Conditions: Tourette Syndrome
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 155
Healthy volunteers: no

Brief summary:
Phase 2, open-label, fixed-dose titration study to evaluate the safety and tolerability of NBI-98854 administered once daily for a total of 24 weeks in children, adolescents, and adults with Tourette Syndrome (TS).

Detailed description:

Arms:
arm 1: Children (6 to 11 years of age) received valbenazine 10 mg once daily for 4 weeks. At the end of Week 4, investigators could escalate the dose to 20 mg or continue with the participant's current dose for the remainder of the treatment period. arm 2: Adolescents (12 to 17 years of age) received valbenazine 20 mg once daily for 4 weeks. At the end of Week 4, investigators could escalate the dose to 40 mg or continue with the participant's current dose for the remainder of the treatment period. arm 3: Adults (18 to 64 years of age) received valbenazine 40 mg once daily for 4 weeks. At the end of Week 4, investigators could escalate the dose to 80 mg or continue with the participant's current dose for the remainder of the treatment period.

Interventions: intervention 1: Valbenazine
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
An Open-Label, Safety and Tolerability Study of NBI-98854 for the 
Treatment of Subjects With Tourette Syndrome 
 
Amendment No. 3 Final Version Date:  01 March 2017 
Amendment No. 2 Final Version Date:  22 June 2016 
Amendment No. 1 Final Version Date:  12 May 2016 
Original Final Version Date:  08 April 2016 
 
Study No.:  NBI-98854-1601 
 
Development Phase:  Phase 2 
 
Sponsor:  
 
Neurocrine Biosciences, Inc. 
 
12780 El Camino Real 
 
San Diego, CA 92130 
 
Telephone:  (858) 617-7600 
 
Facsimile:   (858) 617-7705 
 
 
 
 
 
 
CONFIDENTIAL 
This document is a confidential communication of Neurocrine Biosciences, Inc.  It is agreed that 
no unpublished information contained herein will be published or disclosed without prior 
approval from the sponsor.  However, this document can be disclosed to an appropriate 
Institutional Review Board/Ethics Committee (IRB/EC) or authorized representatives of national 
regulatory authorities under the condition that they respect its confidential nature. 


SIGNATURES: 
I agree to conduct this study in accordance with the requirements of this clinical study protocol 
and also in accordance with the following: 
• Established principles of Good Clinical Practice (GCP) (Harmonized) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA) 
 
CLINICAL STUDY TITLE: 
An Open-Label, Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects 
With Tourette Syndrome 
 
PROTOCOL No.: 
NBI-98854-1601 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
Neurocrine Biosciences, Inc., Study No. NBI-98854-1601 
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LIST OF SPONSOR PERSONNEL 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Medical Monitor: 
Telephone: 
Facsimile:  
Cell Phone: 
Vice President, Clin c
Development:  
Telephone: 
Facsimile:  
Serious Adverse Event Reporting: 
Telephone: 
Facsimile:  
Email:  
 
 
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TABLE OF CONTENTS  
TABLE OF CONTENTS .................................................................................................. 5 
2. 
SYNOPSIS .................................................................................................. 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............. 13 
4. 
ETHICS ....................................................................................................... 15 
5. 
INTRODUCTION ....................................................................................... 15 
5.1. 
Background .................................................................................................. 15 
5.2. 
NBI-98854 ................................................................................................... 16 
5.3. 
Study and Dose Rationale ............................................................................ 17 
6. 
STUDY OBJECTIVES ............................................................................... 18 
7. 
OVERVIEW OF STUDY DESIGN ............................................................ 18 
8. 
STUDY POPULATION .............................................................................. 20 
8.1. 
Inclusion Criteria ......................................................................................... 20 
8.1.1. 
Inclusion Criteria for All Subjects ............................................................... 20 
8.1.2. 
Inclusion Criteria for Pediatric Subjects ...................................................... 22 
8.1.3. 
Inclusion Criteria for Adult Subjects ........................................................... 22 
8.1.4. 
Inclusion Criteria for Adolescent and Adult Subjects ................................. 22 
8.2. 
Exclusion Criteria ........................................................................................ 23 
8.2.1. 
Exclusion Criteria for All Subjects .............................................................. 23 
8.2.2. 
Exclusion Criteria for Pediatric Subjects ..................................................... 24 
8.2.3. 
Exclusion Criteria for Adult Subjects .......................................................... 24 
8.3. 
Subject Identification and Replacement ...................................................... 25 
8.4. 
Randomization ............................................................................................. 25 
9. 
STUDY EVALUATIONS ........................................................................... 25 
9.1. 
Schedule of Assessments ............................................................................. 25 
9.2. 
Pharmacodynamic Assessments .................................................................. 28 
9.2.1. 
Yale Global Tic Severity Scale.................................................................... 28 
9.2.2. 
Rush Video-Based Tic Rating Scale............................................................ 28 
9.2.3. 
Premonitory Urge for Tics Scale ................................................................. 29 
9.2.4. 
Clinical Global Impression Scales ............................................................... 29 
9.2.5. 
Patient Global Impression of Change-Tourette Syndrome .......................... 29 
9.2.6. 
Pediatric Quality of Life Inventory (Pediatric Subjects Only) .................... 29 
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9.2.7. 
Gilles de la Tourette Syndrome-Quality of Life Scale (Adult Subjects 
Only) ............................................................................................................ 30 
9.3. 
Pharmacokinetic Evaluations ....................................................................... 30 
9.4. 
Safety Assessments ...................................................................................... 30 
9.4.1. 
Safety Assessments for All Subjects ........................................................... 31 
9.4.1.1. 
Data Safety Monitoring Board ..................................................................... 31 
9.4.1.2. 
Medical history ............................................................................................ 31 
9.4.1.3. 
Physical examination, including height and weight .................................... 31 
9.4.1.4. 
Vital sign measurements .............................................................................. 31 
9.4.1.5. 
Electrocardiogram ........................................................................................ 32 
9.4.1.6. 
Clinical laboratory assessments ................................................................... 32 
9.4.1.7. 
Columbia-Suicide Severity Rating Scale ..................................................... 33 
9.4.1.8. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................. 34 
9.4.1.9. 
Estimated total blood sample volume required by study ............................. 34 
9.4.2. 
Safety Assessments for Pediatric Subjects Only ......................................... 35 
9.4.2.1. 
Children’s Depression Rating Scale, Revised ............................................. 35 
9.4.2.2. 
Children’s Yale-Brown Obsessive-Compulsive Scale ................................ 35 
9.4.2.3. 
Attention-Deficit Hyperactivity Disorder Rating Scale 5: Home Version .. 36 
9.4.3. 
Safety Assessments for Adult Subjects Only .............................................. 36 
9.4.3.1. 
Yale-Brown Obsessive Compulsive Scale .................................................. 36 
9.4.3.2. 
Structured Interview Guide for the Hamilton Depression Rating Scale ...... 36 
9.5. 
Specific Study Information .......................................................................... 36 
9.5.1. 
Screening (Days -21 to -2) ........................................................................... 37 
9.5.2. 
Baseline (Day -1) ......................................................................................... 37 
9.5.3. 
Treatment Period ......................................................................................... 39 
9.5.3.1. 
Day 1 ............................................................................................................ 39 
9.5.3.2. 
Weeks 2 and 6 .............................................................................................. 39 
9.5.3.3. 
Weeks 4, 8, 12, 16, 20, and 24 (±6 days for each visit) ............................... 39 
9.5.4. 
Follow-Up: Week 28 (±6 days) (or Early Termination) .............................. 41 
9.6. 
Study Duration ............................................................................................. 41 
9.7. 
Prohibitions and Restrictions ....................................................................... 42 
9.7.1. 
Prior and Concomitant Medications ............................................................ 42 
9.7.2. 
Dietary Restrictions ..................................................................................... 42 
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9.7.3. 
Other Restrictions ........................................................................................ 42 
9.8. 
Withdrawal Criteria ..................................................................................... 43 
9.8.1. 
Handling of Withdrawals ............................................................................. 43 
9.8.2. 
Sponsor’s Termination of Study .................................................................. 44 
10. 
STUDY DRUG ............................................................................................ 44 
10.1. 
Study Drug Supplies .................................................................................... 44 
10.2. 
Study Drug Storage ...................................................................................... 44 
10.3. 
Study Drug Packaging and Labeling ........................................................... 44 
10.4. 
Blinding ....................................................................................................... 45 
10.5. 
Study Drug Administration.......................................................................... 45 
10.6. 
Drug Compliance and Accountability ......................................................... 45 
10.7. 
Study Drug Return ....................................................................................... 46 
11. 
ADVERSE EVENTS................................................................................... 46 
11.1. 
Definition ..................................................................................................... 46 
11.2. 
Intensity of Adverse Events ......................................................................... 47 
11.3. 
Relationship to Study Drug ......................................................................... 47 
11.4. 
Recording Adverse Events .......................................................................... 48 
11.5. 
Post-Study Follow-Up of Adverse Events ................................................... 48 
11.6. 
Serious Adverse Events ............................................................................... 49 
11.6.1. 
Definition of a Serious Adverse Event ........................................................ 49 
11.6.2. 
Managing Serious Adverse Events .............................................................. 49 
11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .......................................................................................................... 50 
11.6.4. 
Expedited Safety Reports ............................................................................ 50 
11.7. 
Pregnancy .................................................................................................... 50 
12. 
DOCUMENTATION OF DATA ................................................................ 51 
12.1. 
Case Report Form ........................................................................................ 51 
12.2. 
Data Capture, Review, and Validation ........................................................ 51 
12.3. 
Coding Dictionaries ..................................................................................... 52 
13. 
STATISTICAL AND ANALYTICAL PLAN ............................................ 52 
13.1. 
Analysis Sets ................................................................................................ 52 
13.2. 
Sample Size ................................................................................................. 52 
13.3. 
Handling of Missing Data ............................................................................ 52 
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13.4. 
Enrollment and Disposition of Subjects ...................................................... 52 
13.5. 
Demographics and Baseline Characteristics ................................................ 52 
13.6. 
Study Drug Dosing and Compliance ........................................................... 53 
13.7. 
Pharmacokinetic Data .................................................................................. 53 
13.8. 
Pharmacodynamic Data ............................................................................... 53 
13.9. 
Safety Data ................................................................................................... 53 
13.10. 
Software ....................................................................................................... 53 
13.11. 
Interim Analysis ........................................................................................... 53 
14.
REGULATORY AND ETHICAL ISSUES ................................................ 54
14.1. 
General Legal References ............................................................................ 54 
14.2. 
Institutional Review Board .......................................................................... 54 
14.3. 
Protocol Adherence and Amendments ........................................................ 54 
14.4. 
Required Documents ................................................................................... 54 
14.5. 
Informed Consent ........................................................................................ 54 
14.6. 
Study Monitoring ......................................................................................... 55 
14.7. 
Quality Assurance ........................................................................................ 55 
14.8. 
Record Retention ......................................................................................... 55 
14.9. 
Confidentiality ............................................................................................. 55 
15.
STUDY COMMENCEMENT AND DISCONTINUATION ..................... 56
16.
REFERENCES ............................................................................................ 57
17.
APPENDICES ............................................................................................. 58
17.1. 
Yale Global Tic Severity Scale (YGTSS) ................................................... 58 
17.2. 
Rush Video-Based Tic Rating Scale (RTRS) .............................................. 68 
17.3. 
Premonitory Urge for Tics Scale (PUTS) .................................................... 70 
17.4. 
Clinical Global Impression (CGI)-Tics–Severity Scale .............................. 72 
17.5. 
Clinical Global Impression (CGI)-Tourette Syndrome (TS)–Improvement 
Scale ............................................................................................................. 74 
17.6. 
Patent Global Impression of Change-Tourette Syndrome (PGIC-TS) ........ 76 
17.7. 
Pediatric Quality of Life Inventory (PedsQL) (Pediatric Subjects Only) .... 78 
17.8. 
Gilles de la Tourette Syndrome-Quality of Life Scale (Adult Subjects 
Only) ............................................................................................................ 86 
17.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................... 89 
17.10. 
Children’s Depression Rating Scale, Revised (CDRS-R) ..........................102 
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17.11. 
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) ...........107 
17.12. 
Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale 5: Home 
Version .........................................................................................................129 
17.13. 
Yale-Brown Obsessive Compulsive Scale (Y-BOCS) ................................134 
17.14. 
Structured Interview Guide for the Hamilton Depression Rating Scale 
(SIGH-D-17) ................................................................................................149 
17.15. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................157 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................. 26 
Table 2: 
Estimated Total Blood Sample Volume ...................................................... 35 
Table 3: 
Intensity of Adverse Events ......................................................................... 47 
Table 4: 
Relationship of Adverse Events to Study Drug ........................................... 48 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................. 20 
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2. 
SYNOPSIS 
Protocol Title:  An Open-Label, Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With 
Tourette Syndrome 
Protocol Number: NBI-98854-1601 
Study Centers:  Approximately 60 study sites in the United States. 
Objective: 
To evaluate the safety and tolerability of NBI-98854 (titrated from 10 mg to 20 mg in children, 20 mg to 40 mg in 
adolescents, and 40 mg to 80 mg in adults) administered once daily for up to 24 weeks for the treatment of 
Tourette Syndrome (TS). 
Study Design: 
This is a Phase 2, open-label, fixed-dose titration study to evaluate the safety and tolerability of NBI-98854 
administered once daily for a total of 24 weeks in children, adolescents, and adults with TS.  NBI-98854 doses will 
be titrated from 10 mg to 20 mg in children (6 to 11 years of age), 20 mg to 40 mg in adolescents (12 to 17 years of 
age), and 40 mg to 80 mg in adults (18 to 64 years of age).  Up to 180 male and female subjects (up to 90 pediatric 
subjects [ie, children and adolescents] and up to 90 adult subjects) with a clinical diagnosis of TS will be enrolled. 
Parental or legal guardian informed consent with signed and witnessed pediatric assent for pediatric subjects or 
informed consent for adult subjects must be obtained prior to conduct of any study-related procedures.  Subjects 
will also be asked to sign an optional release form to allow their Rush Video-based Tic Rating Scale (RTRS) 
recordings to be used for educational purposes.  
Subjects who have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit >30 days prior to 
anticipated baseline (Day -1) require screening.  These subjects will be screened to determine eligibility within 20 
days (Days -21 to -2) before baseline (Day -1).  At baseline (Day -1), eligible subjects will return to the study site 
for collection of baseline safety and efficacy assessments. 
Subjects can have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit on the same day as 
baseline (Day -1) for this study provided this study’s informed consent, and assent (if applicable), is obtained 
before the final NBI-98854-1501 or NBI-98854-1505 visit.  This will allow certain pharmacodynamic (PD) and 
safety assessments to be used for both the previous study and the current study.     
On Day -1, all subjects will have baseline study assessments conducted and be assessed for eligibility.  Eligible 
subjects will receive a supply of NBI-98854 (10, 20, or 40 mg, based on their age group) for the first 4 weeks of 
treatment.  Beginning on Day 1, subjects will take study drug once daily at home at approximately the same time 
each day (under the supervision of the subject’s parent/legal guardian for pediatric subjects) throughout the 24-
week treatment period. 
At the end of Week 4, the investigator may escalate the NBI-98854 dose from 10 to 20 mg in children, from 20 to 
40 mg in adolescents, and from 40 to 80 mg in adults, or continue with the subject’s current dose for the remainder 
of the treatment period.  A dose escalation will be allowed if (1) the investigator or designee’s assessment of the 
Clinical Global Impression of Improvement-Tourette Syndrome (CGI-TS) is “minimally improved”, “not 
changed”, “minimally worse”, “much worse”, or “very much worse”, and (2) the safety and tolerability of the 
current dose is acceptable as determined by a physician.  The subject will then continue at this dose until the end of 
the treatment period (ie, the end of Week 24). 
At any time after dose escalation, the investigator may modify the timing of study drug dosing (eg, qam to qhs) 
and/or decrease a subject’s dose (to 10 mg for children, 20 mg for adolescents, or 40 mg for adults) if the subject is 
unable to tolerate the dose increase.  Subjects who are unable to tolerate the starting dose of 10 mg for children, 20 
mg for adolescents, 40 mg for adults, or the resumption of the 10 mg, 20 mg, or 40 mg dose following a tolerability 
issue after the dose escalation at Week 4, will be discontinued from the study. 
Subjects will return to the study site every 4 weeks during the treatment period, at the end of Weeks 4, 8, 12, 16, 
20, and 24.  As much as possible, these visits should occur at approximately the same time of day.  For pediatric 
subjects only, the study site will call the subject or parent/legal guardian at study Week 2 and Week 6 to inquire 
about any study drug-related issues related to compliance or tolerability. 
A follow-up visit will be performed at the end of Week 28 (4 weeks after the last dose of study drug) or early 
termination.  Subjects who withdraw from the study at any time during the treatment period will be asked to 
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complete an early termination visit within 4 weeks.  Safety, PD, and pharmacokinetics (PK) will be assessed at 
scheduled times throughout the study.  The treatment period visits (end of Weeks 4, 8, 12, 16, 20, and 24) and the 
follow-up visit (end of Week 28) will have a visit window of ±6 days. 
Study Population: 
This study will be conducted in up to 180 male and female subjects with a Diagnostic and Statistical Manual of 
Mental Disorders (DSM)-IV or -V diagnosis of TS.  A total of up to 90 pediatric subjects (6 to 17 years of age 
[inclusive]) and up to 90 adult subjects (18 to 64 years of age [inclusive]) will be enrolled into this study.  This 
study will only enroll subjects who had previously participated in and completed the NBI-98854-1501 or 
NBI-98854-1505 study and express an interest in continuing to receive or re-initiate NBI-98854.  
Duration of Treatment and Study Participation: 
The expected duration of study participation for each subject is up to 31 weeks, including a 3-week screening 
period, a 24-week treatment period, and a 4-week follow-up period. 
Investigational Product, Dose, and Mode of Administration: 
NBI-98854 will be supplied as capsules containing 10 mg, 20 mg, or 40 mg of NBI-98854 (free base).  The 
NBI-98854 80 mg dose will be administered as two 40 mg capsules.  The NBI-98854 capsules will be taken with at 
least 4 oz. of water. 
Reference Therapy, Dose, and Mode of Administration:  Not applicable. 
Criteria for Evaluation:   
Pharmacodynamics:  The following PD assessments will be administered at baseline (Day -1), at the end of 
Weeks 4, 8, 12, 16, 20, and 24, and at the follow-up visit (the end of Week 28, or early termination): 
All subjects:  
• 
Yale Global Tic Severity Score (YGTSS) 
• 
Rush Video-based Tic Rating Scale 
• 
Premonitory Urge for Tics Scale (PUTS) 
• 
Clinical Global Impression (CGI)-Tics Severity 
Pediatric subjects only:  
• 
Pediatric Quality of Life Inventory (PedsQL) 
Adult subjects only:   
• 
Gilles de la Tourette Syndrome-Quality of Life (GTS-QOL) 
The CGI-TS (assessed by the investigator) and Patient Global Impression of Change-Tourette Syndrome 
(PGIC-TS) scales will be administered at the end of Weeks 4, 8, 12, 16, 20, and 24, and at the follow-up visit (the 
end of Week 28 or upon early termination) in all subjects.  
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Criteria for Evaluation (continued):   
Plasma Drug Exposure:  Blood samples to evaluate plasma concentrations of NBI-98854, and the metabolite 
NBI-98782, will be collected during the treatment period (end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow 
up visit (end of Week 28, or early termination). 
Safety:  Safety and tolerability will be monitored throughout the study and will include the following assessments:  
All subjects: 
• 
Adverse events (AEs) 
• 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
• 
Serum prolactin 
• 
Hemoglobin A1c 
• 
Vital signs (including orthostatic blood pressures and pulse, respiratory rate, and oral body temperature) 
• 
Physical examinations (including height and weight) 
• 
12-lead electrocardiograms (ECGs) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) (pediatric version will be used for pediatric subjects) 
• 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A)  
Pediatric subjects only:   
• 
Children’s Depression Rating Scale - Revised (CDRS-R), Children’s Yale-Brown Obsessive-Compulsive 
Scale (CY-BOCS), and Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale 5:  Home Version 
Adult subjects only:   
• 
Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Structured Interview Guide for the Hamilton 
Depression Rating Scale (SIGH-D-17) 
If the final study visit for the previous study occurs on the same day as Day -1 of the current study, the PD 
assessments that can apply to both the previous study and the current study include the YGTSS, RTRS, PUTS, and 
CGI-Tics-Severity.  The safety assessment results that can apply to both the previous study and the current study 
include physical examinations (including weight), vital signs, ECGs, ESRS-A, CY-BOCS, CDRS-R, Y-BOCS, and 
SIGH-D-17.  Other Day -1 assessments (including safety labs) must be collected for the current study (even if the 
subject is completing the final visit for the previous study). 
Statistical methods: 
All safety, PK, and PD data will be summarized by treatment and timepoint (as appropriate) using descriptive 
statistics. 
The PD measures in this study include the YGTSS-Total Tic Score (TTS) as scored by the certified site raters 
using Rater Stationsm, RTRS, PUTS, CGI-TS, PGIC-TS, CGI-Tics-Severity, PedsQL(pediatric subjects only), and 
GTS-QOL (adult subjects only). 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADHD 
Attention-Deficit Hyperactivity Disorder 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CBIT 
Comprehensive Behavioral Intervention for Tics 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CDS 
Clinical Drug Safety 
CFR 
Code of Federal Regulations 
CGI-Tics-Severity 
Clinical Global Impression of Tics-Severity 
CGI-TS 
Clinical Global Impression of Improvement-Tourette Syndrome 
Cmax  
Maximum plasma concentration 
CRT 
Controlled room temperature 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CY-BOCS 
Children’s Yale-Brown Obsessive-Compulsive Scale 
CYP 
Cytochrome P450 
DSMB 
Data Safety Monitoring Board 
DSM-IV or -V 
Diagnostic and Statistical Manual of Mental Disorders 4th or 5th 
Editions 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA K2 
Dipotassium ethylenediaminetetraacetic acid 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated 
FDA 
[United States] Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GTS-QOL 
Gilles de la Tourette Syndrome-Quality of Life Scale 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibody 
HIV-Ab 
Human immunodeficiency virus antibody 
HR 
Heart rate 
HRQOL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MAOI 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
PD 
Pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory 
PGIC-TS 
Patient Global Impression of Change-Tourette Syndrome 
PK 
Pharmacokinetic(s) 
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prn 
As needed 
PUTS 
Premonitory Urge for Tics Scale 
QTcF 
Corrected QT interval using Fridericia’s formula 
RTRS 
Rush Video-based Tic Rating Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SIGH-D-17 
Structured Interview Guide for the Hamilton Depression Rating 
Scale 
TEAE 
Treatment-emergent adverse event 
TD 
Tardive dyskinesia 
TS 
Tourette Syndrome 
TTS 
Total Tic Score 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
US 
United States 
VMAT2 
Vesicular monoamine transporter 2 
Y-BOCS 
Yale-Brown Obsessive-Compulsive Scale 
YGTSS 
Yale Global Tic Severity Scale 
 
