Clinical trial NCT02679079
Conditions: Tourette Syndrome
Sponsor: Neurocrine Biosciences
Start date: 2016-03-23; Completion date: 2017-04-14
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2, double-blind, placebo-controlled study to assess the safety and efficacy of NBI-98854 administered once daily (qd) for a total of 6 weeks of treatment. This study will enroll approximately 90 male and female pediatric subjects clinically diagnosed with Tourette Syndrome.

Detailed description:

Arms: arm 1: Administered once daily for 6 weeks arm 2: Administered once daily for 6 weeks arm 3: Administered once daily for 6 weeks
Interventions: intervention 1: NBI-98854 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Amendment 2 Version Date:  29 June 2016 
Protocol Amendment 1 Version Date:  05 November 2015 
Original Final Version Date: 23 June 2015 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of NBI-98854 in Pediatric Subjects with Tourette Syndrome 
 
Study No.:  NBI-98854-1501 
 
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no unpublished information contained herein will be published or disclosed without prior 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: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of 
NBI-98854 in Pediatric Subjects with Tourette Syndrome 
 
PROTOCOL No.: 
NBI-98854-1501 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
Neurocrine Biosciences, Inc., Study No. NBI-98854-1501 
Clinical Study Protocol Amendment No. 2 Final Version
29 June 2016
Confidential
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Neurocrine Biosciences, Inc., Study No. NBl-98854-1501 
Clinical Study Protocol Amendment No. 2 Final Version 
Accepted for the Sponsor: 
SPONSOR: 
29 June 2016 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Phone: (858) 617-7600 
Facsimile: (858) 617-7705 
Confidential 
Page.) 


LIST OF SPONSOR PERSONNEL 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Medical Monitor: 
Telephone: 
Facsimile:  
Cell Phone: 
Sr. Director, Clinica D ve opment:  
Telephone: 
Facsimile:  
Serious Adverse Event Reporting: 
Telephone: 
(866) 626-7792 or (858) 617-7792 
Facsimile:  
(888) 617-7551 
Email:  
 
cds@neurocrine.com 
 
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TABLE OF CONTENTS  
1. 
TITLE PAGE ................................................................................................. 1 
2. 
SYNOPSIS .................................................................................................... 9 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............. 12 
4. 
ETHICS ....................................................................................................... 14 
5. 
INTRODUCTION ....................................................................................... 14 
5.1. 
Background .................................................................................................. 14 
5.2. 
NBI-98854 ................................................................................................... 15 
5.3. 
Study and Dose Rationale ............................................................................ 17 
6. 
STUDY OBJECTIVES ............................................................................... 18 
7. 
OVERVIEW OF STUDY DESIGN ............................................................ 18 
7.1. 
Study Design ................................................................................................ 18 
8. 
STUDY POPULATION .............................................................................. 21 
8.1. 
Inclusion Criteria ......................................................................................... 21 
8.2. 
Exclusion Criteria ........................................................................................ 22 
8.3. 
Subject Identification and Replacement ...................................................... 24 
8.4. 
Randomization ............................................................................................. 24 
9. 
STUDY EVALUATIONS ........................................................................... 24 
9.1. 
Schedule of Assessments ............................................................................. 24 
9.2. 
Screening and Baseline Assessments .......................................................... 26 
9.2.1. 
Genotyping .................................................................................................. 26 
9.3. 
Efficacy Assessments .................................................................................. 26 
9.3.1. 
Yale Global Tic Severity Scale.................................................................... 26 
9.3.2. 
Rush Video-Based Tic Rating Scale............................................................ 26 
9.3.3. 
Premonitory Urge for Tics Scale ................................................................. 27 
9.3.4. 
Clinical Global Impression Scales ............................................................... 27 
9.4. 
Pharmacokinetic Evaluations ....................................................................... 27 
9.5. 
Safety Assessments ...................................................................................... 28 
9.5.1. 
Data Safety Monitoring Board ..................................................................... 28 
9.5.2. 
Vital Sign Measurements ............................................................................. 28 
9.5.3. 
Medical History ........................................................................................... 29 
9.5.4. 
Physical Examination, Including Height and Weight .................................. 29 
9.5.5. 
Electrocardiogram ........................................................................................ 29 
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9.5.6. 
Clinical Laboratory Assessments ................................................................ 29 
9.5.7. 
Columbia-Suicide Severity Rating Scale Children’s Versions ................... 30 
9.5.8. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................. 31 
9.5.9. 
Children’s Depression Rating Scale, Revised ............................................. 31 
9.5.10. 
Children’s Yale-Brown Obsessive-Compulsive Scale ................................ 31 
9.5.11. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version 31 
9.5.12. 
Estimated Total Blood Sample Volume Required by Study ....................... 31 
9.6. 
Specific Study Information .......................................................................... 32 
9.6.1. 
Screening (Weeks -3 to -1) .......................................................................... 32 
9.6.2. 
Baseline (Day -1) ......................................................................................... 33 
9.6.3. 
Treatment Period:  Weeks 2, 4, and 6 (±3 days for each visit) .................... 34 
9.6.4. 
Week 8 (±3 days), Follow-Up/Early Termination ....................................... 35 
9.7. 
Study Duration ............................................................................................. 36 
9.8. 
Prohibitions and Restrictions ....................................................................... 36 
9.8.1. 
Prior and Concomitant Medications ............................................................ 36 
9.8.2. 
Dietary Restrictions ..................................................................................... 37 
9.8.3. 
Other Restrictions ........................................................................................ 37 
9.9. 
Withdrawal Criteria ..................................................................................... 37 
9.9.1. 
Handling of Withdrawals ............................................................................. 38 
9.9.2. 
Sponsor’s Termination of Study .................................................................. 38 
10. 
STUDY DRUG ............................................................................................ 38 
10.1. 
Study Drug Supplies .................................................................................... 38 
10.2. 
Study Drug Storage ...................................................................................... 38 
10.3. 
Study Drug Packaging and Labeling ........................................................... 39 
10.4. 
Blinding ....................................................................................................... 39 
10.5. 
Study Drug Administration.......................................................................... 39 
10.6. 
Drug Compliance and Accountability ......................................................... 40 
10.7. 
Study Drug Return ....................................................................................... 40 
11. 
ADVERSE EVENTS................................................................................... 40 
11.1. 
Definition ..................................................................................................... 40 
11.2. 
Intensity of Adverse Events ......................................................................... 41 
11.3. 
Relationship to Study Drug ......................................................................... 41 
11.4. 
Recording Adverse Events .......................................................................... 42 
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11.5. 
Post-Study Follow-Up of Adverse Events ................................................... 42 
11.6. 
Serious Adverse Events ............................................................................... 43 
11.6.1. 
Definition of a Serious Adverse Event ........................................................ 43 
11.6.2. 
Managing Serious Adverse Events .............................................................. 43 
11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .......................................................................................................... 44 
11.6.4. 
Expedited Safety Reports ............................................................................ 44 
11.7. 
Pregnancy .................................................................................................... 44 
12. 
DOCUMENTATION OF DATA ................................................................ 45 
12.1. 
Case Report Form ........................................................................................ 45 
12.2. 
Data Capture, Review, and Validation ........................................................ 45 
12.3. 
Coding Dictionaries ..................................................................................... 46 
13. 
STATISTICAL AND ANALYTICAL PLAN ............................................ 47 
13.1. 
Analysis Sets ................................................................................................ 47 
13.2. 
Sample Size ................................................................................................. 47 
13.3. 
Handling of Missing Data ............................................................................ 48 
13.4. 
Enrollment and Disposition of Subjects ...................................................... 48 
13.5. 
Demographics and Baseline Characteristics ................................................ 48 
13.6. 
Study Drug Dosing and Compliance ........................................................... 48 
13.7. 
Pharmacokinetic Data .................................................................................. 48 
13.8. 
Efficacy Data ............................................................................................... 48 
13.9. 
Safety Data ................................................................................................... 49 
13.10. 
Software ....................................................................................................... 49 
13.11. 
Interim Analysis ........................................................................................... 50 
14. 
REGULATORY AND ETHICAL ISSUES ................................................ 50 
14.1. 
General Legal References ............................................................................ 50 
14.2. 
Institutional Review Board .......................................................................... 50 
14.3. 
Protocol Adherence and Amendments ........................................................ 50 
14.4. 
Required Documents ................................................................................... 50 
14.5. 
Informed Consent ........................................................................................ 51 
14.6. 
Study Monitoring ......................................................................................... 51 
14.7. 
Quality Assurance ........................................................................................ 51 
14.8. 
Record Retention ......................................................................................... 51 
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14.9. 
Confidentiality ............................................................................................. 51 
15.
STUDY COMMENCEMENT AND DISCONTINUATION ..................... 52
16.
REFERENCES ............................................................................................ 53
17.
APPENDICES ............................................................................................. 55
17.1. 
Yale Global Tic Severity Scale (YGTSS) ................................................... 55 
17.2. 
Rush Video-Based Tic Rating Scale (RTRS) .............................................. 65 
17.3. 
Premonitory Urge for Tics Scale (PUTS) .................................................... 67 
17.4. 
Clinical Global Impression of Tics (CGI-Tics) – Severity .......................... 69 
17.5. 
Clinical Global Impression of Change-Tourette Syndrome (CGI-TS) – 
Improvement ................................................................................................ 71 
17.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Baseline/Screening Version ......................................................................... 73 
17.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since Last 
Visit Version ................................................................................................ 77 
17.8. 
Children’s Depression Rating Scale, Revised (CDRS-R) ........................... 81 
17.9. 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) ........... 86 
17.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version 108 
17.11. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................. 110 
LIST OF TABLES 
Table 1: 
Treatment Groups by Age ........................................................................... 18 
Table 2: 
Schedule of Assessments ............................................................................. 25 
Table 3: 
Estimated Total Blood Sample Volume for Children and Adolescents ...... 32 
Table 4: 
Intensity of Adverse Events ......................................................................... 41 
Table 5: 
Relationship of Adverse Events to Study Drug ........................................... 42 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................. 20 
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2. 
SYNOPSIS 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of NBI-98854 in 
Pediatric Subjects with Tourette Syndrome 
Study Centers: 
Approximately 40 study centers in the United States 
Objectives: 
• 
To evaluate the efficacy of 2 active doses of NBI-98854 (10 mg and 20 mg in children; and 20 mg and 40 mg 
in adolescents) administered once daily in pediatric subjects with Tourette Syndrome (TS). 
• 
To assess the safety and tolerability of repeated daily doses of NBI-98854 in pediatric subjects with TS. 
• 
To evaluate plasma exposure of NBI-98854 and its metabolite, NBI-98782, following repeated daily doses of 
NBI-98854. 
Study Design: 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the 
efficacy, safety, and tolerability of 2 active doses of NBI-98854 (10 mg and 20 mg in children, and 20 mg and 
40 mg in adolescents) relative to placebo, administered once daily for 6 weeks in pediatric subjects with TS.  
Approximately 90 male and female subjects, 6 to 17 years of age, with a Diagnostic and Statistical Manual of 
Mental Disorders, 4th or 5th Editions (DSM-IV or -V) diagnosis of TS will participate.  The subjects will be 
divided into 2 age groups of approximately 45 children (6 to 11 years of age) and 45 adolescents (12 to 17 years of 
age).  Eligible subjects within each age group will be randomized in a 1:1:1 ratio to placebo or 1 of 2 active 
NBI-98854 treatments as depicted in the following table. 
Age Group 
 
