Open-Label Rollover Study for Continuing Valbenazine (NBI-98854) Administration for the Treatment of Tardive Dyskinesia
Phase: PHASE3
Conditions: Tardive Dyskinesia
Sponsor: Neurocrine Biosciences

 
CLINICAL PROTOCOL 
Protocol Amendment 3 Version Date:  19 April 2017 
Protocol Amendment 2 Version Date:  12 August 2016 
Protocol Amendment 1 Version Date:  14 March 2016 
Original Final Version Date:  16 February 2016 
 
Open-Label Rollover Study for Continuing Valbenazine (NBI-98854) 
Administration for the Treatment of Tardive Dyskinesia 
 
 
 
Protocol No.:  NBI-98854-1506 
 
Development Phase:  3b 
 
 
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no unpublished information contained herein will be published or disclosed without prior approval 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 Protocol and 
also in accordance with the following: 
• Established principles of Good Clinical Practices (GCP) (Harmonized) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA) 
CLINICAL STUDY TITLE: 
Open-Label Rollover Study for Continuing Valbenazine (NBI-98854) Administration for the 
Treatment of Tardive Dyskinesia 
 
Protocol No.: 
NBI-98854-1506 
 
Sponsor: 
Neurocrine Biosciences, Inc. 
 
12780 El Camino Real 
 
San Diego, CA 92130 
 
Telephone:  (858) 617-7600 
 
Facsimile: 
(858) 617-7705 
 
As Agreed:  
 
__________________________________  
_____________________ 
Principal Investigator Signature  
 
 
Date 
 
PRINCIPAL INVESTIGATOR:   
_________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
________________________________________________________ 
(Print Site Name) 
 
 
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LIST OF PERSONNEL 
Sponsor  
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
 
Medical Monitor:  
 
Telephone: 
Facsimile: 
 
Cell Phone: 
 
 
Director, Clinical Programs:  
 
Telephone: 
 
Facsimile: 
 
 
Serious Adverse Event Reporting: 
Telephone: 
 
Facsimile: 
Email: 
 
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1.
SYNOPSIS
Title of Study:  Open-Label Rollover Study for Continuing Valbenazine (NBI-98854) 
Administration for the Treatment of Tardive Dyskinesia 
Study Number:  NBI-98854-1506 
Study Centers:  Approximately 40 centers in United States. 
Objectives:  
The objectives of this study are: 
•
To provide continued access to valbenazine for the treatment of tardive dyskinesia (TD) in
approximately 150 subjects with schizophrenia, schizoaffective disorder or mood disorder
who have completed a Phase 3 valbenazine study.
•
To collect long-term safety and tolerability data in subjects receiving valbenazine (40 mg or
80 mg) administered once daily for up to 72 weeks (18 months).
Study Design:  This rollover study will provide subjects who completed a Phase 3 valbenazine 
(NBI-98854) study open-label access to valbenazine for the treatment of TD until valbenazine is 
anticipated to be available commercially or they complete 72 weeks of treatment.  In addition, this 
study is designed to collect long-term safety and tolerability data as well as subject-reported 
information following chronic administration of valbenazine in subjects with TD. 
This is a rollover study with open-label, fixed-doses of valbenazine (40 mg or 80 mg) administered 
once daily (qd) for a total of up to 72 weeks of treatment.  This study will allow enrollment of 
approximately 150 medically stable male and female subjects with TD who had previously 
participated in and completed the NBI-98854-1304 or NBI-98854-1402 Phase 3 study.  Subjects can 
have their final NBI-98854-1304 or NBI-98854-1402 visit on the same day as Day 1 for this rollover 
study provided they sign the current study’s informed consent before the final NBI-98854-1304 or 
NBI-98854-1402 visit.  This will allow certain safety assessments to be used for both studies.  The 
safety assessment results that can apply to both studies include physical examinations (including 
weight), vital signs, and electrocardiograms (ECG). 
All subjects must sign an informed consent form (ICF) prior to the conduct of any study-related 
procedures, including washout of medications disallowed in the study.  Before subjects can provide 
informed consent, the investigator (or designee) must determine whether the subject has the capacity 
to provide consent for participation using the University of California, San Diego Brief Assessment of 
Capacity to Consent (UBACC).  Only subjects who are deemed to have the capacity to provide 
consent may sign the ICF. 
On Day 1, eligible subjects will receive a supply of valbenazine 40 mg qd for the first 4 weeks of the 
treatment period.  On Day 2, valbenazine will be administered at home (in the presence of their 
caregiver, if applicable) in the morning or evening.  After Day 2, the subject will be directed to take 
their dose at about the same time each day (eg, morning or evening). 
At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg qd or continue with 
the subject’s current dose (40 mg qd).  A dose escalation will be allowed at the end of Week 4 based 
on the physician investigator’s (or designee’s) assessments of the safety and tolerability of 
valbenazine as well as clinical impression of TD. 
At any time after dose escalation, the investigator may decrease the dose to 40 mg if the subject is 
unable to tolerate the dose increase.  The subject will continue at this dose (40 mg) until the end of the 
treatment period (end of Week 72).  Subjects who are unable to tolerate the starting dose of 40 mg or 
the resumption of 40 mg will be discontinued from the study.   
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Subjects will return to the clinical site every 4 weeks for assessments and dispensation of valbenazine.  
Subjects who do not want to continue in the study will be terminated from the study.  The final 
assessments will be performed at the end of Week 72 or upon early termination.  The clinic visits 
after Day 1 will have a visit window of -7 or +2 days. 
Study Population:  Approximately 150 medically stable adult male and female subjects with clinical 
diagnosis of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder 
with neuroleptic-induced TD will be enrolled.  This study will only enroll subjects who express an 
interest in continuing to receive or re-initiate valbenazine and had previously participated in and 
completed the NBI-98854-1304 or NBI-98854-1402 study.  Subjects must be psychiatrically stable as 
determined clinically by the physician investigator, including a Brief Psychiatric Rating Scale (BPRS) 
score of <50 at Day 1. 
Duration of treatment and study participation:  The expected duration of study participation for 
each subject is up to 72 weeks. 
Investigational product, dosage, and mode of administration:  Valbenazine will be supplied in 
capsule form containing 40 mg (free base equivalent) of NBI-98854 as the ditosylate salt.  The doses 
that will be used in this study are: 40 mg qd taken as one valbenazine 40 mg capsule and 80 mg qd 
taken as two valbenazine 40 mg capsules.  The subjects must swallow the capsules with at least 4 oz. 
of water and can take valbenazine with or without food.  Valbenazine may be taken in the morning or 
evening.  The subject will be directed to take their dose at about the same time each day.  If treatment 
is interrupted for ≤5 missed consecutive doses, subjects are allowed to resume with their current dose 
regimen (40 mg qd or 80 mg qd).  If treatment is interrupted for >5 missed consecutive doses, 
subjects should contact the investigator before resuming treatment; subjects deemed clinically stable 
by the investigator may resume with their current dose regimen (40 mg qd or 80 mg qd). 
Reference therapy, dosage, and mode of administration:  Not applicable. 
Criteria for evaluation: 
Efficacy: 
• 
Clinical Global Impression of TD-severity (CGI-TD-severity) will be completed by the 
investigator at baseline (Day 1) and at the end of Weeks 12, 24, 36, 48, 60, and 72 or upon 
early termination.  
Safety: 
Safety and tolerability will be monitored throughout the study and will include the following 
assessments: 
• 
Adverse events. 
• 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis). 
• 
Vital signs (including orthostatic blood pressure and pulse). 
• 
Physical examinations. 
• 
12-lead electrocardiogram. 
• 
Suicidal ideation and behavior – evaluated using the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
Additional assessments: 
• 
Patient Satisfaction Questionnaire will be completed by the subject at baseline (Day 1) and at 
the end of Weeks 12, 24, 36, 48, 60, and 72 or upon early termination. 
• 
The Social Functioning Scale (SFS) will be completed by the subject at baseline (Day 1) and 
at the end of Weeks 12, 24, 36, 48, 60, and 72 or upon early termination. 
Statistical methods:  Efficacy, safety, tolerability, and additional assessments will be summarized 
using descriptive statistics. 
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TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................7 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................11 
3. 
ETHICS ......................................................................................................................13 
4. 
INTRODUCTION ......................................................................................................13 
4.1. 
Background .................................................................................................................13 
4.2. 
Valbenazine (NBI-98854) ..........................................................................................13 
4.3. 
Study and Dose Rationale ...........................................................................................15 
5. 
STUDY OBJECTIVES ..............................................................................................16 
6. 
STUDY DESIGN .......................................................................................................16 
7. 
STUDY POPULATION .............................................................................................19 
7.1. 
Subject Inclusion Criteria ...........................................................................................19 
7.2. 
Subject Exclusion Criteria ..........................................................................................20 
7.3. 
Subject Identification and Replacement of Subjects ..................................................21 
7.4. 
Randomization ............................................................................................................21 
8. 
EVALUATIONS ........................................................................................................21 
8.1. 
Schedule of Assessments ............................................................................................21 
8.2. 
Baseline Assessments .................................................................................................25 
8.2.1. 
Brief Psychiatric Rating Scale (BPRS).......................................................................25 
8.3. 
Efficacy Assessment ...................................................................................................25 
8.3.1. 
Clinical Global Impression of Tardive Dyskinesia-Severity (CGI-TD-
severity) ......................................................................................................................25 
8.4. 
Safety Assessments .....................................................................................................25 
8.4.1. 
Medical and Surgical History .....................................................................................26 
8.4.2. 
Physical Examination Including Neurological Assessment, Height, and 
Weight .........................................................................................................................26 
8.4.3. 
Vital Sign Measurements ............................................................................................26 
8.4.4. 
Electrocardiogram .......................................................................................................26 
8.4.5. 
Clinical Laboratory Assessments ...............................................................................27 
8.4.6. 
Estimated Total Blood Sample Volume Required by the Study ................................28 
8.4.7. 
Assessment of Suicidal Ideation and Behavior – Columbia-Suicide Severity 
Rating Scale (C-SSRS) ...............................................................................................28 
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8.5. 
Additional Assessments ..............................................................................................29 
8.5.1. 
Patient Satisfaction Questionnaire ..............................................................................29 
8.5.2. 
Social Functioning Scale ............................................................................................29 
8.6. 
Specific Period Information ........................................................................................29 
8.6.1. 
Baseline (Day 1) .........................................................................................................29 
8.6.2. 
Treatment Period ........................................................................................................31 
8.6.2.1. 
Day 2 ...........................................................................................................................31 
8.6.2.2. 
End of Week 4 ............................................................................................................31 
8.6.2.3. 
End of Weeks 8, 16, 20, 28, 32, 40, 44, 52, 56, 64, and 68 ........................................32 
8.6.2.4. 
End of Weeks 12, 24, 36, 48, and 60 ..........................................................................33 
8.6.2.5. 
End of Week 72 (Final Study Visit or Early Termination) ........................................34 
8.7. 
Duration ......................................................................................................................34 
8.8. 
Restrictions .................................................................................................................34 
8.8.1. 
Prior and Concomitant Medications ...........................................................................34 
8.8.2. 
General and Dietary Restrictions ................................................................................35 
8.9. 
Withdrawal Criteria ....................................................................................................35 
8.9.1. 
Reasons for Withdrawal .............................................................................................35 
8.9.2. 
Handling of Withdrawals ............................................................................................36 
8.9.3. 
Sponsor’s Termination of Study .................................................................................36 
9. 
VALBENAZINE ........................................................................................................36 
9.1. 
Valbenazine Drug Supplies ........................................................................................36 
9.2. 
Supply, Storage, and Return (Drug Accountability) ..................................................37 
9.2.1. 
Drug Packaging and Labeling ....................................................................................37 
9.2.2. 
Valbenazine Storage and Return ................................................................................37 
9.2.3. 
Blinding ......................................................................................................................38 
9.3. 
Valbenazine Administration .......................................................................................38 
9.4. 
Valbenazine Compliance and Accountability ............................................................38 
9.5. 
Valbenazine Drug Return ...........................................................................................38 
10. 
ADVERSE EVENTS..................................................................................................39 
10.1. 
Definition ....................................................................................................................39 
10.1.1. 
Intensity of Adverse Events ........................................................................................39 
10.1.2. 
Relationship to Valbenazine .......................................................................................40 
10.2. 
Recording Adverse Events .........................................................................................40 
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10.3. 
Post-Study Follow-Up of Adverse Events ..................................................................41 
10.4. 
Serious Adverse Events ..............................................................................................41 
10.4.1. 
Definition of a Serious Adverse Event .......................................................................41 
10.4.2. 
Managing Serious Adverse Events .............................................................................42 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................42 
10.4.4. 
Expedited Safety Reports ...........................................................................................42 
10.5. 
Pregnancy ...................................................................................................................43 
11. 
DOCUMENTATION OF DATA ...............................................................................43 
11.1. 
Case Report Forms .....................................................................................................43 
11.2. 
Data Capture, Review, and Validation .......................................................................44 
11.3. 
Coding Dictionaries ....................................................................................................44 
12. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................44 
12.1. 
Analysis Sets ...............................................................................................................44 
12.2. 
Sample Size Determination ........................................................................................44 
12.3. 
Handling of Missing Data ...........................................................................................44 
12.4. 
Disposition of Subjects ...............................................................................................45 
12.5. 
Demographics and Baseline Subject Characteristics ..................................................45 
12.6. 
Valbenazine Dosing and Compliance .........................................................................45 
12.7. 
Efficacy Data ..............................................................................................................45 
12.7.1. 
CGI-TD-Severity ........................................................................................................45 
12.8. 
Safety Data ..................................................................................................................45 
12.9. 
Additional Assessments ..............................................................................................45 
12.9.1. 
Patient Satisfaction Questionnaire ..............................................................................45 
12.9.2. 
Social Functioning Scale ............................................................................................46 
12.10. 
Additional Analyses ....................................................................................................46 
12.11. 
Interim Analysis ..........................................................................................................46 
13. 
REGULATORY AND ETHICAL ISSUES ...............................................................46 
13.1. 
General Legal References ...........................................................................................46 
13.2. 
Institutional Review Board/Ethics Committee ...........................................................46 
13.3. 
Protocol Adherence – Amendments ...........................................................................46 
13.4. 
Required Documents ..................................................................................................46 
13.5. 
Informed Consent .......................................................................................................47 
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13.6. 
Study Monitoring ........................................................................................................47 
13.7. 
Quality Assurance .......................................................................................................47 
13.8. 
Record Retention ........................................................................................................47 
13.9. 
Confidentiality ............................................................................................................48 
14.
STUDY COMMENCEMENT AND DISCONTINUATION ....................................48
15.
REFERENCES ...........................................................................................................49
16.
APPENDICES ............................................................................................................50
 