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4. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) standards 
that meet regulations relating to Good Clinical Practice (GCP).  These standards respect the 
following guidelines: 
• Good Clinical Practice: Consolidated Guideline (International Conference on Harmonisation 
[ICH] of Technical Requirements for the Registration of Pharmaceuticals for Human Use, 
May 1996). 
• United States (US) Code of Federal Regulations (CFR) regulating clinical studies (21 CFR 
parts 50, 54, 56, 312, and 314). 
The ethical requirements of Institutional Review Boards/Ethics Committees (IRBs/ECs) and the 
informed consent forms (ICFs) and assent forms are discussed in Section 14. 
5. 
INTRODUCTION 
5.1. 
Background 
Tourette Syndrome (TS) is a disorder characterized by the presence of chronic motor and 1 or 
more vocal tics that often appear in childhood or early adolescence (American Psychiatric 
Association, 1994).  Tics are defined as rapid, non-rhythmic, stereotyped motor movements or 
vocalizations, and are typically categorized as simple or complex based on their overt features. 
Simple tics are brief, meaningless actions (eg, forceful blinking of the eyes or grunting) and 
complex tics are slower, more purposeful behaviors (eg, gyrating or uttering phrases; Leckman 
et al., 1989; Cavanna and Nani, 2013; Shprecher and Kurlan, 2009).  The tics follow a waxing 
and waning course over time, and must be recurrent for a period of more than one year to 
qualify for diagnosis.  In addition to tic phenomena, TS may also present with a constellation of 
symptoms that are part of a broader “TS spectrum,” which can include obsessive-compulsive 
behaviors, attention-deficit/hyperactivity disorder (ADHD), and impulsive or antisocial 
behavior (Chen et al., 2012; Felling and Singer, 2011). 
Persistent tics can have a significant impact on quality of life and often lead to impaired 
psychosocial functioning.  Some of these problems include, but are not limited to, social 
isolation, bullying, physical discomfort (with pain or injury), and poor academic performance 
(Roessner et al., 2013).  Psychosocial stressors can, in turn, exacerbate tic symptomatology.  It 
is under these conditions that pharmacological interventions may be considered (Chen et al., 
2012; Shprecher and Kurlan, 2009; Roessner et al., 2013). 
Neuropathological models have been proposed to explain the symptomatic features of TS, and 
converging lines of empirical evidence consistently implicate dopaminergic dysfunction and 
dysregulation within prefrontal cortex-basal ganglia circuitry (Felling and Singer, 2011; Pourfar 
et al., 2011).  Functional neuroimaging studies have identified a pattern of prefrontal cortex 
hypermetabolism and reduced striatal activity in TS patients (Baxter and Guze, 1993; Braun et 
al., 1993; Pourfar et al., 2011).  Pharmacotherapeutic approaches aimed at blocking postsynaptic 
dopamine 2 receptors (eg, haloperidol and pimozide) have demonstrated efficacy in reducing TS 
symptoms.  In this regard, modulation of dopaminergic tone through the administration of a 
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vesicular monoamine transporter 2 (VMAT2) inhibitor, like NBI-98854, may also be an 
effective treatment option for tic suppression. 
5.2. 
NBI-98854 
NBI-98854 (valbenazine tosylate) is a highly selective, orally active VMAT2 inhibitor and is 
currently under development at NBI for the treatment of tardive dyskinesia (TD) and TS. 
In nonclinical studies, NBI-98854 appears to cause little or no cytochrome P450 (CYP) enzyme 
inhibition or induction at pharmacologically relevant concentrations.  Metabolism of NBI-98854 
is characterized by hydrolysis of NBI-98854 to NBI-98782, and CYP3A4/5-dependent mono-
oxidation to NBI-136110.  All 3 entities, namely, NBI-98854, NBI-98782, and NBI-136110, 
have the ability to bind to and inhibit VMAT2.  However, NBI-98782 is the most potent and 
appears to be responsible for the majority of the observed pharmacological activity of VMAT2 
inhibition.  NBI-98854 delivers NBI-98782 in a controlled fashion with limited peak-to-trough 
plasma concentration fluctuation and low pharmacokinetic (PK) variability that should limit 
adverse events (AEs) associated with excessive monoamine depletion.  There was no evidence 
of teratogenicity in rats or rabbits. 
Thirteen clinical studies with NBI-98854 have been completed to date:  9 Phase 1 studies, 8 in 
healthy male and female elderly and nonelderly subjects, and 1 in hepatically impaired adults; 
and 4 Phase 2 studies in subjects with TD and a clinical diagnosis of schizophrenia or 
schizoaffective disorder, mood disorder, or gastrointestinal disorder.  In addition, preliminary 
data are available for the 6-week, placebo-controlled period for the ongoing Phase 3 study 
NBI-98854-1304 in subjects with TD and a clinical diagnosis of schizophrenia or 
schizoaffective disorder, or mood disorder.  A total of 510 subjects have received at least 1 dose 
of NBI-98854 and 246 received placebo in these studies.  Clinically and statistically significant 
reductions in TD symptoms have been demonstrated in the phase 2 and phase 3 clinical studies. 
Clinical PK data indicate that when administered orally under fasted conditions, NBI-98854 
appeared to be rapidly absorbed with maximum plasma concentration (Cmax) being reached 
within 1 hour.  An active metabolite, NBI-98782, was formed gradually with Cmax typically 
being reached 4 to 10 hours after dosing.  Plasma concentrations for both NBI-98854 and 
NBI-98782 appeared to decline after reaching maximal concentration and both exhibited an 
apparent terminal half-life of approximately 20 hours in non-elderly adult subjects and 23 to 28 
hours in elderly subjects.  Coadministration of ketoconazole (strong CYP3A4/5 inhibitor) with 
NBI-98854 caused an approximate 1.5- and 1.7-fold increase in Cmax of NBI-98854 and 
NBI-98782, respectively.  Coadministration of NBI-98854 and rifampin resulted in a decrease 
in systemic exposure to NBI-98854, a decrease in systemic exposure to NBI-98782, and an 
increase in Cmax for NBI-136110, but a decrease in area under the plasma concentration versus 
time curve extrapolated to infinity (AUC0–∞) for NBI-136110. 
NBI-98854 has been generally well tolerated in single doses up to 300 mg and in multiple doses 
of up to 100 mg.  In Phase 2 studies and the interim analysis from one Phase 3 study, treatment-
emergent adverse events (TEAEs) were reported by 42.8% and 36.4% of NBI-98854 and 
placebo subjects, respectively.  AEs reported in ≥2% of NBI-98854 subjects and at a higher 
incidence than placebo included somnolence, headache, fatigue, vomiting, dry mouth, akathisia, 
and fall.  Suicidal ideation was reported in a similar percentage of subjects receiving NBI-98854 
or placebo (2.0% and 1.9%, respectively).  Most TEAEs were mild or moderate in intensity.  
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Two deaths have been reported in clinical studies; 1 subject who received placebo died due to 
cardiopulmonary arrest secondary to myocardial infarction and the second subject died possibly 
due to a cardiovascular event (treatment remains blinded).  No treatment-emergent serious AEs 
(SAEs) have been reported in Phase 1 studies.  In Phase 2 studies and the interim analysis from 
one Phase 3 study, SAEs were reported in 17 subjects (4.9%) who received NBI-98854 and 
6 subjects (2.8%) who received placebo.  There were no clinically important differences in the 
number or types of SAEs reported across dose groups.  Only 1 SAE (acute hepatitis) was 
assessed by the investigator as possibly related to study drug.  No cardiovascular, laboratory, or 
vital sign related safety signals have been identified.  Increases in serum prolactin above normal 
laboratory ranges have been noted, but there have been no TEAEs associated with 
hyperprolactinemia.  In general, depression, drug-induced akathisia, and drug-induced 
parkinsonism did not worsen during treatment with NBI-98854. 
Three NBI-98854 studies in subjects with TS are discussed in Section 5.3. 
5.3. 
Study and Dose Rationale 
All subjects in the current study will have previously received NBI-98854 10 mg to 80 mg for 6 
to 8 weeks or placebo in a Phase 2 NBI-98854 study (NBI-98854-1501 or NBI-98854-1505).  In 
the current study, subjects will receive a starting dose of NBI-98854 (10 mg in children [6 to 11 
years of age], 20 mg in adolescents [12 to 17 years of age], and 40 mg in adults) once daily for 4 
weeks.  At the end of Week 4, the investigator may escalate the subject’s dose (to 20 mg in 
children, 40 mg in adolescents, or 80 mg in adults) or continue with the subject’s current dose.  
A dose escalation will be allowed at the end of Week 4 based on the physician investigator’s (or 
designee’s) assessments of the safety and tolerability of NBI-98854 as well as clinical 
impression of TS. 
The initial Phase 1b, open-label, multiple-dose study of the safety, tolerability, PK, and 
pharmacodynamics (PD) of NBI-98854 (NBI-98854-1403) was conducted in 17 male and 
female adolescents with TS (12 to 18 years of age) and 11 male and female children with TS 
(6 to 11 years of age).  Doses of NBI-98854 10 mg, 25 mg, or 50 mg were administered in 
adolescents, and doses of NBI-98854 5 mg and 10 mg were administered in children daily over 
a 14-day treatment period following a multiple ascending dose protocol.  The dose strengths for 
Study NBI-98854-1403 were selected based on prior clinical experience with NBI-98854 in 
adult patients with a diagnosed hyperkinetic movement disorder, TD, as well as thorough PK 
modeling that specified body weight as a key covariate.  Preliminary results from 
NBI-98854-1403 show that these doses have been well-tolerated in both child and adolescent 
age groups, and the observed plasma concentration measures of NBI-98854 and its metabolites 
in the subjects evaluated in both age groups are consistent with the a priori, PK model-based 
predictions of study drug exposure.  
Study NBI-98854-1501 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel group, dose-ranging study to evaluate the efficacy, safety, and tolerability of 2 doses of 
NBI-98854 (10 mg and 20 mg in children [6 to 11 years of age], and 20 mg and 40 mg in 
adolescents [12 to 17 years of age]) relative to placebo, administered once daily for 6 weeks in 
pediatric subjects with TS.  Subjects within each age group will be randomized in a 1:1:1 ratio 
to placebo or 1 of the 2 NBI-98854 doses.  This study opened to screening in March 2016. 
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Study NBI-98854-1505 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel group study to evaluate the efficacy, safety, and tolerability of 2 doses of NBI-98854 
(40 mg and 80 mg) relative to placebo, administered once daily for 8 weeks in adult subjects 
with TS. Subjects will be randomized in a 1:1:1 ratio to placebo or 1 of the 2 NBI-98854 doses.  
This study opened to screening in November 2015.  
Rationale for Dose Selection 
The doses used in this Phase 2 study reflect the doses that are being used in the ongoing Phase 2 
placebo-controlled studies in pediatric and adult subjects with TS.  The doses selected for the 
pediatric subjects are within the NBI-98854 dose range evaluated in Study NBI-98854-1403 and 
have been demonstrated to be safe and well-tolerated in the pediatric TS subjects dosed with 
NBI-98854 to date.  The doses selected for the adult subjects are aligned with those selected for 
evaluation in the Phase 3 TD program. 
6. 
STUDY OBJECTIVES 
The objective of this clinical study is to evaluate the safety and tolerability of NBI-98854 
(titrated from 10 mg to 20 mg in children, 20 mg to 40 mg in adolescents, and 40 mg to 80 mg 
in adults) administered once daily for up to 24 weeks for the treatment of TS. 
7. 
OVERVIEW OF STUDY DESIGN 
This is a Phase 2, open-label, fixed-dose titration study to evaluate the safety and tolerability of 
NBI-98854 administered once daily for a total of 24 weeks in children, adolescents, and adults 
with TS.  NBI-98854 doses will be titrated from 10 mg to 20 mg in children (6 to 11 years of 
age), 20 mg to 40 mg in adolescents (12 to 17 years of age), and 40 mg to 80 mg in adults (18 to 
64 years of age).  Up to 180 male and female subjects (up to 90 pediatric subjects [ie, children 
and adolescents] and up to 90 adult subjects) with a clinical diagnosis of TS will be enrolled.  
The study will include approximately 60 study sites in the United States. 
Parental or legal guardian informed consent with signed and witnessed pediatric assent for 
pediatric subjects or informed consent for adult subjects must be obtained prior to conduct of 
any study-related procedures.  Subjects will also be asked to sign an optional release form to 
allow their Rush Video-based Tic Rating Scale (RTRS) recordings to be used for educational 
purposes.   
Subjects who have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit 
>30 days prior to anticipated baseline (Day -1) require screening.  These subjects will be 
screened to determine eligibility within 20 days (Days -21 to -2) before baseline (Day -1). 
Subjects can have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit on the 
same day as baseline (Day -1) for this study provided that the NBI-98854-1601 informed 
consent, and assent (if applicable), is obtained before the final NBI-98854-1501 or 
NBI-98854-1505 visit.  This will allow certain PD and safety assessments to be used for both 
the previous study and the current study.  The PD assessments that can apply to both the 
previous study and the current study include the Yale Global Tic Severity Score (YGTSS), 
RTRS, Premonitory Urge for Tics Scale (PUTS), and Clinical Global Impression (CGI) of 
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Tics-Severity.  The safety assessment results that can apply to both the previous study and the 
current study include physical examinations (including weight), vital signs, electrocardiograms 
(ECG), Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A), Children’s Yale-Brown 
Obsessive-Compulsive Scale (CY-BOCS; pediatric subjects only), Children’s Depression 
Rating Scale - Revised (CDRS-R; pediatric subjects only), Yale-Brown Obsessive-Compulsive 
Scale (Y-BOCS; adult subjects only), and the Structured Interview Guide for the Hamilton 
Depression Rating Scale (SIGH-D-17; adult subjects only).  All other Day -1 assessments 
(including safety labs) must be collected for the current study (even if the subject is completing 
the final visit for the previous study).    
On Day -1, all subjects will have baseline study assessments conducted and be assessed for 
eligibility.  Eligible subjects will receive a supply of NBI-98854 (10, 20, or 40 mg, based on 
their age group) for the first 4 weeks of treatment.  Beginning on Day 1, subjects will take study 
drug once daily at home at approximately the same time each day (under the supervision of the 
subject’s parent/legal guardian for pediatric subjects) throughout the 24-week treatment period. 
At the end of Week 4, the investigator may escalate the NBI-98854 dose from 10 to 20 mg in 
children, from 20 to 40 mg in adolescents, and from 40 to 80 mg in adults, or continue with the 
subject’s current dose for the remainder of the treatment period.  A dose escalation will be 
allowed if (1) the investigator or designee’s assessment of the Clinical Global Impression of 
Improvement -Tourette Syndrome (CGI-TS) is “minimally improved”, “not changed”, 
“minimally worse”, “much worse”, or “very much worse”, and (2) the safety and tolerability of 
the current dose is acceptable as determined by a physician.  The subject will then continue at 
this dose until the end of the treatment period (ie, the end of Week 24). 
At any time after dose escalation, the investigator may modify the timing of study drug dosing 
(eg, qam to qhs) and/or decrease a subject’s dose (to 10 mg for children, 20 mg for adolescents, 
or 40 mg for adults) if the subject is unable to tolerate the dose increase.  Subjects who are 
unable to tolerate the starting dose of 10 mg for children, 20 mg for adolescents, 40 mg for 
adults, or the resumption of the 10 mg, 20 mg, or 40 mg dose after the dose escalation at Week 
4, will be discontinued from the study. 
Subjects will return to the study site every 4 weeks during the treatment period, at the end of 
Weeks 4, 8, 12, 16, 20, and 24.  As much as possible, these visits should occur at approximately 
the same time of day.  For pediatric subjects only, the study site will call the subject or 
parent/legal guardian approximately 2 weeks and 6 weeks after starting dosing (ie, at study 
Weeks 2 and 6) to inquire about any study drug-related issues with regard to compliance or 
tolerability.   
A follow-up visit will be performed at the end of Week 28 (4 weeks after the last dose of study 
drug) or early termination.  Subjects who withdraw from the study will be asked to complete an 
early termination visit within 4 weeks.  Safety, PD, and PK will be assessed at scheduled times 
throughout the study.  The treatment period visits (end of Weeks 4, 8, 12, 16, 20, and 24) and 
the follow-up visit (end of Week 28) will have a visit window of ±6 days. 
A schematic of the study design is shown in Figure 1. 
 
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Figure 1: 
Study Design Schematic 
Week 
1
4
NBI-98854 
Treatment  Period
16
Follow-up
        -1
Day 
Follow-
up 
Period
8
10 mg or 20 mg NBI-98854
24
12
20
28
Screening 
Screening
 Period
            
