s u m mari es ma y be c o m bi ne d i n t he sa me ta ble f or re p orti n g p ur p oses. 
I nfer e ntial statistics will o nl y be prese nte d f or t he p o ole d wei g ht gr o u ps. 
S u m mar y statistics will be dis pla ye d usi n g t h e f oll o wi n g deci mal precisi o n r ules: t he mi ni m u m 
a n d ma xi m u m will ha ve t he sa me n u m ber of deci mal places as t he d ata; t he m ea n, me dia n, S D, 
a n d S E M will ha ve o ne m ore deci mal place t ha n t he data bei n g s u m marize d. Perce nt a ges will be 
dis pla ye d usi n g o ne d eci mal place; per ce nta ges f or 0 c o u nts will be o mitte d. P- val ues will be 
dis pla ye d usi n g 4 deci mal places. T hese r ules ma y be m o difie d if warra nte d, base d o n practical 
c o nsi derati o ns.  
6. 2.  
A n al ysis Sets  
F or p ur p os es of defi ni n g a nal ysis s ets, “e nr olle d s u bjects” refers t o s u bjects e nr olle d i nt o t he 
st u d y at t he D a y 1 visit (i.e., are n ot s cree n fail ures) as s pecifie d b y t he s u bject e nr oll me nt 
electr o nic case re p ort f or m (e C R F).  


Ne ur ocri ne Bi os cie nces, I n c.  
 
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6. 2. 1.  
Defi niti o n of A n al ysis Sets  
6. 2. 1. 1.  
S af et y A n al ysis Set 
T he safet y a nal ysis set will i ncl u de all e nr olle d s u bjects w h o recei ve at least o ne d ose of o pe n -
la bel st u d y dr u g a n d ha v e a n y saf et y data c ollecte d after t he first d ose of o pe n-la bel st u d y dr u g. 
T he safet y a nal ysis set will be use d f or all s u m maries of pre -ra n d o mizati o n safet y data (e. g., A Es 
a n d cli nical la b or at or y data) a n d all plas ma c o nce ntrati o n data.  
6. 2. 1. 2.  
R a n d o mize d S af et y A n al ysis Set 
T he ra n d o mize d sa f et y a nal ysis set will i ncl u de all ra n d o mize d s u bjects w h o recei v e at least o ne 
d ose of ra n d o mize d st u d y dr u g after t h eir res p ecti ve ra n d o mizati o n visit ( Wee k 8, 1 0, or 1 2) a n d 
ha ve a n y safet y dat a c oll ecte d after t he first d ose of ra n d o mize d st u d y dr u g. T he ra n d o mize d 
safet y a n al ysis set will be use d f or all s u m maries of safet y dat a (e. g., A Es a n d cli nical la b orat or y 
data) t hat i ncl u de p ost-ra n d o mizati o n assess me nts. F or s u bjects ra n d o mize d t o re mai n o n acti ve 
treat me nt, select s u m maries will i ncl u de b ot h pre - a n d p ost-ra n d o mizati o n data. 
6. 2. 1. 3.  
F ull A n al ysis Set  
T he f ull a nal ysis set ( F A S) will i ncl u de all s u bjects w h o are ra n d o mize d t o a treat me nt gr o u p a n d 
ha ve at least o ne p ost-ra n d o mizati o n visit w here l oss of treat me nt res p o ns e is a ble t o be assess e d 
(i.e., s u bject has a c ha n ge fr o m ra n d o mizati o n baseli ne f or b ot h Y G T S S T otal Tic Sc ore [ T T S] 
a n d C GI-Tics - Se v erit y or disc o nti n ues fr o m t he st u d y d uri n g t he wit h dra w al peri o d d ue t o eit her 
lac k of efficac y or a treat me nt-e mer ge nt a d vers e e ve nt [ T E A E] of w orse ni n g of tics). T he F A S 
will be use d f or s u m mari es a n d a nal ys es of efficac y dat a. Treat me nt assi g n me nt f or all 
s u m maries a n d a nal ys es usi n g t he F A S will be base d o n t he ra n d o mizati o n sc he d ule. 
6. 2. 2.  
S u m m ar y of A n al ysis Sets 
A s u m mar y of t he n u m ber a n d per ce nta ge of s u bjects i ncl u de d i n (a n d e x cl u de d fr o m, as 
a p plica ble) eac h a nal ysis set will be pr o vi de d. T he n u m ber a n d perce nt a ge of s u bjects e x cl u de d 
fr o m eac h a nal ysis set b y reas o n f or e x cl usi o n will als o be pr o vi de d. N o n-ra n d o mize d a n d 
ra n d o mize d s u bjects ( prese nted b y treat me nt gr o u p) will be s u m marize d se paratel y. A n 
a d diti o nal “ All S u bjects” c ol u m n will be i ncl u de d. S u m maries will be prese nte d f or eac h 
baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d wei g ht gr o u ps usi n g all e nr olle d 
s u bjects. 
6. 2. 3.  
A p plic at i o n of A n al ysis Sets 
S u m maries of s u bject dis p ositi o n a n d ra n d o mizati o n, a nal ysis set i ncl usi o n/e x cl usi o n stat us, a n d 
i m p orta nt pr ot oc ol de viati o ns (I P Ds) will i ncl u de all e nr olle d s u bjects. All ot her s u m maries b y 
a nal ysis s et are i d e ntifie d i n Ta ble  2. 


Ne ur ocri ne Bi os cie nces, I n c.  
 
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T a ble 2:  
D at a S u m m a ries b y A n al ysis Set 
D at a S u m m a r y/ A n al ysis  
A n al ysis Set  
S afet y  
R a n d o mize d 
S afet y  
F A S  
De m o gra p hics  
X  
 
X  
Baseli ne s u bject c haracteristics  
X  
 
X  
Me dical hist or y  
X  
X  
 
St u d y dr u g e x p os ure  
X  
X  
 
St u d y dr u g d ose r e d ucti o ns  
X  
X  
 
St u d y dr u g d osi n g  
 
 
X  
St u d y dr u g c o m plia nce  
 
 
X  
Plas ma c o nce ntr ati o ns  
X  
 
 
L oss of tr eat me nt r es p o nse ( Secti o n 9. 3 ) 
 
 
X  
Y G T S S  
 
 
X  
C GI -Tics -Se verit y  
 
 
X  
C GI -T S -I m pr o ve m e nt 
 
 
X  
P U T S  
 
 
X  
C & A -G T S -Q O L  
 
 
X  
A d verse e ve nts  
X  
X  
 
Cli nical la b orat or y data  
X  
X  
 
He m o gl o bi n A 1 c  
X  
X  
 
Ser u m pr olacti n  
X  
X  
 
Vital si g ns  
X  
X  
 
Wei g ht  
X  
X  
 
E C G  
X  
X  
 
C -S S R S  
X  
X  
 
C Y -B O C S  
X  
X  
 
C D R S -R  
X  
X  
 
E S R S -A  
X  
X  
 
A D H D r ati n g scale -5  
X  
X  
 
Pri or a n d c o nc o mita nt m e dicati o ns  
X  
X  
 
6. 3.  
B aseli ne Defi niti o n  
T w o defi niti o ns of baseli ne will be use d: 
St u d y b aseli ne:  T he assess me nts c ollecte d at t he Da y 1 st u d y visit will ser ve as t he st u d y 
baseli ne val ue f or all ass ess me nts. If a v al ue is n ot a vaila ble at t he D a y 1 visit, t he n t he last 
meas ure me nt c o llecte d o n or pri or t o t he date of t he Da y 1 st u d y visit (e x cl u di n g a n y 
assess me nts t hat occ ur after t he first d ose of o p e n -la bel st u d y dr u g) will ser ve as st u d y b aseli ne.  
Ra n d o mizati o n baseli ne: T he assess me nts c ollecte d at t he ra n d o mizati o n visit ( Wee k 8, 1 0, or 
1 2) will ser ve as t he ra n d o mizati o n baseli ne val ue f or select p ost-ra n d o mizati o n assess me nts. If a 
val ue is n ot a vaila ble at t he ra n d o mizati o n visit, t he n t he last meas ure me nt c ollecte d o n or pri or 
t o t he ra n d o mizati o n date (e x cl u di n g a n y ass ess me nts t hat occ ur aft er t he first d ose of 
ra n d o mize d st u d y dr u g) will ser ve as r a n d o mizati o n baseli ne.  


Ne ur ocri ne Bi os cie nces, I n c.  
 
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6. 4.  
Deri ve d a n d Tr a nsf or me d D at a  
6. 4. 1.  
St u d y D a y  
St u d y d a y is calc ul ate d r elati ve t o t he date of t h e Da y 1 visit. If t he date of i nterest occ urs o n or 
after t he Da y 1 visit, t he n t he st u d y da y will be cal c ulate d as: date of i nterest – date of Da y 1 visit 
+ 1. If t he d ate of i nter est occ urs pri or t o t he Da y 1 visit, t he n t he st u d y d a y will be calc ulate d as: 
date of i nter est – date of Da y 1 visit. 
6. 4. 2.  
C h a n ge f r o m B aseli ne 
C ha n ge fr o m bas eli ne is calc ulate d as ( p ost baseli n e val ue – bas eli ne val ue).  
Perce nt c h a n ge fr o m bas eli ne is calc ulate d as (c h a n ge fr o m baseli ne/ b aseli ne val ue * 1 0 0).  
If eit her t he b aseli ne or p ost baseli ne val ue is missi n g, t he c ha n ge fr o m baseli ne a n d/ or perce nt 
c ha n ge fr o m baseli ne will als o be missi n g.  T he perce nt c h a n ge fr o m baseli ne will als o be 
missi n g if t he baseli ne v al ue is e q ual t o zer o.  
6. 4. 3.  
H a n dli n g of E arl y Ter mi n ati o n Visit D at a 
A n earl y ter mi nati o n ( E T) visit occ urs w he n a s u bject disc o nti n ues fr o m t he st u d y pri or t o 
c o m pleti n g t he sc h e d ule d Wee k 4 0 visit or is n ot eli gi ble f or ra n d o mizati o n b y Wee k 1 2. T h e 
data c ollecte d at E T visits will be i ncl u de d i n s u m mar y t a bles a n d fi g ures i n acc or d a nce wit h t he 
E T visit ma p pi n g sc he me descri be d i n t his secti o n.  
A n E T visit will be ma p pe d t o t he ne xt sc he d ule d st u d y visit if it occ urs wit hi n 7 da ys pri or t o 
a n d 6 da ys aft er t he e x pecte d st u d y d a y of t he n e xt sc he d ule d visit ( wit h t he re q uire me nt t hat t he 
sc he d ule d visit pri or t o t he E T visit was act uall y c o m plete d b y t he s u bject) f or visits t hat are 
e x pecte d t o occ ur e ver y 2 wee ks a n d wit hi n 1 4 da ys pri or t o a n d 1 3 da ys after f or visits t hat are 
e x pecte d t o occ ur e ver y 4 wee ks.  
Earl y ter mi nati o n visit data w hic h ar e n ot ma p pe d t o a sc he d ule d visit will n ot be i ncl u de d i n b y-
visit a nal yses a n d s u m maries. T he y will be i ncl u de d i n a n y a nal yses t hat l o o k acr oss all a v aila ble 
assess me nts d uri n g t h e tr eat me nt peri o d, i ncl u di n g u nsc h e d ule d visits. T he y will als o be i ncl u de d 
i n a n y a p plica ble b y-s u bj ect data listi n gs. 
Ta ble  3 a n d T a ble  4 dis pla y t h e all o wa ble st u d y da y  ra n ge f or eac h sc h e d ule d visit f or E T visit 
ma p pi n g p ur p os es f or n o n-ra n d o mize d a n d ra n d o mize d s u bjects, res pecti v el y.  
 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
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0 2- A u g - 2 0 1 9 
 
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T a ble 3:  
All o w a ble St u d y D a y R a n ge f or E arl y Ter mi n ati o n Visit M a p pi n g i n N o n-
R a n d o mize d S u bjec ts 
Sc he d ule d Visit  
T ar get St u d y D a y  
Visit Wi n d o w  
( St u d y D a y R a n ge) 
Wee k 2  
1 4  
7 -2 0  
Wee k 4  
2 8  
2 1 -3 4  
Wee k 6  
4 2  
3 5 -4 8  
Wee k 8  
5 6  
4 9 -6 2  
Wee k 1 0  
7 0  
6 3 -7 6  
Wee k 1 2  
8 4  
7 7 -9 0  
F oll o w -u p 1 
9 8 -1 1 2  
> 9 0  
1 S u bj ects w h o are n o nres p o n ders at t he W ee k 1 2 visit a n d w h o were n ot pre vi o usl y ra n d o mi ze 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 n E T visit.  
T a ble 4:  
All o w a ble St u d y D a y R a n ge f or E arl y Ter mi n ati o n Visit M a p pi n g i n 
R a n d o mize d S u bjects  
Sc he d ule d Visit  
T ar get St u d y D a y  
Visit Wi n d o w  
( St u d y D a y R a n ge) 
Wee k 1 0
1 
7 0  
6 3 -7 6  
Wee k 1 2
2 
8 4  
7 7 -9 0  
Wee k 1 4  
9 8  
9 1 -1 0 4  
Wee k 1 6  
1 1 2  
1 0 5 -1 1 8  
Wee k 1 8  
1 2 6  
1 1 9 -1 3 2  
Wee k 2 0  
1 4 0  
1 3 3 -1 4 6  
Wee k 2 4  
1 6 8  
1 5 4 -1 8 1  
Wee k 2 8  
1 9 6  
1 8 2 -2 0 9  
Wee k 3 2  
2 2 4  
2 1 0 -2 3 7  
Wee k 3 6  
2 5 2  
2 3 8 -2 6 5  
Wee k 4 0  
2 8 0  
> 2 6 5  
1 O nl y p ossi ble f or s u bj ects ra n d o mize d at W ee k 8.  
2 O nl y p ossi ble f or s u bj ects ra n d o mize d at W ee ks 8 or 1 0.  
6. 4. 4.  
P ost -r a n d o miz ati o n Ti me p oi nts  
Ti me p oi nts f or p ost- ra n d o mizati o n s u m maries will be defi ne d bas e d o n a p pr o xi mate ti me si nce 
ra n d o mizati o n. Ta ble  5 pr o vi des a list of t he st u d y visits t hat c o ntri b ute t o eac h defi n e d ti me p oi nt 
base d o n t he s u bject’s ra n d o mizati o n visit ( Wee k 8, 1 0, or 1 2). 




Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
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0 2- A u g - 2 0 1 9 
 
2 0 
 
 
  
 
T he i m p utati o n r ules f or first ra n d o mize d d ose dat e are as f oll o ws: 
•  If t he date of t he first d os e of ra n d o mize d st u d y dr u g is c o m pletel y missi n g  or if b ot h t he 
da y a n d  m o nt h are missi n g, t he n t he ra n d o mizati o n date will be use d. 
•  If o nl y t h e da y is missi n g, t he date will be i m p ute d as t he ra n d o mizati o n date if t he m o nt h 
a n d year of t he first d ose of ra n d o mize d st u d y dr u g dat e matc h t he m o nt h a n d year of 
ra n d o mizati o n; if t he m o nt h a n d year o cc ur after t he ra n d o mizati o n date, t he missi n g da y 
will be i m p ute d as t he first da y of t h e m o nt h.  
T he i m p utati o n r ules f or last d ose date are as f oll o ws: 
If t he date of t he last d os e of st u d y dr u g is missi n g i n n o n-ra n d o mize d s u bjects, t he n t he last d ose 
date will be i m p ute d as t he earliest of:  
•  t he Wee k 1 2 visit date,  
•  st u d y disc o nti n uati o n dat e f or s u bjects w h o dis c o nti n ue bef ore Wee k 1 2,  
•  t he last visit ( u p t o Wee k 1 0) pri or t o disc o nti n uati o n + 1 7 or t he date of a n u nsc he d ule d 
d ose re d ucti o n + 1 7, w hic he ver occ urs later. 
If t he date of t he last d os e of st u d y dr u g is missi n g i n ra n d o mize d s u bjects, t he n t he last d ose date 
will be i m p ute d as t he earliest of:  
•  t he Wee k 3 6 visit date,  
•  st u d y disc o nti n uati o n dat e f or s u bjects w h o dis c o nti n ue bef ore Wee k 3 6,  
•  t he last visit pri or t o disc o nti n uati o n + n u m ber of d oses dis pe nse d at t he visit or t he date 
of a n u nsc he d ul e d d ose r e d ucti o n + n u m ber of d oses dis pe nse d, w hic he v er occ urs later.  
6. 5. 2. 2.  
St art D at es f or A d verse E ve nts a n d Pri or a n d C o nc o mit a nt Me dic ati o ns  
Missi n g a n d i nc o m plete ( “ partial”) dates f or A Es a n d c o nc o mita nt me dicati o ns will be i m p ute d 
f or t he p ur p ose of esti mati n g t he ti me of t he e v e nt or me dicati o n usa ge i n relati o ns hi p t o st u d y 
treat me nt. A n y data listi n gs will dis pla y t h e ori gi nal dates as re p orte d i n t he data base.   
T he i m p utati o n r ules f or A E start dates are as f oll o ws:  
•  If t he date is c o m plet el y missi n g, t he date will be i m p ute d as t he date of t h e first d ose of 
st u d y dr u g; 
•  If o nl y t h e da y is missi n g, t he date will be i m p ute d as t he date of t h e first d ose of st u d y 
dr u g if t h e m o nt h a n d year of t he A E st art date m atc h t he m o nt h a n d year of t he first d ose 
of st u d y dr u g; ot her wise, t he missi n g da y will b e i m p ute d as t he first da y of t he m o nt h; 
•  If b ot h t he da y a n d m o nt h are missi n g, t he d ate will be i m p ute d as t he date of t he first 
d ose of st u d y dr u g if t he A E start date is i n t he sa me year as t he first d ose of st u d y dr u g; 
ot her wise, t he missi n g d a y a n d m o nt h will be i m p ute d as 0 1 J a n uar y; 
•  If a n y of t he a b o ve i m p ut ati o ns res ult i n a start dat e t hat is later t ha n a n e xisti n g ( n ot 
i m p ute d) e n d date f or t he e ve nt, t he start dat e will be i m p ute d as t he e n d dat e. 
T he i m p utati o n r ules f or c o nc o mita nt me dicati o n s tart dates are as f oll o ws: 


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•  If t he date is c o m plet el y missi n g, t he date will be i m p ute d as 0 1 J a n uar y i n t he year of t he 
s u bject’s scree ni n g vital si g ns assess me nt; 
•  If o nl y t h e da y is missi n g, t he date will be i m p ute d as t he date of t h e first d ose of st u d y 
dr u g if t h e c o nc o mita nt me dicati o n start date is i n t he sa me m o nt h a n d year as t he first 
d ose of st u d y dr u g; ot her wise, t he missi n g da y will be i m p ute d as t he first d a y of t he 
m o nt h; 
•  If b ot h t he da y a n d m o nt h are missi n g, t he d ate will be i m p ute d as t he date of t he first 
d ose of st u d y dr u g if t he c o nc o mita nt me dicati o n start date is i n t he sa me year as t h e first 
d ose of st u d y dr u g; ot her wise, t he missi n g da y a n d m o nt h will be i m p ute d as 0 1 J a n uar y; 
•  If a n y of t he a b o ve i m p ut ati o ns res ult i n a start dat e w hich is later t ha n a n e xisti n g ( n ot 
i m p ute d) me dicati o n st o p date, t he start dat e will be i m p ute d as t he st o p dat e. 


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7.  
S T U D Y P O P U L A TI O N  
7. 1.  
S u bject Dis p ositi o n  
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 recei ve d at least o ne d os e of st u d y me dicati o n, w h o were ra n d o mize d t o eac h 
treat me nt gr o u p, w h o w ere 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 p eri o d, 
w h o wer e 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 w ere 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. 
T hese s u m maries will be prese nte d f or eac h bas eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or 
t he p o ole d wei g ht gr o u ps usi n g all e nr olle d s u bjects. T he f oll o wi n g gr o u ps will be use d: s u bjects 
e nr olle d b ut n ot ra n d o mi ze d; s u bjects ra n d o mize d t o place b o; s u bjects ra n d o mize d t o N BI-
9 8 8 5 4; all s u bjects.  
A listi n g of ra n d o mize d s u bjects will als o be pr o vi de d a n d will i ncl u de s u bject I D, i nf or m e d 
c o nse nt/asse nt date, e nr oll me nt date, ra n d o mizati o n date, baseli ne w ei g ht gr o u p, a n d ra n d o mize d 
treat me nt gr o u p.  
7. 2.  
Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns descri be d i n t he st u d y- s pecific Pr ot oc ol De viati o n Pla n will be e ntere d i nt o 
t he st u d y data b ase a n d use d t o i de ntif y I P Ds. I m p orta nt pr ot oc ol de viati o ns are pr ot o c ol 
de viati o ns t hat mi g ht si g nifica ntl y aff ect t he c o m plete ness, acc urac y a n d/ or relia bilit y of t h e 
st ud y data or t hat mi g ht si g nifica ntl y affect a s u bject’s ri g hts, s afet y, or well -bei n g. A n 
assess me nt of I P Ds will be perf or me d b y a c o m mittee c o m p ose d of N BI Cli nical De vel o p me nt 
pr oject tea m me m bers pri or t o data base l oc k a n d u n bli n di n g of t he ra n d o mize d t reat me nt 
assi g n me nts. T his c o m mittee will re vie w a listi n g of all pr ot oc ol de viati o ns re p orte d i n t he st u d y 
data base a n d deter mi ne w hic h de viati o ns are I P Ds. I m p ort a nt pr ot oc ol de viati o ns i ncl u de, b ut are 
n ot li mite d t o, t he f oll o wi n g:  
•  Fail ure t o o btai n i nf or m e d c o nse nt fr o m t he s u bject pri or t o perf or mi n g a n y st u d y 
pr oce d ur es. 
•  De viati o ns fr o m ke y i ncl usi o n/e x cl usi o n criteria. 
•  Use of pr o hi bite d c o n c o mita nt me dicati o ns. 
•  Err or i n dr u g dis pe nsi n g w hic h res ults i n a s u bject n ot recei vi n g i nte n de d ra n d o mize d 
treat me nt. 
•  Si g nifica nt de viati o n fr o m pr ot oc ol-s pecifie d d osi n g re gi me n. 
A s u m mar y of t he n u m ber a n d per ce nta ge of s u bjects wit h I P Ds b y de vi ati o n cate g or y will be 
pr o vi de d. Se par ate s u m maries will be pres e nte d f or eac h b aseli ne w ei g ht gr o u p ( < 5 0 k g vs. ≥5 0 
k g) a n d f or t h e p o ole d w ei g ht gr o u ps usi n g all e nr olle d s u bjects. T he f oll o wi n g gr o u ps will be 
use d: s u bjects e nr olle d b ut n ot ra n d o mize d; s u bjects ra n d o mize d t o place b o; s u bjects ra n d o mize d 
t o N BI- 9 8 8 5 4; all s u bjects.  
All pr ot oc ol de viati o ns e ntere d i nt o t he st u d y d ata base will be pres e nte d i n a data listi n g. A n y 
I P Ds will be fl a g ge d i n t he listi n g. 


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7. 3.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d baseli n e c har acteristics data will be s u m marize d usi n g descri pti ve statistics f or 
c o nti n u o us varia bles, a n d fre q ue n c y c o u nts a n d p erce nta ges f or cate g ori cal varia bles. Se parate 
s u m maries will be prese nte d f or eac h bas eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t h e 
p o ole d wei g ht gr o u ps usi n g b ot h t he safet y a n al ysis set a n d t he F A S. T h e F A S s u m mar y will be 
prese nte d b y tr eat me nt a n d will i ncl u de a n a d diti o nal “ All S u bjects” c ol u m n.  
De m o gra p hics i ncl u d e: 
•  A ge ( years)  
•  A ge cat e g or y ( c hil d [ a ges 6 - 1 1], a d olesce nt [a ges 1 2- 1 7])  
•  Se x  
•  Et h nicit y  
•  Race  
St u d y b aseli ne s u bject c h aract eristics i ncl u de:  
•  A ge at T S dia g n osis ( years) 
•  Baseli ne v al ue of T T S  
•  Hei g ht ( m eas ur e d at scr ee ni n g; c m)  
•  Wei g ht ( pres e nte d i n b ot h p o u n ds a n d kil o gra ms) 
•  B o d y mass i n de x ( B MI; meas ure d at scree ni n g; k g/ m 2) 
•  C Y P 2 D 6 ge n ot y pe stat us 
7. 4.  
Me dic al Hist or y a n d Me dic al C o n diti o ns Prese nt at E ntr y  
Me dical hist or y will be s u m marize d i n fre q ue nc y ta bles ( n u m ber a n d p erce nta ge of s u bjects) b y 
Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) S yste m Or ga n Class ( S O C) a n d 
Preferre d Ter m ( P T), wit h S O Cs a n d P Ts wit hi n eac h S O C s orte d al p ha b eticall y. Se p arat e 
s u m maries will be prese nte d f or eac h bas eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t h e 
p o ole d wei g ht gr o u ps usi n g t he safet y a n al ysis set a n d t he ra n d o mize d safet y a n al ysis s et. T he 
ra n d o mize d safet y a n al ysis set will be prese nte d b y treat me nt a n d will i ncl u de a n a d diti o nal “ All 
S u bjects” c ol u m n. 
7. 5.  
St u d y Dr u g D osi n g a n d C o m pli a nce  
7. 5. 1.  
E x p os ure t o St u d y Dr u g  
T he f oll o wi n g e x p os ure d urati o ns will be calc ulat e d: 
•  Pre -ra n d o mizati o n: first ra n d o mize d d ose date – first o pe n-la bel d ose d ate in s u bjects 
w h o are ra n d o mize d; last d ose date – first o pe n-la bel d ose date + 1 i n s u bjects w h o 
are n ot r a n d o mize d, or w h o are ra n d o mize d b ut ne ver recei ve d a d ose of ra n d o mize d 
st u d y dr u g. 
•  P ost-ra n d o mizati o n: last d ose date – first ra n d o mize d d ose date + 1 