 
 
 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................23 
Table 2: 
Estimated Total Blood Sample Volume .....................................................................28 
Table 3: 
Intensity of Adverse Events ........................................................................................40 
Table 4: 
Relationship of Adverse Events to Valbenazine ........................................................40 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................18 
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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
β-hCG 
β-human chorionic gonadotropin  
BMI 
Body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CDS 
Clinical Drug Safety 
CFR 
Code of Federal Regulations 
CGI-TD-severity Clinical Global Impression of Tardive Dyskinesia-Severity 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report forms 
EDC 
Electronic Data Capture 
EDTA K2 
Dipotassium ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
Gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
MAOI 
Monoamine oxidase inhibitors 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
OTC 
Over the counter 
qd 
Once daily 
QTcF 
Corrected QT interval using Fridericia’s formula 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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SD 
Standard deviation 
SEM 
Standard error of the mean 
SFS 
Social Functioning Scale 
SOC 
System organ class 
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
UBACC 
University of California, San Diego Brief Assessment of Capacity to 
Consent 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
US 
United States 
VMAT2 
Vesicular monoamine transporter 2 
WBC 
White blood cell 
WHO Drug 
World Health Organization Drug Dictionary 
 
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3. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) standards 
that meet regulations relating to Good Clinical Practices (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, May 
1996). 
• United States (US) Code of Federal Regulations (CFR) regulating clinical studies (21 CFR 
parts 50, 54, 56, 312, and 314). 
The ethical requirements of Institutional Review Boards/Ethics Committees (IRBs/ECs) and the 
Informed Consent Forms (ICFs) are discussed in Section 13. 
4. 
INTRODUCTION   
4.1. 
Background 
Tardive dyskinesia (TD) is a neurological condition characterized by involuntary movements of 
the orofacial region (ie, tongue, lips, jaw, face), limbs, and trunk.  TD develops with chronic 
neuroleptic drug use and often persists after discontinuation of the offending medication.  Only a 
small proportion of patients who are treated with dopamine receptor blocking drugs develop this 
syndrome.  While isolated case reports of TD after short-term exposure exist, most often TD 
emerges after long-term neuroleptic treatment over months to years.  The Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines chronic exposure to 
neuroleptics and duration of symptoms as the basis for TD diagnosis.  In addition to duration and 
amount of neuroleptic exposure, other risk factors for TD appear to include older age, 
schizophrenia, and cognitive impairment (Margolese et al, 2005).  TD can be disabling, lead to 
bodily harm (eg, lip or tongue lacerations, falls), interfere with activities of daily living, and 
result in social isolation. 
The pathophysiology of TD is not fully understood; however, post-synaptic dopamine 
hypersensitivity in the striatum is the most prominent feature (Margolese et al., 2005).  
Dysregulation of dopaminergic systems is an integral component of several CNS disorders, 
including other hyperkinetic movement disorders and conditions such as schizophrenia and 
bipolar disorder.  The transporter protein vesicular monoamine transporter 2 (VMAT2) plays an 
important role in presynaptic dopamine release, regulating monoamine uptake from the 
cytoplasm to the synaptic vesicle for storage and release.  The differential expression of VMAT2 
in human brain (versus endocrine tissue) makes agents that selectively target VMAT2 potentially 
useful for the treatment of CNS disorders (Weihe and Eiden, 2000). 
4.2. 
Valbenazine (NBI-98854)  
NBI-98854 (valbenazine tosylate) is a highly selective, orally active VMAT2 inhibitor and is 
currently under development at Neurocrine Biosciences, Inc. (NBI) for the treatment of tardive 
dyskinesia (TD) and Tourette syndrome (TS). 
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In nonclinical studies, NBI-98854 appears to cause little or no cytochrome P450 (CYP) enzyme 
inhibition or induction at pharmacologically relevant concentrations.  Metabolism of NBI-98854 
is characterized by hydrolysis of NBI-98854 to NBI-98782, and CYP3A4/5-dependent mono-
oxidation to NBI-136110.  All 3 entities, namely, NBI-98854, NBI-98782, and NBI-136110, 
have the ability to bind to and inhibit VMAT2.  However, NBI-98782 is the most potent and 
appears to be responsible for the majority of the observed pharmacological activity of VMAT2 
inhibition.  NBI-98854 delivers NBI-98782 in a controlled fashion with limited peak-to-trough 
plasma concentration fluctuation and low pharmacokinetic (PK) variability that should limit 
adverse events (AEs) associated with excessive monoamine depletion.  Repeat-dose nonclinical 
toxicology studies conducted in mice, rats, and dogs have revealed no adverse effects at doses of 
60 mg/kg/day in the mouse, 3 mg/kg/day in the rat and 15 mg/kg/day in the dog.  Additionally, 
cardiovascular, pulmonary, and central nervous system (CNS) safety pharmacology studies have 
also been conducted, where the no observed adverse effect level (NOAEL) was equal to or 
exceeded the 15 mg/kg level seen in repeat dose toxicology studies.  NBI-98854 had a modest 
negative effect on rat fertility at 10 mg/kg/day (NOAEL of 3 mg/kg/day).  The NOAEL for 
embryo/fetal development in rats and rabbits was 15 mg/kg/day and 50 mg/kg/day, respectively. 
There was no evidence of teratogenicity in rats or rabbits.  Finally, NBI-98854 was negative in 
in vitro mutagenicity assays (namely, Ames and chromosomal aberration) and an in vivo rat 
micronucleus test. 
Thirteen clinical studies with NBI-98854 have been completed to date:  9 Phase 1 studies, 8 in 
healthy male and female elderly and nonelderly subjects, and 1 in hepatically impaired adults; 
and 4 Phase 2 studies in subjects with TD and a clinical diagnosis of schizophrenia or 
schizoaffective disorder, mood disorder, or gastrointestinal (GI) disorder.  In addition, 
preliminary data are available for the 6-week, placebo-controlled period for the ongoing Phase 3 
study NBI-98854-1304 in subjects with TD and a clinical diagnosis of schizophrenia or 
schizoaffective disorder, or mood disorder.  A total of 510 subjects have received at least 1 dose 
of NBI-98854 and 246 received placebo in these studies.  
Clinical PK data indicate that when administered orally under fasted conditions, NBI-98854 
appeared to be rapidly absorbed with maximum plasma concentration being reached within 
1 hour.  An active metabolite, NBI-98782, was formed gradually with maximum plasma 
concentration typically being reached 4 to 10 hours after dosing.  Plasma concentrations for both 
NBI-98854 and NBI-98782 appeared to decline after reaching maximal concentration and both 
exhibited an apparent terminal half-life of approximately 20 hours in non-elderly adult subjects 
and 23 to 28 hours in elderly subjects.  Coadministration of ketoconazole (strong CYP3A4/5 
inhibitor) with NBI-98854 caused an approximate 1.5- and 1.7-fold increase in Cmax of 
NBI-98854 and NBI-98782, respectively.  Coadministration of NBI-98854 and rifampin (strong 
CYP3A4/5 inducer) led to an approximate 29% and 72% decrease in Cmax and AUC0–∞, 
respectively, for NBI-98854, and an approximate 50% and 77% decrease, respectively, for 
NBI-98782 compared with administration of NBI-98854 alone.  For NBI-136110, concomitant 
administration with rifampin led to a 50% increase in Cmax and a 68% decrease in AUC0–∞ 
compared with administration of NBI-98854 alone.  Administration in subjects with hepatic 
impairment resulted in a Cmax of NBI-98854 of 1.46- and 1.65-fold greater in subjects with 
moderate and severe hepatic impairment, respectively, than in subjects with normal hepatic 
function. 
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NBI-98854 has been generally well tolerated in single doses up to 300 mg and in multiple doses 
of up to 100 mg.  In Phase 2 studies and the interim analysis from one Phase 3 study, treatment-
emergent adverse events (TEAEs) were reported by 42.8% and 36.4% of NBI-98854 and 
placebo subjects, respectively.  AEs reported in ≥2% of NBI-98854 subjects and at a higher 
incidence than placebo included somnolence, headache, fatigue, vomiting, dry mouth, akathisia, 
and fall.  Suicidal ideation was reported in a similar percentage of subjects receiving NBI-98854 
or placebo (2.0% and 1.9%, respectively).  Most TEAEs were mild or moderate in intensity.  
Two deaths have been reported in clinical studies; 1 subject who received placebo died due to 
