A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose Optimization Study to Assess the Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
Phase: PHASE2
Conditions: Tourette Syndrome
Sponsor: Neurocrine Biosciences

1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
 
Amendment No. 2 Final Version Date:  31 July 2018 
Amendment No. 1 Final Version Date:  19 October 2017 
Original Final Version Date:  26 July 2017 
 
A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose 
Optimization Study to Assess the Safety, Tolerability, and Efficacy of NBI-
98854 for the Treatment of Pediatric Subjects with Tourette Syndrome 
 
Study No.:  NBI-98854-TS2003 
 
Development Phase:  Phase 2b 
 
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no unpublished information contained herein will be published or disclosed without prior 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) (Harmonised) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA); Health Canada. 
 
CLINICAL STUDY TITLE: 
A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose Optimization Study to 
Assess the Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric 
Subjects with Tourette Syndrome 
 
PROTOCOL No.: 
NBI-98854-TS2003 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
Neurocrine Biosciences, Inc., Study No. NBI-98854-TS2003 
Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
Confidential
Page 2

Neurocrine Biosciences, Inc., Study No. NBI-98854-TS2003 
Clinical Study Protocol Amendment No. 2 Final Version 
Accepted for the Sponsor: 
SPONSOR: 
Jj3\ 
Date 
31July2018 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Phone: (858) 617-7600 
Facsimile: (858) 617-7705 
Confidential 
Page 3 

LIST OF SPONSOR PERSONNEL 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Medical Monitor:  
Telephone: 
Facsimile: 
Cell Phone: 
Vice President, Clinical Development:  
Telephone: 
Facsimile:  
Serious Adverse Event Report ng:
Telephone: 
Facsimile:  
Email:  
 
 
Neurocrine Biosciences, Inc., Study No. NBI-98854-TS2003 
Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
Confidential
Page 4

TABLE OF CONTENTS  
1. 
TITLE PAGE ................................................................................................. 1 
2. 
SYNOPSIS .................................................................................................. 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............. 14 
4. 
ETHICS ....................................................................................................... 16 
5. 
INTRODUCTION ....................................................................................... 16 
5.1. 
Background .................................................................................................. 16 
5.2. 
NBI-98854 ................................................................................................... 17 
5.3. 
Study and Dose Rationale ............................................................................ 19 
6. 
STUDY OBJECTIVES ............................................................................... 20 
7. 
OVERVIEW OF STUDY DESIGN ............................................................ 20 
8. 
STUDY POPULATION .............................................................................. 24 
8.1. 
Inclusion Criteria ......................................................................................... 24 
8.2. 
Exclusion Criteria ........................................................................................ 25 
8.3. 
Subject Identification and Replacement ...................................................... 27 
8.4. 
Randomization ............................................................................................. 27 
9. 
STUDY EVALUATIONS ........................................................................... 27 
9.1. 
Schedule of Assessments ............................................................................. 27 
9.2. 
Screening and Baseline Assessments .......................................................... 30 
9.2.1. 
Genotyping .................................................................................................. 30 
9.3. 
Efficacy Assessments .................................................................................. 30 
9.3.1. 
Yale Global Tic Severity Scale .................................................................... 30 
9.3.2. 
Premonitory Urge for Tics Scale ................................................................. 30 
9.3.3. 
Clinical Global Impression Scales ............................................................... 31 
9.3.4. 
Gilles de la Tourette Syndrome-Quality of Life for Children and 
Adolescents .................................................................................................. 31 
9.4. 
Pharmacokinetic Evaluations ....................................................................... 31 
9.5. 
Safety Assessments ...................................................................................... 32 
9.5.1. 
Data Safety Monitoring Board..................................................................... 32 
9.5.2. 
Vital Sign Measurements ............................................................................. 32 
9.5.3. 
Medical History ........................................................................................... 32 
9.5.4. 
Physical Examination, Including Height and Weight.................................. 33 
9.5.5. 
Electrocardiogram ........................................................................................ 33 
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9.5.6. 
Clinical Laboratory Assessments ................................................................ 33 
9.5.7. 
Columbia-Suicide Severity Rating Scale Children’s Versions ................... 34 
9.5.8. 
Children’s Depression Rating Scale-Revised .............................................. 35 
9.5.9. 
Children’s Yale-Brown Obsessive Compulsive Scale ................................ 35 
9.5.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale-5:  Home Version . 35 
9.5.11. 
Extrapyramidal Symptom Rating Scale-Abbreviated ................................. 35 
9.5.12. 
Estimated Total Blood Sample Volume Required by Study ....................... 35 
9.6. 
Specific Study Information .......................................................................... 36 
9.6.1. 
Screening (Days -28 to -1) ........................................................................... 36 
9.6.2. 
Day 1 (Baseline Assessments and Start of Dosing) ..................................... 37 
9.6.3. 
Dose Optimization Period:  Weeks 2, 4, and 6 (-2 to +3 Days for Each 
Visit) ............................................................................................................ 38 
9.6.4. 
Dose Maintenance Period:  Weeks 8, 10, and 12 (-2 to +3 Days for Each 
Visit) ............................................................................................................ 40 
9.6.5. 
Follow-Up Period/Early Termination:  Week 14 (-2 to +3 Days) ............... 41 
9.7. 
Study Duration ............................................................................................. 41 
9.8. 
Prohibitions and Restrictions ....................................................................... 42 
9.8.1. 
Prior and Concomitant Medications ............................................................ 42 
9.8.2. 
Dietary Restrictions ..................................................................................... 42 
9.8.3. 
Other Restrictions ........................................................................................ 42 
9.9. 
Withdrawal Criteria ..................................................................................... 43 
9.9.1. 
Handling of Withdrawals ............................................................................. 43 
9.9.2. 
Sponsor’s Termination of Study .................................................................. 43 
10. 
STUDY DRUG ............................................................................................ 44 
10.1. 
Study Drug Supplies .................................................................................... 44 
10.2. 
Study Drug Storage...................................................................................... 44 
10.3. 
Study Drug Packaging and Labeling ........................................................... 45 
10.4. 
Blinding ....................................................................................................... 45 
10.5. 
Study Drug Administration.......................................................................... 45 
10.6. 
Drug Compliance and Accountability ......................................................... 45 
10.7. 
Study Drug Return ....................................................................................... 46 
11. 
ADVERSE EVENTS................................................................................... 46 
11.1. 
Definition ..................................................................................................... 46 
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31 July 2018
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11.2. 
Intensity of Adverse Events ......................................................................... 47 
11.3. 
Relationship to Study Drug ......................................................................... 47 
11.4. 
Recording Adverse Events .......................................................................... 48 
11.5. 
Post-Study Follow-Up of Adverse Events ................................................... 48 
11.6. 
Serious Adverse Events ............................................................................... 49 
11.6.1. 
Definition of a Serious Adverse Event ........................................................ 49 
11.6.2. 
Managing Serious Adverse Events .............................................................. 49 
11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .......................................................................................................... 50 
11.6.4. 
Expedited Safety Reports ............................................................................ 50 
11.7. 
Pregnancy .................................................................................................... 50 
12. 
DOCUMENTATION OF DATA ................................................................ 51 
12.1. 
Case Report Form ........................................................................................ 51 
12.2. 
Data Capture, Review, and Validation ........................................................ 51 
12.3. 
Coding Dictionaries ..................................................................................... 52 
13. 
STATISTICAL AND ANALYTICAL PLAN ............................................ 52 
13.1. 
Analysis Sets ................................................................................................ 53 
13.2. 
Sample Size ................................................................................................. 53 
13.3. 
Handling of Missing Data ............................................................................ 53 
13.4. 
Enrollment and Disposition of Subjects ...................................................... 54 
13.5. 
Demographics and Baseline Characteristics ................................................ 54 
13.6. 
Study Drug Dosing and Compliance ........................................................... 54 
13.7. 
Pharmacokinetic Data .................................................................................. 54 
13.8. 
Efficacy Data ............................................................................................... 54 
13.8.1. 
Primary Efficacy Endpoint .......................................................................... 54 
13.8.2. 
Secondary Efficacy Endpoints ..................................................................... 55 
13.8.3. 
Procedure to Control for Multiple Comparisons ......................................... 56 
13.8.4. 
Exploratory Efficacy Endpoints .................................................................. 57 
13.9. 
Safety Data................................................................................................... 57 
13.10. 
Software ....................................................................................................... 57 
13.11. 
Interim Analysis........................................................................................... 57 
14. 
REGULATORY AND ETHICAL ISSUES ................................................ 57 
14.1. 
General Legal References ............................................................................ 57 
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14.2. 
Institutional Review Board .......................................................................... 58 
14.3. 
Protocol Adherence and Amendments ........................................................ 58 
14.4. 
Required Documents ................................................................................... 58 
14.5. 
Informed Consent ........................................................................................ 58 
14.6. 
Study Monitoring ......................................................................................... 59 
14.7. 
Quality Assurance ........................................................................................ 59 
14.8. 
Record Retention ......................................................................................... 59 
14.9. 
Confidentiality ............................................................................................. 59 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION ..................... 60 
16. 
REFERENCES ............................................................................................ 61 
17. 
APPENDICES ............................................................................................. 63 
17.1. 
Yale Global Tic Severity Scale (YGTSS) ................................................... 63 
17.2. 
Premonitory Urge for Tics Scale (PUTS) .................................................... 68 
17.3. 
Clinical Global Impression of Tics (CGI-Tics) – Severity .......................... 70 
17.4. 
Clinical Global Impression of Tourette Syndrome (CGI-TS) – Improvement 
scale ............................................................................................................. 72 
17.5. 
Gilles de la Tourette Syndrome-Quality of Life for Children and 
Adolescents .................................................................................................. 74 
17.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Baseline/Screening Version ......................................................................... 80 
17.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since Last 
Visit Version ................................................................................................ 84 
17.8. 
Children’s Depression Rating Scale, Revised (CDRS-R) ........................... 88 
17.9. 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) ........... 93 
17.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale-5: Home Version 117 
17.11. 
Extrapyramidal Symptom Rating Scale-Abbreviated ............................... 122 
 
LIST OF TABLES 
Table 1: 
Treatment by Weight Group ........................................................................ 20 
Table 2: 
Schedule of Assessments ............................................................................. 28 
Table 3: 
Estimated Total Blood Sample Volume ...................................................... 36 
Table 4: 
Intensity of Adverse Events ......................................................................... 47 
Table 5: 
Relationship of Adverse Events to Study Drug ........................................... 48 
 