Treatment Group 
Number of Subjects 
(approximate) 
Children, 6 to 11 years old 
 
Placebo 
15 
 
NBI-98854 10 mg 
15 
 
NBI-98854 20 mg 
15 
Adolescents, 12 to 17 years old 
 
Placebo 
15 
 
NBI-98854 20 mg 
15 
 
NBI-98854 40 mg 
15 
After providing parental or legal guardian informed consent with signed and witnessed pediatric assent, subjects 
will be screened to determine eligibility within 21 days (Days -21 to -1) before the start of study drug dosing on 
Day 1.  On Day -1 (baseline; the day before receiving the first dose of study drug), eligible subjects will return to 
the study center for collection of baseline safety and efficacy assessments and collection of a blood sample for 
subsequent determination of their cytochrome P450 2D6 (CYP2D6) metabolizer status.  Subjects who continue to 
be eligible for the study will then be randomized (1:1:1) to placebo or 1 of 2 active NBI-98854 doses determined 
by subject age group.  A 2-week supply of study drug will be dispensed.   
Beginning on Day 1, study drug will be administered once daily in the morning (between 0700 and 1000 hours) at 
home under the supervision of the subject’s parent/legal guardian with a standard breakfast throughout the 6-week 
double-blind treatment period.  The higher NBI-98854 dose in each age group (20 mg in children and 40 mg in 
adolescents) will be titrated in a blinded fashion (children will receive 10 mg and adolescents will receive 20 mg 
for the first week followed by their randomized dose of 20 mg or 40 mg for the remainder of the 6-week treatment 
period).   
A representative from the study center will call the subject or parent/legal guardian 3 to 7 days after the start of 
dosing to inquire about any study drug-related issues vis-à-vis compliance or tolerability. 
At any time, if the subject is unable to tolerate their current dose, the investigator may decrease the subject’s dose.  
The investigator is allowed to reduce the subject’s dose only 1 time during the study.  Subjects who have had a 
dose reduction and are unable to tolerate their new dose will be discontinued from the study. 
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To maintain the study blind, subjects receiving placebo or the lower dose in each age group (10 mg in children and 
20 mg in adolescents) who have a dose reduction will continue to receive their current dose and subjects receiving 
the higher dose in each age group (20 mg in children and 40 mg in adolescents) will have their dose reduced to the 
lower dose, that is, 10 mg in children and 20 mg in adolescents. 
During the double-blind treatment period, subjects will return to the study center at 2-week intervals (Weeks 2, 4, 
and 6; ±3 days for each visit) for study assessments and dispensing of study drug (Weeks 2 and 4 only).  As much 
as possible, these study visits 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 efficacy, safety, and plasma exposure 
throughout the study period.  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. 
All subjects who have completed the 6-week treatment period will enter a 2-week follow-up period with a 
follow-up visit at Week 8 ±3 days (subjects who terminate early will have Week 8 assessments conducted).  
Efficacy, safety, and study drug exposure will be assessed at scheduled times throughout the study. 
Study Population: 
Approximately 90 male and female pediatric subjects with a DSM-IV or -V diagnosis of TS; approximately 
45 children (6 to 11 years of age) and 45 adolescents (12 to 17 years of age) will be enrolled into this study.  The 
subjects must have at least moderate current TS symptomatology, as defined by a Clinical Global Impression of 
Tics (CGI-Tics)–Severity score of ≥4 (ie, moderately ill) and a Yale Global Tic Severity Scale (YGTSS) Total Tic 
Score (TTS) of ≥20 at screening.  In addition, subjects with Tourette’s spectrum diagnoses (eg, obsessive- 
compulsive disorder [OCD], Attention-Deficit Hyperactivity Disorder [ADHD], etc) must have a stable psychiatric 
status at screening. 
Duration of Treatment and Study Participation: 
The expected duration of study participation for each subject is approximately 11 weeks, including up to 21 days of 
screening, a 6-week double-blind treatment period, and a 2-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 
subjects must swallow the capsules with at least 4 oz. of water.  The NBI-98854 capsules will be taken with a 
standard breakfast. 
Reference Therapy, Dose, and Mode of Administration 
Matching placebo capsules are identical in appearance and will be orally administered in a double-blind manner 
according to randomization on an identical schedule to those receiving NBI-98854.  The subjects must swallow the 
capsules with at least 4 oz. of water.  The placebo capsules will be taken with a standard breakfast. 
Criteria for Evaluation:   
Efficacy 
The following efficacy assessments will be administered at screening, baseline (Day -1), at Weeks 2, 4, and 6, and 
at the follow-up visit (Week 8 or upon early termination): 
• 
Yale Global Tic Severity Scale (YGTSS; primary assessment) 
• 
Rush Video-Based Tic Rating Scale (RTRS) 
• 
Premonitory Urge for Tics Scale (PUTS) 
• 
Clinical Global Impression of Change-Tourette Syndrome (CGI-TS)-Improvement 
• 
Clinical Global Impression of Tics (CGI-Tics)-Severity 
The CGI-Tics-Severity scale will be used to rate the investigator’s assessment of the severity of tic symptoms at 
screening and baseline.  Both the CGI-Tics-Severity and CGI-TS-Improvement scales will be assessed by the 
investigator at Weeks 2, 4, and 6, and at the follow-up visit (Week 8 or upon early termination). 
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Criteria for Evaluation:   
Safety 
Safety and tolerability will be monitored throughout the study and will include the following assessments:  
• 
Adverse events (AEs) 
• 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
• 
Serum prolactin 
• 
Vital signs (including orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, respiratory rate, 
and oral body temperature) 
• 
Physical examinations (including height and weight) 
• 
12-lead electrocardiograms (ECGs) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS), Children’s Version 
• 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
• 
Children’s Depression Rating Scale - Revised (CDRS-R) 
• 
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) 
• 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version (ADHD Rating Scale) 
Pharmacokinetics 
Blood samples to evaluate plasma concentrations of NBI-98854, and the metabolite NBI-98782 will be collected 
during the treatment period (Weeks 2, 4, and 6) and at the follow-up visit (Week 8 or upon early termination). 
Statistical methods: 
The YGTSS will serve as the primary assessment of tic behaviors associated with TS.  The primary efficacy 
endpoint is the mean change from baseline (Day -1) to Week 6 in the YGTSS TTS.  Secondary efficacy endpoints 
include the YGTSS Global Tic Severity score mean change from baseline to Week 6, the RTRS total score mean 
change from baseline to Week 6; the PUTS total score mean change from baseline to Week 6, the CGI TS - 
Improvement mean score change from baseline to Week 6, and the CGI-Tics–Severity mean change from baseline 
to Week 6. 
Statistical comparisons between each NBI-98854 treatment group and placebo will be performed for the efficacy 
endpoints.  The primary analysis of the TTS change from baseline will be a mixed-effects model repeated 
measures (MMRM) analysis including the scores at Weeks 2, 4, and 6, based on the per-protocol and intent-to-treat 
analysis sets.  Similar methods of analysis will be used for the baseline secondary efficacy endpoints. 
Safety and plasma drug concentration data will be summarized by age group, treatment, and timepoint using 
descriptive statistics. 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADHD 
Attention-Deficit Hyperactivity Disorder 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
β-hCG 
β-human chorionic gonadotropin 
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 
Clinical Global Impression of Tics  
CGI-TS 
Clinical Global Impression of Change-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 
EC 
Ethics Committee 
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 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibody 
HIV-Ab 
Human immunodeficiency virus antibody 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
MAOI 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model repeated measures 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No observed adverse effect level 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
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 
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
TS 
Tourette syndrome 
TTS 
Total Tic Score 
US 
United States 
VMAT2 
Vesicular monoamine transporter 2 
WBC 
White blood cell 
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) dealing with 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 movement disorder characterized by the presence of chronic motor 
and one or more vocal tics that often appear in childhood or early adolescence (APA DSM-IV, 
1994; APA DSM-V, 2013).  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 
1 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). 
It has been well established that TS is predominantly a disorder of childhood with a mean or 
median age of onset of approximately 6 years of age (Leckman et al., 1998; Robertson, 2011; 
Jankovic and Kurlan, 2011; Swain et al., 2007).  Tic symptomatology usually becomes the most 
severe around age 10 and by the time adulthood is achieved at 18 years of age, the majority of 
patients are either tic-free or their symptoms have significantly improved (Leckman et al., 1998; 
Kurlan, 2010).  TS symptoms may also occur in adults and these tic phenomena appear to be a 
re-emergence or an exacerbation of childhood onset TS (Chouinard and Ford, 2000; Jankovic 
and Kurlan, 2011). 
Persistent tics can have a significant impact on patient quality of life and often lead to impaired 
psychosocial functioning.  Some of these problems include 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 are often considered (Chen et al., 2012; Shprecher & Kurlan, 
2009; Roessner et al., 2013). 
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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 vesicular monoamine transporter 2 (VMAT2) inhibitor, like NBI-98854, 
may also be an effective treatment option for tic suppression. 
Currently the only approved agent with VMAT2 inhibitory activity is tetrabenazine, a 
dopamine-depleting agent recently approved for the treatment of chorea associated with 
Huntington’s disease.  Use of tetrabenazine for the treatment of a variety of hyperkinetic 
movement disorders has also been described (Ondo et al, 1999; Jankovic and Beach, 1997).  
The beneficial pharmacologic effects of tetrabenazine on the targeted hyperkinetic involuntary 
movements have been documented, as well as the adverse effects associated with excessive 
monoamine depletion, such as sedation, depression, akathisia and parkinsonism.  The 
occurrence of these adverse effects with tetrabenazine have resulted in the need for 
individualized dosing, dose titration, and management of treatment-related side effects. 
5.2. 
NBI-98854 
NBI-98854 is an orally active valine ester of a VMAT2 inhibitor (NBI-98782) and is currently 
under development at NBI for the treatment of neuroleptic-induced Tardive dyskinesia (TD), 
TS, and other involuntary movement disorders.  Metabolism of NBI-98854 is characterized by 
conversion of NBI-98854 to NBI-98782, and cytochrome P450 (CYP) 3A4/5 dependent 
mono-oxidation to NBI-136110.  All three 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.   
The intravenous and oral NBI-98854 pharmacokinetics (PK) have been studied in mice, rats, 
monkeys, dogs, and humans.  In animals, orally administered NBI-98854 is rapidly absorbed 
and relatively slowly converted to NBI-98782, such that animals are exposed to both 
NBI-98854 and NBI-98782.  Dose-dependent increases in exposure to both NBI-98854 and 
NBI-98782 were seen in animal studies.  NBI-98854 appears to cause little or no CYP enzyme 
inhibition or induction at pharmacologically relevant concentrations.  The elimination of 
NBI-98782 is in part catalyzed by CYP2D6.  Repeat-dose nonclinical toxicology studies 
conducted in mice, rats, and dogs (up to 9 months duration) have revealed no adverse effects at 
doses of 60 mg/kg/day in the mouse, 3 mg/kg/day in the rat, and 15 mg/kg/day in the dog.  
Radiolabeled absorption, metabolism, distribution, and excretion studies have confirmed that all 
abundant human circulating metabolites were identified as circulating metabolites in both rat 
and dog providing justification for the use of these species for pivotal toxicology studies in the 
safety assessment of NBI-98854.  Additionally, cardiovascular, pulmonary, and central nervous 
system safety pharmacology studies have also been conducted, where the no observed adverse 
effect level (NOAEL) was equal to or exceeded the 15 mg/kg level seen in repeat-dose 
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toxicology studies.  NBI-98854 had a modest negative effect on rat fertility at 10 mg/kg/day 
(NOAEL of 3 mg/kg/day).  The NOAEL for embryo/fetal development in rats and rabbits was 
15 mg/kg/day and 50 mg/kg/day, respectively.  There was no evidence of teratogenicity in the 
rat or rabbits.  Finally, NBI-98854 was negative in in vitro mutagenicity assays (namely, Ames 
and chromosomal aberration) and an in vivo rat micronucleus test. 
Twelve clinical studies with NBI-98854 have been completed to date; eight Phase 1 studies in 
healthy subjects and subjects with hepatic impairment, and four Phase 2 studies in subjects with 
TD and a clinical diagnosis of schizophrenia or schizoaffective disorder, mood disorder, or 
gastrointestinal disorder.  The Phase 1 studies have evaluated the PK of NBI-98854 
administered as an oral solution or capsule formulation, pharmacodynamic assessments 
including serum prolactin and cognitive performance, and safety measures including evaluation 
of cardiovascular risk using triplicate 12-lead electrocardiogram (ECG) and 24-hour Holter 
monitoring.  The Phase 2 studies have included an evaluation of efficacy in the treatment of 
symptoms of TD using the Abnormal Involuntary Movement Scale (AIMS). 
Clinical PK data indicate that when administered orally under fasted conditions, NBI-98854 
appeared to be rapidly absorbed with maximum plasma concentration being reached within 
1 hour.  The metabolite NBI-98782 was formed gradually with maximum plasma concentration 
(Cmax) being reached 4 to 10 hours postdose.  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.  Preliminary data from healthy volunteer studies suggest that 
coadministration of NBI-98854 with strong CYP3A4 or CYP2D6 inhibitors is expected to 
increase the Cmax and area under the plasma concentration versus time curve (AUC) of 
NBI-98782 by approximately 2-fold.  A similar approximately 2-fold increase in NBI-98782 
was observed when NBI-98854 was given to subjects with moderate or severe hepatic 
impairment. 
Results from Phase 2 studies indicated an improvement in the AIMS score after 6 weeks of 
continuous dosing with either NBI-98854 50 mg once daily, continuous dosing at NBI-98854 
100 mg once daily for 2 weeks followed by continuous dosing at NBI-98854 50 mg once daily 
for 4 weeks (NBI-98854-1201), or 6 weeks of titrated doses from 25 mg up to 75 mg 
NBI-98854 once daily (NBI-98854-1202).  Results from an open-label safety extension with 
dosing out to 12 weeks (NBI-98854-1201) continued to show benefit in subjects continuing on 
with 50 mg NBI-98854 daily dosing and also in subjects originally assigned to placebo who 
went on to receive 50 mg NBI-98854 for the 6 weeks of open-label treatment period.  Results 
from the 6-week dose-titration study (NBI-98854-1202) showed a statistically significant 
reduction in AIMS dyskinesia total score in the NBI-98854 group compared to placebo.  A 
statistically significant higher responder rate (ie, ≥50% improvement in AIMS dyskinesia total 
score from baseline) was also observed in the NBI-98854 group compared with placebo. 
NBI-98854 has been generally well tolerated in single doses up to 300 mg and in multiple doses 
of up to 100 mg.  Treatment-emergent adverse events (TEAEs) consistent with the 
pharmacological effects of monoamine reduction (eg, fatigue, insomnia, and nervousness) 
occurred at a lower incidence in the NBI-98854 100 mg dose compared to the 50 mg dose in 
Phase 2 studies.  Most TEAEs were transient and considered mild or moderate in intensity.  
Thirteen treatment-emergent serious adverse events (SAEs) among 10 subjects have been 
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reported.  No SAEs have been 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. 
5.3. 
Study and Dose Rationale 
The present study is the second clinical trial of NBI-98854 in the pediatric TS population, and is 
the first randomized placebo-controlled study of NBI-98854 in these patients.  The initial 
Phase 1b, open-label, multiple-dose study of the safety, tolerability, PK, and PD of NBI-98854 
(Study NBI-98854-1403) is currently ongoing in approximately 18 male and female adolescents 
with TS (12 to 18 years of age) and 18 male and female children with TS (6 to 11 years of age).  
Doses of NBI-98854 10 mg, 25 mg, or 50 mg are being administered in adolescents, and doses 
of NBI-98854 5 mg, 10 mg, or 25 mg are being administered in children following a multiple 
ascending dose protocol over a 14-day treatment period.  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 size as a key covariate.  To date, 12 adolescents with TS have 
received NBI-98854 doses of 10 mg and 25 mg, and 6 children with TS have received the 
NBI-98854 5 mg dose.  Preliminary results show that these doses have been well-tolerated in 
both age groups, and dose escalation has occurred for the final adolescent dosing cohort of 
NBI-98854 50 mg and the middle child dosing cohort of NBI-98854 10 mg.  The a priori, PK 
model-based predictions of study drug exposure in both age groups have been consistent to this 
point with the observed plasma concentration measures of NBI-98854 and its metabolites in the 
subjects evaluated in Study NBI-98854-1403. 
The current study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel group, dose-ranging study to evaluate the efficacy, safety, and tolerability of 2 active 
doses of NBI-98854 (10 mg and 20 mg in children, and 20 mg and 40 mg in adolescents) 
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 one of the two active 
NBI-98854 doses.  The doses selected for this study are aligned with 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 tested to date. 
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6. 
STUDY OBJECTIVES 
The objectives of this clinical study are as follows: 
• To evaluate the efficacy of 2 active doses of NBI-98854 (10 mg and 20 mg in children; and 
20 mg and 40 mg in adolescents) administered once daily in pediatric subjects with TS. 
• To assess the safety and tolerability of repeated daily doses of NBI-98854 in pediatric 
subjects with TS. 
• To evaluate plasma exposure of NBI-98854 and its metabolite, NBI-98782, following 
repeated daily doses of NBI-98854. 
7. 
OVERVIEW OF STUDY DESIGN 
7.1. 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the efficacy, safety, and tolerability of 2 active doses of NBI-98854 (10 mg 
and 20 mg in children, and 20 mg and 40 mg in adolescents) relative to placebo, administered 
once daily for 6 weeks in pediatric subjects with TS.  The expected study duration is 
approximately 11 weeks, including up to 21 days of screening, a 6-week double-blind treatment 
period, and a 2-week follow-up period.  Approximately 90 male and female subjects, 6 to 17 
years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th Editions 
(DSM-IV or -V) diagnosis of TS will participate.  The subjects will be divided into 2 age groups 
of approximately 45 children (6 to 11 years of age) and 45 adolescents (12 to 17 years of age).  
Eligible subjects within each age group will be randomized in a 1:1:1 ratio to placebo or 1 of 
2 active NBI-98854 treatments as depicted in Table 1. 
Table 1: 
Treatment Groups by Age  
Age Group 
 Treatment Group 
Number of Subjects 
(approximate) 
Children, 6 to 11 years old 
 Placebo 
15 
 NBI-98854 10 mg 
15 
 NBI-98854 20 mg 
15 
Adolescents, 12 to 17 years old 
 Placebo 
15 
 NBI-98854 20 mg 
15 
 NBI-98854 40 mg 
15 
Informed consent/assent must be obtained prior to any study-related procedures, including 
washout of medications disallowed in the study.  After providing parental or legal guardian 
informed consent with signed and witnessed pediatric assent, subjects will be screened to 
determine eligibility within 21 days (Days -21 to -1) before the start of study drug dosing on 
Day 1.  Subjects or parents/legal guardians may also be asked to sign an optional release form to 
allow their Rush Video-Based Tic Rating Scale (RTRS) video recordings to be used for 
educational purposes.  On Day -1 (baseline; the day before receiving the first dose of study 
drug), eligible subjects will return to the study center for collection of baseline safety and 
efficacy assessments and collection of a blood sample for determination of their CYP2D6 
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metabolizer status.  Subjects who continue to be eligible for the study will then be randomized 
(1:1:1) to placebo or 1 of 2 active NBI-98854 doses determined by subject age group.  A 
2-week supply of study drug will be dispensed. 
Beginning on Day 1, study drug will be administered once daily in the morning (between 
0700 and 1000 hours) at home under the supervision of the subject’s parent/legal guardian with 
a standard breakfast throughout the 6-week double-blind treatment period.  The higher 
NBI-98854 dose in each age group (20 mg in children and 40 mg in adolescents) will be titrated 
in a blinded fashion (children will receive 10 mg and adolescents will receive 20 mg for the first 
week followed by their randomized dose of 20 mg or 40 mg for the remainder of the 6-week 
treatment period).   
A representative from the study center will call the subject or parent/legal guardian 3 to 7 days 
after the start of dosing to inquire about any study drug-related issues vis-à-vis compliance or 
tolerability. 
At any time, if the subject is unable to tolerate their current dose, the investigator may decrease 
the subject’s dose.  The investigator is allowed to reduce the subject’s dose only 1 time during 
the study.  Subjects who have had a dose reduction and are unable to tolerate their new dose 
will be discontinued from the study. 
To maintain the study blind, subjects receiving placebo or the lower dose in each age group 
(10 mg in children and 20 mg in adolescents) who have a dose reduction will continue to 
receive their current dose and subjects receiving the higher dose in each age group (20 mg in 
children and 40 mg in adolescents) will have their dose reduced to the lower dose, that is, 10 mg 
in children and 20 mg in adolescents. 
During the double-blind treatment period, subjects will return to the study center at 2-week 
intervals (Weeks 2, 4, and 6; ±3 days for each visit) for study assessments and dispensing of 
study drug (Weeks 2 and 4 only).  As much as possible, these study visits 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 efficacy, safety, and plasma exposure 
throughout the study period.  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 (see Section 9.5.1). 
All subjects who have completed the 6-week treatment period will enter a 2-week follow-up 
period with a follow-up visit at Week 8 ±3 days (subjects who terminate early will have Week 8 
assessments conducted).  Efficacy, safety, and study drug exposure will be assessed at 
scheduled times throughout the study. 
Efficacy assessments for TS symptomatology will be performed using the Yale Global Tic 
Severity Scale (YGTSS; primary), the RTRS, the Premonitory Urge for Tics Scale (PUTS), the 
Clinical Global Impression of Change-Tourette Syndrome (CGI-TS)-Improvement scale, and 
the Clinical Global Impression of Tics (CGI-Tics)-Severity scale.  The YGTSS, RTRS, and 
PUTS will be administered at screening, on Day -1 (the day before dosing), during the 
double-blind treatment period (Weeks 2, 4, and 6), and at the follow-up visit (Week 8 or upon 
early termination).   
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The CGI-Tics-Severity will be evaluated at screening and Day -1 (baseline), and then both the 
CGI-Tics-Severity and CGI-TS-Improvement scales will be administered at Weeks 2, 4, and 6, 
and at the follow-up visit (Week 8 or upon early termination). 
Safety assessments will also be collected at scheduled times throughout the study including 
adverse event (AE) monitoring, clinical laboratory tests (hematology, clinical chemistry, and 
urinalysis), serum prolactin, vital sign measurements, physical examinations, 12-lead ECG, 
Columbia Suicide Severity Rating Scale (C-SSRS, Children’s Version), Extrapyramidal 
Symptom Rating Scale-Abbreviated (ESRS-A), Children’s Depression Rating Scale - Revised 
(CDRS-R), the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and the 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version (ADHD Rating 
Scale). 
Blood samples for plasma drug concentration and metabolite analyses will be collected during 
the treatment period (Weeks 2, 4, and 6) and at the follow-up visit (Week 8 or upon early 
termination). 
A schematics of the study design is shown in Figure 1. 
Figure 1: 
Study Design Schematic 
Week
-3
Screening
Randomized, Double-Blind, Placebo-
Controlled Treatment Period
6
Randomization on
Day -1
Screening
Period
2
4
Placebo
8
Follow-up
Follow-up /
Early Term.
10 mg
20 mg
Placebo
20 mg
40 mg
Children   n=45
Adolecents   n=45
 