-21
20 mg 
NBI-
98854
20 mg or 40 mg NBI-98854
10 mg 
NBI-
98854
Children: 6-11 y.o.
Adolescents: 12-17 y.o.
40 mg 
NBI-
98854
40 mg or 80 mg NBI-98854
Adults: 18-64 y.o.
Subjects who enter the study within 30 days of completing NBI-98854-1501 or NBI-98854-1505 are not required 
to undergo screening and the first day of the study is Day -1 (baseline) for these subjects. 
8. 
STUDY POPULATION 
This study will be conducted in up to 180 male and female subjects with a Diagnostic and 
Statistical Manual of Mental Disorders (DSM)-IV or -V diagnosis of TS.  A total of up to 90 
pediatric subjects (6 to 17 years of age [inclusive]) and up to 90 adult subjects (18 to 64 years of 
age [inclusive]) will be enrolled into this study.  This study will only enroll subjects who had 
previously participated in and completed the NBI-98854-1501 or NBI-98854-1505 study and 
express an interest in continuing to receive or re-initiate NBI-98854.  Subjects must meet all the 
inclusion criteria and none of the exclusion criteria in order to qualify for the study. 
8.1. 
Inclusion Criteria 
8.1.1. 
Inclusion Criteria for All Subjects 
To participate in this study, subjects must: 
1. Have documentation of written and witnessed assent from the subject and written informed 
consent from the subject’s parent or legal guardian for pediatric subjects or have provided 
written informed consent for adult subjects. 
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2. Have participated in and completed the NBI-98854-1501 or NBI-98854-1505 Phase 2 study.  
Subjects can have their final NBI-98854-1501 or NBI-98854-1505 visit on the same day as 
Day -1 for this study provided the current study’s informed consent, and assent (if 
applicable), is obtained before the final NBI-98854-1501 or NBI-98854-1505 visit. 
3. Be male or female, aged 6 to 64 years, inclusive. 
4. Be in good general health and expected to complete the study as designed. 
5. Have a DSM-IV or -V diagnosis of TS. 
6. Subjects with TS spectrum diagnoses (eg, obsessive-compulsive disorder [OCD], ADHD) 
must have a stable psychiatric status as clinically determined by the investigator at screening 
(if applicable) and at baseline (Day -1). 
7. If medications are being used to treat TS symptoms and/or TS spectrum diagnoses, subjects 
must be on stable doses of these medications for a minimum of 30 days before baseline 
(Day -1), and the medication regimen is expected to remain stable throughout the study 
period.  The use of dopamine antagonists (eg, pimozide, haloperidol, aripiprazole, 
risperidone, clozapine, olanzapine, ziprasidone) and/or tetrabenazine to treat TS symptoms 
is prohibited.  Other nondopaminergic tic suppression therapy (eg, clonidine, guanfacine) is 
allowed during the study period as long as the dose regimen has been stable for a minimum 
of 30 days before baseline (Day -1). 
8. Subjects with stable medical conditions requiring medications that are not prohibited per 
protocol must be on stable doses of these medications for a minimum of 30 days before 
baseline (Day -1), and the medication regimen is expected to remain stable throughout the 
study period. 
9. Subjects must use contraception consistently from baseline (Day -1) until 30 days after the 
last dose of study drug for female subjects and 90 days after the last dose of study drug for 
male subjects. 
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom). 
• Vaginal sponge impregnated with spermicide used with condom. 
• Intrauterine device (IUD). 
• Hormonal contraception taken for at least 3 months prior to baseline (Day -1). 
The following subjects are not required to use contraception: 
• Subjects who practice total abstinence from sexual intercourse as the preferred lifestyle 
(periodic abstinence is not acceptable). 
• Female subjects not of childbearing potential (ie, have not reached menarche, 
postmenopausal for at least 1 year prior to screening, or surgically sterile [bilateral 
oophorectomy, hysterectomy or bilateral tubal ligation] at least 3 months prior to 
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screening) or with male partners who have been vasectomized at least 3 months prior to 
screening. 
• Male subjects not of child-producing potential (ie, have not reached spermarche or who 
have been vasectomized at least 3 months prior to screening) or with female partners not 
of childbearing potential (as listed above). 
10. Female subjects of childbearing potential must have a negative urine pregnancy test at 
baseline (Day -1). 
11. Be willing to provide authorization (adult subjects) or the subject’s parent or legal guardian 
is willing to provide authorization (pediatric subjects) for access to personal health 
information in conjunction with US Health Insurance Portability and Accountability Act 
(HIPAA).  
12. Be willing and able to adhere to the study regimen and study procedures described in the 
protocol and informed consent/assent forms, including all requirements at the study site and 
return for the follow-up visit. 
8.1.2. 
Inclusion Criteria for Pediatric Subjects 
In addition to the inclusion criteria for all subjects, the following criteria must be met for 
pediatric subjects (age 6 to 17 years of age [inclusive]): 
13. Have a body weight (in kilograms [kg]) greater than or equal to the 5th percentile, but less 
than the 95th percentile of his/her age- and gender-matched weight percentile at baseline 
(Day -1). 
8.1.3. 
Inclusion Criteria for Adult Subjects 
In addition to the inclusion criteria for all subjects, the following criteria must be met for adult 
subjects (age 18 to 64 years of age [inclusive]): 
14. Have a body mass index (BMI) of 18 to 40 kg/m2 (inclusive) at baseline (Day -1). (BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters.) 
8.1.4. 
Inclusion Criteria for Adolescent and Adult Subjects 
In addition to the inclusion criteria for all subjects, the following criteria must be met for 
adolescent and adult subjects (age 12 to 64 years of age [inclusive]): 
15. Must have a negative urine drug screen ([UDS]; negative for amphetamines, 
barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids) at 
screening (if applicable) and at baseline (Day -1) (including results from UDS 
performed at the clinical site and UDS results from the central lab).  At baseline 
(Day -1), results from the UDS performed at the clinical site will be used by the 
investigator to confirm eligibility.  Subjects who are on stable doses of prescribed and 
supervised (not as needed [prn]) benzodiazepines, opiates, or psychostimulants (for 
subjects with comorbid ADHD) are allowed to participate in the study.  Adult subjects 
with a positive UDS for cannabinoids are eligible for participation if the use is for 
medicinal purposes and there is no indication of cannabinoid abuse.  
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16. Must have a negative alcohol breath test at screening (if applicable) and at baseline 
(Day -1). 
8.2. 
Exclusion Criteria 
8.2.1. 
Exclusion Criteria for All Subjects 
Subjects will be excluded from the study if they: 
1. Have an active clinically significant unstable medical condition within 30 days prior to 
baseline (Day -1). 
2. Excessive use of tobacco and/or nicotine-containing products (based on the investigator’s 
assessment) within 30 days of baseline (Day -1). 
3. Have a history of substance (drug or alcohol) dependence or abuse within the 3 months 
before baseline (Day -1), as defined in the DSM-IV (Substance Dependence or Abuse) or 
DSM-V (Substance Use Disorder).  
4. Are currently pregnant or lactating.  
5. Have a known history of neuroleptic malignant syndrome. 
6. Have a known history of long QT syndrome or cardiac arrhythmia. 
7. Have a screening (if applicable) or baseline (Day -1) triplicate average ECG QT interval 
corrected for heart rate using Fridericia’s formula (QTcF) of >450 msec (adult male subjects 
and pediatric subjects) or >470 msec (adult female subjects) or the presence of any clinically 
significant cardiac abnormality. 
8. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to baseline 
(Day -1), with the exception of localized skin cancer or carcinoma in situ of the cervix. 
9. Have received an investigational drug (other than NBI-98854) within 30 days before 
baseline (Day -1) or plan to use an investigational drug (other than NBI-98854) during the 
study. 
10. Receive any excluded concomitant medication (refer to Section 9.7.1). 
11. Have initiated Comprehensive Behavioral Intervention for Tics (CBIT) at baseline (Day -1) 
or plan to initiate CBIT during the study. 
12. Have a significant risk of suicidal or violent behavior.  Pediatric subjects with any lifetime 
suicidal behavior or adult subjects with any suicidal behavior in the past year will be 
excluded.  Any subject with suicidal ideation of type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) in the past year based on the “Baseline/Screening version” of the Columbia Suicide 
Severity Rating Scale (C-SSRS) (assessed at screening or at baseline [Day -1]) will be 
excluded.   
13. Have ingested foods containing poppy seeds within 7 days before baseline (Day -1). 
14. Have an allergy, hypersensitivity, or intolerance to tetrabenazine. 
15. Have a history of or suspected poor compliance in clinical research studies. 
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16. For subjects who require screening only:  Have a clinical laboratory value not within the 
laboratory’s reference range and deemed by the investigator to be clinically significant at 
screening 
17. For subjects who require screening only:  Have a positive human immunodeficiency virus 
antibody (HIV-Ab) test result, hepatitis B surface antigen (HBsAg) test result or positive 
hepatitis C virus antibody (HCV-Ab) test result with a positive HCV polymer chain reaction 
(PCR) result at screening. 
8.2.2. 
Exclusion Criteria for Pediatric Subjects 
In addition to the exclusion criteria for all subjects, the following exclusion criteria apply to 
pediatric subjects (age 6 to 17 years of age [inclusive]): 
18. Have a blood loss ≥250 mL or donated blood within 56 days or donated plasma within 
7 days of baseline (Day -1). 
19. Have history of severe hepatic impairment or have chronic elevation of aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) ≥1.5 times upper limit of  
normal (ULN). 
20. For subjects who require screening only:  Have AST, ALT, gamma-glutamyl transferase 
(GGT), total bilirubin, or serum creatinine levels ≥1.5 times the ULN at screening. 
21. For subjects who require screening only:  Have any of the following hematologic 
abnormalities at screening: 
• Hemoglobin <11.0 g/dL. 
• White blood cell (WBC) count <4.0 × 103/mm3. 
• Platelet count <100,000/mm3. 
8.2.3. 
Exclusion Criteria for Adult Subjects 
In addition to the exclusion criteria for all subjects, the following exclusion criteria apply to 
adult subjects (age 18 to 64 years of age [inclusive]): 
22. Have a blood loss ≥550 mL or donated blood within 30 days of baseline (Day -1). 
23. Have history of severe hepatic impairment or have chronic elevation of AST or ALT ≥2.5 
times ULN. 
24. For subjects who require screening only:  Have any of the following laboratory test 
abnormalities at screening: 
• Serum creatinine >1.5 times the ULN. 
• AST ≥2.5 times ULN. 
• ALT ≥2.5 times ULN. 
• GGT ≥3.0 times ULN.  
• Total bilirubin >1.5 mg/dL. 
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25. For subjects who require screening only:  Have any of the following hematologic 
abnormalities at screening: 
• Hemoglobin <10.0 g/dL. 
• WBC count <3.0 x 103/mm3. 
• Platelet count <100,000/mm3. 
8.3. 
Subject Identification and Replacement 
Subjects will be identified by their unique subject number and initials (first, middle, last).  The 
subject initials and subject number will be noted on electronic case report forms (eCRFs), all 
source documentation, laboratory documents, and ECG tracings.  Subjects who discontinue 
from the study will not be replaced. 
8.4. 
Randomization 
Subjects will not be randomized in this study. 
9. 
STUDY EVALUATIONS 
9.1. 
Schedule of Assessments 
A schedule of assessments that summarizes the frequency and timing of all assessments is 
provided in Table 1.  No protocol-related procedures should be performed before parental or 
legal guardian informed consent with written and witnessed assent (pediatric subjects), or 
informed consent (adult subjects) have been obtained.  Subject-related events and activities 
including specific instructions, procedures, concomitant medications, dispensing of study drug, 
and descriptions of AEs should be recorded in the appropriate source documents and eCRFs.
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Table 1: 
Schedule of Assessments 
Procedurea 
Screeningb  
Baseline 
Open-Label  NBI-98854 Treatment Period 
Follow-up/ET 
Weekc   Day -21 to -2 
Day -1 
Day 1 
4 
8 
12 
16 
20 
24 
28d 
Informed consent/assent 
X 
Xe 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Physical exam (including weight) 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Xe 
 
 
 
 
 
 
 
Xg 
Vital signs 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testi 
X (s,u) 
X (u) 
 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
Xe 
 
 
 
 
 
 
 
 
Clinical laboratory testsj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
UDS and alcohol breath testk 
X 
X 
 
 
 
 
 
 
 
 
Hemoglobin A1c 
 
X 
 
 
 
X 
 
 
X 
X 
Serum prolactin 
 
X 
 
X 
 
X 
 
 
X 
X 
PK blood sample 
 
 
 
X 
X 
X 
X 
X 
X 
X 
YGTSS (including video recording) 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
RTRS 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
PUTS 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
CGI-Tics-Severity  
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
CGI-TS and PGIC-TS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRSl 
Xm 
Xn 
 
X 
X 
X 
X 
X 
X 
X 
ESRS-A 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
NBI-98854 dosing at homeo 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense NBI-98854p 
 