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•  E ntire st u d y: last d ose date – first o pe n-la b el d ose date + 1 
D urati o n of e x p os ure ( n u m ber of da ys) will be s u m marize d wit h descri pti ve statistics. A si n gle 
treat me nt gr o u p ( N BI- 9 8 8 5 4) will be use d f or t he pre-ra n d o mizati o n e x p os ure usi n g t h e safet y 
a nal ysis s et. P ost-ra n d o mizati o n e x p os ure will be s u m marize d b y treat me nt gr o u p usi n g t he 
ra n d o mize d safet y a n al ysis set. E ntire st u d y e x p os ure will be s u m marize d f or s u bjects i n t he 
ra n d o mize d safet y a n al ysis set w h o are ra n d o mize d t o N BI- 9 8 8 5 4. 
T he n u m ber a n d p erce nta ge of s u bjects wit hi n t he f oll o wi n g e x p os ure cate g ories will als o be 
prese nte d:  
Pre -ra n d o mizati o n 
•  > 0 t o < 2 wee ks 
•  ≥2 t o < 4 wee ks  
•  ≥4 t o < 6 wee ks  
•  ≥6 t o < 8 wee ks  
•  ≥8 t o < 1 0 wee ks  
•  ≥1 0 t o < 1 2 wee ks  
•  ≥1 2 wee ks  
P ost-ra n d o mizati o n 
•  > 0 t o < 2 wee ks 
•  ≥2 t o < 4 wee ks  
•  ≥4 t o < 6 wee ks  
•  ≥6 t o < 8 wee ks  
•  ≥8 t o < 1 0 wee ks  
•  ≥1 0 t o < 1 2 wee ks  
•  ≥1 2 t o < 1 6 wee ks  
•  ≥1 6 t o < 2 0 wee ks  
•  ≥2 0 t o < 2 4 wee ks  
•  ≥2 4 t o < 2 8 wee ks  
•  ≥2 8 wee ks  
E ntire St u d y  
•  > 0 t o < 8 wee ks 
•  ≥8 t o < 1 0 wee ks  
•  ≥1 0 t o < 1 2 wee ks  
•  ≥1 2 t o < 1 6 wee ks  


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•  ≥1 6 t o < 2 0 wee ks  
•  ≥2 0 t o < 2 4 wee ks  
•  ≥2 4 t o < 2 8 wee ks  
•  ≥2 8 t o < 3 2 wee ks  
•  ≥3 2 t o < 3 6 wee ks  
•  ≥3 6 wee ks  
Se parate s u m mari es will be prese nt e d f or eac h b as eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or 
t he p o ole d wei g ht gr o u ps. 
7. 5. 2.  
D ose A dj ust me nts a n d D os a ges 
Descri pti ve statistics will be prese nt e d f or t he st u d y dr u g d os a ge recei ve d i m me diatel y pri or t o 
ra n d o mizati o n. Res ults will be prese nte d b y treat me nt gr o u p usi n g t he F A S a n d will i ncl u de a n 
a d diti o nal “ All S u bjects” c ol u m n . F or s u bjects ra n d o mize d t o N BI- 9 8 8 5 4, descri pti ve statistics 
will als o be prese nte d f or st u d y dr u g d osa ges at t h e Wee k 3 6 visit a n d f or t he last d ose recei ve d 
pri or t o st u d y c o m pleti o n or earl y disc o nti n uati o n. T he n u m ber a n d p erce nt a ge of s u bjects 
recei vi n g eac h d os a ge will als o be prese nte d.  
T he n u m ber a n d p erce nta ge of s u bjects wit h a d os e re d ucti o n at a n y ti me o n or pri or t o 
ra n d o mizati o n, or earl y disc o nti n uati o n i n n o n-ra n d o mize d s u bjects, will be prese nte d usi n g t he 
safet y a n al ysis set. T h e n u m ber a n d perce nt a ge of s u bjects wit h a d ose re d u cti o n at a n y ti me 
after r a n d o mizati o n will be prese nt e d b y treat me nt gr o u p usi n g t he ra n d o mize d safet y a nal ysis 
set.  
All s u m maries descri be d i n t his secti o n will be prese nte d f or eac h b aseli ne wei g ht gr o u p ( < 5 0 k g 
vs. ≥5 0 k g) a n d f or t he p o ole d wei g ht gr o u ps.  
7. 5. 3.  
C o m pli a nce  
S u bjects w ill 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 nt er 
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 st u d y ce nter pers o n nel. A 
c o m plia nce c h ec 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 s t u d y visit. T he 
site will t he n e nter w het h er t he s u bject’s d osi n g c o m plia nce si nce t he pre vi o us visit was ≥8 0 % 
i nt o t he e C R F. 
T he n u m ber a n d p erce nta ge of s u bjects i n eac h treat me nt gr o u p w h o are d osi n g c o m plia nt will 
be prese nt e d f or eac h p ost-ra n d o mizati o n ti me p oi nt ( defi ne d i n Ta ble  5). Se parate s u m mari es 
will be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d wei g ht gr o u ps 
usi n g t he F A S.   
 


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8.  
P L A S M A C O N C E N T R A TI O N  D A T A  
T he plas ma c o n ce ntrati o ns of N BI - 9 8 8 5 4 a n d its 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 a n d b y t he last d osa ge recei v e d pri or t o t he bl o o d 
sa m ple bei n g dra w n ( 2 0, 4 0, 6 0, or 8 0 m g). T he d ose at t he Wee k 4 0 visit will reflect t he last 
d ose t he s u bject recei ve d d uri n g t he st u d y treat me nt peri o d (i.e., t he d osa ge at t he s u bject’s Wee k 
3 6 visit). T hese s u m mar y ta bles will be prese nte d f or eac h baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 
k g) o nl y. T h ere will n ot be a p o ole d w ei g ht gr o u ps s u m mar y.  
T he s u m mar y ta bles will als o be ge nerate d f or C Y P 2 D 6 p o or meta b olizers vs. n o n- p o or 
meta b olizers wit hi n eac h baseli ne wei g ht gr o u p.   
C o nce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n ( B L Q) 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 h e l o wer li mits of q ua ntificati o n are as f oll o ws: (a) N BI -
9 8 8 5 4: 1. 0 0 n g/ m L a n d ( b) N BI - 9 8 7 8 2: 0. 1 0 0 n g/ m L. 
T he f oll o wi n g a d diti o nal descri pti ve statistics will be i ncl u de d i n t he plas ma c o nce ntrati o n 
s u m mar y ta bl es: (a) t he n u m ber of plas ma c o n ce ntrati o n val ues greater t h a n or e q ual t o t he l o wer 
li mit of q ua ntificati o n, ( b) t he ge o metric m ea n, a n d (c) t he ge o metric c o effi cie nt of vari ati o n 
( %). 
Plas ma c o nce ntr ati o ns of eac h a nal yte will be s u m marize d wit h b o x pl ots b y N BI - 9 8 8 5 4 d osa ge 
at eac h visit. T hese w ill be prese nt e d f or eac h b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g). 
T he safet y a nal ysis set will be use d f or all plas ma c o nce ntrati o n s u m maries. Data f or s u bj ects 
recei vi n g place b o at t he visit will n ot be i ncl u de d.  


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9.  
E F FI C A C Y  
9. 1.  
Ge ner al C o nsi der ati o ns  
U nless ot her wise s pecifie d, t he F A S will be use d f or all efficac y a nal yses .   
9. 2.  
St atistic al M o dels  
9. 2. 1.  
Mi xe d -Eff ect M o del Re pe ate d Me as ures ( M M R M)  
T he pri mar y a n al ysis of n u merical efficac y vari a bles d uri n g t he wit h dra wal peri o d will be a 
mi x e d -effect m o del re peate d meas ur es ( M M R M) a nal ysis, w hi c h i ncl u des t he c ha n ges fr o m 
ra n d o mizati o n baseli ne ( or ot her de p e n de nt vari a ble) t o eac h p ost-ra n d o mizati o n ti me p oi nt, as 
defi ne d i n Ta ble  5. U nless ot her wise s pecifie d, t he m o del will i ncl u de t he f oll o wi n g ti me p oi nts: 
2 Wee ks P ost-ra n d o mizati o n, 4 Wee ks P ost-ra n d o mizati o n, 6 Wee ks P ost-ra n d o mizati o n, a n d 8 
Wee ks P ost -ra n d o mizati o n. T he m o del will i ncl u de t he ra n d o mizati o n bas eli ne val ue as a 
c o variate, a n d st u d y baseli ne wei g ht gr o u p ( < 5 0 k g , ≥5 0 k g), treat me nt gr o u p ( N BI- 9 8 8 5 4, 
Place b o), ti me p oi nt, treat me nt gr o u p- b y -ti me p oi nt i nteracti o n, a n d ra n d o mizati o n baseli ne val ue-
b y -ti me p oi nt i nteracti o n as fi x e d effects. S u bject will be i ncl u de d as a ra n d o m effect. St u d y site 
will n ot be i ncl u de d i n t he m o del, as t here is a lar ge n u m ber of sites, wit h m ost sites a ntici pate d 
t o e nr oll a s mall n u m ber of s u bjects. 
Treat me nt gr o u p c o m paris o ns of t he N BI- 9 8 8 5 4 treat me nt gr o u p vs. Place b o at eac h ti me p oi nt 
will be perf or me d b y c o nstr ucti n g li near c o ntrasts ( or e q ui vale nt pr o gra m mi n g c o d e) f or 
differe n ces b et wee n tr eat me nt gr o u p least -s q uares ( L S) mea ns. N o mi nal (ra w) t w o-si de d p-
val ues f or testi n g t he statistical si g nifica n ce of t hese differe nces a n d ass o ciate d 9 5 % c o nfi de nce 
i nter vals will be re p ort e d i n s u m mar y ta bles. 
T he M M R M a nal ysis will be i m ple me nte d wit h t he P R O C MI X E D pr oce d ure of 
, usi n g 
t he restricte d ma xi m u m li keli h o o d met h o d, a n u nstr uct ure d wit hi n-s u bject c o varia n ce matri x, 
a n d de n o mi nat or de grees of free d o m fr o m t he K e n war d- R o ger met h o d. If c o n ver ge n ce is n ot 
o btai ne d wit h t he u nstr uct ure d c o varia nce matri x, a T oe plitz c o varia nce str uct ure, f oll o we d b y 
t he heter o ge n e o us a ut or e gr essi ve c o varia nce str uct ure, f oll o we d b y t he c o m p o u n d s y m metr y will 
be use d. 
9. 2. 2.  
A n al ysis of C o v ari a nce  
A n a nal ysis  of c o v aria nce ( A N C O V A) m o del will be use d f or s elect n u merical e n d p oi nts. T he 
m o del will i ncl u de t he ra n d o mizati o n baseli ne val ue as a c o v ariat e, a n d st u d y bas eli ne wei g ht 
gr o u p ( < 5 0 k g, ≥5 0 k g) a n d treat me nt gr o u p ( N BI - 9 8 8 5 4, Place b o) as fi x e d effects. 
U nless ot her wise s pecifie d, missi n g val ues at Wee k 3 6 will be i m p ute d usi n g last o bser vati o n 
carri e d f or w ar d ( L O C F) usi n g t he f oll o wi n g r ules: 
•  If a s u bject disc o nti n ues st u d y pri or t o Wee k 3 6, t he last p ost-ra n d o mizati o n o bser vati o n 
o n or pri or t o disc o nti n uati o n will be use d. 
•  If s u bjects ar e missi n g t h e Wee k 3 6 val ue, t he n t h e last p ost-ra n d o mizati o n o bser vati o n 
pri or t o Wee k 3 6 will be use d. 