cardiopulmonary arrest secondary to myocardial infarction and the second subject died possibly 
due to a cardiovascular event (treatment remains blinded).  No treatment-emergent serious AEs 
(SAEs) have been reported in Phase 1 studies.  In Phase 2 studies and the interim analysis from 
one Phase 3 study, SAEs were reported in 17 subjects (4.9%) who received NBI-98854 and 
6 subjects (2.8%) who received placebo.  There were no clinically important differences in the 
number or types of SAEs reported across dose groups.  Only 1 SAE (acute hepatitis) was 
assessed by the investigator as possibly related to study drug.  No cardiovascular, laboratory, or 
vital sign related safety signals have been identified.  Increases in serum prolactin above normal 
laboratory ranges have been noted, but there have been no TEAEs associated with 
hyperprolactinemia.  In general, depression, drug-induced akathisia, and drug-induced 
parkinsonism did not worsen during treatment with NBI-98854. 
Results from Phase 2 studies indicated an improvement in the Abnormal Involuntary Movement 
Scale (AIMS) score after 6 weeks of continuous dosing with either NBI-98854 50 mg once daily, 
continuous dosing with NBI-98854 100 mg once daily for 2 weeks followed by continuous 
dosing with NBI-98854 50 mg once daily for 4 weeks (NBI-98854-1201; preliminary data), 
6 weeks of titrated doses from 25 mg up to 75 mg NBI-98854 once daily (NBI-98854-1202).  
Preliminary results from the 6-week placebo-controlled treatment period in the Phase 3 study 
(NBI-98854-1304) indicated a statistically significant improvement in the AIMS dyskinesia total 
score mean change from baseline for the NBI-98854 80 mg group compared with placebo.  
Similar results were also observed for the NBI-98854 40 mg group.  Results from an open-label 
safety extension with dosing up to 12 weeks (NBI-98854-1201) showed continued benefit in 
subjects who continued taking NBI-98854 50 mg daily and also in subjects originally assigned to 
placebo who went on to receive NBI-98854 50 mg once daily for the 6 weeks of open-label 
treatment.  Results from the 6 week dose-titration study (NBI-98854-1202) showed a statistically 
significant reduction in the AIMS dyskinesia total score in the NBI-98854 group compared to 
placebo.  A statistically significant higher responder rate (ie, ≥50% improvement in AIMS 
dyskinesia total score from baseline) was also observed in the NBI-98854 group compared with 
placebo. 
4.3. 
Study and Dose Rationale 
All subjects in the current study will have previously received valbenazine 40 mg to 80 mg for 
42 to 48 weeks in a Phase 3 valbenazine study (NBI-98854-1304 or NBI-98854-1402).  In the 
current study, subjects will receive a starting dose of valbenazine 40 mg once daily (qd) for 
4 weeks.  At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg qd or 
continue with the subject’s current dose (40 mg qd).  A dose escalation will be allowed at the end 
of Week 4 based on the physician investigator’s (or designee’s) assessments of the safety and 
tolerability of valbenazine as well as clinical impression of TD. 
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At any time after dose escalation, the investigator may decrease the dose to 40 mg if the subject 
is unable to tolerate the dose increase.  The subject will continue at this dose (40 mg) until the 
end of the treatment period (end of Week 72).  Subjects who are unable to tolerate the starting 
dose of 40 mg or the resumption of 40 mg will be discontinued from the study. 
Clinical data from TD subjects administered repeated doses of valbenazine from 12.5 mg to 
100 mg per day indicate that valbenazine is generally well tolerated and associated with 
dose-related efficacy.  Exposure-response analysis indicates that a steady state maximum plasma 
concentration (Cmax) of 20 to 40 ng/mL NBI-98782 is an appropriate plasma concentration range 
for efficacy.   
Valbenazine doses of 40 mg and 80 mg are associated with exposure to the active metabolite, 
NBI-98782, in the target range of 20 to 40 ng/mL when administered initially as 40 mg qd and 
adjusted upward to 80 mg qd if dyskinesia persists after several weeks of treatment.  These doses 
have been selected to provide exposure associated with acceptable tolerability and robust 
efficacy.  Doses below 40 mg are well tolerated but offer dyskinesia reduction comparable to 
placebo.  Doses above 80 mg afford little incremental benefit but increase the risk of adverse 
events (AEs) reflecting extension of VMAT2 pharmacology.  Because many subject-specific 
factors appear to influence tolerability and efficacy, clinicians will be required to start all 
subjects at 40 mg, the lower of the two doses. 
5. 
STUDY OBJECTIVES 
The objectives of this study are: 
• To provide continued access of valbenazine for the treatment of tardive dyskinesia (TD) 
in approximately 150 subjects with schizophrenia, schizoaffective disorder or mood 
disorder who have completed a Phase 3 valbenazine study. 
• To collect long-term safety and tolerability data in subjects receiving valbenazine (40 mg 
or 80 mg) administered once daily for up to 72 weeks (18 months). 
6. 
STUDY DESIGN 
This rollover study will provide subjects who completed a Phase 3 valbenazine study open-label 
access to valbenazine for the treatment of TD until valbenazine is anticipated to be available 
commercially or they complete 72 weeks of treatment.  In addition, this study is designed to 
collect long-term safety and tolerability data as well as subject-reported information following 
chronic administration of valbenazine in subjects with TD.  
This is a rollover study with open-label, fixed-doses of valbenazine (40 mg qd or 80 mg qd) for a 
total of up to 72 weeks of treatment.  This study will allow enrollment of approximately 
150 medically stable male and female subjects with TD who had previously participated in and 
completed the NBI-98854-1304 or NBI-98854-1402 Phase 3 study.  Subjects can have their final 
NBI-98854-1304 or NBI-98854-1402 visit on the same day as Day 1 for this rollover study 
provided they sign the current study’s informed consent before the final NBI-98854-1304 or 
NBI-98854-1402 visit.  This will allow certain safety assessments to be used for both studies.  
The safety assessment results that can apply to both studies include physical examinations 
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(including weight), vital signs, and electrocardiograms (ECG).  Other Day 1 assessments 
(including safety labs) must be collected for the current study (even if the subject is completing 
the final visit for the previous study).  The study will be conducted in approximately 40 centers 
in the US.  A schematic of the study design is shown in Figure 1. 
All subjects must sign an ICF prior to the conduct of any study-related procedures, including 
washout of medications disallowed in the study.  Before subjects can provide informed consent, 
the investigator (or designee) must determine whether the subject has the capacity to provide 
consent for participation using the University of California, San Diego Brief Assessment of 
Capacity to Consent (UBACC; Jeste et al., 2007).  A copy of the UBACC is provided in 
Appendix 16.1.  Only subjects who are deemed to have the capacity to provide consent may sign 
the ICF. 
On Day 1, eligible subjects will receive a supply of valbenazine 40 mg qd for the first 4 weeks of 
the treatment period.  On Day 2, valbenazine will be administered at home (in the presence of 
their caregiver, if applicable) in the morning or evening.  After Day 2, the subject will be 
directed to take their dose at about the same time each day (eg, morning or evening). 
At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg qd or continue 
with the subject’s current dose (40 mg qd).  A dose escalation will be allowed at the end of 
Week 4 based on the physician investigator’s (or designee’s) assessments of the safety and 
tolerability of valbenazine as well as clinical impression of TD. 
At any time after dose escalation, the investigator may decrease the dose to 40 mg if the subject 
is unable to tolerate the dose increase.  The subject will continue at this dose (40 mg) until the 
end of the treatment period (end of Week 72).  Subjects who are unable to tolerate the starting 
dose of 40 mg or the resumption of 40 mg will be discontinued from the study.  If treatment is 
interrupted for ≤5 missed consecutive doses, subjects are allowed to resume with their current 
dose regimen (40 mg qd or 80 mg qd).  If treatment is interrupted for >5 missed consecutive 
doses, subjects should contact the investigator before resuming treatment; subjects deemed 
clinically stable by the investigator may resume with their current dose regimen (40 mg qd or 
80 mg qd).  
Subjects will return to the clinical site every 4 weeks for assessments and dispensation of 
valbenazine.  Subjects who do not want to continue in the study will be terminated from the 
study.  The final assessments will be performed at the end of Week 72 or early termination. 
The clinic visits after Day 1 will have a visit window of -7 or +2 days. 
 