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8. 
STUDY POPULATION 
This study will be conducted in approximately 90 male and female pediatric subjects with a 
DSM-IV or -V diagnosis of TS.  A total of approximately 45 children (6 to 11 years of age) and 
approximately 45 adolescents (12 to 17 years of age) will be enrolled into this study.  Subjects 
must meet all of the inclusion criteria and none of the exclusion criteria to enter the study. 
8.1. 
Inclusion Criteria 
To participate in this study, subjects must meet the following criteria: 
1. Have documentation of written and witnessed assent from the subject and written informed 
consent from the subject’s parent or legal guardian. 
2. Be male or female, aged 6 to 17 years, inclusive. 
3. Be in good general health, as determined by medical history, physical examination, clinical 
laboratory assessments, and 12-lead ECG. 
4. Have a DSM-IV or -V diagnosis of TS. 
5. Have at least moderate current tic severity, as defined by a CGI-Tics-Severity score of ≥4 
(ie, moderately ill) and a YGTSS, Total Tic Score (TTS) of ≥20 at screening.  This 
determination must be independently confirmed by the blinded external video reviewer 
using a video recording of the subject’s YGTSS assessment administered at the clinical site 
by the investigator (or designee). 
6. Have TS symptoms that impair school, occupational, and/or social function. 
7. 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 
and baseline.  
8. 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). 
9. 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. 
10. Subjects of childbearing potential who do not practice total abstinence must be instructed on 
the proper use of barrier methods of contraception and agree to use hormonal or two forms 
of nonhormonal contraception (dual contraception) consistently from screening until 
30 days after the last dose of study drug. 
Acceptable methods of contraception include the following: 
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• 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 screening. 
Subjects who practice total abstinence from sexual intercourse as the preferred lifestyle are 
not required to use contraception (periodic abstinence is not acceptable). 
11. Female subjects of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at screening and negative urine pregnancy test at 
baseline (Day -1). 
12. 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 screening. 
13. Adolescent subjects (12 to 17 years of age) must have a negative urine drug screen (negative 
for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or 
cannabinoids) at screening and baseline (Day -1).  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. 
14. Adolescent subjects (12 to 17 years of age) must have a negative alcohol breath test at 
screening and baseline (Day -1). 
15. 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 center 
and return for the follow-up visit. 
8.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they: 
1. Have an unstable medical condition or chronic disease (including history of neurological, 
hepatic, renal, cardiovascular, gastrointestinal, pulmonary, or endocrine disease), or 
malignancy that could confound interpretation of study outcome. 
2. Had a medically significant illness within 30 days of screening. 
3. Excessive use of tobacco and/or nicotine-containing products (based on the investigator’s 
assessment) within 30 days of screening. 
4. 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).  
5. Are currently pregnant or lactating.  
6. Have a known history of neuroleptic malignant syndrome. 
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7. Have a known history of long QT syndrome or cardiac arrhythmia. 
8. Have a screening or Day -1 average triplicate ECG QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) of >450 msec or the presence of any clinically significant 
cardiac abnormality. 
9. Have aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl 
transferase (GGT), total bilirubin, or serum creatinine levels greater than the upper limit of 
normal (ULN) at screening.   
10. Have any of the following hematologic abnormalities at screening: 
• Hemoglobin <11.0 g/dL. 
• White blood cell (WBC) count <5.2 × 103/mm3. 
• Platelet count <180,000/mm3. 
11. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to screening, 
with the exception of localized skin cancer or carcinoma in situ of the cervix. 
12. Have biochemistry or hematology not within the laboratory’s reference range and deemed 
by the investigator to be clinically significant at screening. 
13. Have a positive human immunodeficiency virus antibody (HIV-Ab) test result, hepatitis B 
surface antigen (HBsAg) test result, or hepatitis C virus antibody (HCV-Ab) test result at 
screening. 
14. Have received an investigational drug within 30 days before screening or plan to use an 
investigational drug (other than NBI-98854) during the study.   
15. Receive any excluded concomitant medication (refer to Section 9.8.1). 
16. Have initiated Comprehensive Behavioral Intervention for Tics (CBIT) during the screening 
period or at baseline (Day -1) or plan to initiate CBIT during the study. 
17. Have a blood loss ≥250 mL or donated blood within 56 days or donated plasma within 
7 days of baseline (Day -1). 
18. Have a significant risk of suicidal or violent behavior.  Subjects with any lifetime 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) in the 
past year before screening based on the C-SSRS Children’s Version should be excluded. 
19. Have ingested foods containing poppy seeds within 7 days before screening and baseline 
(Day -1). 
20. Have an allergy, hypersensitivity, or intolerance to tetrabenazine. 
21. Have had previous experience with NBI-98854 or had previously participated in an 
NBI-98854 clinical study.  
22. Have a history of or suspected poor compliance in clinical research studies. 
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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 
An Interactive Web Response System (IWRS) will be used to randomize subjects to 1 of 
3 double-blind treatment assignments within each age group during the 6-week double-blind 
treatment period:  placebo or 1 of 2 active doses of NBI-98854 (10 mg or 20 mg in children; 
and 20 mg or 40 mg in adolescents) in a 1:1:1 ratio.  Randomization will occur at baseline 
(Day -1) after the subject is confirmed to have met the eligibility criteria.  Treatment 
assignments will be made according to a computer-generated randomization schedule.  
Investigators or a designee will access the IWRS to obtain randomization assignments. 
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 2.  No protocol-related procedures should be performed before parental or 
legal guardian informed consent with written and witnessed assent 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 2: 
Schedule of Assessments 
Procedure 
Screening 
Period 
Baseline 
Treatment Period 
Follow-Up/ 
Early Terma 
Week 
-3 to -1 
Day -1 
2b 
4b 
6b 
8b 
Visit 
1 
2 
3  
4 
5 
6 
Informed consent/assent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
UPDATE 
 
 
 
 
Medical history 
X 
UPDATE 
 
 
 
 
Physical examination (including weight) 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X (S) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
Clinical laboratory testse 
X 
X 
X 
X 
X 
X 
Urine drug screenf and alcohol breath test 
(adolescents only) 
X 
X 
 
 
 
 
Genotype blood sample 
 
X 
 
 
 
 
Serum prolactin 
 
X 
X 
X 
X 
X 
Plasma sample for NBI-98854 and metabolite 
concentrations 
 
 
X 
X 
X 
X 
YGTSS (including video recording) 
X 
X 
X 
X 
X 
X 
RTRS 
X 
X 
X 
X 
X 
X 
PUTS 
X 
X 
X 
X 
X 
X 
CGI-Tics-Severity 
X 
X 
X 
X 
X 
X 
CGI-TS-Improvement 
 
 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
ESRS-A 
 
X 
X 
X 
X 
X 
CY-BOCS and CDRS-R 
X 
X 
X 
X 
X 
X 
ADHD Rating Scale IV: Home Version 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Study drug dosing at homeg 
 
 
X 
X 
X 
 
Dispense study drugh 
 
X 
X 
X 
 
 
Study drug accountabilityi 
 
 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
Outpatient study center visits 
X 
X 
X 
X 
X 
X 
ADHD=attention-deficit hyperactivity disorder; AE=adverse event; CDRS-R=Children’s Depression Rating Scale - Revised; 
CGI-Tics=Clinical Global Impression of Tics; CGI-TS=Clinical Global Impression of Change-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; HBsAg=hepatitis B surface 
antigen; HCV-Ab=hepatitis C virus antibody; HIV-Ab=human immunodeficiency virus antibody; PUTS=Premonitory Urge 
for Tics Scale; RTRS=Rush Video-Based Tic Rating Scale; S=serum; U=urine; YGTSS=Yale Global Tic Severity Scale. 
a. Two-week follow-up visit for subjects who complete the 6-week treatment period (subjects who terminate early will have 
Week 8 assessments conducted). 
b. As much as possible, these visits 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 efficacy, safety, and plasma exposure throughout the study period. 
Weeks 2, 4, 6, and 8 will have a visit window of ±3 days. 
c. 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. 
d. A serum pregnancy test will be conducted at screening, and urine pregnancy tests will be conducted at all other study visits 
for female subjects of childbearing potential. 
e. Includes hematology, chemistry, and urinalysis.  All blood samples will be obtained under nonfasted conditions.  
f. Urine drug screen will be analyzed by the central laboratory.  In addition, urine testing kits will be provided by the central 
laboratory to confirm negative drug screen on Day -1.  A urine drug screen using a kit provided by the central laboratory may 
be conducted at the clinical site at any time during the study if the subject (adolescent subjects only) is suspected of substance 
or drug abuse. 
g. Study drug will be taken once daily at home starting on Day 1 (between 0700 and 1000 hours) in the presence of the subject’s 
parent/legal guardian.  A representative from the study center will call the subject or parent/legal guardian 3 to 7 days after 
the start of dosing to inquire about any study drug-related issues vis-à-vis compliance or tolerability. 
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h. Study drug will be dispensed on Day -1 and at Weeks 2 and 4.   
i. At Weeks 2, 4, and 6, subjects will return all used and unused study drug and a compliance check will be performed by 
counting the number of capsules returned at each visit. 
9.2. 
Screening and Baseline Assessments 
9.2.1. 
Genotyping 
On Day -1 (baseline), a blood sample will be collected from enrolled subjects for the analysis of 
CYP2D6 status (ie, extensive, intermediate, poor, or ultrarapid metabolizers) after treatment.  
Approximately 4 mL of blood will be collected in tubes containing dipotassium 
ethylenediaminetetraacetic acid (EDTA K2).  After the sample is obtained, it should be 
thoroughly mixed.  The vials will be stoppered and labeled with the study barcode and subject 
number.  The samples will be stored at approximately -20°C within approximately 15 minutes 
of collection.  The collection and submission of medical information will be accomplished with 
strict adherence to professional standards of confidentiality.  Genotyping blood samples 
collected from subjects will be shipped to a central laboratory for analysis. 
9.3. 
Efficacy Assessments 
9.3.1. 
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 (1) confirm the subject’s TS severity as at least 
moderate (at screening only), and (2) determine if the YGTSS interview program was 
administered properly.  The computer software system for the YGTSS administration, Rater 
Station™ (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 TTS 
and the Global Tic Severity Score. 
The YGTSS will be administered at screening, baseline (Day -1), during the double-blind 
treatment period (Weeks 2, 4, and 6), and at the follow-up visit (Week 8 or upon early 
termination).  A copy of the YGTSS is provided in Appendix 17.1.  
9.3.2. 
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.  
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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 blinded central rater using a 
triple-blind scoring process. 
The RTRS will be administered at screening, baseline (Day -1), during the double-blind 
treatment period (Weeks 2, 4, and 6), and at the follow-up visit (Week 8 or upon early 
termination).  A copy of the modified RTRS is provided in Appendix 17.2  
9.3.3. 
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.   
The investigator (or designee) will administer the PUTS at screening, baseline (Day -1), during 
the double-blind treatment period (Weeks 2, 4, and 6), and at the follow-up visit (or upon early 
termination).  A copy of the PUTS is provided in Appendix 17.3. 
9.3.4. 
Clinical Global Impression Scales 
The CGI-Tics–Severity and CGI-TS–Improvement 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 screening, baseline (Day -1), Weeks 2, 4, and 6, and at the 
follow-up visit (Week 8 or upon early termination).  A copy of the CGI-Tics-Severity scale is 
provided in Appendix 17.4. 
The CGI-TS–Improvement 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-Improvement scales will be assessed by the investigator at Weeks 2, 4, and 6 and at the 
follow-up visit (Week 8 or upon early termination).  A copy of the CGI-TS – Improvement 
scale is provided in Appendix 17.5. 
9.4. 
Pharmacokinetic Evaluations 
Blood samples to evaluate plasma concentrations of NBI-98854, and the metabolite NBI-98782 
will be collected during the treatment period (Weeks 2, 4, and 6) and at the follow-up visit (or 
upon early termination).  The exact time of collection will be recorded on the eCRF. 
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For each plasma sample, approximately 2 mL of blood will be collected in tubes containing 
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. 
9.5. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 9.8.1 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, 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 finding of 
treatment-emergent depression, suicidal ideation, psychiatric symptoms (based upon the 
C-SSRS, CDRS-R, CY-BOCS, ADHD Rating Scale, or clinical assessment), the finding will be 
documented as an AE, and appropriate psychiatric evaluation and intervention will be provided. 
9.5.1. 
Data Safety Monitoring Board 
An independent 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. 
9.5.2. 
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, baseline (Day -1), and at Weeks 2, 4, 6, 
and at the follow-up visit (Week 8 or upon early termination).  Vital sign measurements will be 
obtained before any scheduled blood sample collection. 
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9.5.3. 
Medical History 
A medical history will be taken at the screening visit and updated on 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. 
9.5.4. 
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, baseline (Day -1), and at 
Weeks 2, 4, 6, and at the follow-up visit (Week 8 or upon early termination).  Height will be 
measured at screening only.  Height and weight will be measured with subjects not wearing 
shoes. 
9.5.5. 
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 heart 
rate (HR), PR interval, QRS duration, corrected (QTc) interval, and corrected QT interval using 
Fridericia’s formula (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, baseline (Day -1), and at Weeks 2, 
4, 6, and at the follow-up visit (Week 8 or upon early termination). 
9.5.6. 
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 and 
screening 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 (12 to 17 years of age) – 4 mL for hematology and 5 mL for serum 
chemistry (includes screening serum pregnancy tests for female subjects of childbearing 
potential). 
Clinical safety laboratory assessments will be performed at screening, baseline (Day -1), and at 
Weeks 2, 4, 6, and at the follow-up visit (Week 8 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 
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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, 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: 
Serum Prolactin:  Blood samples to determine serum prolactin concentration will be collected at 
baseline (Day -1), at Weeks 2, 4, and 6; and at the follow-up visit (Week 8 or upon early 
termination).  Approximately 2.5 mL (children, 6 to 11 years of age) or 5 mL (adolescents, 
12 to 17 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 HIV-Ab, HBsAg, and HCV-Ab testing at screening (as 
part of clinical chemistry).  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, 12 to 17 years of age). 
Urine Drug Screen and Alcohol Breathalyzer Test:  The urine drug screen 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 urine drug screen and alcohol breathalyzer test will be performed at screening and on Day -1.  
The urine drug screen and alcohol breathalyzer test will be performed only in adolescent 
subjects (12 to 17 years of age).  A urine drug screen using a kit provided by the central 
laboratory may be conducted at the clinical site at any time during the study if the subject 
(adolescent subjects only) is suspected of substance or drug abuse. 
Pregnancy Tests:  A pregnancy test will be conducted for female subjects of childbearing 
potential.  A serum pregnancy test will be conducted at screening and a urine pregnancy test 
will be conducted on Day -1, Weeks 2, 4, and 6; and at the follow-up visit (or upon early 
termination). 
9.5.7. 
Columbia-Suicide Severity Rating Scale Children’s Versions 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu).  There are versions of the questionnaire designed for use at 
screening (Children’s Baseline/Screening version) and at baseline and visits throughout the 
study (Children’s Since Last Visit version).  All versions of the C-SSRS include a series of 
screening questions related to suicidal ideation and suicidal behavior.  Subject responses of 
“yes” to one or more screening questions will prompt additional questions that evaluate 
frequency and intensity of suicidal ideation and/or behavior.  Subjects with any lifetime suicidal 
behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to act, without 
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specific plan) or type 5 (active suicidal ideation with specific plan and intent) in the 1 year 
before screening based on the C-SSRS Children’s version should be excluded (see exclusion 
criterion #18 in Section 8.2). 
The C-SSRS will be administered and scored by the investigator or qualified study center 
personnel at screening, baseline (Day -1), and Weeks 2, 4, 6, at the follow-up visit (or upon 
early termination).  A copy of each Children’s version of the C-SSRS is provided in 
Appendix 17.6 and Appendix 17.7, respectively. 
9.5.8. 
Extrapyramidal Symptom Rating Scale-Abbreviated 
The ESRS-A is a psychometrically validated instrument that assesses 4 types of movement 
disorders:  parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD) (Chouinard and 
Margolese, 2005).  The investigator (or designee) will administer the ESRS-A at baseline 
(Day -1), during the treatment period (Weeks 2, 4, and 6), and at the follow-up visit (Week 8 or 
upon early termination).  A copy of the ESRS-A is provided in Appendix 17.11. 
9.5.9. 
Children’s Depression Rating Scale, Revised 
The CDRS-R is a 17-item, semi-structured interview to determine the severity of depression in 
children.  The investigator (or designee) will administer the CDRS-R at screening, baseline 
(Day -1), and the Weeks 2, 4, 6, at the follow-up visit (or upon early termination).  A copy of 
the CDRS-R is provided in Appendix 17.8. 
9.5.10. 
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 screening, baseline (Day -1), Weeks 2, 4, 6, and at the follow-up visit (or upon 
early termination).  A copy of the CY-BOCS is provided in Appendix 17.9. 
9.5.11. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version 
The ADHD Rating Scale-IV: Home Version will be used to determine the frequency and 
severity of ADHD symptoms and impairments over the past 2 weeks.  The 18-item scale is 
linked directly to DSM-IV diagnostic criteria for ADHD; it consists of 2 subscales: inattention 
(9 items) and hyperactivity-impulsivity (9 items).  It will be completed independently by the 
subject’s parent or guardian at screening, baseline (Day -1), Weeks 2, 4, 6, and at the follow-up 
visit (or upon early termination).  A copy of the ADHD Rating Scale IV: Home Version is 
provided in Appendix 17.10. 
9.5.12. 
Estimated Total Blood Sample Volume Required by Study 
The estimated total blood sample volume for each subject is presented in Table 3.  These 
estimates include samples to be collected during screening, the treatment periods, and the final 
visit (or upon early termination). 
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Table 3: 
Estimated Total Blood Sample Volume for Children and Adolescents 
Parameter 
Number of Samples 
Required 
Approximate 
Volume (mL) 
Approximate Total 
Volume (mL) 
Children (6 to 11 years of age) 
Serum chemistrya 
6 
2.5 
15 
Hematology 
6 
3 
18 
Genotyping 
1 
4 
4 
Serology 
1 
9 
9 
Serum prolactin 
5 
2.5 
12.5 
Pharmacokinetics 
4 
2b 
8 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
66.5 
Adolescents (12 to 17 years of age) 
Serum chemistrya 
6 
5 
30 
Hematology 
6 
4 
24 
Genotyping 
1 
4 
4 
Serology 
1 
10 
10 
Serum prolactin 
5 
5 
25 
Pharmacokinetics 
4 
2b 
8 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
101 
a.  
Includes pregnancy test for female subjects who are of childbearing potential at screening. 
b.  Includes 0.5 mL of discard volume per sample. 
9.6. 
Specific Study Information 
After providing parental or legal guardian informed consent with signed and witnessed pediatric 
assent (as required by the governing IRB), subjects will undergo screening procedures within 
21 days of Day -1.  Subjects or parents or legal guardians may also be asked to sign an optional 
release form to allow their RTRS video recordings to be used for educational purposes. 
9.6.1. 
Screening (Weeks -3 to -1) 
During screening, the following study evaluations and tasks will be performed at the study 
center: 
• Obtain informed consent/assent. 
• Assess inclusion/exclusion criteria. 
• Collect medical history. 
• Perform a physical examination (including height and weight). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
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• Perform a serum pregnancy test (β-hCG) 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 urine drug screen (both only in adolescent subjects). 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
• Administer the PUTS. 
• Administer the CGI-Tics-Severity scale. 
• Administer the C-SSRS (Children’s Screening/Baseline version). 
• Administer the CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale. 
• AE monitoring. 
• Record prior medications. 
All screening procedures must be completed and results evaluated by the investigator before the 
baseline procedures are performed on Day -1. 
The following items will also be conducted at screening: 
• Instruct subjects of childbearing potential who do not practice total abstinence to continue 
using contraception (see inclusion criterion #10 in Section 8.1). 
• Eligible subjects will be instructed to return to the center on Day -1.  The following should 
be taken into account for scheduling purposes:  As much as possible, the Weeks 2, 4, 6, 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 efficacy, safety, and 
plasma exposure throughout the study period.  
9.6.2. 
Baseline (Day -1) 
Subjects will return to the center on Day -1. 
On Day -1, the following study evaluations and procedures will be performed at the study 
center: 
• Update inclusion and exclusion criteria. 
• Update medical history. 
• Perform a physical examination including weight. 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and 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. 
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• Collect urine sample for urinalysis. 
• Perform alcohol breathalyzer test and urine drug screen (both only in adolescent subjects). 
• Collect blood sample for CYP2D6 genotype status. 
• Collect blood sample for serum prolactin. 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
• Administer the PUTS. 
• Administer the CGI-Tics-Severity scale 
• Administer the C-SSRS (Children’s Since Last Visit version). 
• Administer the ESRS-A. 
• Administer the CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale. 
• Access the IWRS to obtain randomization assignments for eligible subjects. 
• Dispense a 2-week supply of study drug and provide instructions on storage and 
administration of the study drug. 
• Instruct subjects to record the date and time of each dose on the labels provided on the study 
drug kit packaging form. 
• Instruct subjects and parents/legal guardians to continue taking study drug daily with a 
standard breakfast between 0700 and 1000 hours.  (The timing of study drug administration 
should remain consistent throughout the treatment period.)  Study drug should be taken in 
the presence of the subject’s parent/legal guardian. 
• Instruct subjects and parents/legal guardians to return to the study center at Week 2 
(±3 days) and to bring their study drug kit. 
• AE monitoring. 
• Record concomitant medications. 
The following will also be conducted before subjects may leave the study center: 
• Instruct subjects of childbearing potential who do not practice total abstinence to continue 
using contraception (see inclusion criterion #10 in Section 8.1). 
• Instruct subjects and parents/legal guardians to notify the investigator by telephone if they 
experience any AEs and before taking any new concomitant medications. 
9.6.3. 
Treatment Period:  Weeks 2, 4, and 6 (±3 days for each visit) 
Subjects and parents/legal guardians will report to the study center at Weeks 2, 4, and 6. 
At Weeks 2, 4, and 6, the following study evaluations and procedures will be performed at the 
study center: 
• Perform a physical examination including weight. 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
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• 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 serum prolactin. 
• Collect PK blood sample for NBI-98854 and metabolite concentrations. 
• Administer the YGTSS, including video recording. 
• Video record subjects for the RTRS. 
• Administer the PUTS. 
• Administer the CGI-Tics-Severity scale. 
• Administer the CGI-TS-Improvement scale. 
• Administer the C-SSRS (Children’s Since Last Visit version). 
• Administer the ESRS-A. 
• Administer the CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale. 
• Dispense a 2-week supply of study drug (Weeks 2 and 4 only). 
• Instruct subjects to record the date and time of each dose on the labels provided on the study 
drug packaging form (Weeks 2 and 4 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 center: 
• Instruct subjects of childbearing potential who do not practice total abstinence to continue 
using contraception (see inclusion criterion #10 in Section 8.1). 
• Instruct subjects and parents/legal guardians to notify the investigator by telephone if they 
experience any AEs and before taking any new concomitant medications. 
9.6.4. 
Week 8 (±3 days), Follow-Up/Early Termination 
At Week 8 (or upon early termination) the following procedures will be performed at the study 
center: 
• Perform a physical examination including weight. 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and 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. 
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• 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. 
• Administer the PUTS. 
• Administer the CGI-Tics–Severity scale 
• Administer the CGI-TS–Improvement scale. 
• Administer the C-SSRS (Children’s Since Last Visit version). 
• Administer the ESRS-A. 
• Administer the CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale. 
• AE monitoring. 
• Record concomitant medications. 
9.7. 
Study Duration 
The expected duration of study participation for each subject is approximately 11 weeks, 
including up to 21 days of screening, a 6-week double-blind treatment period, and a 2-week 
follow-up period. 
9.8. 
Prohibitions and Restrictions 
9.8.1. 
Prior and Concomitant Medications 
The following medications are prohibited from 30 days before screening (unless otherwise 
stated) until the final study visit (or upon early termination) as described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• Antihypertensives:  Reserpine (known to irreversibly bind to VMAT2) is prohibited. 
• Botulinum toxin:  Botulinum toxin injections are prohibited starting 90 days prior to 
screening 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. 
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• As needed (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.  
9.8.2. 
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 Day -1 until the 
follow-up visit.  Foods containing poppy seeds are prohibited from 7 days before screening and 
baseline (Day -1) until the follow-up visit.  Alcohol is prohibited from 48 hours before Day -1 
until the follow-up visit. 
9.8.3. 
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 screening to the follow-up visit 
or upon early termination).  Strenuous activity beyond what is customary for the subject is 
prohibited during the study.  Subjects must agree not to donate blood during the study, 
including the screening period, and for 4 weeks after completion of the study. 
Subjects must not have initiated CBIT during the screening period or at baseline (Day -1) or 
plan to initiate CBIT during the study. 
9.9. 
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 becomes 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 9.8.1). 
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• 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 9.6.4). 
9.9.1. 
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 must have all early termination assessments performed. 
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. 
9.9.2. 
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 centers with subject-specific, study drug kits 
sufficient for the completion of the treatment period of the study together with the 
corresponding certificates of analysis. 
NBI-98854 will be supplied as capsules containing 10, 20, or 40 mg of NBI-98854 (free base).  
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.   
The matching placebo capsules are identical in appearance to the NBI-98854 capsules. 
10.2. 
Study Drug Storage 
NBI-98854 and placebo 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. 
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• 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.  The blistercards will 
contain capsules of NBI-98854 10 mg, 20 mg, or 40 mg; or matching placebo. 
The higher NBI-98854 dose in each age group (20 mg in children and 40 mg in adolescents) 
will be titrated in a blinded fashion (children will receive 10 mg and adolescents will receive 
20 mg for the first week followed by their randomized dose of 20 mg or 40 mg for the 
remainder of the 6-week treatment period). 
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, batch number, 
dosage form, route of administration, study drug kit number, sponsor name and address, 
expiration date, storage condition and the statement “Caution – New Drug: Limited by Federal 
(or US) Law to Investigational Use.” 
10.4. 
Blinding 
This study includes a 6-week double-blind placebo-controlled treatment period during which 
the subject, investigator, all study site personnel, the YGTSS external video reviewer, RTRS 
video rater, and the Sponsor will be blinded to the subject’s treatment. 
The randomization code will be broken for an individual subject if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 
identity of the subject’s treatment assignment, or for regulatory reporting requirements.  All 
attempts to contact the NBI Medical Monitor (refer to Section 11.6.3 for contact information) 
must be made before unblinding a subject.  The unblinding form that contains the date, time, the 
reason the blind was broken, and name of NBI representative contacted must be completed. 
10.5. 
Study Drug Administration 
Study drug will be self-administered once daily in the morning (between 0700 and 1000 hours) 
at home under the supervision of the subject’s parent/legal guardian with a standard breakfast 
and the capsules must be swallowed with at least 4 oz. of water every day for the 6-week 
treatment period.  If a subject forgets or is unable to take the study drug during this time period, 
the subject should take his or her daily dose of study drug as soon as possible but no later than 
1800 hours.  The subject will need to skip the dose for that day if he or she is unable to take the 
study drug before 1800 hours.  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. 
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10.6. 
Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty study drug packaging material to the center 
at each study visit for drug accountability and reconciliation by study center personnel.  A 
compliance check will be performed by counting the capsules returned at each study visit. 
The 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 subject signed the ICF 
until the subject’s final study day (Week 8 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. 
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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 
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 drug administration, unless it 
unexpectedly progresses, or increases in severity following 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 4, 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 4: 
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 5.  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 5: 
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 randomized subjects, each AE will be listed as a separate entry on an AE eCRF.  Screen 
failure subjects will have AE information noted in the source documentation.  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: 
• Serious adverse event, 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 subject has signed the ICF 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, 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: (866) 626-7792 or (858) 617-7792 
 