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Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
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LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................. 23 
Neurocrine Biosciences, Inc., Study No. NBI-98854-TS2003 
Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
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2. 
SYNOPSIS 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose Optimization Study to Assess the 
Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects with Tourette 
Syndrome 
Study Centers:  Approximately 55 study centers in North America. 
Objectives: 
Primary: 
• 
To evaluate the efficacy of NBI-98854, titrated to the subject's optimal dose in the range of 20 mg to 
60 mg for subjects <50 kg and 40 mg to 80 mg for subjects ≥50 kg, administered once daily (qd) for 
the treatment of Tourette syndrome (TS). 
Secondary:  
• 
To evaluate the safety and tolerability of NBI-98854, titrated to the subject's optimal dose in the 
range of 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg for subjects ≥50 kg, administered 
once daily. 
• 
To evaluate plasma exposure measures of NBI-98854 and its active metabolite, NBI-98782, 
following titrated doses of NBI-98854 from 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg 
for subjects ≥50 kg.  
Methodology:  This is a Phase 2b, randomized, double-blind, placebo-controlled, dose-optimization 
study to evaluate the efficacy, safety, and tolerability of NBI-98854 titrated to the subject’s optimal dose 
in the range of 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg for subjects ≥50 kg compared to 
placebo, administered qd for a total of 12 weeks of treatment in pediatric subjects with TS.  
Approximately 120 male and female pediatric 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.  There will be an approximately equal distribution of subjects in each weight group, <50 kg 
and ≥50 kg, enrolled into the study and subjects will be stratified based on their weight.  Eligible 
subjects will be randomized in a 1:1 ratio to NBI-98854 or placebo treatment as depicted in the 
following table: 
Weight Group 
 
Assigned Treatment 
Number of Subjects 
(approximate) 
Subjects <50 kg at baseline 
 