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Figure 1: 
Study Design Schematic 
Week 
1
4
NBI-98854 Treatment Period
Prolactin  
16
C-SSRS = Columbia Suicide Severity Rating Scale; CGI-TD Severity = Clinical Global Impression -Tardive Dyskinesia Severity
Safety Assessments
Day 
C-SSRS
8
Dosing (QD)   
40 mg 
NBI-
98854
40 or 80 mg NBI-98854
24
36
40
12
20
28
32
44
48
52
56
60
64
68 72/ET
CGI-TD Severity
Patient Satisfaction 
Questionnaire  
Social Functioning Scale
 
 
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7. 
STUDY POPULATION 
This study will include approximately 150 medically stable adult male and female subjects with 
clinical diagnosis of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or 
mood disorder with neuroleptic-induced TD.  This study will only enroll subjects who express an 
interest in continuing to receive or re-initiate valbenazine and had previously participated in and 
completed the NBI-98854-1304 or NBI-98854-1402 study.  Subjects must be psychiatrically 
stable as determined clinically by the physician investigator, including a Brief Psychiatric Rating 
Scale (BPRS) score of <50 at Day 1. 
7.1. 
Subject Inclusion Criteria 
To participate in this study, subjects must meet the following criteria: 
1. Be male or female aged 18 to 85 years (inclusive). 
2. Have participated in and completed the NBI-98854-1304 or NBI-98854-1402 Phase 3 study.  
Subjects can have their final NBI-98854-1304 or NBI-98854-1402 visit on the same day as 
Day 1 for this rollover study provided they sign the current study’s informed consent before 
the final NBI-98854-1304 or NBI-98854-1402 visit. 
3. Subjects of childbearing potential must agree to use hormonal or two forms of nonhormonal 
contraception (dual contraception) consistently throughout the study and until 30 days after 
the last dose of valbenazine.   
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 taken for at least 3 months prior to Day 1. 
The following subjects are not required to use contraception:  
• Subjects who practice total abstinence from sexual intercourse as the preferred lifestyle 
(periodic abstinence is not acceptable).   
• Female subjects with partners or male subjects who had been vasectomized at least 
3 months prior to Day 1. 
• Female subjects who have been postmenopausal for at least 1 year prior to Day 1. 
• Female subjects who are surgically sterile (ie, bilateral oophorectomy, hysterectomy, or 
bilateral tubal ligation) at least 3 months prior to Day 1. 
4.   Female subjects who have not been postmenopausal for at least 1 year must have a negative 
urine pregnancy test on Day 1. 
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5.   Maintenance medication(s) for schizophrenia or schizoaffective disorder, mood disorders, 
and other nonprohibited concurrent medications (see Section 8.8.1) should be at a stable dose 
(including no changes to the dose and frequency of ongoing medications and no 
discontinuation of medications) for a minimum of 30 days before Day 1.  Benzodiazepines 
must be at a stable dose for 2 weeks before Day 1.  This criterion will be satisfied if the 
investigator can confirm prior and current medications and doses through reliable subject-
reported information (eg, subject provides a list of medications and doses). 
6.   Subjects with a diagnosis of schizophrenia or schizoaffective disorder who are not using 
antipsychotic medication must have a stable psychiatric status as clinically determined by the 
investigator.  Subjects with a diagnosis of bipolar disorder must be on stable dose of mood 
stabilizer(s) (eg, lithium, valproate, or olanzapine) for a minimum of 30 days before Day 1. 
7.   Be in good general health and expected to complete the study as designed. 
8.   Have a body mass index (BMI) of 18 to 42 kg/m2 (inclusive) on Day 1.  (BMI is defined as 
the subject’s weight in kg divided by the square of the subject’s height in meters.) 
9.   Have adequate hearing, vision, and language skills to perform the procedures specified in the 
protocol. 
10. Have voluntarily provided informed consent and have signed an ICF indicating that the 
purpose of the study has been explained, and are willing and able to adhere to the study 
regimen and procedures described in the ICF.  Subjects must also have been deemed capable 
of providing consent to study participation using the UBACC prior to signing the ICF. 
11. Have a negative urine drug screen (UDS) (negative for amphetamines, barbiturates, 
benzodiazepine, phencyclidine, cocaine, opiates, and cannabinoids) at Day 1 (UDS kit results 
conducted at the clinical site), except for any subject receiving a stable dose of barbiturates, 
benzodiazepines, or opiates.  Subjects with positive cannabinoid results may be allowed to 
participate in the study provided that the subject is given thorough counseling and agrees to 
refrain from using cannabinoids for the duration of his/her study participation.  
12. Have a negative alcohol breath test on Day 1. 
13. Be willing to provide authorization for access to personal health information in conjunction 
with US Health Insurance Portability and Accountability Act (HIPAA). 
7.2. 
Subject Exclusion Criteria 
Subjects will be excluded from the study if they: 
1. Have an active clinically significant unstable medical condition within 30 days prior to 
Day 1. 
2. Have history of severe hepatic impairment or have chronic elevation of aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 times upper limit of normal 
(ULN). 
3. Have clinically significant parkinsonism (eg, tremor, rigidity, bradykinesia, balance/gait 
issues) as assessed by the investigator. 
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4. Have a known history of substance dependence, or substance (drug) or alcohol abuse within 
3 months prior to Day 1 (nicotine and caffeine dependence are not exclusionary), as defined 
in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (eg, DSM-IV). 
5. Have a significant risk of suicidal or violent behavior.  Subjects with any 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 Columbia-
Suicide Severity Rating Scale (C-SSRS) in the 3 months prior to Day 1 (using 
Screening/Baseline version) will be excluded.  
6. Have BPRS total score of ≥50 on Day 1. 
7. Have a known history of neuroleptic malignant syndrome. 
8. Have a known history of long QT syndrome or cardiac arrhythmia. 
9. Have an electrocardiogram (ECG) QT interval corrected for heart rate using corrected QT 
interval using Fridericia’s formula (QTcF) of >450 msec (males) or >470 msec (females) on 
Day 1 or the presence of any clinically significant cardiac abnormality. 
10. Receive any excluded concomitant medication. 
11. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to Day 1, with 
the exception of localized skin cancer or carcinoma in situ of the cervix. 
12. Have received an investigational drug (other than valbenazine) within 30 days prior to Day 1 
or plan to use an investigational drug (other than valbenazine) during the study. 
13. Have a blood loss ≥550 mL or donated blood within 30 days prior to Day 1. 
14. Have an allergy, hypersensitivity, or intolerance to tetrabenazine. 
15. Are currently pregnant or breastfeeding. 
7.3. 
Subject Identification and Replacement of Subjects 
Subjects will be identified by their unique subject number and initials (first, middle, last).  The 
subject initials and subject number will be noted on electronic case report forms (eCRFs), all 
source documentation, laboratory documents, and ECG tracings.  Subjects who discontinue from 
the study after the initiation of dosing will not be replaced. 
7.4. 
Randomization 
Subjects will not be randomized in this study. 
8. 
EVALUATIONS 
8.1. 
Schedule of Assessments 
Table 1 summarizes the frequency and timing of all study assessments and procedures.  Subjects 
will provide written informed consent before any study-related procedures are performed, 
including the cessation of prohibited concomitant medications.  Subject-related activities and 
events including specific instructions, procedures, concomitant medications, dispensing of 
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valbenazine, and descriptions of AEs will be recorded in the appropriate source documents and 
eCRFs. 
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Table 1: 
Schedule of Assessments 
Procedure 
Baseline 
Open-Label Valbenazine Treatment Period 
Week
a Day 1
b DAY 2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72/ET
c 
Visita 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Informed consent/ UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including weight) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead electrocardiogram
d 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy test
e 
X (S,U) 
 
