Clinical trial NCT03698331
Conditions: Tardive Dyskinesia (TD)
Sponsor: Neurocrine Biosciences
Start date: 2018-09-14; Completion date: 2019-04-03
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the potential for clinical dependence and withdrawal symptoms associated with valbenazine.

Detailed description:

Arms: arm 1: Valbenazine or placebo oral capsules administered once daily for 7 weeks. arm 2: Placebo oral capsules administered once daily for 7 weeks.
Interventions: intervention 1: Valbenazine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: vesicular monoamine transporter 2 (VMAT2) inhibitor intervention 2: non-active dosage form

Protocol documents:
Prot_001.pdf: 
1. 
TITLE PAGE
CLINICAL STUDY PROTOCOL 
Amendment No. 3 Final Version Date:  16 April 2019 
Amendment No. 2 Final Version Date:  03 October 2018 
Amendment No. 1 Final Version Date:  06 September 2018 
Original Final Version Date:  17 May 2018 
A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Potential for Clinical Dependence and Withdrawal Symptoms Associated 
with Valbenazine 
Study No.:  NBI-98854-TD4001 
NCT03698331
Development Phase:  4 
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no unpublished information contained herein will be published or disclosed without prior approval 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/Independent Ethics Committee (IRB/IEC) or authorized representatives of national 
regulatory authorities under the condition that they respect its confidential nature. 


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SIGNATURES: 
I agree to conduct this study in accordance with the requirements of this Clinical Study Protocol 
and also in accordance with the following: 
• Established principles of International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA) 
CLINICAL STUDY TITLE:  A Phase 4, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Potential for Clinical Dependence and Withdrawal Symptoms Associated 
with Valbenazine 
 
PROTOCOL No.: 
NBI-98854-TD4001 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
CENTER:  
 
 
________________________________________________________ 
(Print Study Center Name)


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Accepted for the Sponsor:
SPONSOR:
Neurocrine Biosciences, Inc.
12780 El Camino Real
San Diego, CA 92130
Telephone: (858) 617-7600
Facsimile:
(858) 617-7705
___________________
__________________________________
Date


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LIST OF PERSONNEL 
Clinical Laboratory (Safety and Genotyping): 
Covance Central Lab Services, Inc. 
8211 Scicor Dr. 
Indianapolis, IN 46214 
Telephone:  (317) 271-1200 
Bioanalytical: 
Charles River Laboratories and Preclinical Services Montreal  
22022 Transcanadienne 
Senneville, Quebec, Canada H9X 3R3 
Telephone: (514) 630-8200 
Facsimile: 
(514) 630-8230 
 
Sponsor  
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 


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2. 
SYNOPSIS 
Title of study:  A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Potential for 
Clinical Dependence and Withdrawal Symptoms Associated with Valbenazine 
Study number:  NBI-98854-TD4001 
Study center(s):  Approximately 20 study centers in the United States 
Objectives:  
Primary: 
• 
To evaluate the potential for clinical dependence and withdrawal symptoms associated with 
valbenazine following 4 weeks of once-daily treatment with valbenazine or placebo. 
Secondary: 
• 
To evaluate the efficacy of valbenazine administered once daily for up to 4 weeks. 
• 
To evaluate the safety and tolerability of valbenazine administered once daily for up to 4 weeks. 
Study design:  This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the potential 
for clinical dependence and withdrawal symptoms associated with valbenazine.  Approximately 80 medically 
stable male and female subjects (the proportion of males and females will be consistent with that of the patient 
population) with neuroleptic-induced tardive dyskinesia (TD) will be enrolled. 
Before subjects can provide informed consent, the investigator (or designee) must determine whether the subject 
has the capacity to provide consent for study 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 informed consent form (ICF).  All subjects must sign an ICF prior to the conduct of any 
study-related procedures.  Subjects will be screened for eligibility for up to 6 weeks prior to Day -1 (baseline 
visit). 
On Day -1, eligible subjects will be randomized (1:1) to 1 of the 2 treatment arms (randomization will be 
stratified by study site): 
• 
Valbenazine (40 mg for the first week followed by 80 mg for 3 weeks) for the first 4 weeks of the double-
blind treatment period followed by placebo for the last 3 weeks of the double-blind treatment period. 
• 
Placebo for the 7 weeks of the double-blind treatment period.  
An Interactive Web Response System (IWRS) will be used to maintain the study blind.  Study drug will be self-
administered at home (in the presence of the subject’s caregiver, if applicable) beginning on Day 1 of Week 1.  
At any time, the investigator can decrease the subject’s dose to 40 mg if the subject is unable to tolerate the 
80 mg dose (this will be done in a blinded manner; subjects receiving placebo will continue to receive placebo).  
Subjects who are unable to tolerate the 40 mg dose (or placebo) will be discontinued from the study. 
Study sites will call subjects at the end of Weeks 2 and 3 to remind them to take their study drug daily.  Visits 
during Weeks 1 and 4 have a window of ±3 days, visits during Week 5 have no window, and visits during 
Weeks 6 and 7 have a window of ±1 day. 
A blood sample will be collected from randomized subjects on Day -1 to determine their cytochrome P450 
(CYP) 2D6 genotype.  Clinical dependence and withdrawal symptoms, efficacy, pharmacokinetics (PK), safety, 
and tolerability will be assessed at scheduled times throughout the study. 
Study population:  Approximately 80 medically stable male and female subjects (the proportion of males and 
females will be consistent with that of the patient population) aged 18 to 65 years (inclusive) with clinical 
diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder with 
neuroleptic-induced TD will be enrolled.  Subjects must be psychiatrically stable as determined clinically by the 
investigator, including a Brief Psychiatric Rating Scale (BPRS) score of <50 at screening and baseline (Day -1). 
Duration of treatment and study participation:  The expected duration of study participation for each subject 
is approximately 13 weeks, including up to 6 weeks of screening and 7 weeks of double-blind study drug 
treatment. 


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Investigational product, dosage, and mode of administration:  Valbenazine will be supplied as capsules 
containing 20 or 40 mg of valbenazine (free base equivalent as the ditosylate salt).  The doses that will be used 
in this study are:  40 mg once daily taken as two valbenazine 20 mg capsules and 80 mg once daily taken as two 
valbenazine 40 mg capsules.  Subjects will swallow the capsules with at least 250 mL of water and can take the 
study medication with or without food each morning at approximately the same time (between 0700 and 
1000 hours).  
Reference therapy, dosage, and mode of administration:  Matching placebo capsules are identical in 
appearance and will be orally administered.  Subjects will swallow the 2 placebo capsules with at least 250 mL 
of water and can take the study medication with or without food each morning at approximately the same time 
(between 0700 and 1000 hours). 
Criteria for evaluation: 
Clinical dependence and withdrawal symptoms:  
The modified Cocaine Selective Severity Assessment (mCSSA) and Physician Withdrawal Checklist-20 
(PWC-20) will be used to evaluate clinical dependence and withdrawal symptoms and will be administered at 
baseline (Day -1), at the end of Week 4, Week 5 (Days 1, 3, 5, and 7), Week 6 (Days 2, 4, and 7), Week 7 
(Days 2 and 4), and at the final study visit (Week 7 Day 7 or upon early termination).  
The Epworth Sleepiness Scale (ESS), Hamilton Anxiety Rating Scale (HAM-A), and withdrawal-related 
adverse events (AEs) will also be used to assess for clinical dependence and withdrawal symptoms. 
Efficacy:  
The Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) and Clinical Global Impression-
Tardive Dyskinesia-Severity (CGI-TD-S) will be used to rate the investigator’s (or designee) assessments of the 
subject’s overall improvement and severity of TD, respectively.  The CGI-TD-I will be administered during the 
treatment period (end of Week 4), and at the final study visit (Week 7 Day 7 or upon early termination).  The 
CGI-TD-S will be administered at baseline (Day -1), during the treatment period (end of Week 4, Day 7 of 
Weeks 5 and 6), and at the final study visit (Week 7 Day 7 or upon early termination). 
Plasma Drug Exposure: 
Blood samples to evaluate plasma concentrations of valbenazine and the metabolite NBI-98782 (other 
metabolites may be evaluated) will be collected at Weeks 1 and 4. 
Safety:   
Safety and tolerability will be monitored throughout the study and will include the following assessments: 
• 
AEs 
• 
Clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
• 
Vital signs (including orthostatic blood pressure and pulse) 
• 
Physical examinations 
• 
12-lead electrocardiogram (ECG) 
• 
Suicidal ideation and behavior, evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Drug-induced akathisia and extrapyramidal symptoms (EPS), evaluated using the Barnes Akathisia 
Rating Scale (BARS) and Simpson-Angus Scale (SAS) 
• 
Montgomery-Asberg Depression Rating Scale (MADRS). 
Statistical methods:  The primary assessment of withdrawal will be the number of subjects with withdrawal-
related AEs; differences between treatment groups will be tested for statistical significance using Fisher’s exact 
test.  The secondary assessment of withdrawal will be the percentage of subjects in each treatment group who 
experience an increase on the PWC-20 by 5 new symptoms of moderate or severe degree or a worsening of 
symptoms by 2 points during Weeks 5 to 7 compared with Week 4.  Other assessments of withdrawal will be 
the mean worst scores per treatment group on the PWC-20 and mCSSA, which will be summarized using 
descriptive statistics; results from the ESS and the HAM-A will be summarized using descriptive statistics.  
Efficacy, PK, and safety data will be summarized using descriptive statistics.  


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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................11 
4. 
ETHICS ......................................................................................................................13 
5. 
INTRODUCTION ......................................................................................................13 
5.1. 
Background .................................................................................................................13 
5.2. 
Valbenazine (NBI-98854) ..........................................................................................13 
5.3. 
Study and Dose Rationale ...........................................................................................15 
6. 
STUDY OBJECTIVES ..............................................................................................15 
7. 
STUDY DESIGN .......................................................................................................15 
8. 
STUDY POPULATION .............................................................................................16 
8.1. 
Subject Inclusion Criteria ...........................................................................................16 
8.2. 
Subject Exclusion Criteria ..........................................................................................18 
8.3. 
Subject Identification and Replacement of Subjects ..................................................20 
8.4. 
Randomization ............................................................................................................20 
9. 
STUDY EVALUATIONS ..........................................................................................20 
9.1. 
Schedule of Assessments ............................................................................................20 
9.2. 
Screening and Baseline Assessments .........................................................................23 
9.2.1. 
Genotyping .................................................................................................................23 
9.2.2. 
Brief Psychiatric Rating Scale ....................................................................................23 
9.3. 
Clinical Dependence and Withdrawal Symptoms Assessments .................................23 
9.3.1. 
Modified Cocaine Selective Severity Assessment .....................................................23 
9.3.2. 
Physician Withdrawal Checklist-20 ...........................................................................24 
9.3.3. 
Epworth Sleepiness Scale ...........................................................................................24 
9.3.4. 
Hamilton Anxiety Rating Scale ..................................................................................24 
9.4. 
Efficacy Assessments .................................................................................................24 
9.4.1. 
Clinical Global Impression-Tardive Dyskinesia-Improvement ..................................24 
9.4.2. 
Clinical Global Impression-Tardive Dyskinesia-Severity ..........................................25 


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9.5. 
Pharmacokinetics Assessment ....................................................................................25 
9.6. 
Safety Assessments .....................................................................................................25 
9.6.1. 
Vital Sign Measurements ............................................................................................25 
9.6.2. 
Medical History ..........................................................................................................26 
9.6.3. 
Physical Examination Including Height and Weight ..................................................26 
9.6.4. 
Electrocardiogram .......................................................................................................26 
9.6.5. 
Clinical Laboratory Assessments ...............................................................................26 
9.6.6. 
Columbia-Suicide Severity Rating Scale ....................................................................27 
9.6.7. 
Barnes Akathisia Rating Scale....................................................................................28 
9.6.8. 
Simpson-Angus Scale .................................................................................................28 
9.6.9. 
Montgomery-Asberg Depression Rating Scale using the Structured 
Interview Guide for the MADRS ...............................................................................28 
9.7. 
Specific Study Information .........................................................................................29 
9.7.1. 
Screening (Week -6 to -1) ...........................................................................................29 
9.7.2. 
Baseline (Day -1) ........................................................................................................29 
9.7.3. 
Double-Blind Treatment Period (Weeks 1 to 7) .........................................................30 
9.7.3.1. 
Week 1 (±3 days) ........................................................................................................30 
9.7.3.2. 
Week 4 (±3 days) ........................................................................................................31 
9.7.3.3. 
Week 5, Days 1, 3, 5, and 7 ........................................................................................32 
9.7.3.4. 
Week 6, Days 2, 4, and 7 (±1 day) .............................................................................32 
9.7.3.5. 
Week 7, Days 2 and 4 (±1 day) ..................................................................................32 
9.7.4. 
Final Study Visit (Week 7 Day 7 [±1 day] or Early Termination) .............................33 
9.8. 
Study Duration ............................................................................................................33 
9.9. 
Prohibitions and Restrictions ......................................................................................34 
9.9.1. 
Prior and Concomitant Medications ...........................................................................34 
9.9.2. 
Dietary Restrictions ....................................................................................................34 
9.9.3. 
Other Restrictions .......................................................................................................35 
9.10. 
Withdrawal Criteria ....................................................................................................35 
9.10.1. 
Reasons for Withdrawal .............................................................................................35 
9.10.2. 
Handling of Withdrawals ............................................................................................35 
9.10.3. 
Sponsor’s Termination of Study .................................................................................36 
10. 
STUDY DRUG ...........................................................................................................36 
10.1. 
Study Drug Supplies ...................................................................................................36 


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10.1.1. 
Valbenazine ................................................................................................................36 
10.1.2. 
Placebo ........................................................................................................................36 
10.2. 
Study Drug Storage .....................................................................................................36 
10.3. 
Study Drug Packaging and Labeling ..........................................................................37 
10.4. 
Blinding ......................................................................................................................37 
10.5. 
Study Drug Preparation and Administration ..............................................................37 
10.6. 
Study Drug Compliance and Accountability ..............................................................37 
10.7. 
Study Drug Return ......................................................................................................38 
11. 
ADVERSE EVENTS..................................................................................................38 
11.1. 
Definition ....................................................................................................................38 
11.1.1. 
Intensity of Adverse Events ........................................................................................39 
11.1.2. 
Relationship to Study Drug ........................................................................................39 
11.2. 
Recording Adverse Events .........................................................................................40 
11.3. 
Poststudy Follow-Up of Adverse Events ....................................................................40 
11.4. 
Serious Adverse Events ..............................................................................................41 
11.4.1. 
Definition of a Serious Adverse Event .......................................................................41 
11.4.2. 
Managing Serious Adverse Events .............................................................................41 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................42 
11.4.4. 
Expedited Safety Reports ...........................................................................................42 
11.5. 
Pregnancy ...................................................................................................................42 
12. 
DOCUMENTATION OF DATA ...............................................................................43 
12.1. 
Case Report Forms .....................................................................................................43 
12.2. 
Data Capture, Review, and Validation .......................................................................43 
12.3. 
Coding Dictionaries ....................................................................................................44 
13. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................44 
13.1. 
Overview .....................................................................................................................44 
13.2. 
Analysis Sets ...............................................................................................................44 
13.3. 
Safety Analysis Set .....................................................................................................44 
13.3.1. 
Dependence and Withdrawal Analysis Set .................................................................44 
13.3.2. 
Efficacy Analysis Set ..................................................................................................45 
13.4. 
Sample Size Determination ........................................................................................45 
13.5. 
Handling of Missing Data ...........................................................................................45 


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13.6. 
Disposition of Subjects ...............................................................................................45 
13.7. 
Important Protocol Deviations ....................................................................................45 
13.8. 
Demographics and Baseline Subject Characteristics ..................................................45 
13.9. 
Study Drug Dosing and Compliance ..........................................................................45 
13.10. 
Clinical Dependence and Withdrawal Data ................................................................45 
13.11. 
Pharmacokinetic Data .................................................................................................46 
13.12. 
Efficacy Data ..............................................................................................................46 
13.13. 
Safety Data ..................................................................................................................46 
13.14. 
Software ......................................................................................................................46 
13.15. 
Interim Analysis ..........................................................................................................46 
14. 
REGULATORY AND ETHICAL ISSUES ...............................................................47 
14.1. 
General Legal References ...........................................................................................47 
14.2. 
Institutional Review Board/Independent Ethics Committee ......................................47 
14.3. 
Protocol Adherence – Amendments ...........................................................................47 
14.4. 
Required Documents ..................................................................................................47 
14.5. 
Informed Consent .......................................................................................................47 
14.6. 
Study Monitoring ........................................................................................................48 
14.7. 
Quality Assurance .......................................................................................................48 
14.8. 
Record Retention ........................................................................................................48 
14.9. 
Confidentiality ............................................................................................................48 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................49 
16. 
REFERENCES ...........................................................................................................50 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................21 
Table 2: 
Intensity of Adverse Events ........................................................................................39 
Table 3: 
Relationship of Adverse Events to Study Drug ..........................................................40 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................16 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-∞ 
area under the plasma concentration versus time curve from 0 hours 
extrapolated to infinity 
β-hCG 
β-human chorionic gonadotropin 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CFR 
Code of Federal Regulations 
CGI-TD-I 
Clinical Global Impression-Tardive Dyskinesia-Improvement 
CGI-TD-S 
Clinical Global Impression-Tardive Dyskinesia-Severity 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CRT 
controlled room temperature 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA K2 
dipotassium ethylenediaminetetraacetic acid 
EPS 
extrapyramidal symptoms 
EPSE 
extrapyramidal side effects 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
gamma-glutamyl transferase 
HAM-A 
Hamilton Anxiety Rating Scale 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C virus antibody 
HIV-Ab 
human immunodeficiency virus antibody 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 


