Clinical trial NCT03891862
Conditions: Tardive Dyskinesia (TD)
Sponsor: Neurocrine Biosciences
Start date: 2019-03-18; Completion date: 2020-01-30
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the persistence of effect of valbenazine 40 mg and 80 mg.

Detailed description:

Arms: arm 1: Participants received valbenazine 40 mg once daily for 1 week, then 80 mg once daily for the remainder of the 8-week open label period. arm 2: Participants received placebo (matching valbenazine) once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 weeks. arm 3: Participants received valbenazine 80 mg once daily for 8 weeks. Randomization into this arm occurred after open-label treatment with valbenazine once daily for 8 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_000.pdf: 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Amendment No. 2 Final Version Date:  14 May 2019 
Amendment No. 1 Final Version Date:  13 September 2018 
Original Final Version Date:  18 July 2018 
 
A Phase 4, Double-Blind, Placebo-Controlled, Randomized 
Withdrawal Study to Evaluate the Persistence of Effect and 
Safety of Valbenazine for the Treatment of Tardive Dyskinesia  
 
Study No.:  NBI-98854-TD4002 
 
Development Phase:  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no unpublished information contained herein will be published or disclosed without prior approval 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/Ethics Committee (IRB/EC) or authorized representatives of national regulatory authorities 
under the condition that they respect its confidential nature. 


Neurocrine Biosciences, Inc., Study No. NBI-98854-TD4002 
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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, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the 
Persistence of Effect and Safety of Valbenazine for the Treatment of Tardive Dyskinesia 
 
PROTOCOL No.: 
NBI-98854-TD4002 
 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
 
 
 






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2. 
SYNOPSIS 
Protocol Title:  A Phase 4, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to 
Evaluate the Persistence of Effect and Safety of Valbenazine for the Treatment of Tardive Dyskinesia 
Study Site(s):  Approximately 50 study sites in North America. 
Objectives: 
Primary:  
• 
To evaluate the persistence of effect of valbenazine in subjects with tardive dyskinesia (TD) 
who receive placebo in a double-blind, randomized withdrawal period following open-label 
treatment with valbenazine. 
Secondary:  
• 
To evaluate the relationship between subject clinical characteristics and persistence of effect of 
valbenazine during the double-blind, placebo-controlled treatment period. 
• 
To evaluate the effect of valbenazine on measures of quality of life and disability when 
administered once daily for up to 16 weeks. 
• 
To evaluate the safety and tolerability of valbenazine administered once daily for up to 
16 weeks. 
Study Design:  This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the 
persistence of effect of valbenazine 40 mg and 80 mg.  Approximately 120 medically stable male and 
female subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-
induced TD or mood disorder with neuroleptic-induced TD will be enrolled. 
The study includes an initial open-label treatment period for 8 weeks, followed by a double-blind, 
placebo-controlled treatment period for 8 weeks, for a total of up to 16 weeks of treatment.  A final 
study visit will be conducted at Week 20 or upon early termination.   
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). 
Eligible subjects will be enrolled in the study on Day 1.  Valbenazine will be self-administered (in the 
presence of the subject’s caregiver, if applicable) beginning on Day 1; the subject will be directed to 
take their dose at about the same time each day.  During the open-label treatment period, subjects will 
receive 40 mg for the first week followed by 80 mg for 7 weeks. 


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At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo.  Subjects randomized 
to valbenazine will continue with the same dose as the last dose they received during the open-label 
treatment period.  Randomization will be stratified based on the use of concomitant antipsychotic 
medication; this will include up to 40 subjects who are not using antipsychotic medications (ie, have 
not used antipsychotic medication for at least 60 days prior to screening and have no plans for 
resuming antipsychotic treatment during the course of the study) and the remaining subjects will be 
using concomitant antipsychotic medications. 
At any time during treatment (open-label and placebo-controlled treatment periods), subjects who are 
unable to tolerate the 80 mg dose will have their dose decreased to 40 mg (during the double-blind, 
placebo-controlled treatment period, 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 will be 
discontinued from the study. 
Persistence of effect, safety, health-related quality of life, disability, and pharmacokinetics (PK) will be 
assessed at scheduled times throughout the study.  Visits during the open-label treatment period, the 
double-blind, placebo-controlled treatment period, and the final study visit will have windows of 
±6 days. 
Study Population:  Approximately 120 medically stable male and female subjects with clinical 
diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder 
with neuroleptic-induced TD will be enrolled.  The subjects must be 18 to 85 years of age (inclusive) 
and have moderate or severe TD as assessed by an External Abnormal Involuntary Movement Scale 
(AIMS) Reviewer, based on the subject’s AIMS video recording conducted at screening.  Subjects 
must be psychiatrically stable as determined clinically by the investigator (or designee), including a 
Brief Psychiatric Rating Scale (BPRS) score of <50 at screening. 
Duration of Treatment and Study Participation:  The expected duration of study participation for 
each subject is approximately 26 weeks, including up to 6 weeks of screening, 16 weeks of treatment, 
and a final study visit 4 weeks after the last dose of study drug. 
Investigational Product, Dosage and Mode of Administration:  Valbenazine will be supplied as 
capsules containing 20 and 40 mg of valbenazine (free base equivalent).  The doses that will be used in 
this study are:  40 mg (taken as two 20 mg capsules) and 80 mg (taken as two 40 mg capsules).  
Subjects will swallow the capsules with at least 250 mL of water.  Study drug may be taken with or 
without food and should be taken at about the same time each day. 
Reference Therapy, Dose and Mode of Administration:  Matching placebo capsules identical in 
appearance will be taken orally once daily with at least 250 mL of water.  Study drug may be taken 
with or without food and should be taken at about the same time each day. 
Criteria for Evaluation:  
Persistence of effect: 
Persistence of effect after randomization to either placebo or valbenazine will be determined based on 
the AIMS, adverse events (AEs) of TD, and discontinuation from the study due to lack of efficacy 
during the double-blind, placebo-controlled treatment period.  Persistence of effect after randomization 
to either placebo or valbenazine will be based primarily on the mean changes from the randomization 
visit (end of Week 8) in the AIMS dyskinesia total score to each visit during the double-blind, placebo-
controlled treatment period. 
The AIMS will be administered by the investigator (or designee) at screening, on Day 1, end of 
Weeks 8, 12, 16, and at the final study visit (end of Week 20 or early termination).  Each AIMS 
administration will be video recorded following standardized guidelines.  An External AIMS Reviewer 
will evaluate the subject’s global severity of TD at screening to determine eligibility.  Blinded, Central 


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AIMS Video Raters will score AIMS Items 1 through 7 of the AIMS video recordings from Day 1, end 
of Weeks 8, 12, 16, and the final study visit (end of Week 20 or early termination).  
Health-related quality life and disability: 
The EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) (to assess health-related quality of life) and the 
Sheehan Disability Scale (SDS) (to assess disability) will be completed by the subject on Day 1, at 
Weeks 8 and 16, and at the final study visit (end of Week 20 or early termination). 
Plasma drug exposure: 
Blood samples to evaluate plasma concentrations of valbenazine and the active metabolite NBI-98782 
(other metabolites may be evaluated) will be collected on Day 1, and at the end of Weeks 8, 12, and 
16. 
Safety: 
Safety and tolerability will be monitored throughout the study and will include the following 
assessments for all subjects:  
All subjects: 
• 
AEs 
• 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
• 
Vital signs (including orthostatic blood pressures and pulse) 
• 
Physical examinations 
• 
12-lead electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior – evaluated using the Columbia-Suicide Severity Rating Scale  
(C-SSRS) 
• 
BPRS 
Statistical Methods:  Descriptive statistics, including confidence intervals, will be used to evaluate the 
persistence of effect of valbenazine during the double-blind, placebo-controlled treatment period.  The 
primary measure of persistence of effect is the mean change from the end of the open-label treatment 
period (Week 8) in the AIMS dyskinesia total score (based on AIMS scores provided by blinded, 
Central AIMS Video Raters) in subjects who receive placebo during the double-blind, placebo-
controlled treatment period.  The relationship between subject clinical characteristics (including 
psychiatric diagnosis, age, gender, concomitant use of antipsychotic medications, and other 
parameters) and the persistence of effect of valbenazine during the double-blind, placebo-controlled 
treatment period will be evaluated using descriptive statistics and graphical methods.  Safety, PK, 
health-related quality of life, and disability data will be summarized with descriptive statistics.  