Placebo 
30 
 
NBI-98854 (20 to 60 mg) 
30 
Subjects ≥50 kg at baseline 
 
Placebo 
30 
 
NBI-98854 (40 to 80 mg) 
30 
For subjects randomized to active treatment, the starting dose will be NBI-98854 20 mg for subjects 
<50 kg at baseline and NBI-98854 40 mg for subjects ≥50 kg at baseline, which may be escalated in 
increments of 20 mg every 2 weeks to a maximum of 60 mg for subjects <50 kg and 80 mg for subjects 
≥50 kg to achieve an optimal dose of NBI-98854 for each subject.  To maintain the study blind, subjects 
randomized to placebo in each weight group will be subjected to the same dose escalation requirements 
but will receive only placebo during the treatment period.   
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Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
Confidential
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Dose escalations will occur at the end of Weeks 2 and 4 based on the following 2 criteria:  1) the 
subject’s tics are not sufficiently controlled per physician investigator assessment; and 2) an evaluation 
by the physician investigator indicates that the subject is tolerating the study drug at the current dose and 
would likely be able to tolerate the next dose level.  During the first 6 weeks of the 12-week double-
blind treatment period, the physician investigator may escalate a subject’s dose to the next dose level, 
continue with the subject’s current dose, or reduce to the subject’s prior tolerated dose (in subjects who 
have had a dose escalation).  After Week 6, subjects will continue to receive their optimized dose of 
NBI-98854 or placebo for an additional 6-week dose maintenance period.  If a subject’s optimal dose 
has already been established at Week 2 (or at Week 4), no further dose escalation will be allowed during 
the dose optimization period and the subject will continue at that dose until the end of the 12-week 
treatment period.  At any time after Week 2, the physician investigator may decrease the dose to the 
previous dose for any subject who had a dose escalation and who is unable to tolerate a given dose 
increase.  The subject will continue at that dose until the end of the 12-week treatment period.  The 
investigator may reduce the subject’s dose only one time.  Subjects who are unable to tolerate the 
starting dose or resumption of the previous dose will be discontinued from the study.  Follow-up 
assessments will be conducted at the end of Week 14 (2 weeks after the last dose of the study drug). 
After providing parental or legal guardian informed consent with signed and witnessed pediatric assent, 
subjects will be screened to determine eligibility within 28 days (Days -28 to -1) before the start of study 
drug dosing on Day 1.  On Day 1 (baseline), eligible subjects will return to the study center for 
collection of baseline safety and efficacy assessments, and the 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) to placebo or NBI-98854, with 
assigned dose based on weight group at baseline.  A 2-week supply of study drug will be dispensed. 
Beginning on Day 1, study drug will be administered qd at home at the subject’s bedtime under the 
supervision of the subject’s parent/legal guardian.  Subjects will continue to self-administer the study 
drug daily at approximately the same time for the duration of the 12-week treatment period.  Subjects 
will return to the study center at fixed intervals (end of Weeks 2, 4, 6, 8, 10, and 12) for study 
assessments and dispensing of study drug (Weeks 2, 4, 6, 8, and 10 only).  As much as possible, these 
study visits and the follow-up visit should occur at the same time as the Day 1 (baseline) visit to 
standardize the time of day for the assessment of efficacy, safety, and plasma exposure.  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 with respect to compliance or tolerability.  
All subjects who complete the 12-week treatment period will enter a 2-week follow-up period with a 
follow-up visit at Week 14 (subjects who terminate early will have Week 14 assessments conducted).  
Efficacy, safety, and study drug exposure will be assessed at scheduled times throughout the study.  The 
treatment period visits (Weeks 2, 4, 6, 8, 10, and 12) and the follow-up visit (Week 14) will have a visit 
window of -2 or +3 days.  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. 
Efficacy assessments for TS are the Yale Global Tic Severity Scale (YGTSS; primary), Clinical Global 
Impression of Tourette Syndrome-Improvement scale (CGI-TS-Improvement), Clinical Global 
Impression of Tics-Severity scale (CGI-Tics-Severity), the Premonitory Urge for Tics Scale (PUTS), 
and the Gilles de la Tourette Syndrome – Quality of Life Scale for Children and Adolescents 
(C&A-GTS-QOL).  The YGTSS, PUTS, and C&A-GTS-QOL will be administered at screening, on 
Day 1 (baseline), and at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination).  At 
screening and Day 1 (baseline), the CGI-Tics-Severity scale will be used, and then both the 
CGI-TS-Improvement and CGI-Tics-Severity will be used to rate the overall severity and improvement 
of tics at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination). 
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The YGTSS will serve as the primary assessment of tic behaviors associated with TS.  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 a trained and certified rater (eg, 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.  An external video 
reviewer, not affiliated with the site, will access the central server to view the recording and 1) confirm 
the subject’s TS severity is at least moderate based on a CGI-Tics-Severity of ≥4 (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 trained and certified rater to enter a score for each item of the scale based on subject and 
parent responses during the structured clinical interview.  The software will also generate individual 
scores for each item of the scale (tandem rating) and will generate the Total Tic Score (TTS) and the 
Global Tic Severity Score. 
Safety assessments including adverse event (AE) monitoring, clinical laboratory tests (hematology, 
clinical chemistry, and urinalysis), vital sign measurements, physical examinations, 12-lead 
electrocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS, Children’s Version), 
Children’s Depression Rating Scale - Revised (CDRS-R), the Children’s Yale-Brown Obsessive 
Compulsive Scale (CY-BOCS), the Attention-Deficit Hyperactivity Disorder Rating Scale-5:  Home 
Version (ADHD Rating Scale-5), and Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
will also be collected at scheduled times throughout the study. 
Blood samples for plasma drug and metabolite concentration analyses will be at Day 1 (baseline) and at 
Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination).  Subjects/caregivers will be 
asked to record and provide dosing times from the evening before the treatment period visits when 
pharmacokinetic (PK) samples are collected. 
Study Population:  Approximately 120 male and female pediatric subjects (6 to 17 years of age) with a 
DSM-IV or -V diagnosis of TS; approximately 60 subjects <50 kg and 60 subjects ≥50 kg will be 
enrolled into this study.  The subjects must have at least moderate current TS symptoms, as defined by a 
CGI-Tics-Severity score of ≥4 (ie, moderately ill) at screening.  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 as determined by the physician investigator. 
Duration of Treatment and Study Participation:  The expected duration of study participation for 
each subject is approximately 18 weeks, including up to 28 days of screening, a 12-week double-blind 
treatment period, and 2 weeks of follow-up, or early termination. 
Investigational Product, Dose, and Mode of Administration:  NBI-98854 will be supplied as capsules 
containing 20 mg or 40 mg of NBI-98854 (free base equivalent).  Subjects must swallow the capsules at 
bedtime with at least 4 ounces of water with or without food.  
Reference Therapy, Dose, and Mode of Administration:  Matching placebo capsules are identical in 
appearance and will be orally administered in a double-blinded manner (2 placebo capsules) per 
randomization on an identical schedule to those receiving NBI-98854.  Subjects must swallow the 
capsules at bedtime with at least 4 ounces of water. 
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Criteria for Evaluation:   
Efficacy:  The following efficacy assessments will be administered at screening, Day 1 (baseline), and 
at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination): 
• 
YGTSS; TTS as the primary assessment 
• 
PUTS 
• 
C&A-GTS-QOL. 
The CGI-Tics-Severity will be used to rate the overall severity of tics beginning at screening and Day 1 
(baseline), and then both CGI-Tics-Severity and CGI-TS-Improvement will be administered at Weeks 2, 
4, 6, 8, 10, 12, and 14 (final study visit or at early termination). 
Pharmacokinetics:  Blood samples for plasma study drug and metabolite concentration analyses will be 
collected at Day 1 (baseline) and at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or early 
termination).  Subjects/caregivers will be asked to record and provide dosing times from the evening 
before the treatment period visits when PK samples are collected. 
Safety:  Safety and tolerability will be monitored throughout the study and will include the following 
assessments:  
• 
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 ECGs 
• 
C-SSRS, Children’s Version 
• 
CDRS-R 
• 
CY-BOCS 
• 
ADHD-5 Rating Scale 
• 
ESRS-A. 
Statistical Methods:  The primary efficacy endpoint is the change from baseline (Day 1) to the end of 
Week 12 in the YGTSS TTS as generated by the certified site rater using the Rater Station™.  The 
secondary efficacy endpoints are:  change from baseline to the end of Week 12 in CGI-Tics-Severity 
score, TTS responder status at Week 12 (a responder is defined as having a ≥30% reduction in TTS from 
baseline), and CGI-TS-Improvement responder status at Week 12 (a responder is defined as having a 
CGI-TS-Improvement score of either a 1 [“very much improved”] or 2 [“much improved”]).  
Exploratory efficacy endpoints will include the change from baseline to the end of Week 12 for the 
PUTS total score, CGI-TS-Improvement score at the end of Week 12, change from baseline to the end of 
Week 12 for the C&A-GTS-QOL score, as well as changes from baseline to the end of Week 12 for the 
Global Tic Severity and Impairment scores from the YGTSS.  Efficacy data will also be summarized 
from other timepoints (eg, Weeks 2 through 10).  
Statistical comparisons between NBI-98854 and placebo will be performed for the efficacy endpoints for 
the pooled weight groups (<50 kg, ≥50 kg) and data will also be summarized for each weight group 
separately.  The analyses will include comparisons at specified timepoints.  The primary analysis of the 
YGTSS TTS change from baseline will be a mixed-effect model repeated measures (MMRM) analysis 
of the pooled weight groups including the scores at Weeks 2, 4, 6, 8, 10, and 12 based on the full 
analysis set (FAS).  Supplemental sensitivity analyses of the primary efficacy endpoint will also be 
conducted. 
Safety and plasma study drug and metabolite concentration data will be summarized for the pooled 
weight groups and each weight group separately, using descriptive statistics.  
Neurocrine Biosciences, Inc., Study No. NBI-98854-TS2003 
Clinical Study Protocol Amendment No. 2 Final Version
31 July 2018
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADHD 
Attention-Deficit Hyperactivity Disorder 
ADHD Rating Scale-5 
Attention-Deficit Hyperactivity Disorder Rating Scale-5:  Home Version 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
AUC0-∞  
AUC from 0 hours extrapolated to infinity 
β-hCG 
β-human chorionic gonadotropin 
C&A-GTS-QOL 
Gilles de la Tourette Syndrome – Quality of Life Scale for Children and 
Adolescents 
CBIT 
Comprehensive Behavioral Intervention for Tics 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CDS 
Clinical Drug Safety 
CFR 
Code of Federal Regulations 
CGI-Tics-Severity 
Clinical Global Impression of Tics-Severity scale 
CGI-TS-Improvement 
Clinical Global Impression of Tourette Syndrome-Improvement scale 
Cmax  
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
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 
FAS 
Full analysis set 
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 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
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MAOI 
Monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
NBI 
Neurocrine Biosciences, Inc. 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PUTS 
Premonitory Urge for Tics Scale 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
t½  
Terminal half life 
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
tmax  
Time to maximum plasma concentration 
TS 
Tourette syndrome 
TTS 
Total Tic Score 
ULN 
Upper limit of normal 
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 of Technical Requirements for the Registration of Pharmaceuticals for 
Human Use [ICH; current version]). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies 
(21 CFR parts 50, 54, 56, 312, and 314). 
• Guidance for Clinical Trial Sponsors:  Clinical Trial Applications, Effective 29 May 2013, 
Health Canada Therapeutic Products Directorate, Health Products and Food Branch.  
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, most 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 
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that pharmacological interventions are often considered (Chen et al., 2012; Shprecher and 
Kurlan, 2009; Roessner et al., 2013). 
Neuropathological models have been proposed to explain the symptomatic features of TS, and 
converging lines of empirical evidence consistently implicate dopaminergic dysfunction and 
dysregulation within prefrontal cortex-basal ganglia circuitry (Felling and Singer, 2011; Pourfar 
et al., 2011).  Functional neuroimaging studies have identified a pattern of prefrontal cortex 
hypermetabolism and reduced striatal activity in TS patients (Baxter and Guze, 1993; Braun et 
al., 1993; Pourfar et al., 2011).  Pharmacotherapeutic approaches aimed at blocking 
postsynaptic dopamine-2 receptors (eg, haloperidol and pimozide) have demonstrated efficacy 
in reducing TS symptoms.  In this regard, modulation of dopaminergic tone through the 
administration of a vesicular monoamine transporter 2 (VMAT2) inhibitor, like NBI-98854, 
may also be an effective treatment option for tic suppression. 
5.2. 
NBI-98854 
NBI-98854 (valbenazine tosylate) is a selective, orally active VMAT2 inhibitor developed by 
NBI.  NBI-98854 is under development for the treatment of TS.  NBI-98854 was approved by 
the US Food and Drug Administration (FDA) in April 2017 for the treatment of adults with 
tardive dyskinesia (TD), under the trade name INGREZZA®. 
In nonclinical studies, NBI-98854 appears to cause little or no cytochrome P450 (CYP) enzyme 
inhibition or induction at pharmacologically relevant concentrations.  NBI-98854 is a moderate 
inhibitor of P-glycoprotein (P-gp), but only at concentrations that could be achieved in the 
gastrointestinal (GI) tract and is not an inhibitor of a panel of other drug transporters.  
Metabolism of NBI-98854 is characterized by hydrolysis of NBI-98854 to NBI-98782, and 
CYP3A4/5-dependent mono-oxidation to NBI-136110.  NBI-98782 is metabolized in part by 
CYP2D6.  All 3 entities, namely, NBI-98854, NBI-98782, and NBI-136110, can bind to and 
inhibit VMAT2.  However, NBI-98782 is the most potent and appears to be responsible for 
most of the observed pharmacological activity of VMAT2 inhibition. 
NBI-98854 appears to be rapidly absorbed with a time to maximum plasma concentration (tmax) 
typically ranging from approximately 0.5 to 1.0 hours.  NBI-98854 reaches steady state within 
1 week.  The active metabolite NBI-98782 gradually forms with a tmax of 4 to 8 hours and both 
NBI-98854 and NBI-98782 are eliminated with a terminal half-life (t½) of 15 to 22 hours.  
Coadministration of ketoconazole (strong CYP3A4/5 inhibitor) with NBI-98854 led to a 1.5- 
and 1.6-fold increase in the maximum plasma concentration (Cmax) of NBI-98854 and 
NBI-98782, respectively, and a 2.1-fold increase in the area under the plasma concentration 
versus time curve (AUC) from 0 hours extrapolated to infinity (AUC0–∞) of NBI-98854 and 
NBI-98782.  Coadministration of NBI-98854 and rifampin (strong CYP3A4/5 inducer) led to an 
approximate 30% and 70% decrease in Cmax and AUC0–∞, respectively, for valbenazine, and an 
approximate 50% and 80% decrease, respectively, for NBI-98782 compared with administration 
of NBI-98854 alone.  Coadministration of NBI-98854 80 mg and 0.5 mg digoxin resulted in an 
approximate 1.9-fold increase in the Cmax of digoxin.  The effect of NBI-98854 on digoxin 
AUC0–∞ was modest (1.4-fold increase) and the mean t½ of digoxin was similar with and 
without NBI-98854 administration.  Midazolam Cmax and AUC0–∞ were similar with and 
without NBI-98854 administration. 
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NBI-98854 for the treatment of TS has been evaluated in 3 completed Phase 1b and Phase 2 
studies in patients with TS.  These include 2 studies in pediatric subjects (NBI-98854-1403 and 
NBI-98854-1501) and 1 study in adults (NBI-98854-1505).  The initial Phase 1b, open-label, 
multiple-dose study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of NBI-98854 (NBI-98854-1403) was conducted in children (6 to 11 years of age) and 
adolescents (12 to 18 years of age) with TS.  Doses of NBI-98854 5 mg and 10 mg were 
administered in children and doses of NBI-98854 10 mg, 25 mg, or 50 mg were administered in 
adolescents daily over a 14-day treatment period following a multiple ascending dose protocol.  
Study NBI-98854-1501 was a Phase 2, multicenter, randomized, double-blind, placebo-
controlled, parallel group, dose-ranging study to evaluate the efficacy, safety, and tolerability of 
2 doses of NBI-98854 (10 mg and 20 mg in children [6 to 11 years of age], and 20 mg and 
40 mg in adolescents [12 to 17 years of age]) relative to placebo, administered once daily (qd) 
for 6 weeks in 98 pediatric subjects with TS.  Subjects within each age group were randomized 
in a 1:1:1 ratio to placebo or 1 of the 2 NBI-98854 doses.  Study NBI-98854-1505 was a Phase 
2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate 
the efficacy, safety, and tolerability of 2 doses of NBI-98854 (40 mg and 80 mg) relative to 
placebo, administered qd for 8 weeks in 124 adult subjects with TS.  Subjects were randomized 
in a 1:1:1 ratio to placebo or 1 of the 2 NBI-98854 doses.   
PD results from NBI-98854-1403 revealed reductions from baseline (Day -1) to Day 14 in the 
Yale Global Tic Severity Scale (YGTSS) total tic score (TTS) in both children and adolescents, 
and this decrease was observed irrespective of dose.  The mean point reduction in TTS for all 
subjects across all doses tested was -9.4 points at Day 14, which represents a 31% decrease 
from the mean baseline score.  Mean reductions from baseline were also observed in the 
YGTSS impairment score for both age groups.  The Phase 2, NBI-98854-1501 study in children 
and adolescents did not meet its primary efficacy endpoint of a significant change from baseline 
to Week 6 in the TTS between the placebo and active groups.  A comprehensive exposure-
response analysis indicated that the doses selected for this study were too low to provide 
adequate plasma exposures for tic reduction in most pediatric subjects.  For the subset of 
subjects with NBI-98854 exposures in the relevant range, there was a reduction in tics 
(range:  -11.3 to -13.7 points on the TTS) compared with the subset of subjects with sub-
therapeutic exposures (range:  -4.7 to -8.3 points on the TTS).  Although the efficacy results in 
participating adults in the NBI-98854-1505 study showed an improvement in overall symptoms 
of TS as measured by the secondary endpoint, Clinical Global Impression of Change (p=0.015 
[nominal]), the prespecified primary endpoint, the change from baseline in the YGTSS at Week 
8 was not met (p=0.18).   
NBI-98854 has been generally well tolerated in single doses up to 300 mg and in multiple doses 
of up to 100 mg in healthy volunteers and patients with TD.  Over 850 subjects have been 
exposed to NBI-98854 in TD clinical studies.  In TS patients, safety results from 
NBI-98854-1403 show that the doses were well tolerated in both child and adolescent age 
groups.  There were no deaths or serious adverse events (SAEs) reported during the study and 
no child discontinued due to an adverse event (AE).  Two adolescents (both in the NBI-98854 
50 mg group) discontinued due to AEs.  One subject discontinued on Day 2 due to the AEs of 
agitation, headache, visual impairment, vomiting, and worsening of bradycardia and the other 
subject discontinued on Day 4 due to the AEs of increased anxiety and insomnia.  Preliminary 
safety results from the Phase 2, NBI-98854-1501 pediatric study suggest that all doses tested 
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(NBI-98854 10 mg and 20 mg in children and NBI-98854 20 mg and 40 mg in adolescents) 
were well tolerated in these pediatric subjects with TS.  The most frequently reported AEs were 
headache, somnolence, upper respiratory tract infection, insomnia, and sedation.  There were no 
deaths and only one SAE in the placebo group (conversion disorder).  Preliminary results from 
NBI-98854-1505 showed that the most frequently reported AEs were somnolence (20.2% 
NBI-98854-treated subjects and 2.5% of placebo subjects), fatigue (14.3% NBI-98854 and 
2.5% placebo), and akathisia (13.1% NBI-98854 and 0% placebo).  Seventeen subjects (13.7%) 
discontinued from the study due to AEs, and most of these subjects received NBI-98854 80 mg 
(13/17 subjects) and the most common reason for AE discontinuation was akathisia (reported in 
5 subjects).  Four subjects experienced SAEs during the study; the SAEs included pelvic 
inflammatory disease (placebo subject; moderate and not related to NBI-98854), pneumothorax 
(80 mg subject; moderate and unlikely related to NBI-98854), hypersensitivity (80 mg subject; 
moderate and possibly related to NBI-98854), and pneumonia streptococcal, septic shock, renal 
failure acute, and brachial plexus injury (40 mg subject; severe and unlikely related to 
NBI-98854).   
5.3. 
Study and Dose Rationale 
This is a Phase 2b, randomized, double-blind, placebo-controlled, dose-optimization study to 
evaluate the efficacy, safety, and tolerability of NBI-98854 titrated to the subject’s optimal dose 
in the range of 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg for subjects ≥50 kg 
compared to placebo, administered qd for a total of 12 weeks of treatment in pediatric subjects 
with TS.  Subjects must have at least moderate current TS symptoms, as defined  
by a Clinical Global Impression of Tics-Severity scale (CGI-Tics-Severity) score of ≥4 
(ie, moderately ill) at screening. 
Rationale for Dose Selection and Regimen 
Subjects will be randomized in a double-blind manner to qd doses of NBI-98854 for 12 weeks.  
For subjects randomized to active treatment, the starting dose will be NBI-98854 20 mg for 
subjects <50 kg and NBI-98854 40 mg for subjects ≥50 kg, which may be escalated in 
increments of 20 mg every 2 weeks to a maximum of 60 mg for subjects <50 kg and 80 mg for 
subjects ≥50 kg to achieve an optimal dose of NBI-98854 for each subject. 
The current starting doses of NBI-98854 (ie, 20 mg or 40 mg) have been well tolerated in 
previous studies in pediatric subjects with TS (NBI-98854-1403 and NBI-98854-1501).  The 
dose optimization scheme based on efficacy, tolerability, and safety assessments, as well as 
bedtime dosing will allow subjects to potentially receive an optimal dose (ie, one that is both 
well tolerated and efficacious) during the treatment period.  Furthermore, the intermediate and 
high doses have been predicted to potentially provide adequate plasma levels of NBI-98782 for 
a greater proportion of subjects to achieve clinically meaningful tic suppression based on 
exposure-response modeling. 
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6. 
STUDY OBJECTIVES 
The objectives of this clinical study are as follows: 
Primary: 
• To evaluate the efficacy of NBI-98854, titrated to the subject’s optimal dose in the range 
of 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg for subjects ≥50 kg, 
administered qd for the treatment of TS. 
Secondary:  
• To evaluate the safety and tolerability of NBI-98854, titrated to the subject’s optimal 
dose in the range of 20 mg to 60 mg for subjects <50 kg and 40 mg to 80 mg for subjects 
≥50 kg, administered qd. 
• To evaluate plasma exposure measures of NBI-98854 and its active metabolite, 
NBI-98782, following titrated doses of NBI-98854 from 20 mg to 60 mg for subjects 
<50 kg and 40 mg to 80 mg for subjects ≥50 kg. 
7. 
OVERVIEW OF STUDY DESIGN 
This is a Phase 2b, randomized, double-blind, placebo-controlled, dose-optimization study to 
evaluate the efficacy, safety, and tolerability of NBI-98854 titrated to the subject’s optimal dose 
in the range of 20 mg to 60 mg for subjects <50 kg at baseline and 40 mg to 80 mg for subjects 
≥50 kg at baseline compared to placebo, administered qd for a total of 12 weeks of treatment in 
pediatric subjects with TS.  Approximately 120 male and female pediatric 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.  There will be an approximately equal 
distribution of subjects in each weight group, <50 kg and ≥50 kg, enrolled into the study and 
subjects will be stratified based on their weight.  Eligible subjects will be randomized in a 1:1 
ratio to NBI-98854 or placebo treatment as shown in Table 1. 
Table 1: 
Treatment by Weight Group 
Weight Group 
 