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IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IWRS 
Interactive Web Response System 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAOI 
monoamine oxidase inhibitor 
mCSSA 
modified Cocaine Selective Severity Assessment 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
prn 
as needed 
PWC-20 
Physician Withdrawal Checklist-20 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SIGMA 
Structured Interview Guide for the MADRS 
t½ 
terminal half-life 
TD 
tardive dyskinesia 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
TS 
Tourette syndrome 
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 
 
 


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4. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) standards 
that meet regulations relating to Good Clinical Practice (GCP).  These standards respect the 
following guidelines: 
• Good Clinical Practice (GCP):  Consolidated Guideline (International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH; current 
version]). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR 
parts 50, 54, 56, 312, and 314). 
The ethical requirements of Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs) and the informed consent forms (ICFs) are discussed in Section 14. 
5. 
INTRODUCTION 
5.1. 
Background 
Valbenazine (valbenazine tosylate, NBI-98854) is a selective, orally active vesicular monoamine 
transporter 2 (VMAT2) inhibitor developed by NBI.  Valbenazine was approved by the US Food 
and Drug Administration (FDA) in April 2017 for the treatment of adults with tardive dyskinesia 
(TD), under the trade name INGREZZA®.  Valbenazine is also under development for the 
treatment of Tourette syndrome (TS).   
TD is a neurological condition characterized by involuntary movements of the orofacial region 
(ie, tongue, lips, jaw, face), the extremities, and trunk.  While isolated case reports of TD after 
short-term exposure exist, most often TD develops after long-term neuroleptic drug use and often 
persists after discontinuation of such medications.  The Diagnostic and Statistical Manual of 
Mental Disorders (DSM) Fifth Edition (DSM-5) defines chronic exposure to neuroleptics as a 
criterion 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. 
5.2. 
Valbenazine (NBI-98854) 
In nonclinical studies, valbenazine appears to cause little or no cytochrome P450 (CYP) enzyme 
inhibition or induction at pharmacologically relevant concentrations.  Valbenazine is a moderate 
inhibitor of P-glycoprotein (P-gp), but only at concentrations that could be achieved in the 
gastrointestinal (GI) tract, and is not an inhibitor of a panel of other drug transporters.  
Metabolism of valbenazine is characterized by hydrolysis of valbenazine to NBI-98782, and 
CYP3A4/5-dependent mono-oxidation to NBI-136110.  NBI-98782 is metabolized in part by 
CYP2D6.  All 3 entities, namely, valbenazine, 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. 


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Phase 1 clinical studies with valbenazine have been conducted in healthy subjects (including 
drug-drug interaction studies conducted with digoxin, ketoconazole, midazolam, and rifampin), 
in hepatically impaired subjects, and in children and adolescents with TS.  Phase 2 and 3 studies 
have been conducted in subjects with TD and a clinical diagnosis of schizophrenia or 
schizoaffective disorder or mood disorder.  Over 850 subjects have been exposed to valbenazine 
in clinical studies. 
Valbenazine appears to be rapidly absorbed with a time to maximum plasma concentration (tmax) 
typically ranging from approximately 0.5 to 1.0 hours.  Valbenazine reaches steady state within 
1 week.  The active metabolite NBI-98782 gradually forms with a tmax of 4 to 8 hours and both 
valbenazine and NBI-98782 are eliminated with a terminal half-life (t½) of 15 to 22 hours.  
Coadministration of ketoconazole (strong CYP3A4/5 inhibitor) with valbenazine led to a 1.5- 
and 1.6-fold increase in the maximum plasma concentration (Cmax) of valbenazine and 
NBI-98782, respectively, and a 2.1-fold increase in the area under the plasma versus time 
concentration curve (AUC) from 0 hours extrapolated to infinity (AUC0-∞) of valbenazine and 
NBI-98782.  Coadministration of valbenazine and rifampin (strong CYP3A4/5 inducer) led to an 
approximate 30% and 70% decrease in Cmax and AUC0–∞, respectively, for valbenazine, and an 
approximate 50% and 80% decrease, respectively, for NBI-98782 compared with administration 
of valbenazine alone.  Coadministration of valbenazine 80 mg and 0.5 mg digoxin resulted in an 
approximate 1.9-fold increase in the Cmax of digoxin.  The effect of valbenazine on digoxin 
AUC0–∞ was modest (1.4-fold increase) and the mean t½ of digoxin was similar with and without 
valbenazine administration.  Midazolam Cmax and AUC0–∞ were similar with and without 
valbenazine administration. 
Results from the completed 6-week placebo-controlled treatment period in the TD Phase 3 study 
(NBI-98854-1304) indicated a statistically significant improvement in the Abnormal Involuntary 
Movement Scale (AIMS) dyskinesia total score mean change from baseline for valbenazine 
80 mg compared with placebo. 
Valbenazine has been generally well-tolerated in single doses up to 300 mg and in multiple doses 
of up to 100 mg.  During the TD 6-week placebo-controlled period in 3 Phase 2 and 3 studies 
(NBI-98854-1201, -1202, and -1304), adverse reactions reported ≥3% and >placebo were 
somnolence (somnolence, fatigue, and sedation; 10.9% valbenazine vs 4.2% placebo), 
anticholinergic effects (dry mouth, constipation, disturbance in attention, vision blurred, and 
urinary retention; 5.4% vs 4.9%), balance disorders/fall (fall, gait disturbance, dizziness, balance 
disorder; 4.1% vs 2.2%), and headache (3.4% vs 2.7%).  Other adverse reactions observed during 
premarketing evaluation of valbenazine (≥1% and >placebo), including long-term studies with 
up to 48 weeks of treatment, were blood glucose increased, weight increased, respiratory 
infections, drooling, dyskinesia, extrapyramidal symptoms (EPS; non-akathisia), anxiety, and 
insomnia.  Overall, the incidence of adverse events (AEs) leading to discontinuation during the 
TD 6-week placebo-controlled period in 3 Phase 2 and 3 studies was similar between 
NBI-98854-treated subjects (10 subjects, 4%) compared to those who received placebo 
(8 subjects, 5%). 
Serious adverse events (SAEs) reported in >2 subjects across the clinical development program 
included schizophrenia (7 subjects); suicidal ideation (6 subjects); and schizoaffective disorder, 
abdominal pain, mental status change, syncope, and chronic obstructive pulmonary disease 
(3 subjects each).  SAEs considered possibly related to study drug were reported in 4 subjects: 


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hepatitis acute, suicidal ideation, confusional state, and hypersensitivity; all in subjects taking 
valbenazine.  Valbenazine does not appear to increase suicidality.  Valbenazine may prolong the 
QT interval, although the degree of QT prolongation is not clinically significant at concentrations 
expected with recommended dosing (40 and 80 mg).  A dose-related increase in prolactin, 
alkaline phosphatase and bilirubin was observed in controlled studies. 
5.3. 
Study and Dose Rationale 
The present study is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate 
the potential for clinical dependence and withdrawal symptoms associated with valbenazine in 
medically stable subjects with schizophrenia, schizoaffective disorder, or mood disorder and TD.  
In order to maintain the study blind, subjects will be randomized to receive placebo throughout 
the double-blind treatment period, or valbenazine for the first 4 weeks of the double-blind 
treatment period followed by placebo for the remaining 3 weeks. 
The commercial starting dose of valbenazine 40 mg once daily was selected for this study, 
increased to the recommended dose of 80 mg once daily after 1 week of treatment. 
6. 
STUDY OBJECTIVES 
Primary: 
• To evaluate the potential for clinical dependence and withdrawal symptoms associated with 
valbenazine following 4 weeks of once-daily treatment with valbenazine or placebo. 
Secondary: 
• To evaluate the efficacy of valbenazine administered once daily for up to 4 weeks. 
• To evaluate the safety and tolerability of valbenazine administered once daily for up to 
4 weeks. 
7. 
STUDY DESIGN 
This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the potential 
for clinical dependence and withdrawal symptoms associated with valbenazine.  Approximately 
80 medically stable male and female subjects (the proportion of males and females will be 
consistent with that of the patient population) with neuroleptic-induced TD will be enrolled. 
Before subjects can provide informed consent, the investigator (or designee) must determine 
whether the subject has the capacity to provide consent for study 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.  All subjects 
must sign an ICF prior to the conduct of any study-related procedures.  Subjects will be screened 
for eligibility for up to 6 weeks prior to Day -1 (baseline visit). 
On Day -1, eligible subjects will be randomized (1:1) to 1 of the 2 treatment arms 
(randomization will be stratified by study site): 


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• Valbenazine (40 mg for the first week followed by 80 mg for 3 weeks) for the first 4 weeks 
of the double-blind treatment period followed by placebo for the last 3 weeks of the double-
blind treatment period. 
• Placebo for the 7 weeks of the double-blind treatment period. 
An Interactive Web Response System (IWRS) will be used to maintain the study blind.  Study 
drug will be self-administered at home (in the presence of the subject’s caregiver, if applicable) 
beginning on Day 1 of Week 1.  At any time, the investigator can decrease the subject’s dose to 
40 mg if the subject is unable to tolerate the 80 mg dose (this will be done in a blinded manner; 
subjects receiving placebo will continue to receive placebo).  Subjects who are unable to tolerate 
the 40 mg dose (or placebo) will be discontinued from the study. 
Study sites will call subjects at the end of Weeks 2 and 3 to remind them to take their study drug 
daily.  A final study visit will be conducted at Week 7 Day 7 or at early termination.  Visits 
during Weeks 1 and 4 have a window of ±3 days, visits during Week 5 have no window, and 
visits during Weeks 6 and 7 have a window of ±1 day. 
A blood sample will be collected from randomized subjects on Day -1 to determine their 
CYP2D6 genotype.  Clinical dependence and withdrawal symptoms, efficacy, pharmacokinetics 
(PK), safety, and tolerability will be assessed at scheduled times throughout the study. 
A schematic of the study design is provided in Figure 1. 
Figure 1: 
Study Design Schematic 
 
ET=early termination. 
a  Subjects will receive valbenazine (40 mg for 1 week increased to 80 mg for 3 weeks) for 4 weeks followed by 
placebo for 3 weeks. 
b  Subjects will receive placebo for 7 weeks. 
8. 
STUDY POPULATION 
8.1. 
Subject Inclusion Criteria 
To participate in this study, subjects must meet the following criteria: 
1. Be male or female aged 18 to 65 years (inclusive).  
2. Subjects of childbearing potential must agree to use contraception consistently from 
screening until 30 days (females) or 90 days (males) after the last dose of study drug.  A 


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female subject of childbearing potential includes those who are not surgically sterile (ie, 
bilateral oophorectomy, hysterectomy or bilateral tubal ligation for at least 3 months prior to 
screening) and those who have not been postmenopausal for at least 1 year.  A male subject 
of childbearing potential is defined as a subject who has not been vasectomized at least 
3 months prior to screening. 
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom). 
• Vaginal sponge impregnated with spermicide used with a condom. 
• Intrauterine device (IUD). 
• Hormonal contraception taken for at least 3 months prior to screening. 
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 male partners not of childbearing potential or male subjects not of 
childbearing potential. 
• Female subjects not of childbearing potential. 
3. Female subjects of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at screening and a negative urine pregnancy test at 
baseline (Day -1).  
4. Have one of the following clinical diagnoses for at least 3 months prior to screening: 
• Schizophrenia or schizoaffective disorder as defined in the DSM (eg, DSM-IV or -5).   
• Mood disorder as defined in the DSM (eg, DSM-IV or -5). 
This criterion will be satisfied if the subject is able to provide a medical record of the 
diagnosis or reliable self-reported medical history and medications taken for the disorder.  If 
the subject is unable to provide a medical record, the investigator must confirm the 
psychiatric diagnosis based on an evaluation using the Mini International Neuropsychiatric 
Interview (MINI) (applicable module must be used to assess underlying disease). 
5. Have a clinical diagnosis of neuroleptic-induced TD as defined in the DSM (eg, DSM-IV 
or -5) for at least 3 months prior to screening.  This criterion will be satisfied if the subject is 
able to provide a medical record of the TD diagnosis or the investigator can confirm the TD 
diagnosis based on physical examination, and reliable self-reported medical history and 
medication use that show evidence of involuntary movements associated with dopamine 
antagonist/antipsychotic medication exposure that are clearly distinct from the typical 
parkinsonism associated with EPS or extrapyramidal side effects (EPSE). 
6. Maintenance medication(s) for schizophrenia or schizoaffective disorder, mood disorders, 
and other protocol-allowed concurrent medications should be at a stable dose (including no 
changes to the dose and frequency of ongoing medications and no new or discontinued 
medications for a minimum of 30 days before baseline [Day -1]), and these doses are 
expected to remain stable during the study.  This criterion will be satisfied if the investigator 


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can confirm prior and current medications and doses through reliable subject-reported 
information (eg, subject provides a list of medications and doses).   
7. Subjects (eg, those 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, olanzapine) for a minimum of 30 days before 
baseline (Day -1). 
8. Be in good general health and expected to complete the clinical study as designed. 
9. Have a body mass index (BMI) of 18 to 42 kg/m2 (inclusive) at screening.  (BMI is defined 
as the subject’s weight in kg divided by the square of the subject’s height in meters.) 
10. Have adequate hearing, vision, reading, and language skills to perform the procedures 
specified in the protocol. 
11. 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 study 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. 
12. Have a negative urine drug screen (UDS) (negative for amphetamines, methamphetamine, 
barbiturates, benzodiazepines, phencyclidine, cocaine, opiates, methadone, tricyclic 
antidepressants, or cannabinoids) at screening (central laboratory results) and baseline 
(Day -1) (UDS kit results conducted at the study site) except for any subject receiving a 
stable dose (ie, no as needed [prn] use) of benzodiazepines, opiates, or tricyclic 
antidepressants.  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, and has a negative UDS 
after retesting a minimum of 4 weeks after the initial positive result. 
13. Have a negative alcohol breath test at screening and baseline (Day -1). 
14. Be willing to provide authorization for access to personal health information in conjunction 
with US Health Insurance Portability and Accountability Act (HIPAA). 
8.2. 
Subject Exclusion Criteria 
Subjects will be excluded from the study if they: 
1. Have an active, clinically significant unstable medical condition within 1 month (30 days) 
prior to baseline (Day -1). 
2. Have a Simpson-Angus Scale (SAS) score ≥3 on two or more items at screening or baseline 
(Day -1), excluding Items 8 and 10. 
3. Have a known history of substance dependence, or substance (drug) or alcohol abuse within 
the 3 months prior to baseline (Day -1) (nicotine and caffeine dependence are not 
exclusionary), as defined in the DSM (eg, DSM-IV or -5). 
4. Have a Brief Psychiatric Rating Scale (BPRS) total score of ≥50 at screening or baseline 
(Day -1). 