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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................12 
4. 
ETHICS ......................................................................................................................14 
5. 
INTRODUCTION ......................................................................................................14 
5.1. 
Background .................................................................................................................14 
5.2. 
Valbenazine (NBI-98854) ..........................................................................................14 
5.3. 
Study and Dose Rationale ...........................................................................................16 
6. 
STUDY OBJECTIVES ..............................................................................................16 
7. 
STUDY DESIGN .......................................................................................................16 
8. 
STUDY POPULATION .............................................................................................18 
8.1. 
Inclusion Criteria ........................................................................................................18 
8.2. 
Exclusion Criteria .......................................................................................................20 
8.2.1. 
Exclusion Criteria for All Subjects .............................................................................20 
8.2.2. 
Exclusion Criteria for Subjects with Clinical Diagnosis of Mood Disorder ..............22 
8.3. 
Subject Identification and Replacement .....................................................................22 
8.4. 
Randomization ............................................................................................................22 
9. 
STUDY EVALUATIONS ..........................................................................................22 
9.1. 
Schedule of Assessments ............................................................................................22 
9.2. 
Screening and Baseline Assessments .........................................................................25 
9.2.1. 
Brief Psychiatric Rating Scale ....................................................................................25 
9.2.2. 
Genotyping .................................................................................................................25 
9.3. 
Persistence of Effect ...................................................................................................25 
9.3.1. 
Abnormal Involuntary Movement Scale ....................................................................25 
9.3.1.1. 
AIMS Administrator ...................................................................................................26 
9.3.1.2. 
AIMS Video Recording and External AIMS Reviewer .............................................26 
9.3.1.3. 
Blinded, Central AIMS Video Raters .........................................................................26 
9.4. 
Health-Related Quality of Life and Disability Assessments ......................................26 
9.4.1. 
EuroQol 5 Dimensions 5 Levels .................................................................................26 
9.4.2. 
Sheehan Disability Scale ............................................................................................27 
9.5. 
Plasma Drug Exposure ...............................................................................................27 


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9.6. 
Safety Assessments .....................................................................................................27 
9.6.1. 
Physical Examination, Including Height and Weight.................................................27 
9.6.2. 
Vital Sign Measurements ............................................................................................28 
9.6.3. 
Electrocardiogram .......................................................................................................28 
9.6.4. 
Clinical Laboratory Assessments ...............................................................................28 
9.6.5. 
Columbia-Suicide Severity Rating Scale ....................................................................29 
9.7. 
Specific Study Information .........................................................................................30 
9.7.1. 
Screening (Weeks -6 to -1) .........................................................................................30 
9.7.2. 
Treatment Period (Day 1 [baseline] to end of Week 16, including the open-
label treatment period and the double-blind, placebo-controlled treatment 
period) .........................................................................................................................30 
9.7.2.1. 
Baseline (Day 1) .........................................................................................................30 
9.7.2.2. 
End of Week 4 (±6 days) ............................................................................................31 
9.7.2.3. 
End of Week 8 (±6 days) ............................................................................................32 
9.7.2.4. 
End of Week 12 (±6 days) ..........................................................................................32 
9.7.2.5. 
End of Week 16 (±6 days) ..........................................................................................33 
9.7.3. 
Final Study Visit (end of Week 20 [±6 days]) or Early Termination .........................33 
9.8. 
Study Duration ............................................................................................................34 
9.9. 
Prohibitions and Restrictions ......................................................................................34 
9.9.1. 
Prior and Concomitant Medications ...........................................................................34 
9.9.2. 
Medications to Treat Psychiatric and Medical Conditions .........................................34 
9.9.3. 
Prohibited Medications ...............................................................................................34 
9.9.4. 
General and Dietary Restrictions ................................................................................35 
9.10. 
Withdrawal Criteria ....................................................................................................35 
9.10.1. 
Handling of Withdrawals ............................................................................................36 
9.10.2. 
Sponsor’s Termination of Study .................................................................................36 
10. 
STUDY DRUG ...........................................................................................................36 
10.1. 
Study Drug Supplies ...................................................................................................36 
10.2. 
Study Drug Storage.....................................................................................................36 
10.3. 
Study Drug Packaging and Labeling ..........................................................................37 
10.4. 
Blinding ......................................................................................................................37 
10.5. 
Study Drug Administration.........................................................................................37 
10.6. 
Drug Compliance and Accountability ........................................................................37 


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10.7. 
Study Drug Return ......................................................................................................38 
11. 
ADVERSE EVENTS..................................................................................................38 
11.1. 
Definition ....................................................................................................................38 
11.2. 
Intensity of Adverse Events ........................................................................................39 
11.3. 
Relationship to Study Drug ........................................................................................39 
11.4. 
Recording Adverse Events .........................................................................................40 
11.5. 
Post-Study Follow-Up of Adverse Events ..................................................................40 
11.6. 
Serious Adverse Events ..............................................................................................41 
11.6.1. 
Definition of a Serious Adverse Event .......................................................................41 
11.6.2. 
Managing Serious Adverse Events .............................................................................41 
11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................42 
11.6.4. 
Expedited Safety Reports ...........................................................................................42 
11.7. 
Pregnancy ...................................................................................................................42 
12. 
DOCUMENTATION OF DATA ...............................................................................43 
12.1. 
Case Report Form .......................................................................................................43 
12.2. 
Data Capture, Review, and Validation .......................................................................43 
12.3. 
Coding Dictionaries ....................................................................................................44 
13. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................44 
13.1. 
Analysis Sets ...............................................................................................................44 
13.2. 
Sample Size ................................................................................................................44 
13.3. 
Handling of Missing Data ...........................................................................................44 
13.4. 
Disposition of Subjects ...............................................................................................44 
13.5. 
Demographics and Baseline Characteristics ...............................................................45 
13.6. 
Study Drug Dosing and Compliance ..........................................................................45 
13.7. 
Persistence of Effect ...................................................................................................45 
13.8. 
Health-Related Quality of Life and Disability Data ...................................................45 
13.9. 
Plasma Drug Exposure ...............................................................................................45 
13.10. 
Safety Data..................................................................................................................45 
13.11. 
Software ......................................................................................................................46 
13.12. 
Interim Analysis..........................................................................................................46 
14. 
REGULATORY AND ETHICAL ISSUES ...............................................................46 
14.1. 
General Legal References ...........................................................................................46 