CDS facsimile: 
(888) 617-7551 
 
CDS e-mail:  
cds@neurocrine.com 
 
NBI Medical Monitor:  
Telephone: 
(858) 617-7250 
 
 
 
 
 
 
 
 
 
Cell phone: 
(858) 431-6012 
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 two forms of 
nonhormonal contraception or hormonal contraception (see inclusion criterion #10 in 
Section 8.1) until 30 days after the last dose of study drug.  If at any time between the time the 
subject signs the ICF 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 center 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 
.  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). 
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13. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive and inferential 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.  The term “inferential statistics” refers to hypothesis tests 
which will be performed to assess differences between each NBI-98854 treatment group and 
placebo for selected efficacy variables.  Note that descriptive statistics will be presented both by 
treatment group within each age group and by “pooled” treatment group (placebo, NBI-98854 
low dose, and NBI-98854 high dose) without regard to age group, unless specified otherwise.  
Only pooled treatment groups will be used for inferential statistics.  The pooled treatment 
groups are defined as follows: 
• Placebo: Placebo treatment, children and adolescents. 
• NBI-98854 low dose: NBI-98854 10 mg (children) and NBI-98854 20 mg (adolescents). 
• NBI-98854 high dose: NBI-98854 20 mg (children) and NBI-98854 40 mg (adolescents). 
The primary efficacy endpoint in this study is the YGTSS TTS mean change from baseline 
(Day -1) to Week 6.  Inferential statistics will be calculated for this endpoint as well as for other 
(secondary) efficacy endpoints, which include the YGTSS Global Tic Severity score mean 
change from baseline to Week 6, the RTRS total score mean change from baseline to Week 6, 
the PUTS total score mean change from baseline to Week 6, the CGI-TS-Improvement mean 
score change from baseline to Week 6, and the CGI-Tics-Severity mean score change from 
baseline to Week 6.  Exploratory analyses of Week 2 and Week 4 values of these endpoints will 
also be performed.  Nominal two-sided p-values will be reported for all hypothesis tests (ie, 
without any adjustments for multiplicity). 
The analysis plan provided in this protocol represents a brief description of the planned 
analyses.  A comprehensive and detailed statistical analysis plan (SAP) will be generated prior 
to final study database lock and treatment unblinding.  The SAP may include a number of 
additional analyses and data summaries not described in this protocol. 
13.1. 
Analysis Sets 
Three analysis sets will be defined for this study.  The safety analysis set will include all 
subjects who are randomized to a treatment group and receive at least one dose of study drug.  
The intent-to-treat (ITT) analysis set will include all subjects in the safety analysis set who have 
at least one evaluable TTS during the 6-week double-blind treatment period.  The per-protocol 
(PP) analysis set will include all subjects in the ITT analysis set who have no efficacy-related 
important protocol deviations.  Additional PP analysis set criteria may be specified in the SAP. 
13.2. 
Sample Size 
The study sample size of 30 subjects per (pooled) treatment group is based on a power 
calculation for the TTS change from baseline using a two-sample t-test with a two-sided Type I 
error of 0.05.  This sample size provides 80% power to detect an effect size of approximately 
0.75 and 90% power to detect an effect size of approximately 0.85.  Note that the effect size is 
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defined as an NBI-98854 treatment group versus placebo mean difference divided by the 
common SD.   
Effect sizes for the TTS from published reports of placebo-controlled TS trials generally range 
from approximately 0.6 to slightly greater than 1.0 (Jankovic et al, 2010; Yoo et al, 2013; 
ClinicalTrials NCT01727700).  The effect sizes of 0.75 and 0.85 mentioned in the above 
paragraph are representative of effect sizes seen in clinical studies with other drugs being 
evaluated for the treatment of TS. 
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 randomized to each treatment group, who received at least 1 dose of study drug, who 
completed the 6-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, body mass index (BMI), CYP2D6 genotype status, age at TS diagnosis, and 
baseline values for the TTS) will be summarized with descriptive statistics for each treatment 
group and for the overall study population.  Medical history will also be summarized. 
13.6. 
Study Drug Dosing and Compliance 
The number of doses of study drug taken during the double-blind, placebo-controlled treatment 
period will be summarized with descriptive statistics by visit (Weeks 2, 4, and 6).  The 
cumulative estimated number of doses taken through Week 6 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 (Weeks 2, 4, 6, and 8).  Concentrations below the lower limit 
of quantification will be set equal to zero for all plasma concentration summaries. 
13.8. 
Efficacy Data 
The efficacy measures in this study include the YGTSS, RTRS, PUTS, CGI-Tics-Severity, and 
CGI-TS–Improvement.  A number of derived variables based on these measures (eg, the TTS) 
will be summarized with descriptive statistics by visit, and inferential statistics will be 
calculated for selected variables as described in the following paragraphs.  The SAP will 
provide a full description of the derived variables that will be summarized for these efficacy 
measures. 
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The TTS changes from baseline (Day -1) and the Global Tic Severity score changes from 
baseline (Day -1) at Weeks 2, 4, and 6 will be analyzed with a mixed-effects model repeated 
measures (MMRM) that includes the baseline value as a covariate and treatment group 
(placebo, NBI-98854 low dose, or NBI-98854 high dose), age group (children or adolescents), 
visit (Week 2, 4, or 6), treatment group by visit interaction, and baseline by visit interaction as 
fixed effects.  Subject will be included as a random effect.  
Least-squares (LS) mean differences between each NBI-98854 treatment group and placebo at 
each visit will be tested for significance and summarized with 2-sided 95% confidence intervals.  
Nominal 2-sided p values will be reported for all hypothesis tests.  Note that the primary 
comparisons of interest are those for the Week 6 visit; comparisons at Weeks 2 and 4 are 
considered to be exploratory. 
Similar MMRM analyses will be performed for the RTRS total score and PUTS total score.   
The CGI-Tics–Severity and CGI-TS–Improvement scores will be summarized by visit with 
both continuous variable descriptive statistics (using numeric scores that range from 1 through 
7) and with frequency tables (based on the response category descriptors).  Additionally, the 
percentage of subjects who are “Much Improved” or “Very Much Improved” on the 
improvement scale will be summarized. 
Hypothesis tests comparing each NBI-98854 treatment group to placebo at Weeks 2, 4, and 6 
will be performed for the numeric CGI-Tics – Severity and CGI-TS – Improvement scores 
using an MMRM model similar to the model described above for the TTS. 
The descriptive and inferential statistical summaries for the efficacy variables will be presented 
for both the ITT and PP analysis sets. 
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, C-SSRS, ESRS-A, CY-BOCS, CDRS-R, and ADHD 
Rating Scale 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. 
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13.11. 
Interim Analysis 
An interim analysis is not planned for this study. 
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. 
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14.5. 
Informed Consent 
All parents or legal guardians will provide informed consent with signed and witnessed 
pediatric assent 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.  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, Health Canada 
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. 
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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. 
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 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study material be delivered to the study site.  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. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition. 2013. 
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, Nani A. Tourette syndrome and consciousness of action. Tremor Other 
Hyperkinet Mov (NY). 2013 Sep 23;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 S, Ford B. Adult onset tic disorders. J Neurol Neurosurg Psychiatry. 2000 
Jun;68(6):738-43. 
Chouinard G and Margolese HC.  Manual for the Extrapyramidal Symptom Rating Scale 
(ESRS).  Schizophr Res. 2005 Jul 15;76(2-3):247-65. 
ClinicalTrials.gov Identifier: NCT01727700. Otsuka Pharmaceutical Development & 
Commercialization, Inc. Study evaluating the safety and efficacy of fixed-dose once-daily 
aripiprazole in children and adolescents with Tourette’s Disorder 
https://www.clinicaltrials.gov/ct2/show/NCT01727700?term=NCT01727700&rank=1 
[Accessed 05 June 2015]. 
Felling RJ, Singer HS. Neurobiology of Tourette syndrome: current status and need for further 
investigation. J Neurosci. 2011 Aug 31;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. 
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. 
Neurology 1997; 48(2):358-62. 
Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled 
study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psychiatry. 2010 
Jan;81(1):70-3. 
Jankovic J, Kurlan R. Tourette syndrome: evolving concepts. Mov Disord. 2011 
May;26(6):1149-56. 
Kurlan R. Clinical practice. Tourette's Syndrome. N Engl J Med. 2010 Dec 9;363(24):2332-8. 
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. 
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Leckman JF, Zhang H, Vitale A, Lahnin F, Lynch K, Bondi C, et al. Course of tic severity in 
Tourette syndrome: the first two decades. Pediatrics. 1998 Jul;102(1 Pt 1):14-9. 
Ondo WG, Hanna PA, Jankovic J.  Tetrabenazine treatment for tardive dyskinesia: assessment 
by randomized videotape protocol. Am J Psychiatry 1999; 156(8):1279-81. 
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 15;76(11):944-52. 
Robertson MM. Gilles de la Tourette syndrome: the complexities of phenotype and treatment. 
Br J Hosp Med (Lond). 2011 Feb;72(2):100–7. 
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 15;24(1):15-24. 
Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF. Tourette syndrome and tic disorders: 
a decade of progress. J Am Acad Child Adolesc Psychiatry. 2007 Aug;46(8):947–68. 
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. 
Yoo HK, Joung YS, Lee JS, Song DH, Lee YS, Kim JW, et al. A multicenter, randomized, 
double-blind, placebo-controlled study of aripiprazole in children and adolescents with 
Tourette’s disorder. J Clin Psychiatry. 2013;74(8):e772-80. 
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17. 
APPENDICES 
17.1. 
Yale Global Tic Severity Scale (YGTSS) 
 
 
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17.2. 
Rush Video-Based Tic Rating Scale (RTRS) 
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17.3. 
Premonitory Urge for Tics Scale (PUTS) 
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17.4. 
Clinical Global Impression of Tics (CGI-Tics) – Severity 
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17.5. 
Clinical Global Impression of Change-Tourette Syndrome (CGI-TS) 
– Improvement 
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17.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Baseline/Screening Version 
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17.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since 
Last Visit Version 
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17.8. 
Children’s Depression Rating Scale, Revised (CDRS-R) 
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17.9. 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) 
 
 
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17.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home 
Version 
 
 
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17.11. 
Extrapyramidal Symptom Rating Scale-Abbreviated 
 
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SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
1 
STATISTICAL ANALYSIS PLAN 
PHASE 2 
FINAL 
DATE OF PLAN: 
05 May 2017 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI 98854-1501 
STUDY TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO ASSESS THE SAFETY AND EFFICACY OF NBI-98854 IN PEDIATRIC 
SUBJECTS WITH TOURETTE SYNDROME 
SPONSOR: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA  92130 
Telephone:  (858) 617-7600 
CONFIDENTIAL 




Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
3 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY OBJECTIVES ................................................................................................7 
2.1. 
Study Design Overview ................................................................................................7 
2.2. 
Efficacy, Pharmacokinetic Blood Sampling, and Safety Assessments for All 
Subjects .........................................................................................................................8 
3. 
STATISTICAL ANALYSES .......................................................................................9 
3.1. 
General Statistical Procedures ......................................................................................9 
3.2. 
Sample Size Calculation .............................................................................................10 
3.3. 
Pooling of Sites ...........................................................................................................10 
3.4. 
Handling of Early Termination Visit Data .................................................................10 
3.5. 
Handling of Missing Data ...........................................................................................11 
3.5.1. 
Missing and Incomplete Dates ....................................................................................11 
3.6. 
Coding Dictionary ......................................................................................................12 
3.7. 
Analysis Sets ...............................................................................................................12 
3.7.1. 
Definition of Analysis Sets .........................................................................................12 
3.7.2. 
Summary of Analysis Sets ..........................................................................................13 
3.7.3. 
Application of Analysis Sets ......................................................................................13 
3.8. 
Subject Randomization and Disposition .....................................................................14 
3.9. 
Protocol Deviations ....................................................................................................15 
3.10. 
Demographic Data and Baseline Characteristics ........................................................15 
3.11. 
Medical History ..........................................................................................................15 
3.12. 
Study Drug Dosing and Compliance ..........................................................................15 
3.13. 
Dose Reduction Summary ..........................................................................................16 
3.14. 
Pharmacokinetic Data .................................................................................................17 
3.15. 
Efficacy Data ..............................................................................................................17 
3.15.1. 
Efficacy Endpoints ......................................................................................................17 
3.15.2. 
Primary Efficacy Endpoint .........................................................................................19 
3.15.3. 
Key Secondary Efficacy Endpoint ..............................................................................20 
3.15.4. 
Procedure to Control for Multiplicity .........................................................................21 
3.15.5. 
Sensitivity Analyses for Primary Efficacy Endpoint ..................................................21 
3.15.6. 
Sensitivity Analysis for Key Secondary Efficacy Endpoint .......................................24 


Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
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3.15.7. 
Secondary Efficacy Endpoints ....................................................................................24 
3.15.7.1. 
YGTSS TTS Responder Analysis ..............................................................................24 
3.15.7.2. 
YGTSS Impairment Score ..........................................................................................24 
3.15.7.3. 
YGTSS Global Tic Severity Score .............................................................................25 
3.15.7.4. 
Rush Video-based Tic Rating Scale (RTRS) ..............................................................26 
3.15.7.5. 
Premonitory Urge for Tics Scale (PUTS) ...................................................................26 
3.15.7.6. 
CGI-Tics-Severity .......................................................................................................27 
3.15.7.7. 
CGI-TS-Improvement Responder Analysis ...............................................................28 
3.16. 
Safety Data ..................................................................................................................28 
3.16.1. 
Adverse Events ...........................................................................................................28 
3.16.1.1. 
Adverse Event Overall Summary ...............................................................................29 
3.16.1.2. 
Adverse Events Resulting in Premature Study Discontinuation ................................29 
3.16.1.3. 
Adverse Events Resulting in Study Drug Dose Reductions .......................................29 
3.16.1.4. 
Deaths and Other Serious Adverse Events .................................................................30 
3.16.2. 
Clinical Laboratory Data ............................................................................................30 
3.16.3. 
Physical Examination and Weight ..............................................................................32 
3.16.4. 
Vital Signs ..................................................................................................................32 
3.16.5. 
Electrocardiogram .......................................................................................................33 
3.16.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions (C-SSRS) .................34 
3.16.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) ...............................35 
3.16.8. 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) ..........................36 
3.16.9. 
Children’s Depression Rating Scale, Revised (CDRS-R) ..........................................36 
3.16.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version ...............36 
3.16.11. 
Prior and Concomitant Medications ...........................................................................37 
3.17. 
Additional Data Presentations ....................................................................................37 
3.17.1. 
Inclusion and Exclusion Criteria ................................................................................37 
3.17.2. 
Serology Test Results .................................................................................................37 
3.17.3. 
Pregnancy Test Results ...............................................................................................37 
3.17.4. 
Urine Drug Screen and Alcohol Breath Test ..............................................................37 
4. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS .................................38 
5. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................38 
6. 
REFERENCES ...........................................................................................................39 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADHD 
Attention-Deficit Hyperactivity Disorder 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification 
BLQ 
Below the limit of quantification 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CGI-Tics 
Clinical Global Impression of Tics 
CGI-TS 
Clinical Global Impression of Change – Tourette Syndrome 
CMH 
Cochran-Mantel-Haenszel 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CY-BOCS 
Children’s Yale-Brown Obsessive-Compulsive Scale 
CYP2D6 
Cytochrome P450 2D6 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESRS-A 
Extrapyramidal Symptom Rating Scale - Abbreviated 
ET 
Early termination 
GGT 
Gamma-glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C antibody 
HIV-Ab 
Human immunodeficiency virus antibody 
IPD 
Important protocol deviation 
ITT 
Intent-to-treat 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
n, N 
Sample size (number of subjects) 
NBI 
Neurocrine Biosciences, Inc. 
PK 
Pharmacokinetic(s) 


Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
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Abbreviation 
Term 
ADHD 
Attention-Deficit Hyperactivity Disorder 
PP 
Per-protocol 
PT 
Preferred term 
PUTS 
Premonitory Urge for Tics Scale 
QTcF 
Fridericia’s correction of QT interval  
RTRS 
Rush Video-Based Tic Rating Scale 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS® 
SAS®  statistical software 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TS 
Tourette Syndrome 
TTS 
Total Tic Score 
WHO 
World Health Organization 
YGTSS 
Yale Global Tic Severity Scale 


Neurocrine Biosciences, Inc. 
NBI-98854-1501 Statistical Analysis Plan 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed description of the analyses, tables, 
figures, and listings that will be prepared to summarize the data from the Phase 2 study described 
in Neurocrine Biosciences, Inc. (NBI) Protocol NBI-98854-1501. 
2. 
STUDY OBJECTIVES 
The objectives of this study are: 
 To evaluate the efficacy of 2 active doses of NBI-98854 (10 mg and 20 mg in children; and 
20 mg and 40 mg in adolescents) administered once daily in pediatric subjects with Tourette 
Syndrome (TS). 
 To assess the safety and tolerability of repeated daily doses of NBI-98854 in pediatric 
subjects with TS. 
 To evaluate plasma exposure of NBI-98854 and its metabolite, NBI-98782, following 
repeated daily doses of NBI-98854. 
2.1. 
Study Design Overview 
This 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 (10 mg and 20 mg 
in children, and 20 mg and 40 mg in adolescents) relative to placebo, administered once daily for 
6 weeks in pediatric subjects with TS.  Approximately 90 male and female subjects, 6 to 17 years 
of age, with a diagnosis of TS will participate.  The subjects will be divided into 2 age groups of 
approximately 45 children (6 to 11 years of age) and 45 adolescents (12 to 17 years of age).  
Eligible subjects within each age group will be randomized in a 1:1:1 ratio to placebo or 1 of 2 
NBI-98854 treatment groups as depicted in the following table. 
Table 1: 
Study Randomization Schematic 
Age Group 
 
Treatment Group 
Number of Subjects 
(approximate) 
Children, 6 to 11 years old 
 
Placebo 
15 
 
NBI-98854 10 mg 
15 
 
NBI-98854 20 mg 
15 
Adolescents, 12 to 17 years old 
 
Placebo 
15 
 
NBI-98854 20 mg 
15 
 
NBI-98854 40 mg 
15 
Subjects will be screened to determine eligibility within 21 days (Days -21 to -1) before the start 
of study drug dosing on Day 1.  On Day -1 (baseline; the day before receiving the first dose of 
study drug), eligible subjects will return to the study center for collection of baseline safety and 
efficacy assessments and collection of a blood sample for subsequent determination of their 
CYP2D6 metabolizer status.  Subjects who continue to be eligible for the study will then be 


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randomized (1:1:1) to placebo or 1 of 2 NBI-98854 doses determined by subject age group.  A 2-
week supply of study drug will be dispensed.   
Beginning on Day 1 (the day after the Day -1 visit), study drug will be administered once daily 
in the morning at home throughout the 6-week treatment period.  The higher NBI-98854 dose in 
each age group (20 mg in children and 40 mg in adolescents) will be titrated in a blinded fashion 
(children will receive 10 mg and adolescents will receive 20 mg for the first week followed by 
their randomized dose of 20 mg or 40 mg for the remainder of the 6-week treatment period).   
At any time, if the subject is unable to tolerate their current dose, the investigator may decrease 
the subject’s dose.  The investigator is allowed to reduce the subject’s dose only 1 time during 
the study.  Subjects who have had a dose reduction and are unable to tolerate their new dose will 
be discontinued from the study. 
To maintain the study blind, subjects receiving placebo or the lower dose in each age group 
(10 mg in children and 20 mg in adolescents) who have a dose reduction will continue to receive 
their current dose, and subjects receiving the higher dose in each age group (20 mg in children 
and 40 mg in adolescents) will have their dose reduced to the lower dose, that is, 10 mg in 
children and 20 mg in adolescents. 
During the treatment period, subjects will return to the study center at 2-week intervals (Weeks 
2, 4, and 6) for study assessments and dispensing of study drug (Weeks 2 and 4 only).  All 
subjects who have completed the 6-week treatment period will enter a 2-week follow-up period 
with a follow-up visit at Week 8 (subjects who terminate early will have Week 8 assessments 
conducted).  Efficacy, safety, and study drug exposure will be assessed at scheduled times 
throughout the study. 
2.2. 
Efficacy, Pharmacokinetic Blood Sampling, and Safety Assessments 
for All Subjects 
Efficacy assessments for TS symptomatology include the Total Tic Score (TTS) from the Yale 
Global Tic Severity Scale (YGTSS) as the primary efficacy variable, and the YGTSS 
Impairment and Global Tic Severity scores, the Rush Video-Based Tic Rating Scale (RTRS), the 
Premonitory Urge for Tics Scale (PUTS), the Clinical Global Impression of Change-Tourette 
Syndrome (CGI-TS)-Improvement scale, and the Clinical Global Impression of Tics 
(CGI-Tics)-Severity scale as secondary efficacy variables.  The YGTSS, RTRS, and PUTS will 
be administered at screening, on Day -1 (the day before dosing), during the double-blind 
treatment period (Weeks 2, 4, and 6), and at the follow-up visit (Week 8) or early termination.  
Note that all efficacy analyses for YGTSS-related variables are based on the certified site rater 
scores.  Computer-generated tandem scores are also collected in the study database and will be 
presented in data listings only.    
The CGI-Tics-Severity will be evaluated at screening and Day -1 (baseline), and then both the 
CGI-Tics-Severity and CGI-TS-Improvement scales will be administered at Weeks 2, 4, and 6 
and at the follow-up visit (Week 8) or early termination.   
Blood samples to evaluate plasma concentrations of NBI-98854 and the metabolite NBI-98782 
will be collected during the treatment period (Weeks 2, 4, and 6) and at the follow-up visit 
(Week 8) or early termination. 


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Safety assessments performed at scheduled times throughout the study include adverse event 
(AE) monitoring, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), serum 
prolactin, vital sign measurements, physical examinations, 12-lead ECG, Columbia Suicide 
Severity Rating Scale (C-SSRS, Children’s Version), Extrapyramidal Symptom Rating Scale-
Abbreviated (ESRS-A), Children’s Depression Rating Scale - Revised (CDRS-R), Children’s 
Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Attention-Deficit Hyperactivity 
Disorder Rating Scale IV: Home Version (ADHD Rating Scale). 
3. 
STATISTICAL ANALYSES 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the study database. Analyses defined subsequent to locking the database will be 
considered post hoc analyses and will be applied as exploratory methodology. Any post hoc 
analyses will be clearly identified in the clinical study report. 
3.1. 
General Statistical Procedures 
Descriptive and inferential 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.  The term “inferential statistics” refers to hypothesis tests which will be 
performed to assess differences between the NBI-98854 treatment groups and the placebo group 
for selected efficacy variables.  All hypothesis tests will be tests of the null hypothesis of no 
difference between the treatment groups being compared versus the two-sided alternative 
hypothesis that there is a difference.   
Descriptive statistics will be presented both by treatment group within each age group and by 
“pooled” treatment groups (placebo, NBI-98854 low dose, and NBI-98854 high dose) without 
regard to age group, unless specified otherwise.  Only pooled treatment groups will be used in 
the calculation of inferential statistics.  The pooled treatment groups are defined as follows: 
 Placebo: Placebo (children and adolescents). 
 NBI-98854 low dose: NBI-98854 10 mg (children) and NBI-98854 20 mg (adolescents). 
 NBI-98854 high dose: NBI-98854 20 mg (children) and NBI-98854 40 mg (adolescents). 
The primary efficacy endpoint in this study is the YGTSS Total Tic Score (TTS) mean change 
from baseline (Day -1) to Week 6 based on the certified site rater scores (note that all statistical 
summaries and analyses of the YGTSS data are based on the site rater scores).  Inferential 
statistics will be calculated for this endpoint as well as for secondary efficacy endpoints, which 
include  the YGTSS Impairment score mean change from baseline to Week 6, the YGTSS 
Global Tic Severity score mean change from baseline to Week 6, the RTRS total score mean 
change from baseline to Week 6, the PUTS total score mean change from baseline to Week 6, 
the CGI-TS-Improvement mean score at Week 6 (which is the key secondary efficacy endpoint), 
and the CGI-Tics-Severity score mean change from baseline to Week 6.  A responder analysis 
will be performed also for the TTS and the CGI-TS-Improvement scale.  Inferential analyses of 
Week 2 and Week 4 values of these endpoints will performed in addition to the Week 6 values 
(with the exception of the RTRS total score).  Nominal (raw) two-sided p-values will be reported 


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for all hypothesis tests, although a procedure to control for multiplicity will be applied when 
interpreting the results of the analyses of the primary efficacy endpoint and the key secondary 
efficacy endpoint. 
A comprehensive set of data listings including all randomized subjects will be provided.  These 
listings will include both measured and derived values.  Observations in data listings will be 
sorted by age group, subject, and timepoint (if applicable). 
The derived variable “study day” is used in a number of calculations for data summaries and 
listings.  This variable is calculated as the number of days after a subject’s Day -1 (“baseline”) 
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. 
All analyses, tables, figures, and listings will be generated using SAS® software (version 9.3 or 
later), unless stated otherwise. 
3.2. 
Sample Size Calculation 
The protocol-specified sample size of 30 subjects per pooled treatment group is based on a 
power calculation for the TTS change from baseline using a two-sample t-test with a two-sided 
Type I error of 0.05.  This sample size provides approximately 80% power to detect an effect 
size of 0.75 and approximately 90% power to detect an effect size of 0.85.  Note that the effect 
size is defined as the mean difference between an NBI-98854 treatment group and the placebo 
group divided by the common SD (eg, a mean difference of 8 divided by an SD of 10 yields an 
effect size of 0.8).   
Standard deviations reported in the literature for TS studies evaluating changes in the TTS (with 
or without placebo controls) have generally been in the range of 7.5 to 9.5, and in placebo-
controlled studies, mean differences between active and placebo arms have been in the range of 
5 to 9 (Jankovic et al., 2010; Yoo et al., 2013; ClinicalTrials.gov NCT01727700).  The effect 
sizes of 0.75 and 0.85 mentioned in the above paragraph are representative of effect sizes seen in 
these published reports. 
3.3. 
Pooling of Sites 
Approximately 30 study centers are expected to participate in the study.  With the exception of 
the summary of subject randomization by site, study sites will be pooled in all analyses, tables, 
and figures, since the majority of sites in this study are of a relatively small size, with fewer than 
five subjects expected to be enrolled.  In addition, study site will not be included as a factor in 
any statistical models. 
3.4. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject withdraws from the study prior to 
completing the scheduled Week 8 visit.  An ET visit will be mapped to the next scheduled study 
visit if it occurs within 7 days prior to and 6 days after the expected study day of the next 


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scheduled visit (with the requirement that the scheduled visit prior to the ET visit was actually 
completed by the subject).  An ET visit at Day 49 or later will be mapped to the Week 8 visit.  
Early termination visit data which are not mapped to a scheduled visit will be displayed in 
applicable by-subject data listings but not included in by-visit analyses and 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 2 
14 
7-20 
Week 4 
28 
21-34 
Week 6 
42 
35-48 
Week 8 
56 
49+ 
3.5. 
Handling of Missing Data 
Missing values for outcome measures will not be replaced with imputed values except as noted 
in Table 2 for the ET visit mapping to a scheduled visit for summary and analysis purposes and 
as described for sensitivity analyses of efficacy endpoints which involve multiple or single 
imputation.   
In the event a Day -1 (baseline) visit value is missing, the screening visit value may be used for 
the calculation of change (or shift) from baseline or in a statistical model. 
Derived scale total scores (eg, the TTS), which are calculated as the sum of the scores of the 
individual scale items, will be set equal to missing if any of the individual scale item scores are 
missing.    
Special rules for handling missing and incomplete dates are described below. 
3.5.1. 
Missing and Incomplete Dates 
Missing and incomplete (“partial”) dates for AEs and concomitant medications will be imputed 
only for the purpose of estimating the time of the event or medication usage in relationship to 
study treatment; however, all data listings will display the original dates as reported in the 
database.     
The imputation rules for AE start dates are as follows: 
 If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug; 
 If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the month and year match the month and year of the first dose; otherwise, the day 
will be imputed as the first day of the month; 
 If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose; otherwise, the day and 
month will be imputed as 01 January; 


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 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 is missing, 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 randomized study drug; 
otherwise, the day will be imputed as the first day of the month; 
 If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose; otherwise, the missing 
day and month will be imputed as 01 January; 
 If any of the above imputations result in a start date which is later than an existing 
complete (not imputed) medication stop date, the start date will be set equal to the stop 
date. 
3.6. 
Coding Dictionary 
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. 
3.7. 
Analysis Sets 
3.7.1. 
Definition of Analysis Sets 
Three analysis sets will be defined for this study.   
The safety analysis set will include all subjects who are randomized to a treatment group and 
dispensed study drug, with the following two exclusions: (a) subjects who withdraw from the 
study and return all previously dispensed study drug with all doses present, and (b) subjects who 
have no postbaseline safety data collected. The safety analysis set will be used for all summaries 
of safety data (eg, AEs and clinical laboratory data) and pharmacokinetic plasma concentration 
data.  For the summaries of data based on the safety analysis set, subjects who are dispensed the 
incorrect treatment at the time of randomization, and remain on the same incorrect treatment 
during the study, will be assigned to the treatment actually received in all summary tables and 
figures.  Subjects who are dispensed a combination of correct and incorrect treatments during the 
study will be assigned to the randomized treatment in all summary tables and figures. 
The primary efficacy analysis set is the intent-to-treat (ITT) analysis set, which will include all 
subjects in the safety analysis set who have a baseline and at least one post-randomization TTS 
value reported at a scheduled or mapped ET visit during the 6-week treatment period.  The ITT 
analysis set will be used for summaries and analyses of efficacy data.  Treatment assignment for 
all summaries and analyses using the ITT analysis set will be based on the randomization 
schedule. 
The per-protocol (PP) analysis set will include all subjects in the ITT analysis set who have a 
TTS value for the Week 6 visit (including an ET visit mapped to Week 6), have no efficacy-


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related important protocol deviations (IPDs; described in Section 3.9) and, for subjects in the 
NBI-98854 treatment groups, have a detectable plasma concentration of NBI-98854 at the 
Week 6 visit, which is a measure of treatment dosing compliance. The PP analysis set will be 
used for supportive summaries and analyses of the efficacy data.  Treatment group assignment 
for the PP analysis set will follow the rules described above for the safety analysis set.     
3.7.2. 
Summary of Analysis Sets 
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) each analysis set will be provided for each treatment group within age group, for the 
pooled treatment groups, and overall (for all randomized subjects).  The number and percentage 
of subjects excluded from each analysis set by reason for exclusion will also be provided. 
3.7.3. 
Application of Analysis Sets 
Summaries of subject disposition, randomization by study site, analysis set inclusion/exclusion 
status, and IPDs will include all randomized subjects.  All other summaries by analysis set are 
identified in Table 3. 