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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 screening (using 
Baseline/Screening version) or baseline (Day -1) (using Since Last Visit version) will be 
excluded. 
6. Have a known history of neuroleptic malignant syndrome. 
7. Have a known history of long QT syndrome or cardiac arrhythmia. 
8. Have a screening or baseline (Day -1) average triplicate electrocardiogram (ECG) corrected 
QT interval using Fridericia’s formula (QTcF) of >450 msec (males) or >470 msec (females) 
or the presence of any clinically significant cardiac abnormality.  
9. Receive any excluded concomitant medication as detailed in Section 9.9.1. 
10. Have any of the following laboratory test abnormalities at screening: 
• Serum creatinine >1.5 times the upper limit of normal (ULN). 
• Aspartate aminotransferase (AST) ≥2.5 times ULN. 
• Alanine aminotransferase (ALT) ≥2.5 times ULN. 
• Gamma-glutamyl transferase (GGT) ≥3.0 times ULN.   
• Total bilirubin >1.5 mg/dL.  Subjects with a documented diagnosis of Gilbert's syndrome 
are not required to meet the bilirubin criteria.  
11. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to screening, 
with the exception of localized skin cancer or carcinoma in situ of the cervix. 
12. Have any of the following hematologic abnormalities at screening:  
• Hemoglobin <10 g/dL. 
• White blood cell (WBC) count <3.0 × 103/mm3. 
• Platelet count <100,000/mm3.  
13. Have other laboratory results not within the laboratory’s reference range and deemed by the 
investigator to be clinically significant. 
14. Have a positive human immunodeficiency virus antibody (HIV-Ab) test result or hepatitis B 
surface antigen (HBsAg) test result at screening.  Subjects with positive hepatitis C virus 
antibody (HCV-Ab) and confirmatory positive polymerase chain reaction (PCR) reflex test 
results at screening will be allowed to participate in the study provided that the subject is 
asymptomatic as assessed by the investigator and does not meet the liver function test 
abnormalities for ALT, AST, GGT, and total bilirubin in exclusion criterion #10. 
15. Have received an investigational drug within 30 days or 5 half-lives (if known), whichever is 
longer, prior to baseline (Day -1) or plan to use an investigational drug during the study. 
16. Have had a blood loss ≥550 mL or donated blood within 30 days prior to baseline (Day -1). 
17. Have an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors (eg, tetrabenazine, 
deutetrabenazine). 
18. Have had previous experience with valbenazine (INGREZZA or NBI-98854) or had 
previously participated in a valbenazine clinical study. 


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19. Are currently pregnant or lactating. 
8.3. 
Subject Identification and Replacement of Subjects 
Subjects will be identified by their unique subject number and initials (first, middle, last; a 
hyphen may be used if a subject does not have a middle name).  The subject initials and subject 
number will be noted on electronic case report forms (eCRFs), all source documentation, 
laboratory documents, and ECG tracings.  Subjects who discontinue from the study will not be 
replaced. 
8.4. 
Randomization 
On Day -1, eligible subjects will be randomized (1:1) to 1 of the 2 treatment arms 
(randomization will be stratified by study site): 
• Valbenazine (40 mg for the first week followed by 80 mg for 3 weeks) for the first 4 weeks 
of the double-blind treatment period followed by placebo for the last 3 weeks of the double-
blind treatment period. 
• Placebo for the 7 weeks of the double-blind treatment period.   
The subjects, investigators, and Sponsor will be blinded to the treatment assignment 
(programmed on the IWRS). 
9. 
STUDY EVALUATIONS 
9.1. 
Schedule of Assessments 
A schedule of assessments is shown in Table 1.  Subjects will provide written informed consent 
before any study-related procedures are performed.  Subject-related events and activities 
including specific instructions, procedures, concomitant medications, dispensing of study drug, 
and descriptions of AEs should be recorded in the appropriate source documents and case report 
forms (CRFs). 
 


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Table 1: 
Schedule of Assessments 
Procedure 
Screening Period 
Baseline 
Double-Blind 
Treatment Period 
Final Study Visit/ ETc 
Weeka   
-6 to -1 
Day -1 
1 
4 
5 
6 
7 
7 
Dayb 
-- 
-- 
-- 
-- 
1 
3 
5 
7 
2 
4 
7 
2 
4 
7 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UBACC / Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
update 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
update 
 
 
 
 
 
 
 
 
 
 
 
 
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 
12-lead ECGe 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy testf 
X (s) 
X (u) 
X (u) 
X (u) 
 
 
 
X (u) 
 
 
X (u) 
 
 
X (u) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsg 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Genotype blood sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screenh 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Alcohol breath testi 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
PK plasma samplej 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-TD-S 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
CGI-TD-I 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
C-SSRS 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
BPRS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
SAS 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
ESS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-A 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
mCSSA and PWC-20 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dosing at homek 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Study drug accountabilityl 
 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
AE monitoring 
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 
Call to subjectsm 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Definitions and footnotes are on the following page. 


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AE=adverse event; BARS=Barnes Akathisia Rating Scale; BPRS=Brief Psychiatric Rating Scale; CGI-TD-I=Clinical Global Impression-Tardive Dyskinesia-
Improvement; CGI-TD-S=Clinical Global Impression-Tardive Dyskinesia-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
ESS=Epworth Sleepiness Scale; ET=early termination; HAM-A=Hamilton Anxiety Rating Scale; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C 
virus antibody; HIV-Ab=human immunodeficiency virus antibody; MADRS=Montgomery-Asberg Depression Rating Scale; mCSSA=modified Cocaine 
Selective Severity Assessment; PK=pharmacokinetic; PWC-20=Physician Withdrawal Checklist-20; QTcF=corrected QT interval using Fridericia’s formula; 
s=serum; SAS=Simpson-Angus Scale; u=urine; UBACC=University of California, San Diego Brief Assessment of Capacity to Consent. 
 
a. 
Day 1 of Week 1 (ie, the day after Day -1) is the first day of dosing; study drug will be self-administered at home and subjects are not required to come to 
the study site.  Visits during Weeks 1 and 4 have a window of ±3 days, visits during Week 5 have no window, and visits during Weeks 6 and 7 have a 
window of ±1 day.  As much as possible, study visits should be scheduled at approximately the same time of day. 
b. Day 1 of Week 5, for example, is the first day of all subjects receiving placebo treatment. 
c. 
Final study visit for subjects who complete the study (or upon early termination). 
d. The UBACC will be used to determine whether the subject has the capacity to provide informed consent.  All subjects must provide informed consent prior 
to any study-related procedures.   
e. 
A standard 12-lead ECG will be conducted in triplicate (at least 1 minute apart and within 15 minutes) after the subject has rested supine for at least 
5 minutes.  The ECG parameters that will be assessed include heart rate, QT, QTcF, and PR intervals, and QRS duration based on the ECG machine readings 
(QTcF may need to be calculated). 
f. 
Pregnancy tests are required for all women of childbearing potential.  Serum pregnancy tests will be conducted at screening.  A urine pregnancy test will be 
conducted at baseline (Day -1) and subsequent visits.  The urine pregnancy test result at baseline (Day -1) will be used to confirm eligibility.  
g. Clinical laboratory tests include hematology, clinical chemistry, and urinalysis.  All blood samples will be obtained under non-fasted conditions. 
h. Urine drug screen will be analyzed at screening, baseline (Day -1), and Week 4 by the central lab.  In addition, a urine drug screen kit provided by the central 
lab will used at the site at baseline (Day -1) to confirm eligibility, and at Week 6 (Day 2), and Week 7 (Day 2).  Subjects who test positive for cannabinoids 
during screening should retest 4 weeks from last exposure to cannabinoids (must be within screening window).  A urine drug screen using a kit provided by 
the central laboratory may be conducted at the clinical site at any time during the study if the subject is suspected of substance or drug abuse. 
i. 
Subjects should not consume alcohol within 24 hours of their visits at Week 4, Week 6 (Day 2), or Week 7 (Day 2). 
j. 
Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
k. Subjects will self-administer study drug daily beginning on Day 1 of Week 1 (at approximately the same time each day, between 0700-1000 hours) at home 
in the presence of their caregiver (if applicable).  Subject or caregiver will record the daily date and time of dosing on the drug packaging form provided.   
l. 
At the end of Weeks 1, 4, 6, and 7 (or early termination), subjects will return all used and unused study drug and a compliance check will be performed by 
counting the capsules returned at each study visit. 
m. Study sites will call subjects at the end of Weeks 2 and 3 to remind them to take their study drug daily. 
 
 


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9.2. 
Screening and Baseline Assessments 
9.2.1. 
Genotyping 
A blood sample will be collected from subjects for the analysis of CYP2D6 status (ie, normal, 
intermediate, poor, or ultrarapid metabolizers) on Day -1.  Approximately 2 mL of blood will be 
collected in tubes containing dipotassium ethylenediaminetetraacetic acid (EDTA K2).  After the 
sample is obtained, it should be thoroughly mixed.  The vials will be stoppered and labeled with 
the study barcode and subject number.  The samples will be stored at approximately -20°C 
within approximately 15 minutes of collection.  The collection and submission of medical 
information will be accomplished with strict adherence to professional standards of 
confidentiality.  Genotyping blood samples collected from subjects will be shipped to a central 
laboratory for analysis. 
9.2.2. 
Brief Psychiatric Rating Scale 
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 site personnel will administer and score the scale at screening 
and at baseline (Day -1), and subjects must have a BPRS total score <50 to be eligible for study 
participation (see exclusion criterion #4).  If possible, the same person should administer and 
score the scales at all timepoints. 
9.3. 
Clinical Dependence and Withdrawal Symptoms Assessments 
9.3.1. 
Modified Cocaine Selective Severity Assessment 
The modified Cocaine Selective Severity Assessment (mCSSA) is a validated instrument that 
measures early cocaine abstinence signs and symptoms (Kampman et al., 1998).  The mCSSA is 
an 18-item instrument primarily drawn from symptoms commonly reported in the literature as 
being associated with early cocaine abstinence, including depression, fatigue, anhedonia, 
anxiety, irritability, sleep disturbance, and inability to concentrate.  The instrument includes 
additional symptoms such as paranoia, carbohydrate craving, bradycardia, and suicidality.  Items 
are rated on scales of 0 to 7 or 0 to 8, with separate scale descriptions for each item.  The scale 
has been modified to be specific to study drug (valbenazine or placebo) instead of cocaine; 
specifically, “cocaine” was replaced with “study drug” in question #4 and in the 2 visual analog 
scales. 


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The mCSSA will be administered by the investigator or qualified study site personnel at baseline 
(Day -1), Weeks 4, 5 (Days 1, 3, 5, and 7), 6 (Days 2, 4, and 7), 7 (Days 2 and 4), and the final 
study visit (Week 7 Day 7 or early termination).  If possible, the same person should administer 
the mCSSA for an individual subject at all timepoints. 
9.3.2. 
Physician Withdrawal Checklist-20 
The Physician Withdrawal Checklist-20 (PWC-20) is a validated 20-item physician-rated 
instrument that assesses potential symptoms of withdrawal on a severity scale in the following 
areas:  gastrointestinal, mood, sleep, motor, somatic, perception, and cognition (Rickels et al., 
2008).  Items are rated on a scale from 0 to 3, with total scores ranging from 0 to 60. 
The PWC-20 will be administered by the investigator or qualified study site personnel at baseline 
(Day -1), Weeks 4, 5 (Days 1, 3, 5, and 7), 6 (Days 2, 4, and 7), 7 (Days 2 and 4), and the final 
study visit (Week 7 Day 7 or early termination).  If possible, the same person should administer 
the PWC-20 for an individual subject at all timepoints. 
9.3.3. 
Epworth Sleepiness Scale 
The Epworth Sleepiness Scale (ESS) is a validated instrument to assess subject’s sleepiness 
(Chervin et al., 1997).  The instrument lists 8 daytime situations in which the subject rates his/her 
tendency to become sleepy on a scale from 0 (would never doze) to 3 (high chance of dozing).  
The total score ranges from 0 to 24.  
Subjects will complete the ESS at screening, baseline (Day -1), Weeks 4, 5 (Days 1, 3, 5, and 7), 
6 (Days 2, 4, and 7), 7 (Days 2 and 4), and the final study visit (Week 7 Day 7 or early 
termination). 
9.3.4. 
Hamilton Anxiety Rating Scale 
The Hamilton Anxiety Rating Scale (HAM-A) is a validated, clinician-rated instrument to 
evaluate the severity of anxiety (Maier et al., 1988).  The HAM-A is composed of 14 items, each 
of which is scored from 0 (not present) to 4 (very severe).  The total score ranges from 0 to 56. 
The investigator or other qualified site personnel will administer the HAM-A at screening, 
baseline (Day -1), Weeks 4, 5 (Days 1, 3, 5, and 7), 6 (Days 2, 4, and 7), 7 (Days 2 and 4), and 
the final study visit (Week 7 Day 7 or early termination).  If possible, the same person should 
administer and score the scale at all timepoints.    
9.4. 
Efficacy Assessments 
9.4.1. 
Clinical Global Impression-Tardive Dyskinesia-Improvement 
The Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) scale will be used 
to assess overall improvement since the initiation of study drug dosing on a 7-point scale (range; 
1=very much improved to 7=very much worse).  The investigator or qualified study site 
personnel will rate the scale at the scheduled times.  If possible, the same person should rate the 
CGI-TD-I at all visits.       


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CGI-TD-I will be assessed at Week 4 and the final study visit (Week 7 Day 7 or early 
termination). 
9.4.2. 
Clinical Global Impression-Tardive Dyskinesia-Severity 
The Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S), 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).   
The investigator or qualified study site personnel will rate the scale at the scheduled times.  If 
possible, the same person should rate the CGI-TD-S at all visits.       
The CGI-TD-S will be assessed at baseline (Day -1), Weeks 4, 5 (Day 7), 6 (Day 7), and the 
final study visit (Week 7 Day 7 or early termination). 
9.5. 
Pharmacokinetics Assessment 
Blood samples to determine plasma concentrations of valbenazine and its metabolite NBI-98782 
(other metabolites may be evaluated) will be collected at the end of Weeks 1 and 4.  Subjects 
will be asked to record and provide dosing times on the days when PK blood samples are 
collected.  The exact time of collection will be recorded on the eCRF. 
For each sample, approximately 2 mL of blood will be collected in tubes containing EDTA K2.  
The blood samples will be processed and stored according to the procedure as specified in the 
laboratory manual.  Samples will be shipped on dry ice to the central laboratory for analysis. 
9.6. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 9.9.1  and Section 11, respectively.  Additional safety assessments are described in the 
following sections. 
For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments (eg, repeat analysis), until the cause of the abnormality is 
determined and/or until the value returns to baseline (or within normal limits), or the investigator 
deems the abnormality to be of no clinical significance. 
Appropriate psychiatric evaluation and intervention will be provided for any treatment-emergent 
suicidal behavior or clinically significant suicidal ideation. 
9.6.1. 
Vital Sign Measurements 
Vital sign measurements will include orthostatic systolic and diastolic blood pressure, orthostatic 
pulse rate, respiratory rate (recorded supine only), and oral body temperature.  Blood pressure 
will be measured using a calibrated automatic blood pressure cuff after the subject has been 
supine for at least 5 minutes and after approximately 2 minutes of standing.  The automatic blood 
pressure cuff will also provide pulse rate measurement.  Vital sign measurements will be 
obtained before any scheduled blood sample collection.   


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Vital sign measurements will be collected during screening, at baseline (Day -1), Weeks 1, 4, 5 
(Days 1, 3, 5, and 7), 6 (Days 2, 4, and 7), 7 (Days 2 and 4), and the final study visit (Week 7 
Day 7 or early termination).  
9.6.2. 
Medical History 
A medical history will be taken at the screening visit and updated at baseline (Day -1) and as 
needed throughout the study.  
The subject’s psychiatric history will be documented and will include the subject’s age at first 
diagnosis of schizophrenia, 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.   
9.6.3. 
Physical Examination Including Height and Weight 
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system.  A complete 
physical examination including weight will be performed at screening, baseline (Day -1), 
Weeks 1, 4, 5 (Day 7), 6 (Day 7), and the final study visit (Week 7 Day 7 or early termination).  
Height will be measured at screening only.  Height and weight will be measured with subjects 
not wearing shoes. 
9.6.4. 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicate (at least 1 minute apart and within 
15 minutes) after the subject has rested supine for at least 5 minutes.  The ECG parameters that 
will be assessed include heart rate, PR interval, QRS duration, QT interval, and QTcF (machine 
readings or calculated).  Additionally, the occurrence of de- and re-polarization and rhythm 
disorders or other abnormalities will be assessed.  Based on the review of these parameters, the 
investigator or designee will note if the ECG is Normal, Abnormal not Clinically Significant, or 
Abnormal Clinically Significant.  If the ECG is Abnormal Clinically Significant, the investigator 
or designee will provide a description of the abnormality recorded on the AE eCRF.  
The 12-lead ECG will be conducted at screening, baseline (Day -1), Weeks 1 and 4, and the final 
study visit (Week 7 Day 7 or early termination). 
9.6.5. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory.  In addition, certain 
laboratory assessments (alcohol breath test, UDS, and urine pregnancy test) will be performed by 
the study site at baseline (Day -1) to confirm subject eligibility.  The central laboratory will 
provide instructions and supplies to the study staff before study initiation and instructions will be 
included in a laboratory manual.  The laboratory test battery will include routine and screening 
laboratory tests.  Laboratory samples will be collected in the following approximate amounts:  
3 mL for hematology, 1 mL for clinical chemistry (includes serum pregnancy tests), 3 mL for 
serology, and 2 mL for genotyping.  Approximate total blood sample volume per subject is 
25 mL (including PK samples). 