Assigned Treatment 
Number of Subjects 
(approximate) 
Subjects <50 kg at baseline 
 
Placebo 
30 
 
NBI-98854 (20 to 60 mg) 
30 
Subjects ≥50 kg at baseline 
 
Placebo 
30 
 
NBI-98854 (40 to 80 mg) 
30 
For subjects randomized to active treatment, the starting dose will be NBI-98854 20 mg for 
subjects <50 kg at baseline and NBI-98854 40 mg for subjects ≥50 kg at baseline, which may be 
escalated in increments of 20 mg every 2 weeks to a maximum of 60 mg for subjects <50 kg 
and 80 mg for subjects ≥50 kg to achieve an optimal dose of NBI-98854 for each subject.  To 
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maintain the study blind, subjects randomized to placebo in each weight group will be subjected 
to the same dose escalation requirements, but will receive only placebo during the treatment 
period.  Dose escalations will occur at the end of Weeks 2 and 4 based on the following 2 
criteria:  1) the subject’s tics are not sufficiently controlled per physician investigator 
assessment; and 2) an evaluation by the physician investigator indicates that the subject is 
tolerating the study drug at the current dose and would likely be able to tolerate the next dose 
level.  During the first 6 weeks of the 12-week double-blind treatment period, the physician 
investigator may escalate a subject’s dose to the next dose level, continue with the subject’s 
current dose, or reduce to the subject’s prior tolerated dose (in subjects who have had a dose 
escalation).  After Week 6, subjects will continue to receive their optimized dose of NBI-98854 
or placebo for an additional 6-week dose maintenance period.  If a subject’s optimal dose has 
already been established at Week 2 (or at Week 4), no further dose escalation will be allowed 
during the dose optimization period and the subject will continue at that dose until the end of 
the 12-week treatment period.  At any time after Week 2, the physician investigator may 
decrease the dose to the previous dose for any subject who had a dose escalation and who is 
unable to tolerate a given dose increase.  The subject will continue at that dose until the end of 
the 12-week treatment period.  The investigator may reduce the subject’s dose only one time.  
Subjects who are unable to tolerate the starting dose or resumption of the previous dose will be 
discontinued from the study.  Follow-up assessments will be conducted at the end of Week 14 
(2 weeks after the last dose of the study drug). 
After providing parental or legal guardian informed consent with signed and witnessed pediatric 
assent, subjects will be screened to determine eligibility within 28 days (Days -28 to -1) before 
the start of study drug dosing on Day 1.  On Day 1 (baseline), eligible subjects will return to the 
study center for collection of baseline safety and efficacy assessments, and the 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 randomized (1:1) to placebo or NBI-98854, 
with assigned dose based on weight group at baseline.  A 2-week supply of study drug will be 
dispensed. 
Beginning on Day 1, study drug will be administered qd at home at the subject’s bedtime under 
the supervision of the subject’s parent/legal guardian.  Subjects will continue to self-administer 
the study drug daily at approximately the same time for the duration of the 12-week treatment 
period.  Subjects will return to the study center at fixed intervals (end of Weeks 2, 4, 6, 8, 10, 
and 12) for study assessments and dispensing of study drug (Weeks 2, 4, 6, 8, and 10 only).  As 
much as possible, these study visits and the follow-up visit should occur at the same time as the 
Day 1 (baseline) visit to standardize the time of day for the assessment of efficacy, safety, and 
plasma exposure.  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 with 
respect to compliance or tolerability.  All subjects who complete the 12-week treatment period 
will enter a 2-week follow-up period with a follow-up visit at Week 14 (subjects who terminate 
early will have Week 14 assessments conducted).  Efficacy, safety, and study drug exposure 
will be assessed at scheduled times throughout the study.  The treatment period visits (Weeks 2, 
4, 6, 8, 10, and 12) and the follow-up visit (Week 14) will have a visit window of -2 or +3 days.  
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. 
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Efficacy assessments for TS are the YGTSS (primary), the CGI-TS-Improvement, 
CGI-Tics-Severity, the Premonitory Urge for Tics Scale (PUTS), and the Gilles de la Tourette 
Syndrome – Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL).  The 
YGTSS, PUTS, and C&A-GTS-QOL will be administered at screening, on Day 1 (baseline), 
and at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination).  At screening 
and Day 1 (baseline), the CGI-Tics-Severity scale will be used, and then both the 
CGI-TS-Improvement and CGI-Tics-Severity will be used to rate the overall severity and 
improvement of tics at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination). 
Safety assessments including AE monitoring, clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis), vital sign measurements, physical examinations, 12-lead 
electrocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS, Children’s 
Version), Children’s Depression Rating Scale - Revised (CDRS-R), the Children’s Yale-Brown 
Obsessive Compulsive Scale (CY-BOCS), the Attention-Deficit Hyperactivity Disorder Rating 
Scale-5:  Home Version (ADHD Rating Scale-5), and Extrapyramidal Symptom Rating Scale-
Abbreviated (ESRS-A) will also be collected at scheduled times throughout the study. 
Blood samples for plasma drug and metabolite concentration analyses will be at Day 1 
(baseline) and at Weeks 2, 4, 6, 8, 10, 12, and 14 (final study visit or at early termination).  
Subjects/caregivers will be asked to record and provide dosing times from the evening before 
the treatment period visits when PK samples are collected. 
A schematic of the study design is shown in Figure 1. 
 