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14.2. 
Institutional Review Board .........................................................................................46 
14.3. 
Protocol Adherence and Amendments .......................................................................46 
14.4. 
Required Documents ..................................................................................................46 
14.5. 
Informed Consent .......................................................................................................47 
14.6. 
Study Monitoring ........................................................................................................47 
14.7. 
Quality Assurance .......................................................................................................47 
14.8. 
Record Retention ........................................................................................................47 
14.9. 
Confidentiality ............................................................................................................48 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................48 
16. 
REFERENCES ...........................................................................................................49 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................23 
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 .............................................................................................18 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
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 
BMI 
body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CFR 
Code of Federal Regulations 
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 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA K2 
dipotassium ethylenediaminetetraacetic acid 
EPSE 
extrapyramidal side effects 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C virus antibody 
HIV-Ab 
human immunodeficiency virus antibody 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IRB/EC 
Institutional Review Board/Ethics Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
OTC 
over-the-counter 
PK 
pharmacokinetic(s) 
prn 
as needed 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 


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SAP 
Statistical Analysis Plan 
SDS 
Sheehan Disability Scale 
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:  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/Ethics Committees (IRBs/ECs) 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 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. 
Phase 1 clinical studies with valbenazine have been conducted in healthy subjects (including 
drug-drug interaction studies conducted with digoxin, ketoconazole, midazolam, and rifampin), 


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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 concentration 
versus time 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 (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: 
hepatitis acute, suicidal ideation, confusional state, and hypersensitivity; all in subjects taking 
valbenazine.  Valbenazine does not appear to increase suicidality.  Valbenazine may prolong the 


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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 commercial starting dose of valbenazine 40 mg once daily was selected for this study and 
increased to the recommended dose of 80 mg once daily after 1 week of treatment. 
As part of the Phase 2 and 3 placebo-controlled and open-label clinical studies, TD severity was 
assessed after discontinuation of valbenazine.  Results from these studies indicated that not all 
subjects have a return of TD after washout.  As such, there is interest in understanding the 
potential factors associated with possible clinical remission. 
6. 
STUDY OBJECTIVES 
The objectives of this clinical study are as follows: 
Primary:  
• To evaluate the persistence of effect of valbenazine in subjects with TD who receive 
placebo in a double-blind, randomized withdrawal period following open-label treatment 
with valbenazine. 
Secondary:  
• To evaluate the relationship between subject clinical characteristics and persistence of 
effect of valbenazine during the double-blind, placebo-controlled treatment period. 
• To evaluate the effect of valbenazine on measures of quality of life and disability when 
administered once daily for up to 16 weeks. 
• To evaluate the safety and tolerability of valbenazine administered once daily for up to 
16 weeks. 
7. 
STUDY DESIGN 
This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the persistence 
of effect of valbenazine 40 mg and 80 mg.  Approximately 120 medically stable male and female 
subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with 
neuroleptic-induced TD or mood disorder with neuroleptic-induced TD will be enrolled. 
The study includes an initial open-label treatment period for 8 weeks, followed by a 
double-blind, placebo-controlled treatment period for 8 weeks, for a total of up to 16 weeks of 
treatment.  A final study visit will be conducted at Week 20 or upon early termination.   
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; 
Jeste et al., 2007).  Only subjects who are deemed to have the capacity to provide consent may 


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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). 
Eligible subjects will be enrolled in the study on Day 1.  Valbenazine will be self-administered 
(in the presence of the subject’s caregiver, if applicable) beginning on Day 1; the subject will be 
directed to take their dose at about the same time each day.  During the open-label treatment 
period, subjects will receive 40 mg for the first week followed by 80 mg for 7 weeks.   
At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo.  Subjects 
randomized to valbenazine will continue with the same dose as the last dose they received during 
the open-label treatment period.  Randomization will be stratified based on the use of 
concomitant antipsychotic medication; this will include up to 40 subjects who are not using 
antipsychotic medications (ie, have not used antipsychotic medication for at least 60 days prior 
to screening and have no plans for resuming antipsychotic treatment during the course of the 
study) and the remaining subjects will be using concomitant antipsychotic medications. 
At any time during treatment (open-label and placebo-controlled treatment periods), subjects 
who are unable to tolerate the 80 mg dose will have their dose decreased to 40 mg (during the 
double-blind, placebo-controlled treatment period, 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 will be discontinued from the study. 
Persistence of effect, safety, health-related quality of life, disability, and pharmacokinetics (PK) 
will be assessed at scheduled times throughout the study.  Visits during the open-label treatment 
period, the double-blind placebo-controlled treatment period, and the final study visit will have 
windows of ±6 days. 
The study design schematic is provided in Figure 1. 


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Figure 1: 
Study Design Schematic 
 
a During the open-label treatment period, subjects will receive 40 mg for the first week followed by 80 mg for  
7 weeks.  At any time during treatment, subjects who are unable to tolerate the 80 mg dose will have their dose 
decreased to 40 mg.  Subjects randomized to valbenazine will continue with the same dose as the last dose they 
received during the open-label treatment period. 
8. 
STUDY POPULATION 
Approximately 120 medically stable male and female subjects with clinical diagnoses of 
schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder with 
neuroleptic-induced TD will be enrolled.  The subjects must be 18 to 85 years of age (inclusive) 
and have moderate or severe TD as assessed by an External AIMS Reviewer, based on the 
subject’s AIMS video recording conducted at screening.  Subjects must be psychiatrically stable 
as determined clinically by the investigator (or designee), including a Brief Psychiatric Rating 
Scale (BPRS) score of <50 at screening.  
8.1. 
Inclusion Criteria  
To participate in this study, subjects must meet the following criteria: 
1. Be male or female aged 18 to 85 years (inclusive). 
2. 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 the study drug.  A 
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 for at least 
3 months prior to screening. 
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom).  
• Vaginal sponge impregnated with spermicide used with a condom. 
Screening
Period
Final Visit / 
Early Termination
Open-Label
Treatment Period
Double-Blind, Placebo-Controlled 
Treatment Period
Week
-6 to -1
1
8
16
20
4
12
Valbenazine
(40 or 80 mg)a
Valbenazine (40 or 80 mg)a,
or Placebo 


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• 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 on 
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 or reliable self-reported 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 parkinsonism 
associated with extrapyramidal symptoms or extrapyramidal side effects (EPSE). 
6. Have moderate or severe TD as assessed by an External AIMS Reviewer using a video 
recording of the subject’s AIMS assessment administered at the clinical site by the 
investigator (or designee) at screening. 
7. 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 discontinuation of 
medications for a minimum of 30 days before Day 1).  Benzodiazepines must be at a stable 
dose for 2 weeks before Day 1.  This criterion will be satisfied if the investigator can confirm 
prior and current medications and doses through reliable subject-reported information (eg, 
subject provides a list of medications and doses). 
8. Subjects (including 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 