X 
 
X 
X 
X 
X 
X 
 
 
NBI-98854 accountabilityq 
 
 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visits 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pediatric subjects only 
PedsQL, CDRS-R, CY-BOCS, ADHD Rating Scale 5: Home Version 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
Adults subjects only 
GTS-QOL, Y-BOCS, SIGH-D-17 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
Footnotes and definitions appear on the next page. 
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ADHD=attention-deficit hyperactivity disorder; AE=adverse event; CDRS-R=Children’s Depression Rating Scale-Revised; CGI-Tics-Severity=Clinical Global 
Impression of Tics-Severity; CGI-TS=Clinical Global Impression of Improvement-Tourette Syndrome; C-SSRS=Columbia Suicide Severity Rating Scale; 
CY-BOCS=Children’s Yale-Brown Obsessive-Compulsive Scale; ECG=electrocardiogram; ESRS-A= Extrapyramidal Symptom Rating Scale-Abbreviated; 
GTS-QOL=Gilles de la Tourette Syndrome-Quality of Life; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus antibody; HIV-Ab=human 
immunodeficiency virus antibody; PedsQL=Pediatric Quality of Life Inventory; PGIC-TS=Patient Global Impression of Change-Tourette Syndrome; 
PK=pharmacokinetic; PUTS=Premonitory Urge for Tics Scale; RTRS=Rush Video-based Tic Rating Scale; S=serum; SIGH-D-17=Structured Interview Guide 
for the Hamilton Depression Rating Scale; U=urine; UDS=urine drug screen; Y-BOCS=Yale-Brown Obsessive-Compulsive Scale; YGTSS=Yale Global Tic 
Severity Scale. 
a As much as possible, the study visits should occur at approximately the same time of day in order to standardize the timing of safety, PD, and plasma exposure 
measurements during each visit.  
b Screening is not required for subjects who completed NBI-98854-1501 or NBI-98854-1505 within 30 days prior to Day -1. 
c The study visits after Day -1 will have a visit window of ±6 days. 
d Final study visit for subjects who complete the study (or early termination). 
e Not required for subjects who underwent screening. 
f For subjects completing the final NBI-98854-1501 or NBI-98854-1505 visit on the same day as Day -1, the NBI-98854-1501 or NBI-98854-1505 assessment 
will be used for Day -1 (not applicable to the PedsQL, ADHD Rating Scale 5: Home Version, or the GTS-QOL). 
g Measurement of height at follow-up/early termination visit required for pediatric subjects only. 
h A standard 12-lead ECG will be conducted in triplicate (1 to 3 minutes apart) after the subject has rested supine for at least 5 minutes. 
i Pregnancy tests are only required for subjects of childbearing potential.  Urine and serum pregnancy tests will be conducted at screening (if applicable).  Both 
pregnancy test results obtained at screening (if applicable) and the urine pregnancy test obtained at baseline (Day -1) will be used to confirm eligibility. 
j Clinical laboratory tests include hematology, chemistry, and urinalysis.  All blood samples will be obtained under non-fasted conditions. 
k For adolescents and adults only.  Urine drug screen (UDS) collected at screening (if applicable) and on Day -1 will be analyzed by the central lab; the UDS 
collected at screening and analyzed by the central lab will be used to confirm eligibility (if applicable).  In addition, a UDS kit provided by the central lab will 
be used at the clinical site to confirm eligibility at screening (if applicable) and on Day -1.  A UDS using a kit provided by the central lab may be conducted at 
the clinical site at any time during the study if the subject is suspected of substance or drug abuse. 
l The Children’s Version will be used for pediatric subjects. 
m The "Screening/Baseline" version will be administered at screening. 
n At baseline (Day -1), the "Since Last Visit" version will be administered to subjects who underwent screening, and the “Screening/Baseline” version will be 
administered to subjects who did not undergo screening. 
o Study drug will be administered once daily at home at approximately the same time each day under the supervision of the subject’s parent/legal guardian (for 
pediatric subjects) throughout the 24-week treatment period.  Day 1 is the first day of dosing, and subjects are not required to come to the study site.  Subjects 
or their parents/legal guardians will record daily the date and time of dosing on the drug packaging form provided.  For pediatric subjects only, the study site 
will call the subject or parent/legal guardian approximately 2 weeks and  6 weeks after starting dosing (ie, at study Weeks 2 and 6) to inquire about any study 
drug-related issues related to compliance or tolerability. 
p Subjects will receive a 4-week supply (two kits) of NBI-98854 at Day -1 and will need to return to study site every 4 weeks to obtain a 4-week supply of 
NBI-98854.  
q At the end of Weeks 4, 8, 12, 16, 20, and 24 subjects will return all used and unused study drug, and a compliance check will be performed by counting the 
capsules returned at the visit. 
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9.2. 
Pharmacodynamic Assessments 
9.2.1. 
Yale Global Tic Severity Scale 
The YGTSS will serve as the primary assessment of tic behaviors associated with TS (Leckman 
et al., 1989).  The YGTSS is designed to rate the overall severity of motor and phonic tic 
symptoms across a range of dimensions:  number, frequency, intensity, complexity, and 
interference.  The scale also includes an impairment assessment.  The YGTSS will be 
administered by the investigator (or qualified designee) using a computer-based structured 
clinical interview.  At each timepoint, the YGTSS interview will be video recorded in its 
entirety.  The video recording will follow a standardized set of guidelines and the recorded 
video will be uploaded to a secure central server.  A blinded, external video reviewer will access 
the central server to view the recording and determine if the YGTSS interview program was 
administered properly.  The computer software system for the YGTSS administration, Rater 
Stationsm (Bracket Global, LLC; Philadelphia, PA), will prompt the investigator (or a qualified 
designee), a trained and certified rater, to enter a score for each item of the scale based on 
subject and parent responses during the structured clinical interview.  The software will also 
generate individual scores for each item of the scale (tandem rating) and will generate the total 
tic score (TTS) and the Global Tic Severity Score.  A copy of the YGTSS is provided in 
Appendix 17.1. 
The YGTSS will be administered at baseline (Day -1) (not required for subjects who have their 
final NBI-98854-1501 or NBI-98854-1505 study visit on Day -1), during the treatment period 
(the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or 
upon early termination). 
9.2.2. 
Rush Video-Based Tic Rating Scale 
A modified RTRS will be used in this study that includes short video recordings to measure 
5 tic variables:  number of body areas affected, frequency of motor and phonic tics, and severity 
of motor and phonic tics (Goetz et al., 1999).  Subjects must be video recorded while seated 
comfortably in a quiet room facing the camera with their hands in their lap and feet on the floor.  
If desired, subjects may read a book, or draw or color pictures as long as these activities do not 
block the camera’s view of their face, neck and shoulders, arms, and legs.  The subject’s parent 
or legal guardian may be present in the room and should sit quietly away from the camera’s 
view.  Subjects should be video recorded for a total of approximately 10 minutes.  The 
investigator (or designee) should be present for approximately the first 2.5 minutes to aid the 
subject in adjusting to the procedure.  The subject should then be video recorded alone for 
approximately 5 minutes.  The investigator (or designee) should then re-enter the room and 
remain seated quietly in a corner of the room for approximately the last 2.5 minutes of the video 
recording.  The RTRS videos will be reviewed and scored by a central rater blinded to treatment 
sequence.  A copy of the RTRS is provided in Appendix 17.2. 
The RTRS will be administered at baseline (Day -1) (not required for subjects who have their 
final NBI-98854-1501 or NBI-98854-1505 study visit on Day -1), during the treatment period 
(the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or 
upon early termination). 
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9.2.3. 
Premonitory Urge for Tics Scale 
The PUTS is a valid and reliable instrument for quantifying the premonitory urge phenomena 
associated with tics (Woods et al., 2005).  Each of the 9 items in the PUTS is rated on a 4-point 
scale (1=not at all true, 2=a little true, 3=pretty much true, 4=very much true) and summed to 
yield at a total score reflecting the presence and frequency of pre-tic (ie, premonitory) urges 
along with relief that may be experienced after tics have been completed.  A copy of the PUTS 
is provided in Appendix 17.3. 
The investigator (or designee) will administer the PUTS at baseline (Day -1) (not required for 
subjects who have their final NBI-98854-1501 or NBI-98854-1505 study visit on Day -1), 
during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up 
visit (the end of Week 28 or upon early termination). 
9.2.4. 
Clinical Global Impression Scales 
The CGI-Tics–Severity and CGI-TS scales will be used to rate the subject’s overall severity of 
tics and overall improvement of TS.   
The CGI-Tics–Severity scale will be used to assess overall severity on a 7-point scale (range; 
1=normal, not at all ill to 7=among the most extremely ill patients).  The CGI-Tics-Severity will 
be assessed by the investigator at baseline (Day -1) (not required for subjects who have their 
final NBI-98854-1501 or NBI-98854-1505 study visit on Day -1), during the treatment period 
(the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or 
upon early termination).  A copy of the CGI-Tics–Severity scale is provided in Appendix 17.4. 
The CGI-TS scale will be used to assess overall improvement since the initiation of study drug 
dosing on a 7-point scale (range; 1=very much improved to 7=very much worse).  CGI-TS 
scales will be assessed by the investigator during the treatment period (the end of Weeks 4, 8, 
12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or upon early termination).  
A copy of the CGI-TS scale is provided in Appendix 17.5. 
9.2.5. 
Patient Global Impression of Change-Tourette Syndrome 
Subjects will evaluate the change in their TS symptoms since initiation of study drug dosing by 
choosing one of seven responses (Very Much Improved; Much Improved; Minimally Improved; 
Not Changed; Minimally Worse; Much Worse; Very Much Worse). 
The Patient Global Impression of Change-Tourette Syndrome (PGIC-TS) will be administered 
during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up 
visit (the end of Week 28 or upon early termination).  A copy of the PGIC-TS scale is provided 
in Appendix 17.6. 
9.2.6. 
Pediatric Quality of Life Inventory (Pediatric Subjects Only) 
The Pediatric Quality of Life Inventory (PedsQL) is a valid and reliable instrument that 
systematically assesses subjects’ and parents’ perceptions of health-related quality of life 
(HRQOL) in pediatric subjects with chronic health conditions (Varni et al., 1999).  The PedsQL 
is based on a modular approach to measuring HRQOL and includes a 15-item core measure of 
global HRQOL and 8 supplemental modules that assess specific symptom or treatment domains.   
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The PedsQL will be administered at baseline (Day -1), during the treatment period (the end of 
Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or upon early 
termination).  Three versions of the PedsQL will be used in this study, based on the age of the 
subject:  young child (ages 5-7 years), child (ages 8-12 years), and teen (ages 13-17 years).  
Copies of each version of the PedsQL are provided in Appendix 17.7. 
9.2.7. 
Gilles de la Tourette Syndrome-Quality of Life Scale (Adult Subjects Only) 
The Gilles de la Tourette Syndrome – Quality of Life Scale (GTS-QOL) is a valid, disease-
specific, patient-reported scale for the measurement of HRQOL in patients with TS (Cavanna et 
al., 2008).  The GTS-QOL comprises 27 items with 4 subscales (psychological, physical, 
obsessional, and cognitive).  The GTS-QOL will be administered at baseline (Day -1), during 
the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the 
end of Week 28 or upon early termination).  A copy of the GTS-QOL is provided in 
Appendix 17.8. 
9.3. 
Pharmacokinetic Evaluations 
Blood samples to evaluate plasma concentrations of NBI-98854, and the metabolite NBI-98782 
will be collected during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at 
the follow-up visit (the end of Week 28 or upon early termination). 
For each plasma sample, approximately 2 mL of blood will be collected in tubes containing 
dipotassium ethylenediaminetetraacetic acid (EDTA K2).  Once obtained, the samples should be 
thoroughly mixed.  If the sample is not centrifuged immediately, the collection tube will be 
placed upright in a test tube rack and kept on crushed ice.  Within 1 hour of collection, samples 
will be centrifuged at approximately 2,000 g for 10 minutes, preferably under refrigerated 
conditions (2 to 8°C).  The separated plasma will be aspirated using a disposable pipette and 
then transferred in approximately equal volumes into 2 vials.  The vials will be stoppered and 
labeled with the study barcode, subject number, primary or back-up sample designation (PK A 
and PK B, respectively), and nominal study date.  The samples will be stored at 
approximately -20°C within approximately 15 minutes of centrifugation.  The date and actual 
24-hour clock time of each collection will be recorded on the eCRF.  The duplicate plasma 
sample at each timepoint will be stored and used as backup.  These samples (including a 
manifest with additional information) will be shipped to a central laboratory for analysis to be 
stored at approximately -70°C.  Plasma samples remaining at the end of the study may be used 
for exploratory assessments. 
9.4. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 9.7.1 and Section 11, respectively.  Additional safety assessments are described in the 
following sections. 
Any abnormal vital sign measurement, physical examination finding, clinical laboratory test, or 
ECG parameter deemed clinically significant by the investigator will be repeated or followed, 
including test results obtained at the final study visit or upon early termination, until the value 
returns to baseline (or within normal limits), or the investigator deems the abnormality to be of 
no clinical significance.  If the investigator determines that a subject has a clinically significant 
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finding of treatment-emergent depression, suicidal ideation, psychiatric symptoms (based upon 
the C-SSRS, CDRS-R, CY-BOCS, Y-BOCS, SIGH-D-17, ADHD Rating Scale, or clinical 
assessment), the finding will be documented as an AE, and appropriate psychiatric evaluation 
and intervention will be provided. 
9.4.1. 
Safety Assessments for All Subjects 
9.4.1.1. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will periodically review ongoing 
clinical safety data to ensure the safety and well-being of the study subjects.  The safety data 
review may result in recommendation for early termination of the study or changes to the 
protocol and informed consent based on unexpected adverse findings.  A DSMB charter will 
describe the responsibilities, timing of meetings, and data review procedures for the members to 
follow. 
9.4.1.2. 
Medical history 
A medical history will be taken at screening (if applicable) and at baseline (Day -1).  The age at 
TS diagnosis will be documented for all subjects; if necessary, subject age at TS onset can be 
estimated by the investigator based upon available clinical information. 
9.4.1.3. 
Physical examination, including height and weight 
The complete physical examination will consist of an assessment of general appearance, skin 
and mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system.  A complete 
physical examination including weight will be performed at screening (if applicable), baseline 
(Day -1) (not required for subjects who have their final NBI-98854-1501 or NBI-98854-1505 
study visit on Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), 
and at the follow-up visit (the end of Week 28 or upon early termination).  Height will be 
measured at screening (if applicable), baseline (Day -1; not required for subjects who underwent 
screening) and at the end of Week 28 (or upon early termination) (height measurement at the 
end of Week 28 or upon early termination is not required for adult subjects) only.  Height and 
weight will be measured with subjects not wearing shoes. 
9.4.1.4. 
Vital sign measurements 
Vital signs will include orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, 
respiratory rate (recorded only supine), and oral body temperature.  Blood pressure will be 
measured using a calibrated automatic blood pressure cuff after the subject has been supine for 
at least 5 minutes and after approximately 2 minutes of standing.  The automatic blood pressure 
cuff will also provide pulse rate measurement. 
Vital sign measurements will be collected at screening (if applicable), baseline (Day -1) (not 
required for subjects who have their final NBI-98854-1501 or NBI-98854-1505 study visit on 
Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the 
follow-up visit (the end of Week 28 or upon early termination).  Vital sign measurements will 
be obtained before any scheduled blood sample collection. 
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9.4.1.5. 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicate (1 to 3 minutes apart) after the subject has 
rested supine for at least 5 minutes.  The ECG parameters that will be assessed include HR, PR 
interval, QRS duration, QT interval, and QTcF (machine readings or calculated).  Additionally, 
the occurrence of de- and re-polarization and rhythm disorders or other abnormalities will be 
assessed.  Based on the review of these parameters, the investigator or designee will note if the 
ECG is Normal, Abnormal not Clinically Significant, or Abnormal Clinically Significant.  If the 
ECG is Abnormal Clinically Significant, the investigator or designee will provide a description 
of the abnormality recorded on the AE eCRF. 
The 12-lead ECG recordings will be conducted at screening (if applicable), baseline (Day -1) 
(not required for subjects who have their final NBI-98854-1501 or NBI-98854-1505 study visit 
on Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the 
follow-up visit (the end of Week 28 or upon early termination). 
9.4.1.6. 
Clinical laboratory assessments 
All clinical laboratory assessments will be performed by a central laboratory, which will 
provide instructions and supplies to the study staff before study initiation.  The instructions will 
be included in a laboratory manual.  The laboratory test battery will include routine laboratory 
tests.  Laboratory samples will be collected in the following approximate amounts:  Children 
(6 to 11 years of age) – 3 mL for hematology and 2.5 mL for serum chemistry; adolescents and 
adults (12 to 64 years of age) – 4 mL for hematology and 5 mL for serum chemistry (includes 
serum pregnancy tests for female subjects of childbearing potential). 
Clinical safety laboratory assessments will be performed at screening (if applicable) baseline 
(Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the 
follow-up visit (the end of Week 28 or upon early termination).  There are no fasting 
requirements for laboratory assessments. 
The following clinical safety laboratory assays will be performed: 
Hematology:  complete blood count including WBC count with differential, red blood cell 
count, hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red cell 
distribution width (RDW), and mean platelet volume (MPV).  
Clinical Chemistry:  sodium, potassium, calcium, magnesium, chloride, blood urea nitrogen, 
bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate dehydrogenase, ALT, 
AST, gamma-glutamyl transferase (GGT), creatine kinase, total bilirubin, total cholesterol, 
triglycerides, total protein, and glucose. 
Urinalysis:  specific gravity, nitrite, ketones, protein, urobilinogen, glucose, bilirubin, leukocyte 
esterase, occult blood, and pH; microscopic examination of sediment will be performed only if 
the results of the urinalysis dipstick evaluation are positive for glucose, protein, leukocyte 
esterase, or blood. 
The following additional laboratory tests will be performed: 
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Hemoglobin A1c:  Blood samples for hemoglobin A1c will be collected at baseline (Day -1), at 
the end of weeks 12, 24, and at the follow-up visit (the end of Week 28 or upon early 
termination).  Approximately 2 mL in EDTA K2 will be collected in all subjects. 
Serum Prolactin:  Blood samples to determine serum prolactin concentration will be collected at 
baseline (Day -1), at the end of Weeks 4, 12, and 24, and at the follow-up visit (the end of 
Week 28 or upon early termination).  Approximately 2.5 mL (children, 6 to 11 years of age) or 
5 mL (adolescents and adults, 12 to 64 years of age) of blood will be collected into a serum 
separator tube.  Serum prolactin samples will be shipped to a central laboratory for analysis. 
Serology:  Blood will be collected for human immunodeficiency virus antibody (HIV-Ab), 
hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody (HCV-Ab) testing at 
screening (if applicable) or at baseline (Day -1).  The results of the anti-HIV-Ab testing will be 
retained by the study site under confidential restriction.  The following approximate amounts 
will be collected:  9 mL (children, 6 to 11 years of age) or 10 mL (adolescents and adults, 
12 to 64 years of age).   
Urine Drug Screen and Alcohol Breathalyzer Test:  The UDS will test for amphetamines, 
barbiturates, phencyclidine, benzodiazepines, cannabinoids, cocaine, and opiates.  Urine testing 
kits will be provided by the central laboratory to confirm negative drug screen prior to dosing.  
A separate urine sample will also be sent to the central laboratory for analysis.  A UDS and 
alcohol breathalyzer test will be performed at screening (if applicable) and at baseline (Day -1).  
The UDS and alcohol breathalyzer test will be performed only in adolescent and adults subjects 
(12 to 64 years of age).  A UDS using a kit provided by the central lab may be conducted at the 
clinical site at any time during the study if the subject is suspected of substance or drug abuse. 
Pregnancy Tests:  Pregnancy tests will be conducted for female subjects of childbearing 
potential only; subjects will be required to comply with protocol-required pregnancy testing 
from the time of menarche.  A serum pregnancy test and a urine pregnancy test will be 
conducted at screening (if applicable); urine pregnancy tests will be conducted at screening (if 
applicable), baseline (Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, 
and 24), and at the follow-up visit (the end of Week 28 or upon early termination). 
9.4.1.7. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu).  At the screening visit, or baseline visit for subjects that do not 
require a screening visit, the Baseline/Screening version will be administered (Children's 
Baseline/Screening version for pediatric subjects).  For all subsequent visits (except for 
unscheduled visits), the Since Last Visit version will be administered (Children's Since Last 
Visit version for pediatric subjects).  All versions of the C-SSRS include a series of screening 
questions related to suicidal ideation and suicidal behavior.  Subject responses of “yes” to 1 or 
more screening questions will prompt additional questions that evaluate frequency and intensity 
of suicidal ideation and/or behavior.  Copies of each version of the C-SSRS are provided in 
Appendix 17.9. 
The C-SSRS will be administered and scored by the investigator or qualified study site 
personnel at screening (if applicable), baseline (Day -1), during the treatment period (the end of 
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Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end of Week 28 or upon early 
termination). 
9.4.1.8. 
Extrapyramidal Symptom Rating Scale-Abbreviated 
The ESRS-A is a psychometrically valid instrument that assesses four types of movement 
disorders:  Parkinsonism, akathisia, dystonia, and TD (Chouinard and Margolese, 2005).  The 
investigator (or designee) will administer the ESRS-A at baseline (Day -1) (not required to be 
repeated for subjects who had this assessment conducted at their final NBI-98854-1501 or NBI-
98854-1505 study visit), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, 24), and 
at the follow-up visit (the end of Week 28 or upon early termination).  A copy of the ESRS-A is 
provided in Appendix 17.15. 
9.4.1.9. 
Estimated total blood sample volume required by study 
The estimated total blood sample volume for each subject is presented in Table 2.  These 
estimates include samples to be collected at screening (if applicable), baseline (Day -1), the 
treatment periods, and the final visit (or upon early termination). 
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Table 2: 
Estimated Total Blood Sample Volume  
Parameter 
Number of Samples 
Required 
Approximate 
Volume (mL) 
Approximate Total 
Volume (mL) 
Children (6 to 11 years of age) 
Serum chemistrya 
9b 
2.5 
22.5 
Hematology 
9b 
3 
27 
Hemoglobin A1c 
4 
2 
8 
Serology 
1 
9 
9 
Serum prolactin 
5 
2.5 
12.5 
Pharmacokinetics 
7 
2c 
14 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
93 
Adolescents (12 to 17 years of age) 
Serum chemistrya 
9b 
5 
45 
Hematology 
9b 
4 
36 
Hemoglobin A1c 
4 
2 
8 
Serology 
1 
10 
10 
Serum prolactin 
5 
5 
25 
Pharmacokinetics 
7 
2
c 
14 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
138 
Adults (18 to 64 years of age) 
Serum chemistrya 
9b 
5 
45 
Hematology 
9b 
4 
36 
Hemoglobin A1c 
4 
2 
8 
Serology 
1 
10 
10 
Serum prolactin 
5 
5 
25 
Pharmacokinetics 
7 
2c 
14 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
138 
a Includes pregnancy test at screening (if applicable) for female subjects who are of childbearing potential. 
b Subjects who do not require screening will only require 8 samples. 
c Includes 0.5 mL of discard volume per sample. 
9.4.2. 
Safety Assessments for Pediatric Subjects Only 
9.4.2.1. 
Children’s Depression Rating Scale, Revised 
The CDRS-R is a 17-item, semi-structured interview to determine the severity of depression in 
children.  The investigator (or designee) will administer the CDRS-R at baseline (Day -1) (not 
required for subjects who have their final NBI-98854-1501 study visit on Day -1), during the 
treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up visit (the end 
of Week 28 or upon early termination).  A copy of the CDRS-R is provided in Appendix 17.10. 
9.4.2.2. 
Children’s Yale-Brown Obsessive-Compulsive Scale 
The CY-BOCS is a semistructured interview designed to rate the severity of obsessive and 
compulsive symptoms in children.  The investigator (or designee) will administer the CY-BOCS 
at baseline (Day -1) (not required for subjects who have their final NBI-98854-1501 study visit 
on Day -1), during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the 
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follow-up visit (the end of Week 28 or upon early termination).  A copy of the CY-BOCS is 
provided in Appendix 17.11. 
9.4.2.3. 
Attention-Deficit Hyperactivity Disorder Rating Scale 5: Home Version 
The ADHD Rating Scale 5:  Home Version will be used to determine the frequency and severity 
of ADHD symptoms and impairments over the past month.  The scale comes in 2 versions:  
child (ages 5-10 years) and adolescent (ages 11-17 years).  Both versions consist of 2 symptom 
subscales, Inattention (9 items) and Hyperactivity–Impulsivity (9 items), as well as a Total 
Scale (18 items).  In addition, 6 domains of impairment that are common among children with 
ADHD are assessed: relationships with significant others (family members for the home version 
and teachers for the school version), peer relationships, academic functioning, behavioral 
functioning, homework performance, and self-esteem.  
 It will be completed independently by the subject’s parent or guardian at baseline (Day -1), 
during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up 
visit (the end of Week 28 or upon early termination).  Copies of both versions of the ADHD 
Rating Scale 5: Home Version are provided in Appendix 17.12. 
9.4.3. 
Safety Assessments for Adult Subjects Only 
9.4.3.1. 
Yale-Brown Obsessive Compulsive Scale 
The Y-BOCS is a semistructured interview designed to rate the severity of obsessive and 
compulsive symptoms.  The investigator (or designee) will administer the Y-BOCS at baseline 
(Day -1) (not required for subjects who have their final NBI-98854-1505 study visit on Day -1), 
during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up 
visit (the end of Week 28 or upon early termination). A copy of the Y-BOCS is provided in 
Appendix 17.13. 
9.4.3.2. 
Structured Interview Guide for the Hamilton Depression Rating Scale 
The Hamilton Depression Rating Scale is one of the most commonly used scales for rating 
depression.  To standardize the administration of this scale, the investigator (or designee) will 
use the SIGH-D-17.  This clinician-rated interview consists of 17 items.  Each item on the 
questionnaire is scored on a 3, 4, or 5-point scale and individual item scores are summed up to 
yield a total score.  The investigator (or designee) will administer the SIGH-D-17 at baseline 
(Day -1) (not required for subjects who have their final NBI-98854-1505 study visit on Day -1), 
during the treatment period (the end of Weeks 4, 8, 12, 16, 20, and 24), and at the follow-up 
visit (the end of Week 28 or upon early termination).  A copy of the SIGH-D-17 is provided in 
Appendix 17.14. 
9.5. 
Specific Study Information 
Study visits during the treatment period at the end of weeks 4, 8, 12, 16, 20, 24, and 28 (or upon 
early termination) will have a visit window of ±6 days. 
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9.5.1. 
Screening (Days -21 to -2) 
Subjects who have their final NBI-98854-1501 or NBI-98854-1505 visit >30 days prior to 
anticipated baseline (Day -1) must undergo screening.  These subjects will be screened to 
determine eligibility within 20 days (Days -21 to -2) before baseline (Day -1). 
During screening, the following will be performed: 
• Obtain informed consent/assent. 
• Assess inclusion/exclusion criteria. 
• Collect medical history. 
• Perform a physical examination (including weight). 
• Measure height 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a serum pregnancy test (human chorionic gonadotropin [β-hCG]) and a urine 
pregnancy test only for female subjects of childbearing potential. 
• Collect blood sample for serology testing (HIV-Ab, HBsAg, and HCV-Ab). 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Perform alcohol breathalyzer test and UDS (both only in adolescent and adult subjects). 
• Administer the C-SSRS (Children’s Screening/Baseline version for pediatric subjects and 
Screening/Baseline version for adult subjects). 
• Record prior medications. 
• Monitor for AEs 
9.5.2. 
Baseline (Day -1) 
Subjects who have their final NBI-98854-1501 or NBI-98854-1505 visit on the same day as 
Day -1 for the current study can have certain PD and safety assessments to be used for both the 
previous study and the current study.  The PD assessments that can apply to both the previous 
study and the current study include the YGTSS, RTRS, PUTS, and CGI-Tics-Severity.  The 
safety assessment results that can apply to both the previous study and the current study include 
physical examinations (including weight), vital signs, ECGs, ESRS-A, CY-BOCS (pediatric 
subjects only), CDRS-R (pediatric subjects only), Y-BOCS (adult subjects only), and the SIGH-
D-17 (adult subjects only). 
The following evaluations and tasks will be performed at baseline (Day -1): 
• Obtain informed consent/assent (not required for subjects who underwent screening). 
• Assess inclusion/exclusion criteria. 
• Collect medical history. 
• Perform a physical examination (including weight). 
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• Measure height (not required for subjects who underwent screening). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a urine pregnancy test only for female subjects of childbearing potential. 
• Collect blood sample for serology testing (not required for subjects who underwent 
screening). 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Perform alcohol breathalyzer test and UDS (both only in adolescent and adult subjects). 
• Collect blood sample for hemoglobin A1c. 
• Collect blood sample for serum prolactin. 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
• Give the PUTS to the subject or parent/legal guardian to complete. 
• Administer the CGI-Tics-Severity scale. 
• Administer the C-SSRS (Children’s version for pediatric subjects; the “Since Last Visit” 
version will be administered to subjects who underwent screening, and the 
“Screening/Baseline” version will be administered to subjects who did not undergo 
screening). 
• Administer the ESRS-A. 
• Administer the PedsQL, CDRS-R, and CY-BOCS (pediatric subjects only). 
• Give the ADHD Rating Scale 5:  Home Version to the subject or parent/legal guardian to 
complete (pediatric subjects only). 
• Administer the GTS-QOL, Y-BOCS, and SIGH-D-17 (adult subjects only). 
• Record prior medications. 
After completion of these assessments, if the subject is eligible for the study the clinical site will 
access the Interactive Web Response System (IWRS) to obtain an identification number for a 
kit containing a 4-week supply of NBI-98854 to be dispensed to the subject. At this point, the 
subject will be considered enrolled in the study. 
Enrolled subjects will: 
• Be monitored for AEs. 
• Be instructed to take NBI-98854 at home at approximately the same time each day (in the 
presence of their caregiver, if applicable) beginning the following day (Day 1).  NBI-98854 
must be swallowed with at least 4 oz. of water. 
• Instruct subjects or parents/legal guardians to record the date and time of each dose on the 
labels provided on the study drug packaging form. 
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• Be instructed to continue using contraception (other than subjects not required to use 
contraception; see inclusion criterion #9 in Section 8.1). 
• Be instructed to return to the site for the Week 4 visit.  The following should be taken into 
account for scheduling purposes:  As much as possible, the Weeks 4, 8, 12, 16, 20, 24 and 
the follow-up visit should occur at approximately the same time as the baseline (Day -1) 
visit in order to standardize the time of day for the assessment of safety, PD, and plasma 
exposure throughout the study period.  
• Be instructed to contact the clinical site immediately without waiting for the next scheduled 
visit to report AEs or before starting any new medication. 
• Be instructed to return all unused NBI-98854 and packaging at the next scheduled visit. 
9.5.3. 
Treatment Period 
9.5.3.1. 
Day 1 
Beginning on Day 1, subjects will take NBI-98854 at home at approximately the same time 
each day (in the presence of their caregiver, if applicable).  NBI-98854 must be swallowed with 
at least 4 oz. of water.  
9.5.3.2. 
Weeks 2 and 6 
For pediatric subjects only, the study site will call the subject or parent/legal guardian 
approximately 2 weeks and 6 weeks after starting dosing (ie, at study Weeks 2 and 6) to inquire 
about any study drug-related issues related to compliance or tolerability. 
9.5.3.3. 
Weeks 4, 8, 12, 16, 20, and 24 (±6 days for each visit) 
Subjects and parents/legal guardians (if applicable) will report to the study site at the end of 
Weeks 4, 8, 12, 16, 20, and 24. 
At the end of Weeks 4, 8, 12, 16, 20, and 24 the following study evaluations and procedures will 
be performed at the study site: 
• Perform a physical examination including weight. 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a urine pregnancy test for female subjects of childbearing potential. 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis. 
• Collect blood sample for hemoglobin A1c (Weeks 12 and 24 only). 
• Collect blood sample for serum prolactin (Weeks 4, 12, and 24 only). 
• Collect PK blood sample for NBI-98854 and metabolite concentrations. 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
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• Give the PUTS to the subject or parent/legal guardian to complete. 
• Administer the CGI-Tics-Severity scale. 
• Administer the CGI-TS scale. 
• Give the PGIC-TS scale to the subject or parent/legal guardian to complete. 
• Administer the C-SSRS (Children’s Since Last Visit version for pediatric subjects and Since 
Last Visit version for adults). 
• Administer the ESRS-A. 
• Administer the PedsQL, CDRS-R, and CY-BOCS (pediatric subjects only). 
• Give the ADHD Rating Scale 5:  Home Version to the subject or parent/legal guardian to 
complete (pediatric subjects only). 
• Administer the GTS-QOL, Y-BOCS, and SIGH-D-17 (adult subjects only). 
• Dispense a 4-week supply of study drug (Weeks 4, 8, 12, 16, and 20 only). 
• Instruct subjects or parents/legal guardians to record the date and time of each dose on the 
labels provided on the study drug packaging form (Weeks 4, 8, 12, 16, and 20 only). 
• Perform compliance check by counting the capsules returned. 
• AE monitoring. 
• Record concomitant medications. 
The following will also be conducted before subjects may leave the study site: 
• Instruct subjects to continue using contraception (other than subjects not required to use 
contraception; see inclusion criterion #9 in Section 8.1). 
• Instruct subjects and parents/legal guardians (if applicable) to notify the investigator by 
telephone if they experience any AEs and before taking any new concomitant medications. 
Dose Titration Assessment 
At the end of Week 4 of the treatment period, the investigator may escalate a child’s dose to 
20 mg, an adolescent’s dose to 40 mg, an adult’s dose to 80 mg, or continue with the subject’s 
current dose for the remainder of the treatment period.  A dose escalation will be allowed at the 
end of Week 4 if (1) the investigator or designee’s assessment of the CGI-TS is “minimally 
improved”, “not changed”, “minimally worse”, “much worse”, or “very much worse”, and (2) 
the safety and tolerability of the current dose is acceptable as determined by a physician.  The 
subject will then continue at the 20 mg dose (for children), 40 mg dose (for adolescents), or 
80 mg dose (for adults) until the end of the treatment period (ie, the end of Week 24).   
At any time after dose escalation, the investigator may decrease the dose to 10 mg for a child, 
20 mg for an adolescent, or 40 mg for an adult if the subject is unable to tolerate the dose 
increase.  The subject will then continue at the 10 mg, 20 mg, or 40 mg dose until the end of the 
treatment period (end of Week 24).  Subjects who are unable to tolerate the starting dose of 
10 mg for children, 20 mg for adolescents, or 40 mg for adults, or the resumption of the 10 mg, 
20 mg, or 40 mg dose following a tolerability issue after the dose escalation at Week 4, will be 
discontinued from the study. 
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Once a determination of dose escalation, maintenance, or reduction (for subjects who had their 
dose escalated at the end of Week 4) is made, the IWRS will be accessed to obtain an 
identification number for a kit containing a 4-week supply of study drug to be dispensed to the 
subject. 
9.5.4. 
Follow-Up: Week 28 (±6 days) (or Early Termination) 
At the follow-up visit (the end of Week 28 or upon early termination) the following procedures 
will be performed at the study site: 
• Perform a physical examination including height and weight (height is measured in pediatric 
subjects only). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a urine pregnancy test for female subjects of childbearing potential. 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis. 
• Collect blood sample for hemoglobin A1c. 
• Collect blood sample for serum prolactin. 
• Collect PK blood sample for NBI-98854 and metabolite concentrations. 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
• Give the PUTS to the subject or parent/legal guardian to complete. 
• Administer the CGI-Tics–Severity scale. 
• Administer the CGI-TS scale. 
• Give the PGIC-TS scale to the subject or parent/legal guardian to complete. 
• Administer the C-SSRS (Children’s Since Last Visit version for pediatric subjects and Since 
Last Visit version for adults). 
• Administer the ESRS-A. 
• Administer the PedsQL, CDRS-R, and CY-BOCS (pediatric subjects only). 
• Give the ADHD Rating Scale 5:  Home Version to the subject or parent/legal guardian to 
complete (pediatric subjects only). 
• Administer the GTS-QOL, Y-BOCS, and SIGH-D-17 (adult subjects only). 
• AE monitoring. 
• Record concomitant medications. 
9.6. 
Study Duration 
The expected duration of study participation for each subject is up to 31 weeks, including a 
3-week screening period, a 24-week treatment period, and a 4-week follow-up period. 
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9.7. 
Prohibitions and Restrictions 
9.7.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter medications, including dietary and herbal supplements, 
taken by subjects during the 30 days before baseline (Day -1) and during the study will be 
entered on the Prior and Concomitant Medications eCRF.  Any additions, deletions, or changes 
in the dose of these medications will be entered on the eCRF with indication, dose, route, and 
dates of drug administration. 
The following medications are prohibited from 30 days before baseline (Day -1) (unless 
otherwise stated) until the final study visit (or upon early termination) as described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• Botulinum toxin:  Botulinum toxin injections for the treatment of TS symptoms are 
prohibited starting 90 days prior to baseline (Day -1) and during the study. 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenytoin, phenobarbital, rifabutin, 
rifampin, primidone, St. John's Wort, carbamazepine) are prohibited. 
• Dopamine agonists and precursors:  Dopamine receptor agonists (eg, ropinirole) and 
precursors (eg, carbidopa/levodopa) are prohibited. 
• Dopamine antagonist: Dopamine antagonists (eg, pimozide, haloperidol, aripiprazole, 
risperidone, clozapine, olanzapine, ziprasidone) are prohibited. 
• Monoamine oxidase inhibitors (MAOIs):  All MAOIs (eg, isocarboxazid, phenelzine, 
selegiline, tranylcypromine) are prohibited. 
• VMAT2 inhibitors:  VMAT2 inhibitor medications (eg, tetrabenazine, reserpine) are 
prohibited, except for study drug. 
• prn use:  As needed use of the following medications is strictly prohibited: anticholinergics, 
benzodiazepines, antipsychotics, psychostimulants, mood stabilizers, antidepressants, 
opiates, strong CYP3A4 inhibitors, and strong CYP2D6 inhibitors.  
9.7.2. 
Dietary Restrictions 
Subjects are not permitted to consume more than 6 caffeine-containing beverages a day. 
Grapefruit juice or grapefruit products are prohibited from 7 days before baseline (Day -1) until 
the follow-up visit.  Foods containing poppy seeds are prohibited from 7 days before baseline 
(Day -1) until the follow-up visit.  For adult subjects only, moderate alcohol consumption (1 to 
2 drinks per day or 7 to 14 drinks per week) is allowed from 48 hours before baseline (Day -1) 
until the follow-up visit. 
9.7.3. 
Other Restrictions 
Excessive use of tobacco and other products containing nicotine (including nicotine gum and 
patches) are prohibited during the study (ie, from 30 days before baseline [Day -1] to the 
follow-up visit or upon early termination).  Strenuous activity beyond what is customary for the 
subject is prohibited during the study. 
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Subjects must agree not to donate blood during the study, including the screening period, and 
for 4 weeks after completion of the study.  Adult male subjects must agree to refrain from 
donating sperm for 90 days after the last dose of study drug. 
Subjects must not have initiated CBIT at baseline (Day -1) or plan to initiate CBIT during the 
study. 
9.8. 
Withdrawal Criteria 
Subjects are free to discontinue their participation in the study at any time.  The investigator 
must withdraw any subject from the study if that subject requests to be withdrawn. 
The investigator must withdraw the subject from the study if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE become unacceptable/intolerable. 
• If the subject is unable to tolerate the starting dose or resumption of the previous dose.   
• QTcF value >500 msec (cardiologist verified).  
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation 
with specific plan and intent) based on the C-SSRS. 
• Does not follow guidelines specified in the protocol. 
• Is lost to follow up. 
• Subject is confirmed to be pregnant. 
The investigator or NBI may withdraw the subject from the study for other reasons as described 
below.  These should be discussed on a case-by-case basis with the NBI medical monitor (or 
designee) prior to withdrawing the subject from the study. 
• Develops a clinically significant laboratory (eg, ALT or AST ≥2.5 times ULN) or ECG 
abnormality. 
• Requires a medication that is prohibited by the protocol (refer to Section 9.7.1). 
• Is non-compliant with the dosing regimen (<80% dosing compliance) as verified by drug 
accountability (Refer to Section 10.6).  
All subjects prematurely discontinuing the study, regardless of cause, must have all early 
termination assessments performed (see Section 9.5.4). 
9.8.1. 
Handling of Withdrawals 
If a subject prematurely withdraws from the study, either at his/her request, at the request of the 
parent or legal guardian, or at the investigator’s discretion, the investigator will record the 
reason for withdrawal on the relevant eCRF.  All subjects who withdraw from the study 
prematurely will be asked to have all early termination assessments performed within 4 weeks. 
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It is crucial to obtain follow-up data for any subject withdrawn because of an AE, abnormal 
laboratory test, vital sign measurement, physical examination or ECG finding.  In any case, 
every effort must be made to undertake safety follow-up procedures. 
9.8.2. 
Sponsor’s Termination of Study 
NBI reserves the right to discontinue the study at any time for clinical or administrative reasons. 
Such a termination must be implemented by the investigator, if instructed to do so by NBI in a 
time frame that is compatible with the subjects’ well-being. 
10. 
STUDY DRUG 
10.1. 
Study Drug Supplies 
NBI or its designee will provide the study sites with subject-specific, study drug kits sufficient 
for the completion of the treatment period of the study. 
NBI-98854 will be supplied as capsules containing 10, 20, or 40 mg of NBI-98854 (free base).  
The NBI-98854 80 mg dose will be administered as two 40 mg capsules.  The NBI-98854 10, 
20, and 40 mg capsules are a white, opaque, HPMC No. 3 size capsule containing 10, 20, and 
40 mg, respectively of NBI-98854 (dose is of the free base) and is formulated using Capsugel 
shells. 
10.2. 
Study Drug Storage 
NBI-98854 capsules must be stored at controlled room temperature (CRT) (20˚C to 25˚C or 
68˚F to 77˚F) under the conditions specified in the Investigator’s Brochure and in a locked area 
accessible only to the pharmacist (or designee) until dispensing.  Excursions outside this range 
will be allowed provided they meet the following conditions: 
• Storage between refrigerated conditions (2˚C or 36˚F) and CRT (25˚C or 77˚F) for an 
unspecified length of time. 
• Storage at temperatures above 25˚C (77˚F) but no more than 30˚C (86˚F) for up to 3 months. 
• Storage at temperatures above 30˚C (86˚F) but no more than 40˚C (104˚F) for up to 
24 hours. 
10.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice and GCP rules.  The study drugs will be sent to authorized staff at the study site.  The 
authorized study staff member must confirm receipt of the study drug to NBI or its designee via 
the IWRS. 
Study drug will be supplied as capsules in child-resistant blistercard dispensers; each blistercard 
contains enough study drug for 14 days of dosing plus 3 extra dose days.  At each visit that 
NBI-98854 is dispensed (see Table 1), subjects will receive 2 blistercards.  The blistercards will 
contain capsules of NBI-98854 10 mg, 20 mg, or 40 mg. 
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Each blistercard dispenser will be labeled with a single-panel label and secured with tamper 
evident seals.  Label text will include but is not limited to the protocol number, dosage form, 
route of administration, study drug kit number, sponsor name and address, storage condition and 
the statement “Caution – New Drug: Limited by Federal (or US) Law to Investigational Use.” 
10.4. 
Blinding 
Not applicable as this is an open-label study. 
10.5. 
Study Drug Administration 
On Day -1, eligible children 6 to 11 years of age will receive a supply of NBI-98854 10 mg, 
eligible adolescents 12 to 17 years of age will receive a supply of NBI-98854 20 mg, and 
eligible adults 18 to 64 years of age will receive a supply of NBI-98854 40 mg, for the first 
4 weeks of the treatment period.  Beginning on Day 1, study drug will be administered once 
daily at home at approximately the same time each day under the supervision of the subject’s 
parent/legal guardian and the capsules must be swallowed with at least 4 oz. of water every day 
throughout the 24-week treatment period.   
At the end of Week 4 of the treatment period, the investigator may escalate a child’s dose to 
20 mg, an adolescent’s dose to 40 mg, an adult’s dose to 80 mg, or continue with the subject’s 
current dose for the remainder of the treatment period.  A dose escalation will be allowed at the 
end of Week 4 if (1) the investigator or designee’s assessment of the CGI-TS is “minimally 
improved”, “not changed”, “minimally worse”, “much worse”, or “very much worse”, and (2) 
the safety and tolerability of the current dose is acceptable as determined by a physician.  The 
subject will then continue at the 20 mg dose (for children), 40 mg dose (for adolescents), or 
80 mg dose (for adults) until the end of the treatment period (ie, the end of Week 24). 
At any time after dose escalation, the investigator may decrease the dose to 10 mg for a child, 
20 mg for an adolescent, or 40 mg for an adult, if the subject is unable to tolerate the dose 
increase.  The subject will then continue at the 10 mg, 20 mg, or 40 mg dose until the end of the 
treatment period (end of Week 24).  Subjects who are unable to tolerate the starting dose of 
10 mg for children, 20 mg for adolescents, 40 mg for adults, or the resumption of the 10 mg, 
20 mg, or 40 mg dose following a tolerability issue after the dose escalation at Week 4, will be 
discontinued from the study. 
If a subject forgets or is unable to take study drug within a few hours of the normal dosing time, 
the subject should skip his or her daily dose and resume normal dosing the following day.   
If a subject changes dosing time (eg, changes from morning to evening dosing), the subject 
should dose at the new time the following day.  Subjects or their parents/legal guardians will 
record the date and time of study drug dosing each day on the labels provided on the study drug 
packaging form. 
10.6. 
Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty study drug packaging material to the site at 
each study visit for drug accountability and reconciliation by study site personnel.  A 
compliance check will be performed by counting the capsules returned at each study visit. 
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The quantity of study drug dispensed, used, and returned will be recorded on a dispensing log or 
otherwise documented.  The quantity of study drug lost or destroyed must also be accounted for 
and documented.  The designated pharmacist or qualified personnel will be responsible for 
maintaining accurate records of the quantity and dates of all study drug supplies received, 
dispensed, and returned. 
10.7. 
Study Drug Return 
Written documentation to account for study drug and study drug materials is mandatory; all 
unused study drug and study drug materials must be kept in a secure location for final 
accountability and reconciliation.  Returned study drug and study drug material must be 
accounted for on a study drug return form provided by NBI or designee.  The investigator must 
provide a written explanation for any destroyed or missing study drug or study drug materials. 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee.  Study drug return forms must be completed for 
the shipment of returns and sent with the study drug and study drug materials.  One copy of the 
study drug return form will be retained in the investigator’s study file. 
All returned study drug and study drug materials should be stored, inventoried, reconciled, and 
returned according to applicable state and federal regulations and study procedures. 
11. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the ICF/assent is signed 
until the subject’s final study day (Week 28 or upon early termination).   
11.1. 
Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  During the study, clinically significant adverse changes 
in clinical status, ECGs, laboratory values (not associated with an AE or concurrent medical 
condition), or physical examinations are considered AEs.  Any subject complaint associated 
with such an abnormal finding will also be reported as an AE. 
Adverse events include, but are not limited to:  (1) a worsening or change in nature, severity, or 
frequency of conditions present at the start of the study; (2) subject deterioration due to primary 
illness; (3) intercurrent illness; and (4) drug interaction. 
If at any time after the baseline visit (Day -1), the subject’s response to the suicidal ideation 
section of the C-SSRS is worse than the baseline assessment; it will be documented as an AE.  
All suicidal behaviors will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
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drug, must be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
study drug.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before study drug administration, unless it 
unexpectedly progresses, or increases in severity following study drug administration. 
• Recurrence of TS symptoms, unless worsened from baseline. 
• Pregnancy. 
11.2. 
Intensity of Adverse Events 
Adverse events must be graded for intensity.  An intensity category of mild, moderate, or 
severe, as defined in Table 3, must be entered on the AE eCRF.  It should be noted that the term 
“severe” used to grade intensity is not synonymous with the term “serious.” 
Table 3: 
Intensity of Adverse Events 
Grade  
Intensity 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities 
of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
 