X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) X (U) 
Clinical laboratory tests
f 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine drug screen
g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum prolactin 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS
h 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-TD-severity 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Patient Satisfaction Questionnaire 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Social Functioning Scale 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Daily valbenazine dosing at home
i 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense valbenazine
j 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Valbenazine accountability
k 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and footnotes appear on the following page. 
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Definitions:  BPRS=Brief Psychiatric Rating Scale; CGI-TD-severity=Clinical Global Impression of Tardive Dyskinesia-Severity; C-SSRS=Columbia-Suicide 
Severity Rating Scale; ECG=electrocardiogram; ET=early termination; QTcF=corrected QT interval using Fridericia’s formula; S=serum; U=urine; 
UBACC=University of California, San Diego Brief Assessment of Capacity to Consent. 
a The visits after Day 1 will have a visit window of -7 or +2 days. 
b For subjects completing the final NBI-98854-1304 or NBI-98854-1402 visit on the same day as Day 1, the NBI-98854-1304 or NBI-98854-1402 assessments 
for physical examination (including weight), vital signs, and ECG will be used for Day 1. 
c Final visit for subjects who complete the study (or early termination). 
d A standard 12-lead ECG will be conducted after the subject has rested supine for at least 5 minutes.  The ECG parameters that will be assessed include heart 
rate, QT interval, QTcF, PR interval, and QRS duration based on the ECG machine readings.  
e Pregnancy tests are only required for female subjects who are not postmenopausal for at least 1 year prior to Day 1.  Urine and serum pregnancy tests will be 
conducted at Day 1.  The urine pregnancy test result on Day 1 will be used to confirm eligibility. 
f Clinical laboratory tests include hematology, clinical chemistry, and urinalysis.  All blood samples will be obtained under non-fasted conditions. 
g Urine drug screen (UDS) collected on Day 1 will be analyzed by the central lab.  In addition, a UDS kit provided by the central lab will be used at the clinical 
site to confirm eligibility on Day 1.  A UDS using a kit provided by the central lab may be conducted at the clinical site at any time during the study if the 
subject is suspected of substance or drug abuse. 
h The "Screening/Baseline" version should be used at baseline (Day 1) and "Since Last Visit" version should be used at all subsequent visits. 
i Starting on Day 2, subjects will self-administer valbenazine daily (in the morning or evening, at approximately the same time each day) at home in the presence 
of their caregiver (if applicable).  
j Subjects will receive a 4-week supply of valbenazine on Day 1 and will need to return to clinical site every 4 weeks to obtain a 4-week supply of valbenazine. 
k At the end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 subjects will return all unused valbenazine, and a compliance check 
will be performed by counting the capsules returned at the visit. 
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8.2. 
Baseline Assessments 
8.2.1. 
Brief Psychiatric Rating Scale (BPRS) 
The BPRS is a clinician-rated tool designed to assess the severity of psychopathology in patients 
with schizophrenia and other psychotic disorders (Overall and Gorham, 1962, 1988).  The BPRS 
includes 18 items that address somatic concern, anxiety, emotional withdrawal, conceptual 
disorganization, guilt feelings, tension, mannerisms and posturing, grandiosity, depressive mood, 
hostility, suspiciousness, hallucinatory behaviors, motor retardation, uncooperativeness, unusual 
thought content, blunt affect, excitement, and disorientation.   
The severity of each of the 18 items of the BPRS is rated on a scale of 1 (not present) to 7 
(extremely severe) (total score range: 18 to 126).  Higher scores represent greater symptom 
severity.   
The investigator or other qualified clinical site personnel will administer and score the scale at 
baseline (Day 1), and subjects must have a BPRS total score <50 to be eligible for study 
participation (see exclusion criterion #6).  A copy of the BPRS is provided in Appendix 16.2. 
8.3. 
Efficacy Assessment 
8.3.1. 
Clinical Global Impression of Tardive Dyskinesia-Severity (CGI-TD-severity)  
The CGI-TD-severity, which is based on a 7-point scale (range:  1=normal, not at all ill to 
7=among the most extremely ill patient), will be used to rate the overall global severity of TD.  
This scale is a modification of a scale developed by the Psychopharmacology Research Branch 
of the National Institute of Mental Health (Guy, 1976).  A copy of the CGI-TD-severity is 
provided in Appendix 16.3. 
The investigator or qualified clinician designee (eg, psychologist or social worker) will rate the 
scale at the scheduled times.  If possible, the same person should rate the CGI-TD-severity at all 
visits.     
The CGI-TD-severity will be completed by the investigator at baseline (Day 1) and during the 
treatment period at the end of Weeks 12, 24, 36, 48, 60, and 72 (final study visit or upon early 
termination). 
8.4. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 8.8.1 and Section 10, respectively.  Additional safety assessments are described in the 
following sections. 
Any abnormal vital sign measurement, clinical laboratory test, physical examination finding, or 
ECG parameter deemed clinically significant by the investigator will be repeated as needed, 
including test results obtained on 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 
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the C-SSRS or clinical assessment), the finding will be documented as an AE, and appropriate 
psychiatric evaluation and intervention will be provided. 
For subjects completing the final NBI-98854-1304 or NBI-98854-1402 visit on the same day as 
Day 1, the NBI-98854-1304 or NBI-98854-1402 assessments for physical examination 
(including weight), vital signs, and ECG will be used for Day 1. 
8.4.1. 
Medical and Surgical History 
A general medical and surgical history will be obtained at baseline (Day 1).  
The subject’s psychiatric history will be documented and will include the subject’s age at first 
diagnosis of schizophrenia or schizoaffective disorder or mood disorder, and age at TD 
diagnosis.  If necessary, subject age at onset can be estimated by the investigator based upon 
available clinical information. 
8.4.2. 
Physical Examination Including Neurological Assessment, Height, and Weight 
A complete physical examination will consist of an assessment of the following: general 
appearance; skin and mucosa; head, eyes, ears, nose, throat; lymph nodes; chest/lungs; 
cardiovascular; abdomen; extremities; musculoskeletal; and neurological system.  
A physical examination including weight will be conducted at baseline (Day 1) and during the 
treatment period at Weeks 12, 24, 36, 48, 60, and 72 (final study visit or upon early termination).  
Height will be recorded at baseline (Day 1) only.  Height and weight will be recorded with 
subjects wearing ordinary indoor clothing without shoes.  Height and weight will be used to 
calculate the BMI (kg/m2). 
8.4.3. 
Vital Sign Measurements 
Vital sign measurements, including orthostatic systolic and diastolic blood pressure, orthostatic 
pulse rate, respiratory rate (supine), and oral body temperature will be measured at the visits 
stated below.  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 baseline (Day 1) and during the treatment period at 
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 (final study visit or 
upon early termination). 
8.4.4. 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicate (1 to 3 minutes apart) after the subject has 
rested supine for at least 5 minutes.  The ECG parameters that will be assessed include HR, PR 
interval, QRS duration, QT interval, and QTcF (machine readings or calculated).  Additionally, 
the occurrence of de- and re-polarization and rhythm disorders or other abnormalities will be 
assessed.  Based on the review of these parameters, the investigator or designee will note if the 
ECG is Normal, Abnormal Not Clinically Significant, or Abnormal Clinically Significant.  If the 
ECG is Abnormal Clinically Significant, the investigator or designee will provide a description 
of the abnormality recorded on the AE eCRF. 
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The 12-lead ECG recordings will be conducted at baseline (Day 1) and during the treatment 
period at Weeks 4, 12, 24, 36, 48, 60, and 72 (final study visit or upon early termination).  
8.4.5. 
Clinical Laboratory Assessments 
All clinical laboratory tests will be analyzed by a central laboratory (unless otherwise noted 
below), which will provide instructions and supplies to the clinical site staff before study 
initiation.  Laboratory samples will be collected in the following approximate amounts: 4 mL for 
hematology, 4mL for hemoglobin A1c (HbA1c), and 5 mL for clinical chemistry (includes 
serum pregnancy test at baseline). 
The routine laboratory tests (hematology, clinical chemistry, and urinalysis) will be performed 
under non-fasted conditions at baseline (Day 1) and during the treatment period at Weeks 12, 24, 
36, 48, 60, and 72 (final study visit or upon early termination). 
The following clinical safety laboratory assays will be performed: 
Hematology:  complete blood count including white blood cell (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).  A sample for 
HbA1c will also be collected (approximately 4 mL in dipotassium ethylenediaminetetraacetic 
acid [EDTA K2]). 
Clinical Chemistry:  sodium, potassium, calcium, magnesium, chloride, blood urea nitrogen, 
bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate dehydrogenase, AST, 
ALT, gamma-glutamyl transferase (GGT), creatine kinase, total bilirubin, total cholesterol, 
triglycerides, total protein, and glucose. 
Urinalysis:  specific gravity, nitrite, ketones, protein, urobilinogen, glucose, bilirubin, leukocyte 
esterase, occult blood, and pH; microscopic examination of sediment will be performed only if 
the results of the urinalysis dipstick evaluation are positive for protein, leukocyte esterase, or 
blood. 
The following additional laboratory tests will be performed: 
Urine Drug Screen:  UDS collected at baseline (Day 1) will be analyzed by the central lab for 
amphetamines, barbiturates, benzodiazepines, phencyclidine, cocaine, opiates, and cannabinoids.  
In addition, a UDS kit provided by the central lab will be used at the clinical site to confirm 
eligibility at baseline (Day 1).  A UDS using a kit provided by the central lab may be conducted 
at the clinical site at any time during the study if the subject is suspected of substance or drug 
abuse. Subjects with a positive cannabinoid result may be allowed to participate in the study 
provided that the subject is given thorough counseling and agrees to refrain from using 
cannabinoids for the duration of his/her study participation.  Subjects receiving a chronic and 
stable dose of benzodiazepines, barbiturates, or opiates are allowed into the study (refer to 
Section 8.8.1).  
Alcohol:  An alcohol breathalyzer test will be conducted at baseline (Day 1) at the clinical site to 
confirm eligibility.  This test may be randomly performed at any time during the study at the 
investigator’s discretion. 
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Pregnancy Test:  Pregnancy tests will be performed throughout the study for female subjects who 
are not postmenopausal for at least 1 year.  A serum pregnancy test (β-human chorionic 
gonadotropin [β-hCG]) will be conducted for all female subjects on Day 1 (as part of clinical 
chemistry) and analyzed by the central laboratory.  A urine pregnancy test will be performed at 
the clinical site at baseline (Day 1) to confirm eligibility, as well as at Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 (final study visit or upon early termination). 
Prolactin:  Blood samples to determine serum prolactin concentration will be collected at 
baseline (Day 1) and during the treatment period at Weeks 12, 24, 36, 48, 60, and 72 (final study 
visit or upon early termination).  Approximately 5 mL of blood will be collected into a serum 
separator tube.  Serum prolactin samples will be shipped to a central laboratory for analysis. 
For any abnormal tests deemed clinically significant, repeat analysis will be performed until the 
cause of the abnormality is determined or until the value returns to baseline (or within normal 
limits), or the investigator deems the abnormality to be of no clinical significance. 
8.4.6. 
Estimated Total Blood Sample Volume Required by the Study 
The estimated total blood sample volume for each subject is presented in Table 2.  These 
estimates include samples to be collected during baseline and the treatment period (or upon early 
termination). 
Table 2: 
Estimated Total Blood Sample Volume 
Parameter 
Number of Samples 
Required 
Approximate 
Volume (mL) 
Approximate Total 
Volume (mL) 
Clinical chemistry
a 
7 
5 
35 
Hematology 
7 
4 
28 
HbA1c 
7 
4 
28 
Prolactin 
7 
5 
35 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
126 
a Includes pregnancy test for female subjects at baseline (Day 1). 
8.4.7. 
Assessment of Suicidal Ideation and Behavior – Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
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 
baseline (Day 1: Screening/Baseline version) and visits throughout the study (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 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 in the 3 months prior to Day 1 (using 
Screening/Baseline version) should be excluded (see exclusion criterion #5).  A copy of the 
C-SSRS (Screening/Baseline and Since Last Visit) is provided in Appendix 16.4. 
The C-SSRS will be administered and scored by the investigator or other qualified clinical site 
personnel who have completed C-SSRS certification.  The C-SSRS will be administered at 
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baseline (Day 1) and during the treatment period at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 52, 56, 60, 64, 68, and 72 (final study visit or upon early termination).  The 
“Screening/Baseline” version of the scale will be used to evaluate subject eligibility at baseline 
(Day 1) and the “Since Last Visit” version will be used at all other visits. 
If at any time after baseline (Day 1) the subject’s response to the suicidal ideation section of the 
C-SSRS is worse than the baseline (Day 1) assessment (past 3 months), it will be documented as 
an AE.  All suicidal behaviors will be documented as an AE.  Appropriate psychiatric evaluation 