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9. 3.  
A n al ysis of t he Pri m ar y Effic ac y E n d p oi nt  
9. 3. 1.  
Pri m ar y Effic ac y A n al ysis 
T he pri mar y efficac y e n d p oi nt is 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 p eri 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 ra n d o mizati o n baseli ne ( Secti o n 6. 3 ) a n d 2) a n i n crease i n C GI-Tics -
Se verit y s c ore of ≥2 p oi nts fr o m t he ra n d o mizati o n baseli ne. If t hes e 2  crit eria are met at 
a s u bject’s last o bser v e d visit d uri n g t he wit h dra w al peri o d (e. g., Wee k 3 6 or E T), t he n it 
will be c o nsi dere d as l oss of treat me nt res p o nse. Or, 
•  Disc o nti n uati o n fr o m st u d y 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. 
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 date of 
l oss of treat me nt res p o ns e, defi ne d as t he earliest of: 
•  T he date of t h e first visit of t he 2 c o nsec uti ve visits w here t he l oss of treat me nt res p o nse 
criteri o n base d o n t h e Y G T S S T T S a n d C GI- Ti cs -Se verit y is met.  
•  T he date of t h e last visit if t he l oss of treat me nt res p o nse criteri o n bas e d o n t he Y G T S S 
T T S a n d C GI -Tics -Se v erit y is met at a s u bject’s last o bser ve d visit d uri n g t he wit h dra wal 
peri o d (e. g., Wee k 3 6 or E T).  
•  T he disc o nti n uati o n date f or s u bjects w h o disc o nti n ue fr o m t he st u d y 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.  
T he pri mar y a n al ysis of t he pri mar y efficac y e n d p oi nt will be a l o g -ra n k test stratifie d b y 
baseli ne wei g ht gr o u p. K a pla n -Meier ( K M) 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 m e dia n, u p per, a n d l o w er q uartiles a n d ass ociate d c o nfi de nce i nter v als will 
be calc ul ate d w here p ossi ble. 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 ns e pri or t o c o m pleti o n or disc o nti n uati o n fr o m t he wit h dra wal peri o d will 
be ce ns or e d at t heir last o bser ve d visit d uri n g t h e wit h dra wal peri o d (i.e., Wee k 3 6 visit date or 
E T visit).  
K M pl ots of t he ti me t o l oss of treat me nt res p o ns e will be prese nte d b y treat me nt. F or t he 
pri mar y efficac y a nal ysis, K M pl ots will als o be prese nte d b y treat me nt wit hi n eac h bas eli ne 
wei g ht gr o u p.  
T hese a n al ys es will be i m ple me nte d wit h t he P R O C LI F E T E S T pr o ce d ure of 
 
T he hazar d r ati o ( N BI-9 8 8 5 4 vs. Place b o) a n d its 9 5 % c o nfi de n ce i nter v al f or ti me t o l oss of 
treat me nt res p o ns e will be calc ul ate d usi n g t h e P R O C P H R E G pr oce d ure i n  
, wit h baseli ne 
wei g ht gr o u p i ncl u de d i n t he m o del. 
9. 3. 2.  
Se nsiti vit y A n al yses of t he Pri m ar y Effic ac y Res ults 
M o dificati o ns of t he pri mar y effi cac y a nal ysis ( d escri be d i n Secti o n  9. 3. 1 ): 
T he l o g- ra n k test a n d K M esti mates f or l oss of treat me nt res p o nse will be re peat e d wit h 
ra n d o mizati o n visit ( Wee k 8, 1 0, 1 2) i ncl u de d as a stratificati o n fact or. 


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As s u p p orti ve a nal yses, t he l o g- ra n k test a n d K M esti mates f or l oss of treat me nt res p o nse will 
als o be calc ul ate d usi n g t he f oll o wi n g strate gies f or ha n dli n g earl y disc o nti n uati o ns: 
•  Disc o nti n uati o ns d ue t o A Es are treate d as l oss of res p o nse. Disc o nti n uati o ns f or 
reas o ns ot her t h a n A Es or lac k of efficac y still res ult i n ce ns ore d ti me t o l oss of 
res p o nse. 
•  Disc o nti n uati o ns f or a n y reas o n are treate d as l oss of res p o nse. 
K M pl ots of t he ti me t o l oss of treat me nt res p o ns e usi n g t he des cri be d met h o ds will be prese nte d 
b y treat me nt.  
Perce nta ge of s u bjects wit h l oss of treat me nt res p o nse: 
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he n u m ber a n d perce nta ge of 
s u bjects wit h l oss of treat me nt res p o nse at a n y ti m e d uri n g t h e wit h dra w al peri o d. S u bjects w h o 
disc o nti n ue t he st u d y pri or t o t he Wee k 3 6 visit will be classifie d as l osi n g treat me nt res p o ns e. 
S u m maries will be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d 
wei g ht gr o u ps. F or t h e p o ole d wei g ht gr o u ps s u m mar y, a n a n al ysis c o m p ari n g t he N BI- 9 8 8 5 4 
treat me nt gr o u p t o t he Place b o tr eat me nt gr o u p will be perf or me d usi n g t he C oc hra n-Ma nt el -
Hae nszel ( C M H) pr o ce d ure, wit h baseli ne w ei g ht gr o u p as a stratificati o n varia ble.  
9. 4.  
A n al ysis of t he Sec o n d ar y Effic ac y E n d p oi nts  
9. 4. 1.  
Y G T S S T T S  
C ha n ge fr o m r a n d o mizati o n baseli ne t o t he 8 wee ks p ost-ra n d o mizati o n ti me p oi nt a n d t o t he 
Wee k 3 6 st u d y visit i n t he Y G T S S T T S as ge nerat e d b y t h e certifie d site rat er usi n g t h e 
Rater Stati o n T M  are sec o n dar y e n d p oi nts. C ha n ges fr o m ra n d o mizati o n baseli ne t o ot her 
ti me p oi nts or visits are e x pl orat or y efficac y e n d p oi nts. 
T he T T S is defi ne d as t h e s u m of t he Y G T S S m ot or tic se verit y sc ore a n d p h o nic ( v ocal) tic 
se verit y sc or e. T he m ot or tic se verit y sc ore is calc ulate d as t he s u m of t he s c ores f or t he 5 m ot or 
tic ite ms ( n u m ber, fre q u e nc y, i nte nsit y, c o m ple xit y, a n d i nterfere nce). T h e sc ore f or eac h ite m 
ca n ra n ge fr o m 0 t o 5, f or a ma xi m u m t otal sc ore of 2 5. T he v ocal ( p h o nic) tic se verit y sc ore is 
calc ulate d si milarl y. T he T T S val ue ca n ra n ge fr o m 0 t o 5 0, wit h hi g her sc ores re pre se nti n g 
gr eater se verit y. If a n y o ne of t he 5 ite ms f or t he m ot or or v ocal tic se verit y sc ore is n ot sc ore d 
(i.e., has a missi n g v al ue), t he ass ociate d se v erit y s c ore will be set e q ual t o missi n g.  If a n y of 
t hese ite ms has a missi n g val ue at a gi ve n visit, t he T T S val ue f or t h e visit will als o be set e q ual 
t o missi n g.  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d val ues at st u d y 
baseli ne, ra n d o mizati o n baseli ne, a n d at eac h ti m e p oi nt (as defi ne d i n T a ble  5) t hat occ urs after 
ra n d o mizati o n. C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t h e p ost-ra n d o mizati o n 
ti me p oi nts. T hese s u m maries will be pres e nte d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps. 
T he c ha n ge fr o m r a n d o mizati o n baseli ne at eac h ti m e p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n 
will be a nal yze d usi n g a n M M R M a nal ysis f or t he p o ole d wei g ht gr o u ps, as descri be d i n 
Secti o n  9. 2. 1 . 


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T he c h a n ge fr o m r a n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y visit will be a nal yze d f or t he 
p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o del, as descri be d i n Secti o n  9. 2. 2 . Missi n g val ues at 
Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p. Si milar gra p hs will be prese nt e d f or t he c ha n ges fr o m ra n d o mizati o n 
baseli ne . T hese gra p hs will be prese nte d b y bas eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or 
t he p o ole d wei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
9. 4. 2.  
C GI -Tics -Se v erit y  
C h a n ge fr o m r a n d o mizati o n baseli ne t o t he 8 wee ks p ost-ra n d o mizati o n ti me p oi nt a n d t o t he 
Wee k 3 6 st u d y visit i n t he C GI- Tics -Se v erit y sc ore are s ec o n d ar y e n d p oi nts. C ha n ges fr o m 
ra n d o mizati o n baseli ne t o ot her ti me p oi nts or visits are e x pl orat or y efficac y en d p oi nts. 
Eac h of t he C GI -Tics -Se verit y res p o nse cate g ori es will be assi g ne d a n u merical sc ore as f oll o ws:  
•  N or mal, n ot at all ill = 1  
•  B or derli ne ill = 2  
•  Mil dl y ill = 3  
•  M o deratel y ill = 4  
•  Mar ke dl y ill = 5  
•  Se verel y ill = 6  
•  A m o n g t he m ost e xtre mel y ill patie nt = 7  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d n u merical sc ores at 
st u d y baseli ne, ra n d o mizati o n baseli ne, a n d at eac h ti me p oi nt (as defi ne d i n Ta ble  5) t hat occ urs 
after r a n d o mizati o n . C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t he p ost-
ra n d o mizati o n ti me p oi nts. Fre q u e nc y c o u nts usi n g t he res p o nse cate g ori es will als o be prese nte d. 
T hese s u m maries w ill be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t h e 
p o ole d wei g ht gr o u ps. 
T he c ha n ge fr o m r a n d o mizati o n baseli ne at eac h ti me p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n 
will be a nal yze d usi n g a n M M R M a nal ysis f or t he p o ole d wei g ht gr o u ps, as descri be d i n 
Secti o n  9. 2. 1 . 
T he c ha n ge fr o m r a n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y visit will be a nal yze d f or t he 
p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o del, as descri be d i n Secti o n  9. 2. 2 . Missi n g val ues at 
Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p. Si milar gra p hs will be  prese nt e d f or t he c ha n ges fr o m ra n d o mizati o n 
baseli ne. T hese gra p hs will be prese nte d b y bas eli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or 
t he p o ole d wei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  


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9. 5.  
A n al ysis of t he E x pl or at or y Effic ac y E n d p oi nts  
9. 5. 1.  
Y G T S S  
9. 5. 1. 1.  
Y G T S S T T S Res p o n der A n al ysis  
A T T S res p o n der is defi n e d, o n a per- visit basis, as a s u bject w h ose T T S val ue is re d uce d b y at 
least 3 0 % fr o m st u d y bas eli ne at t he s pecifi e d p ost baseli ne visit.  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he n u m ber a n d perce nta ge of 
s u bjects classifie d as T T S res p o n ders at eac h ti me p oi nt ( defi ne d i n Ta ble  5). T hese s u m maries 
will be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d wei g ht 
gr o u ps.  
Descri pti ve statistics will als o be prese nte d f or t he n u m ber a n d perce nt a ge of s u bjects classifie d 
as T T S res p o n ders at t he Wee k 3 6 st u d y visit. Missi n g val ues will be i m p ut e d usi n g 
n o nres p o n der i m p utati o n ( N RI). T hes e s u m maries will be prese nte d b y b aseli ne wei g ht gr o u p 
( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d wei g ht gr o u ps. F or t he p o ole d w ei g ht gr o u p s s u m maries, 
a n a nal ysis c o m pari n g t h e N BI - 9 8 8 5 4 treat me nt gr o u p t o t he Place b o treat me nt gr o u p will be 
perf or me d usi n g t he C M H pr oce d ure, wit h bas eli ne wei g ht gr o u p as a stratificati o n varia ble.  
9. 5. 1. 2.  
Y G T S S I m p air me nt Sc ore  
T he Y G T S S I m p air me nt sc ore ca n ra n ge i n val ue fr o m 0 t o 5 0, wit h hi g her sc ores re pres e nti n g 
m ore se ver e i m pair me nt.   
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d val ues at st u d y 
baseli ne, ra n d o mizati o n baseli ne, a n d at eac h  ti m e p oi nt (as defi ne d i n T a ble  5) t hat occ urs after 
ra n d o mizati o n. C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t h e p ost-ra n d o mizati o n 
ti mep oi nts. T hese s u m maries will be pres e nte d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps. 
T he c ha n ge fr o m r a n d o mizati o n baseli ne at eac h ti me p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n 
will be a nal yze d usi n g a n M M R M a nal ysis f or  t he p o ole d wei g ht gr o u ps, as descri be d i n 
Secti o n  9. 2. 1 . 
T he c ha n ge fr o m r a n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y visit will be a nal yze d f or t he 
p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o del, as descri be d i n Secti o n  9. 2. 2 . Missi n g val ues at 
Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues  of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p. Si milar gra p hs will be prese nt e d f or t he c ha n ges fr o m ra n d o mizati o n 
baseli ne. T hese gra p hs will be prese nte d f or t he p o ole d wei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
9. 5. 1. 3.  
Y G T S S Gl o b al Tic Se verit y Sc ore  
T he Y G T S S Gl o bal Tic Se verit y s c ore is t he s u m of t he T T S a n d t he Y G T S S I m pair me nt sc ore. 
T he Y G T S S Gl o bal Tic Se verit y s c ore at a gi ve n s u bject visit will be set e q ual t o missi n g if 