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The following clinical safety laboratory assays will be performed at screening, baseline (Day -1), 
Week 4, and the final study visit (Week 7 Day 7 or early termination): 
Hematology:  complete blood count including WBC count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, and platelet count, mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red 
cell distribution width (RDW). 
Clinical Chemistry:  sodium, potassium, calcium, magnesium, phosphorus, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate 
dehydrogenase, AST, ALT, 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 nitrite, protein, leukocyte esterase, 
or blood. 
The following additional laboratory tests will be performed: 
Serology:  Blood will be collected for HIV-Ab, HBsAg, and HCV-Ab and reflex PCR testing at 
screening. 
UDS and Alcohol Breath Test:  The UDS will test for amphetamines, methamphetamine, 
barbiturates, phencyclidine, benzodiazepines, cannabinoids, cocaine, methadone, tricyclic 
antidepressants, and opiates.  A UDS will be performed at screening, baseline (Day -1), and 
Week 4 by a certified central laboratory.  In addition, a UDS will be conducted at the clinical site 
at baseline (Day -1) using a UDS kit provided by the central laboratory and the results will be 
used to confirm study eligibility, and at Week 6 (Day 2) and Week 7 (Day 2).  Subjects who test 
positive for cannabinoids during screening should retest 4 weeks from last exposure to 
cannabinoids (must be within screening window).  A UDS using a kit provided by the central 
laboratory may be conducted at the clinical site at any time during the study if the subject is 
suspected of substance or drug abuse. 
The alcohol breath test will be performed at screening, baseline (Day -1), Week 4, Week 6 
(Day 2), and Week 7 (Day 2). 
Pregnancy Test:  Pregnancy tests will be performed for all female subjects of childbearing 
potential.  A serum pregnancy test (β-hCG) will be performed at screening.  A urine pregnancy 
test will be performed at the clinical site at baseline (Day -1; a negative test result is required to 
be eligible for the study) and at Weeks 1, 4, 5 (Day 7), 6 (Day 7), and the final study visit 
(Week 7 Day 7 or early termination).  
9.6.6. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu).  There are versions of the questionnaire designed for use at 
screening (Baseline/Screening version) and at baseline 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 1 or more screening 


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questions will prompt additional questions that evaluate frequency and intensity of suicidal 
ideation and/or behavior.  Subjects with any lifetime suicidal behavior or suicidal ideation of 
type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active 
suicidal ideation with specific plan and intent) in the 3 months before screening or baseline 
(Day -1) based on the C-SSRS should be excluded (see exclusion criterion #5). 
The C-SSRS will be administered and scored by the investigator or qualified study site personnel 
at screening, baseline (Day -1), Week 4, and the final study visit (Week 7 Day 7 or early 
termination).  Of note, the Since Last Visit version of the C-SSRS will be administered at 
Week 4 and at the final study visit (Week 7 Day 7 or early termination), but the lookback period 
will be since the last C-SSRS assessment, not since the subject’s last visit.  If possible, the same 
person should administer and score the scale at all timepoints. 
9.6.7. 
Barnes Akathisia Rating Scale 
The Barnes Akathisia Rating Scale (BARS) is a validated 4-item scale to assess the presence and 
severity of drug-induced akathisia (Barnes, 1989).  This scale includes both objective items (eg, 
observed restlessness) and subjective items (eg, subject’s awareness of restlessness and related 
distress), together with a global assessment of akathisia.  Global assessment is made on a scale of 
0 to 5 (0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 
5=severe akathisia). 
The investigator or other qualified site personnel will administer and score the BARS at the 
scheduled times.  The BARS will be administered at baseline (Day -1), Week 4, and the final 
study visit (Week 7 Day 7 or early termination).  If possible, the same person should administer 
and score this scale at all timepoints. 
9.6.8. 
Simpson-Angus Scale 
The SAS is a validated 10-item scale to evaluate the presence and severity of drug-induced 
parkinsonism and other extrapyramidal symptoms (Simpson and Angus, 1970).  The 10 items 
focus on clinician-assessed EPSE and each item is rated on a 0 to 4 scale of increasing severity 
with definitions given for each anchor point.  The SAS will also be used as a screening tool; 
subjects will be excluded if they have a score ≥3 on two or more items at screening or baseline 
(Day -1), excluding Items 8 and 10 (see exclusion criterion #2). 
The investigator or other qualified site personnel will administer and score the scale at screening, 
baseline (Day -1), Week 4, and the final study visit (Week 7 Day 7 or early termination).  If 
possible, the same person should administer and score the scales at all timepoints. 
9.6.9. 
Montgomery-Asberg Depression Rating Scale using the Structured Interview 
Guide for the MADRS 
The Montgomery-Asberg Depression Rating Scale (MADRS) is a validated rating scale designed 
to measure changes in the severity of depressive symptoms (Montgomery and Asberg, 1979).  
The MADRS consists of 10 items scored on a 7-point scale (0 to 6) with increasing number 
value indicating increasing severity for each item with anchor points provided at 2-point 
intervals.  Scoring is based on a structured clinical interview following the Structured Interview 
Guide for the MADRS (SIGMA; Williams and Kobak, 2008). 


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The investigator or other qualified site personnel will administer and score the scale at screening, 
baseline (Day -1), Week 4, and the final study visit (Week 7 Day 7 or early termination).  If 
possible, the same person should administer and score the scale at all timepoints. 
9.7. 
Specific Study Information 
After providing informed consent (as required by the governing IRB), subjects will undergo 
screening procedures within 6 weeks of Day -1.  As much as possible, study visits should be 
scheduled at approximately the same time of day. 
9.7.1. 
Screening (Week -6 to -1) 
Informed Consent Process:  The ICF will be reviewed with subjects.  The UBACC will then be 
administered (Jeste et al., 2007).  Only subjects who are deemed to have the capacity to provide 
consent may sign the ICF.  The ICF must be signed prior to the start of any screening procedures. 
During screening, the following study evaluations and tasks will be performed at the study site: 
• Assess inclusion/exclusion criteria. 
• Collect medical history. 
• Perform physical examination (including height and weight). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform a 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a serum pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect blood sample for serology testing (HBsAg, HCV-Ab, and HIV-Ab). 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis and UDS. 
• Perform alcohol breath test. 
• Administer the C-SSRS (Screening/Baseline version). 
• Administer the BPRS. 
• Administer the SAS. 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the MADRS. 
• AE monitoring. 
• Record prior and concomitant medications. 
Subjects will be asked to refrain from taking prohibited medications as specified in Section 9.9. 
9.7.2. 
Baseline (Day -1) 
The following study evaluations and procedures will be performed on Day -1: 
• Update inclusion and exclusion criteria. 


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• Update medical history.  
• Perform physical examination (including weight).  
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature.  
• Perform a 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test for female subjects of childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for genotyping. 
• Perform UDS (using the UDS kit to confirm eligibility and collect central laboratory sample). 
• Perform alcohol breath test. 
• Randomization. 
• Administer the CGI-TD-S. 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Administer the BARS. 
• Administer the SAS. 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the MADRS. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• Dispense study drug. 
• AE monitoring. 
• Record concomitant medications. 
Subjects will be instructed to begin taking study drug the following day (ie, Week 1 Day 1) as 
detailed in Section 10.5.  
9.7.3. 
Double-Blind Treatment Period (Weeks 1 to 7) 
Study sites will call subjects at the end of Weeks 2 and 3 to remind them to take their study drug 
daily. 
9.7.3.1. 
Week 1 (±3 days) 
The following study evaluations and procedures will be performed at the end of Week 1: 
• Perform physical examination (including weight).  
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature.  


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• Perform a 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test for female subjects of childbearing potential. 
• Collect PK blood sample. 
• Dispense study drug. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 
9.7.3.2. 
Week 4 (±3 days) 
The following study evaluations and procedures will be performed at the end of Week 4: 
• Perform physical examination (including weight).  
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature.  
• Perform a 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test for female subjects of childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Perform UDS. 
• Perform alcohol breath test. 
• Collect PK blood sample. 
• Administer the CGI-TD-S. 
• Administer the CGI-TD-I. 
• Administer the C-SSRS (Since Last Visit version; lookback period to Day -1 [baseline]). 
• Administer the BARS. 
• Administer the SAS. 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the MADRS. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• Dispense study drug. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 


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9.7.3.3. 
Week 5, Days 1, 3, 5, and 7 
The following study evaluations and procedures will be performed on Week 5, Days 1, 3, 5, 
and 7: 
• Physical examination (Day 7 only). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform a urine pregnancy test for female subjects of childbearing potential (Day 7 only).  
• Administer the CGI-TD-S (Day 7 only). 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• AE monitoring. 
• Record concomitant medications. 
9.7.3.4. 
Week 6, Days 2, 4, and 7 (±1 day) 
The following study evaluations and procedures will be performed on Week 6, Days 2, 4, and 7: 
• Physical examination (Day 7 only). 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 
• Perform a urine pregnancy test for female subjects of childbearing potential (Day 7 only). 
• Perform UDS (Day 2 only). 
• Perform alcohol breath test (Day 2 only).  
• Administer the CGI-TD-S (Day 7 only). 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• Dispense study drug (Day 7 only). 
• Study drug accountability (Day 7 only). 
• AE monitoring. 
• Record concomitant medications. 
9.7.3.5. 
Week 7, Days 2 and 4 (±1 day) 
The following study evaluations and procedures will be performed on Week 7, Days 2 and 4: 
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature. 


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• Perform UDS (Day 2 only). 
• Perform alcohol breath test (Day 2 only).  
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• AE monitoring. 
• Record concomitant medications. 
9.7.4. 
Final Study Visit (Week 7 Day 7 [±1 day] or Early Termination) 
The following study evaluations and procedures will be performed at Week 7 Day 7 or early 
termination: 
• Perform physical examination (including weight).  
• Collect vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and oral body temperature.  
• Perform a 12-lead ECG in triplicate (at least 1 minute apart and within 15 minutes). 
• Perform a urine pregnancy test for female subjects of childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Administer the CGI-TD-S. 
• Administer the CGI-TD-I. 
• Administer the C-SSRS (Since Last Visit version; lookback period to Week 4). 
• Administer the BARS. 
• Administer the SAS. 
• Administer the ESS. 
• Administer the HAM-A. 
• Administer the MADRS. 
• Administer the mCSSA. 
• Administer the PWC-20. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 
9.8. 
Study Duration 
The expected duration of study participation for each subject is approximately 13 weeks, 
including up to 6 weeks of screening and 7 weeks of double-blind study drug treatment. 


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9.9. 
Prohibitions and Restrictions 
9.9.1. 
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 screening and during the study will be 
entered on the Prior and Concomitant Medications eCRF.  All medications taken for indications 
of schizophrenia/schizoaffective disorder, mood disorder, EPSE, and TD within the last 2 years 
will also be entered on the Prior and Concomitant Medications eCRF.  Any additions, deletions, 
or changes in the dose of these medications will be entered on the eCRF with indication, dose, 
route, and dates of drug administration. 
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 new or discontinued medications) for a 
minimum of 30 days before baseline (Day -1), and these doses are expected to remain stable 
during the study.  Benzodiazepines must be at a stable dose (ie, no prn use) for 2 weeks before 
baseline (Day -1).  Investigators should document doses of current medication through medical 
or pharmacy records, confirmation with the subject’s caregivers (if applicable), or through 
reliable subject-reported information (eg, provide a list of medications and doses). 
Prohibited medications:  The following medications are prohibited from 30 days prior to 
baseline (Day -1) (unless otherwise stated) until the final study visit (or early termination) as 
described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenytoin, 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, deutetrabenazine, 
reserpine) are prohibited (except for valbenazine administered per the current protocol). 
As needed (prn) use:  As needed use of the following medications is strictly prohibited: 
anticholinergics, benzodiazepines, opiates, tricyclic antidepressants, antipsychotics, mood 
stabilizers, antidepressants, strong CYP3A4 inhibitors and inducers, and strong CYP2D6 
inhibitors. 
9.9.2. 
Dietary Restrictions 
Subjects must refrain from excessive consumption of alcohol (ie, no more than 2 alcoholic 
beverages daily) or more than 7 alcoholic beverages weekly within 7 days of baseline (Day -1) 
and not consume any alcohol within 48 hours of baseline (Day -1).  Subjects must refrain from 


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excessive consumption of alcohol (ie, no more than 2 alcoholic beverages daily) during the 
remainder of the study.  Subjects should not consume alcohol within 24 hours of their visits at 
Week 4, Week 6 (Day 2), or Week 7 (Day 2). 
9.9.3. 
Other Restrictions 
Subjects must not donate blood within 30 days or donate plasma within 7 days of baseline 
(Day -1) and until 30 days after the final study visit or early termination.  Male subjects must 
agree to refrain from donating sperm for 90 days after the last dose of study drug.  Subjects must 
continue using contraception for 30 days after the last dose of study drug for females and 90 days 
after the last dose of study drug for males. 
Participation in another investigational drug study is prohibited for at least 30 days after the last 
dose of study drug or 30 days after study completion, whichever is longer. 
9.10. 
Withdrawal Criteria 
9.10.1. 
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. 
The investigator must withdraw the subject from the study if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable. 
• If the subject is unable to tolerate the starting dose or resumption of the previous dose.   
• QTcF value >500 msec (cardiologist verified) on any ECG tracing.  
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) based on the C-SSRS. 
• Is lost to follow-up. 
• Subject is confirmed to be pregnant. 
The investigator or NBI may withdraw the subject from the study for other reasons as described 
below.  These should be discussed on a case-by-case basis with the NBI Medical Monitor (or 
designee) prior to withdrawing the subject from the study. 
• Develops a clinically significant laboratory (eg, ALT or AST ≥2.5 times ULN) or ECG 
abnormality. 
• Requires a medication that is prohibited by the protocol. 
All subjects prematurely discontinuing the study, regardless of cause, should be encouraged to 
have all early termination assessments performed. 
9.10.2. 
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 


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eCRF.  All subjects who withdraw from the study prematurely will be asked to have all early 
termination assessments performed. 
It is crucial to obtain follow-up data for any subject withdrawn because of an AE, abnormal 
laboratory test, vital sign measurement, physical examination, or ECG finding.  In any case, 
every effort must be made to undertake safety follow-up procedures. 
9.10.3. 
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. 
10. 
STUDY DRUG 
10.1. 
Study Drug Supplies 
10.1.1. 
Valbenazine 
Valbenazine will be supplied as capsules containing 20 or 40 mg of valbenazine (free base 
equivalent as the ditosylate salt).  The doses that will be used in this study are:  40 mg once daily 
taken as two valbenazine 20 mg capsules and 80 mg once daily taken as two valbenazine 40 mg 
capsules.  Subjects randomized to receive valbenazine will receive 40 mg for the first week and 
80 mg for the remainder of their valbenazine treatment. 
10.1.2. 
Placebo 
Placebo capsules identical in appearance to valbenazine capsules will be used in this study.  
Subjects randomized to placebo will take 2 placebo capsules daily on an identical schedule as 
subjects randomized to valbenazine for the first 4 weeks of the study.  All subjects will take 
2 placebo capsules daily for the last 3 weeks of the study.  
10.2. 
Study Drug Storage 
Study drug must be stored at controlled room temperature (CRT) (20˚C to 25˚C or 68˚F to 77˚F) 
under the conditions specified in the Investigator’s Brochure and in a locked area accessible only 
to the pharmacist (or designee) until dispensing.  Excursions outside this range will be allowed 
provided they meet the following conditions: 
• Storage between refrigerated conditions (2˚C or 36˚F) and CRT (25˚C or 77˚F) for an 
unspecified length of time. 
• Storage at temperatures above 25˚C (77˚F) but no more than 30˚C (86˚F) for up to 
3 months. 
• Storage at temperatures above 30˚C (86˚F) but no more than 40˚C (104˚F) for up to 
24 hours. 