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stable dose of mood stabilizer(s) (eg, lithium, valproate, olanzapine) for a minimum of 
30 days before Day 1. 
9. Be in good general health and expected to complete the clinical study as designed. 
10. 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). 
11. Have adequate hearing, vision, and language skills to perform the procedures specified in the 
protocol. 
12. 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. 
13. Have a negative urine drug screen (UDS) (for amphetamines, barbiturates, benzodiazepines, 
phencyclidine, cocaine, methamphetamine, methadone, tricyclic antidepressants, and opiates) 
at screening (central laboratory results) and Day 1 (UDS kit results conducted at the study 
center), except for any subject receiving a stable dose of benzodiazepines, tricyclic 
antidepressants, or opiates.  Subjects with positive cannabinoid results may be allowed to 
participate in the study provided that the subject is given thorough counseling and agrees to 
refrain from using cannabinoids for the duration of his/her study participation. 
14. Have a negative alcohol breath test at screening and Day 1. 
15. Be willing to provide authorization for access to personal health information in conjunction 
with US Health Insurance Portability and Accountability Act (HIPAA). 
8.2. 
Exclusion Criteria 
8.2.1. 
Exclusion Criteria for All Subjects 
Subjects will be excluded from the study if they: 
1. Have an active, clinically significant unstable medical condition within 1 month (30 days) 
prior to Day 1. 
2. Have comorbid abnormal involuntary movement(s) (eg, parkinsonism, akathisia) that is more 
prominent than TD as assessed by an External AIMS Reviewer using a video recording of 
the subject's AIMS administration at screening. 
3. Have a known history of substance dependence, or substance (drug) or alcohol abuse within 
the 3 months prior to Day 1 (nicotine and caffeine dependence are not exclusionary), as 
defined in the DSM (eg, DSM-IV). 
4. Have BPRS total score of ≥50 at screening. 
5. Have a significant risk of suicidal or violent behavior.  Subjects with any suicidal behavior 
within 3 months prior to screening will be excluded.  In addition, subjects with suicidal 
ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or 
type 5 (active suicidal ideation with specific plan and intent) based on the Columbia-Suicide 


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Severity Rating Scale (C-SSRS) in the 3 months prior to screening (using Baseline/Screening 
version) or Day 1 (using Since Last Visit version) will also be excluded.  
6. Have been hospitalized for psychiatric disorder within 6 months prior to Day 1. 
7. Have a known history of neuroleptic malignant syndrome. 
8. Have a known history of long QT syndrome or cardiac arrhythmia. 
9. Have a screening or 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. 
10. Receive any prohibited medication (see Section 9.9.3). 
11. 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. 
12. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to Day 1, with 
the exception of localized skin cancer or carcinoma in situ of the cervix. 
13. 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. 
14. Have other laboratory results not within the laboratory's reference range and deemed by the 
investigator to be clinically significant. 
15. 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, or total bilirubin in exclusion criterion #11. 
16. Have received an investigational drug within 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1 or plan to use an investigational drug (other than valbenazine) during 
the study. 
17. Have a blood loss ≥550 mL or donated blood within 30 days prior to Day 1. 
18. Currently receiving tetrabenazine or deutetrabenazine. 
19. Have used valbenazine (INGREZZA) within 30 days of screening. 


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20. Have an allergy, hypersensitivity, or intolerance to VMAT2 inhibitors (eg, tetrabenazine, 
deutetrabenazine), or have a history of hypersensitivity to valbenazine or any component of 
INGREZZA. 
21. Are currently pregnant or breastfeeding. 
8.2.2. 
Exclusion Criteria for Subjects with Clinical Diagnosis of Mood Disorder 
In addition to the exclusion criteria for all subjects, the following criteria must not be met for 
subjects with mood disorder: 
22. Have had mood episodes (hypomania, mania, depressive, etc.) within 2 months prior to 
Day 1. 
23. Have history of rapid cycling (>4 mood episodes per year) or ultra-rapid cycling (>4 mood 
episodes per month). 
8.3. 
Subject Identification and Replacement 
Subjects will be identified by their unique subject number and initials (first, middle, last; a 
hyphen may be used for subjects with no middle initial).  The subject initials and subject number 
will be noted on electronic case report forms (eCRFs), all source documentation, laboratory 
documents, and ECG tracings.  Subjects who discontinue from the study after the initiation of 
dosing may be replaced at the discretion of the Sponsor. 
8.4. 
Randomization 
Subjects will be randomized (1:1) to receive valbenazine or placebo at the end of Week 8.  
Subjects randomized to valbenazine will continue with the same dose as the last dose they 
received during the open-label treatment period.  Randomization will be stratified based on the 
use of concomitant antipsychotic medication; this will include up to 40 subjects who are not 
using antipsychotic medications (ie, have not used antipsychotic medication for at least 60 days 
prior to screening and have no plans for resuming antipsychotic treatment during the course of 
the study) and the remaining subjects will be using concomitant antipsychotic medications. 
9. 
STUDY EVALUATIONS 
9.1. 
Schedule of Assessments 
A schedule of assessments that summarizes the frequency and timing of all assessments is 
provided in Table 1. 
No protocol-related procedures should be performed before informed consent has been obtained.  
Subject-related events and activities including specific instructions, procedures, concomitant 
medications, dispensing of study drug, and descriptions of AEs should be recorded in the 
appropriate source documents and eCRFs.


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Table 1: 
Schedule of Assessments 
Procedure 
Screening 
Period 
Open-Label Treatment Period 
Double-blind, Placebo-Controlled 
Treatment Period 
Final Study 
Visit/ETb 
Week 
-6 to -1 
Day 1 
Baseline 
4 
8 
12 
16 
20 
Visita 
1 
2 
3 
4 
5 
6 
7 
UBACC/Informed consentc 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
update 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
Medical history 
X 
update 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
X 
X 
X 
Heightd 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
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 
X 
X 
X 
Urine drug screenh 
X 
X 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
Genotype blood sample 
X 
 
 
 
 
 
PK plasma samplei 
 
X 
 
X 
X 
X 
 
AIMS (with video recording)j 
X 
X 
 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
 
X 
 
X 
 
X 
X 
SDS 
 
X 
 
X 
 
X 
X 
Valbenazine/placebo dosingk 
 
X 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Valbenazine/placebo accountabilityl 
 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Definitions and footnotes appear on the following page. 


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AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BPRS=Brief Psychiatric Rating Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EQ-5D-5L=EuroQol 5 Dimensions 5 Levels; ET=early termination; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C 
antibody; HIV-Ab=human immunodeficiency virus antibody; PK=pharmacokinetic(s); s=serum; SDS=Sheehan Disability Scale; u=urine; UBACC=University 
of California, San Diego Brief Assessment of Capacity to Consent. 
 
a. 
All study visits, except screening, will have visit window of ±6 days. 
b. Final study visit for subjects who complete the study (or early termination). 
c. 
The UBACC will be used to determine whether the subject has the capacity to provide informed consent.  
d. Physical examination will include measurement of weight and height without shoes (height will be measured at screening only). 
e. 
A standard 12-lead ECG will be conducted in triplicate (at least 1 minute apart and within 15 minutes) after the subject has rested supine for at least 
5 minutes.  The ECG parameters that will be assessed include heart rate, QT, QTcF, 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.  A serum pregnancy test will be conducted at screening.  A urine pregnancy test will be 
conducted on Day 1 and at all subsequent visits. 
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 by the central lab.  A UDS kit provided by the central lab will be used at the site to confirm eligibility on 
Day 1. 
i. 
Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected.  PK sample on 
Day 1 must be predose. 
j. 
The AIMS will be administered by the investigator (or designee).  AIMS Items 11 to 12 will be completed by the investigator (or designee) administering the 
AIMS; AIMS Items 8 to 10 will be scored by the investigator (or designee) administering the AIMS.  If possible, the same person should administer the 
AIMS for an individual subject at all timepoints.  Subjects will be video recorded during the AIMS administration.  An External AIMS Reviewer will 
evaluate the subject’s global severity of TD at screening to determine eligibility.  Blinded, Central AIMS Video Raters will review the AIMS video 
recordings on Day 1, end of Weeks 8, 12, 16, and at the final study visit (end of Week 20 or early termination) and will score AIMS Items 1 through 7. 
k. Subjects will self-administer study drug in the presence of their caregiver (if applicable).  The subject will be directed to take their dose at about the same 
time each day.  Subject or caregiver will record the daily date and time of dosing on the drug packaging form provided.   
l. 
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. 
 