11.3. 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the criteria outlined in Table 4.  An AE is deemed associated with the use of 
the study drug “if there is a reasonable possibility that the drug caused the AE” (otherwise 
referred to as a suspected adverse reaction).  Reasonable possibility means there is evidence to 
suggest a causal relationship between the drug and the AE (Title 21 CFR 312.32 [a]). 
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Table 4: 
Relationship of Adverse Events to Study Drug 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the drug or in 
which the drug level has been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is confirmed by improvement on 
stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure. 
Possible 
An adverse event in which there is reasonable possibility that the drug caused the event.  
Reasonable possibility means there is evidence to suggest a causal relationship between the 
drug and the adverse event. 
Unlikely 
A reaction that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or suspected response pattern to the suspected drug; but that could 
reasonably be explained by known characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
 
11.4. 
Recording Adverse Events 
For enrolled subjects, each AE will be listed as a separate entry on an AE eCRF.  The 
investigator (or designee) will provide information on dates and times of onset and resolution, 
intensity, seriousness, frequency, action(s) taken, changes in study drug usage, relationship to 
study drug, and outcome. 
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to NBI or its designee: 
• SAE, including death (Refer to Section 11.6). 
• Pregnancy (refer to Section 11.7). 
• Events of suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with specific 
plan and intent) based on the C-SSRS. 
11.5. 
Post-Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  If 
resolved, a resolution date should be documented on the eCRF.   
Adverse events ongoing at the final visit or upon early termination will be followed for as long 
as necessary to adequately evaluate the subject’s safety or until the event stabilizes or resolves 
or until the subject is lost to follow up.  The investigator is responsible for ensuring that follow 
up includes any supplemental investigations as may be indicated to elucidate the nature and/or 
causality of the AE.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals, as is 
practical. 
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11.6. 
Serious Adverse Events 
All SAEs will be recorded from the time the ICF/assent is signed until 30 days after the last 
dose of study drug. 
11.6.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcomes: 
• Death. 
• A life threatening AE.  Life threatening means that the subject was, in the view of the 
investigator or sponsor, at immediate risk of death from the reaction as it occurred.  It does 
not mean that hypothetically the event might have caused death if it occurred in a more 
serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization for 
elective treatment or a preexisting condition that did not worsen during the clinical 
investigation is not considered an AE.  Hospitalization or nursing home admission for the 
purpose of caregiver respite is not considered an AE.  Complications that occur during 
hospitalization are AEs, and if a complication prolongs hospitalization, the event is 
considered serious.  Treatment in a hospital emergency room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization.  These events may be considered serious when, based on appropriate 
medical judgment, they may jeopardize the health of the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed.  Any other event thought by the 
investigator to be serious should also be reported, following the reporting requirements 
detailed in this section.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
11.6.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible.  The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject.  The subject will remain under observation as long as 
medically indicated.  Appropriate laboratory studies will be conducted until all parameters 
return to normal or are otherwise explained or stable.  The subject will be followed until the 
SAE resolves or until the subject is medically stabilized.  The investigator (or designee) will 
notify the NBI Medical Monitor (and the IRB, if necessary) immediately (within 24 hours) of 
the SAE and the outcome of the SAE. 
If within the time of informed consent until 30 days after the last dose of study drug or final 
study visit (whichever is longer in duration), an investigator becomes aware of an SAE, then the 
event must be documented and reported as described in Section 11.6.3. 
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11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events 
Serious AEs and other immediately reportable events (defined in Section 11.4) must be reported 
within 24 hours of first knowledge of the event by study personnel to the NBI Medical Monitor 
or NBI Clinical Drug Safety (CDS) Department.  Reports of SAEs or pregnancies should be 
followed by a fax or email of the SAE or Pregnancy Form.  It is important that the investigator 
provide his or her assessment of relationship to study drug at the time of the initial SAE report.  
For SAEs or Other Immediately Reportable Events, contact CDS: 
 
CDS telephone: 
 
CDS facsimile: 
 
CDS e-mail:  
 
NBI Medical Monitor:  
Telephone: 
 
 
 
 
 
 
 
 
 