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10.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice and GCP rules.  The study drugs will be sent to authorized staff at the study site.  The 
authorized study staff member must confirm receipt of the study drug to NBI or its designee. 
Study drug will be supplied as capsules in child-resistant blistercard dispensers; each blistercard 
contains enough study drug for 7 days of dosing plus 3 extra dose days or 14 days of dosing plus 
3 extra dose days.  The blistercards will contain capsules of valbenazine or placebo. 
Each blistercard dispenser will be labeled with a single-panel label and secured with tamper 
evident seals.  Label text will include, but is not limited to, the protocol number, dosage form, 
route of administration, Sponsor name and address, storage condition and the statement “Caution 
– New Drug:  Limited by Federal (or US) Law to Investigational Use.” 
10.4. 
Blinding 
This study includes a 7-week, randomized, double-blind, placebo-controlled treatment period 
during which the subject, investigator, all study center personnel, and the Sponsor will be 
blinded to the subject’s treatment.  An IWRS will be used to maintain the study blind.  Although 
all subjects will receive placebo for the final 3 weeks of the study, investigators, study center 
personnel, and the Sponsor will remain blinded to subjects’ initial treatment.  Additionally, 
subjects will not be informed that they will receive placebo for the final 3 weeks of the study, 
and the study design will be explained to subjects in manner that this information is not revealed. 
The randomization code will be broken for an individual subject only if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 
identity of the subject’s treatment assignment, or for regulatory reporting requirements.  All 
attempts to contact the NBI medical monitor (refer to Section 11.4.3 for contact information) 
must be made before unblinding a subject.  The unblinding form that contains the date, time, the 
reason the blind was broken, and name of NBI representative contacted must be completed. 
10.5. 
Study Drug Preparation and Administration 
Study drug will be administered once daily at home and the capsules must be swallowed with at 
least 250 mL of water, with or without food, each morning at approximately the same time 
(between 0700 and 1000 hours).  If a subject forgets or is unable to take the study drug on a 
given day, the subject should skip that dose and resume normal dosing the following day.  
Subjects or their caregiver will record the date and time of study drug dosing each day on the 
labels provided on the study drug packaging form. 
10.6. 
Study Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty drug packaging material to the center at 
specified study visits for drug accountability and reconciliation by study center personnel.  A 
compliance check will be performed by counting the capsules returned at each study visit.  A 
representative from the study center will call the subjects at the end of Weeks 2 and 3 to remind 
them to take their study drug daily. 


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The quantity of study drug dispensed, used, and returned will be recorded on a dispensing log or 
otherwise documented.  The quantity of study drug lost or destroyed must also be accounted for 
and documented.  The designated pharmacist or qualified personnel will be responsible for 
maintaining accurate records of the quantity and dates of all study drug supplies received, 
dispensed, and returned. 
10.7. 
Study Drug Return 
Written documentation to account for study drug and study drug materials is mandatory; all 
unused study drug and study drug materials must be kept in a secure location for final 
accountability and reconciliation.  Returned study drug and study drug material must be 
accounted for on a study drug return form provided by NBI or designee.  The investigator must 
provide a written explanation for any destroyed or missing study drug or study drug materials on 
the study drug return form. 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee.  Study drug return forms must be completed for the 
shipment of returns and sent with the study drug and study drug materials.  One copy of the 
study drug return form will be retained in the investigator’s study file. 
All returned study drug and study drug materials should be stored, inventoried, reconciled, and 
returned according to applicable state and federal regulations and study procedures. 
11. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject has signed the 
ICF until the subject’s final study visit (or upon early termination). 
11.1. 
Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of conditions present at the start of the study; (2) subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction. 
If at any time after baseline the subject’s response to the suicidal ideation section of the C-SSRS 
is worse than the baseline assessment, it will be documented as an AE.  All suicidal behaviors 
will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based on 


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signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
drug, must be documented in the subject’s medical records, in accordance with the investigator’s 
normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for duration, intensity, 
frequency, seriousness, outcome, other actions taken, and relationship to the study drug.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before drug administration, unless it 
unexpectedly progresses, or increases in severity following drug administration.  
• Treatment failure or lack of efficacy. 
• Pregnancy 
11.1.1. 
Intensity of Adverse Events 
AEs must be graded for intensity.  An intensity category of mild, moderate, or severe, as defined 
in Table 2, must be entered on the AE eCRF.  It should be noted that the term “severe” used to 
grade intensity is not synonymous with the term “serious.” 
Table 2: 
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. 
11.1.2. 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the criteria outlined in Table 3.  An AE is deemed associated with the use of the 
study drug “if there is a reasonable possibility that the drug caused the AE” (otherwise referred 
to as a suspected adverse reaction).  Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the AE (Title 21 CFR 312.32 [a]). 


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Table 3: 
Relationship of Adverse Events to Study Drug 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the drug or in 
which the drug level has been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is confirmed by improvement on 
stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure. 
Possible 
An adverse event in which there is reasonable possibility that the drug caused the event.  
Reasonable possibility means there is evidence to suggest a causal relationship between the 
drug and the adverse event. 
Unlikely 
A reaction that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or suspected response pattern to the suspected drug; but that could 
reasonably be explained by known characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
11.2. 
Recording Adverse Events 
For randomized subjects, each AE will be listed as a separate entry on an AE eCRF.  Screen 
failure subjects will have AE information noted only in the source document.  The investigator 
(or designee) will provide information on dates of onset and resolution, intensity, seriousness, 
frequency, action(s) taken, changes in study drug usage, relationship to study drug, and outcome.   
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to NBI or its designee: 
• SAE, including death (see Section 11.4). 
• Pregnancy (see Section 11.5). 
• Treatment unblinding for any reason. 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) based on the C-SSRS. 
11.3. 
Poststudy Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  If 
resolved, a resolution date should be documented on the eCRF. 
AEs ongoing at the final visit or 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. 


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11.4. 
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 study drug or final study visit, whichever is longer in duration. 
11.4.1. 
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, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
11.4.2. 
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 
NBI Medical Monitor (and the IRB/IEC, if necessary) immediately (within 24 hours) of the SAE 
and the outcome of the SAE. 


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If an investigator becomes aware of an SAE within the time of informed consent until 30 days 
after the last dose of study drug or final study visit, whichever is longer in duration, then the 
event must be documented and reported as described in Section 11.4.3. 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events 
SAEs and other immediately reportable events (defined in Section 11.2) must be reported within 
24 hours of first knowledge of the event by study personnel to the NBI Medical Monitor or NBI 
Drug Safety and Pharmacovigilance (DSPV) Department.  Reports of SAEs and pregnancies 
must be followed by a fax or email of the SAE or Pregnancy Form.  It is important that the 
investigator provides his or her assessment of relationship to study drug at the time of the initial 
SAE report. 
For SAEs and other immediately reportable events, contact DSPV: 
11.4.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 11.1.2) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life-threatening experience within 7 calendar 
days to the applicable regulatory authority(ies); 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/IEC 
as soon as possible.  Documentation of the submission to the IRB/IEC and receipt by the 
IRB/IEC (if applicable) must be retained for each safety report. 
11.5. 
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 contraception (see 
inclusion criterion #2 in Section 8.1) until 30 days (females) or 90 days (males) after the last 
dose of study drug.  If at any time between the time the subject signs the ICF and the last study 
visit, a subject believes she is pregnant, the subject will be instructed to return to the study center 
within 24 hours and undergo a serum pregnancy test to confirm pregnancy.  
All confirmed pregnancies in subjects who received study drug must be immediately reported to 
NBI (see Section 11.4.3 for contact information), followed by fax or email of the pregnancy form 
to NBI DSPV.  A first trimester ultrasound will be required for all confirmed pregnancies.  


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Pregnancies in subjects who received valbenazine will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 
12. 
DOCUMENTATION OF DATA 
12.1. 
Case Report Forms 
The eCRF data for this study are being collected with an electronic data capture (EDC) system 
(Rave®) provided by Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific eCRFs will comply with Title 21 CFR Part 11.  The documentation related to the 
validation of the EDC system is available through the vendor, Medidata, while the validation of 
the study specific eCRFs will be conducted by NBI and the required documentation will be 
maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs.  All data 
entered into the eCRF will be supported by source documentation.  The eCRF for each subject 
must be reviewed by the investigator and signed on the appropriate eCRF page(s).  This should 
be done as soon as possible after the subject completes the study.   
The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF.  All change information, including the date, person 
performing the corrections, and reason for the change will be available via the electronic audit 
trail, which is part of the EDC system.  The eCRFs will be reviewed periodically for 
completeness, legibility, and acceptability by NBI (or designee).  NBI will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify eCRF 
entries.  The Principal Investigator will review the eCRFs for completeness and accuracy and 
enter his or her electronic signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access.  Such access will be removed from 
study centers at the end of the center’s participation in the study.  Data from the EDC system will 
be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at that 
time as a durable record of the center’s eCRF data.  Although not required, the investigator may 
make paper printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI and/or health authority representatives at any time.  The Principal Investigator 
will agree to the inspection of study-related records by health authority representatives and/or 
NBI. 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
Any discrepancies will be corrected on-line by authorized study center personnel.  After 


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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 study center (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. 
12.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Prior and concomitant medications will be coded using the 
chosen version of the World Health Organization Drug Dictionary. 
13. 
STATISTICAL AND ANALYTICAL PLAN 
13.1. 
Overview 
Descriptive and inferential statistical methods will be used to evaluate and summarize the data 
from this study.  The term “descriptive statistics” refers to the number of subjects (n), mean, 
median, SD, SEM, minimum, and maximum for continuous and ordinal categorical variables; 
and refers to the number and percentage of subjects for categorical variables.  The term 
“inferential statistics” refers to hypothesis tests which will be performed to assess differences 
between the treatment groups for selected variables.  All such hypothesis tests will be tests of the 
null hypothesis of no difference between the treatment groups being compared versus the 2-sided 
alternative hypothesis that there is a difference.  A 2-sided level of significance of 0.05 will be 
used in this study.  Unless stated otherwise, “treatment group” refers to the treatment the subject 
is randomly assigned to receive on Day -1. 
The analysis plan provided in this protocol represents a brief description of the planned analyses.  
The comprehensive statistical analysis plan (SAP) will be generated prior to final study database 
lock.  The SAP may include a number of additional analyses and data summaries not described 
in this protocol. 
13.2. 
Analysis Sets 
13.3. 
Safety Analysis Set 
The safety analysis set will include all subjects who are randomized to a treatment group, take at 
least one dose of study drug, and have any postbaseline safety data.  Treatment assignment will 
be based on randomized treatment.  The safety analysis set will be used for all summaries of 
safety data (e.g., AEs, clinical laboratory data) and plasma concentration data.  
13.3.1. 
Dependence and Withdrawal Analysis Set 
The dependence and withdrawal analysis set will include all subjects in the safety analysis set 
who enter the withdrawal period (ie, subject is dispensed study drug at Week 4).  The 


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dependence and withdrawal analysis set will be used for summaries and analyses of clinical 
dependence and withdrawal symptoms data. 
13.3.2. 
Efficacy Analysis Set 
The efficacy analysis set will include all subjects who are randomized to a treatment group, take 
at least one dose of study drug, and have a CGI-TD-I or CGI-TD-S assessment at Week 4. 
Treatment assignment will be based on randomized treatment.  The efficacy analysis set will be 
used for all summaries of efficacy data.   
13.4. 
Sample Size Determination 
The sample size for this study is consistent with typical evaluations of dependence and 
withdrawal. 
13.5. 
Handling of Missing Data 
In general, all available study data will be included in relevant summaries and data displays, 
including any available data for subjects with incomplete or missing data.  Specific rules for 
handling missing data values (including any imputation rules) will be identified in the SAP. 
13.6. 
Disposition of Subjects 
A summary of subject disposition will be prepared that displays the number of subjects who 
were randomized, who completed through Week 4, who entered the withdrawal period, and who 
completed the study.  The number of subjects who discontinued from the study will be displayed 
also by reason for discontinuation. 
13.7. 
Important Protocol Deviations 
A summary of the number and percentage of subjects with important protocol deviations by 
deviation category and by treatment group will be provided for all randomized subjects. 
13.8. 
Demographics and Baseline Subject Characteristics 
Demographic data, subject baseline characteristics, and medical history will be summarized with 
descriptive statistics. 
13.9. 
Study Drug Dosing and Compliance 
The number and percentage of subjects who are dose compliant (at least 80% of expected 
number of doses taken) will be summarized with descriptive statistics by visit.   
The number and percentage of subjects with a dose reduction will be summarized. 
13.10. 
Clinical Dependence and Withdrawal Data 
The primary assessment of withdrawal will be the number of subjects with withdrawal-related 
AEs (preferred terms will be prespecified in the SAP); differences between treatment groups will 
be tested for statistical significance using Fisher’s exact test.  The secondary assessment of 


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withdrawal will be the percentage of subjects in each treatment group who experience an 
increase on the PWC-20 by 5 new symptoms of moderate or severe degree or a worsening of 
symptoms by 2 points during Weeks 5 to 7 compared with Week 4 (Rickels et al., 2008).  Other 
assessments of withdrawal will be the mean worst scores per treatment group on the PWC-20 
and mCSSA, which will be summarized using descriptive statistics.  Additionally, the percentage 
of subjects in each treatment group with a PWC-20 total score of 0 to 15, 16 to 30, 31 to 45, and 
46 to 60 at each timepoint (baseline [Day -1], Weeks 4, 5 [Days 1, 3, 5, and 7], 6 [Days 2, 4, and 
7], 7 [Days 2 and 4], and the final study visit [Week 7 Day 7 or early termination]) will be 
summarized using descriptive statistics.  The ESS and HAM-A data will be summarized by visit 
with descriptive statistics.  Key assessments of clinical dependence and withdrawal will be 
summarized descriptively by study site. 
13.11. 
Pharmacokinetic Data 
The plasma concentrations of valbenazine and its metabolite NBI-98782 will be summarized 
with descriptive statistics by timepoint (Weeks 1 and 4) and the valbenazine dose (40 mg or 
80 mg) received prior to that timepoint.  Concentrations below the lower limit of quantification 
will be set equal to zero for all plasma concentration summaries. 
13.12. 
Efficacy Data 
The efficacy measures in this study include the CGI-TD-I and the CGI-TD-S.  For the CGI-TD-I, 
descriptive statistics will be presented for each visit.  For the CGI-TD-S, descriptive statistics 
will be presented for each visit and for the changes from baseline (Day -1) to each postbaseline 
visit. 
13.13. 
Safety Data 
Treatment-emergent adverse events (TEAEs), categorized by MedDRA system organ class 
(SOC) and/or preferred term (PT) will be summarized in frequency tables.  The TEAE summary 
tables will include the number of unique subjects experiencing each event and percentage of 
subjects experiencing each event. 
Summary tables will be presented including all TEAEs. 
Additional summaries will be presented for TEAEs leading to study drug dose reductions, 
premature discontinuations from the study, SAEs, and deaths. 
Clinical laboratory, vital signs, ECG, C-SSRS, BPRS, BARS, SAS, and MADRS data will be 
summarized by visit with descriptive statistics.  Potentially clinically significant (PCS) values for 
selected clinical laboratory and vital signs variables will be summarized. 
13.14. 
Software 
Statistical calculations and summaries will be generated using SAS software version 9.4 or later. 
13.15. 
Interim Analysis 
An interim analysis is not planned for this study. 


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14. 
REGULATORY AND ETHICAL ISSUES 
14.1. 
General Legal References 
The study will be carried out according to provisions of the US CFR, the US FDA, and the ICH 
Guidelines for GCP.  All clinical work conducted under this protocol is subject to GCP 
regulations.  This includes an inspection by NBI or its representative, health authority, or 
IRB/IEC representatives at any time.  The investigator must agree to the inspection of 
study-related records by health authority representatives and/or NBI or its designee. 
14.2. 
Institutional Review Board/Independent Ethics Committee 
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study center.  
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to NBI.  The investigator must agree to make any 
required progress reports to the IRB/IEC, as well as reports of SAEs, life-threatening problems, 
or death. 
14.3. 
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/IEC will be notified of all 
amendments to the protocol.  Amendments to the protocol will not be implemented until written 
IRB/IEC approval has been received. 
14.4. 
Required Documents 
The investigator must provide NBI or its designee with the following documents before the 
enrollment of any subject (originals should be kept by the investigator in the investigator’s study 
regulatory document binder): 
• Signed copy of the protocol signature page. 
• Investigator’s Brochure acknowledgement 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. 
• Letter of approval from the IRB/IEC for both protocol and consent form. 
• Copy of the IRB/IEC approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
14.5. 
Informed Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. 


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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. 
14.6. 
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 will respond to inquiries.  In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
14.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed to 
ensure that all procedures are in compliance with GCP and FDA Guidelines, and according to 
national law.  Quality assurance audits may be performed at the discretion of NBI. 
14.8. 
Record Retention 
Federal regulations require that records of drug disposition, eCRFs, and all reports of this 
investigation shall be retained by the investigator for a minimum of 2 years after notification by 
NBI that the regulatory authorities have been notified of the study’s termination, or 2 years after 
approval of the marketing application.  If the investigator is unable to retain the study documents 
for the required amount of time, NBI must be informed of the individual who will be assuming 
this responsibility. 
14.9. 
Confidentiality 
NBI or its designee, and the study center 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. 