 
 


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9.2. 
Screening and Baseline Assessments 
9.2.1. 
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 subjects must have a BPRS total score <50 to be eligible for study participation (see 
exclusion criterion #4).  The investigator or other qualified site personnel will also administer 
and score the scale on Day 1, end of Weeks 4, 8, 12, 16, and the final study visit (end of 
Week 20 or early termination). 
9.2.2. 
Genotyping 
A blood sample will be collected from enrolled subjects for the analysis of CYP2D6 status (ie, 
normal, intermediate, poor, or ultrarapid metabolizers) on Day 1.  Approximately 4 mL of blood 
will be collected in tubes containing dipotassium ethylenediaminetetraacetic acid (EDTA K2).  
After the sample is obtained, it should be thoroughly mixed.  The vials will be stoppered and 
labeled with the study barcode and subject number.  The collection and submission of medical 
information will be accomplished with strict adherence to professional standards of 
confidentiality.  Genotyping blood samples collected from subjects will be shipped to a central 
laboratory for analysis. 
9.3. 
Persistence of Effect 
9.3.1. 
Abnormal Involuntary Movement Scale 
The severity of TD will be assessed using the AIMS rating scale.  This scale was developed by 
the Psychopharmacology Research Branch of the National Institute of Mental Health 
(Guy, 1976).  The AIMS rates a total of 10 items with 9 items rating involuntary movement from 
0 (no dyskinesia) to 4 (severe dyskinesia).  Items 1 through 7 include facial and oral movements 
(Items 1 to 4), extremity movements (Items 5 to 6), and trunk movements (Item 7).  The AIMS 
dyskinesia total score for Items 1 to 7 ranges from 0 to 28; a higher score reflects increased 
severity.  Items 8, 9 and 10 rate global judgments with Item 10 being rated based only on the 
subject’s report of his/her awareness of abnormal movements from 0 (no awareness) to 4 (aware, 
severe distress).  Items 11 and 12 are yes/no questions concerning problems with teeth and/or 
dentures. 


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The AIMS (with video recording) will be administered by the investigator (or designee) at 
screening, Day 1, end of Weeks 8, 12, 16, and at the final study visit (end of Week 20 or early 
termination).  
9.3.1.1. 
AIMS Administrator 
During the study, the AIMS will be administered at the study site by the investigator (or 
designee) according to the AIMS administration procedure provided by NBI or designee.  AIMS 
Items 11 to 12 will be completed by the investigator (or designee) administering the AIMS; 
AIMS Items 8 to 10 will be scored by the investigator (or designee) administering the AIMS.  If 
possible, the same person should administer the AIMS for an individual subject at all timepoints. 
9.3.1.2. 
AIMS Video Recording and External AIMS Reviewer 
Subjects will be video recorded for the duration of the AIMS administration (approximately 
10 minutes) according to standardized guidelines provided by NBI (or designee).  Video 
recordings of the AIMS administration will be uploaded to a secure, central AIMS server, 
managed by a core laboratory.  Access to the dedicated central AIMS server will be limited and 
will require the user to provide a user identification and password to access the secure server and 
the subject’s video recording.  The AIMS video recording uploaded to the server will be viewed 
by the External AIMS Reviewer and Sponsor-designated representatives.  The External AIMS 
Reviewer will review the video recordings to determine if the subject has moderate or severe TD 
at screening (see inclusion criterion #6). 
9.3.1.3. 
Blinded, Central AIMS Video Raters 
The AIMS video recording files will be reviewed and scored by blinded, Central AIMS Video 
Raters.  A triple-blind consensus scoring will be conducted by these raters according to scoring 
guidelines developed by NBI.  NBI (or designee) will provide the blinded, Central AIMS Video 
Raters a password-protected media (eg, flash drive) containing the subjects’ randomized AIMS 
video recording files to review and score.  The central raters will be blinded to the subjects’ 
study visits and treatment assignments.  Two blinded, Central AIMS Video Raters will together 
review each AIMS video file from beginning to end and must agree on the score (0 to 4) for 
AIMS Items 1 to 7.  The blinded, Central AIMS Video Raters will review and score the AIMS 
video recordings conducted at Day 1, end of Weeks 8, 12, 16, and at the final study visit (end of 
Week 20 or early termination).  
9.4. 
Health-Related Quality of Life and Disability Assessments 
9.4.1. 
EuroQol 5 Dimensions 5 Levels 
The EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) is a general, single index measure for 
describing and valuing health (Herdman et al., 2011).  It defines health in terms of 5 dimensions:  
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.  Each 
dimension has 5 levels:  no problems, slight problems, moderate problems, severe problems, and 
extreme problems.  The subject indicates his/her health state by checking the box next to the 
most appropriate statement.  The scores for the 5 dimensions can be combined into a 5-digit 
number that describes the patient’s health state.  Subjects also rate their overall health on a 0 to 


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100 hash-marked, vertical visual analogue scale (EQ-VAS).  The endpoints are labeled ‘The best 
health you can imagine’ and ‘The worst health you can imagine.’ 
The EQ-5D-5L will be administered at Day 1, end of Weeks 8, 16, and at the final visit (end of 
Week 20 or early termination).  
9.4.2. 
Sheehan Disability Scale 
The Sheehan Disability Scale (SDS) is a brief, validated measure of functional impairment in a 
number of psychiatric disorders to measure the effect of treatment on disability 
(Leon et al., 1997).  It includes 3 self-rated items designed to measure how work, social life, and 
family life are impaired by current psychiatric symptoms.  Each item includes an 11-point analog 
scale that uses visual-spatial, numeric, and verbal descriptive anchors to represent the degree of 
disruption (0 [none at all] to 10 [extremely]).  It also assesses the number of days a subject was 
unable to work/attend school and the number of days a subject was underproductive in the past 
week. 
The SDS will be administered at Day 1, end of Weeks 8, 16, and at the final visit (end of 
Week 20 or early termination). 
9.5. 
Plasma Drug Exposure 
Blood samples to evaluate plasma concentrations of valbenazine and the active metabolite 
NBI-98782 (other metabolites may be evaluated) will be collected on Day 1 (predose), and at the 
end of Weeks 8, 12, and 16. 
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.  The remaining 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. 
Physical Examination, Including Height and Weight 
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system.  A complete 
physical examination including weight will be performed at screening, Day 1, end of Weeks 4, 8, 


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12, 16, and at the final visit (end of Week 20 or early termination).  Height will be measured at 
screening only.  Height and weight will be measured with subjects not wearing shoes. 
9.6.2. 
Vital Sign Measurements 
Vital signs will include orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, 
respiratory rate (recorded only supine), and oral body temperature.  Blood pressure will be 
measured using a calibrated automatic blood pressure cuff after the subject has been supine for at 
least 5 minutes and after approximately 2 minutes of standing.  The automatic blood pressure 
cuff will also provide pulse rate measurement. 
Vital sign measurements will be collected at screening, Day 1, end of Weeks 4, 8, 12, 16, and at 
the final visit (end of Week 20 or early termination).  Vital sign measurements will be obtained 
before any scheduled blood sample collection. 
9.6.3. 
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 recordings will be conducted at screening, Day 1, end of Weeks 4, 8, 12, 16, 
and at the final visit (end of Week 20 or early termination). 
9.6.4. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory.  Results from 
samples collected at screening must be reviewed by the investigator or qualified designee before 
enrollment to confirm each subject’s eligibility.  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. 
The routine laboratory tests (hematology and clinical chemistry) and urinalysis will be performed 
under non-fasted conditions at screening, Day 1, end of Weeks 4, 8, 12, 16, and at the final visit 
(end of Week 20 or early termination).  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 4 mL for genotyping.  Approximate total blood sample 
volume per subject is 43 mL (including PK [2 mL per sample]). 