Cell phone: 
11.6.4. 
Expedited Safety Reports 
Neurocrine Biosciences, Inc. or its representatives will submit an Expedited Safety Report for 
any suspected adverse reaction (as defined in Section 11.3) that is considered both serious and 
unexpected within 15 calendar days and for any unexpected fatal or life threatening experience 
within 7 calendar days via telephone or facsimile; or according to country specific regulations. 
Neurocrine Biosciences, Inc. or its representatives will send copies of each safety report 
submitted to regulatory authorities to the investigators.  The safety report must be submitted to 
the appropriate IRB as soon as possible.  Documentation of the submission to the IRB and 
receipt by the IRB (if applicable) must be retained for each safety report. 
11.7. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  However, all 
pregnancies in female subjects who received NBI-98854 will be followed to assess for 
congenital anomaly.  Subjects must be counseled at all visits to continue using contraception 
(other than subjects not required to use contraception; see inclusion criterion #9 in Section 8.1) 
until 30 days after the last dose of study drug for female subjects and 90 days after the last dose 
of study drug for male subjects.  If at any time between the time the subject signs the ICF/assent 
and the last study visit a subject believes she is pregnant, the subject will be instructed to stop 
taking the study medication and return to the study site within 24 hours and undergo a serum 
pregnancy test to confirm pregnancy. 
All confirmed pregnancies, in subjects who received study drug, must be immediately reported 
to NBI (refer to Section 11.6.3 for contact information), followed by fax or email of the 
pregnancy form to NBI CDS.  A first trimester ultrasound will be required for all confirmed 
pregnancies.  Pregnancies in subjects who received NBI-98854 will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 
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12. 
DOCUMENTATION OF DATA 
12.1. 
Case Report Form 
The CRF data for this study are being collected with an electronic data capture (EDC) system 
(Rave®) provided by Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific eCRFs will comply with Title 21 CFR Part 11.  The documentation related to the 
validation of the EDC system is available through the vendor, Medidata, while the validation of 
the study specific eCRFs will be conducted by NBI and the required documentation will be 
maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs.  All data 
entered into the eCRF will be supported by source documentation.  The eCRF for each subject 
must be reviewed by the investigator and signed on the appropriate eCRF page(s).  This should 
be done as soon as possible after the subject completes the study.   
The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF.  All change information, including the date, person 
performing the corrections, and reason for the change will be available via the electronic audit 
trail, which is part of the EDC system.  The eCRFs will be reviewed periodically for 
completeness, legibility, and acceptability by NBI (or designee).  NBI will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify 
eCRF entries.  The Principal Investigator will review the eCRFs for completeness and accuracy 
and enter his or her electronic signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC system 
will be archived on appropriate data media (CD ROM, etc.) and provided to the investigator at 
that time as a durable record of the site's eCRF data.  Although not required, the investigator 
may make paper printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI and/or health authority representatives at any time.  The Principal 
Investigator will agree to the inspection of study-related records by health authority 
representatives and/or NBI. 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
Any discrepancies will be corrected on-line by authorized site personnel.  After completion of 
the entry process, automated (computer-generated) logic checks will run in order to identify 
items such as inconsistent study dates.  In addition, manual review/checks may be performed by 
NBI on the data.  Any inconsistencies/errors/omissions identified will be sent to the site (via an 
electronic query) for the necessary corrections to be made to the eCRF.  Once entered and saved 
in an eCRF, data immediately become part of the study database and are available to NBI. 
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12.3. 
Coding Dictionaries 
Adverse events and medical history will be coded using the chosen version of the Medical 
Dictionary for Regulatory Activities (MedDRA).  Prior and concomitant medications will be 
coded using the chosen version of the World Health Organization Drug Dictionary (WHO 
Drug). 
13. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive statistical methods will be used to evaluate and summarize the data from this study. 
The term “descriptive statistics” refers to the number of subjects (n), mean, median, standard 
deviation (SD), standard error of the mean (SEM), minimum, and maximum for continuous and 
ordinal categorical variables; and refers to the number and percentage of subjects for categorical 
variables.  Descriptive statistics will be presented for each age group (note that additional 
summaries by treatment as well as pooled data summaries may be specified in the detailed 
statistical analysis plan [SAP]). 
The analysis plan provided in this protocol represents a brief description of the planned 
analyses.  The comprehensive SAP will be generated prior to final study database lock.  The 
SAP may include a number of additional analyses and data summaries not described in this 
protocol. 
13.1. 
Analysis Sets 
A single analysis set, the safety analysis set, will be defined for this study. The safety analysis 
set will include all subjects who take at least one dose of study drug and have any postdosing 
safety data. 
13.2. 
Sample Size 
The sample size calculation for this open-label safety study is based on practical considerations 
and not on a statistical power calculation. 
13.3. 
Handling of Missing Data 
Conventions for the handling of missing data will be described in the SAP. 
13.4. 
Enrollment and Disposition of Subjects 
The summary of subject enrollment and disposition will display the number of subjects who 
were enrolled, who received at least 1 dose of study drug, who completed the 24-week treatment 
period, and who completed the study.  The number of subjects who did not complete the study 
will also be summarized, both overall and according to the reason for early discontinuation. 
13.5. 
Demographics and Baseline Characteristics 
Demographic data (age, gender, race, and ethnicity) and baseline characteristics (including 
height, weight, BMI, CYP2D6 genotype status (data obtained from NBI-98854-1501 or 
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NBI-98854-1505 study results), age at TS diagnosis, and baseline values for the TTS) will be 
summarized with descriptive statistics.  Medical history will also be summarized. 
13.6. 
Study Drug Dosing and Compliance 
The number and percentage of subjects who are dosing compliant (>80% of doses taken) during 
the treatment period will be summarized by visit.  Cumulative dosing compliance through 
Week 24 will be summarized as well. 
13.7. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and the metabolite NBI-98782 will be summarized 
with descriptive statistics by visit.  Concentrations below the lower limit of quantification will 
be set equal to zero for all plasma concentration summaries. 
13.8. 
Pharmacodynamic Data 
The PD measures in this study are: 
• All subjects: YGTSS, RTRS, PUTS, CGI-Tics-Severity, CGI-TS, and PGIC-TS. 
• Pediatric subjects only: PedsQL. 
• Adult subjects only:  GTS-QOL. 
For each PD measure, descriptive statistics will be presented for each visit and for the changes 
from baseline (Day -1) to each postbaseline visit. 
13.9. 
Safety Data 
TEAEs, categorized by system organ class (SOC) and preferred term (PT) as defined by the 
MedDRA, will be summarized in frequency tables.  The TEAE summary tables will include the 
number of events, number of unique subjects experiencing each event, and percentage of 
subjects experiencing each event. 
Summary tables will be presented including all TEAEs, only TEAEs that are considered to be 
possibly or definitely related to study drug, and TEAEs according to maximum intensity.   
Additional summaries will be presented for TEAEs leading to premature discontinuation from 
the study, SAEs, and deaths. 
Clinical laboratory, vital signs, ECG, ESRS-A, C-SSRS, CY-BOCS, CDRS-R, ADHD Rating 
Scale 5:  Home Version, Y-BOCS, and SIGH-D-17 data will be summarized by visit with 
descriptive statistics.  Clinically significant physical examination findings will be displayed in a 
data listing.  Prior and concomitant medications will also be summarized. 
13.10. 
Software 
Statistical calculations and summaries will be generated using SAS software version 9.3 or later. 
13.11. 
Interim Analysis 
An interim analysis is not planned for this study. 
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14. 
REGULATORY AND ETHICAL ISSUES 
14.1. 
General Legal References 
The study will be carried out according to the provision of the US CFR, the US Food and Drug 
Administration (FDA), and the ICH Guidelines for GCP.  All clinical work conducted under 
this protocol is subject to GCP rules.  This includes an inspection by NBI or its representative, 
health authority, or IRB representatives at any time.  The investigator must agree to the 
inspection of study related records by health authority representatives and/or NBI or its 
designee. 
14.2. 
Institutional Review Board 
The final approved protocol, the ICF, and assent document will be reviewed by the IRB for the 
clinical site.  The committee’s decision concerning conduct of the study will be sent in writing 
to the investigator and a copy will be forwarded to NBI.  The investigator must agree to make 
any required progress reports to the IRB, as well as reports of SAEs, life threatening problems, 
or death.  
14.3. 
Protocol Adherence and Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly.  Any 
changes in the protocol will require a formal amendment.  Such amendments will be agreed 
upon and approved in writing by the investigator and NBI.  The IRB will be notified of all 
amendments to the protocol.  Amendments to the protocol will not be implemented until written 
IRB approval has been received.  
14.4. 
Required Documents 
The investigator must provide to NBI or its representatives the following documents before the 
enrollment of any subject (copies should be kept by the investigator in the investigator’s 
regulatory document binder): 
• Signed copy (original) of the approved protocol. 
• Completed and signed statement of investigator (Form FDA 1572). 
• Curriculum vitae and current medical license of the investigator and subinvestigators. 
• Financial disclosure information as required. 
• Letter of approval from the IRB for the protocol, consent form, and assent form. 
• Copy of the IRB approved written ICF and assent to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
14.5. 
Informed Consent 
For pediatric subjects, all parents or legal guardians will provide informed consent with signed 
and witnessed pediatric assent before the performance of any study related procedures. 
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Adult subjects will provide their written informed consent before the performance of any study-
related procedures. 
Each subject’s chart will include the signed ICF with signed and witnessed pediatric assent for 
study participation (if applicable).  When the study treatment is completed and the eCRF has 
been monitored, the ICF and signed and witnessed pediatric assent will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the signed 
ICF and the signed and witnessed pediatric assent in this central study folder. 
14.6. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include emails, telephone calls and on-site visits.  During the on-site 
visits, the eCRFs will be reviewed for completeness and adherence to the protocol.  As part of 
the data audit, source documents will be made available for review by the study monitor.  The 
study monitor will also perform drug accountability checks and may periodically request review 
of the investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.  The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and respond to inquiries.  In addition, the investigator 
will permit inspection of the study files by authorized representatives of the regulatory agencies. 
14.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed 
to ensure that all procedures are in compliance with GCP and FDA Guidelines, and according to 
national law.  Quality assurance audits may be performed at the discretion of NBI. 
14.8. 
Record Retention 
Federal regulations require that records of drug disposition, eCRFs, and all reports of this 
investigation shall be retained by the investigator for a minimum of 2 years after notification by 
NBI that the regulatory authorities have been notified of the study's termination, or 2 years after 
approval of the marketing application.  If the investigator is unable to retain the study 
documents for the required amount of time, NBI must be informed of the individual who will be 
assuming this responsibility. 
14.9. 
Confidentiality 
NBI and the clinical site affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, all data will be identified only by an 
identification number and, where applicable, subject’s initials and birth date. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of NBI; it 
shall not be disclosed to others without written consent of NBI; and shall not be used except in 
the performance of this study. 
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The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To allow the 
use of the information derived from this clinical study and to ensure compliance with current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Subject entry should not begin until after the required regulatory documents are confirmed as 
received and the Investigator Meeting/Initiation Meeting has occurred.  All personnel expected 
to be involved in the conduct of the study will undergo orientation to include review of study 
protocol, instructions for eCRF completion, AE reporting, and overall responsibilities including 
those for drug accountability and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow up examination.  Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 
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16. 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition. 1994. 
Baxter LR, Guze BH. Neuroimaging.  In: Kurlan, R. (Ed), Handbook of Tourette syndrome and 
related tic and behavioral disorders.  Rochester: Marcel Decker Inc.; 1993. 
Braun AR, Stoetter B, Randolph C, Hsiao JK, Vladar K, Gernert J, et al. The functional 
neuroanatomy of Tourette's syndrome: an FDG-PET study. I. Regional changes in cerebral 
glucose metabolism differentiating patients and controls. Neuropsychopharmacology. 1993 
Dec;9(4):277-91. 
Cavanna AE, Schrag A, Morley D, Orth M, Robertson MM, Joyce E, et al. The Gilles de la 
Tourette syndrome-quality of life scale (GTS-QOL): development and validation. Neurology. 
2008 Oct;71(18):1410-6. 
Cavanna AE, Nani A. Tourette syndrome and consciousness of action. Tremor Other 
Hyperkinet Mov (NY). 2013 Sep;3. 
Chen JJ, Ondo WG, Dashtipour K, Swope DM. Tetrabenazine for the treatment of hyperkinetic 
movement disorders: a review of the literature. Clin Therapeutics. 2012;34:1487-1504. 
Chouinard G and Margolese HC.  Manual for the Extrapyramidal Symptom Rating Scale 
(ESRS).  Schizophr Res. 2005 Jul 15;76(2-3):247-65. 
Felling RJ, Singer HS. Neurobiology of Tourette syndrome: current status and need for further 
investigation. J Neurosci. 2011 Aug;31(35):12387-95. 
Goetz CG, Pappert EJ, Louis ED, Raman R, Leurgans S. Advantages of a modified scoring 
method for the Rush Video-based Tic Rating Scale. Mov Disord. 1999 May;14(3):502-6. 
Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, et al. The Yale Global 
Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child 
Adolesc Psychiatry. 1989 Jul;28(4):566-73. 
Pourfar M, Feigin A, Tang CC, Carbon-Correll M, Bussa M, Budman C, et al.  Abnormal 
metabolic brain networks in Tourette syndrome. Neurology. 2011 Mar;76(11):944-52. 
Roessner V, Schoenefeld K, Buse J, Bender S, Ehrlich S, Münchau A. Pharmacological 
treatment of tic disorders and Tourette Syndrome. Neuropharmacology. 2013 May;68:143-9. 
Shprecher D, Kurlan R. The management of tics. Mov Disord. 2009 Jan;24(1):15-24. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999 Feb;37(2):126-39. 
Woods DW, Piacentini J, Himle MB, Chang S. Premonitory Urge for Tics Scale (PUTS): initial 
psychometric results and examination of the premonitory urge phenomenon in youths with Tic 
disorders. J Dev Behav Pediatr. 2005 Dec;26(6):397-403. 
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SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
 
 
NBI-98854-1601 Statistical Analysis Plan 
 
06Mar2018 
 
1 
 
 
  
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 2 
 
VERSION: 1.0 
 
DATE OF PLAN: 
 
06 March 2018 
 
BASED ON: 
Protocol Amendment No. 3 Final Version Date: 01 March 2017 
 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI-98854-1601 
STUDY TITLE: 
An Open-Label, Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects with 
Tourette Syndrome 
 
SPONSOR: 
Neurocrine Biosciences, Inc.  
12780 El Camino Real 
San Diego, CA 92130 
858.617.7660 
 
 
 


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NBI-98854-1601 Statistical Analysis Plan 
 
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NBI-98854-1601 Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................7 
3. 
STUDY OBJECTIVE ...................................................................................................7 
4. 
STUDY DESIGN .........................................................................................................7 
4.1. 
Summary of Study Design ............................................................................................7 
4.2. 
Sample Size Considerations .........................................................................................9 
4.3. 
Randomization ..............................................................................................................9 
4.4. 
Clinical Assessments ....................................................................................................9 
5. 
PLANNED ANALYSES ............................................................................................10 
5.1. 
Interim Analyses .........................................................................................................10 
5.2. 
Final Analyses ............................................................................................................10 
6. 
STATISTICAL ANALYSES .....................................................................................10 
6.1. 
General Statistical Considerations ..............................................................................10 
6.2. 
Definition of Baseline .................................................................................................11 
6.3. 
Pooling of Sites ...........................................................................................................11 
6.4. 
Handling of Early Termination Visit Data .................................................................11 
6.5. 
Handling of Missing Data ...........................................................................................12 
6.6. 
Coding Dictionaries ....................................................................................................13 
6.7. 
Analysis Sets ...............................................................................................................13 
6.8. 
Subject Enrollment and Disposition ...........................................................................13 
6.9. 
Protocol Deviations ....................................................................................................14 
6.10. 
Demographics .............................................................................................................14 
6.11. 
Baseline Subject Characteristics .................................................................................15 
6.12. 
Medical History ..........................................................................................................15 
6.13. 
Study Drug Dosing .....................................................................................................15 
6.13.1. 
Study Drug Dosing Compliance .................................................................................15 
6.13.2. 
Dose Escalation at Week 4 .........................................................................................15 
6.13.3. 
Dose Reductions after Week 4 ...................................................................................15 
6.14. 
Pharmacokinetic Data .................................................................................................15 
6.15. 
Pharmacodynamic Assessments .................................................................................16 
6.15.1. 
Yale Global Tic Severity Scale (YGTSS) ..................................................................16 


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6.15.2. 
Rush Video-Based Tic Rating Scale (RTRS) .............................................................16 
6.15.3. 
Premonitory Urge for Tics Scale (PUTS) ...................................................................16 
6.15.4. 
Clinical Global Impression of Tics-Severity (CGI-Tics-Severity) .............................17 
6.15.5. 
Clinical Global Impression of Improvement-Tourette Syndrome (CGI-TS) .............17 
6.15.6. 
Patient Global Impression of Change-Tourette Syndrome (PGIC-TS) ......................17 
6.15.7. 
Pediatric Quality of Life Inventory (PedsQL; Pediatric Subjects Only) ....................18 
6.15.8. 
Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL; Adult 
Subjects Only) ............................................................................................................18 
6.16. 
Safety Assessments .....................................................................................................19 
6.16.1. 
Adverse Events ...........................................................................................................19 
6.16.2. 
Clinical Laboratory Data ............................................................................................21 
6.16.3. 
Physical Examination and Weight ..............................................................................22 
6.16.4. 
Vital Signs ..................................................................................................................23 
6.16.5. 
Electrocardiogram .......................................................................................................23 
6.16.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................24 
6.16.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) ...............................25 
6.16.8. 
Children’s Depression Rating Scale, Revised (CDRS-R) ..........................................26 
6.16.9. 
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) ..........................26 
6.16.10. 
Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale 5: Home 
Version ........................................................................................................................26 
6.16.11. 
Yale-Brown Obsessive Compulsive Scale (Y-BOCS) ...............................................27 
6.16.12. 
Structured Interview Guide for the Hamilton Depression Rating Scale 
(SIGH-D-17) ...............................................................................................................27 
6.16.13. 
Prior and Concomitant Medications ...........................................................................27 
6.17. 
Additional Data Presentations ....................................................................................28 
6.17.1. 
Inclusion and Exclusion Criteria Deviations ..............................................................28 
6.17.2. 
Serology ......................................................................................................................28 
6.17.3. 
Pregnancy Tests ..........................................................................................................28 
6.17.4. 
Urine Drug Screen and Alcohol Breathalyzer Test ....................................................28 
7. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSES ................................28 
8. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................28 
9. 
REFERENCES ...........................................................................................................29 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping ..........................12 
Table 3: 
Potentially Clinically Significant Criteria for Selected Clinical Laboratory 
Variables .....................................................................................................................21 
Table 4: 
Potentially Clinically Significant Criteria for Selected Vital Signs ...........................23 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CGI-Tics-Severity 
Clinical Global Impression of Tics-Severity  
CGI-TS 
Clinical Global Impression of Improvement-Tourette Syndrome 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CY-BOCS 
Children’s Yale-Brown Obsessive-Compulsive Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated 
GGT 
Gamma-glutamyl transferase 
GTS-QOL 
Giles de la Tourette Syndrome-Quality of Life Scale 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
PedsQL 
Pediatric Quality of Life Inventory 
PGIC-TS 
Patient Global Impression of Change-Tourette Syndrome 
PK 
Pharmacokinetic(s) 
PUTS 
Premonitory Urge for Tics Scale 
QTcF 
Corrected QT interval using Fridericia’s formula 
RTRS 
Rush Video-based Tic Rating Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SIGH-D-17 
Structured Interview Guide for the Hamilton Depression Rating Scale 
TEAE 
Treatment-emergent adverse event 


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TS 
Tourette syndrome 
TTS 
Total tic score 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WHO 
World Health Organization  
Y-BOCS 
Yale-Brown Obsessive-Compulsive Scale 
YGTSS 
Yale Global Tic Severity Scale 
2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the clinical study report (CSR) for protocol NBI-98854-1601. 
This SAP provides details on analysis sets and on how analysis variables will be derived and 
missing data will be handled, and describes the statistical methods to be used to summarize the 
pharmacodynamic (PD), pharmacokinetic (PK), and safety data for the CSR. 
Deviations from the final approved SAP will be documented in the CSR. 
3. 
STUDY OBJECTIVE  
The objective of this clinical study is to evaluate the safety and tolerability of NBI-98854 
(titrated from 10 mg to 20 mg in children, 20 mg to 40 mg in adolescents, and 40 mg to 80 mg in 
adults) administered once daily for up to 24 weeks for the treatment of Tourette syndrome (TS). 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 2, open-label, fixed-dose titration study to evaluate the safety and tolerability of 
NBI-98854 administered once daily for a total of 24 weeks in children, adolescents, and adults 
with TS.  NBI-98854 doses will be titrated from 10 mg to 20 mg in children (6 to 11 years of 
age), 20 mg to 40 mg in adolescents (12 to 17 years of age), and 40 mg to 80 mg in adults (18 to 
64 years of age).  Up to 180 male and female subjects (up to 90 pediatric subjects [ie, children 
and adolescents] and up to 90 adult subjects) with a clinical diagnosis of TS will be enrolled.  
The study will include approximately 60 study sites in the United States. 
Subjects who have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit >30 
days prior to anticipated baseline (Day -1) require screening.  These subjects will be screened to 
determine eligibility within 20 days (Days -21 to -2) before baseline (Day -1). 
Subjects can have their final Phase 2 study (NBI-98854-1501 or NBI-98854-1505) visit on the 
same day as baseline (Day -1) for this study provided that the NBI-98854-1601 informed 


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consent, and assent (if applicable), is obtained before the final NBI-98854-1501 or NBI 98854 
1505 visit.  This will allow certain PD and safety assessments to be used for both the previous 
study and the current study.  The PD assessments that can apply to both the previous study and 
the current study include the Yale Global Tic Severity Score (YGTSS), RTRS, Premonitory 
Urge for Tics Scale (PUTS), and Clinical Global Impression (CGI) of Tics Severity.  The safety 
assessment results that can apply to both the previous study and the current study include 
physical examinations (including weight), vital signs, electrocardiograms (ECG), Extrapyramidal 
Symptom Rating Scale-Abbreviated (ESRS-A), Children’s Yale-Brown Obsessive-Compulsive 
Scale (CY-BOCS; pediatric subjects only), Children’s Depression Rating Scale - Revised 
(CDRS-R; pediatric subjects only), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; adult 
subjects only), and the Structured Interview Guide for the Hamilton Depression Rating Scale 
(SIGH-D-17; adult subjects only).  All other Day -1 assessments (including safety labs) must be 
collected for the current study (even if the subject is completing the final visit for the previous 
study).    
On Day -1, all subjects will have baseline study assessments conducted and be assessed for 
eligibility.  Eligible subjects will receive a supply of NBI-98854 (10, 20, or 40 mg, based on 
their age group) for the first 4 weeks of treatment.  Beginning on Day 1, subjects will take study 
drug once daily at home at approximately the same time each day (under the supervision of the 
subject’s parent/legal guardian for pediatric subjects) throughout the 24-week treatment period. 
At the end of Week 4, the investigator may escalate the NBI-98854 dose from 10 to 20 mg in 
children, from 20 to 40 mg in adolescents, and from 40 to 80 mg in adults, or continue with the 
subject’s current dose for the remainder of the treatment period.  A dose escalation will be 
allowed if (1) the investigator or designee’s assessment of the Clinical Global Impression of 
Improvement -Tourette Syndrome (CGI-TS) is “minimally improved”, “not changed”, 
“minimally worse”, “much worse”, or “very much worse”, and (2) the safety and tolerability of 
the current dose is acceptable as determined by a physician.  The subject will then continue at 
this dose until the end of the treatment period (ie, the end of Week 24). 
At any time after dose escalation, the investigator may modify the timing of study drug dosing 
(eg, qam to qhs) and/or decrease a subject’s dose (to 10 mg for children, 20 mg for adolescents, 
or 40 mg for adults) if the subject is unable to tolerate the dose increase.  Subjects who are 
unable to tolerate the starting dose of 10 mg for children, 20 mg for adolescents, 40 mg for 
adults, or the resumption of the 10 mg, 20 mg, or 40 mg dose after the dose escalation at Week 4, 
will be discontinued from the study. 
Subjects will return to the study site every 4 weeks during the treatment period, at the end of 
Weeks 4, 8, 12, 16, 20, and 24.       
A follow-up visit will be performed at the end of Week 28 (4 weeks after the last dose of study 
drug) or early termination.  Subjects who withdraw from the study will be asked to complete an 
early termination visit within 4 weeks.  Safety, PD, and PK will be assessed at scheduled times 
throughout the study.  The treatment period visits (end of Weeks 4, 8, 12, 16, 20, and 24) and the 
follow-up visit (end of Week 28) will have a visit window of ±6 days. 