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Clinical Protocol Amendment No. 3 Final Version 
16 April 2019 
Confidential  
49 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To allow the 
use of the information derived from this clinical study and to ensure compliance to current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study material be delivered to the study site.  Subject entry should not begin until after 
the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred.  All personnel expected to be involved in the conduct 
of the study will undergo orientation to include review of study the protocol, instructions for 
eCRF completion, AE reporting, and overall responsibilities including those for drug 
accountability and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow-up examination.  Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 


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16 April 2019 
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50 
16. 
REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition. Washington, DC: American Psychiatric Association. 1994. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition. Washington, DC: American Psychiatric Association. 2013. 
Barnes TR.  A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6. 
Chervin RD, Aldrich MS, Pickett R, Guilleminault C. Comparison of the results of the Epworth 
Sleepiness Scale and the Multiple Sleep Latency Test. J Psychosom Res. 1997 Feb;42(2):145-55. 
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, 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. 1976. 
Jeste DV, Palmer BW, Appelbaum PS, Golshan S, Glorioso D, Dunn LB, et al.  A new brief 
instrument for assessing decisional capacity for clinical research. Arch Gen Psychiatry. 2007 
Aug;64(8):966-74. 
Kampman KM, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, D'Angelo L, et al. 
Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav. 1998 Jul-
Aug;23(4):449-61. 
Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity and 
sensitivity to change in anxiety and depressive disorders. J Affect Disord. 1988 Jan-
Feb;14(1):61-8. 
Margolese HC, Chouinard G, Kolivakis TT, 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 Aug;50(9):541-7. 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J 
Psychiatry. 1979 Apr; 134:382-9. 
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 Jan;24:97-9. 
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). 
J Clin Psychopharmacol. 2008 Aug;28(4):447-51. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-9. 
Williams JB, Kobak KA.  Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA).  Brit J Psychiatry. 2008 Jan;192(1):52-
8. 


 
 
1 
 
PROTOCOL AMENDMENT SUMMARY 
Study Protocol Number: 
NBI-98854-TD4001 
Current Amendment and 
Date: 
Amendment No. 3 Final Version Date:  16 April 2019 
Previous Protocol 
Versions: 
Amendment No. 2 Final Version Date:  03 October 2018 
Amendment No. 1 Final Version Date:  06 September 2018 
Original Protocol Final Version Date:  17 May 2018 
Protocol Title: 
A Phase 4, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Potential for Clinical Dependence and 
Withdrawal Symptoms Associated with Valbenazine 
Development Phase: 
Phase 4 
Sponsor: 
Neurocrine Biosciences, Inc., San Diego, CA  
Telephone:  (858) 617-7600 
Facsimile:   (858) 617-7705 
 
The NBI-98854-TD4001 protocol was amended to include the following changes: 
1 
Removed reference to adjudication of withdrawal-related adverse events by an 
independent group of blinded consultants. 
2 
Updated the protocol to indicate that the number of subjects who entered the withdrawal 
period will be captured in the disposition summary table. 
3 
Updated the protocol to include the new analysis sets. 
4 
Updated the protocol to indicate that treatment-emergent adverse event tables will not 
include the number of events and there will not be a summary table by maximum 
intensity. 
5 
Changed to Medical Monitor to 
 
6 
Changed Clinical Drug Safety to Drug Safety and Pharmacovigilance. 
 
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/Independent Ethics Committee (IRB/EC) or 
authorized representatives of national regulatory authorities under the condition that they respect its confidential 
nature. 

SAP_000.pdf: 
Neurocrine Biosciences, Inc. 
NBI-98854-TD4001 
Statistical Analysis Plan 
09Oct2019 
STATISTICAL ANALYSIS PLAN 
PHASE 4 
VERSION: 
Amendment No. 1 Final Version 
Original Version Date: 22 April 2019 
DATE OF PLAN: 
09Oct2019 
BASED ON: 
Protocol Amendment No. 3 Final Version: 16 April 2019 
Protocol Amendment No. 2 Final Version: 03 October 2018 
Protocol Amendment No. 1 Final Version: 06 September 2018 
Original Version Date: 17 May 2018 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI-98854-TD4001
NCT03698331 
STUDY TITLE: 
A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Potential for 
Clinical Dependence and Withdrawal Symptoms Associated with Valbenazine 
SPONSOR: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
858-617-7600
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
CONFIDENTIAL 
1 


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Statistical Analysis Plan 
 
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SIGNATURE PAGE 
 
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This document has been reviewed and accepted by: 
 
 
 
 
 
 
  
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................7 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
3.1. 
Study Objectives ...........................................................................................................8 
3.1.1. 
Primary Objective .........................................................................................................8 
3.1.2. 
Secondary Objective .....................................................................................................8 
4. 
STUDY DESIGN .........................................................................................................9 
4.1. 
Summary of Study Design ............................................................................................9 
4.2. 
Sample Size Considerations .........................................................................................9 
4.3. 
Randomization ..............................................................................................................9 
4.4. 
Clinical Assessments ..................................................................................................10 
5. 
PLANNED ANALYSES ............................................................................................11 
5.1. 
Interim Analyses .........................................................................................................11 
5.2. 
Final Analyses ............................................................................................................11 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................12 
6.1. 
General Statistical Procedures ....................................................................................12 
6.2. 
Analysis Sets ...............................................................................................................12 
6.2.1. 
Definition of Analysis Sets .........................................................................................12 
6.2.2. 
Summary of Analysis Sets ..........................................................................................13 
6.2.3. 
Application of Analysis Sets ......................................................................................13 
6.3. 
Baseline Definition .....................................................................................................14 
6.4. 
Derived and Transformed Data ..................................................................................14 
6.4.1. 
Study Day ...................................................................................................................14 
6.4.2. 
Change from Baseline .................................................................................................14 
6.4.3. 
Handling of Early Termination Visit Data .................................................................15 
6.5. 
Handling of Missing Data ...........................................................................................15 
6.5.1. 
Missing Outcome Measures .......................................................................................15 
6.5.2. 
Missing Dates .............................................................................................................16 
7. 
STUDY POPULATION .............................................................................................17 
7.1. 
Subject Disposition .....................................................................................................17 
7.2. 
Protocol Deviations ....................................................................................................17 


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7.3. 
Demographic and Baseline Characteristics ................................................................18 
7.4. 
Medical History and Medical Conditions Present at Entry ........................................18 
7.5. 
Study Drug Dosing, Compliance, and Dose Reductions ............................................18 
7.5.1. 
Compliance .................................................................................................................18 
7.5.2. 
Dose Reductions .........................................................................................................19 
8. 
CLINICAL DEPENDENCE AND WITHDRAWAL DATA ....................................20 
8.1. 
Adverse Events During the Withdrawal Period..........................................................20 
8.2. 
Physician Withdrawal Checklist-20 ...........................................................................20 
8.3. 
Modified Cocaine Selective Severity Assessment .....................................................21 
8.4. 
Epworth Sleepiness Scale ...........................................................................................21 
8.5. 
Hamilton Anxiety Rating Scale ..................................................................................21 
9. 
PLASMA CONCENTRATION DATA .....................................................................23 
10. 
EFFICACY .................................................................................................................24 
10.1.1. 
Clinical Global Impression-Tardive Dyskinesia-Improvement ..................................24 
10.1.2. 
Clinical Global Impression-Tardive Dyskinesia-Severity ..........................................24 
11. 
SAFETY .....................................................................................................................25 
11.1. 
Adverse Events ...........................................................................................................25 
11.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study........................25 
11.1.2. 
Adverse Events Resulting in Study Drug Dose Reductions .......................................26 
11.1.3. 
Deaths and Other Serious Adverse Events .................................................................26 
11.2. 
Clinical Laboratory Data ............................................................................................26 
11.3. 
Vital Signs ..................................................................................................................28 
11.4. 
Body Weight ...............................................................................................................28 
11.5. 
Electrocardiogram .......................................................................................................28 
11.6. 
Columbia-Suicide Severity Rating Scale ....................................................................29 
11.7. 
Barnes Akathisia Rating Scale....................................................................................30 
11.8. 
Simpson-Angus Scale .................................................................................................30 
11.9. 
Montgomery-Asberg Depression Rating Scale ..........................................................31 
11.10. 
Prior and Concomitant Medications ...........................................................................31 
12. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS .................................32 
13. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................33 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2:      Data Summaries by Analysis Set ................................................................................14 
Table 3: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables ............27 
Table 4: 
Potentially Clinically Significant Criteria for Vital Signs Variables ..........................28 
 
LIST OF FIGURES  
Figure 1: Study Design Schematic ...................................................................................................9 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
AE 
Adverse event 
ALP  
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index 
CGI-TD-I 
Clinical Global Impression-Tardive Dyskinesia-Improvement 
CGI-TD-S 
Clinical Global Impression-Tardive Dyskinesia-Severity 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EPS 
Extrapyramidal symptoms 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
GGT 
Gamma-glutamyl transferase 
HAM-A 
Hamilton Anxiety Rating Scale 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IWRS 
Interactive Web Response System 
MADRS 
Montgomery-Asberg Depression Rating Scale 
mCSSA 
Modified Cocaine Selective Severity Assessment 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
PK 
Pharmacokinetic 
PT 
Preferred term  
PWC-20 
Physician Withdrawal Checklist-20 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SEM 
Standard error of the mean  
SOC  
System organ class  
TD 
Tardive dyskinesia 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays that will be prepared to summarize the data from the Phase 4 study described in 
Neurocrine Biosciences, Inc. (NBI) Protocol NBI-98854-TD4001. 
This SAP was developed in accordance with ICH E9 guidance. All decisions regarding the final 
analysis, as defined in this SAP document, will be made prior to database lock and unblinding of 
the study data. Further information related to study design and methodology can be found in the 
protocol. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of this clinical study is: 
• To evaluate the potential for clinical dependence and withdrawal symptoms associated with 
valbenazine following 4 weeks of once-daily treatment with valbenazine or placebo. 
3.1.2. 
Secondary Objective 
The secondary objectives of this study are:  
• To evaluate the efficacy of valbenazine administered once daily for up to 4 weeks. 
• To evaluate the safety and tolerability of valbenazine administered once daily for up to 
4 weeks. 
 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the potential 
for clinical dependence and withdrawal symptoms associated with valbenazine.  Approximately 
80 medically stable male and female subjects (the proportion of males and females will be 
consistent with that of the patient population) with neuroleptic-induced tardive dyskinesia (TD) 
will be enrolled. 
Subjects will be screened for eligibility for up to 6 weeks prior to Day -1 (baseline visit). 
On Day -1, eligible subjects will be randomized (1:1) to 1 of the 2 treatment arms 
(randomization will be stratified by study site): 
• Valbenazine (40 mg for the first week followed by 80 mg for 3 weeks) for the first 4 weeks 
of the double-blind treatment period followed by placebo for the last 3 weeks of the double-
blind treatment period. 
• Placebo for the 7 weeks of the double-blind treatment period. 
Clinical dependence and withdrawal symptoms, efficacy, pharmacokinetics (PK), safety, and 
tolerability will be assessed at scheduled times throughout the study. 
A schematic of the study design is provided in Figure 1. 
Figure 1: Study Design Schematic  
 
ET=early termination. 
a  Subjects will receive valbenazine (40 mg for 1 week increased to 80 mg for 3 weeks) for 4 weeks followed by 
placebo for 3 weeks. 
b  Subjects will receive placebo for 7 weeks. 
 
4.2. 
Sample Size Considerations 
The sample size for this study is consistent with typical evaluations of dependence and 
withdrawal. 
4.3. 
Randomization 
Subjects will be randomized 1:1 to valbenazine or placebo.  Randomization will be stratified by 
study site.  


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4.4. 
Clinical Assessments 
Assessments of clinical dependence and withdrawal symptoms include:  
• Physician Withdrawal Checklist-20 (PWC-20), 
• modified Cocaine Selective Severity Assessment (mCSSA), 
• Epworth Sleepiness Scale (ESS), and 
• Hamilton Anxiety Rating Scale (HAM-A). 
The mCSSA and PWC-20 assessments are collected at baseline (Day -1) and every visit starting 
after Week 1. The ESS and HAM-A assessments are collected at screening, baseline (Day -1), 
and every visit starting after Week 1.  AEs will also be reviewed for potential withdrawal 
symptoms. 
Efficacy assessments include:  
• Clinical Global Impression-Tardive Dyskinesia-Improvement (CGI-TD-I) and 
• Clinical Global Impression-Tardive Dyskinesia-Severity (CGI-TD-S). 
The CGI-TD-S assessment is collected at baseline (Day -1), Week 4, Week 5 Day 7, Week 6 
Day 7, and Week 7 Day 7 or early termination.  The CGI-TD-I assessment is collected at Week 4 
and Week 7 Day 7 or early termination. 
Pharmacokinetic assessments:  
Blood samples for plasma drug and metabolite concentration analyses are collected at Week 1 
and Week 4.  Subjects are asked to record and provide dosing times on the days when these 
samples are collected. 
Safety assessments include: 
• AEs, 
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis), 
• Vital signs (including orthostatic blood pressure and pulse), 
• Physical examinations, 
• 12-lead electrocardiogram (ECG), 
• Suicidal ideation and behavior, evaluated using the Columbia-Suicide Severity Rating 
Scale (C-SSRS), 
• Drug-induced akathisia, evaluated using the Barnes Akathisia Rating Scale (BARS), 
• Drug-induced parkinsonism and extrapyramidal symptoms (EPS), evaluated using the 
Simpson-Angus Scale (SAS), and 
• Changes in the severity of depressive symptoms using the Montgomery-Asberg 
Depression Rating Scale (MADRS). 
 
See Table 1 of the study protocol for a complete schedule of safety assessments. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
No interim analysis is planned for this study. 
5.2. 
Final Analyses 
Final analyses, as specified in the protocol and in this SAP, will be performed after the study 
database has been locked and treatment code has been unblinded. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the study database and unblinding the treatment group assignments. Analyses 
defined subsequent to locking the database and unblinding will be considered post hoc analyses 
and will be applied as exploratory methodology. Any post hoc analyses will be clearly identified 
in the clinical study report. 
6.1. 
General Statistical Procedures 
Descriptive statistical methods will be used to summarize the data from this study.  The term 
“descriptive statistics” refers to the number of subjects, mean, median, standard deviation (SD), 
standard error of the mean (SEM), minimum, and maximum for continuous and ordinal 
categorical variables; and refers to the number and/or percentage of subjects (or events) for 
categorical variables.  
Unless stated otherwise, “treatment group” refers to the treatment the subject is randomly 
assigned to receive on Day -1 (ie, valbenazine or placebo). 
Select tables will include an “All Subjects” group, which combines both treatment groups and 
includes all subjects being summarized in the table.  
The double-blind (DB) treatment period will be further separated into treatment periods of 
interest for the analysis of selected variables.  The DB treatment period starting after Day -1 
through the end of the Week 4 visit will be referred to as the “Valbenazine/Placebo Period.”  The 
DB treatment period starting after the Week 4 visit through Week 7 Day 7 (final study visit) will 
be referred to as the “Withdrawal Period.”  Subsequent mention of summaries by “treatment 
period” will be defined as the aforementioned.   
Summary statistics will be displayed using the following decimal precision rules: the minimum 
and maximum will have the same number of decimal places as the data; the mean, median, SD, 
and SEM will have one more decimal place than the data being summarized. Percentages will be 
displayed using one decimal place; percentages for 0 counts will be omitted. These rules may be 
modified if warranted, based on practical considerations.  
6.2. 
Analysis Sets  
6.2.1. 
Definition of Analysis Sets 
6.2.1.1. 
Safety Analysis Set 
The safety analysis set will include all subjects who are randomized to a treatment group, take at 
least one dose of study drug, and have any postbaseline safety data. The safety analysis set will 
be used for all summaries of safety data (e.g., AEs, clinical laboratory data) and plasma 
concentration data.  For the summaries of data based on the safety analysis set, subjects who are 
dispensed the incorrect treatment at the time of randomization, and remain on the same incorrect 
treatment during the study, will be assigned to the treatment actually received in all summary 
tables and figures. Subjects who are dispensed a combination of correct and incorrect treatments 
during the study will be assigned to the randomized treatment in all summary tables and figures. 


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6.2.1.2. 
 Dependence and Withdrawal Analysis Set  
The dependence and withdrawal analysis set will include all subjects in the safety analysis set 
who enter the Withdrawal Period (ie, subject is dispensed a kit at Week 4).  The dependence and 
withdrawal analysis set will be used for summaries and analyses of clinical dependence and 
withdrawal symptoms data.  
6.2.1.3. 
Efficacy Analysis Set  
The efficacy analysis set will include all subjects who are randomized to a treatment group, take 
at least one dose of study drug, and have a CGI-TD-I or CGI-TD-S assessment at Week 4. The 
efficacy analysis set will be used for all summaries of efficacy data.   
6.2.2. 
Summary of Analysis Sets 
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) each analysis set will be provided for each treatment group. The number and 
percentage of subjects excluded from each analysis set by reason for exclusion will also be 
provided. An additional “All Subjects” column will be included. 
6.2.3. 
Application of Analysis Sets 
Summaries of subject disposition, randomization by study site, analysis set inclusion/exclusion 
status, and IPDs will include all randomized subjects. All other summaries by analysis set are 
identified in Table 2. 