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eit her of t he T T S or I m p air me nt sc ores are missi n g. T he Y G T S S Gl o bal Tic Se verit y sc ore val ue 
ca n ra n ge fr o m 0 t o 1 0 0.  
Descri pti ve statistics will be prese nt e d b y treat me nt  gr o u p f or t he o bser ve d val ues at st u d y 
baseli ne, ra n d o mizati o n baseli ne, a n d at eac h ti m e p oi nt (as defi ne d i n T a ble  5) t hat occ urs after 
ra n d o mizati o n. C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t h e p ost-ra n d o mizati o n 
ti me p oi nts. T hese s u m maries will be pres e nte d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps. 
T he c ha n ge fr o m r a n d o mizati o n baseli ne at eac h ti me p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n 
will be a nal yze d usi n g a n M M R M a nal ysis f or t he p o ole d wei g ht gr o u ps, as descri be d i n 
Secti o n  9. 2. 1 . 
T he c h a n ge fr o m r a n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y visit will be a nal yze d f or t he 
p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o del, as descri be d i n Secti o n  9. 2. 2 . Missi n g val ues at 
Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p. Si milar gra p hs will be prese nt e d f or t he c ha n ges fr o m ra n d o mizati o n 
baseli ne. T hese gra p hs will be prese nte d f or t he p o ole d wei g ht gr o u ps. 
T he  L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
9. 5. 2.  
C GI -T S -I m pr o ve me nt  
9. 5. 2. 1.  
C GI -T S -I m pr o ve me nt  
Eac h of t he C GI -T S -I m pr o ve me nt res p o ns e cat e g ories will be assi g n e d a n u merical sc ore as 
f oll o ws: 
•  Ver y m uc h i m pr o ve d = 1 
•  M uc h i m pr o ve d = 2 
•  Mi ni mall y i m pr o v e d = 3  
•  N ot c ha n ge d = 4  
•  Mi ni mall y w orse = 5  
•  M uc h w orse = 6  
•  Ver y m uc h w orse = 7  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d n u merical sc ores at 
ra n d o mizati o n baseli n e a n d at eac h ti me p oi nt (as defi ne d i n Ta ble  5) t hat o cc urs after 
ra n d o mizati o n. Fre q ue n c y c o u nts usi n g t he res p o nse cate g ories will als o be prese nte d. T h ese 
s u m maries will be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d 
wei g ht gr o u ps.  
T he o bser ve d val ues at eac h ti me p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n will be a nal yze d 
usi n g a n M M R M a nal ysis f or t he p o ole d w ei g ht gr o u ps. T he m o del will be si milar t o t hat 
descri be d i n Secti o n  9. 2. 1  wit h t he f oll o wi n g c h a n ges: o bser ve d v al ues are use d i nstea d of 
c ha n ges fr o m ra n d o mizati o n baseli ne. T he n u meri cal sc ore at ra n d o mizati o n will be use d as t he 
c o variate.  


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
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T he o bser ve d val ues at t h e Wee k 3 6 st u d y visit will be a nal yz e d f or t he p o ol e d wei g ht gr o u ps 
usi n g a n A N C O V A m o d el, as descri b e d i n Secti o n  9. 2. 2 . Missi n g val ues at Wee k 3 6 will be 
i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p . T hes e gra p hs will be prese nte d f or t he p o ole d w ei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
9. 5. 2. 2.  
C GI -T S -I m pr o ve me nt Res p o n der A n al ysis 
A s u bject is classifie d as a C G I-T S -I m pr o v e me nt res p o n der at a gi ve n visit if t heir C GI-T S -
I m pr o v e me nt sc or e is eit her a “ 1 ” ( “ ver y m uc h i m pr o ve d”) or a “ 2 ” (“ m uc h i m pr o ve d”) at t he 
visit.  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he n u m ber a n d perce nta ge of 
s u bjects classifie d as C GI-T S -I m pr o ve m e nt res p o n ders at eac h ti me p oi nt ( defi ne d i n Ta ble  5). 
T hese s u m maries will be prese nte d b y b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t h e 
p o ole d wei g ht gr o u ps.  
Descri pti ve statistics will als o be prese nte d f or t he n u m ber a n d perce nt a ge of s u bjects classifie d 
as C GI -T S -I m pr o v e me nt res p o n ders at t he Wee k 3 6 st u d y visit. Missi n g val ues will be i m p ute d 
usi n g N RI. T hes e s u m maries will be prese nt e d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps. F or t he p o ole d wei g ht gr o u ps s u m maries, a n a nal ysis c o m pari n g 
t he N BI- 9 8 8 5 4 treat me nt gr o u p t o t he Place b o treat me nt gr o u p will be perf or me d usi n g t he C M H 
pr oce d ur e, wit h baseli ne wei g ht gr o u p as a stratificati o n varia ble.  
9. 5. 3.  
Pre m o nit or y Ur ge f or Tics Sc ale  
T he P U T S is a n i nstr u me nt f or q ua ntif yi n g t h e pre m o nit or y ur ge p h e n o me n a ass ociate d wit h tics. 
It c o nsists of 9 ite ms, eac h of w hic h is sc ore 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 u e 
T he P U T S t otal sc ore is calc ulate d as t he s u m of t he sc ores f or t he 9 ite ms. T he P U T S t otal sc ore 
val ue ca n ra n ge fr o m 9 t o 3 6 . If a n y o ne of t he 9 ite ms is n ot sc ore d (i.e., h as a missi n g val ue), 
t he P U T S t otal sc ore will be set e q ual t o missi n g.  
Descri p ti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d val ues at st u d y 
baseli ne, ra n d o mizati o n baseli ne, a n d at eac h ti m e p oi nt (as defi ne d i n T a ble  5) t hat occ urs after 
ra n d o mizati o n. C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t h e p ost-ra n d o mizati o n 
ti me p oi nts. T hese s u m maries will be pres e nte d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps. 
T he c ha n ge fr o m r a n d o mizati o n baseli ne at eac h ti me p oi nt t hr o u g h 8 wee ks p ost-ra n d o mizati o n 
will be a nal yze d usi n g a n M M R M a nal ysis f or t he p o ole d wei g ht gr o u ps, as descri be d i n 
Secti o n  9. 2. 1 . 


Ne ur ocri ne Bi os cie nces, I n c.  
 
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3 4 
 
 
  
 
T he c ha n ge fr o m r a n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y visit will be a nal yze d f or t he 
p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o del, as descri be d i n Secti o n  9. 2. 2 . Missi n g val ues at 
Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d v al ues at eac h ti me p oi nt will be s u m marize d i n li ne gra p hs 
b y treat me nt gr o u p. Si milar gra p hs wil l be prese nt e d f or t he c ha n ges fr o m ra n d o mizati o n 
baseli ne. T hese gra p hs will be prese nte d f or t he p o ole d wei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
9. 5. 4.  
Gilles de l a T o urette S y n dr o me -Q u alit y of Life Sc ale f or C hil dre n a n d 
A d olesce nts  
T he C & A -G T S -Q O L h as t w o parts:  
( 1) a 2 7-ite m scale w hic h i ncl u des 4 fact ors (s u bscales), wit h eac h of t he 2 7 ite ms sc ore d o n 
a 5-p oi nt scale ( 1 = ne v er, 2 =rar el y, 3 =s o meti mes, 4 = ofte n, 5 =al w a ys); a n d  
( 2) a vis ual a nal o g scale ( V A S) w hic h ra n ges i n val u e fr o m 0 t o 1 0 0, wit h 0 re prese nti n g 
e xtre mel y u n ha p p y/ dissatisfie d wit h life, a n d 1 0 0 re pres e nti n g e xtre mel y h a p p y/satisfie d 
wit h life.   
T he C & A -G T S -Q O L t ot al sc ore is calc ulate d as t he s u m of t he  sc ores f or t he 2 7 ite ms. If a n y 
o ne of t he 2 7 ite ms is n ot sc ore d (i.e., h as a missi n g val u e), t he t otal sc ore will be set e q ual t o 
missi n g.  
Sc ores will be cal c ulate d f or eac h of t he 4 C & A -G T S - Q O L fact ors i n a si milar fas hi o n. T hes e 
fact ors a n d t h e c orres p o n di n g ite m n u m bers are as f oll o ws:  
•  Ps yc h ol o gical ( 1 6, 1 7, 1 8, 1 9, 2 0, 2 1, 2 2, 2 3, 2 4, 2 5, 2 7) 
•  P h ysical a n d acti vities of dail y li vi n g ( 1, 2 , 3, 4, 5, 6, 2 6) 
•  O bsessi ve -c o m p ulsi ve ( 7, 8, 9, 1 0, 1 5) 
•  C o g niti ve ( 1 1, 1 2, 1 3, 1 4) 
T he t otal sc ore a n d eac h fact or will be n or m alize d t o a val ue t hat ca n ra n ge fr o m 0 t o 1 0 0 b y 
usi n g t he f oll o wi n g f or m ula: 
1 0 0 ×
𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑠𝑠𝑜𝑜𝑜𝑜𝑜𝑜−𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑜𝑜𝑜𝑜𝑜𝑜𝑚𝑚𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑠𝑠𝑜𝑜𝑜𝑜𝑜𝑜
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑜𝑜𝑜𝑜𝑜𝑜𝑚𝑚𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑠𝑠𝑜𝑜𝑜𝑜𝑜𝑜−𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑜𝑜𝑜𝑜𝑜𝑜𝑚𝑚𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑠𝑠𝑜𝑜𝑜𝑜𝑜𝑜 
T w o versi o ns of t his i nstr u me nt are use d i n t his tri al: 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 8 years. Sc ori n g is i de ntical f or b ot h versi o ns a n d all 
res ults will be c o m bi ne d f or a nal yses. 
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he o bser ve d C & A -G T S -Q O L 
n or malize d t otal sc ores, t he 4 n or malize d fact or s c ores, a n d t he V A S sc ores at st u d y bas eli ne, 
ra n d o mizati o n baseli ne, a n d at eac h ti me p oi nt (as defi ne d i n Ta ble  5) t hat occ urs after 
ra n d o mizati o n. C ha n ge fr o m ra n d o mizati o n baseli ne will be i ncl u de d f or t h e p ost-ra n d o mizati o n 
ti me p oi nts. T hese s u m maries will be pres e nte d b y baseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d 
f or t he p o ole d w ei g ht gr o u ps.   


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
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F or t he n or m alize d t otal sc ores , t he c h a n ge fr o m ra n d o mizati o n baseli ne at eac h ti me p oi nt 
t hr o u g h 8 w ee ks p ost-r a n d o mizati o n will be a nal yze d usi n g a n M M R M a nal ysis f or t he p o ole d 
wei g ht gr o u ps, as descri b e d i n Secti o n 9. 2. 1 .  
F or  t he n or m alize d t otal sc ores, t he c h a n ge fr o m ra n d o mizati o n baseli ne t o t he Wee k 3 6 st u d y 
visit will be a nal yz e d f or t he p o ole d wei g ht gr o u ps usi n g a n A N C O V A m o d el, as descri b e d i n 
Secti o n  9. 2. 2 . Missi n g val ues at Wee k 3 6 will be i m p ute d usi n g L O C F. 
Mea n ( ± S E M) val ues of t he o bser ve d n or malize d t otal sc ores at eac h ti me p oi nt will be 
s u m marize d i n li ne gra p hs b y treat me nt gr o u p. Si milar gra p hs will be pres e nte d f or t he c ha n ges 
fr o m ra n d o mizati o n baseli ne. T hese gra p hs will be prese nt e d f or t he p o ol e d wei g ht gr o u ps. 
T he L S mea ns ( ± S E M) fr o m t he M M R M a nal ysis res ults will be s u m marize d i n si milar li ne 
gr a p hs f or t he p o ol e d wei g ht gr o u ps.  
 