and intervention will be provided for any treatment-emergent suicidal behavior or clinically 
significant suicidal ideation. 
8.5. 
Additional Assessments 
8.5.1. 
Patient Satisfaction Questionnaire 
Subjects will evaluate their satisfaction with valbenazine treatment by choosing 1 of 5 responses 
(very satisfied, somewhat satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, or 
very dissatisfied).  The Patient Satisfaction Questionnaire will be completed by the subjects at 
baseline (Day 1) and during the treatment period at Weeks 12, 24, 36, 48, 60, and 72 (final study 
visit or upon early termination).  A copy of the Patient Satisfaction Questionnaire is provided in 
Appendix 16.5. 
8.5.2. 
Social Functioning Scale 
The Social Functioning Scale (SFS; Birchwood et al, 1990) is a 79-item scale designed to assess 
social functioning.  Abilities and performance in seven areas are assessed: social engagement, 
interpersonal communication, activities of daily living, recreation, social activities, competence 
at independent living, and occupation/employment.  Raw scores of the subscales are converted to 
scale score equivalents with a mean of 100 and an SD of 15.  This scale has been shown to be a 
reliable, valid, and sensitive measure of social functioning (Birchwood et al. 1990). 
The SFS will be completed by the subject at baseline (Day 1) and during the treatment period at 
the end of Weeks 12, 24, 36, 48, 60, and 72 (final study visit or upon early termination).  A copy 
of the SFS is provided in Appendix 16.6. 
8.6. 
Specific Period Information 
Study visits during the treatment period at the end of weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, 52, 56, 60, 64, 68, and 72 (or upon early termination) will have a visit window of -7 or 
+2 days. 
8.6.1. 
Baseline (Day 1) 
For subjects completing the final NBI-98854-1304 or NBI-98854-1402 visit on the same day as 
Day 1, the NBI-98854-1304 or NBI-98854-1402 assessments for physical examination 
(including weight), vital signs, and ECG will be used for Day 1. 
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The following evaluations and tasks will be performed at baseline (Day 1): 
• The ICF will be reviewed with subjects.  The UBACC will then be administered.  Only 
subjects who are deemed to have the capacity to provide consent may sign the ICF.  The ICF 
must be signed prior to any additional study procedures. 
• Assess inclusion/exclusion criteria. 
• Collect medical and surgical history. 
• Perform a physical examination (including height and weight without shoes; perform BMI 
calculation). 
• Perform alcohol breath test. 
• Perform UDS using kit provided by central laboratory. 
• Perform urine pregnancy test for all female subjects who are not postmenopausal for at least 
1 year. 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressure, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform serum pregnancy test (β-hCG) for all female subjects who are not postmenopausal 
for at least 1 year. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect blood sample for serum prolactin. 
• Collect urine sample for urinalysis. 
• Record prior medications. 
• Administer C-SSRS (Screening/Baseline version). 
• Administer CGI-TD-severity.  
• Administer Patient Satisfaction Questionnaire and SFS. 
• Administer BPRS. 
After completion of these assessments, if the subject is eligible for the study the clinical site will 
access the Interactive Web Response System (IWRS) to obtain an identification number for a kit 
containing a 4-week supply of valbenazine to be dispensed to the subject.  At this point, the 
subject will be considered enrolled in the study.  
Enrolled subjects will: 
• Be monitored for AEs. 
• Be instructed to take valbenazine at home (in the presence of their caregiver, if applicable) at 
approximately the same time each day (eg, morning or evening) beginning the following day 
(Day 2).  Valbenazine may be taken with or without food and must be swallowed with at 
least 4 oz. of water.  
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• Be instructed to contact the clinical site immediately without waiting for the next scheduled 
visit to report AEs or before starting any new medication.   
• Be instructed to return to the clinical site in approximately 4 weeks for their next visit.  
• Be instructed to return all unused valbenazine and packaging at the next scheduled visit. 
8.6.2. 
Treatment Period 
8.6.2.1. 
Day 2 
Beginning on Day 2, subjects will take valbenazine at home (in the presence of their caregiver, if 
applicable) in the morning or evening; subsequent doses should be taken at approximately the 
same time each day.  Valbenazine may be taken with or without food and must be swallowed 
with at least 4 oz. of water. 
8.6.2.2. 
End of Week 4 
The following procedures will be conducted at the end of Week 4 (-7 or +2 days): 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform urine pregnancy test for all female subjects who are not postmenopausal for at least 
1 year. 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart).  
• Administer C-SSRS (Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications.  
• Valbenazine accountability. 
Dose Titration Assessment: 
At the end of Week 4, a dose escalation will be allowed based on the physician investigator’s (or 
designee’s) assessments of safety and tolerability of valbenazine as well as clinical impression of 
TD.   
The investigator may decrease the dose to 40 mg at any time after the end of Week 4 (including 
between scheduled study visits) for any subject who is unable to tolerate the 80 mg dose.  These 
subjects will receive 40 mg for the remainder of the treatment period or will be discontinued 
from the study if they are unable to tolerate the 40 mg dose. 
Once a determination of dose escalation or maintenance is made, the IWRS will be accessed to 
obtain an identification number for a kit containing a 4-week supply of valbenazine to be 
dispensed to the subject.  For subjects who have a dose increase, the investigator will inform the 
subject that a dose reduction to 40 mg is allowed if the subject is unable to tolerate the 80 mg 
dose.   
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Subjects will be reminded: 
• To take valbenazine at home (in the presence of their caregiver, if applicable) at 
approximately the same time each day (eg, morning or evening).  Valbenazine may be taken 
with or without food and must be swallowed with at least 4 oz. of water. 
• To contact the clinical site immediately without waiting for the next scheduled visit to report 
AEs or before starting any new medication.   
• To return to the clinical site in approximately 4 weeks for their next scheduled visit.  
• To return all unused valbenazine and packaging at the next scheduled visit. 
8.6.2.3. 
End of Weeks 8, 16, 20, 28, 32, 40, 44, 52, 56, 64, and 68 
The following procedures will be conducted at the end of Weeks 8, 16, 20, 28, 32, 40, 44, 52, 56, 
64, and 68 (-7 or +2 days for each visit): 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform urine pregnancy test for all female subjects who are not postmenopausal for at least 
1 year. 
• Administer C-SSRS (Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications.  
• Valbenazine accountability. 
The investigator may decrease the dose to 40 mg at any time after the end of Week 4 (including 
between scheduled visits) for any subject who is unable to tolerate the 80 mg dose.  These 
subjects will receive 40 mg for the remainder of the treatment period or will be discontinued 
from the study if they are unable to tolerate the 40 mg dose. 
Once a determination of dose maintenance or reduction (for subjects who had their dose 
escalated to 80 mg at the end of Week 4), the IWRS will be accessed to obtain an identification 
number for a kit containing a 4-week supply of valbenazine to be dispensed to the subject.  For 
subjects receiving 80 mg, the investigator will inform the subject that a dose reduction to 40 mg 
is allowed if the subject is unable to tolerate the 80 mg dose. 
At each visit, subjects will be reminded: 
• To take valbenazine at home (in the presence of their caregiver, if applicable) at 
approximately the same time each day (eg, morning or evening).  Valbenazine may be taken 
with or without food and must be swallowed with at least 4 oz. of water.   
• To contact the clinical site immediately without waiting for the next scheduled visit to report 
AEs or before starting any new medication.   
• To return to the clinical site in approximately 4 weeks for their next scheduled visit.  
• To return all unused valbenazine and packaging at the next scheduled visit. 
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8.6.2.4. 
End of Weeks 12, 24, 36, 48, and 60 
The following procedures will be conducted at the end of Weeks 12, 24, 36, 48, and 60 (-7 or 
+2 days for each visit): 
• Perform a physical examination (including weight without shoes). 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart).   
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for serum prolactin. 
• Perform urine pregnancy test for all female subjects who are not postmenopausal for at least 
1 year. 
• Administer C-SSRS (Since Last Visit version). 
• Administer CGI-TD-severity.  
• Administer Patient Satisfaction Questionnaire and SFS. 
• AE monitoring. 
• Record concomitant medications.  
• Valbenazine accountability. 
The investigator may decrease the dose to 40 mg at any time after the end of Week 4 (including 
between scheduled visits) for any subject who is unable to tolerate the 80 mg dose.  These 
subjects will receive 40 mg for the remainder of the treatment period or will be discontinued 
from the study if they are unable to tolerate the 40 mg dose. 
Once a determination of dose maintenance or reduction (for subjects who had their dose 
escalated to 80 mg at the end of Week 4) is made, the IWRS will be accessed to obtain an 
identification number for a kit containing a 4-week supply of valbenazine to be dispensed to the 
subject.  For subjects receiving 80 mg, the investigator will inform the subject that a dose 
reduction to 40 mg is allowed if the subject is unable to tolerate the 80 mg dose. 
At each visit, subjects will be reminded: 
• To take valbenazine at home (in the presence of their caregiver, if applicable) at 
approximately the same time each day (eg, morning or evening).  Valbenazine may be taken 
with or without food and must be swallowed with at least 4 oz. of water.   
• To contact the clinical site immediately without waiting for the next scheduled visit to report 
AEs or before starting any new medication.   
• To return to the clinical site in approximately 4 weeks for their next scheduled visit. 
• To return all unused valbenazine and packaging at the next scheduled visit. 
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8.6.2.5. 
End of Week 72 (Final Study Visit or Early Termination) 
The following procedures will be conducted at the end of Week 72 (final study visit or upon 
early termination) (-7 or +2 days): 
• Perform a physical examination (including weight without shoes). 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart).   
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for serum prolactin. 
• Perform urine pregnancy test for all female subjects who are not postmenopausal for at least 
1 year. 
• Administer C-SSRS (Since Last Visit version). 
• Administer CGI-TD-severity. 
• Administer Patient Satisfaction Questionnaire and SFS. 
• AE monitoring. 
• Record concomitant medications.  
• Valbenazine accountability. 
• Instruct female subjects of childbearing potential to continue using contraception until 
30 days after the last dose of valbenazine (see inclusion criterion #3). 
8.7. 
Duration 
The expected duration of study participation for each subject is up to 72 weeks. 
8.8. 
Restrictions 
8.8.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter (OTC) medications, including dietary and herbal 
supplements, taken by subjects during the 30 days before Day 1 and during the study will be 
collected.   
Medications to treat psychiatric and medical conditions:  All coexistent diseases or 
conditions will be treated in accordance with prevailing medical practice.  Maintenance 
medication(s) for schizophrenia or schizoaffective disorder, mood disorders, and other 
nonprohibited concurrent medications should be at a stable dose (including no changes to the 
dose and frequency of ongoing medications and no discontinuation of medications) for a 
minimum of 30 days before Day 1.  Benzodiazepines must be at a stable dose for 2 weeks before 
Day 1.  Investigators should document doses of current medication through medical or pharmacy 
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records, confirmation with the subject’s caregivers (if applicable), or through reliable 
subject-reported information (eg, provide a list of medications and doses).   
Washout of Prohibited Medications:  Subjects should discontinue prohibited medications for 
at least 30 days before undergoing Day 1 procedures provided they sign an ICF before 
discontinuation.  
Prohibited medications:  The following medications are prohibited from 30 days prior to Day 1 
(unless otherwise stated) until the final visit (or early termination) as described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• Cytochrome P450 (CYP) 3A4 inducers: Strong inducers of CYP3A4 (eg, phenobarbital, 
rifabutin, rifampin, primidone, St. John's Wort) are prohibited. 
• Dopamine agonists and precursors: Dopamine receptor agonists (eg, ropinirole) and 
precursors (eg, carbidopa/levodopa) are prohibited.  
• Monoamine oxidase inhibitors (MAOIs):  All MAOIs (eg, isocarboxazid, phenelzine, 
selegiline, tranylcypromine) are prohibited. 
• VMAT2 Inhibitors:  VMAT2 inhibitor medications (eg, tetrabenazine, reserpine) are 
prohibited, except for valbenazine. 
8.8.2. 
General and Dietary Restrictions 
Subjects must agree to adhere to the following prohibitions and restrictions during the study in 
order to be eligible to participate:  
• Not to use any prohibited concomitant medication (Refer to Section 8.8.1). 
• Limit alcohol use to less than 7 drinks per week during the course of the study. 
• Not to donate blood during the study and for 4 weeks after completion of the study. 
• Not to participate in an investigational drug study for at least 30 days after the last dose 
of valbenazine or 30 days after study completion, whichever is longer. 
8.9. 
Withdrawal Criteria 
8.9.1. 
Reasons for Withdrawal 
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 or becomes 
pregnant. 
The investigator must withdraw the subject from the study if the subject experiences any of the 
following:  
• If the type, frequency, or severity of any AE become unacceptable/intolerable. 
• QTcF value >500 msec (confirmed by a cardiologist). 
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• 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 or ECG abnormality. 
• Requires a medication that is prohibited by the protocol (refer to Section 8.8.1). 
 