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Table 2: Data Summaries by Analysis Set 
Data Summary/Analysis 
Analysis Set 
Safety 
Dependence and 
Withdrawal  
Efficacy  
Demographics 
X  
X 
 
Baseline subject characteristics 
X  
X 
 
Medical history 
X 
 
 
Study drug dose reductions 
X 
 
 
Study drug compliance 
X 
 
 
PWC-20 
 
X 
 
mCSSA 
 
X 
 
ESS 
 
X 
 
HAM-A 
 
X 
 
Plasma concentrations 
X 
 
 
CGI-TD-S 
 
 
X 
CGI-TD-I 
 
 
X 
Adverse events 
X 
X 
 
Clinical laboratory data 
X 
 
 
Vital signs 
X 
 
 
Weight 
X 
 
 
ECG 
X 
 
 
C-SSRS 
X 
 
 
BARS 
X 
 
 
SAS 
X 
 
 
MADRS 
X 
 
 
Prior and concomitant medications 
X 
 
 
6.3. 
Baseline Definition 
The assessments collected at the Day -1 study visit will serve as the baseline value for all 
assessments. With the exception of C-SSRS, if a Day -1 visit value is not available, then the last 
measurement collected on or prior to the date of the Day -1 study visit will serve as baseline.  
6.4. 
Derived and Transformed Data 
6.4.1. 
Study Day 
Study day is calculated relative to the date of the Day -1 visit. If the date of interest occurs on or 
after the Day -1 visit, then the study day will be calculated as: date of interest – date of Day -1 
visit + 1. If the date of interest occurs prior to the Day -1 visit, then the study day will be 
calculated as: date of interest – date of Day -1 visit. 
6.4.2. 
Change from Baseline 
Change from baseline is calculated as (postbaseline value – baseline value). 


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If either the baseline or postbaseline value is missing, the change from baseline will also be 
missing.   
6.4.3. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject discontinues from the study prior to 
completing the scheduled Week 7 Day 7 visit. The data collected at ET visits will be included in 
summary tables and figures in accordance with the ET visit mapping scheme described in this 
section.  
For the purpose of data summarization, a visit window will be applied to account for ET visits.  
An ET visit will be mapped to Week 1 if it occurs within 3 days prior to or 3 days after the 
expected study day of the Week 1 visit.  An ET visit which occurs within 3 days prior to or 3 
days after the expected study day of the Week 4 visit will be mapped to Week 4.  ET visits 
occurring at a scheduled visit after Week 4 will be mapped to the scheduled visit.  If the ET visit 
occurs after Week 4 and between scheduled visits, the ET visit will be mapped to the next 
scheduled visit (with the requirement that the scheduled visit prior to the ET visit was completed 
by the subject).  
Early termination visit data which are not mapped to a scheduled visit will not be included in by-
visit analyses and summaries. They will be included in any analyses that look across all available 
assessments during the treatment period, including unscheduled visits. They will also be included 
in any applicable by-subject data listings. 
6.5. 
Handling of Missing Data 
6.5.1. 
Missing Outcome Measures 
6.5.1.1. 
Clinical Dependence and Withdrawal Assessments 
Missing data from clinical dependence and withdrawal assessments (PWC-20, mCSSA, ESS, 
and HAM-A) during the Withdrawal Period will be handled using the following imputation 
rules:  
• If an individual item or total score from an assessment is intermediate missing (ie, 
missing between 2 observed visits), the item or total score will be imputed with the 
higher of the subject’s observed value immediately preceding or following the 
assessment with the missing value.  Imputed values for intermediate missing data will be 
included in by-visit summaries. 
• Missing total scores as a result of dropout will be imputed with the highest total score 
from subjects in the same treatment group with observed total scores at the same visit.  
This imputation method will only be used to determine the maximum (worst) total score 
per subject in the Withdrawal Period for dropouts and will not be included in by-visit 
summaries.   
Assessments missed prior to the Withdrawal Period will not be imputed. 


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6.5.2. 
Missing Dates  
6.5.2.1. 
Start Dates for Adverse Events and Prior and Concomitant Medications 
Missing and incomplete (“partial”) dates for AEs and concomitant medications will be imputed 
for the purpose of estimating the time of the event or medication usage in relationship to study 
treatment. Any data listings will display the original dates as reported in the database.   
The imputation rules for AE start dates are as follows: 
• If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug; 
• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the month and year match the month and year of the first dose of study drug; 
otherwise, the missing day will be imputed as the first day of the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose of study drug; 
otherwise, the missing day and month will be imputed as 01 January; 
• If any of the above imputations result in a start date that is later than an existing (not 
imputed) end date for the event, the start date will be imputed as the end date. 
The imputation rules for concomitant medication start dates are as follows: 
• If the date is completely missing, the date will be imputed as 01 January in the year of the 
subject’s screening vital signs assessment; 
• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the date is in the same month and year as the first dose of study drug; otherwise, 
the missing day will be imputed as the first day of the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose of study drug; 
otherwise, the missing day and month will be imputed as 01 January; 
• If any of the above imputations result in a start date which is later than an existing (not 
imputed) medication stop date, the start date will be imputed as the stop date. 


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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
The summary of subject enrollment and disposition will display the number of subjects who 
were randomized to each treatment group, who completed through Week 4 of the study period 
(excluding ET visits mapped to Week 4), who entered the Withdrawal Period (indicated by 
dispensing of study drug at the Week 4 visit), and who completed the study (ie, up to Week 7 
Day 7 excluding ET visits mapped to Week 7 Day 7). The number of subjects who did not 
complete the study will also be summarized, both overall and according to the reason for early 
discontinuation. 
A separate summary of randomization by study site will be presented. This summary will display 
the number of subjects randomized to each treatment group by site. 
All of the summaries described in this section will be presented by each treatment group as well 
as overall. 
A listing of randomized subjects will be provided and will include subject ID, informed consent 
date, randomization date, and randomized treatment group.  A listing of lot numbers will also be 
provided. 
7.2. 
Protocol Deviations 
Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into 
the clinical trial management system.  Prior to database lock, all major protocol deviations that 
have been entered into the clinical trial management system will be exported to a file and 
integrated into the study data. 
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being. An assessment of IPDs will be performed by a committee 
composed of NBI Clinical Development project team members prior to database lock and 
unblinding of the randomized treatment assignments. This committee will review a listing of all 
major protocol deviations reported in the study database and determine which deviations are 
IPDs. Important protocol deviations include, but are not limited to, the following:  
• Failure to obtain informed consent from the subject prior to performing any study 
procedures. 
• Deviations from key inclusion/exclusion criteria. 
• Use of prohibited concomitant medications. 
• Error in drug dispensing which results in a subject not receiving intended randomized 
treatment. 
• Significant deviation from protocol-specified dosing regimen. 
A summary of the number and percentage of subjects with IPDs by deviation category will be 
presented by treatment group. An additional “All Subjects” column will also be included.  
All major protocol deviations will be presented in a data listing and any that are classified as 
IPDs will be flagged in the listing. 


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7.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized using descriptive statistics for 
continuous variables, and frequency counts and percentages for categorical variables. Results 
will be presented by treatment group. An additional “All Subjects” column will also be included.  
Demographics include: 
• Age (years) 
• Sex 
• Ethnicity 
• Race 
Baseline subject characteristics include: 
• Primary clinical diagnosis  
• Age at first diagnosis of schizophrenia, schizoaffective disorder, or mood disorder 
(years) 
• Age at TD diagnosis (years)  
• Height (measured at screening; cm) 
• Weight (presented in both pounds and kilograms) 
• Body mass index (BMI; calculated using height collected at the screening visit and 
weight collected at the Day -1 visit; kg/m2) 
• CYP2D6 genotype 
7.4. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized in a frequency table (number and percentage of subjects) by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT) by treatment group, with SOCs and PTs within each SOC sorted 
alphabetically. An additional “All Subjects” column will also be included. 
7.5. 
Study Drug Dosing, Compliance, and Dose Reductions 
7.5.1. 
Compliance 
At the end of Weeks 1, 4, 6, and 7, subjects will return all used and unused study drug and a 
compliance check will be performed by counting the capsules returned at each study visit.  The 
site will then enter whether the subject’s dosing compliance since the previous visit was ≥80% 
into the eCRF. 
The number and percentage of subjects in each treatment group who are dosing compliant 
(defined as ≥80%) will be presented for each postbaseline visit through Week 7 Day 7. 


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7.5.2. 
Dose Reductions 
Subjects randomized to the valbenazine arm will receive 40 mg for the first week of treatment 
and 80 mg until the end of Week 4 (Week 5 Day 1 will be the first dose of placebo for subjects 
randomized to the valbenazine arm). If a subject is unable to tolerate the 80 mg dose, the daily 
dosage will be reduced to 40 mg.  Subjects unable to tolerate the 40 mg dose (or placebo) will be 
discontinued from the study.   
The number and percentage of subjects with dose reductions will be summarized by treatment 
group at Week 4.  Dose reductions at unscheduled visits prior to Week 4 will be included in the 
summary.  


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8. 
CLINICAL DEPENDENCE AND WITHDRAWAL DATA 
8.1. 
Adverse Events During the Withdrawal Period  
A withdrawal-emergent adverse event is an adverse event that begins during the Withdrawal 
Period.   
Summaries of withdrawal-emergent AEs will be presented in frequency tables by treatment 
group and will include the number and percentage of unique subjects experiencing each event at 
least once during the Withdrawal Period.  
Two versions of the frequency table will be presented: 
• Frequency of withdrawal-emergent AEs by SOC and PT, with SOCs and PTs within each 
SOC sorted by decreasing frequency (in the valbenazine/placebo arm); 
• Frequency of withdrawal-emergent AEs by PT, with PT sorted by decreasing frequency 
(in the valbenazine/placebo arm). 
8.2. 
Physician Withdrawal Checklist-20 
The PWC-20 is a validated 20-item physician-rated instrument that assesses potential symptoms 
of withdrawal on a severity scale in the following areas:  gastrointestinal, mood, sleep, motor, 
somatic, perception, and cognition.  Items are rated on a scale from 0 to 3 (0=not present, 
1=mild, 2=moderate, and 3=severe), with the total score ranging from 0 to 60.   
The PWC-20 total score (observed values and intermediate missing imputed values) will be 
summarized with descriptive statistics by treatment group and visit (baseline; Week 4; Week 5 
Days 1, 3, 5, and 7; Week 6 Days 2, 4, and 7; Week 7 Days 2 and 4; and Week 7 Day 7).  The 
PWC-20 total scores will also be assessed categorically using the following ranges: total scores 
of 0 to 15, 16 to 30, 31 to 45, and 46 to 60.  The number and percentage of subjects who fall into 
each category will be presented in a table by visit and treatment group. 
The mean worst PWC-20 total score per treatment group during the Withdrawal Period will be 
presented in a table with descriptive statistics by taking the worst total score per subject between 
Weeks 5 and 7.  A subject’s worst total score will be based on the maximum of the subject’s 
highest observed total score or, in the case of dropout, the subject’s highest imputed total score 
(as described in Section 6.5.1).  The table will also include descriptive statistics for baseline and 
Week 4 (withdrawal baseline) total scores and the change in the worst total score during the 
Withdrawal Period from baseline and withdrawal baseline by treatment group.   
Additionally, subjects will be assessed to determine if they have worsening symptoms between 
Weeks 5 and 7 (ie, during the Withdrawal Period) when compared to their Week 4 reported 
symptoms.  A subject’s symptoms are considered to be worsening if they meet at least one of the 
following criteria: 
• Subject presents with at least 5 new symptoms at any time during the Withdrawal Period 
of moderate or severe degree (note: the new symptoms do not have to be reported at the 
same visit),  
• Subject reports a worsening of any of the symptoms (as recorded at the Week 4 visit) by 
2 points during at least one visit during the Withdrawal Period. 


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The number and percentage of subjects with worsening symptoms will be summarized by 
treatment group in a table.   
8.3. 
Modified Cocaine Selective Severity Assessment  
The mCSSA is an 18-item instrument primarily drawn from symptoms commonly reported in the 
literature as being associated with early cocaine abstinence, including depression, fatigue, 
anhedonia, anxiety, irritability, sleep disturbance, and inability to concentrate.  The instrument 
includes additional symptoms such as paranoia, carbohydrate craving, bradycardia, and 
suicidality.  The scale has been modified to be specific to study drug (valbenazine or placebo) 
instead of cocaine; specifically, "cocaine" was replaced with "study drug" in question #4. Items 
are rated on scales of 0 to 7 or 0 to 8, with separate scale descriptions for each item.  The total 
score ranges from 0 to 127. 
The mCSSA total score (observed values and intermediate missing imputed values) will be 
summarized with descriptive statistics by treatment group and visit (baseline; Week 4; Week 5 
Days 1, 3, 5, and 7; Week 6 Days 2, 4, and 7; Week 7 Days 2 and 4; and Week 7 Day 7).   
The mean worst mCSSA total score per treatment group during the Withdrawal Period will be 
presented in a table with descriptive statistics based on the worst total score per subject between 
Weeks 5 and 7.  A subject’s worst total score will be based on the maximum of the subject’s 
highest observed total score or, in the case of dropout, the subject’s highest imputed total score 
(as described in Section 6.5.1).  The table will also include descriptive statistics for baseline and 
Week 4 (withdrawal baseline) total scores and the change in the worst total score during the 
Withdrawal Period from baseline and withdrawal baseline by treatment group.   
8.4. 
Epworth Sleepiness Scale 
The ESS is a validated instrument to assess subject’s sleepiness.  The instrument lists 8 daytime 
situations in which the subject rates his/her tendency to become sleepy on a scale from 0 (would 
never doze) to 3 (high chance of dozing).  The total score ranges from 0 to 24.   
For the ESS total score (observed values and intermediate missing imputed values), descriptive 
statistics will be presented for baseline and all postbaseline visits by treatment group.   
The mean worst ESS total score per treatment group during the Withdrawal Period will be 
presented in a table with descriptive statistics based on the worst total score per subject between 
Weeks 5 and 7.  A subject’s worst total score will be based on the maximum of the subject’s 
highest observed total score or, in the case of dropout, the subject’s highest imputed total score 
(as described in Section 6.5.1).  The table will also include descriptive statistics for baseline and 
Week 4 (withdrawal baseline) total scores and the change in the worst total score during the 
Withdrawal Period from baseline and withdrawal baseline by treatment group.   
8.5. 
Hamilton Anxiety Rating Scale  
The HAM-A is a 14-item scale used to evaluate the severity of anxiety.  Each of the items is 
scored from 0 (not present) to 4 (very severe).  The total score ranges from 0 to 56.  
For the HAM-A total score (observed values and intermediate missing imputed values), 
descriptive statistics will be presented for baseline and all postbaseline visits by treatment group.   


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The mean worst HAM-A total score per treatment group during the Withdrawal Period will be 
presented in a table with descriptive statistics based on the worst total score per subject between 
Weeks 5 and 7.  A subject’s worst total score will be based on the maximum of the subject’s 
highest observed total score or, in the case of dropout, the subject’s highest imputed total score 
(as described in Section 6.5.1).  The table will also include descriptive statistics for baseline and 
Week 4 (withdrawal baseline) total scores and the change in the worst total score during the 
Withdrawal Period from baseline and withdrawal baseline by treatment group.   
 
 
 


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9. 
PLASMA CONCENTRATION DATA 
The plasma concentrations of valbenazine (NBI-98854) and its metabolite NBI-98782 will be 
summarized with descriptive statistics by visit (Week 1 and Week 4) and the valbenazine dose 
(40 mg or 80 mg) received prior to that visit.  Concentrations below the lower limit of 
quantification will be set equal to zero for all plasma concentration summaries.  The lower limits 
of quantification are as follows: (a) NBI-98854: 1.00 ng/mL and (b) NBI-98782: 0.100 ng/mL. 
The following additional descriptive statistics will be included in the plasma concentration 
summary tables: (a) the number of plasma concentration values greater than or equal to the lower 
limit of quantification, (b) the geometric mean, and (c) the geometric coefficient of variation 
(%). 