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Figure 1: 
Study Design Schematic 
Week 
Screening 
Dose Optimization Period
4
-1
2
Follow-up
Follow-up 
Period  / ET
<50 kg
≥50 kg
6
Dose Maintenance Period
8
12
Screening Period
14
-28
Day 
1
Randomization on Day 1
20 mg 
NBI-98854
20 or 40 mg 
NBI-98854
20 or 40 or 60 mg 
NBI-98854
Screening 
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
40 mg 
NBI-98854
40 or 60 mg 
NBI-98854
40 or 60 or 80 mg 
NBI-98854
Placebo
Placebo
40 or 60 or 80 mg NBI-98854
Follow-up
10
 
 
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8. 
STUDY POPULATION 
This study will be conducted in approximately 120 male and female pediatric subjects (6 to 
17 years of age) with a DSM-IV or -V diagnosis of TS.  A total of approximately 60 subjects 
<50 kg and approximately 60 subjects ≥50 kg will be enrolled into this study.  Subjects must 
meet all 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 pediatric assent from the subject and written 
informed consent from the subject’s parents 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) at screening.  This determination must be independently confirmed by 
the external video reviewer using a video recording of the subject’s YGTSS assessment 
administered at the clinical site by a trained and certified rater. 
6. Have TS symptoms that cause marked distress or significant impairment in school, 
occupational, and/or social function. 
7. Subjects must have a stable psychiatric status (such as TS spectrum diagnoses 
[eg, obsessive-compulsive disorder, ADHD]) as clinically determined by the investigator. 
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 Day 1 
(baseline), and the medication regimen is expected to remain stable throughout the study 
period.  The use of concomitant dopamine antagonists (eg, pimozide, haloperidol, 
aripiprazole) and/or tetrabenazine to treat TS symptoms is prohibited.  Other 
nondopaminergic tic suppression therapy (eg, clonidine, guanfacine) is allowed during the 
study period if the dose regimen has been stable for a minimum of 30 days before Day 1 
(baseline). 
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 
Day 1 (baseline), and the medication regimen is expected to remain stable throughout the 
study period. 
10. Subjects of childbearing potential must agree to use contraception consistently from 
screening until 30 days (females) or 90 days (males) after the last dose of study drug.  A 
female subject of childbearing potential is defined as a female capable of becoming 
pregnant, which includes subjects who have had their first menstrual cycle (ie, menarche) 
and are not surgically sterile (ie, bilateral oophorectomy, hysterectomy or bilateral tubal 
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ligation for at least 3 months prior to screening).  A male subject of childbearing potential is 
defined as a subject who has reached spermarche and has not been vasectomized for at least 
3 months prior to screening.   
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom).  
• Vaginal sponge impregnated with spermicide used with a condom. 
• Intrauterine device (IUD). 
• Hormonal contraception being 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 
Day 1 (baseline). 
12. Have a body weight (in kg) greater than or equal to the 5th 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, benzodiazepines, phencyclidine, cocaine, opiates, or 
cannabinoids) at screening (based on results from central laboratory) and Day 1 (baseline; 
based on results from on-site urine drug screen kit).  Subjects who are on stable doses of 
prescribed and supervised (not as needed [prn]) benzodiazepines, opiates, or 
psychostimulants (for subjects with comorbid ADHD) can participate in the study. 
14. Adolescent subjects (12 to 17 years of age) must have a negative alcohol breath test at 
screening and Day 1 (baseline).  
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 significant 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. 
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4. Have a history of substance (drug or alcohol) dependence or abuse within the 3 months 
before Day 1 (baseline), 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. 
7. Have a known history of long QT syndrome or cardiac arrhythmia. 
8. Have a screening or Day 1 average triplicate ECG corrected QT interval using Fridericia's 
formula (QTcF) of >450 msec or the presence of any clinically significant cardiac 
abnormality. 
9. Have serum creatinine levels greater than the upper limit of normal (ULN) at screening, or 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), or total bilirubin >1.5 times the ULN at screening.  Subjects with a 
documented diagnosis of Gilbert's syndrome are not required to meet the bilirubin criteria. 
10. Have any of the following hematologic abnormalities at screening: 
• Hemoglobin <11.0 g/dL. 
• White blood cell (WBC) count <4.0 × 103/mm3. 
• Platelet count <100,000/mm3. 
11. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to screening, 
except for 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) with 
confirmatory positive polymerase chain reaction reflex test result at screening. 
14. Have received any investigational product within a time period equal to 5 half-lives of the 
product, if known, or a minimum of 30 days before screening, whichever is longer, or plan 
to use an investigational drug (other than NBI-98854) during the study. 
15. Have received any excluded concomitant medication as detailed in Section 9.8.1. 
16. Have initiated Comprehensive Behavioral Intervention for Tics (CBIT) during the screening 
period or at Day 1 (baseline) 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 Day 1 (baseline). 
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 an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors (eg, tetrabenazine). 
20. Have a history of or suspected poor compliance in clinical research studies. 
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21. Have previous experience with NBI-98854 or previously participated in an NBI-98854 
clinical study. 
8.3. 
Subject Identification and Replacement 
Subjects will be identified by their unique subject number and initials (first, middle, last; a 
hyphen may be used if the subject has no middle name).  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 
2 double-blind treatment assignments within each weight group:  placebo or NBI-98854 
(starting NBI-98854 dose of 20 mg in subjects <50 kg and 40 mg in subjects ≥50 kg) in a 1:1 
ratio.  Randomization will occur on Day 1 after the subject is confirmed to have met the 
eligibility criteria.  Treatment assignments will be made per 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 pediatric 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 
Procedurea 
Screening Period 
Treatment Period 
Follow-up Period 
Day 1b 
Dose Optimization  
Dose Maintenance 
Follow-up/ ET 
Week  
Day -28 to -1 
Baseline  Dosing 
2 
4 
6 
8 
10 
12 
14c 
Visit 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Treatment assignment script/videod 
X 
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 
X 
X 
X 
12-lead ECGe 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testf 
X (s) 
X (u) 
 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsg 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine drug screen (adolescents) 
X 
X 
 
 
 
 
 
 
 
 
Alcohol breath test (adolescents) 
X 
X 
 
 
 
 
 
 
 
 
Genotype blood sampleh 
X 
 
 
 
 
 
 
 
 
Blood sample for prolactin 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sample for PK assessments 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
YGTSS (including video recording) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PUTS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CGI-Tics-Severity  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CGI-TS-Improvement 
 
 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CY-BOCS and CDRS-R 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ADHD Rating Scale-5: Home Version 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
ESRS-A 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
C&A-GTS-QOL 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug dosing at homei 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug accountabilityj 
 
 
 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Call to subjectk 
 
 
 
X 
 
 
 
 
 
 
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ADHD=attention-deficit hyperactivity disorder; AE=adverse event; C&A-GTS-QOL=Gilles de la Tourette Syndrome – Quality of Life Scale for Children and 
Adolescents; CDRS-R=Children’s Depression Rating Scale - Revised; CGI-Tics-Severity=Clinical Global Impression Tics-Severity scale; 
CGI-TS-Improvement=Clinical Global Impression of Tourette Syndrome-Improvement scale; C-SSRS=Columbia-Suicide Severity Rating Scale; CY-
BOCS=Children’s Yale-Brown Obsessive Compulsive Scale; ECG=electrocardiogram; ESRS-A=Extrapyramidal Symptom Rating Scale-Abbreviated; ET=early 
termination; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus antibody; HIV-Ab=human immunodeficiency virus antibody; PK=pharmacokinetic; 
QTcF=corrected QT interval using Fridericia’s formula; PUTS=Premonitory Urge for Tics Scale; s=serum; u =urine; YGTSS=Yale Global Tic Severity Scale. 
a As much as possible, study visits should occur at approximately the same time as the Day 1 visit to standardize the time of day for the assessment of efficacy, 
safety, and plasma exposure throughout the study period. 
b Day 1 is the day of baseline assessments and randomization.  Day 1 is also the first day of dosing; study drug will be administered at home at bedtime.  Visits 
will have a window of -2 to +3 days. 
c Final study visit for subjects who complete the study (or early termination). 
d Subjects will be shown the video titled “Your Role in a Clinical Trial, Some Information about Research Studies” (at screening only) and informed about the 
placebo-controlled design of the study using the treatment assignment script provided by the Sponsor (on Day 1 [baseline] only). 
e A standard 12-lead ECG will be conducted in triplicate (at least 1 minute apart and within 15 minutes) after the subject has rested supine for at least 5 minutes.  
The ECG parameters will be based on the ECG machine readings (QTcF may be calculated). 
f 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. 
g Clinical laboratory tests include hematology, clinical chemistry and urinalysis.  All blood samples will be obtained under nonfasted conditions. 
h Blood sample for genotyping will be analyzed for enrolled subjects only. 
i Study drug will be administered once daily at the subject’s bedtime at home under the supervision of their parent/guardian.  The date and time of each dosing of 
study drug will be recorded. 
j Subjects will return all used and unused study drug, and a compliance check will be performed by counting the capsules returned at each study visit. 
k Sites are to call subjects within 3 to 7 days from Day 1 to inquire about compliance or tolerability issues. 
 