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The following clinical safety laboratory assays will be performed:  
Hematology:  complete blood count, including WBC count with differential, red blood cell 
count, hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin, mean corpuscular 
volume, mean corpuscular hemoglobin concentration, and red cell distribution width.  
Clinical Chemistry:  sodium, potassium, calcium, phosphorus, magnesium, 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:  ketones, protein, glucose, leukocyte esterase, occult blood, and pH by dipstick; 
microscopic examination of sediment will be performed only if the results of the urinalysis 
dipstick evaluation are positive for nitrites, protein, leukocyte esterase, or blood. 
The following additional laboratory tests will be performed: 
Serology:  Blood will be collected for HIV-Ab, HBsAg, and HCV-Ab testing at screening.  
Urine Drug Screen 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 by a 
certified central laboratory.  A UDS will be conducted at the clinical site at Day 1 using a urine 
drug kit provided by the central laboratory and the results will be used to confirm study 
eligibility. 
The alcohol breath test will be performed at screening and at Day 1. 
Pregnancy Tests:  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 on Day 1 (a negative test result is required to be eligible 
for the study) and at the end of Weeks 4, 8, 12, 16, and at the final visit (end of Week 20 or early 
termination).  
9.6.5. 
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 
questions will prompt additional questions that evaluate frequency and intensity of suicidal 
ideation and/or behavior.  Subjects with any lifetime suicidal behavior within 3 months prior to 
screening will be excluded.  In addition, subjects with suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) in the 3 months before screening or Day 1 based on the C-SSRS will 
also be excluded (see exclusion criterion #5). 
The C-SSRS will be administered and scored by the investigator or qualified study site personnel 
at screening, Day 1, end of Weeks 4, 8, 12, 16, and at the final visit (end of Week 20 or early 
termination). 


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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. 
9.7.1. 
Screening (Weeks -6 to -1) 
Informed Consent Process:  The ICF will be reviewed with subjects.  The UBACC will then be 
administered.  Only subjects who are deemed to have the capacity to provide consent may sign 
the ICF.  The ICF must be signed prior to the start of any screening procedures. 
During screening, the following study evaluations and tasks will be performed at the study site: 
• Administer the UBACC (only subjects who are deemed to have the capacity to provide 
consent may sign the ICF). 
• Obtain informed consent. 
• 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 serum pregnancy test (β-hCG) for all 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. 
• Perform UDS and alcohol breath test. 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Screening/Baseline version). 
• Administer the BPRS. 
• AE monitoring. 
• Record prior and concomitant medications. 
Subjects will be asked to refrain from taking prescription or over-the-counter (OTC) medications 
as specified in Section 9.9. 
9.7.2. 
Treatment Period (Day 1 [baseline] to end of Week 16, including the open-label 
treatment period and the double-blind, placebo-controlled treatment period)  
9.7.2.1. 
Baseline (Day 1) 
The following study evaluations and procedures will be performed on Day 1: 
• Update inclusion and exclusion criteria. 
• Update medical history.  


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• 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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Perform UDS (using the urine drug kit to confirm eligibility). 
• Perform alcohol breath test. 
• Collect blood sample for genotyping (enrolled subjects only). 
• Collect blood sample for PK (predose). 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Administer the EQ-5D-5L. 
• Administer the SDS. 
• Dispense study drug. 
• AE monitoring. 
• Record concomitant medications.  
9.7.2.2. 
End of Week 4 (±6 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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Dispense study drug. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications.  


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9.7.2.3. 
End of Week 8 (±6 days) 
The following study evaluations and procedures will be performed at the end of Week 8: 
• Randomization of subjects. 
• 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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for PK. 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Administer the EQ-5D-5L. 
• Administer the SDS. 
• Dispense study drug. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 
9.7.2.4. 
End of Week 12 (±6 days) 
The following study evaluations and procedures will be performed at the end of Week 12: 
• 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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for PK. 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Dispense study drug. 


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• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 
9.7.2.5. 
End of Week 16 (±6 days) 
The following study evaluations and procedures will be performed at the end of Week 16: 
• 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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect blood sample for PK. 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 
• Administer the EQ-5D-5L. 
• Administer the SDS. 
• Study drug accountability. 
• AE monitoring. 
• Record concomitant medications. 
9.7.3. 
Final Study Visit (end of Week 20 [±6 days]) or Early Termination 
The following procedures will be conducted at the final study visit (the end of Week 20) or at 
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 (using pregnancy test kit) for all female subjects of 
childbearing potential.  
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Administer the AIMS (including video recording). 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BPRS. 


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• Administer the EQ-5D-5L. 
• Administer the SDS. 
• AE monitoring. 
• Record concomitant medications. 
Instruct subjects to continue using contraception until 30 days after the last dose of study drug 
for females and 90 days after the last dose of study drug for males (see inclusion criterion #2). 
9.8. 
Study Duration 
The expected duration of study participation for each subject is approximately 26 weeks, 
including up to 6 weeks of screening, 16 total weeks of treatment, and a final study visit 4 weeks 
after the last dose of study drug. 
9.9. 
Prohibitions and Restrictions 
9.9.1. 
Prior and Concomitant Medications 
All prescription and 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. 
9.9.2. 
Medications to Treat Psychiatric and Medical Conditions 
All coexistent diseases or conditions will be treated in accordance with prevailing medical 
practice.  All medications to treat the subject’s psychiatric and medical conditions should be on a 
stable treatment regimen (including no changes to the dose and frequency of ongoing 
medications and no new or discontinued medications) for a minimum of 30 days before Day 1, 
and are expected to remain stable during the study.  Benzodiazepines must be at a stable dose for 
at least 2 weeks before 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). 
9.9.3. 
Prohibited Medications 
The following medications are prohibited from 30 days prior to screening (unless otherwise 
stated) until the final study visit (end of Week 20 or early termination) as described below: 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• Botulinum toxin:  Botulinum toxin injections are prohibited starting 90 days prior to 
screening and during the study. 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenobarbital, rifabutin, rifampin, 
primidone, St. John's Wort) are prohibited.   