All subjects prematurely discontinuing the study, regardless of cause, must have all early 
termination assessments performed (see Section 8.6.2.5). 
8.9.2. 
Handling of Withdrawals 
If a subject prematurely withdraws from the study, either at his/her request 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 (unless the subject has withdrawn consent and refuses further 
intervention). 
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.  Every effort 
must be made to undertake safety follow-up procedures. 
8.9.3. 
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. 
9. 
VALBENAZINE 
9.1. 
Valbenazine Drug Supplies 
NBI or its designee will provide the clinical site with valbenazine sufficient for the study, with 
the corresponding certificates of analysis. 
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The valbenazine capsule is a pearlescent purple opaque cap/pearlescent white opaque body, hard 
gelatin No. 1 size capsule with an axial orientated printed black bar, containing 40 mg (free base) 
NBI-98854 ditosylate salt.  Subjects must swallow valbenazine capsule(s) with at least 4 oz. of 
water.   
9.2. 
Supply, Storage, and Return (Drug Accountability) 
9.2.1. 
Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice and GCP rules.  Valbenazine will be sent to an authorized staff member at the clinical 
site.  The authorized clinical site staff member must confirm receipt of valbenazine to NBI or its 
designee via the IWRS. 
Valbenazine will be supplied as capsules in child-resistant bottles.  Each bottle will contain 
30 capsules of valbenazine 40 mg.  Subjects will be provided with enough valbenazine for 
28 days of dosing plus 2 extra days of dosing (ie, 1 bottle for subjects receiving 40 mg and 
2 bottles for subjects receiving 80 mg). 
Each bottle 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, valbenazine kit number, Sponsor name and address, storage condition and the 
statement “Caution – New Drug: Limited by Federal (or US) Law to Investigational Use”. 
9.2.2. 
Valbenazine Storage and Return 
Valbenazine capsules must be stored at controlled room temperature (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. 
Valbenazine should be stored and inventoried according to applicable state and federal 
regulations and study procedures. 
Written documentation to account for valbenazine and drug packaging materials (bottles) is 
mandatory; all unused valbenazine and drug packaging materials must be kept in a secure 
location for final accountability and reconciliation.  Returned valbenazine and drug packaging 
materials must be accounted for on a valbenazine return form provided by NBI or the designee.  
The investigator must provide a written explanation for any destroyed or missing valbenazine or 
drug packaging 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.  Valbenazine return forms must be completed for 
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the shipment of returns and sent with the valbenazine and drug packaging materials.  One copy 
of the valbenazine return form will be retained in the investigator’s study file. 
All returned valbenazine and drug packaging materials should be stored, inventoried, reconciled, 
and returned according to applicable state and federal regulations and study procedures. 
9.2.3. 
Blinding 
This is an open-label study. 
9.3. 
Valbenazine Administration 
The valbenazine doses that will be used in this study are 40 mg (taken as one 40 mg capsule) and 
80 mg (taken as two 40 mg capsules).  Subjects will self-administer valbenazine (in the presence 
of their caregiver, if applicable) at approximately the same time each day.  Subjects may take 
valbenazine with or without food and must swallow it with at least 4 oz. of water every day 
during the treatment period.  If treatment is interrupted for ≤5 missed consecutive doses, subjects 
are allowed to resume with their current dose regimen (40 mg qd or 80 mg qd).  If treatment is 
interrupted for >5 missed consecutive doses, subjects should contact the investigator before 
resuming treatment; subjects deemed clinically stable by the investigator may resume with their 
current dose regimen (40 mg qd or 80 mg qd). 
9.4. 
Valbenazine Compliance and Accountability 
Subjects will bring all unused valbenazine and empty drug packaging material to the clinical site 
at each visit for drug accountability and reconciliation by clinical site personnel.  A compliance 
check will be performed by counting the capsules returned at each scheduled visit.   
The quantity of valbenazine dispensed, used, and returned will be recorded on a dispensing log 
or otherwise documented.  The quantity of valbenazine 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 valbenazine supplies received, 
dispensed, and returned. 
9.5. 
Valbenazine Drug Return 
Written documentation to account for valbenazine and drug packaging materials is mandatory; 
all unused valbenazine and drug packaging materials must be kept in a secure location for final 
accountability and reconciliation.  Returned valbenazine and drug packaging materials must be 
accounted for on a valbenazine return form provided by NBI or the designee.  The investigator 
must provide a written explanation for any destroyed or missing valbenazine or drug packaging 
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.  Valbenazine return forms must be completed for 
the shipment of returns and sent with valbenazine and drug packaging materials.  One copy of 
the valbenazine return form will be retained in the investigator’s study file.   
All returned valbenazine and drug packaging materials should be stored, inventoried, reconciled, 
and returned according to applicable state and federal regulations and study procedures. 
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10. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or by other means, will be recorded from the time the subject has signed the ICF until 
the subject’s final study visit (Week 72 or upon early termination).  Note, AEs and serious 
adverse events (SAEs) will be collected for enrolled subjects only. 
10.1. 
Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  During the study, clinically significant adverse changes in 
clinical status, ECGs, laboratory values (not associated with an AE or concurrent medical 
condition), or physical examinations are considered AEs.  Any subject complaint associated with 
such an abnormal finding will also be reported as an AE. 
Adverse events include, but are not limited to:  (1) a worsening or change in nature, severity, or 
frequency of conditions present at the start of the study; (2) subject deterioration due to primary 
illness; (3) intercurrent illness; and (4) drug interaction. 
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 
valbenazine, 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 
valbenazine.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before valbenazine administration, unless it 
unexpectedly progresses, or increases in severity following valbenazine administration. 
• Pregnancy (see Section 10.5). 
10.1.1. 
Intensity of Adverse Events 
Adverse events must be graded for intensity.  An intensity category of mild, moderate, or severe, 
as defined in Table 3, must be entered on the AE eCRF.  It should be noted that the term 
“severe” used to grade intensity is not synonymous with the term “serious.” 
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Table 3: 
Intensity of Adverse Events 
Grade  
Intensity 
Mild 
An adverse event 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 adverse event 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 adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
10.1.2. 
Relationship to Valbenazine 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
valbenazine using the criteria outlined in Table 4.  An AE is deemed associated with the use of 
valbenazine “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]). 
Table 4: 
Relationship of Adverse Events to Valbenazine 
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. 
10.2. 
Recording Adverse Events 
For enrolled subjects, each AE will be listed as a separate entry on an AE eCRF.  The 
investigator will provide information on dates and times of onset and resolution, intensity, 
seriousness, frequency, action(s) taken, changes in valbenazine usage, relationship to 
valbenazine, 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 designee: 
• SAE, including death (see Section 10.4). 
• Pregnancy (see Section 10.5). 
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10.3. 
Post-Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  If 
resolved, a resolution date should be documented on the eCRF.   
Adverse events ongoing at the final visit or at 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. 
10.4. 
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 investigational product or until the subject begins taking commercial product, 
whichever comes first. 
10.4.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcome: 
• 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 pre-existing 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, 
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convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
10.4.2. 
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 
Medical Monitor (and the IRB, if necessary) immediately (within 24 hours) of the SAE and the 
outcome of the SAE. 
If an investigator becomes aware of an SAE within the time of informed consent until 30 days 
after the last dose of investigational product or until the subject begins taking commercial 
product, whichever comes first, then the event must be documented and reported as described in 
Section 10.4.3. 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
Serious AEs and other immediately reportable events (defined in Section 10.2) 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.  Serious AEs and pregnancies must 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 valbenazine at the time of the initial SAE report.  
For SAEs and other immediately reportable events, contact CDS: 
CDS telephone: 
 