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4.2. 
Sample Size Considerations 
The sample size for this study is based on practical considerations and not on a statistical power 
calculation. 
4.3. 
Randomization 
Subjects are not randomized to treatment in this study. 
4.4. 
Clinical Assessments 
Pharmacodynamics:  The following PD assessments will be administered at baseline (Day -1), 
at the end of Weeks 4, 8, 12, 16, 20, and 24, and at the follow-up visit (the end of Week 28, or 
early termination): 
All subjects:  
• YGTSS  
• RTRS 
• PUTS  
• CGI-Tics Severity 
Pediatric subjects only:  
• Pediatric Quality of Life Inventory (PedsQL) 
Adult subjects only:   
• Gilles de la Tourette Syndrome-Quality of Life (GTS-QOL) 
The CGI-TS (assessed by the investigator) and Patient Global Impression of Change-Tourette 
Syndrome (PGIC-TS) scales will be administered at the end of Weeks 4, 8, 12, 16, 20, and 24, 
and at the follow-up visit (the end of Week 28 or upon early termination) in all subjects. 
Plasma Drug Exposure:  Blood samples to evaluate plasma concentrations of NBI-98854 and 
the metabolite NBI-98782 will be collected during the treatment period (end of Weeks 4, 8, 12, 
16, 20, and 24), and at the follow-up visit (end of Week 28, or early termination). 
Safety:  Safety and tolerability will be monitored throughout the study and will include the 
following assessments:  
All subjects: 
• Adverse events (AEs) 
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
• Serum prolactin 
• Hemoglobin A1c 
• Vital signs (including orthostatic blood pressures and pulse, respiratory rate, and oral 
body temperature) 
• Physical examinations (including height and weight) 
• 12-lead ECGs 
• Columbia Suicide Severity Rating Scale (C-SSRS) (pediatric version will be used for 
pediatric subjects) 


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• ESRS-A  
Pediatric subjects only:   
• CDRS-R, CY-BOCS, and Attention-Deficit Hyperactivity Disorder (ADHD) Rating 
Scale 5:  Home Version 
Adult subjects only:   
• Y-BOCS and SIGH-D-17 
5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
An interim analysis is not planned for this study. 
5.2. 
Final Analyses 
A single, final analysis will be performed after the study database has been locked. 
6. 
STATISTICAL ANALYSES 
6.1. 
General Statistical Considerations 
Descriptive statistical methods will be used to summarize the data from this study.  The term 
“descriptive statistics” refers to the number of subjects (n), mean, median, standard deviation 
(SD), standard error of the mean (SEM), minimum, and maximum for continuous variables; and 
refers to the number and/or percentage of subjects (or events) for categorical variables.     
Unless stated otherwise, each table of descriptive statistics and associated figures will summarize 
data according to the following treatment groups: 
Children:  
NBI-98854 10 mg (subjects whose dose is not escalated to 20 mg at Week 4) 
NBI-98854 20 mg (subjects whose dose is escalated to 20 mg at Week 4 and maintained 
at that dose for the duration of the treatment period) 
NBI-98854 20/10 mg (subjects whose dose is escalated to 20 mg at Week 4 and 
subsequently reduced to 10 mg at any time during the treatment period) 
Adolescents:  
NBI-98854 20 mg (subjects whose dose is not escalated to 40 mg at Week 4) 
NBI-98854 40 mg (subjects whose dose is escalated to 40 mg at Week 4 and maintained 
at that dose for the duration of the treatment period) 
NBI-98854 40/20 mg (subjects whose dose is escalated to 40 mg at Week 4 and 
subsequently reduced to 20 mg at any time during the treatment period) 


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Adults:  
NBI-98854 40 mg (subjects whose dose is not escalated to 80 mg at Week 4) 
NBI-98854 80 mg (subjects whose dose is escalated to 80 mg at Week 4 and maintained 
at that dose for the duration of the treatment period) 
NBI-98854 80/40 mg (subjects whose dose is escalated to 80 mg at Week 4 and 
subsequently reduced to 40 mg at any time during the treatment period) 
Note that subjects who discontinue from the study prior to the Week 4 dose escalation visit will 
be included in the treatment group corresponding to the starting dose for their age group.  In 
addition, it should be noted that while the data at Week 4 will be summarized by treatment group 
as described above, all subjects will have received only the starting dose for their age group up to 
that timepoint. 
A comprehensive set of data listings including all enrolled subjects will be provided.  These 
listings will include both measured (as reported) and derived values.  Observations in data 
listings will typically be sorted by age group, subject, and timepoint (if applicable). 
The derived variable “study day” is used in calculations for data summaries and listings.  This 
variable is calculated as the number of days after a subject’s Day -1 visit.  Study Day 1, then, is 
the day after the Day -1 visit. 
Summary statistics will be presented using a significant figure rule: the median, minimum, and 
maximum will have the same number of significant figures as the data; the mean will have one 
more significant figure than the data being summarized; the SD and SEM will have the same 
number of significant figures as the mean; and the sample size (N) will be reported as an integer.  
This rule may be modified if warranted, based on practical considerations. 
6.2. 
Definition of Baseline 
The term “baseline” as used in this SAP normally refers to the baseline visit (Day -1), and 
baseline values will therefore be those reported at Day -1.  However, there may be cases where a 
value is reported after the nominal Day -1 timepoint (but prior to the first dose of study drug) or 
a Day -1 value is missing but a screening value is available.  For purposes of analysis, the value 
of an analyte or measurement closest to (and prior to) the first dose of study drug will be used as 
“baseline” in summary tables and figures. 
6.3. 
Pooling of Sites 
With the exception of the summary of subject enrollment by site, study sites will be pooled in all 
tables and graphs, as the majority of sites in this study are expected to enroll a small number of 
subjects. 
6.4. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject discontinues from the study prior to 
completing the scheduled Week 28 visit.  The data collected at ET visits will be included in 
summary tables and figures in accordance with the ET visit mapping scheme described in this 
section.   


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An ET visit will be mapped to Week 4 if it occurs within 7 days prior to and 6 days after the 
expected study day of the Week 4 visit (but only if the subject has not completed a scheduled 
Week 4 visit).  For study visits after Week 4, an ET visit will be mapped to the next scheduled 
study visit if it occurs within 14 days prior to and 13 days after the expected study day of the 
visit (note that, for Week 28, only the lower bound of the study day range is applicable).  If an 
ET visit falls outside the allowable study day range (see table below) for the next scheduled visit 
that follows a scheduled visit which was completed by the subject, the ET visit will not be 
mapped.  An ET visit also will not be mapped to a visit during the treatment period if the ET 
visit does not occur within one week of the subject’s last dose of study drug (note that dates for 
both the ET visit and the last dose of study drug must be present in the database for this to be 
confirmed).   
Early termination visit data that are not mapped to a scheduled visit will be displayed in data 
listings but not included in by-visit summaries.   
Table 2 displays the allowable study day range for each scheduled visit for ET visit mapping 
purposes. 
Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping 
 
Scheduled Visit 
 
Target Study Day 
Time Interval 
(Study Day Range) 
Week 4 
28 
21-34 
Week 8 
56 
42-69 
Week 12 
84 
70-97 
Week 16 
112 
98-125 
Week 20 
140 
126-153 
Week 24 
168 
154-181 
Week 28 
196 
182 + 
6.5. 
Handling of Missing Data 
Missing values for outcome measures will not be replaced with imputed values except as noted 
above for the ET visit data mapped to scheduled visits for data summary purposes.  
Missing and incomplete (“partial”) dates for AEs and concomitant medications will be imputed 
only to estimate the time of the event or medication usage in relationship to study treatment 
periods (eg, pretreatment period vs. treatment period); however, all data listings will display the 
original dates as reported on the eCRF.     
The imputation rules for AE start dates are as follows: 
• If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug; 
• If only the day component is missing from the date, the date will be imputed as the date 
of the first dose of study drug if the date is in the same month and year as the first dose of 
study drug; otherwise, the missing day component will be imputed as the first day of the 
month; 


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• If both the day and month components are missing from the date, the date will be 
imputed as the date of the first dose of study drug if the date is in the same year as the 
first dose; otherwise, the missing components will be imputed as 01 January; 
• If any of the above imputations result in a start date that is later than an existing complete 
(not imputed) end date for the event, the start date will be set equal to the end date. 
The imputation rules for concomitant medication start dates are as follows: 
• If the date is completely missing, the date will be imputed as 01 January in the year of the 
subject’s screening vital signs assessment; 
• If only the day component is missing from the date, the date will be imputed as the date 
of the first dose of study drug if the date is in the same month and year as the first dose of 
study drug; otherwise, the missing day component will be imputed as the first day of the 
month; 
• If both the day and month components are missing from the date, the date will be 
imputed as the date of the first dose of study drug if the date is in the same year as the 
first dose; otherwise, the missing components will be imputed as 01 January; 
• If any of the above imputations result in a start date which is later than an existing 
complete (not imputed) medication stop date, the start date will be set equal to the stop 
date. 
6.6. 
Coding Dictionaries  
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 12.0).  Prior and concomitant medications will be coded using the World 
Health Organization (WHO) Drug Dictionary. 
6.7. 
Analysis Sets  
The safety analysis set will be the single analysis set used for this study.  The safety analysis set 
will include all enrolled subjects who take at least one dose of study drug and have any data 
collected after the initial dose of study drug.  However, if it is unknown whether the subject took 
at least one dose of study drug but the subject has postbaseline data in the study database, the 
subject will be included in the safety analysis set. 
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) the safety analysis set will be provided for each treatment group by age group (ie, a 
separate summary table will be presented for each age group).  The number and percentage of 
subjects excluded from the safety analysis set by reason for exclusion will also be provided. 
Summaries of subject enrollment and disposition, enrollment by study site, and analysis set 
inclusion/exclusion status will include all enrolled subjects.  All other summaries will be based 
on the safety analysis set. 
6.8. 
Subject Enrollment and Disposition 
Subject enrollment and disposition will be summarized for each age group and for the overall 
study population (ie, with age groups combined).   


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The summary for each age group will display, by treatment group and overall (ie, “all subjects”), 
the number and percentage of subjects who enrolled in the study, discontinued from the study 
prior to or at the Week 4 visit, discontinued from the study early, and completed the study (ie, 
completed their scheduled Week 28 visit).  The summary will also present the number and 
percentage of subjects who discontinued from the study early according to the reason for 
discontinuation as per the eCRF. 
A separate summary of enrollment and disposition will be presented with age groups combined.  
This table will not include treatment group but will otherwise provide the same information 
displayed in the by-age group summary tables. 
A summary of enrollment by study site will be presented for each age group.  This summary will 
display the number of subjects enrolled at each site, by treatment group and for all subjects. 
An additional table will be presented for each age group that displays the number of subjects in 
each treatment group (and overall) who completed each study visit.  This summary is based on 
the safety analysis set rather than all enrolled subjects. 
6.9. 
Protocol Deviations 
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being.  An assessment of which protocol deviations are 
considered IPDs will be performed by a committee composed of NBI Clinical Development 
project team members.  Important protocol deviations may include, but are not limited to the 
following:   
• Failure to obtain informed consent from the subject prior to performing any study 
procedures 
• Deviations from key inclusion/exclusion criteria 
• Use of prohibited concomitant medications 
• Error in drug dispensing which results in a subject not receiving intended treatment 
• Significant deviation from protocol-specified dosing regimen 
 
The number and percentage of subjects with IPDs will be summarized for each age group by 
deviation category, treatment group, and for all subjects. 
6.10. 
Demographics 
The following demographic data will be summarized with descriptive statistics for each age 
group by treatment group and for all subjects: 
• Age 
• Gender 
• Race 
• Ethnicity 


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6.11. 
Baseline Subject Characteristics 
The following baseline subject characteristics will be summarized with descriptive statistics for 
each age group by treatment group and for all subjects: 
• Weight (in units of pounds and kilograms) 
• Weight percentile (pediatric subjects only) 
• Height 
• Body mass index 
• Age at TS diagnosis 
• CYP2D6 genotype classification 
• Baseline YGTSS total tic score (TTS) 
6.12. 
Medical History  
Medical history will be summarized for each age group in frequency tables (number and 
percentage of subjects) by MedDRA System Organ Class (SOC) and Preferred Term (PT) by 
treatment group and for all subjects. 
6.13. 
Study Drug Dosing 
6.13.1. 
Study Drug Dosing Compliance 
Study drug dosing compliance (defined as the subject having taken at least 80% of doses since 
their previous visit as captured on the eCRF) will be summarized by visit (beginning with Week 
4). The number and percentage of subjects who were dose compliant will be summarized for 
each age group by treatment group and for all subjects. 
6.13.2. 
Dose Escalation at Week 4 
The number and percentage of subjects whose dose was increased from the starting dose level to 
the higher dose level (eg, from 10 mg to 20 mg for children) will be summarized for each age 
group and for age groups combined.  The reason for dose maintenance at Week 4 (adverse event, 
clinical impression of TS, or “other”) will also be summarized (number and percentage of 
subjects in each category).  Note that this summary is not “by treatment group”. 
6.13.3. 
Dose Reductions after Week 4 
The dose reduction summary will present the number of subjects with a dose reduction at any 
time after Week 4 during the treatment period for each age group and for age groups combined.  
The number of subjects with a dose reduction will be displayed by dose reduction reason 
category (adverse event, clinical impression of TS, or “other”).     
Note that this summary is not “by treatment group”. 
6.14. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and its metabolite NBI-98782 will be summarized with 
descriptive statistics for each age group by visit (Weeks 4, 8, 12, 16, 20, 24, and 28) and the most 
recent NBI-98854 dose level received by a subject prior to that visit.     


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Concentrations below the lower limit of quantification (BLQ) will be set equal to zero for all 
plasma concentration summaries. The lower limits of quantification are as follows: (a) NBI-
98854: 1.00 ng/mL and (b) NBI 98782: 0.100 ng/mL. 
The following additional descriptive statistics will be included in the plasma concentration 
summary tables: (a) the number of plasma concentration values greater than or equal to the lower 
limit of quantification, (b) the geometric mean, and (c) the geometric coefficient of variation 
(%). 
6.15. 
Pharmacodynamic Assessments 
6.15.1. 
Yale Global Tic Severity Scale (YGTSS) 
The following three analysis variables are based on the YGTSS:  (a) the TTS, (b) the Impairment 
score, and (c) the Global Tic Severity score. 
The TTS is defined as the sum of the YGTSS motor tic severity score and phonic (vocal) tic 
severity score.  The motor tic severity score is calculated as the sum of the scores for the 5 motor 
tic items (number, frequency, intensity, complexity, and interference).  The score for each item 
can range from 0 to 5, for a maximum total score of 25.  The vocal (phonic) tic severity score is 
calculated similarly.  If any one of the 5 items for the motor or vocal tic severity score is not 
scored (ie, has a missing value), the associated severity score will be set equal to missing.   If any 
of these items has a missing value at a given subject visit, the TTS value for the subject visit will 
also be set equal to missing.  The TTS value can range from 0 to 50. 
The YGTSS Impairment score is captured directly in the eCRF.  This score can range in value 
from 0 to 50. 
The YGTSS Global Tic Severity score is the sum of the TTS and the Impairment score.  The 
YGTSS Global Tic Severity score at a given subject visit will be set equal to missing if either of 
the TTS or Impairment scores are missing.  The YGTSS Global Tic Severity score value can 
range from 0 to 100. 
For each of these three variables, descriptive statistics will be presented for the observed values 
at each visit and for the changes from baseline to each postbaseline visit.  These summaries will 
be presented for each age group by treatment group and for all subjects.  
Figures will also be presented for the TTS observed values and changes from baseline (mean 
values ± SEM) for each age group by treatment group.   
6.15.2. 
Rush Video-Based Tic Rating Scale (RTRS) 
The RTRS videos recorded during the study were to be scored by a blinded central rater; 
however, the scoring was not performed.  Therefore, no summaries will be presented for the 
RTRS. 
6.15.3. 
Premonitory Urge for Tics Scale (PUTS) 
The PUTS consists of 9 items, each of which is scored on a 4-point scale (1=not at all true, 2=a 
little true, 3=pretty much true, 4=very much true).  The PUTS total score is calculated as the sum 


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of the scores for the 9 items.  The maximum possible total score is 36.  If any one of the 9 items 
is not scored (ie, has a missing value), the PUTS total score will be set equal to missing. 
Descriptive statistics will be presented for the PUTS total score observed values at each visit and 
for the changes from baseline to each postbaseline visit.  These summaries will be presented for 
each age group by treatment group and for all subjects. 
6.15.4. 
Clinical Global Impression of Tics-Severity (CGI-Tics-Severity) 
Each of the CGI-Tics-Severity response categories will be assigned a numerical score as follows: 
• Normal, not at all ill = 1 
• Borderline ill = 2 
• Mildly ill = 3 
• Moderately ill = 4 
• Markedly ill = 5 
• Severely ill = 6 
• Among the most extremely ill patient = 7 
Descriptive statistics (including both frequency counts [using response categories] and 
continuous variable statistics [based on numerical scores]) will be presented for each age group 
by treatment group and for all subjects for the CGI-Tics-Severity data at each visit.  Changes 
from baseline to each postbaseline visit will be summarized also for the numerical scores with 
continuous variable descriptive statistics.   
6.15.5. 
Clinical Global Impression of Improvement-Tourette Syndrome (CGI-TS) 
Each of the CGI-TS response categories will be assigned a numerical score as follows: 
• Very much improved = 1 
• Much improved = 2 
• Minimally improved = 3 
• Not changed = 4 
• Minimally worse = 5 
• Much worse = 6 
• Very much worse = 7 
Descriptive statistics (including both frequency counts [using response categories] and 
continuous variable statistics [based on numerical scores]) will be presented for each age group 
by treatment group and for all subjects for the CGI-TS data at each visit. 
6.15.6. 
Patient Global Impression of Change-Tourette Syndrome (PGIC-TS) 
Each of the PGIC-TS response categories will be assigned a numerical score as follows: 
• Very much improved = 1 
• Much improved = 2 
• Minimally improved = 3 
• Not changed = 4 
• Minimally worse = 5 


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• Much worse = 6 
• Very much worse = 7 
Descriptive statistics (including both frequency counts [using response categories] and 
continuous variable statistics [based on numerical scores]) will be presented for each age group 
by treatment group and for all subjects for the PGIC-TS data at each visit. 
6.15.7. 
Pediatric Quality of Life Inventory (PedsQL; Pediatric Subjects Only) 
Three age-specific versions of the PedsQL were used in this study:  one for young children (age 
5 through 7), one for older children (age 8 through 12), and one for teens (age 13 through 18).  
Each version consists of 23 items across 4 domains, with each item scored on a 3-point scale for 
young children (0=not at all true, 2=sometimes, 4=a lot) and a 5-point scale for older children 
and teens (0=never, 1=almost never, 2=sometimes, 3=often, 4=almost always).  The PedsQL 
total score is calculated as the sum of the scores for the 23 items.  The maximum possible total 
score is 92.  If any one of the 23 items is not scored (ie, has a missing value), the PedsQL total 
score will be set equal to missing. 
In addition to the total score, the scores for each domain (physical functioning, emotional 
functioning, social functioning, and school functioning) will be calculated in a similar manner as 
the sum of the scores for the items within each domain. 
Descriptive statistics will be presented for the PedsQL total score and each domain score 
observed values at each visit and for the changes from baseline to each postbaseline visit.  These 
summaries will be presented for each pediatric age group by treatment group and for all subjects. 
6.15.8. 
Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL; Adult Subjects 
Only) 
The GTS-QOL has two parts: (1) a 27-item scale which includes 4 factors (subscales), with each 
of the 27 items scored on a 5-point scale (0=no problem, 1=slight problem, 2=moderate problem, 
3=marked problem, 4=extreme problem) and (2) a visual analog scale (VAS) which ranges in 
value from 0 to 100.  The GTS-QOL total score is calculated as the sum of the scores for the 27 
items and is then normalized to value which can range from 0 to 100 by the following formula: 
(100 x [(observed score – minimum possible score) / (maximum possible score -minimum 
possible score)]) 
If any one of the 27 items is not scored (ie, has a missing value), the total score will be set equal 
to missing. 
Scores will be calculated (and normalized to a 0 to 100 range using the formula above) for each 
of the 4 GTS-QOL factors in a similar fashion.  These factors and the items included in each 
factor are as follows (item numbers are displayed): 
• Psychological (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27) 
• Physical and activities of daily living (1, 2, 3, 4, 5, 6, 26) 
• Obsessive-compulsive (7, 8, 9, 10, 15) 
• Cognitive (11, 12, 13, 14) 


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Descriptive statistics will be presented for the GTS-QOL total score, each factor score, and the 
VAS score observed values at each visit and for the changes from baseline to each postbaseline 
visit.  These summaries will be presented by treatment group and for all subjects. 
6.16. 
Safety Assessments 
6.16.1. 
Adverse Events 
6.16.1.1. Treatment-Emergent Adverse Event Frequency Tables 
A treatment-emergent adverse event (TEAE) is an adverse event (AE) not present prior to the 
initiation of study drug dosing, or is an already present event that worsens either in intensity or 
frequency following the initiation of study drug dosing.  The determination of whether an AE is 
treatment emergent is based on the AE onset date relative to the date of the subject’s first dose of 
study drug.  If the AE onset date and date of the first dose of study drug are the same, or if the 
AE onset date is unknown, it will be assumed that the AE is a TEAE. 
TEAEs, categorized by MedDRA (Version 12.0) system organ class (SOC) and preferred term 
(PT), will be summarized in frequency tables.  In these tables, SOCs and PTs within each SOC 
will be sorted alphabetically.  TEAEs categorized by PT only will be presented also.  Unless 
stated otherwise, the frequency tables will include the number of events reported, and the number 
and percentage of unique subjects experiencing each event one or more times during the study 
interval summarized in the table.  A description of each summary table is provided below.  All 
TEAE summary tables will be presented for each age group separately.  
Adverse events with an onset date prior to the date of the first dose of study drug will be 
presented only in a data listing. 
TEAEs Reported through Week 4 Visit 
TEAEs with an onset date during the first 4 weeks of the study (through the Week 4 visit) will be 
summarized separately from TEAEs with an onset date after the Week 4 visit, as all subjects 
receive the same dose (within an age group) during the first 4 weeks of treatment. These tables 
will therefore not be “by treatment” and will summarize data for all subjects within each age 
group. 
In addition to the summaries that include all TEAEs, summaries will be presented for TEAEs 
considered to be possibly or definitely related to study drug (“treatment related”) and for TEAEs 
categorized according to the maximum intensity reported for a given subject. For these additional 
summaries, TEAEs will be presented by PT only (ie, not by SOC), with PTs sorted according to 
decreasing frequency of subjects reporting each event. 
TEAEs Reported after Week 4 Visit 
TEAEs with an onset date after the Week 4 visit will be summarized by treatment group and for 
all subjects.   
Similar tables will be presented including only TEAEs considered to be possibly or definitely 
related to study drug and categorizing TEAEs according to the maximum intensity reported for a 
given subject.  In these summaries, TEAEs will be presented by PT only, based on the “all 
subjects” column.   