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1 0.  
S A F E T Y  
U nless ot her wise s pecifie d, s u m maries f or eac h a n al ysis des cri be d i n t his secti o n will be 
prese nte d se p ar atel y f or eac h b aseli ne wei g ht gr o u p ( < 5 0 k g vs. ≥5 0 k g) a n d f or t he p o ole d 
wei g ht gr o u ps.  
1 0. 1.  
Ge ner al C o nsi der ati o ns  
1 0. 1. 1.  
B y -visit S u m m aries  
T he f oll o wi n g t a b le f or m ats will be use d w he n s u m marizi n g b y-visit data:  
Pre -ra n d o mizati o n: descri pti ve statistics of o bser ve d a n d c h a n ge fr o m st u d y bas eli ne val ues will 
be prese nt e d at st u d y b as eli ne a n d at eac h sc h e d ul e d p ost baseli ne visit t hr o u g h Wee k 1 2. A 
F oll o w- u p visit, as descri be d i n Ta ble  3, will als o be i ncl u de d. Res ults will be prese nt e d f or a 
si n gle treat me nt gr o u p ( N BI- 9 8 8 5 4) usi n g t he safet y a nal ysis set. Assess m e nts occ urri n g after 
ra n d o mizati o n i n s u bjects w h o are ra n d o mize d will be e x cl u de d. F or select assess me nts (cli nical 
la b orat or y dat a, vital si g ns, b o d y w ei g ht, a n d E C G data), a s u m mar y at “ Pre-ra n d o mizati o n 
E n d p oi nt” will als o be i ncl u de d. 
“ Pre-r a n d o mizati o n E n d p oi nt” will be defi ne d as: 
•  F or r a n d o mize d s u bjects: t he last val ue at a n y s c he d ule d visit occ urri n g aft er t he first 
d ose of o pe n-l a bel st u d y dr u g a n d o n or pri or t o t h e date of t he first d ose of ra n d o mize d 
st u d y dr u g  
•  F or n o n- ra n d o mize d s u bjects: t he Wee k 1 2 visit data if a vaila bl e; ot her wis e t he last val ue 
at a n y sc he d ule d visit or E T visit occ urri n g aft er t he first d ose of o p e n-la bel st u d y dr u g 
a n d o n or pri or t o t he Wee k 1 2 visit or disc o nti n uati o n ( w hic he ver o cc urs first)  
P ost-ra n d o mizati o n : descri pti ve statistics of o bser ve d a n d c h a n ge fr o m st u d y bas eli ne val ues will 
be prese nt e d at st u d y b as eli ne, ra n d o mizati o n baseli ne, a n d at eac h ti me p oi nt (as defi ne d i n 
Ta ble  5) t hat occ urs after ra n d o mizati o n. Res ults will be prese nte d b y treat me nt gr o u p ( N BI-
9 8 8 5 4 or Place b o) usi n g t he ra n d o mize d safet y a n al ysis set. St u d y b aseli ne will be use d w he n 
calc ulati n g c ha n ge fr o m baseli ne. F or select assess me nts (cli nical la b orat or y dat a, vital si g ns, 
b o d y w ei g ht, a n d E C G d ata) , a s u m mar y at “ P ost-ra n d o mizati o n E n d p oi nt” will als o be i ncl u de d.  
“ P ost-ra n d o mizati o n E n d p oi nt” will be defi ne d as:  
•  T he Wee k 3 6 visit data f or s u bjects w h o c o m plete t he wit h dra wal peri o d a n d ha ve 
a vaila ble data  
•  T he last val ue at a n y sc h e d ule d visit or E T visit occ urri n g after t h e first d ose of 
ra n d o mize d st u d y dr u g a n d o n or pri or t o t he Wee k 3 6 visit or disc o nti n uati o n ( w hic he ver 
occ urs first) f or s u bject s w h o disc o nti n ue st u d y or ot her wise ha v e missi n g data 
E ntire St u d y : f or sel ect assess me nts (cli nical la b orat or y d ata, vital si g ns, b o d y w ei g ht, a n d E C G 
data), des cri pti ve statistics of o bser ve d a n d c ha n ge fr o m st u d y b aseli ne val u es will be prese nte d 
at stu d y bas eli ne a n d at eac h sc he d ul e d p ost baseli ne visit t hr o u g h Wee k 4 0. Res ults will be 
prese nte d o nl y f or s u bjects w h o are r a n d o mize d t o N BI- 9 8 8 5 4, usi n g t he ra n d o mize d safet y 
a nal ysis s et. A s u m mar y at “ P ost -ra n d o mizati o n E n d p oi nt” will als o be i ncl u de d. 


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1 0. 1. 2.  
Tre at me nt Peri o d Defi niti o ns  
Ta ble  6 pr o vi des a d escri pti o n of t he treat me nt peri o ds t hat will be use d t o descri be A Es a n d 
assess me nt -base d a b n or malitie s (s uc h as la b orat or y p ote ntiall y cli nicall y si g nifica nt [ P C S] 
val ues or “ Y es” r es p o nses i n t he C- S S R S ite ms).  
 




Ne ur ocri ne Bi os cie nces, I n c.  
 
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1 0. 2.  
A d verse E ve nts  
A d verse e ve nts ar e rec or de d i n t he e C R F. Eac h A E will be c o de d t o S O C a n d P T usi n g 
Me d D R A ( Versi o n 1 2. 0).   
A T E A E is a n A E n ot pr ese nt pri or t o t he i nitiati o n of st u d y dr u g d osi n g, or is a n alrea d y pres e nt 
e ve nt t hat w orse ns eit her i n i nte nsit y or fre q ue nc y f oll o wi n g t he i nitiati o n of st u d y dr u g d osi n g. 
T he deter mi nati o n of w h et her a n A E is treat me nt -e mer ge nt is base d o n t h e A E o nset date relati ve 
t o t he date of t he s u bject’s first d ose of st u d y dr u g. If t he A E o nset d ate a n d date of t he first d ose 
of st u d y dr u g are t h e sa m e, or if t he A E o ns et date is u n k n o w n, it will be ass u me d t hat t he A E is 
a T E A E.  
T he fre q u e nc y ta bl es will i ncl u de t he n u m ber a n d perce nt a ge of u ni q u e s u bjects e x perie nci n g 
eac h e ve nt at least o n ce d uri n g t he s p ecifie d trea t me nt peri o d. Se parate s u m maries will be 
prese nte d f or eac h treat me nt peri o d defi n e d i n Ta ble  6.  
T w o versi o ns of t he pri m ar y T E A E fre q u e nc y ta bl es will be prese nte d: 
•  Fre q u e nc y of T E A Es b y S O C a n d P T, wit h S O Cs a n d P Ts wit hi n eac h S O C s orte d b y 
decreasi n g fr e q ue nc y ( n u m ber of u ni q ue s u b jects) i n t he N BI- 9 8 8 5 4 treat m e nt gr o u p. If 
m ore t ha n o ne N BI- 9 8 8 5 4 treat me nt gr o u p is i ncl u de d, t he gr o u p t hat c o m bi nes all d oses 
or e ntire st u d y will be us e d w he n s orti n g; 
•  Fre q u e nc y of T E A Es b y P T, wit h P T s orte d b y decreasi n g fre q u e nc y ( n u m ber of u ni q ue 
s u bjects) i n t he N BI- 9 8 8 5 4 treat me nt gr o u p. If m ore t ha n o ne N BI-9 8 8 5 4 treat me nt 
gr o u p is i ncl u de d, t h e gr o u p t hat c o m bi nes all d oses or e ntire st u d y will be use d w he n 
s orti n g. 
T he n u m ber a n d p erce nta ge of s u bjects wit h se vere T E A Es will als o be s u m marize d. T hese 
ta bles will i ncl u de b ot h S O C a n d P T, s orte d i n t he sa me met h o d as t he pri m ar y T E A E ta bl e. T he 
first li ne of t he ta ble will dis pla y t he n u m ber a n d p erce nt a ge of s u bjects wit h at least o ne se v ere 
T E A E.  
A E o ver vie w s u m mar y ta bles will be pr o vi de d f or eac h p eri o d w hic h s u m marize t he n u m ber a n d 
perce nt a 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 d ose re d u cti 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 eri o us T E A E, a n d a n y T E A E res ulti n g i n d eat 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, s e vere) re p orte d f or eac h 
s u bject d uri n g t h e s pecifi e d treat me nt peri o d. 
1 0. 2. 1.  
A d verse E ve nts Res ulti n g i n Pre m at ure Disc o nti n u ati o n fr o m St u d y  
T he n u m ber a n d p erce nta ge of s u bjects wit h a T E A E res ulti n g i n st u d y dis c o nti n uat i o n will be 
prese nte d b y P T wit hi n S O C f or eac h treat me nt peri o d ( prese nt e d i n t he sa me met h o d as t he 
pri mar y T E A E ta ble). M ore t ha n o ne A E ca n c o ntri b ute t o st u d y disc o nti n uati o n per s u bject. T he 
first li ne of t he ta ble will dis pla y t he n u m ber a n d p erce nt a ge of s u bjects wit h at least o ne T E A E 
lea di n g t o st u d y disc o nti n uati o n.  
A listi n g of T E A Es r es ulti n g i n pre mat ure st u d y disc o nti n uati o n will be pr o vi de d w hic h i ncl u des 
wei g ht gr o u p, s u bject I D, treat me nt gr o u p, last treat me nt recei ve d pri or t o t he o nset ti me of t he 
T E A E(s) lea di n g t o disc o nti n uati o n, st u d y d a y of t he disc o nti n uati o n, a n d ot her rele v a nt 


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i nf or mati o n fr o m t he A E e C R F. N ote t hat “last treat me nt recei ve d pri or t o t he o nset ti me of t he 
T E A E[s] lea di n g t o disc o nti n uati o n” reflects t he act ual d osa ge recei ve d pri or t o t he A E. 
1 0. 2. 2.  
A d verse E ve nts Res ulti n g i n St u d y Dr u g D ose Re d ucti o ns  
T he n u m ber a n d p erce nta ge of s u bjects wit h a T E A E res ulti n g i n a d os e re d ucti o n will be 
prese nte d b y P T wit hi n S O C f or eac h treat me nt peri o d ( prese nt e d i n t he sa me met h o d as t he 
pri mar y T E A E ta ble). M ore t ha n o ne A E ca n c o ntri b ute t o a d ose re d u cti o n per s u bject. T he first 
li ne of t he ta ble will dis pla y t he n u m b er a n d p erce nta ge of s u bjects wit h at least o ne T E A E 
lea di n g t o d ose re d u cti o n.  
1 0. 2. 3.  
De at hs a n d Ot her Seri o us A d verse E ve nts  
S u m mar y ta bles of s eri o us a d verse e ve nts ( S A Es) will be prese nte d f or eac h treat me nt peri o d. 
T he ta bles will i ncl u de t he fre q u e nc y of S A Es pres e nte d b y P T wit hi n S O C ( prese nte d i n t he 
sa me met h o d as t he pri m ar y T E A E ta bl e). 
Se parate listi n gs of S A Es  a n d fatal T E A Es will als o be pr o vi de d. Eac h listi n g will i ncl u de w ei g ht 
gr o u p, s u bject I D, tr eat m e nt gr o u p, last treat me nt recei v e d pri or t o t he o nset ti me of t he S A E or 
fatal T E A E, st u d y da y of t he S A E or fatal T E A E, a n d a n y a d diti o nal rel e va nt i nf or mati o n fr o m 
t he A E e C R F. 
1 0. 2. 4.  
S u m m aries b y N BI - 9 8 8 5 4 D ose 
T o hel p u n dersta n d a n y p ote ntial d ose- relat e d safet y si g nals, select s u m maries will be prese nte d 
w here s u bjects ar e a nal yze d b y t he N BI - 9 8 8 5 4 d osa ge dis pe nse d at t he ra n d o mizati o n visit 
(re gar dless of a n y s ubs e q ue nt d ose re d u cti o ns): 
•  Place b o  
•  N BI - 9 8 8 5 4 2 0 m g  
•  N BI - 9 8 8 5 4 4 0 m g 
•  N BI - 9 8 8 5 4 6 0 m g 
•  N BI - 9 8 8 5 4 8 0 m g 
•  N BI - 9 8 8 5 4 All D oses 
T hese s u m maries will i ncl u de all s u bjects i n t he ra n d o mize d safet y a nal ysis set, a n d will be 
prese nte d f or t he f oll o wi n g pr e vi o usl y d esc ri be d t a bles: 
•  A E o ver vie w t a ble 
•  T E A Es b y S O C a n d P T  
•  S A Es b y S O C a n d P T  
T hese s u m maries will o nl y be pr ese nte d f or t he p ost-ra n d o mizati o n treat me nt peri o d. 
1 0. 3.  
Cli nic al L a b or at or y D at a  
Re peat cli nical la b or at or y sa m ples ma y b e c ollecte d at a n y ti me d uri n g t his st u d y d ue t o eit her 
missi n g or a b n or mal r es ults. T he ge n eral r ule f or s u m marizi n g t hese data is t o i ncl u de t he 


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ori gi nal sa m ple res ults i n a n y b y - visit s u m mar y ta bles a n d gra p hs. Re p eat or u nsc he d ule d 
assess me nts will be i ncl u de d i n a n y la b a b n or m alit y s u m maries.  
B y -visit s u m maries  
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne he m at ol o g y, cli nical c he mistr y, he m o gl o bi n A 1c, 
a n d pr olacti n data will be s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt, as descri be d 
i n Secti o n 1 0. 1. 1 .  
T he pr olacti n data will als o be s u m marize d f or eac h se x se paratel y.  
S hift  ta bles 
S hift ta bles will be prese nte d f or selecte d cli nical la b orat or y varia bles bas e d o n t he refere n ce 
ra n ge-b ase d cate g ori es of “ L o w,” “ N or mal,” or “ Hi g h.” A cli nical la b orat or y varia ble val u e will 
be assi g n e d t o o ne of t hese t hree cate g ori es acc or di n g t o t he refere nce ra n ges pr o vi de d b y t he 
ce ntral cli nical la b orat or y.  
T he f oll o wi n g s hift ta bl es will be prese nte d: 
•  S hift fr o m st u d y baseli ne t o “ Pre -ra n d o mizati o n E n d p oi nt” (as defi ne d i n S ecti o n 1 0. 1. 1 ) 
usi n g t he safet y a nal ysis set  
•  S hift fr o m st u d y baseli ne t o “ P ost-ra n d o mizati o n E n d p oi nt” (as defi n e d i n 
Secti o n  1 0. 1. 1 ) usi n g t he ra n d o mize d safet y a n al ysis set, prese nte d b y treat me nt gr o u p 
Eac h s hift ta ble will ha ve t hree r o ws a n d t hree c ol u m ns, wit h r o ws reflecti n g t he refere n ce ra n ge 
cate g or y at baseli ne, a n d c ol u m ns reflecti n g t he refere n ce ra n ge cate g or y at p ost baseli ne. A 
“ T otal” r o w a n d “ T otal ” c ol u m n will als o be i ncl u de d. S u bjects wit h a missi n g baseli ne v al ue or 
w h o d o n ot ha ve t he s pecifie d p ost baseli ne data will n ot be i ncl u de d i n t he ta bles f or t hat 
varia ble. T h e n u m ber a n d perce nt a g e of s u bjects i n eac h s hift cate g or y will be dis pla ye d i n t he 
ta ble; perce nta ges will be base d o n t he n u m ber of s u bjects i ncl u de d i n t he ta ble. 
S hift ta bles will be prese nte d f or t he f oll o wi n g cli nical la b orat or y v aria bles:  
•  as partate tr a nsa mi nase ( A S T),  
•  ala ni ne tra ns a mi nase ( A L T),  
•  al kali ne p h os p hatase ( A L P),  
•  ga m ma -gl uta m yl tr a nsfer ase ( G G T),  
•  t otal bilir u bi n,  
•  creati ne ki n ase,  
•  creati ni ne,  
•  bl o o d urea nitr o ge n ( B U N),  
•  w hite bl o o d cell c o u nt,  
•  a bs ol ute ne utr o p hil c o u nt,  
•  he m o gl o bi n, a n d  
•  platelet c o u nt. 