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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, normal, intermediate, poor, or ultra-rapid metabolizers).  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.  The video 
recording will follow a standardized set of guidelines and the recorded video will be uploaded 
to a secure central server.  An external video reviewer, not affiliated with the site, will access 
the central server to view the recording and 1) confirm the subject’s TS severity is at least 
moderate based on a CGI-Tics-Severity of ≥4 (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.  
As much as possible, a given subject should have the same rater throughout the study.  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, Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 12, and at 
the final follow-up visit (Week 14), or early termination.  A copy of the YGTSS is provided in 
Appendix 17.1.  
9.3.2. 
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 pretic (ie, premonitory) urges 
along with relief that may be experienced after tics have been completed.   
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The investigator (or designee) will administer the PUTS at screening, Day 1 (baseline), 
Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up visit (Week 14), or early termination.  A copy 
of the PUTS is provided in Appendix 17.2. 
9.3.3. 
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, Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 12 and at the 
final follow-up visit (Week 14), or early termination.  A copy of the CGI-Tics-Severity scale is 
provided in Appendix 17.3. 
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, 6, 8, 10, 12 and 
at the final follow-up visit (Week 14), or early termination.  A copy of the 
CGI-TS-Improvement scale is provided in Appendix 17.4. 
9.3.4. 
Gilles de la Tourette Syndrome-Quality of Life for Children and Adolescents 
The C&A-GTS-QOL is a valid and reliable instrument to assess the quality of life in children 
and adolescents with TS (Cavanna et al., 2013).  It consists of 27 items and 4 subscales 
(psychological, physical, obsessive-compulsive, and cognitive).  Each item is rated across 5 
response options:  “Never,” “Rarely,” “Sometimes,” “Often,” and “Always.”  There are 2 
versions of this instrument:  1 version for children aged 6 to 12 years and 1 version for 
adolescents aged 13 to 18 years.  The C&A-GTS-QOL also includes a visual analog scale, 
assessing how satisfied the subject feels with his/her life (range of 0 to 100, with 100 
representing the greatest satisfaction). 
The subject will complete the C&A-GTS-QOL at screening, Day 1 (baseline), Weeks 2, 4, 6, 8, 
10, 12 and at the final follow-up visit (Week 14), or early termination.  The subject can receive 
assistance filling out the questionnaire if needed.  Copies of both versions of the 
C&A-GTS-QOL are 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 at Day 1 (baseline) and at Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up 
visit (Week 14), or early termination.  The exact time of collection will be recorded on the 
eCRF. 
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 
2000 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 
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volumes into 2 vials.  The vials will be stoppered and labeled with the study barcode, subject 
number and primary or back-up sample designation (PK A and PK B, respectively).  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-5, 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 unblinded 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, Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 
12, and at the final follow-up visit (Week 14), or early termination.  Vital sign measurements 
will be obtained before any scheduled blood sample collection. 
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. 
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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, Day 1 (baseline), and at 
Weeks 2, 6, 12, and at the final follow-up visit (Week 14), or 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 (at least 1 minute apart and within 
15 minutes) after the subject has rested supine for at least 5 minutes.  The ECG parameters that 
will be assessed include heart rate, PR interval, QRS duration, corrected QT interval, and QTcF 
(machine readings or calculated).  Additionally, the occurrence of de- and re-polarization and 
rhythm disorders or other cardiac 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, Day 1 (baseline), and at Weeks 2, 
4, 6, 8, 10, 12 and at the final follow-up visit (Week 14), or 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 clinical 
chemistry; adolescents (12 to 17 years of age) – 4 mL for hematology and 5 mL for clinical 
chemistry (includes screening serum pregnancy tests for female subjects of childbearing 
potential). 
Clinical safety laboratory assessments will be performed at screening, Day 1 (baseline), and at 
Weeks 2, 4, 6, 8, 10, 12, and at the final follow-up visit (Week 14), or early termination.  There 
are no fasting requirements for laboratory assessments. 
The following clinical safety laboratory assays will be performed: 
Hematology:  complete blood count including WBC count with differential, red blood cell 
count, hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red cell 
distribution width (RDW), and mean platelet volume (MPV). 
Clinical Chemistry:  sodium, potassium, calcium, magnesium, chloride, blood urea nitrogen, 
bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate dehydrogenase, ALT, 
AST, GGT, creatine kinase, total bilirubin, total cholesterol, triglycerides, total protein, and 
glucose. 
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Urinalysis:  specific gravity, nitrites, 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 nitrites, 
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 
Day 1 (baseline), at Weeks 2, 6, 8, 10, 12 and at the final follow-up visit (Week 14), or 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.  Prolactin results will remain blinded to the 
investigator. 
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 Breath 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 for preliminary confirmation of negative drug 
screen at the site 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, 6, 8, 10, 12 and at the final follow-up visit (Week 14), 
or 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 
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, Day 1 (baseline), and Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up 
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visit (Week 14), or 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. 
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, Day 1 
(baseline), and at Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up visit (Week 14), or early 
termination.  A copy of the CDRS-R is provided in Appendix 17.8. 
9.5.9. 
Children’s Yale-Brown Obsessive Compulsive Scale 
The CY-BOCS is a semi-structured interview designed to rate the severity of obsessive and 
compulsive symptoms in children.  The investigator (or designee) will administer the 
CY-BOCS at screening, Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 12, and at the final follow-up 
visit (Week 14), or early termination.  A copy of the CY-BOCS is provided in Appendix 17.9. 
9.5.10. 
Attention-Deficit Hyperactivity Disorder Rating Scale-5:  Home Version 
The ADHD Rating Scale-5:  Home Version will be used to determine the frequency and 
severity of ADHD symptoms and impairments over the past 2 weeks.  The scale comes in 
2 versions:  child (ages 5 to 10 years) and adolescent (ages 11 to 17 years).  Both versions 
consist of 2 symptom subscales, Inattention (9 items), and Hyperactivity–Impulsivity (9 items), 
as well as a Total Scale (18 items).  In addition, 6 domains of impairment that are common 
among children with ADHD are assessed:  relationships with significant others (family 
members for the home version and teachers for the school version), peer relationships, academic 
functioning, behavioral functioning, homework performance, and self-esteem.   
It will be completed independently by the subject’s parent or guardian at Day 1 (baseline), 
Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up visit (Week 14), or early termination.  A copy 
of the ADHD Rating Scale-5:  Home Version is provided in Appendix 17.10. 
9.5.11. 
Extrapyramidal Symptom Rating Scale-Abbreviated 
The ESRS-A is a psychometrically validated instrument that assesses 4 types of movement 
disorders:  parkinsonism, akathisia, dystonia, and dyskinesia (Chouinard and Margolese, 2005).  
The investigator (or designee) will administer the ESRS-A at screening, Day 1 (baseline), 
Weeks 2, 4, 6, 8, 10, 12 and at the final follow-up visit (Week 14) or upon early termination.  A 
copy of the ESRS-A is provided in Appendix 17.11.  
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 period, and the final 
visit (Week 14 or upon early termination). 
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Table 3: 
Estimated Total Blood Sample Volume 
Parameter 
Number of Samples 
Required 
Approximate 
Volume (mL) 
Approximate Total 
Volume (mL) 
Children (6 to 11 years of age) 
Clinical chemistrya 
9 
2.5 
22.5 
Hematology 
9 
3 
27 
Genotyping 
1 
4 
4 
Serology 
1 
9 
9 
Serum prolactin 
8 
2.5 
20 
Pharmacokinetics 
8 
2 
16 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
98.5 
Adolescents (12 to 17 years of age) 
Clinical chemistrya 
9 
5 
45 
Hematology 
9 
4 
36 
Genotyping 
1 
4 
4 
Serology 
1 
10 
10 
Serum prolactin 
8 
5 
40 
Pharmacokinetics 
8 
2 
16 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
151 
a Includes pregnancy test for female subjects who are of childbearing potential at screening. 
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 
28 days of Day -1. 
9.6.1. 
Screening (Days -28 to -1) 
During screening, the following study evaluations and tasks will be performed at the study 
center: 
• Obtain informed consent/pediatric assent. 
• Subjects will be shown the video titled “Your Role in a Clinical Trial, Some Information 
About Research Studies.” 
• 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 (at least 1 minute apart and within 15 minutes). 
• 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. 
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• Collect urine sample for urinalysis. 
• Perform alcohol breathalyzer test and urine drug screen (both only in adolescent subjects). 
• Administer the YGTSS, including video recording. 
• 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 ESRS-A. 
• Administer the C&A-GTS-QOL. 
• AE monitoring. 
• Record prior medications. 
All screening procedures must be completed, and results must be 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 considered for scheduling purposes:  as much as possible, visits should occur at 
approximately the same time as the Day 1 (baseline) visit to standardize the time of day for 
the assessment of efficacy, safety, and plasma exposure throughout the study period.  
9.6.2. 
Day 1 (Baseline Assessments and Start of Dosing) 
Subjects and parents/legal guardians will return to the center on Day 1. 
On Day 1, the following baseline study evaluations and tasks will be performed at the study 
center: 
• Subjects will be informed about the placebo-controlled design of the study using the 
treatment assignment script provided by the Sponsor. 
• 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 (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test only for female subjects of childbearing potential. 
• 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). 
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• Collect blood sample for CYP2D6 genotype status (for randomized subjects only). 
• Collect blood sample for serum prolactin. 
• Collect PK blood sample for NBI-98854 and metabolite concentrations. 
• Administer the YGTSS, including video recording. 
• Administer the PUTS. 
• Administer the CGI-Tics-Severity scale. 
• Administer the C-SSRS (Children’s Since Last Visit version). 
• Administer the CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale-5. 
• Administer the ESRS-A. 
• Administer the C&A-GTS-QOL. 
• 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 to begin taking study drug nightly at bedtime under supervision of their 
parents/legal guardians, beginning on Day 1.  (The timing of study drug administration 
should remain consistent throughout the treatment period.) 
• Instruct subjects and parents/legal guardians to return to the study center at Week 2 (-2 to 
+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. 
Sites are to call subjects within 3 to 7 days after the Day 1 visit to inquire about compliance or 
tolerability issues.  Note, subsequent study visits will be 14 days from the previous visit; for 
example, the Week 2 visit will be on Day 15 (-2 to +3 days) and the Week 4 visit will be on 
Day 29 (-2 to +3 days). 
9.6.3. 
Dose Optimization Period:  Weeks 2, 4, and 6 (-2 to +3 Days for Each Visit) 
Subjects and parents/legal guardians will return to the study center at Weeks 2, 4, and 6. 
The following study evaluations and tasks will be performed at the study center: 
• Perform a physical examination including weight (Weeks 2 and 6 only). 
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• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• Perform 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test only 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. 
• 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 CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale-5. 
• Administer the ESRS-A. 
• Administer the C&A-GTS-QOL. 
• Perform compliance check by counting the capsules returned. 
• AE monitoring. 
• Record concomitant medications. 
Dose Escalation Assessment 
At the end of Week 2 and Week 4 visits, a dose escalation will occur based on the following 2 
criteria:  1) the subject’s tics are not sufficiently controlled per physician investigator 
assessment; and 2) an evaluation by the physician investigator indicates that the subject is 
tolerating the study drug at the current dose and would likely be able to tolerate the next dose 
level.  Based on these criteria, the physician investigator will choose 1 of the following dosing 
options: 
• Dose escalation, which will occur in 20 mg increments (to maintain the study blind, subjects 
randomized to placebo will be subjected to the same dose escalation requirements but will 
receive only placebo during the treatment period): 
− Subjects <50 kg at baseline:  from 20 mg to 40 mg (Week 2); from 40 mg to 60 mg 
(Week 4). 
− Subjects ≥50 kg at baseline:  from 40 mg to 60 mg (Week 2); from 60 mg to 80 mg 
(Week 4). 
• Maintenance of current dose (with no further dose increases). 
• Dose reduction to previous dose in subjects who have had a dose escalation.  The physician 
investigator may decrease the dose to the previous dose at any time after the end of Week 2 
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(including between scheduled study visits) for any subject who is unable to tolerate a given 
dose increase.  Subjects will receive this dose for the remainder of the treatment period. 
Once a determination of dose escalation, maintenance, or reduction is made, the IWRS will be 
accessed to obtain an identification number for a kit containing a 2-week supply of study drug 
to be dispensed to the subject.  The subject will remain blinded to dose escalations made during 
the treatment period; however, the investigator may inform the subject that a dose adjustment is 
possible if the subject is unable to tolerate a given dose increase. 
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. 
• Instruct subjects to record the date and time of each dose on the labels provided on the study 
drug packaging form. 
9.6.4. 
Dose Maintenance Period:  Weeks 8, 10, and 12 (-2 to +3 Days for Each Visit) 
At Weeks 8, 10, and 12 the following study evaluations and tasks will be performed at the study 
center: 
• Perform a physical examination including weight (Week 12 only). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• Perform 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test only 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. 
• 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 CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale-5. 
• Administer the ESRS-A. 
• Administer the C&A-GTS-QOL. 
• Dispense a 2-week supply of study drug (Weeks 8 and 10 only). 
• Perform compliance check by counting the capsules returned. 
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• 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. 
• Instruct subjects to record the date and time of each dose on the labels provided on the study 
drug packaging form. 
9.6.5. 
Follow-Up Period/Early Termination:  Week 14 (-2 to +3 Days) 
At Week 14 (or upon early termination) the following study evaluations and tasks 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 (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test only 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. 
• 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 CY-BOCS and CDRS-R. 
• Administer the ADHD Rating Scale-5. 
• Administer the ESRS-A. 
• Administer the C&A-GTS-QOL. 
• AE monitoring. 
• Record concomitant medications. 
9.7. 
Study Duration 
The expected duration of study participation for each subject is approximately 18 weeks, 
including up to 28 days of screening, a 12-week, double-blind treatment period, and 2 weeks of 
follow-up, or early termination. 
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9.8. 
Prohibitions and Restrictions 
9.8.1. 
Prior and Concomitant Medications 
All prescription and over the counter medications, including dietary and herbal supplements, 
taken by subjects during the 30 days before baseline (Day 1) and during the study will be 
entered on the Prior and Concomitant Medications eCRF.  Any additions, deletions, or changes 
in the dose of these medications will be entered on the eCRF with indication, dose, route, and 
dates of drug administration. 
The following medications are prohibited from 14 days before Day 1 (baseline) (unless 
otherwise stated) until the final study visit (or upon early termination) as described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine. 
• Botulinum toxin:  Botulinum toxin injections for treatment of TS are prohibited starting 
90 days prior to Day 1 (baseline). 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenytoin, phenobarbital, rifabutin, 
rifampin, primidone, St. John's Wort, carbamazepine). 
• CYP3A4 inhibitors:  Strong inhibitors of CYP3A4 (eg, itraconazole, ketoconazole, 
clarithromycin). 
• Dopamine agonists and precursors:  Dopamine agonists (eg, ropinirole) and precursors 
(eg, carbidopa/levodopa). 
• Dopamine antagonist:  Dopamine antagonists (eg, pimozide, haloperidol, aripiprazole, 
risperidone, clozapine, olanzapine, ziprasidone) are prohibited.  Depot neuroleptics are 
prohibited starting 15 weeks prior to Day 1 (baseline). 
• Monoamine oxidase inhibitors (MAOIs):  All MAOIs (eg, isocarboxazid, phenelzine, 
selegiline, tranylcypromine). 
• VMAT2 inhibitors:  VMAT2 inhibitor medications (eg, tetrabenazine, reserpine), except for 
study drug. 
• As needed use of the following medications:  anticholinergics, benzodiazepines, 
antipsychotics, psychostimulants, mood stabilizers, antidepressants, opiates, 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.  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. 
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Subjects must not have initiated CBIT during the screening period or at Day 1 (baseline) 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. 
• 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). 
• 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 9.6.5). 
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. 
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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. 
NBI-98854 will be supplied as capsules containing 20 or 40 mg of NBI-98854 (free base 
equivalent).  The NBI-98854 20 and 40 mg capsules are a white, opaque, hydroxypropyl 
methylcellulose (HPMC) No. 3 size capsule containing 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. 
All subjects will receive the starting dose of study drug beginning on Day 1.  At Weeks 2 and 4, 
subjects may have their dose increased based on protocol-specified efficacy and safety criteria.  
Dosing information is provided below.   
Subjects <50 kg at baseline: 
• Starting dose:  20 mg NBI-98854 (one 20 mg capsule and one placebo capsule) or 
placebo (2 capsules) 
• Week 2:  40 mg NBI-98854 (two 20 mg capsules) or placebo (2 capsules) 
• Week 4:  60 mg NBI-98854 (one 20 mg and one 40 mg capsule) or placebo (2 capsules) 
Subjects ≥50 kg at baseline: 
• Starting dose:  40 mg NBI-98854 (two 20 mg capsules) or placebo (2 capsules) 
• Week 2:  60 mg NBI-98854 (one 20 mg and one 40 mg capsule) or placebo (2 capsules) 
• Week 4:  80 mg NBI-98854 (two 40 mg capsules) or placebo (2 capsules) 
If a subject’s optimal dose has already been established at Week 2 (or at Week 4), no further 
dose escalation will be allowed during the dose optimization period and the subject will 
continue at that dose until the end of the 12-week treatment period.  However, subjects who had 
a dose escalation may have a dose reduction at any time. 
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. 
• Storage at temperatures above 30˚C (86˚F) but no more than 40˚C (104˚F) for up to 
24 hours. 
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10.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed per 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 20 mg or 40 mg; or matching placebo. 
Each blistercard dispenser will be labeled with a single-panel label and secured with tamper 
evident seals.  Label text will include but is not limited to the protocol number, dosage form, 
route of administration, study drug kit number, sponsor name and address, storage condition, 
and the statement “Caution – New Drug:  Limited by Federal (or US) Law to Investigational 
Use.” 
10.4. 
Blinding 
This study includes a 12-week, double-blind, placebo-controlled treatment period during which 
the subject, investigator, all study site personnel, 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 administered qd at bedtime at home under the supervision of the subject’s 
parent/legal guardian and the capsules must be swallowed with at least 4 ounces of water, with 
or without food, every day for the 12-week treatment period.  If a subject forgets or is unable to 
take the study drug at bedtime, the subject should skip that dose and resume normal dosing the 
following day.  Subjects or their parents/legal guardians will record the date and time of study 
drug dosing each day on the labels provided on the study drug packaging form. 
10.6. 
Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty study drug packaging material to the 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. 
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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 visit (Week 14 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. 
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of conditions present at the start of the study; (2) subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction. 
If at any time after the baseline visit (Day 1), the subject’s response to the suicidal ideation 
section of the C-SSRS is worse than the baseline assessment; it will be documented as an AE.  
All suicidal behaviors will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
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.  
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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 
AEs 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: 
• SAE, including death (Refer to Section 11.6). 
• Pregnancy (refer to Section 11.7). 
• Events of suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with specific 
plan and intent) based on the C-SSRS. 
11.5. 
Post-Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  If 
resolved, a resolution date should be documented on the eCRF.   
AEs 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: 
 