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TEAEs Reported during Posttreatment Period 
TEAEs with an onset date after the Week 24 visit will be summarized by treatment group and for 
all subjects.   
TEAEs Reported at Any Time During Study 
TEAEs reported at any time during the study will be summarized for all subjects (ie, without 
regard to treatment group). 
6.16.1.2. Adverse Event Overall Summaries 
Overall summary tables will be presented which summarize the number and percentage of 
subjects with any TEAE, any treatment-related TEAE (ie, possibly or definitely related per 
electronic case report form [eCRF]), any severe TEAE, any TEAE leading to study 
discontinuation, any serious TEAE, and any TEAE resulting in death.  An overall summary table 
will be presented for each of the study intervals described above and will include the same 
treatment group columns as in the frequency tables. 
6.16.1.3. Adverse Events Resulting in a Study Drug Dose Reduction 
A summary of TEAEs resulting in a study drug dose reduction in subjects with a dose escalation 
at Week 4 will be presented.  The summary table for each age group will display the PTs for the 
TEAEs resulting in a dose reduction, with the PTs sorted in order of decreasing frequency (based 
on number of subjects).  The first line of the table will display the total number of subjects with a 
dose reduction. 
A listing of TEAEs resulting in a study drug dose reduction will be included in the study report 
(this listing will include data for all three age groups and will be sorted by age group).  The 
listing will include age group, subject, study day of the dose reduction, and both the PT and 
reported term for all TEAEs that resulted in the dose reduction 
6.16.1.4. Adverse Events Resulting in Premature Study Discontinuation 
A summary table of TEAEs resulting in premature study discontinuation will be presented for 
each age group for the following study periods: 
• Through Week 4 visit 
• After Week 4 visit 
These summary tables will include both the SOC and PT, with data summarized by treatment 
group (for TEAEs occurring after Week 4) and for all subjects.  Note that the onset date of the 
TEAE(s) resulting in study discontinuation (not the date of discontinuation) will be the basis for 
determining the study period assignment. 
A listing of TEAEs resulting in premature study discontinuation will be presented in the study 
report, sorted by age group and subject.  The listing will include age group, subject, treatment 
group, study period when the TEAE which resulted in study discontinuation occurred, study day 
of the TEAE onset, and both the PT and reported (verbatim) term for all TEAEs that resulted in 
the premature study discontinuation (note that this is determined from the AE eCRF “action 
taken” field). 


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6.16.1.5. Deaths and Other Serious Adverse Events 
The frequency of SAEs will be summarized in tables using the approach described above for 
TEAEs resulting in premature study discontinuation.  The table formats (which include both the 
SOC and PT) for the SAE tables will match those used for the TEAE premature study 
discontinuation tables.   Deaths will be presented in a listing only.   
Listings of SAEs and deaths will be presented in the study report, with each listing sorted by age 
group and subject.  These listings will include age group, subject, treatment group, study period 
when the death or SAE occurred, study day of the death or SAE, and all other AE-specific 
information reported on the AE eCRF. 
6.16.2. 
Clinical Laboratory Data 
The hematology, clinical chemistry, hemoglobin A1c, and serum prolactin data at each visit will 
be summarized for each age group with descriptive statistics by treatment group and for all 
subjects.  Both observed values and changes from baseline will be summarized.   
The prolactin data will be summarized for each gender separately in addition to the summary 
described above. 
Shift tables for each age group will be presented for selected clinical laboratory variables based 
on the reference (“normal”) range-based categories of “Low,” “Normal,” or “High.”  A clinical 
laboratory variable value will be assigned to one of these three categories according to the 
reference ranges provided by the central clinical laboratory.   
Each shift table will have three rows and three columns, with rows reflecting the reference range 
category at baseline, and columns reflecting the reference range category at the subject’s final 
study visit.  Subjects with missing data for a clinical laboratory variable at either timepoint will 
not be included in tables for that variable.  The shift tables will be presented for each treatment 
group and for all subjects. 
Shift tables will be displayed for the following clinical laboratory variables: aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
total bilirubin, creatine kinase, creatinine, BUN, prolactin, hemoglobin A1c, white blood cell 
count, absolute neutrophil count, hemoglobin, and platelet count. 
Summaries of sponsor-defined potentially clinically significant (PCS) values will be presented 
by age group for the following clinical laboratory variables:  ALT, AST, creatinine kinase, GGT, 
total bilirubin, white blood cell count, neutrophil count, creatinine, and BUN.  The number and 
percentage of subjects with one or more PCS values at any time after baseline will be 
summarized by treatment group and for all subjects.  Note that data collected at both scheduled 
and unscheduled study visits will be included in this assessment.  The criteria for identifying 
PCS values are provided in Table 3. 
Table 3: 
Potentially Clinically Significant Criteria for Selected Clinical Laboratory 
Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 


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Variable  
PCS Threshold 
AST 
>3 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
Absolute Neutrophil count 
<1.5 x 1000/µL 
Creatinine 
>1.5 x Day -1 value or > 1.5 x ULN 
BUN 
>30 mg/dL (> 10.71 mmol/L) 
A listing of all subjects with any PCS value will be presented in the study report. This listing will 
include the values of the clinical laboratory variables in Table 3 at all study visits for each 
subject with one or more PCS values. The listing will be sorted by age group and subject, and 
will include age group, subject, treatment group, visit, study day of visit, and all laboratory 
results for the analytes with a PCS value.  Values that meet the PCS criteria will be flagged with 
an asterisk in the listing. 
Scatter plots for prolactin will be created for each age group which display the subjects’ final 
study visit values vs. baseline values.  Each plot will include a 45-degree (“y=x”) reference line.  
A separate plot will be generated for each treatment group and for all subjects.   
The clinical laboratory data listings will include associated normal/reference ranges (if 
provided).  In addition, values outside the normal range will be flagged as “L” if below the lower 
limit of normal and as “H” if above the upper limit of normal.  There will also be a flag for 
clinical significance based on the investigator’s assessment of out-of-range values.  The 
urinalysis data will be presented in data listings only. 
Repeat clinical laboratory samples may be collected at any time during this study due to either 
missing or abnormal results.  The general rule of thumb for summarizing these data is to include 
the original sample results in summary tables and graphs (subject to the definition of “baseline” 
as per Section 6.2.  All sample results (original and repeat) will be included in data listings. 
6.16.3. 
Physical Examination and Weight 
Clinically significant physical examination findings will be presented in a data listing in the 
study report.  The listing will include age group, subject, treatment group, visit at which the 
finding was reported, study day of the visit, and the clinically significant finding.  
Body weight, which is measured during the physical examination, will be summarized in units of 
kilograms with descriptive statistics (both observed values and changes from baseline) for each 
age group at each visit by treatment group and for all subjects. 


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6.16.4. 
Vital Signs 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics for each age group at 
each visit by treatment group and for all subjects.  Both observed values and changes from 
baseline will be summarized.    
Sponsor-defined PCS values for systolic blood pressure, diastolic blood pressure, and heart rate 
will be summarized for each age group by treatment group and for all subjects.  The number and 
percentage of subjects with one or more PCS values at any time after baseline will be 
summarized.  Note that data collected at both scheduled and unscheduled study visits will be 
included in this assessment.  The criteria for identifying PCS values are provided in Table 4. 
Table 4: 
Potentially Clinically Significant Criteria for Selected Vital Signs 
Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Systolic Blood 
Pressure 
<90 mmHg 
 
≥20 mmHg 
>180 mmHg 
 
≥20 mmHg 
Diastolic Blood 
Pressure 
<50 mmHg 
 
≥10 mmHg 
>105 mmHg 
 
≥15 mmHg 
Heart Rate 
<50 bpm 
 
≥15 bpm 
>120 bpm 
 
≥15 bpm 
Note that both supine and standing values of blood pressures and heart rate will be included in 
the identification and summary of PCS values. 
A listing of all subjects with a PCS value will be presented in the study report.  This listing will 
include vital signs data at all study visits for each subject with one or more PCS values.  The 
listing will be sorted by age group, subject, and visit, and will include age group, subject, 
treatment group, visit, study day of visit, systolic blood pressure (supine and standing), diastolic 
blood pressure (supine and standing), and heart rate (supine and standing).  Values that meet the 
PCS criteria will be flagged with an asterisk in the listing. 
6.16.5. 
Electrocardiogram 
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and Fridericia’s correction of QT interval [QTcF]) measured at each visit will be 
averaged for the purpose of analysis.  For the overall assessment categorical variable (the 
investigator’s assessment of the ECG as Normal, Abnormal not Clinically Significant, or 
Abnormal Clinically Significant), which is also reported in triplicate, the value that represents 
the greatest degree of abnormality will be used in all summary tables. 
The ECG variables will be summarized with descriptive statistics (frequency tables for the 
overall assessment categorical variable) for each age group at each visit by treatment group and 
for all subjects.  Both observed values and changes from baseline will be summarized (for the 
overall categorical assessment, only observed values will be summarized). 


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Categorical summaries will be presented for the QT and QTcF interval data.  For these 
summaries, a subject’s highest reported postbaseline value (including assessments at both 
scheduled and unscheduled study visits) will be used to determine in which category(s) the 
subject will be counted.   
Two categorical summaries will be presented by age group for the QT and QTcF intervals (each 
interval will be summarized separately).  For the first summary, the number and percentage of 
subjects in each treatment group (and for all subjects) whose highest reported postbaseline 
QT/QTcF value meets the following thresholds will be summarized: 
• Greater than 450 msec 
• Greater than 480 msec 
• Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects in each 
treatment group (and for all subjects) whose largest QT/QTcF increase from their baseline value 
meets the following thresholds:  
• Greater than 30 msec 
• Greater than 60 msec 
6.16.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS data will be summarized for each age group as follows:  
• Screening/baseline lifetime assessment by treatment group and for all subjects  
• Screening/baseline “past 1 year” assessment by treatment group and for all subjects  
• All postbaseline assessments (after Day -1 through final visit) by treatment group and for 
all subjects 
Note that the screening/baseline assessments are completed at the screening visit for subjects 
who have a screening visit and at the Day -1 visit for subjects who do not have a screening visit. 
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category).  These C-SSRS items and categories are as follows: 
• Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
• Suicidal Ideation Category:  Any of items (1) through (5) 
• Suicidal Behavior Items 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 


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(10) 
Completed suicide 
• Suicidal Behavior Category:  Any of items (6) through (10) 
• Suicidal Ideation or Behavior Category:  Any of items (1) through (10) 
For the postbaseline period, the C-SSRS responses for all assessments for a subject (including 
both scheduled and unscheduled visits) will be evaluated, and a “Yes” response for any 
assessment will be considered as a “Yes” for the subject.     
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to the “past 1 year” assessment scores will be presented.  The shift table scores 
are defined as the following: 
0=No suicidal ideation 
1=Wish to be dead 
2=Non-specific active suicidal thoughts 
3=Active suicidal ideation with any methods (not plan) without intent to act 
4=Active suicidal ideation with some intent to act, without specific plan 
5=Active suicidal ideation with specific plan and intent 
The shift tables will display, for each age group, the number and percentage of subjects within 
each cell of a 6 x 6 table for each treatment group and for all subjects, with the rows representing 
the “past 1 year” score and the columns representing the maximum score recorded during the 
postbaseline period (across all visits, including unscheduled visits).  Subjects missing either a 
“past 1 year” score or all postbaseline scores will not be included in the shift tables. 
A summary listing of individual subject data will be presented for the C-SSRS data and will be 
provided in the study report.  This summary will list subjects with a positive response for 
suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent at any time 
after Day -1.   The listing will be in the form of a table, with each row representing a subject visit 
(including treatment group and study day for that visit), and a column for each suicidal ideation 
item (1 – 5), each suicidal behavior item (6 – 10), and a final column for self-injurious behavior 
without suicidal intent.  The cells of the table will be populated with “Y” or “N,” representing 
either a positive or negative response, respectively, for each item in the table (ie, for each column 
of the table).  A separate table will be presented for each age group. 
6.16.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
The ESRS-A assesses 4 types of movement disorders: parkinsonism, dystonia, akathisia, and 
tardive dyskinesia.  The ESRS-A consists of four subscales, one for each type of movement 
disorder.  The ESRS-A contains 10 items to evaluate parkinsonism, 6 items to evaluate dystonia, 
6 items to evaluate dyskinesia, and 2 items to evaluate akathisia.  Each item score can range from 
0 to 5, for a maximum possible parkinsonism score of 50, maximum possible dystonia score of 
30, maximum possible dyskinesia score of 30, and maximum possible akathisia score of 10.  A 
Clinical Global Impression of Severity (CGI-S) is also completed for each type of movement 
disorder, and is also is scored on a 0 to 5 scale.   
The subscale scores for each type of movement disorder (parkinsonism, akathisia, dystonia, and 
tardive dyskinesia) will be calculated as the sum of the scores of the individual items comprising 
each subscale.  The overall total score will be calculated as the sum of each of the subscale 


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scores.  If any one of the items is not scored (ie, has a missing value), the associated subscale 
score and total score will be set equal to missing.  The CGI-S scores will be summarized 
separately from the subscale scores. 
For each of the subscale scores for parkinsonism, akathisia, dystonia, and tardive dyskinesia, the 
overall total score, and the CGI-S score for each subscale, descriptive statistics will be presented 
for the observed values at each visit and for the changes from baseline to each postbaseline visit.  
These summaries will be presented for each age group by treatment group and for all subjects. 
6.16.8. 
Children’s Depression Rating Scale, Revised (CDRS-R) 
The CDRS-R is a 17-item, semi-structured interview to determine the severity of depression in 
children.  The CDRS-R total score is calculated as the sum of the 17 items making up the CDRS-
R.  Each item score ranges from 1 to 7 except for items 4, 5, and 16, which range from 1 to 5.  
The maximum possible total score is 113.  If any one of the 17 items is not scored (ie, has a 
missing value), the total score will be set equal to missing. 
The total score observed values at each visit and changes from baseline to each postbaseline visit 
will be summarized for the children and adolescent age groups with descriptive statistics by 
treatment group and for all subjects.  
6.16.9. 
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) 
The CY BOCS is a semi-structured interview designed to rate the severity of obsessive and 
compulsive symptoms in children.   
The CY-BOCS obsession subtotal score is calculated as the sum of the scores for items 1 through 
5 of the CY-BOCS scale (excluding item 1b), and the CY-BOCS compulsion subtotal score is 
calculated as the sum of the scores for items 6 through 10 of the CY-BOCS scale (excluding item 
6b).  The CY-BOCS total score is the sum of the obsession and compulsion subtotal scores.  
Each item score ranges from 0 to 4, with a maximum possible obsession subtotal score of 20, a 
maximum possible compulsion subtotal score of 20, and a maximum possible total score of 40.  
If any one of these 10 items is not scored (ie, has a missing value), the associated subtotal score 
and total score will be set equal to missing. 
The observed values of the total score and subtotal scores for obsession and compulsion at each 
visit and changes from baseline to each postbaseline visit will be summarized for the children 
and adolescent age groups with descriptive statistics by treatment group and for all subjects. 
6.16.10. 
Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale 5: Home Version 
The ADHD Rating Scale 5: Home Version will be used to determine the frequency and severity 
of ADHD symptoms and impairments over the past month in children.  The 30-item scale 
consists of 2 subscales: Inattention (the sum of the scores for items 1 through 9) and 
Hyperactivity-Impulsivity (the sum of the scores for items 16 through 24), as well as a Total 
Scale raw score defined as the sum of the Inattention and Hyperactivity-Impulsivity subscale 
scores.  Each item score ranges from 0 to 3, for a maximum possible Inattention score of 27, a 
maximum possible Hyperactivity-Impulsivity score of 27, and a maximum possible Total Scale 
raw score of 54.  If any one of the 18 items is not scored (ie, has a missing value), the affected 
subscale score(s) and Total Scale raw score will be set equal to missing. 


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The ADHD Rating Scale 5: Home version also includes 6 domains of impairment associated 
with each of the 2 subscales described above (items 10 through 15 for Inattention and items 25 
through 30 for Hyperactivity-Impulsivity).  These domains will be included in data listings but 
will not be summarized in tables. 
The observed values of the Total Scale raw score and the Inattention and Hyperactivity-
Impulsivity subscale scores at each visit and changes from baseline to each postbaseline visit will 
be summarized for children and adolescent age groups with descriptive statistics by treatment 
group and for all subjects.  
6.16.11. 
Yale-Brown Obsessive Compulsive Scale (Y-BOCS) 
The Y-BOCS is a semi-structured interview designed to rate the severity of obsessive and 
compulsive symptoms in adults.   
The Y-BOCS obsession subtotal score is calculated as the sum of the scores for items 1 through 
5 of the Y-BOCS scale (excluding item 1b), and the Y-BOCS compulsion subtotal score is 
calculated as the sum of the scores for items 6 through 10 of the Y-BOCS scale (excluding item 
6b).  The Y-BOCS total score is the sum of the obsession and compulsion subtotal scores.  Each 
item score ranges from 0 to 4, with a maximum possible obsession subtotal score of 20, a 
maximum possible compulsion subtotal score of 20, and a maximum possible total score of 40.  
If any one of these 10 items is not scored (ie, has a missing value), the associated subtotal score 
and total score will be set equal to missing. 
The observed values of the total score and subtotal scores for obsession and compulsion at each 
visit and changes from baseline to each postbaseline visit will summarized with descriptive 
statistics for the adult age group by treatment group and for all subjects. 
6.16.12. 
Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D-
17) 
The SIGH-D-17 is a 17-item, semi-structured questionnaire for rating depression in adults.  The 
SIGH-D-17 total score is calculated as the sum of the 17 items making up the SIGH-D-17.  Each 
item is scored on a 3, 4, or 5-point scale.  The maximum possible total score is 53.  If any one of 
the 17 items is not scored (ie, has a missing value), the total score will be set equal to missing.  
Note that a score of 3 for Item 8 (loss of weight) represents “not assessed”, and should be 
ignored in calculating the total score. 
The observed values of the total score at each visit and changes from baseline to each 
postbaseline visit will summarized with descriptive statistics for the adult age group by treatment 
group and for all subjects 
6.16.13. 
Prior and Concomitant Medications 
The number and percentage of subjects using prior medications (taken within the 30 days prior to 
Day -1 [and including Day -1]) and concomitant medications (taken during the study after Day -
1) classified by WHO Drug Anatomical Therapeutic Chemical Classification (ATC) Level 3 
category (or Level 2 if there is not an applicable Level 3 category) and preferred name will be 
summarized for each age group by treatment group and for all subjects for each study period as 
described in the next paragraph.  A subject may take the same medication more than once or 


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multiple medications for a subject may be classified under the same ATC level or preferred 
name.  A subject is counted only once for each level of medication classification within a 
summary. 
Medications will be assigned to one or both of two study periods (pretreatment period vs. 
postbaseline period) based on the medication start and stop dates relative to the first dose of 
study drug.  For example, medications that were started and stopped prior to the date of the first 
dose of study drug will be assigned to the pretreatment period only, while medications started 
prior to the first dose of study drug and either stopped during the postbaseline period or indicated 
as “ongoing” will be assigned to both the pretreatment period and the postbaseline period. 
6.17. 
 Additional Data Presentations 
6.17.1. 
Inclusion and Exclusion Criteria Deviations 
Inclusion and exclusion criteria deviations will be presented in a data listing by age group and 
subject. 
6.17.2. 
Serology 
Serology data (ie, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody [HCV-
Ab]) will be presented in a data listing by age group and subject. 
6.17.3. 
Pregnancy Tests 
Pregnancy test results will be presented in a data listing by age group and subject. 
6.17.4. 
Urine Drug Screen and Alcohol Breathalyzer Test 
Urine drug screen and alcohol breathalyzer test results will be presented in a data listing by age 
group and subject. 
7. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSES 
The analyses described in this SAP are consistent with the planned analyses described in the 
study protocol except for the following: 
• Study drug dosing compliance will be “by visit” only and not cumulative (Section 6.13.1) 
• RTRS scores will not be summarized (Section 6.15.2) 
8. 
 PERFORMANCE QUALIFICATION OF SAS® PROGRAMS 
The data from this study will be summarized using SAS® 9.3 (or a later release if available).  All 
SAS® programs used in the production of tables, figures, and listings described in this SAP will 
undergo performance qualification (verification that the program produces the intended output) 
in accordance with department standard operating procedures.  The performance qualification 
may include independent programming and/or peer review of the SAS® log files.  In addition, 
tables, figures, and listings will be independently reviewed for completeness and accuracy. 


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9. 
REFERENCES 
None.