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P ote ntiall y cli nicall y si g nifica nt ( P C S) val ues  
S u m maries of s p o ns or- defi ne d P C S val ues will be prese nte d f or t he f oll o wi n g cli nical la b orat or y 
varia bles: A L T, A S T, A L P, cr eati ne ki nas e, G G T, t otal bilir u bi n, w hite bl o o d cell c o u nt, 
a bs ol ute ne utr o p hil c o u nt, creati ni ne, a n d B U N. T he criteri a f or i de ntif yi n g P C S cli nical 
la b orat or y val u es ar e pr o vi de d i n Ta ble  7.  
T he n u m ber a n d p erce nta ge of s u bj ects wit h P C S val ues t hat are re p orte d at a n y p ost bas eli ne 
visit (sc he d ule d or u nsc h e d ule d) will be s u m marize d. Res ults will be prese nte d f or eac h of t he 
treat me nt peri o ds des cri b e d f or a b n or mal assess m e nts i n Ta ble  6. 
T a ble 7: 
P ot e nti all y Cli nic all y Si g nific a nt Criteri a f or Cli nic al L a b or at or y V ari a bles  
V ari a ble  
P C S T hres h ol d  
A L T  
> 3 x U L N ( u p per li mit of n or mal) 
A S T  
> 3 x U L N 
A L P  
> 2. 5 x U L N 
Creati ne ki nase  
> 5 x U L N 
G G T  
> 3 x U L N 
T otal bilir u bi n  
> 1. 5 x U L N 
W hite bl o o d cell c o u nt 
≤2. 8 x 1 0 0 0/ µ L  
A bs ol ute ne utr o p hil c o u nt  
< 1. 5 x 1 0 0 0/ µ L  
Creati ni ne  
> 1. 5 x baseli ne val ue or > 1. 5 x U L N 
B U N  
> 3 0 m g/ d L ( > 1 0. 7 1 m m ol/ L)  
Fi g ures  
Scatter pl ots of select e d varia bles will be creat e d w hic h dis pla y t he f oll o wi n g:  
•  St u d y b aseli ne vs. “ Pr e -r a n d o mizati o n E n d p oi nt” (as defi ne d i n Secti o n 1 0. 1. 1 ) usi n g t he 
safet y a n al ysis set 
•  St u d y b aseli ne vs. “ P ost-ra n d o mizati o n E n d p oi nt” (as defi ne d i n Secti o n 1 0. 1. 1 ) usi n g 
t he ra n d o mize d safet y a n al ysis set, prese nte d b y treat me nt gr o u p 
S u bjects wit h a baseli ne a n d p ost baseli ne val ue will be i ncl u de d. Eac h pl ot will i ncl u de a 4 5 
de gree (“ y = x ”) ref ere n ce li ne. T he pl ots will be ge nerate d f or A L T, A S T, creati ne ki nase, G G T, 
t otal bilir u bi n, a n d pr olacti n. 
B o x pl ots will be prese nte d f or t he pr olacti n data, as descri be d i n t he b y- visit s u m maries a b o ve. 
Se parate pl ots will als o be prese nt e d f or eac h s e x.  


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1 0. 4.  
Vit al Si g ns  
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne vital si g ns data, i ncl u di n g ort h ostatic bl o o d 
press ures a n d heart rate ( calc ulate d as sta n di n g val ue mi n us s u pi ne val ue), will be s u m marize d 
wit h descri pti ve statistics b y visit/ti me p oi nt, as descri be d i n Secti o n  1 0. 1. 1 .   
S u m maries of s p o ns or- defi ne d P C S val ues will be prese nte d f or s yst olic bl o o d press ure, diast olic 
bl o o d press ure, a n d h eart rate. T he criteria f or i de ntif yi n g P C S vital si g ns val ues f or c hil dre n ( 6 
t o 1 1 years of a ge at st u d y bas eli ne) a n d a d olesce nts ( 1 2 t o 1 7 years of a ge at st u d y bas eli ne) are 
pr o vi de d i n Ta ble  8 a n d Ta ble  9, res p ecti vel y. 
T he n u m ber a n d p erce nta ge of s u bjects wit h P C S val ues t hat are re p orte d at a n y p ost bas eli ne 
visit (sc he d ule d or u nsc h e d ule d) will be s u m marize d. Res ults will be prese nte d f or eac h of t he 
treat me nt peri o ds des cri b e d f or a b n or mal assess m e nts i n Ta ble  6. 
T a ble 8: 
P ot e nti all y Cli nic all y Si g nific a nt Criteri a f or Vit al Si g ns V ari a bles i n 
C hil dre n ( 6 t o 1 1 ye ars of a ge) 
V ar i a ble N a me 
P C S – L o w if:  
P C S – Hi g h if:  
O bser ve d 
V al ue is:  
 
A N D  
Decre ase fr o m 
B aseli ne is:  
O bser ve d 
V al ue is:  
 
A N D  
I ncre ase fr o m 
B aseli ne is:  
S yst olic Bl o o d 
Press ure  
 N/ A 
 
≥2 0 m m H g  
> 1 3 0 m m H g 
 
≥2 0 m m H g  
Diast olic Bl o o d 
Press ure  
 N/ A  
 
≥1 0 m m H g  
> 8 5 m m H g  
 
≥1 0 m m H g  
Heart Rate  
 N/ A  
 
≥1 5 b p m  
> 1 3 0 b p m 
 
≥1 0 b p m  
T a ble 9: 
P ot e nti all y Cli nic all y Si g nific a nt Criteri a f or Vit al Si g ns V ari a bles i n 
A d olesce nts ( 1 2 t o 1 7 y e ars of a ge) 
V ari a ble N a me 
P C S – L o w if:  
P C S – Hi g h if:  
O bser ve d 
V al ue is:  
 
A N D  
Decre ase fr o m 
B aseli ne is:  
O bser ve d 
V al ue is:  
 
A N D  
I ncre ase fr o m 
B aseli ne is:  
S yst olic Bl o o d 
Press ure  
 N/ A 
 
≥2 0 m m H g  
> 1 4 5 m m H g 
 
≥2 0 m m H g  
Diast olic Bl o o d 
Press ure  
 N/ A  
 
≥1 0 m m H g  
> 9 0 m m H g 
 
≥1 0 m m H g  
Heart Rate  
 N/ A  
 
≥1 5 b p m  
> 1 1 0 b p m 
 
≥1 0 b p m  
B ot h s u pi ne a n d sta n di n g val ues of bl o o d press ures a n d heart rate will be i n cl u de d i n t he 
i de ntificati o n a n d s u m mar y of P C S val ues. St u d y baseli ne will be use d w h e n deter mi ni n g a n y 
i ncreas es or decreases fr o m baseli ne. 
1 0. 5.  
B o d y Wei g ht  
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne b o d y w ei g ht d ata (i n u nits of kil o gra ms) will be 
s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt, as descri be d i n Secti o n 1 0. 1. 1 .   


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1 0. 6.  
Electr oc ar di o gr a m  
T he tri plicate val ues of t he q ua ntitati ve E C G vari a bles ( heart rat e, P R i nter val, Q R S d urati o n, 
Q T i nter val, a n d Fri dericia’s c orr ecti o n of Q T i nter val [ Q Tc F]) meas ure d at eac h visit will be 
a vera ge d f or t h e p ur p ose of a nal ysis. F or t h e cat e g orical E C G i nter pretati o n varia ble (t h e 
i n vesti gat or’s assess me nt of t he E C G as “ 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”), w hi c h is als o re p orte d i n tri plicate , t h e val ue t hat re prese nts 
t he gr eatest d e gree of a b n or malit y will be use d i n all s u m mar y ta bl es. If less t ha n 3 val ues are 
rec or d e d at a n assess me nt, t he n t he a vera ge/ greatest a b n or malit y of t he a vaila ble val ue(s) will be 
use d. 
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne val u es f or t he q ua ntitati ve E C G varia bles will be 
s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt as descri be d i n Secti o n 1 0. 1. 1 . 
Fre q u e nc y c o u nts a n d perce nta ges f or t he E C G i nt er pret ati o n varia ble cate g ories will als o be 
s u m marize d. 
Cate g orical s u m maries will be prese nte d f or t he Q T a n d Q Tc F i nter val d ata. F or t hese 
s u m maries, a s u bject’s hi g hest r e p orte d p ost bas eli ne val ue (i ncl u di n g val u es re p orte d at 
u nsc he d ule d visits) will be use d t o deter mi ne i n w hic h cate g or y(s) t he s u bject will be c o u nte d. 
T he a vera ge d tri plicate v al ues will be use d w he n deter mi ni n g eac h s u bj ect’s hi g hest re p orte d 
val ues.  
T w o cate g orical s u m mari es will be prese nte d f or t he Q T a n d Q T c F i nter vals (eac h i nter val will 
be s u m marize d se par atel y). F or t he first s u m mar y, t he n u m ber a n d perce nta ge of s u bjects w h ose 
hi g hest r e p orte d Q T or Q Tc F p ost bas eli ne val ue meets t he f oll o wi n g t hres h ol ds will be 
s u m marize d: 
•  Greater t ha n 4 5 0 msec 
•  Greater t ha n 4 8 0 msec 
•  Greater t ha n 5 0 0 msec 
T he sec o n d cate g ori cal s u m mar y will dis pla y t he n u m ber a n d perce nt a ge of s u bjects w h ose 
lar gest Q T or Q Tc F i ncrease fr o m t heir st u d y bas eli ne val ue meets t he f oll o wi n g t hres h ol ds:  
•  Greater t ha n 3 0 msec  
•  Greater t ha n 6 0 msec  
T he n u m ber a n d p erce nta ge of s u bj ects i n eac h of t he s pecifie d cate g ories usi n g assess me nts 
c ollecte d at a n y p ost baseli ne visit (sc he d ule d or u nsc he d ule d) will be s u m marize d. Res ults will 
be prese nt e d f or eac h of t he treat me nt peri o ds descri be d f or a b n or mal assess me nts i n Ta ble  6.    
1 0. 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 data will be prese nte d i n t he f oll o wi n g s u m maries:  
•  Scree ni n g/lifeti me assess me nt  
•  Scree ni n g/ past 1 year ass ess me nt  
•  St u d y b aseli ne ass ess me nt  
•  Pre -ra n d o mizati o n treat me nt peri o d 
•  P ost- ra n d o mizati o n treat me nt peri o d 