CDS facsimile: 
 
CDS e-mail:  
 
NBI Medical Monitor:  
Telephone: 
 
 
 
 
 
 
 
 
 
Cell phone: 
11.6.4. 
Expedited Safety Reports 
Neurocrine Biosciences, Inc. or its representatives will submit an Expedited Safety Report for 
any suspected adverse reaction (as defined in Section 11.3) that is considered both serious and 
unexpected within 15 calendar days and for any unexpected fatal or life-threatening experience 
within 7 calendar days via telephone or facsimile; or according to country-specific regulations. 
Neurocrine Biosciences, Inc. or its representatives will send copies of each safety report 
submitted to regulatory authorities to the investigators.  The safety report must be submitted to 
the appropriate IRB as soon as possible.  Documentation of the submission to the IRB and 
receipt by the IRB (if applicable) must be retained for each safety report. 
11.7. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  However, all 
pregnancies in female subjects who received NBI-98854 will be followed to assess for 
congenital anomaly.  Subjects must be counseled at all visits to continue using contraception 
(see inclusion criterion #10 in Section 8.1) until 30 days (females) or 90 days (males) 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 case report form data for this study are being collected with an electronic data capture 
(EDC) system (Rave®) provided by Medidata Solutions Incorporated, NY, USA.  The EDC 
system and the study-specific eCRFs will comply with Title 21 CFR Part 11.  The 
documentation related to the validation of the EDC system is available through the vendor, 
Medidata, while the validation of the study specific eCRFs will be conducted by NBI and the 
required documentation will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs.  All data 
entered into the eCRF will be supported by source documentation.  The eCRF for each subject 
must be reviewed by the investigator and signed on the appropriate eCRF page(s).  This should 
be done as soon as possible after the subject completes the study.   
The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF.  All change information, including the date, person 
performing the corrections, and reason for the change will be available via the electronic audit 
trail, which is part of the EDC system.  The eCRFs will be reviewed periodically for 
completeness, legibility, and acceptability by NBI (or designee).  NBI will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify 
eCRF entries.  The Principal Investigator will review the eCRFs for completeness and accuracy 
and enter his or her electronic signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC system 
will be archived on appropriate data media (CD ROM, etc.) and provided to the investigator at 
that time as a durable record of the site's eCRF data.  Although not required, the investigator 
may make paper printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI and/or health authority representatives at any time.  The Principal 
Investigator will agree to the inspection of study-related records by health authority 
representatives and/or NBI. 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
Any discrepancies will be corrected on-line by authorized site personnel.  After completion of 
the entry process, automated (computer-generated) logic checks will run in order to identify 
items such as inconsistent study dates.  In addition, manual review/checks may be performed by 
NBI on the data.  Any inconsistencies/errors/omissions identified will be sent to the site (via an 
electronic query) for the necessary corrections to be made to the eCRF.  Once entered and saved 
in an eCRF, data immediately become part of the study database and are available to NBI. 
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12.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Prior and concomitant medications will be coded using the 
chosen version of the World Health Organization Drug Dictionary (WHO Drug). 
13. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive 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, SD, 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 the NBI-98854 treatment group and the placebo treatment group for selected efficacy 
variables based on the pooled weight groups (<50 kg and ≥50 kg).  Note that descriptive 
statistics will be presented for the pooled weight groups and for each weight group separately, 
unless specified otherwise.  Only pooled weight groups will be used for inferential statistics.  
The primary efficacy endpoint is the change from baseline (Day 1) to the end of Week 12 in the 
YGTSS TTS as generated by the certified site rater using the Rater Station software.  The 
secondary efficacy endpoints are:  change from baseline to the end of Week 12 in 
CGI-Tics-Severity score, TTS responder status at Week 12 (a responder is defined as having a 
≥30% reduction in TTS from baseline), and CGI-TS-Improvement responder status at Week 12 
(a responder is defined as having a CGI-TS-Improvement score of either a 1 [“very much 
improved”] or a 2 [“much improved”]).  Exploratory efficacy endpoints include the PUTS total 
score change from baseline to the end of Week 12, the CGI-TS-Improvement score at the end of 
Week 12, the C&A-GTS-QOL total score change from baseline to the end of Week 12, as well 
as changes from baseline to the end of Week 12 for the Global Tic Severity and Impairment 
scores from the YGTSS.  Efficacy data will also be summarized from other timepoints (eg, 
Weeks 2 through 10). 
The primary method of analysis of the YGTSS TTS change from baseline will be a mixed-
effect model repeated measures (MMRM) analysis including the scores at Weeks 2, 4, 6, 8, 10, 
and 12 based on the full analysis set (FAS).  Supplemental sensitivity analyses of the primary 
efficacy endpoint will also be conducted. 
Nominal (raw) two-sided p values will be reported for all hypothesis tests, although a procedure 
to control for multiple comparisons will be applied when interpreting the statistical significance 
of the results of the analyses of the primary efficacy endpoint and the secondary efficacy 
endpoints.  
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 study database lock and treatment unblinding.  The SAP may include additional analyses and 
data summaries not described in this protocol and will include detailed descriptions of graphical 
data displays that will support the tabular summaries. 
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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, take at least one dose of study drug, and 
have any postbaseline safety data.  The FAS will include all subjects who are randomized to a 
treatment group and who have at least one evaluable TTS change from baseline during the 
12-week, double-blind treatment period.  The per-protocol (PP) analysis set will include all 
subjects in the FAS who have a detectable plasma concentration of NBI-98854 at Week 12 
(unless randomized to placebo) and no efficacy-related important protocol deviations.  
Additional analysis set criteria may be specified in the SAP. 
13.2. 
Sample Size 
The protocol-specified sample size of 60 subjects per treatment group is based on a power 
calculation for the YGTSS TTS change from baseline using a two-sample t-test with a two-
sided Type I error of 0.05.  Power calculations based on this sample size under 3 dropout rate 
scenarios for 2 hypothesized effect sizes are summarized in the table below.  Note that the effect 
size is defined as the mean difference between the 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).  
 