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Table 3: 
Data Summaries by Analysis Set 
 
Data Summary/Analysis 
Analysis Set 
Safety 
ITT 
PP 
Demographics 
X 
X 
X 
Baseline subject characteristics 
X 
X 
X 
Medical history 
X 
 
 
Study drug dosing (including dose reductions) 
X 
X 
 
Pharmacokinetic plasma concentration data 
X 
 
 
YGTSS 
 
X 
X 
RTRS 
 
X 
X 
PUTS 
 
X 
X 
CGI-Tics-Severity 
 
X 
X 
CGI-TS-Improvement 
 
X 
X 
Adverse events 
X 
 
 
C-SSRS 
X 
 
 
CY-BOCS 
X 
 
 
CDRS-R 
X 
 
 
ADHD rating scale IV 
X 
 
 
ESRS-A 
X 
 
 
Vital signs 
X 
 
 
Physical examination 
X 
 
 
Weight 
X 
 
 
ECG 
X 
 
 
Clinical laboratory data 
X 
 
 
Prior and Concomitant medications 
X 
 
 
3.8. 
Subject Randomization and Disposition 
The summary of subject randomization and disposition will display the number of subjects who 
were randomized into each treatment group, completed the 6-week treatment period (defined as 
having completed a scheduled Week 6 visit [note that this does not include ET visits mapped to 
Week 6]), and completed the study (defined as having a scheduled Week 8 visit [note that this 
does not include ET visits mapped to Week 8]).  The number of subjects who did not complete 
the study will be displayed both overall and by reason for discontinuation.   
A separate summary of randomization by study site will be presented.  This summary will 
display the number of subjects randomized to each treatment group by site. 
An additional table will display the number of subjects in each treatment group who completed 
each study visit (screening through Week 8; including mapped ET visits).  This table will be 
based on the safety analysis set. 
These summaries will be presented separately for each age group and for the pooled treatment 
groups.  Each summary table will include an “all subjects” column in addition to the columns for 
each treatment group. 


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3.9. 
Protocol Deviations 
Significant protocol deviations, which are described in the study-specific Protocol Deviation 
Plan, will be entered into the study database and used to identify important protocol deviations 
(IPDs).  Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being.  An assessment of IPDs will be performed by a committee 
composed of NBI Clinical Development project team members prior to database lock.  This 
committee will review a listing of all significant protocol deviations reported in the study 
database and determine which deviations are IPDs.  The committee will also indicate which IPDs 
are efficacy-related deviations that exclude a subject from the PP analysis set.  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 randomized 
treatment. 
 Significant deviation from protocol-specified dosing regimen. 
 Significant deviations in YGTSS administration. 
A summary of the number and percentage of subjects with IPDs by deviation category, treatment 
group within age group, and by pooled treatment groups, will be provided for all randomized 
subjects.  All significant protocol deviations will be presented in a data listing. 
3.10. 
Demographic Data and Baseline Characteristics 
Demographic data (age, gender, race, and ethnicity) and baseline characteristics (age at TS 
diagnosis, baseline value of TTS, height, weight (in units of both pounds and kilograms), body 
mass index [BMI], and CYP2D6 genotype status) will be summarized using descriptive statistics 
and frequency counts.  These data will be summarized by treatment group within age group and 
by pooled treatment groups.  Each summary table will include an “all subjects” column. 
3.11. 
Medical History 
Medical history will be summarized in frequency tables (number and percentage of subjects) by 
MedDRA System Organ Class (SOC) and Preferred Term (PT) by treatment group within age 
group and by pooled treatment groups. 
3.12. 
Study Drug Dosing and Compliance 
Study drug dosing compliance is calculated as the ratio of the estimated number of doses taken 
by a subject to the expected number of doses that should have been taken (given the length of 
time the subject participated in the study treatment period) and is expressed as a percentage.  A 
subject is classified as being compliant with study drug administration if their calculated value is 
80% or greater.  The number and percentage of subjects in each treatment group (both by 
treatment group within age group and by pooled treatment groups) who are compliant will be 
presented for Weeks 2, 4, and 6, and for the full treatment period.  


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The number of doses taken by each subject between two consecutive visits will be estimated by 
calculating the difference between the number of capsules dispensed at the first visit and the 
number of capsules returned at the subsequent visit (note that the number of doses taken is equal 
to the number of capsules taken, as each dose is 1 capsule of study drug per study protocol).  If 
an ET visit occurs between scheduled visits, the ET visit data will be used in the calculation. If a 
subject fails to return the study drug kit dispensed at the previous visit, it will be assumed that 
the number of doses taken by the subject is equal to the number of days between visits (inclusive 
of the day of the second visit; not to exceed the number of doses dispensed), as subjects are 
expected to take one dose per day.  If a subject is lost to follow-up between scheduled visits, 
their dosing data will be limited to the last visit at which they were present. 
The estimated number of doses taken by a subject across all visits during the treatment period is 
calculated as the sum of the number of doses taken between each consecutive pair of visits 
during the treatment period. 
The expected number of doses that should have been taken by a subject between or across visits 
is based on the expected number of days the subject should have dosed with study drug during 
the interval of interest, which in turn is based on the duration of the subject’s study participation 
during the interval (which may be shorter, for example, if the subject withdraws from the study).   
The expected number of days of dosing (and hence, expected number of doses that should have 
been taken) is calculated as the difference between the visit date of the second of the two visits 
and the study drug kit dispense date at the first of the two visits.  Note that the expected number 
of days of dosing cannot exceed the total number of doses actually dispensed (each study drug 
kit in this study contains 17 doses of study drug).  If an ET visit occurs between scheduled visits, 
the ET visit date will be used in the calculation.  If a subject is lost to follow-up between 
scheduled visits, they will be excluded from the compliance calculations for all visits occurring 
after the last visit at which they were present.  If a subject has a missed visit but has previously 
been dispensed an extra study drug kit that would have been dispensed at the missed visit, they 
will be excluded from the compliance calculations for all visits beginning with the missed visit, 
but will be included in the overall treatment period calculations described in the next paragraph. 
The dosing compliance calculation across all visits during the study treatment period will follow 
the logic described above, with the expected number of days of dosing being equal to the 
difference between the Week 6 (or ET) visit date and the study drug kit dispense date for the 
Day -1 visit. The estimated number of doses taken by a subject across all visits during the study 
is calculated as the sum of the number of doses taken between each consecutive pair of visits 
during the treatment period.  If a subject is lost to follow-up prior to Week 6, their dosing 
compliance will be based on the last study visit at which they were present.   
3.13. 
Dose Reduction Summary 
The dose reduction summaries will present the number and percentage of subjects with a dose 
reduction for each treatment group within each age group and for each of the pooled treatment 
groups at Weeks 2 and 4.  Dose reductions at unscheduled visits prior to Week 4 will be included 
in the summary for the next scheduled visit (ie, Week 2 or Week 4).  Dose reductions at 
unscheduled visits after Week 4 will be summarized as “After Week 4” in the table. The table 
will include the total number and percentage of subjects with a dose reduction at any time during 
the treatment period.  Note that these summaries include all reports of dose reductions, including 


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those for the placebo and NBI-98854 low dose treatment groups (which are not true dose 
reductions).  
3.14. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and its active metabolite NBI-98782 will be 
summarized with descriptive statistics by visit (Weeks 2, 4, 6, and 8) and the most recent NBI-
98854 dose received by a subject prior to that visit (this is due to the possibility of a subject 
having a dose reduction from 20 mg to 10 mg or from 40 mg to 20 mg).  Note that the dose level 
at the Week 8 visit will reflect the last dose the subject received during the study treatment 
period (ie, the dose level at the subject’s Week 6 visit).  These summary tables will be presented 
separately for each age group only.  There will not be a pooled treatment groups summary.   
These summaries will also be generated separately for CYP2D6 poor metabolizers vs. non-poor 
metabolizers within each age group.  
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 (%). 
Plasma concentrations of each PK analyte will be summarized with box plots by NBI-98854 
dose level at each visit. 
3.15. 
Efficacy Data 
3.15.1. 
Efficacy Endpoints 
The efficacy endpoints for this study are described in detail in the following sections of this SAP.  
An overall summary of the efficacy endpoints is presented below in Table 4. 


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Table 4: 
Efficacy Endpoints and Classification 
Efficacy Endpoint 
Endpoint Classification  
YGTSS Total Tic Score (TTS) mean change from baseline to Week 6 
Primary 
CGI-TS-Improvement mean score at Week 6 
Key secondary 
Percentage of subjects classified as YGTSS TTS responders at Week 6 
Secondary 
YGTSS Impairment score mean change from baseline to Week 6 
Secondary 
YGTSS Global Tic Severity score mean change from baseline to Week 6 
Secondary 
Rush Video-based Tic Rating Scale (RTRS) total score mean change from 
baseline to Week 6 
Secondary 
Premonitory Urge for Tics Scale (PUTS) total score mean change from 
baseline to Week 6 
Secondary 
CGI-Tics-Severity score mean change from baseline to Week 6 
Secondary 
Percentage of subjects classified as CGI-TS-Improvement responders at 
Week 6  
Secondary 
YGTSS Total Tic Score (TTS) mean change from baseline to mean of Week 
4 and Week 6 values 
Exploratory 
YGTSS Total Tic Score (TTS) mean change from baseline to Weeks 2 and 
4 
Exploratory 
CGI-TS-Improvement mean score at Weeks 2 and 4 
Exploratory 
Percentage of subjects classified as YGTSS TTS responders at Weeks 2 and 
4 
Exploratory 
YGTSS Impairment score mean change from baseline to Weeks 2 and 4 
Exploratory 
YGTSS Global Tic Severity score mean change from baseline to Weeks 2 
and 4 
Exploratory 
Premonitory Urge for Tics Scale (PUTS) total score mean change from 
baseline to Weeks 2 and 4 
Exploratory 
CGI-Tics-Severity score mean change from baseline to Weeks 2 and 4 
Exploratory 
Percentage of subjects classified as CGI-TS-Improvement responders at 
Weeks 2 and 4 
Exploratory 
 
 
 
 
 
 
 
 


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3.15.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the mean change from baseline (Day -1) to Week 
6 in the YGTSS TTS (Total Tic Score) based on the certified site rater scores.  Mean changes 
from baseline to Weeks 2 and 4 are exploratory efficacy endpoints. 
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. 
Descriptive statistics will be presented by treatment group for the TTS observed values (ie, the 
raw data) and changes from baseline at each visit from screening through Week 8 (note that 
changes from baseline will be presented only for postbaseline visits in all such summaries 
described in this SAP).  Descriptive statistics will be presented for both the ITT and the PP 
analysis sets.  These summaries will be presented by treatment group within age group and by 
pooled treatment groups.  
The primary analysis of the TTS will be a mixed-effect model repeated measures (MMRM) 
analysis, which includes the changes from baseline to Weeks 2, 4, and 6, and is based on the ITT 
analysis set.  The model will include the baseline TTS as a covariate, and age group, pooled 
treatment groups, visit (Week 2, 4, or 6), pooled treatment groups by visit interaction, and 
baseline covariate by visit interaction as fixed effects.  Subject will be included as a random 
effect.  Study site will not be included in the model, as there is a large number of sites 
(approximately 30), with most sites enrolling a small number of subjects.  
Treatment group comparisons for each NBI-98854 treatment group vs. placebo at each visit (ie, 
Weeks 2, 4, and 6) will be performed by constructing linear contrasts (or equivalent 
programming code) for differences between treatment group least-squares (LS) means.  Nominal 
two-sided p-values for testing the significance of these differences and associated 95% 
confidence intervals will be reported in summary tables; however, interpretation of the p-values 
for the two active pooled treatment group comparisons to placebo at Week 6 will be based on a 
procedure which controls for multiplicity that is described below in Section 3.15.4.  
A supportive analysis using the MMRM model will be performed with the PP analysis set. 
The MMRM analysis will be implemented with the PROC MIXED procedure of SAS®, using 
the restricted maximum likelihood method, an unstructured within-subject covariance matrix, 
and denominator degrees of freedom from the Kenward-Roger method. In the event that 
convergence is not obtained with the unstructured covariance matrix, a Toeplitz covariance 
structure will be used. 
An additional supportive analysis of the TTS change from baseline to Week 6 will be performed 
using an analysis of covariance (ANCOVA) model.  The ANCOVA model will include the 
baseline TTS as a covariate and age group and pooled treatment groups as fixed effects.  This 
analysis will be performed using both the ITT and PP analysis sets. 


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An exploratory ANCOVA will be performed for the TTS change from baseline to the mean of 
the Week 4 and Week 6 TTS values for each subject.  The ANCOVA model will be identical to 
the model described in the previous paragraph with the exception of the response variable.  Both 
ITT and PP analyses will be performed. 
Mean (±SEM) values of the TTS at each visit (Day -1 through Week 8) will be summarized in 
line graphs by treatment group.  Similar graphs will be presented for the changes from baseline.  
These graphs will be based on the ITT analysis set and will be presented by treatment group 
within age group and by pooled treatment groups. 
The LS means (±SEM) from the MMRM analysis will be summarized in line graphs by pooled 
treatment groups for both the ITT and PP analysis sets.   
An additional graph will be presented for the TTS changes from baseline to Week 6.  This will 
be a display of the empirical distribution function for each treatment group (both within age 
group and pooled), and will be based on the ITT analysis set. 
3.15.3. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint for this study is the CGI-TS-Improvement mean score at 
Week 6.  Mean scores at Weeks 2 and 4 are exploratory efficacy endpoints. 
Each of the CGI-TS-Improvement response categories will be assigned a numerical score as 
follows: 
Very much improved = 1 
Much improved = 2 
Minimally improved = 3 
Not changed = 4 
Minimally worse = 5 
Much worse = 6 
Very much worse = 7 
Descriptive statistics (including both frequency counts [using response categories] and 
continuous variable statistics [using numerical scores]) will be presented by treatment group for 
the CGI-TS-Improvement data at each visit from Week 2 through Week 8.  Descriptive statistics 
will be presented for both the ITT and the PP analysis sets.  These summaries will be presented 
by treatment group within age group and by pooled treatment groups. 
The primary analysis of the CGI-TS-Improvement numerical scores will be an MMRM analysis 
which includes the scores at Weeks 2, 4, and 6 and is based on the ITT analysis set.  The 
MMRM model will be similar to the model described above for the TTS analysis, with the 
exception that the covariate in the model will be the baseline value of the CGI-Tics-Severity 
numerical score.  As indicated above for the TTS, nominal two-sided p-values for testing the 
significance of pooled treatment group differences and associated 95% confidence intervals will 
be reported in summary tables; however, interpretation of the p-values for the two active pooled 
treatment groups comparisons to placebo at Week 6 will be based on a procedure which controls 
for multiplicity that is described below in Section 3.15.4. 
A supportive analysis of the CGI-TS-Improvement numerical scores will be performed using the 
MMRM analysis based on the PP analysis set. 


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An additional supportive analysis of the CGI-TS-Improvement numerical scores at Week 6 will 
be performed using an ANCOVA model.  The ANCOVA model will include age group and 
pooled treatment groups as fixed effects and the baseline value of the CGI-Tics-Severity 
numerical score as a covariate.  This analysis will be performed using both the ITT and PP 
analysis sets. 
Mean (±SEM) values of the CGI-TS-Improvement numerical scores at each visit will be 
summarized in line graphs by treatment group. These graphs will be based on the ITT analysis 
set and will be presented by treatment group within age group and by pooled treatment groups. 
The LS means (±SEM) from the MMRM analysis of the CGI-TS-Improvement numerical scores 
at Weeks 2 through 6 will be summarized in line graphs by pooled treatment groups for both the 
ITT and PP analysis sets. 
3.15.4. 
Procedure to Control for Multiplicity 
A fixed-sequence testing procedure will be followed for the primary and key secondary efficacy 
endpoint analyses in order to control for multiple comparisons (ie, comparing each of the two 
NBI-98854 pooled treatment groups to placebo for each of the two endpoints).  The fixed-
sequence testing procedure will consist of performing the hypothesis tests in the following pre-
specified order: 
 Week 6 TTS mean change from baseline:  NBI-98854 high dose treatment group vs. 
placebo treatment group 
 Week 6 TTS mean change from baseline:  NBI-98854 low dose treatment group vs. 
placebo treatment group 
 Week 6 CGI-TS-Improvement mean score:  NBI-98854 high dose treatment group vs. 
placebo treatment group 
 Week 6 CGI-TS-Improvement mean score:  NBI-98854 low dose treatment group vs. 
placebo treatment group 
In order for a test result in the above list to be considered statistically significant, all of the test 
results higher in the list must be significant at the 0.05 level of significance.  
3.15.5. 
Sensitivity Analyses for Primary Efficacy Endpoint 
An underlying assumption of the MMRM analysis is that missing data are considered to be 
missing at random (MAR).  In addition to assessing the number of subjects who prematurely 
discontinue from the study prior to Week 6 along with the reasons for premature study 
discontinuation, three sensitivity analyses of the TTS changes from baseline will be performed to 
assess the impact of deviations from the assumption that the missing TTS data are MAR.  These 
analyses, described below, are based on the ITT analysis set. 
Tipping Point - Sensitivity Analysis #1 
Step 1 of Sensitivity Analysis #1 (Imputation of Missing Data) 
The initial step will be to impute missing TTS values at Weeks 2, 4 and 6 using the SAS® 
procedure PROC MI.   The data will first be examined to determine if the pattern of missing data 
is monotone or non-monotone across visits from Day -1 (baseline) through Week 6.  If the 
pattern of missing data is monotone (which will be the case if the missingness is purely due to 