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•  E ntire st u d y tr eat me nt peri o d  
T he scree ni n g a n d st u d y baseli ne s u m maries will i ncl u de t he f oll o wi n g c ol u m ns: 
•  N BI - 9 8 8 5 4: all s u bjects i n t he safet y a n al ysis set 
•  N BI - 9 8 8 5 4: all s u bjects i n t he ra n d o mize d safet y a nal ysis s et w h o are ra n d o mize d t o 
N BI - 9 8 8 5 4 
•  Place b o: all s u bjects i n t he ra n d o mize d safet y a nal ysis set w h o are ra n d o mize d t o 
place b o  
Eac h treat me nt peri o d s u m mar y will dis p la y t he n u m ber a n d perce nt a ge of s u bjects w h o re p ort 
“ Yes” t o s pecific C -S S R S ite ms or cate g ories of ite ms (a cat e g or y is assi g ne d a “ Y es” val u e if a 
“ Yes” is r e p orte d f or a n y ite m i n t he cate g or y) at a n y ti me d uri n g t he s pecifie d treat me nt peri o d, 
usi n g t he treat me nt peri o ds a n d a nal ysis sets defi n e d f or a b n or mal assess m e nts i n Ta ble  6.  
T he C -S S R S ite ms a n d cate g ories are as f oll o ws:  
•  S uici dal I deati o n Ite ms 
( 1)  
Wis h t o be dea d 
( 2) 
N o n -s pecific acti ve s uici dal t h o u g hts 
( 3)  
Acti ve s uici dal i deati o n wit h a n y met h o ds ( n ot pl a n) wit h o ut i nte nt t o act 
( 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  
( 5) 
Acti ve s uici dal i dea ti o n wit h s pecific pla n a n d i nt e nt 
•  S uici dal I deati o n Cate g or y: A n y of ite ms ( 1) t hr o u g h ( 5) 
•  S uici dal Be ha vi or It e ms ( n ot c ollecte d f or t he Scree ni n g/ past 1 year assess me nt)  
( 6) 
Pre parat or y acts or b e ha vi or  
( 7)  
A b orte d atte m pt 
( 8) 
I nterr u pte d atte m pt 
( 9) 
N o n -fatal s uici de atte m pt 
( 1 0)  
C o m plete d s uici de 
•  S uici dal Be ha vi or Cat e g or y: A n y of ite ms ( 6) t hr o u g h ( 1 0) 
•  S uici dal I deati o n or Be ha vi or Cate g or y: A n y of ite ms ( 1) t hr o u g h ( 1 0) 
I n a d diti o n t o t he s u m maries descri b e d a b o ve, s hift ta bles c o m pari n g p ost baseline s uici dal 
i deati o n sc ores t o st u d y b aseli ne sc or es will be prese nte d f or eac h treat me nt peri o d. T he s hift 
ta ble sc ores are d efi ne d as t he f oll o wi n g: 
0 = N o s uici dal i deati o n 
1 = Wis h t o be dea d 
2 = N o n- s pecific acti ve s uici dal t h o u g hts 
3 = Acti ve s uici da l i deati o n wit h a n y met h o ds ( n ot pla n) wit h o ut i nte nt t o act 
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  
5 = Acti ve s uici dal i deati o n wit h s pecific pla n a n d i nte nt  
T he s hift ta bles will dis pla y t h e n u m ber a n d p erce nta ge of s u bjects wit hi n eac h cell of a 6  x 6 
ta ble, wit h t he r o ws re prese nti n g t he st u d y baseli n e sc ore a n d t he c ol u m ns re prese nti n g t he 
ma xi m u m sc ore rec or de d acr oss all p ost baseli ne assess me nts (i ncl u di n g b ot h sc he d ule d a n d 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
4 6 
 
 
  
 
u nsc he d ule d visits) d uri n g t he s pecifie d treat me nt peri o d. S u bjects missi n g eit her a bas eli ne 
sc ore or all p ost baseli ne sc ores will n ot a p pear i n t he ta ble. 
1 0. 8.  
E xtr a p yr 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 S R S - A assesses 4 t y p es of m o ve me nt dis or d ers: par ki ns o nis m, d yst o nia, a kat hisia, a n d 
d ys ki nesia. T h e E S R S - A c o nsists of f o ur s u bscales, o ne f or eac h t y pe of m o ve me nt dis or der. T h e 
E S R S - A c o ntai ns 1 0 ite ms t o e val uate par ki ns o nis m, 6 ite ms t o e val uate d yst o nia, 6 ite ms t o 
e val uate d ys ki nesia, a n d 2 ite ms t o e val uate a kat hisia . Eac h ite m sc ore ca n ra n ge fr o m 0 t o 5, f or 
a ma xi m u m p ossi ble par ki ns o nis m sc ore of 5 0, ma xi m u m p ossi ble d yst o ni a sc ore of 3 0, 
ma xi m u m p ossi ble d ys ki nesia sc ore of 3 0, a n d ma xi m u m p ossi ble a kat hisia sc ore of 1 0. A 
Cli nical Gl o bal I m pr essi o n of M o ve me nt S e verit y ( C GI- S) is als o c o m plete d f or eac h t y pe of 
m o ve me nt dis or der, a n d is als o is sc ore d o n a 0 t o 5 scale. 
T he s u bscale s c ores f or eac h t y pe of m o ve m e nt dis or der ( p ar ki ns o nis m, a k at hisia, d yst o nia, a n d 
d ys ki nesia) will be calc ul ate d as t he s u m of t he s c ores of t he i n di vi d ual ite ms c o m prisi n g eac h 
s u bscale. T he o v erall t otal sc ore will be calc ulate d as t he s u m of eac h of t he s u bscale sc ores. If 
a n y o n e of t he ite ms is n ot sc ore d (i.e., h as a missi n g val ue), t he ass oci ate d s u bscale sc ore a n d 
t otal sc ore will be set e q u al t o missi n g. T he C GI-S sc ores will be s u m marize d se paratel y fr o m 
t he s u bscale sc ores. 
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne val u es f or eac h s u bscale sc ore, t otal sc ore a n d 
C GI -S sc ore will be s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt, as descri be d i n 
Secti o n  1 0. 1. 1 .  
1 0. 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 s e 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 C Y - B O C S o bsessi o n s u bt otal sc ore is calc ul ate d as t he s u m of t he s c ores f or ite ms 1 t hr o u g h 
5 of t he C Y- B O C S scale (e x cl u di n g ite m 1 b), a n d t he C Y- B O C S c o m p ulsi o n s u bt otal sc ore is 
calc ulate d as t he s u m of t he sc ores f or ite ms 6 t hr o u g h 1 0 of t h e C Y- B O C S scale (e x cl u di n g ite m 
6 b). T he C Y- B O C S t otal sc ore is t he s u m of t he o bsessi o n a n d c o m p ulsi o n s u bt otal sc ores. Eac h 
ite m sc ore ra n ges fr o m 0 t o 4, wit h a ma xi m u m p ossi ble o bsessi o n s u bt otal sc ore of 2 0, a 
ma xi m u m p ossi ble c o m p ulsi o n s u bt otal sc ore of 2 0, a n d a ma xi m u m p ossi ble t otal sc ore of 4 0. If 
a n y o n e of t hes e 1 0 ite ms is n ot sc ore d (i.e., has a missi n g val ue), t he ass ociate d s u bt otal sc ore 
a n d t otal sc ore will be set e q ual t o missi n g. 
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne val u es f or t he o bsessi o n s u bt otal, c o m p ulsi o n 
s u bt otal a n d t otal sc ores will be s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt, as 
descri be d i n Secti o n  1 0. 1. 1 . 
1 0. 1 0.  
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 s e verit y of d e pressi o n i n 
c hil dre n.  
T he C D R S -R t otal sc ore is calc ulate d as t h e s u m of t he 1 7 ite ms ma ki n g u p t he C D R S -R. Eac h 
ite m sc ore ra n ges fr o m 1 t o 7 wit h t he e x ce pti o n of ite ms 4, 5, a n d 1 6, w hic h ra n ge fr o m 1 t o 5. 


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
4 7 
 
 
  
 
T he ma xi m u m p ossi ble t otal sc ore is 1 1 3. If a n y o ne of t he 1 7 ite ms is n ot sc ore d ( i.e., h as a 
missi n g val ue), t he t otal sc ore will be set e q u al t o missi n g.  
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne val u es f or t he t otal sc ore will be s u m marize d wit h 
descri pti ve statistics b y visit/ti me p oi nt, as descri be d i n Secti o n  1 0. 1. 1 . 
1 0. 1 1.  
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 A D H D Rati n g Scal e - 5: H o me Versi o n 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 o ver t he 2 wee ks pri or t o eac h visit.  
T he scale c o nsists of 2 s y m pt o m s u bscales: I n atte nti o n ( 9 ite ms) a n d H y p eracti vit y -I m p ulsi vit y 
( 9 ite ms). T he I natte nti o n s u bscale a n d H y p eracti vit y-I m p ulsi vit y s u bscale sc ores are eac h 
deri ve d b y s u m mi n g u p t he 9 rele v a nt ite m sc ores. Eac h ite m sc ore ra n ges fr o m 0 t o 3, t heref ore 
eac h s u bscale sc ore has a ra n ge of 0 t o 2 7. T h e T otal Scale ra w s c ore is d efi ne d as t he s u m of t he 
I n atte nti o n a n d H y peracti vit y-I m p ulsi vit y s u bscale sc ores, a n d h as a ra n ge of 0 t o 5 4. If a n y o n e 
of t he 1 8 ite ms is n ot sc ore d (i.e., h as a missi n g val ue), t he affect e d s u bscal e sc ore(s) a n d T ot al 
Scale ra w s c ore will be set e q ual t o missi n g.  
T he scale als o assesses 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 a n d 
a d olesce nts wit h A D H D: relati o ns hi ps wit h fa mil y me m bers, peer rel ati o ns hi ps, aca de mic 
f u ncti o ni n g, be h a vi oral f u ncti o ni n g, h o me w or k p erf or ma n ce, a n d self-estee m. Eac h d o mai n 
i m pair me nt ite m ra n ges fr o m 0-3 a n d is assesse d after c o m pleti n g eac h of t he 2 s u bscales (i. e., 
eac h i m pair me nt ite m is assesse d t wice). T he s c ore f or eac h d o mai n is defi ne d as t he hi g her 
( w orst) of t he t w o s c ores. A t otal i m pair me nt sc ore is defi ne d as t he s u m of t he 6 i m pair me nt 
ite ms ( usi n g t he hi g her of t he t w o sc ores) a n d h as a ra n ge of 0 t o 1 8. If a n y o ne of t he 1 2 
i n di vi d ual ite ms is n ot sc ore d (i.e., h as a missi n g v al ue), t he t otal i m pair me nt sc ore will be set 
e q ual t o missi n g.  
T w o versi o ns of t his i nstr u me nt are use d i n t his tri al: 1 versi o n is f or c hil dre n a ge d 5 t o 1 0 years 
a n d 1 versi o n is f or a d olesce nts a ge d 1 1 t o 1 7 years. Sc ori n g is i de ntical f or b ot h versi o ns a n d all 
res ults will be c o m bi ne d f or a nal yses. 
T he o bser ve d a n d c h a n ge fr o m st u d y b aseli ne val u es f or t he I n atte nti o n a n d H y p eracti vit y-
I m p ulsi vit y s u bscale sc or es, t he T otal Scale ra w sc ore, a n d t he T ot al I m p air me nt sc ore will be 
s u m marize d wit h descri pti ve statistics b y visit/ti me p oi nt, as descri be d i n Secti o n 1 0. 1. 1 . 
1 0. 1 2.  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
Pri or me dicati o ns a n d c o nc o mita nt me dicati o ns will be s u m marize d b y W orl d Healt h 
Or ga nizati o n ( W H O) Dr u g A n at o mical T hera pe utic C he mical Classificati o n ( A T C) Le vel 3 
cate g or y ( or Le v el 2 if t here is n ot a n a p plica ble Le vel 3 cat e g or y) a n d preferre d n a me.  
Me dicati o ns will be assi g ne d t o o ne, t w o, or t hree st u d y peri o ds b ase d o n t h e me dicati o n start 
a n d st o p dates relati ve t o st u d y dr u g d osi n g a n d ra n d o mizati o n. 
•  Prest u d y/scr ee ni n g: me di cati o ns wit h  a start date pri or t o o pe n -la bel st u d y dr u g 
d osi n g 
•  D uri n g t h e pre- ra n d o mizati o n treat me nt or p osttreat me nt: me dicati o ns o n g oi n g at t he 
ti me of first o pe n-la bel st u d y dr u g d osi n g or wit h a start date after first d ose of o pe n-


Ne ur ocri ne Bi os cie nces, I n c.  
 
N BI - 9 8 8 5 4- T S 2 0 0 5 
Statistical A nal ysis Pla n  
 
0 2- A u g - 2 0 1 9 
 
4 8 
 
 
  
 
la bel st u d y dr u g, e x cl u di n g me dicati o ns starte d after t he first d ose of ra n d o mize d 
st u d y dr u g  
•  D uri n g ra n d o mize d treat me nt or p osttreat me nt: me dicati o ns o n g oi n g at t he ti me of 
first ra n d o mize d st u d y dr u g d osi n g or wit h a start date after t he first d ose of 
ra n d o mize d st u d y dr u g. 
A gi ve n m e dicati o n ca n be assi g n e d t o m ulti ple st u d y peri o ds i n t he ta b ular s u m maries, 
de pe n di n g o n its start a n d e n d dates. 
T he n u m ber a n d p erce nta ge of s u bjects usi n g me di cati o ns i n eac h W H O Dr u g A T C cate g or y 
( Le vel 3/ preferre d n a me) will be s u m marize d b y st u d y peri o d. A s u bject m a y t a ke t he sa m e 
me dicati o n m ore t ha n o n ce or m ulti ple me dicati o ns f or a s u bject ma y b e cl assifie d u n der t he 
sa me A T C le vel or pr ef erre d na me. A s u bj ect is c o u nte d o nl y o nce f or eac h le vel of me dicati o n 
classificati o n wit hi n a s u m mar y.  
T he f oll o wi n g c ol u m ns will be i ncl u de d i n t he s u m maries: 
•  N BI -9 8 8 5 4: all s u bjects i n t he safet y a n al ysis set ( n ote: o mitte d fr o m t he “ d uri n g 
ra n d o mize d treat me nt or p osttreat me nt” s u m mar y) 
•  N BI - 9 8 8 5 4: all s u bjects i n t he ra n d o mize d safet y a nal ysis s et w h o are ra n d o mize d t o 
N BI - 9 8 8 5 4 
•  Place b o: all s u bjects i n t he ra n d o mize d safet y a nal ysis set w h o are ra n d o mize d t o 
place b o