CDS facsimile: 
 
CDS e-mail:  
 
NBI Medical Monitor:  
Telephone: 
 
 
 
 
 
 
 
 
 
 
Cell phone: 
 
10.4.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 10.1.2) 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. 
NBI 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. 
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10.5. 
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 valbenazine will be followed to assess for 
congenital anomaly.  Subjects must be counseled at all visits to continue using hormonal or 
2 forms of nonhormonal contraception (see inclusion criterion #3 in Section 7.1) until 30 days 
after the last dose of valbenazine.  If at any time between the time the subject signs the ICF and 
the last visit, a subject believes she is pregnant, the subject will be instructed to return to the 
clinical site within 24 hours and undergo a serum pregnancy test to confirm pregnancy.  
All confirmed pregnancies in subjects who received valbenazine must be immediately reported 
to NBI (see Section 10.4.3 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 valbenazine will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 
11. 
DOCUMENTATION OF DATA 
11.1. 
Case Report Forms 
The CRF data for this study are being collected with an electronic data capture (EDC) system 
(
) provided by 
.  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, 
a, 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. 
a 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 
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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. 
11.2. 
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. 
11.3. 
Coding Dictionaries 
Adverse events and medical history will be coded using the chosen version of the Medical 
Dictionary for Regulatory Activities (MedDRA).  Prior and concomitant medications will be 
coded using the chosen version of the World Health Organization Drug Dictionary (WHO Drug). 
12. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive statistical methods will be used to summarize the data from this study.  The term 
“descriptive statistics” refers to the number of subjects (n), mean, median, standard deviation 
(SD), standard error of the mean (SEM), minimum, and maximum for continuous variables; and 
refers to the number and/or percentage of subjects (or events) for categorical variables.  Data 
summaries will include tables, figures, and listings. 
12.1. 
Analysis Sets 
Analysis sets, which represent subsets of the study population defined for analysis-related 
purposes, will be described in detail in the study Statistical Analysis Plan (SAP).  The SAP will 
be developed subsequent to the development of this protocol, but before finalizing the study 
database. 
12.2. 
Sample Size Determination 
The sample size for this study is based on practical considerations and not on a statistical power 
calculation. 
12.3. 
Handling of Missing Data 
In general, all available study data will be included in relevant data displays, including any 
available data for subjects with incomplete or missing data.  Specific rules for handling missing 
data values will be identified in the SAP. 
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12.4. 
Disposition of Subjects 
A summary of subject disposition will be prepared that displays the number of subjects who 
were enrolled and completed the study.  The number of subjects who did not complete the study 
will be displayed both overall and by reason for discontinuation. 
12.5. 
Demographics and Baseline Subject Characteristics 
Demographic data and subject baseline characteristics will be summarized with descriptive 
statistics. 
12.6. 
Valbenazine Dosing and Compliance 
The estimated number of doses of valbenazine taken during the 4-week intervals between 
consecutive scheduled visits during the treatment period will be summarized with descriptive 
statistics by visit.  The cumulative estimated number of doses taken through Week 72 will be 
summarized also.  Additionally, the number of subjects who have a dose reduction will be 
summarized. 
12.7. 
Efficacy Data 
12.7.1. 
CGI-TD-Severity 
Descriptive statistics will be presented for CGI-TD-severity score at each assessment and for the 
changes from baseline (Day 1) to each assessment after Day 1. 
12.8. 
Safety Data 
Treatment-emergent AEs (TEAEs), categorized by system organ class (SOC) and preferred term 
as defined by MedDRA, will be summarized.  A TEAE is defined as any AE that occurs after the 
first dose of valbenazine through the final study visit.  Any AE that occurred before the first dose 
of valbenazine will be considered a pretreatment AE.  
The TEAE tables will include the number of events, number of unique subjects experiencing 
each event, and percentage of subjects experiencing each event.   
AEs will be also be tabulated in terms of the number and percentage of subjects experiencing 
events by intensity and relationship to valbenazine.  
Separate listings will be generated for pretreatment AEs, TEAEs, SAEs and deaths, and AEs 
leading to premature discontinuation from the study.  
Clinical laboratory, vital signs, physical examination, and ECG data will be summarized with 
descriptive statistics and frequency tables as appropriate.  Prior and concomitant medications 
will be presented in data listings. 
12.9. 
Additional Assessments 
12.9.1. 
Patient Satisfaction Questionnaire 
Descriptive statistics will be presented for Patient Satisfaction Questionnaire score at each 
assessment and for the changes from baseline (Day 1) to each assessment after Day 1. 
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12.9.2. 
Social Functioning Scale 
Descriptive statistics will be presented for SFS score at each assessment and for the changes 
from baseline (Day 1) to each assessment after Day 1. 
12.10. 
Additional Analyses 
Additional analyses may be performed for this study. 
12.11. 
Interim Analysis 
An interim analysis is not planned for this study. 
13. 
REGULATORY AND ETHICAL ISSUES 
13.1. 
General Legal References 
The study will be carried out according to the provision of the US CFR, the US Food and Drug 
Administration (FDA), and the International Conference on Harmonisation 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. 
13.2. 
Institutional Review Board/Ethics Committee 
The final approved protocol and the ICF will be reviewed by the IRB/EC at 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 agrees to make any required progress 
reports to the IRB/EC, as well as reports of SAEs, life-threatening problems, or death. 
13.3. 
Protocol Adherence – 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. 
13.4. 
Required Documents 
The investigator must provide NBI or its designee with the following documents before the 
enrollment of any subject (copies should be kept by the investigator in the investigator’s study 
regulatory binder): 
• Signed copy (original) of the protocol signature page. 
• Completed and signed statement of investigator (Form FDA 1572). 
• Financial disclosure documentation as required. 
• Curriculum vitae and current medical license of the investigator and sub-investigators. 
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• Letter of approval from the IRB/EC for both protocol and ICF. 
• Copy of the IRB/EC approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
13.5. 
Informed Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. 
Each subject’s chart will include the signed ICF for study participation.  When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study. 
13.6. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include 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. 
13.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed to 
ensure that all procedures are in compliance with GCP and FDA Guidelines and according to 
national law.  Quality assurance audits may be performed at the discretion of NBI. 
13.8. 
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. 
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13.9. 
Confidentiality 
NBI or its designee, 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 initials. 
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 they deem necessary.  To allow 
the use of the information derived from this clinical study and to ensure compliance to current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
14. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Subject entry should not begin until after the required regulatory documents are confirmed as 
received and the Initiation Visit 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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15. 
REFERENCES 
Birchwood M, Smith J, Cochrane R, Wetton S, Copestake S. The Social Functioning Scale. The 
development and validation of a new scale of social adjustment for use in family intervention 
programmes with schizophrenic patients. Br J Psychiatry. 1990;157:853-9. 
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, 1976, US 
Department of Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD:  
National Institute of Mental Health – Clinical Global Impression - Improvement, p. 217-22. 
Jeste D, Palmer B, Appelbaum P, Golsham S, Glorioso S, Dunn LB, et al.  A new brief 
instrument for assessing decisional capacity for clinical research.  Arch Gen Psychiatry. 
2007;64(8):966-74. 
Margolese H, Chouinard G, Kolivakis T, Beauclair L, Miller R. Tardive dyskinesia in the era of 
typical and atypical antipsychotics. Part 1: Pathophysiology and mechanisms of induction. Can J 
Psychiatry. 2005;50:541-7. 
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS). Psychological Reports. 
1962;10:799-812.  
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): Recent developments in 
ascertainment and scaling.  Psychopharmacol Bull. 1988;24:97-9. 
Weihe E, Eiden LE. Chemical neuroanatomy of the vesicular amine transporters. FASEB J. 2000 
Dec;14:2435–49. 
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16. 
APPENDICES 
 
 
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Neurocrine Biosciences, Inc., Protocol No. NBI-98854-1506 
Clinical Study Protocol Amendment No. 3 Final Version
 
Confidential
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