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dropouts) the regression method of PROC MI will be used to impute the missing data. If the 
pattern of missing data is non-monotone, the Markov chain Monte Carlo (MCMC) method of 
PROC MI will be used to create a monotone data set, using default system values for the 
parameters CHAIN, NBITER and NITER (along with IMPUTE=MONOTONE).  This data set 
can then be analyzed using the regression method of PROC MI.  In either case, 100 imputed data 
sets will be generated using a random number generator seed value of 122706.   The SAS® 
statements (or equivalent) provided below will be used for the imputation of missing data.  Note 
that “Treat” represents pooled treatment groups (placebo, NBI-98854 low dose, or NBI-98854 
high dose), “Age” is age group, “Baseline” is the Day -1 TTS value, and Week2, Week4, and 
Week6 are the TTS values at Weeks 2, 4, and 6, respectively. 
PROC MI NIMPUTE=100 SEED=122706 MINIMUM=0 MAXIMUM=50 
OUT=Imputed; 
CLASS Treat Age; 
MONOTONE REGRESSION; 
VAR Treat Age Baseline Week2 Week4 Week6; 
Step 2 of Sensitivity Analysis #1 (Creation of Additional Data Sets with NBI-98854 Treatment 
Group Imputed TTS Scores Made Worse in a Step-Wise Fashion)   
The sensitivity analysis itself will involve the creation of additional data sets based on the fully 
imputed data sets created in Step 1, with a step-wise “worsening-score” algorithm applied to the 
NBI-98854 treatment groups, but not to the placebo treatment group.  Since the primary endpoint 
is the TTS mean change from baseline to Week 6, the scores at Weeks 2 and 4, which were used 
for missing data imputation purposes, will not be used in any subsequent calculations or 
analyses.  Therefore, the worsening-score algorithm will be applied only to the NBI-98854 
treatment group imputed Week 6 TTS values (also note that the method of analysis for the 
imputed data sets described below in Step 3 is an ANCOVA of the Week 6 TTS changes from 
baseline).  
The worsening-score algorithm will involve increasing (or “worsening”) the imputed Week 6 
TTS values in the two NBI-98854 treatment groups by a percentage of the imputed value in a 
pre-specified, step-wise fashion.  Imputed Week 6 TTS values in the placebo treatment group 
will not be made worse in this algorithm and will remain at the initially imputed values. 
The initial percentage value to be applied is 10%.  This will be increased in fixed increments of 
10% until the p-value for the comparison of the NBI-98854 high dose treatment group to the 
placebo treatment group (obtained as described below in Step 3 from PROC MIANALYZE 
applied to the results of 100 ANCOVAs for each imputed data set) exceeds the 0.05 level of 
significance.  Note that the maximum possible value for the TTS is 50; therefore an imputed 
Week 6 TTS value adjusted according to this algorithm cannot exceed the value of 50. 
This sensitivity analysis represents a tipping point analysis based on “delta adjustments,” which 
is a commonly used approach to assess the impact of missing data in clinical trials (O’Kelly and 
Ratitch, 2014). 
Step 3 of Sensitivity Analysis #1 
The TTS changes from baseline to Week 6 will be calculated for each of the imputed data sets 
from the original PROC MI output and for the additional sets of data created according to the 


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worsened-score algorithm described above in Step 2.  The imputed data sets will be analyzed 
using the ANCOVA model specified above in Section 3.15.2, using either PROC MIXED or 
PROC GLM.     
PROC MIANALYZE will then be used to combine results from the 100 ANCOVAs for the 
imputed data sets to provide the following statistics: 
 LS mean for each treatment group 
 LS mean difference between each NBI-98854 treatment group and the placebo treatment 
group, along with the corresponding two-sided 95% confidence intervals and p-values 
Jump to Reference (J2R) - Sensitivity Analysis #2 
The J2R method is based on the concept that missing values for subjects in the NBI-98854 
treatment groups who drop out prior to the Week 6 visit will tend to be similar to values for 
subjects in the reference (placebo) group who have similar baseline characteristics.  This is 
plausible under the assumption that treatment with NBI-98854 offers symptomatic, and not 
disease-modifying treatment, and as such, subjects who stop taking active study drug will no 
longer benefit from its therapeutic effect, but will still be subject to any placebo (or study 
participation related) effects. 
The J2R analysis will be implemented using the SAS® procedures PROC MI and PROC 
MIANALYZE.  If the pattern of missing data across study visits during the treatment period is 
non-monotone, a monotone data set will be created using PROC MI with the MCMC method, a 
seed value of 122706, and system default values for the parameters CHAIN, NBITER, and 
NITER (along with IMPUTE=MONOTONE).  The number of imputed data sets created in this 
step will be 100. 
The actual J2R imputation will follow the sequential model approach described in Chapter 7.4.3 
of O’Kelly and Ratitch (2014).  With this approach, the placebo treatment group data are used to 
impute missing values for the NBI-98854 treatment groups, one visit at a time in a sequential 
fashion.  At each visit imputation step, PROC MI with the same seed specified in the preceding 
paragraph (and 100 imputed data sets) will be implemented, using the monotone regression 
method with age group and the baseline TTS as explanatory variables.  Note that missing data 
values in the placebo treatment group are imputed under the MAR assumption (using PROC MI 
with the monotone regression method), prior to imputing missing data values in the NBI-98854 
treatment groups. 
The final step of this analysis will consist of performing an ANCOVA analysis of the TTS 
changes from baseline to Week 6 using the imputed data sets and then combining the results of 
these analyses using PROC MIANALYZE.   
Baseline Observation Carried Forward (BOCF) – Sensitivity Analysis #3 
The use of a BOCF analysis as a sensitivity analysis is described in a publication authored by Dr. 
Lisa LaVange of the FDA/CDER Office of Biostatistics (LaVange, 2014).  This analysis will be 
implemented by imputing missing Week 6 TTS values in all three pooled treatment groups with 
the baseline values (ie, a subject’s missing Week 6 value will be set equal to their baseline 
value). The TTS changes from baseline to Week 6, including BOCF-imputed missing values for 
Week 6, will then be analyzed using the ANCOVA model, using either PROC MIXED or PROC 


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GLM.  As this is a single-imputation method, the use of PROC MI and PROC MIANALYZE is 
not required. 
3.15.6. 
Sensitivity Analysis for Key Secondary Efficacy Endpoint 
Sensitivity analyses will also be performed for the key secondary efficacy endpoint, the CGI-TS-
Improvement mean score at Week 6, using the ITT analysis set.   Tipping point and J2R analyses 
similar to those described above for the TTS will be performed, using a random number 
generator seed value of 339614 for the PROC MI part of the analyses.   
A third sensitivity analysis will be performed using a method similar in principle to the BOCF 
analysis described for the TTS.  For this sensitivity analysis, subjects whose CGI-TS-
Improvement score at Week 6 is missing will have their missing score imputed with a value of 4, 
which reflects the CGI-TS-Improvement response category of “not changed”.   This imputed 
data set will then be analyzed using an ANCOVA model.   
3.15.7. 
Secondary Efficacy Endpoints 
3.15.7.1. YGTSS TTS Responder Analysis 
A TTS responder is defined, on a per-visit basis, as a subject whose TTS value is reduced by at 
least 30% from baseline at the specified postbaseline visit. The percentage of subjects classified 
as TTS responders will be summarized for each treatment group within age group and for the 
pooled treatment groups at Weeks 2, 4, 6, and 8 for both the ITT and PP analysis sets.  
The percentage of subjects classified as TTS responders at Week 6 is a secondary efficacy 
endpoint.  An analysis comparing each pooled NBI-98854 treatment group to the pooled placebo 
treatment group will be performed for this endpoint with the ITT analysis set using the Cochran-
Mantel-Haenszel (CMH) procedure, with age group as a stratification variable.  A separate CMH 
analysis will be performed for each active treatment group comparison to placebo (NBI-98854 
high dose vs. placebo and NBI-98854 low dose vs. placebo). 
A supportive analysis of the percentage of subjects classified as TTS responders at Week 6 will 
be performed using the PP analysis set. 
The percentages of subjects classified as TTS responders at Weeks 2 and 4 are exploratory 
endpoints.  These endpoints will be analyzed using the CMH procedure at each of these visits 
with both the ITT and PP analysis sets. 
Bar graphs displaying the percentage of subjects classified as TTS responders will be presented 
by treatment group for each study visit from Week 2 through Week 8 for the ITT and PP analysis 
sets. 
3.15.7.2. YGTSS Impairment Score 
The YGTSS Impairment score can range in value from 0 to 50.  The YGTSS Impairment score 
mean change from baseline (Day -1) to Week 6 is a secondary efficacy endpoint.  Mean changes 
from baseline to Weeks 2 and 4 are exploratory efficacy endpoints. 
Descriptive statistics will be presented by treatment group within age group and by pooled 
treatment groups for the YGTSS Impairment score observed values (ie, the raw data) and 


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changes from baseline at each visit from screening through Week 8.  Descriptive statistics will be 
presented for both the ITT and the PP analysis sets.   
The analysis of the YGTSS Impairment score changes from baseline at each visit from Week 2 
through Week 6 will be performed using a MMRM model similar to the model described in 
Section 3.15.2 for the TTS change from baseline, based on the ITT analysis set.  The covariate 
for this MMRM model will be the YGTSS Impairment score at baseline.  A supportive analysis 
of the YGTSS Impairment score changes from baseline will be performed using the PP analysis. 
Mean (±SEM) values of the YGTSS Impairment score at each visit (Day -1 through Week 8) 
will be summarized in line graphs by treatment group within age group and by pooled treatment 
groups.  Similar graphs will be presented for the changes from baseline.  These graphs will be 
based on the ITT analysis set. 
The LS means (±SEM) from the MMRM analysis of the YGTSS Impairment score changes from 
baseline will be summarized in line graphs by pooled treatment group for both the ITT and PP 
analysis sets. 
3.15.7.3. YGTSS Global Tic Severity Score 
The YGTSS Global Tic Severity score is the sum of the TTS and the YGTSS 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.  
The YGTSS Global Tic Severity score mean change from baseline (Day -1) to Week 6 is a 
secondary efficacy endpoint.  Mean changes from baseline to Weeks 2 and 4 are exploratory 
efficacy endpoints.  
Descriptive statistics will be presented by treatment group within age group and by pooled 
treatment groups for the YGTSS Global Tic Severity score observed values (ie, the raw data) and 
changes from baseline at each visit from screening through Week 8.  Descriptive statistics will be 
presented for both the ITT and the PP analysis sets.   
An analysis of the YGTSS Global Tic Severity score changes from baseline to Weeks 2, 4 and 6 
will be performed using a MMRM model similar to the model described in Section 3.15.2 for the 
TTS change from baseline, based on the ITT analysis set.  The covariate for this MMRM model 
will be the YGTSS Global Tic Severity score at baseline.  A supportive analysis of the YGTSS 
Global Tic Severity scores will be performed using the PP analysis set. 
Mean (±SEM) values of the YGTSS Global Tic Severity score at each visit (Day -1 through 
Week 8) will be summarized in line graphs by treatment group within age group and by pooled 
treatment groups.  Similar graphs will be presented for the changes from baseline.  These graphs 
will be based on the ITT analysis set. 
The LS means (±SEM) from the MMRM analysis of the YGTSS Global Tic Severity score 
changes from baseline will be summarized in line graphs by pooled treatment group for both the 
ITT and PP analysis sets. 


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3.15.7.4. Rush Video-based Tic Rating Scale (RTRS) 
The modified RTRS used in this study 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. The RTRS videos for Day -1 and Week 6 (or final on-treatment visit for subjects 
who discontinue from the study prior to their scheduled Week 6 visit) will be reviewed and 
scored by a pair of blinded central raters using a consensus scoring process.  The raters will be 
blinded to both treatment and visit sequence.  The summaries and analyses of the RTRS data, 
then, will be limited to the scores recorded for these two visits for each subject.  
The RTRS total score is calculated as the sum of the 5 domain scores (number of body areas 
affected, motor tic frequency, phonic tic frequency, severity of motor tics, and severity of phonic 
tics).  The score for each domain can range from 0 to 4, for a maximum possible total score of 
20.  If any one of the 5 domains is not scored (ie, has a missing value), the total score will be set 
equal to missing.  
The RTRS total score mean change from baseline (Day -1) to Week 6 (or final on-treatment visit 
if prior to Week 6) is a secondary efficacy endpoint. 
Descriptive statistics will be presented by treatment group within age group and by pooled 
treatment groups for the RTRS total score observed values (ie, the raw data) at each visit and 
changes from baseline.  Descriptive statistics will be presented for both the ITT and the PP 
analysis sets.   
An analysis of the RTRS total score changes from baseline to Week 6 (or final on-treatment visit 
if prior to Week 6) will be performed using an ANCOVA model similar to the model described 
in Section 3.15.2 for the TTS change from baseline, based on the ITT analysis set.  The covariate 
for this analysis is the RTRS total score at baseline.  A supportive analysis of the RTRS total 
scores will be performed using the PP analysis set. 
Mean (±SEM) values of the RTRS total score for each treatment group within age group and for 
pooled treatment groups at each visit will be summarized in bar graphs.  A similar graph will be 
presented for the changes from baseline.  These graphs will be based on the ITT analysis set. 
The LS means (±SEM) from the ANCOVA analysis of the RTRS total score changes from 
baseline to Week 6 (or final on-treatment visit if prior to Week 6) will be summarized in a bar 
graph by pooled treatment group for both the ITT and PP analysis sets. 
3.15.7.5. 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 
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. 
The PUTS total score mean change from baseline (Day -1) to Week 6 is a secondary efficacy 
endpoint.  Mean changes from baseline to Weeks 2 and 4 are exploratory efficacy endpoints.  
Descriptive statistics will be presented by treatment group within age group and by pooled 
treatment groups for the PUTS total score observed values (ie, the raw data) and changes from 
baseline at each visit from screening through Week 8.  Descriptive statistics will be presented for 
both the ITT and the PP analysis sets.   


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An analysis of the PUTS total score changes from baseline to Weeks 2, 4, and 6 will be 
performed using a MMRM model similar to the model described in Section 3.15.2 for the TTS 
change from baseline, based on the ITT analysis set.  The covariate for this MMRM analysis is 
the PUTS total score at baseline.  A supportive analysis of the PUTS total scores will be 
performed using the PP analysis set. 
Mean (±SEM) values of the PUTS total score at each visit (Day -1 through Week 8) will be 
summarized in line graphs by treatment group within age group and by pooled treatment groups.  
Similar graphs will be presented for the changes from baseline.  These graphs will be based on 
the ITT analysis set. 
The LS means (±SEM) from the MMRM analysis of the PUTS total score changes from baseline 
to Weeks 2, 4 and 6 will be summarized in line graphs by pooled treatment group for both the 
ITT and PP analysis sets. 
3.15.7.6. 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 
The CGI-Tics-Severity numerical score mean change from baseline (Day -1) to Week 6 is a 
secondary efficacy endpoint.  Mean changes from baseline to Weeks 2 and 4 are exploratory 
efficacy endpoints.  
Descriptive statistics (including both frequency counts [using response categories] and 
continuous variable statistics [using numerical scores]) will be presented by treatment group 
within age group and by pooled treatment groups for the CGI-Tics-Severity data at each visit 
from screening through Week 8.  Changes from baseline for the numerical scores will be 
summarized also.  Descriptive statistics will be presented for both the ITT and the PP analysis 
sets.  
An analysis of the CGI-Tics-Severity numerical score changes from baseline to Weeks 2, 4, and 
6 will be performed using a MMRM model similar to the model described in Section 3.15.2 for 
the TTS changes from baseline, based on the ITT analysis set.  The covariate for this MMRM 
analysis is the CGI-Tics-Severity numerical score at baseline.  A supportive analysis of the CGI-
Tics-Severity numerical scores will be performed using the PP analysis set. 
Mean (±SEM) values of the CGI-Tics-Severity numerical scores at each visit (Day -1 through 
Week 8) will be summarized in line graphs by treatment group within age group and by pooled 
treatment groups.  Similar graphs will be presented for the changes from baseline.  These graphs 
will be based on the ITT analysis set. 