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• CYP3A4 inhibitors:  Strong inhibitors of CYP3A4 (eg, itraconazole, ketoconazole, 
clarithromycin). 
• 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. 
• Stimulants:  Stimulants (eg, amphetamine, methylphenidate, ephedrine, pseudoephedrine, 
phenylephrine, and phenylpropanolamine) are prohibited. 
• VMAT2 inhibitors:  VMAT2 inhibitor medications (eg, tetrabenazine, deutetrabenazine, 
reserpine) are prohibited, except for valbenazine. 
As needed use of the following medications is strictly prohibited:  anticholinergics, 
benzodiazepines, opiates, antipsychotics, mood stabilizers, antidepressants, tricyclic 
antidepressants, strong CYP3A4 inhibitors and inducers, and strong CYP2D6 inhibitors. 
9.9.4. 
General and Dietary Restrictions 
Subjects must agree to adhere to the following prohibitions and restrictions during the study in 
order to be eligible to participate: 
• Return to the study center at baseline (Day 1), end of Weeks 4, 8, 12, 16, and at the final 
visit (end of Week 20 or early termination). 
• Not to use any prohibited concomitant medication.  
• Subjects must limit alcohol use to less than 7 drinks per week during the course of the 
study. 
• Not to donate blood during the study, including the screening period, and for 4 weeks after 
completion of the study.  Male subjects must agree to refrain from donating sperm during 
the study and for 90 days after the last dose of the study drug. 
• Not to participate in an investigational drug study 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 
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 (value must be verified by a cardiologist) 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. 


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• Subject is confirmed to be pregnant. 
The investigator or NBI may withdraw the subject from the study if the subject experiences any 
of the following: 
• Develops a clinically significant laboratory (eg, ALT or AST ≥2.5 times ULN or total 
bilirubin >2.0 times ULN) or ECG abnormality. 
• Requires a medication that is prohibited by the protocol (refer to Section 9.9.3). 
All subjects prematurely discontinuing the study, regardless of cause, should be encouraged have 
all early termination assessments performed, if possible (see Section 9.7.3). 
9.10.1. 
Handling of Withdrawals 
If a subject prematurely withdraws from the study, either at his/her request, or at the 
investigator’s discretion, the investigator will record the reason for withdrawal on the relevant 
eCRF.  All subjects who withdraw from the study prematurely should 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. 
9.10.2. 
Sponsor’s Termination of Study 
NBI reserves the right to discontinue the study at any time for clinical or administrative reasons.  
Such a termination must be implemented by the investigator, if instructed to do so by NBI in a 
time frame that is compatible with the subjects’ well-being. 
10. 
STUDY DRUG 
10.1. 
Study Drug Supplies 
Valbenazine will be supplied as capsules containing 20 and 40 mg of valbenazine (free base 
equivalent).  The doses that will be used in this study are:  40 mg (taken as two 20 mg capsules) 
and 80 mg (taken as two 40 mg capsules).   
The matching placebo capsules are identical in appearance to the valbenazine capsules. 
10.2. 
Study Drug Storage 
Valbenazine and placebo capsules must be stored at controlled room temperature (CRT) 
(20˚C to 25˚C or 68˚F to 77˚F) under the conditions specified in the Investigator’s Brochure and 
in a locked area accessible only to the pharmacist (or designee) until dispensing.  Excursions 
outside this range will be allowed provided they meet the following conditions: 
• Storage between refrigerated conditions (2˚C or 36˚F) and CRT (25˚C or 77˚F) for an 
unspecified length of time. 
• Storage at temperatures above 25˚C (77˚F) but no more than 30˚C (86˚F) for up to 
3 months. 


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• Storage at temperatures above 30˚C (86˚F) but no more than 40˚C (104˚F) for up to 
24 hours. 
10.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice and GCP regulations.  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 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 double-blind, placebo-controlled treatment period during which the 
subject, investigator, all study site personnel, and the Sponsor will be blinded to the subject’s 
treatment. 
The randomization code will be broken for an individual subject if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 
identity of the subject’s treatment assignment, or for regulatory reporting requirements.  All 
attempts to contact the NBI Medical Monitor (refer to Section 11.6.3 for contact information) 
must be made before unblinding a subject.  The unblinding form that contains the date, time, the 
reason the blind was broken, and name of NBI representative contacted must be completed. 
10.5. 
Study Drug Administration 
Study drug will be administered once daily, and the capsules must be swallowed with at least 
250 mL of water, with or without food.  The subject will be directed to take their dose at about 
the same time each day.  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. 
Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty study drug packaging material to the center 
at study visits for drug accountability and reconciliation by study site personnel.  A compliance 
check will be performed by counting the capsules returned at each study visit. 
The quantity of study drug dispensed, used, and returned will be recorded on a dispensing log or 
otherwise documented.  The quantity of study drug lost or destroyed must also be accounted for 
and documented.  The designated pharmacist or qualified personnel will be responsible for 


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maintaining accurate records of the quantity and dates of all study drug supplies received, 
dispensed, and returned. 
10.7. 
Study Drug Return 
Written documentation to account for study drug and study drug materials is mandatory; all 
unused study drug and study drug materials must be kept in a secure location for final 
accountability and reconciliation.  Returned study drug and study drug material must be 
accounted for on a study drug return form provided by NBI or designee.  The investigator must 
provide a written explanation for any destroyed or missing study drug or study drug materials. 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee.  Study drug return forms must be completed for the 
shipment of returns and sent with the study drug and study drug materials.  One copy of the 
study drug return form will be retained in the investigator’s study file. 
All returned study drug and study drug materials should be stored, inventoried, reconciled, and 
returned according to applicable state and federal regulations and study procedures. 
11. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject signed the ICF 
until the subject’s final study visit (end of Week 20 or 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. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
drug, must be documented in the subject’s medical records, in accordance with the investigator’s 
normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for duration, intensity, 
frequency, seriousness, outcome, other actions taken, and relationship to the study drug.  


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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. 
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. 
• Pregnancy. 
11.2. 
Intensity of Adverse Events 
AEs must be graded for intensity.  An intensity category of mild, moderate, or severe, as defined 
in Table 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 AE that is usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic intervention.  The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the research participant. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects clinical status, or 
may require intensive therapeutic intervention. 
11.3. 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the criteria outlined in Table 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. 
11.4. 
Recording Adverse Events 
For enrolled subjects, each AE will be listed as a separate entry on an AE eCRF.  Screen failure 
subjects will have AE information noted in the source documentation.  The investigator (or 
designee) will provide information on dates and times of onset and resolution, intensity, 
seriousness, frequency, action(s) taken, changes in study drug usage, relationship to study drug, 
and outcome. 
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to NBI or its designee: 
• SAE, including death (refer to Section 11.6). 
• Pregnancy (refer to Section 11.7). 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) based on the C-SSRS. 
11.5. 
Post-Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up.  If 
resolved, a resolution date should be documented on the eCRF.   
AEs ongoing at the final study visit (end of Week 20 or early termination) will be followed for as 
long as necessary to adequately evaluate the subject’s safety or until the event stabilizes or 
resolves or until the subject is lost to follow-up.  The investigator is responsible for ensuring that 
follow-up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals, as is 
practical. 