Dropout Rate 
Number of Subjects per 
Treatment Group 
Effect Size 
Power 
0% 
60 
0.75 
98% 
0.85 
99% 
10% 
54 
0.75 
97% 
0.85 
99% 
15% 
51 
0.75 
96% 
0.85 
98% 
 
Standard deviations reported in the literature for TS studies evaluating changes in the YGTSS 
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 above are representative of effect sizes seen in these 
published reports. 
13.3. 
Handling of Missing Data 
Conventions for the handling of missing data will be described in the SAP. 
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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 completed the dose optimization period (ie, up 
to Week 6), who competed the dose maintenance period (ie, up to Week 12), 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. 
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. 
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 YGTSS TTS) will be summarized with descriptive statistics.  Medical 
history will be summarized according to MedDRA System Organ Class (SOC) and Preferred 
Term (PT). 
13.6. 
Study Drug Dosing and Compliance 
The number and percentage of subjects who are dose compliant (at least 80% of expected 
number of doses taken) will be summarized with descriptive statistics by visit (Weeks 2, 4, 6, 8, 
10, and 12).   
The number and percentage of subjects with dose adjustments will be summarized by visit.  
13.7. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and the metabolite NBI-98782 will be summarized 
with descriptive statistics by visit (Day 1 and Weeks 2, 4, 6, 8, 10, 12, and 14) and dose (last 
dose received prior to blood sample being drawn).  Concentrations below the lower limit of 
quantification will be set equal to zero for all plasma concentration summaries.  These data will 
be summarized for each weight group separately. 
13.8. 
Efficacy Data 
The efficacy measures in this study include the YGTSS, PUTS, CGI-Tics-Severity, 
CGI-TS-Improvement, and C&A-GTS-QOL.  Several derived variables based on these 
measures (eg, the YGTSS TTS) will be summarized with descriptive statistics, 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. 
13.8.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the change from baseline (Day 1) to the end of 
Week 12 in the YGTSS TTS (Total Tic Score) as generated by the certified site rater using the 
Rater Station.  Changes from baseline to Weeks 2 through 10 are exploratory efficacy 
endpoints. 
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Descriptive statistics will be presented by treatment group for the TTS observed values (ie, the 
raw data) and changes from baseline at each visit through Week 14.  Descriptive statistics will 
be presented for both the FAS and the PP analysis set.    
The primary analysis of the TTS will be an MMRM analysis, which includes the changes from 
baseline to Weeks 2, 4, 6, 8, 10, and 12, and is based on the FAS.  The model will include the 
baseline TTS as a covariate, and weight group, treatment group, visit, treatment group 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 are many sites 
(approximately 55), with most sites anticipated to enroll a small number of subjects.  
Treatment group comparisons of the NBI-98854 treatment group vs. placebo at each visit will 
be performed by constructing linear contrasts (or equivalent programming code) for differences 
between treatment group least-squares (LS) means.  Nominal (raw) two-sided p values for 
testing the significance of these differences and associated 95% confidence intervals will be 
reported in summary tables.  
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.  If convergence is not 
obtained with the unstructured covariance matrix, a Toeplitz covariance structure will be used. 
Additional supportive analyses of the TTS change from baseline to the end of Week 12 will be 
performed using analysis of covariance (ANCOVA) models.  The ANCOVA models will 
include the baseline TTS as a covariate and weight group and treatment group as fixed effects.  
Response (outcome) variables for the ANCOVAs include the Week 12 TTS score (ie, a 
complete cases analysis) and the last on-treatment TTS score (ie, a last-observation-carried 
forward [LOCF] analysis).  These analyses will be performed using the FAS. 
Additional analyses, including sensitivity analyses to assess the missing at random assumption 
of the MMRM, will be described in the SAP. 
13.8.2. 
Secondary Efficacy Endpoints 
CGI-Tics-Severity 
A secondary efficacy endpoint for this study is the change from baseline to the end of Week 12 
in CGI-Tics-Severity score.  Changes from baseline to Weeks 2 through 10 are exploratory 
efficacy endpoints. 
Descriptive statistics will be presented by treatment group for the CGI-Tics-Severity observed 
values (ie, the raw data) and changes from baseline at each visit through Week 14.  Frequency 
counts using the response categories will also be presented by visit.  Descriptive statistics will 
be presented for both the FAS and the PP analysis set.    
The primary analysis of CGI-Tics-Severity will be an MMRM analysis which includes the 
changes from baseline to Weeks 2, 4, 6, 8, 10, and 12 and is based on the FAS.  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 score.  As 
indicated above for the TTS MMRM analysis, nominal two-sided p values for testing the 
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significance of treatment group differences and associated 95% confidence intervals will be 
reported in summary tables; however, interpretation of the p value for the treatment group 
comparison at Week 12 will be based on a procedure which controls for multiple comparisons 
(Section 13.8.3). 
A supportive analysis of the CGI-Tics-Severity scores will be performed using the MMRM 
analysis based on the PP analysis set.  Additional supportive analyses of the CGI-Tics-Severity 
scores will be described in the SAP. 
Responder Endpoints 
The following response statuses at Week 12 will serve as additional secondary endpoints: 
• TTS responder:  a subject whose TTS value is reduced by at least 30% from baseline. 
• CGI-TS-Improvement responder:  a subject whose CGI-TS-Improvement score is either a 
1 (“very much improved”) or a 2 (“much improved”). 
Response at Weeks 2 through 10 are exploratory efficacy endpoints. 
The TTS responder criterion was selected based on a review of studies examining the threshold 
of tic reduction associated with meaningful clinical response (Storch et al., 2011; Jeon et al., 
2013). 
Descriptive statistics for each responder definition will be presented by treatment group for the 
number and percentage of subjects classified as responders at each postbaseline visit.  
Analyses comparing the NBI-98854 treatment group to placebo will be performed using the 
Cochran-Mantel-Haenszel (CMH) procedure, with baseline weight group as a stratification 
variable. 
13.8.3. 
Procedure to Control for Multiple Comparisons 
A fixed-sequence testing procedure will be followed for the primary and secondary efficacy 
endpoints analyses to control for multiple comparisons (ie, comparing treatment groups for each 
of the endpoints).  The fixed-sequence testing procedure will consist of performing the 
hypothesis tests in the following prespecified order: 
1. Primary endpoint:  YGTSS TTS change from baseline to Week 12 (NBI-98854 vs. 
placebo treatment groups using the FAS). 
2. Secondary endpoint:  CGI-Tics-Severity change from baseline to Week 12 (NBI-98854 
vs. placebo treatment groups using the FAS). 
3. Secondary endpoint:  TTS response at Week 12 (NBI-98854 vs. placebo treatment groups 
using the FAS). 
4. Secondary endpoint:  CGI-TS-Improvement response at Week 12 (NBI-98854 vs. placebo 
treatment groups using the FAS). 
Each step in the sequential testing procedure uses a local two-sided 0.05 level of significance 
for the null hypothesis being tested.  The null hypothesis at each step of the procedure can only 
be rejected if all null hypotheses in prior steps were rejected. 
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13.8.4. 
Exploratory Efficacy Endpoints 
Efficacy endpoints not described in the preceding paragraphs are considered exploratory 
endpoints.  Exploratory efficacy endpoints will include the PUTS total score change from 
baseline to the end of Week 12, CGI-TS-Improvement score at the end of Week 12, 
C&A-GTS-QOL total score change from baseline to the end of Week 12, as well as mean 
changes from baseline to the end of Week 12 for the Global Tic Severity and Impairment scores 
from the YGTSS.  Efficacy data will also be summarized from other timepoints (eg, Weeks 2 
through 10).  Details regarding the analyses of these endpoints will be provided in the SAP. 
13.9. 
Safety Data 
Treatment-emergent adverse events (TEAEs), categorized by MedDRA SOC and/or PT will be 
summarized in frequency tables.  The TEAE summary tables will include the number and 
percentage of unique subjects experiencing each event. 
Summary tables will be presented including all TEAEs and TEAEs according to maximum 
intensity.   
Additional summaries will be presented for TEAEs leading to study drug dose reductions, 
premature discontinuations from the study, SAEs, and fatal TEAEs. 
Clinical laboratory, vital signs, ECG, C-SSRS, ESRS-A, CY-BOCS, CDRS-R, and ADHD 
Rating Scale-5 data will be summarized with descriptive statistics.  Potentially clinically 
significant (PCS) values for selected clinical laboratory and vital signs variables will be 
summarized.  Prior and concomitant medications will be summarized according to WHO Drug 
Anatomical Therapeutic Chemical Classification (ATC) categories. 
Any additional planned safety analyses will be described in the SAP. 
13.10. 
Software 
Statistical calculations and summaries will be generated using SAS software version 9.4 or 
later. 
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 FDA, Health 
Canada, 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. 
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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 (originals should be kept by the investigator in the investigator’s 
regulatory document binder): 
• Signed copy of the approved protocol. 
• Investigator’s Brochure acknowledgement page. 
• Completed and signed statement of investigator (Form FDA 1572 and/or Clinical Trial Site 
Information Form – as applicable). 
• Curriculum vitae and current medical license of the investigator and subinvestigators. 
• Financial disclosure information as required. 
• Letter of approval from the IRB for the protocol, consent form, and assent form. 
• Copy of the IRB approved written ICF and assent to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
14.5. 
Informed Consent 
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. 
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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. 
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. 
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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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