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The LS means (±SEM) from the MMRM analysis of the CGI-Tic-Severity numerical score 
changes from baseline to Weeks 2, 4, and 6 will be summarized in line graphs by pooled 
treatment group for both the ITT and PP analysis sets. 
3.15.7.7. CGI-TS-Improvement Responder Analysis 
A subject is classified as a CGI-TS-Improvement responder at a given visit if their CGI-TS-
Improvement score is either a “1” (“very much improved”) or a “2” (“much improved”) at the 
visit.  
The number and percentage of CGI-TS-Improvement responders will be summarized by 
treatment group within age group and by pooled treatment groups at Weeks 2, 4, 6, and 8.  The 
CGI-TS-Improvement responder summary statistics will be presented for both the ITT and the 
PP analysis sets.   
The percentage of subjects classified as CGI-TS-Improvement responders at Week 6 is a 
secondary efficacy endpoint.  An analysis comparing each pooled NBI-98854 treatment group to 
the pooled placebo treatment group will be performed for this endpoint with the ITT analysis set 
using the CMH procedure, with age group as a stratification variable.  A separate CMH analysis 
will be performed for each active treatment group comparison to placebo (NBI-98854 high dose 
vs. placebo and NBI-98854 low dose vs. placebo). 
A supportive analysis of the percentage of subjects classified as CGI-TS-Improvement 
responders at Week 6 will be performed using the PP analysis set. 
The percentages of subjects classified as CGI-TS-Improvement responders at Weeks 2 and 4 are 
exploratory endpoints.  These endpoints will be analyzed using the CMH procedure at each of 
these visits with both the ITT and PP analysis sets. 
Bar graphs displaying the percentage of subjects classified as CGI-TS-Improvement responders 
at Weeks 2 through 8 will be presented by treatment group within age group and by pooled 
treatment groups for the ITT and the PP analysis sets. 
An additional analysis of the CGI-TS-Improvement responder rates at Week 6 will be performed 
which incorporates an imputed value of “non-responder” for subjects in the ITT analysis set with 
missing values at the Week 6 timepoint.  This analysis can be considered as a sensitivity analysis 
with regard to the potential issue of missing data in interpreting the Week 6 analysis results for 
the CGI-TS-Improvement data.  
3.16. 
Safety Data 
3.16.1. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is any reaction, side effect, or other untoward 
event, regardless of relationship to study drug, that is newly reported or considered a worsening 
or change in nature, severity, or frequency of conditions present at the start of the study which 
occurs any time after first dose of study drug. 
TEAEs, categorized by MedDRA (Version 12.0) system organ class (SOC) and preferred term 
(PT), will be summarized by treatment group within age group and by pooled treatment groups 
in frequency tables.  Each table will also include a separate column for all NBI-98854 treated 
subjects (ie, excluding placebo subjects).  Unless stated otherwise, the frequency tables will 


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include the number of events reported, and the number and percentage of unique subjects 
experiencing each event one or more times during the study.  SOCs will be displayed in order of 
decreasing frequency (number of subjects with TEAEs in the SOC based on the “all NBI-98854 
treated subjects” column), and within each SOC, PTs will be displayed in a similar fashion in 
order of decreasing frequency of subjects with TEAEs in the PT based on the “all NBI-98854 
treated subjects” column. 
Two versions of the primary TEAE frequency table will be presented:  (a) the first version as 
described above which includes both SOC and PT, with each sorted in decreasing frequency 
based on the “all NBI-98854 treated subjects” column, and (b) a second version which does not 
include SOCs but does include PTs sorted in decreasing frequency based on the “all NBI-98854 
treated subjects” column.  
Frequency tables will also be presented including only TEAEs considered to be possibly or 
definitely related to study drug and, in addition, categorizing TEAEs according to the maximum 
intensity reported for a given subject.  These tables will include both SOC and PT. 
AEs with an onset date during screening (prior to study drug dosing) will be presented only in a 
data listing. 
3.16.1.1. Adverse Event Overall Summary 
An overall summary table will be provided for each treatment group summary (by treatment 
group within age group and by pooled treatment groups) which summarizes the number and 
percentage of subjects with any TEAE, any treatment-related TEAE (ie, possibly or definitely 
related), any severe TEAE, any TEAE leading to dose reduction, any TEAE leading to study 
discontinuation, any serious TEAE, and any TEAE resulting in death.  These tables will include 
an “all NBI-98854 treated subjects” column. 
3.16.1.2. Adverse Events Resulting in Premature Study Discontinuation 
Summary tables of TEAEs resulting in premature study discontinuation will be presented by 
treatment group within age group and by pooled treatment groups.  These summary tables will 
display the PTs for the TEAEs resulting in study discontinuation, with the PTs sorted in order of 
decreasing frequency in the “all NBI-98854 treated subjects” column.  The first line of each table 
will display the overall frequency for each treatment group column. 
A listing of TEAEs resulting in premature study discontinuation will be provided which includes 
age group, subject, treatment group, last treatment received prior to the onset time of the 
TEAE(s) leading to discontinuation, study day of the discontinuation, and other information from 
the AE eCRF.  Note that “last treatment received prior to the onset time of the TEAE[s] leading 
to discontinuation” reflects the reduced dose for subjects with a dose reduction prior to study 
discontinuation. 
3.16.1.3. Adverse Events Resulting in Study Drug Dose Reductions 
Summary tables of TEAEs resulting in study drug dose reductions will be presented by treatment 
group within age group and by pooled treatment groups.  Note that subjects randomized to the 
placebo and NBI-98854 low dose treatment groups who have a reported dose reduction actually 
remain on the randomized dose, while subjects randomized to the NBI-98854 high dose 
treatment groups will have an actual dose reduction. 


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These summary tables will display the PTs for the TEAEs resulting in a dose reduction, with the 
PTs sorted in order of decreasing frequency in the “all NBI-98854 treated subjects” column.  The 
first line of each table will display the overall frequency for each treatment group column. 
A listing of TEAEs resulting in study drug dose reductions will be provided.  This listing will 
include age group, subject, treatment group, study day of the dose reduction, and additional 
information from the AE eCRF.  
 
3.16.1.4. Deaths and Other Serious Adverse Events  
The frequency of serious TEAEs will be summarized in tables using the table format described 
above for the summary of TEAEs leading to study discontinuation.  Deaths will be presented in a 
listing only.   
Listings of all SAEs and deaths will be provided which include age group, subject, treatment 
group, last treatment received prior to the onset time of the SAE or TEAE leading to death, study 
day of the SAE or death, and additional information from the AE eCRF. 
3.16.2. 
Clinical Laboratory Data 
The hematology, clinical chemistry, and prolactin data will be summarized with descriptive 
statistics by treatment group within age group and by pooled treatment groups at each scheduled 
visit from screening (from Day -1 for prolactin) through Week 8.  Both observed values and 
changes from baseline (Day -1) will be summarized.   
The prolactin data at each scheduled visit will be summarized by treatment group within age 
group and by pooled treatment groups for each gender separately, in addition to the summaries 
described above. 
Shift tables will be presented for selected clinical laboratory variables based on the reference 
range-based categories of “Low,” “Normal,” or “High.”  A clinical laboratory variable value will 
be assigned to one of these three categories according to the reference ranges provided by the 
central clinical laboratory.  Shift tables will be presented by treatment group within age group 
and by pooled treatment groups. 
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 Week 6.  Subjects 
with missing data for a clinical laboratory variable at either baseline or at Week 6 will not be 
included in tables for that variable.  The number and percentage of subjects in each shift category 
will be displayed in the table. 
Shift tables will be presented for the following clinical laboratory variables: aspartate 
transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), total 
bilirubin, creatine kinase, creatinine, blood urea nitrogen, prolactin, white blood cell count, 
absolute neutrophil count, hemoglobin, and platelet count. 
Summaries of sponsor-defined potentially clinically significant (PCS) values will be presented 
for the following clinical laboratory variables:  ALT, AST, creatinine kinase, GGT, total 
bilirubin, white blood cell count, absolute neutrophil count, creatinine, and BUN.  The number 
and percentage of subjects with PCS values that are reported at any postbaseline visit (scheduled 


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or unscheduled) will be summarized by treatment group within age group and by pooled 
treatment groups.  The criteria for identifying PCS clinical laboratory values are provided in 
Table 5. 
Table 5: 
Potential Clinically Significant Criteria for Clinical Laboratory Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 
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 subjects with PCS values at any postbaseline visits for any of the variables listed in 
the table above will be presented.  The listing will include age group, subject, treatment group, 
visit, study day, and, for each subject, all laboratory results (including all scheduled and 
unscheduled visits) for the variables with a PCS value for that subject.  Values that meet the PCS 
criteria will be flagged with an asterisk in the listing. 
Scatter plots of selected variables will be created which display Week 6 values vs. baseline 
values.  Each plot will include a 45 degree (“y=x”) reference line.  The plots will be generated 
for ALT, AST, creatine kinase, GGT, total bilirubin, and prolactin by treatment group within age 
group and by pooled treatment groups. 
Additional graphs will be presented for the prolactin data.  These graphs will display mean 
(±SEM) prolactin values by treatment group within age group and by pooled treatment groups at 
each scheduled visit (Day -1 through Week 8) in a line graph layout.  A separate graph will be 
presented for each gender. 
The clinical laboratory data listings will include associated reference ranges if available.  In 
addition, values outside the reference 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 for summarizing these data is to include the 
original sample results in summary tables and graphs.  One exception to this rule is when there 
are missing results from the original samples at screening – in this situation, the results of a 


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repeat screening sample will be substituted for the missing results in summary tables and graphs.  
All sample results (original and repeat) will be included in data listings. 
3.16.3. 
Physical Examination and Weight 
Clinically significant physical examination findings will be presented by subject and visit in a 
listing.  The listing will include age group, subject, treatment group, visit at which the finding 
was reported, study day, 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 [Day -1]) 
by treatment group within age group and by pooled treatment groups at each scheduled visit 
from screening through Week 8. 
3.16.4. 
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 by treatment group 
within age group and by pooled treatment groups at each scheduled visit from screening through 
Week 8.  Both observed values and changes from baseline (Day -1) will be summarized. 
Sponsor-defined PCS values for systolic blood pressure, diastolic blood pressure, and heart rate 
will be summarized by treatment group within age group and by pooled treatment groups.  The 
number and percentage of subjects with PCS values at any postbaseline visit (scheduled or 
unscheduled) will be presented in the summary tables.  The criteria for identifying PCS vital 
signs values for each age group are provided in Table 6. 
Table 6: 
Potentially Clinically Significant Criteria for Vital Signs 
Children 
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 
  N/A 
 
≥20 mmHg 
>130 mmHg 
 
≥20 mmHg 
Diastolic Blood 
Pressure 
  N/A 
 
≥10 mmHg 
>85 mmHg 
 
≥10 mmHg 
Heart Rate 
  N/A 
 
≥15 bpm 
>130 bpm 
 
≥10 bpm 
Adolescents 
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 
  N/A 
 
≥20 mmHg 
>145 mmHg 
 
≥20 mmHg 


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Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Diastolic Blood 
Pressure 
  N/A 
 
≥10 mmHg 
>90 mmHg 
 
≥10 mmHg 
Heart Rate 
  N/A 
 
≥15 bpm 
>110 bpm 
 
≥10 bpm 
Note that both supine and standing values of blood pressures and heart rate at all postbaseline 
visits will be included in the identification and summary of PCS values. 
A listing of vital signs data at all visits (scheduled and unscheduled) for subjects with PCS values 
will be presented.  The listing will include age group, subject, treatment group, visit, study day, 
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. 
3.16.5. 
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) by treatment group within age group and by pooled 
treatment groups at each scheduled visit from screening through Week 8.  Both observed values 
and changes from baseline (Day -1) will be summarized (for the overall categorical assessment, 
only observed values will be summarized).   
Categorical summaries will be presented for the QT and QTcF interval data.  For these 
summaries, a subject’s highest reported postbaseline value (including values reported at 
unscheduled visits) will be used to determine in which category(s) the subject will be counted.   
Two categorical summaries will be presented for the QT and QTcF intervals (each interval will 
be summarized separately).  For the first summary, the number and percentage of subjects in 
each treatment group within age group and in each of the pooled treatment groups whose highest 
reported QT/QTcF postbaseline value meets the following thresholds will be summarized: 
 Greater than 450 msec 
 Greater than 480 msec 
 Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects in each 
treatment group within age group and in each of the pooled treatment groups whose largest 
QT/QTcF increase from their baseline value meets the following thresholds:  
 Greater than 30 msec 
 Greater than 60 msec 


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3.16.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions (C-SSRS) 
The C-SSRS data will be presented in the following summaries: 
 Screening/lifetime assessment by treatment group within age group, by pooled treatment 
groups, and for all subjects combined. 
 Screening/past 1 year assessment by treatment group within age group, by pooled 
treatment groups, and for all subjects combined. 
 Baseline (Day -1) assessment by treatment group within age group, by pooled treatment 
groups, and for all subjects combined. 
 All postbaseline assessments (Day 1 through Week 8, including unscheduled visit 
assessments) by treatment group within age group and by pooled treatment groups. 
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category).  These C-SSRS items and categories are as follows: 
 Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
 Suicidal Ideation Category:  Any of items (1) through (5) 
 Suicidal Behavior Items (not reported for the Screening/past 1 year assessment) 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(10) 
Completed suicide 
 Suicidal Behavior Category:  Any of items (6) through (10) 
 Suicidal Ideation or Behavior Category:  Any of items (1) through (10) 
For the “all postbaseline assessments” summary, each subject’s C-SSRS responses for all 
postbaseline assessments during the study will be evaluated, and a “Yes” response 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 baseline scores will be presented.  The shift table scores are defined as the 
following: 
0=No suicidal ideation 
1=Wish to be dead 
2=Non-specific active suicidal thoughts 
3=Active suicidal ideation with any methods (not plan) without intent to act 
4=Active suicidal ideation with some intent to act, without specific plan 
5=Active suicidal ideation with specific plan and intent 


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The shift tables will display the number and percentage of subjects within each cell of a 6 x 6 
table for each treatment group within age group and for each of the pooled treatment groups, 
with the rows representing the baseline score and the columns representing the maximum score 
recorded across all postbaseline assessments (including both scheduled and unscheduled visits). 
Subjects missing either a baseline score or all postbaseline scores will not appear in the table.  
A summary listing of individual subject data will be presented for the C-SSRS which lists data at 
all visits for subjects with a positive response for suicidal ideation, suicidal behavior, or self-
injurious behavior without suicidal intent at any postbaseline assessment during the study.   The 
listing will be in the form of a table, with each row representing a subject visit (scheduled and 
unscheduled).  The listing will include age group, subject, treatment group, visit, timepoint (for 
screening assessments), study day of the 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). 
3.16.7. 
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
Amendment 2 of the clinical study protocol added the ESRS-A assessment tool to evaluate 
extrapyramidal symptoms, therefore it is expected that data will be available for all subject visits 
that take place after the date of the IRB approval at each site. 
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 ESRS-A is administered at baseline (Day -1) 
and at Weeks 2, 4, 6, and 8. 
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 
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. 
Each of the subscale scores for parkinsonism, akathisia, dystonia, and tardive dyskinesia, and the 
overall total score at each visit will summarized with descriptive statistics by treatment group 
within age group and by pooled treatment groups. Changes from baseline at each postbaseline 
visit will also be summarized. 
The CGI-S scores for each subscale at each visit will summarized with descriptive statistics by 
treatment group within age group and by pooled treatment groups. Changes from baseline at 
each postbaseline visit will also be summarized. 


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3.16.8. 
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 subtotal scores for obsession and compulsion, and the total score at each visit (screening, 
Day -1, Weeks 2, 4, 6, and Week 8) will summarized with descriptive statistics by treatment 
group within age group and by pooled treatment groups.  Changes from baseline (Day -1) at each 
postbaseline visit will also be summarized. 
3.16.9. 
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 with the exception of items 4, 5, and 16, which range 
from 1 to 5.  The maximum possible total score is 113.  If any one of the 17 items is not scored 
(ie, has a missing value), the total score will be set equal to missing. 
The total score at each visit (screening, Day -1, and Weeks 2, 4, 6, and 8) will be summarized 
with descriptive statistics by treatment group within age group and by pooled treatment groups.  
Changes from baseline (Day -1) at each postbaseline visit will also be summarized. 
3.16.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale IV: Home Version 
The ADHD Rating Scale-IV: Home Version will be used to determine the frequency and severity 
of ADHD symptoms and impairments over the 2 weeks prior to each visit.  The 18-item scale 
consists of 2 subscale scores: Inattention (the sum of the item scores for the odd-numbered 9 
items) and Hyperactivity-Impulsivity (the sum of the item scores for the even-numbered 9 
items), 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. 
The Inattention and Hyperactivity-Impulsivity subscale scores, as well as the Total Scale raw 
score at each visit (screening, Day -1, and Weeks 2, 4, 6, and 8), will be summarized with 
descriptive statistics by treatment group within age group and by pooled treatment groups.  
Changes from baseline (Day -1) at each postbaseline visit will also be summarized.  


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3.16.11. 
Prior and Concomitant Medications 
Prior medications and concomitant medications will be summarized 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.  
Medications will be assigned to one or two study periods (prestudy or during screening vs. 
during the treatment or posttreatment follow-up periods) based on the medication start and stop 
dates relative to study drug dosing. For example, medications that were started and stopped prior 
to the date of the first dose of study drug will be assigned to the prestudy/screening period only, 
while medications started prior to the first dose of study drug and either stopped during the study 
or indicated as “ongoing” will be assigned to both the prestudy/screening and treatment period. 
A given medication can therefore be assigned to one or two study periods in the tabular 
summaries, depending on its start and end dates.  
The number and percentage of subjects using medications in each WHO Drug ATC category 
(Level 3/preferred name) will be summarized by treatment group and study period as described 
in the next paragraph. A subject may take the same medication more than once or multiple 
medications for a subject may be classified under the same ATC level or preferred name. A 
subject is counted only once for each level of medication classification within a summary.  
The summary of medications taken prestudy or during screening will be presented by treatment 
group within age group and by pooled treatment groups.  An “all subjects” column will be 
included in these summaries.  Medications taken during the study after the initiation of dosing 
(ie, during the treatment or posttreatment follow-up periods) will be summarized by treatment 
group within age group and by pooled treatment groups. 
3.17. 
Additional Data Presentations 
3.17.1. 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria confirmation results will be presented in a data listing by subject. 
3.17.2. 
Serology Test Results 
Serology assessments (ie, Human immunodeficiency virus antibody [HIV-Ab], Hepatitis B 
surface antigen [HBsAg], and Hepatitis C antibody [HCV-Ab]) collected at screening will be 
reviewed at the study site to ensure the entry criteria are met.  The HBsAg and HCV-Ab test 
results will be presented in a listing by subject.  The results of the HIV-Ab test will not be listed, 
but will be kept on file at the study site. 
3.17.3. 
Pregnancy Test Results 
Serum and urine pregnancy test results will be presented in a listing by subject. 
3.17.4. 
Urine Drug Screen and Alcohol Breath Test 
Urine drug screen and alcohol breath test results for adolescents only will be presented in a 
listing by subject. 


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4. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS 
The methods of analysis described in this SAP are generally consistent with the methods 
described in the clinical study protocol (Amendment 2).   One important change from the 
protocol is specification of the mean CGI-TS-Improvement score at Week 6 as the key secondary 
efficacy endpoint.   In addition, sensitivity analyses have been added to the SAP for the primary 
and key secondary efficacy endpoints, and a procedure to control for multiplicity has been 
included with respect to the primary and key secondary efficacy endpoints.  The RTRS total 
score method of analysis has been changed from the MMRM to the ANCOVA, as the RTRS 
videos will be scored at a single postbaseline visit.  The SAP also includes additional endpoints 
and data summaries not mentioned in the study protocol, including the TTS responder analysis 
and the PCS value summaries for clinical laboratory data and vital signs. 
5. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS 
The analysis and summary of data from this study will be performed using SAS® 9.3 (or a later 
release if available).  All SAS® programs used in the production of statistical analyses, tables, 
listings, and figures 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, listings, and statistical analysis output 
will be independently reviewed for completeness and accuracy. 


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6. 
REFERENCES 
ClinicalTrials.gov Identifier: NCT01727700. Otsuka Pharmaceutical Development & 
Commercialization, Inc. Study evaluating the safety and efficacy of fixed-dose once-daily 
aripiprazole in children and adolescents with Tourette’s Disorder 
https://www.clinicaltrials.gov/ct2/show/NCT01727700?term=NCT01727700&rank=1 [Accessed 
05 June 2015]. 
Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled 
study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psychiatry. 2010 
Jan;81(1):70-3. 
LaVange LM.  The role of statistics in regulatory decision making.  Therapeutic Innovation and 
Regulatory Science.  2014; 48(1) 10-19. 
O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. West 
Sussex, United Kingdom: John Wiley & Sons, Ltd. 2014; 292-297, 309-310. 
Yoo HK, Joung YS, Lee JS, Song DH, Lee YS, Kim JW, et al. A multicenter, randomized, 
double-blind, placebo-controlled study of aripiprazole in children and adolescents with 
Tourette’s disorder. J Clin Psychiatry. 2013;74(8):e772-80.