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10. 
EFFICACY  
10.1.1. 
Clinical Global Impression-Tardive Dyskinesia-Improvement 
The CGI-TD-I scale is a 7-point scale (range; 1=very much improved to 7=very much worse) 
used to assess overall improvement in TD symptoms since the initiation of study drug dosing.  
For the CGI-TD-I, descriptive statistics will be presented for observed values at Week 4 and 
Week 7 Day 7 visits by treatment group.   
The CGI-TD-I categorical responses will be summarized in a table which will display the 
number and percentage of subjects in each category by treatment group and visit (Week 4 and 
Week 7 Day 7).   
CGI-TD-I responders (number and percentage of subjects) will also be summarized in a 
frequency table by treatment group and visit.  A subject is classified as a responder if their CGI-
TD-I score is either a “1” (“very much improved”) or a “2” (“much improved”). 
10.1.2. 
Clinical Global Impression-Tardive Dyskinesia-Severity  
 
The CGI-TD-S scale is a 7-point scale (range; 1=normal, not at all ill to 7=among the most 
extremely ill patient) used to assess the overall global severity of TD.  For the CGI-TD-S, 
descriptive statistics will be presented for baseline and postbaseline visits by treatment group.  
Both observed values and changes from baseline will be summarized.  An additional table will 
be presented with observed values and changes from Week 4 (withdrawal baseline) for 
assessments collected during the Withdrawal Period.  Figures showing the mean (+/-SD) for the 
observed and change from baseline values vs. study visits will be generated by treatment group.   
The CGI-TD-S categorical responses will also be summarized in a table which will display the 
number and percentage of subjects in each category by treatment group and visit (including 
baseline). 
 


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11. 
SAFETY 
Results will be presented by treatment group using the safety analysis set, as described in 
Section 6.2.1.1. 
11.1. 
Adverse Events 
Adverse events are recorded in the eCRF. Each AE will be coded to a SOC and PT using 
MedDRA (Version 21.0).   
A treatment-emergent adverse event (TEAE) is an AE not present prior to the initiation of study 
drug dosing, or is an already present event that worsens either in intensity or frequency following 
the initiation of study drug dosing.  Investigators will be asked to respond “Yes” or “No” on the 
CRF as to whether the AE started after the subject took the first dose of study drug.  An AE with 
a response of “Yes” will be classified as a TEAE.  If the investigator’s response is missing, then 
the treatment emergent status will be derived based on the AE onset date and time relative to the 
date and time of the subject’s first dose of study drug.  If the AE onset date and time are 
unknown, it will be assumed that the AE is a TEAE.  If the AE onset time is unknown but the 
AE onset date is the same date as the first dose of study drug, it will be assumed that the AE is a 
TEAE.   
TEAEs will be summarized in frequency tables by treatment group.  The frequency tables will 
include the number and percentage of unique subjects experiencing each event at least once 
during the DB treatment period.   
Two versions of the primary TEAE frequency tables will be presented: 
• Frequency of TEAEs by SOC and PT, with SOCs and PTs within each SOC sorted by 
decreasing frequency (in the valbenazine/placebo arm); 
• Frequency of TEAEs by PT, with PT sorted by decreasing frequency (in the 
valbenazine/placebo arm). 
Overall summary tables will be provided which summarize the number and percentage of unique 
subjects with any TEAE, any TEAE leading to dose reduction, any TEAE leading to study 
discontinuation, any serious TEAE, and any TEAE resulting in death in the DB treatment period.  
The summary tables will also include the frequency distribution of the maximum TEAE intensity 
(mild, moderate, severe) reported for each subject during the DB treatment period. 
11.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study 
Summary tables of TEAEs resulting in early discontinuation from the study will be presented by 
treatment group.  The number and percentage of subjects with a TEAE resulting in study 
discontinuation will be presented by PT within SOC (presented in the same method as the 
primary TEAE table).  More than one AE can contribute to study discontinuation per subject. 
The first line of the table will display the number and percentage of subjects with at least one 
TEAE leading to study discontinuation.   
A listing of TEAEs resulting in premature study discontinuation will be provided which includes 
subject ID, treatment group, last treatment received prior to the onset time of the TEAE(s) 
leading to discontinuation, study day of the discontinuation, and other relevant information from 


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the AE eCRF. Note that “last treatment received prior to the onset time of the TEAE[s] leading 
to discontinuation” reflects the actual dose level received prior to the AE. 
11.1.2. 
Adverse Events Resulting in Study Drug Dose Reductions 
Summary tables of TEAEs resulting in study drug dose reductions will be presented by treatment 
group. The number and percentage of subjects with a TEAE resulting in a dose reduction will be 
presented by PT within SOC (presented in the same method as the primary TEAE table). More 
than one AE can contribute to a dose reduction per subject. The first line of the table will display 
the number and percentage of subjects with at least one TEAE leading to dose reduction.  
11.1.3. 
Deaths and Other Serious Adverse Events 
Summary tables of serious adverse events (SAEs) will be presented by treatment group.  The 
number and percentage of subjects with an SAE will be presented by PT within SOC (presented 
in the same method as the primary TEAE table).  The first line of the table will display the 
number and percentage of subjects with at least one SAE.   
Separate listings of SAEs and fatal TEAEs will also be provided. Each listing will include 
subject ID, treatment group, last treatment received prior to the onset time of the SAE or fatal 
TEAE, study day of the SAE or fatal TEAE, and any additional relevant information from the 
AE eCRF. 
11.2. 
Clinical Laboratory Data 
The hematology and clinical chemistry data will be summarized with descriptive statistics by 
treatment group at baseline, Week 4, and Week 7 Day 7. Both observed values and changes from 
baseline will be summarized.  
Shift tables will be presented for selected clinical laboratory variables based on the reference 
range-based categories of “Low,” “Normal,” or “High.” A clinical laboratory variable value will 
be assigned to one of these three categories according to the reference ranges provided by the 
central clinical laboratory.  
Two shift tables will be presented by treatment period: shifts from baseline to Week 4 (or last 
available assessment in the Valbenazine/Placebo Period) and shifts from baseline to Week 7 Day 
7 (or last available assessment in the Withdrawal Period).  Each shift table will have three rows 
and three columns, with rows reflecting the reference range category at baseline, and columns 
reflecting the reference range category at the specified postbaseline visit. A “Total” row and 
“Total” column will also be included. Subjects with a missing baseline value or who do not have 
postbaseline data will not be included in the tables for that variable. The number and percentage 
of subjects in each shift category will be displayed in the table; percentages will be based on the 
number of subjects included in the table. 
Shift tables will be presented for the following clinical laboratory variables:  
• aspartate aminotransferase (AST),  
• alanine aminotransferase (ALT),  
• alkaline phosphatase (ALP),  


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• gamma-glutamyl transferase (GGT),  
• total bilirubin,  
• creatine kinase,  
• creatinine,  
• blood urea nitrogen,  
• white blood cell count,  
• absolute neutrophil count,  
• hemoglobin, and  
• platelet count. 
Summaries of sponsor-defined potentially clinically significant (PCS) values will be presented 
for the following clinical laboratory variables: ALT, AST, creatine kinase, GGT, total bilirubin, 
white blood cell count, absolute neutrophil count, creatinine, and BUN. The number and 
percentage of subjects with PCS values that are reported at any postbaseline visit (scheduled or 
unscheduled) within each treatment period will be summarized by treatment period and treatment 
group. The criteria for identifying PCS clinical laboratory values are provided in Table 3. 
Table 3: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 
AST 
>3 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
Absolute neutrophil count 
<1.5 x 1000/µL 
Creatinine 
>1.5 x baseline value or > 1.5 x ULN 
BUN 
>30 mg/dL (> 10.71 mmol/L) 
 
Repeat clinical laboratory samples may be collected at any time during this study due to either 
missing or abnormal results. The general rule for summarizing these data is to include the 
original sample results in summary tables. Exceptions to this rule are: (1) all available lab values 
will be used in the PCS tables and (2) if there are missing results from the original lab samples at 
screening, the results of a repeat screening sample will be substituted for the missing results in 
summary tables.  


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11.3. 
Vital Signs 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics by treatment group at 
all scheduled visits from baseline through Week 7 Day 7.  Observed values, changes from 
baseline, and changes from Week 4 (to post Week 4 visits) will be summarized.  
Summaries of sponsor-defined PCS values will be presented for systolic blood pressure, diastolic 
blood pressure, and heart rate. The number and percentage of subjects with PCS values that are 
reported at any postbaseline visit (scheduled or unscheduled) within each treatment period will 
be summarized by treatment period and treatment group. The criteria for identifying PCS vital 
signs values are provided in Table 4. 
Table 4: 
Potentially Clinically Significant Criteria for Vital Signs Variables 
Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Systolic Blood 
Pressure 
 <90 mmHg 
 
≥20 mmHg 
>180 mmHg 
 
≥20 mmHg 
Diastolic Blood 
Pressure 
 <50 mmHg 
 
≥10 mmHg 
>105 mmHg 
 
≥15 mmHg 
Heart Rate 
 <50 bpm 
 
≥15 bpm 
>120 bpm 
 
≥15 bpm 
Both supine and standing values of blood pressures and heart rate will be included in the 
identification and summary of PCS values. 
11.4. 
Body Weight  
The body weight data (in units of kilograms) will be summarized with descriptive statistics by 
treatment group at baseline and each scheduled postbaseline visit through Week 7 Day 7. Both 
observed values and changes from baseline will be summarized.  
11.5. 
Electrocardiogram 
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and Fridericia’s correction of QT interval [QTcF]) measured at each visit will be 
averaged (and rounded to one decimal place) for the purpose of analysis. For the categorical 
ECG interpretation variable (the investigator’s assessment of the ECG as “Normal”, “Abnormal, 
not Clinically Significant”, or “Abnormal, Clinically Significant”), which is also reported in 
triplicate, the value that represents the greatest degree of abnormality will be used in all summary 
tables. If less than three values are recorded at an assessment, then the average/greatest 
abnormality of the available value(s) will be used. 
The quantitative ECG variables will be summarized with descriptive statistics by treatment group 
at baseline, Week 1, Week 4, and Week 7 Day 7.  Both observed and change from baseline 
values will be summarized. Frequency counts and percentages for the investigator ECG 
interpretation variable categories will be summarized at each visit.  


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Categorical summaries will be presented for the QT and QTcF interval data for each treatment 
period. For these summaries, a subject’s highest reported postbaseline value (including values 
reported at unscheduled visits) within each treatment period will be used to determine in which 
category(s) the subject will be counted. The averaged triplicate values will be used when 
determining each subject’s highest reported values. 
Two categorical summaries will be presented for the QT and QTcF intervals (each interval will 
be summarized separately) for each treatment period. For the first summary, the number and 
percentage of subjects in each treatment group whose highest reported QT or QTcF postbaseline 
value meets the following thresholds will be summarized: 
• Greater than 450 msec 
• Greater than 480 msec 
• Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects in each 
treatment group whose largest QT or QTcF increase from their baseline value meets the 
following thresholds:  
• Increase greater than 30 msec 
• Increase greater than 60 msec 
11.6. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS data will be presented in the following summaries: 
• Screening/lifetime assessment by treatment group and for “All Subjects”  
• Screening/past 3 months assessment by treatment group and for “All Subjects” 
• Baseline (Day -1) assessment by treatment group and for “All Subjects” 
• Each treatment period by treatment group.  
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category). These C-SSRS items and categories are as follows: 
• Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
• Suicidal Ideation Category: Any of items (1) through (5) 
• Suicidal Behavior Items (not reported for the screening/past 3 months assessment) 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 


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(10) 
Completed suicide 
• Suicidal Behavior Category: Any of items (6) through (10) 
• Suicidal Ideation or Behavior Category: Any of items (1) through (10) 
For the “all postbaseline assessments” summary, each subject’s C-SSRS responses for all 
postbaseline assessments during the treatment period will be evaluated, and a “Yes” response for 
any assessment will be considered as a “Yes” for the subject. 
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline scores will be presented. The shift table scores are defined as the 
following: 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Active suicidal ideation with any methods (not plan) without intent to act 
4 = Active suicidal ideation with some intent to act, without specific plan 
5 = Active suicidal ideation with specific plan and intent 
The shift tables will display the number and percentage of subjects within each cell of a 6 x 6 
table for each treatment group, with the rows representing the baseline score and the columns 
representing the maximum score recorded across all postbaseline assessments (including both 
scheduled and unscheduled visits) within each treatment period. Subjects missing either a 
baseline score or all postbaseline scores will not appear in the table.  
11.7. 
Barnes Akathisia Rating Scale 
The BARS is a 4-item scale to assess the presence and severity of drug-induced akathisia.  This 
scale includes both objective items (eg, observed restlessness) and subjective items (eg, subject’s 
awareness of restlessness and related distress) rated on a scale of 0 to 3, together with a global 
assessment of akathisia.  Global assessment is rated on a scale of 0 to 5 (0=absent; 
1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe 
akathisia).  The total score is calculated as the sum of the objective and subjective items (items 1-
3 of the assessment) and ranges from 0 to 9.  If any one of these 3 items is not scored (ie, has a 
missing value), the associated total score will be set equal to missing. 
The total score and the global assessment score at each visit (baseline, Week 4, and Week 7 Day 
7) will be summarized with descriptive statistics by treatment group. Changes from baseline at 
each postbaseline visit will also be summarized. 
11.8. 
Simpson-Angus Scale 
The SAS is a 10-item scale to evaluate the presence and severity of drug-induced parkinsonism 
and other extrapyramidal symptoms.  Each item is rated on a 0 to 4 scale of increasing severity 
with definitions given for each anchor point.  The global score is calculated as the average of the 
10 items.  If any one of these 10 items is not scored (ie, has a missing value), the associated 
global score will be set equal to missing. 


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The global score at each visit (baseline, Week 4, and Week 7 Day 7) will be summarized with 
descriptive statistics by treatment group. Changes from baseline at each postbaseline visit will 
also be summarized. 
11.9. 
Montgomery-Asberg Depression Rating Scale  
The MADRS is a 10-item scale designed to measure changes in severity of depressive 
symptoms.  Each item is scored on a 7-point scale (0 to 6) with increasing number value 
indicating increasing severity for each item with anchor points provided at 2-point intervals. The 
total score ranges from 0 to 60.  If any one of these 10 items is not scored (ie, has a missing 
value), the associated total score will be set equal to missing. 
The total score at each visit (baseline, Week 4, and Week 7 Day 7) will be summarized with 
descriptive statistics by treatment group. Changes from baseline at each postbaseline visit will 
also be summarized. 
11.10. 
Prior and Concomitant Medications 
Prior medications and concomitant medications will be summarized by World Health 
Organization (WHO) Drug Anatomical Therapeutic Chemical Classification (ATC) Level 3 
category (or Level 2 if there is not an applicable Level 3 category) and preferred name. 
Medications will be assigned to one, two, or three study periods based on the medication start 
and stop dates relative to study drug dosing and Withdrawal Period: 
• Pre-study/screening: medications with a start date prior to study drug dosing  
• During the Valbenazine/Placebo Period: medications ongoing at the time of first 
dose of study drug or with a start date after the first dose of study drug, 
excluding medications started after the first dose of study drug in the Withdrawal 
Period (Week 5 Day 1) 
• During the Withdrawal Period: medications ongoing at the Week 5 Day 1 visit 
(first dosing day in the Withdrawal Period) or with a start date on or after the 
Week 5 Day 1 visit. 
A given medication can be assigned to multiple study periods in the tabular summaries, 
depending on its start and end dates. 
The number and percentage of subjects using medications in each WHO Drug ATC category 
(Level 3/preferred name) will be summarized by treatment group and study period. A subject 
may take the same medication more than once or multiple medications for a subject may be 
classified under the same ATC level or preferred name. A subject is counted only once for each 
level of medication classification within a summary. An “All Subjects” column will be included 
in these summaries.  


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12. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS 
Feedback from the FDA on the SAP was received on 31 July 2019 and 18 September 2019 and 
resulted in the following deviations from the protocol-specified analyses.  Adverse events 
occurring during the Withdrawal Period will not be further classified as “withdrawal-related” 
based on a prespecified list of preferred terms.  Additionally, the difference between treatment 
groups in number of subjects with withdrawal-related AEs will not be tested for statistical 
significance.  All AEs beginning in the Withdrawal Period will be summarized by treatment 
group as described in Section 8.1 of this SAP.  In addition, key assessments of clinical 
dependence and withdrawal will not be summarized descriptively by study site as described in 
the protocol.  


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13. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS 
The analysis and summary of data from this study will be performed using SAS® 9.4 (or a later 
release if available).  All SAS® programs used in the production of statistical analyses, tables, 
listings, and figures described in this SAP will undergo performance qualification (verification 
that the program produces the intended output) in accordance with department standard operating 
procedures.  The performance qualification may include independent programming and/or peer 
review of the SAS® log files.  In addition, tables, figures, listings, and statistical analysis output 
will be independently reviewed for completeness and accuracy.