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11.6. 
Serious Adverse Events 
All SAEs will be recorded from the time the subject has signed the ICF until 30 days after the 
last dose of study drug or the final study visit, whichever is longer. 
11.6.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcomes: 
• Death. 
• A life-threatening AE.  Life threatening means that the subject was, in the view of the 
investigator or sponsor, at immediate risk of death from the reaction as it occurred.  It does 
not mean that hypothetically the event might have caused death if it occurred in a more 
serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization for 
elective treatment or a preexisting condition that did not worsen during the clinical 
investigation is not considered an AE.  Hospitalization or nursing home admission for the 
purpose of caregiver respite is not considered an AE.  Complications that occur during 
hospitalization are AEs, and if a complication prolongs hospitalization, the event is 
considered serious.  Treatment in a hospital emergency room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization.  These events may be considered serious when, based on appropriate 
medical judgment, they may jeopardize the health of the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed.  Any other event thought by 
the investigator to be serious should also be reported, following the reporting requirements 
detailed in this section.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
11.6.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible.  The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject.  The subject will remain under observation as long as 
medically indicated.  Appropriate laboratory studies will be conducted until all parameters return 
to normal or are otherwise explained or stable.  The subject will be followed until the SAE 
resolves or until the subject is medically stabilized.  The investigator (or designee) will notify the 
NBI Medical Monitor (and the IRB, if necessary) immediately (within 24 hours) of the SAE and 
the outcome of the SAE. 
If within the time of informed consent until 30 days after the last dose of study drug or final 
study visit, whichever is longer, an investigator becomes aware of an SAE, then the event must 
be documented and reported as described in Section 11.6.3. 


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11.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events 
Serious AEs and other immediately reportable events (defined in Section 11.4) must be reported 
within 24 hours of first knowledge of the event by study personnel to the NBI Medical Monitor 
or NBI Drug Safety and Pharmacovigilance (DSPV) Department.  Reports of SAEs or 
pregnancies should be followed by a fax or email of the SAE or Pregnancy Form.  It is important 
that the investigator provides his or her assessment of relationship to study drug at the time of the 
initial SAE report.  
For SAEs or Other Immediately Reportable Events, contact DSPV: 
 
DSPV telephone: (866) 626-7792 or (858) 617-7792 
 
DSPV facsimile: (888) 617-7551 
 
DSPV e-mail:  
cds@neurocrine.com 
 
NBI Medical Monitor:  
 
 
 
 
 
 
 
 
 
 
 
 
 
11.6.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 11.3) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life-threatening experience within 7 calendar 
days 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 as 
soon as possible.  Documentation of the submission to the IRB and receipt by the IRB (if 
applicable) must be retained for each safety report. 
11.7. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  However, all 
pregnancies in female subjects who received valbenazine will be followed to assess for 
congenital anomaly.  Subjects must be counseled at all visits to continue using contraception (see 
inclusion criterion #2) until 30 days after the last dose of study drug for females and 90 days 
after the last dose of study drug for males.  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 site within 24 hours and undergo a serum pregnancy test to confirm 
pregnancy. 
All confirmed pregnancies, in subjects who received study drug, must be immediately reported 
to NBI (refer to Section 11.6.3 for contact information), followed by fax or email of the 
pregnancy form to NBI DSPV.  A first trimester ultrasound will be requested for all confirmed 
pregnancies.  Pregnancies in subjects who received valbenazine will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 


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12. 
DOCUMENTATION OF DATA 
12.1. 
Case Report Form 
The case report form (CRF) data for this study are being collected with an electronic data capture 
(EDC) system (Rave®) provided by Medidata Solutions Incorporated, NY, USA.  The EDC 
system and the study-specific eCRFs will comply with Title 21 CFR Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, while the 
validation of the study specific eCRFs will be conducted by NBI and the required documentation 
will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs.  All data 
entered into the eCRF will be supported by source documentation.  The eCRF for each subject 
must be reviewed by the investigator and signed on the appropriate eCRF page(s).  This should 
be done as soon as possible after the subject completes the study.   
The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF.  All change information, including the date, person 
performing the corrections, and reason for the change will be available via the electronic audit 
trail, which is part of the EDC system.  The eCRFs will be reviewed periodically for 
completeness, legibility, and acceptability by NBI (or designee).  NBI will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify eCRF 
entries.  The Principal Investigator will review the eCRFs for completeness and accuracy and 
enter his or her electronic signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC system 
will be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at 
that time as a durable record of the site’s eCRF data.  Although not required, the investigator 
may make paper printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI and/or health authority representatives at any time.  The Principal Investigator 
will agree to the inspection of study-related records by health authority representatives and/or 
NBI. 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
Any discrepancies will be corrected on-line by authorized site personnel.  After completion of 
the entry process, automated (computer-generated) logic checks will run in order to identify 
items such as inconsistent study dates.  In addition, manual review/checks may be performed by 
NBI on the data.  Any inconsistencies/errors/omissions identified will be sent to the site (via an 
electronic query) for the necessary corrections to be made to the eCRF.  Once entered and saved 
in an eCRF, data immediately become part of the study database and are available to NBI. 


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12.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Prior and concomitant medications will be coded using the 
chosen version of the World Health Organization Drug Dictionary (WHO Drug). 
13. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive statistics and graphical methods will be used to 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.  Two-sided 95% confidence 
intervals will be presented for selected variables. 
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 and unblinding of the treatment group assignments.  The SAP may include a number of 
additional analyses and data summaries not described in this protocol. 
13.1. 
Analysis Sets 
Analysis sets will be defined in the SAP. 
13.2. 
Sample Size 
Approximately 120 subjects will be enrolled in this study.  The 1:1 randomization to placebo or 
valbenazine during the double-blind, placebo-controlled treatment period will therefore provide a 
sample size of approximately 60 subjects in the placebo arm.  The SD for the AIMS dyskinesia 
total score change from the end of the open-label treatment period (end of Week 8) to visits 
during the double-blind, placebo-controlled treatment period in the placebo treatment arm is 
estimated to be 4.0 based on results from the previously reported Phase 3 study 
NBI-98854-1304.  With this SD and a sample size of 60, the overall width of a two-sided 95% 
confidence interval for the AIMS dyskinesia total score mean change will be approximately 2.0.  
The width of the confidence interval will increase to approximately 2.2 if the placebo treatment 
arm sample size is 50 and to approximately 2.5 if the sample size is 40. 
13.3. 
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 if 
warranted.  
13.4. 
Disposition of Subjects 
A summary of subject disposition will be prepared that displays the number of subjects who 
were enrolled, who were randomized at the Week 8 visit, who completed the double-blind, 
placebo-controlled treatment period, and who completed the final scheduled study visit.  The 


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number of subjects who discontinued early from the study will be displayed by reason for study 
discontinuation. 
13.5. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be summarized with descriptive statistics or 
frequency tables as appropriate.  Medical history will also be summarized. 
13.6. 
Study Drug Dosing and Compliance 
The number and percentage of subjects who are dose compliant (at least 80% of expected 
number of doses taken) will be summarized with descriptive statistics.   
The number and percentage of subjects with a dose reduction will be summarized. 
13.7. 
Persistence of Effect 
Persistence of effect after randomization to either placebo or valbenazine will be based primarily 
on the mean changes from the randomization visit (end of Week 8) in the AIMS dyskinesia total 
score to visits during the double-blind, placebo-controlled treatment period.  Descriptive 
statistics, including two-sided 95% confidence intervals for the mean, will be calculated for the 
changes from the end of Week 8 to each visit during the double-blind, placebo-controlled 
treatment period for each treatment arm.  Additional measures of persistence of effect that will 
be summarized include AEs of TD and early discontinuation from the study due to lack of 
efficacy during the double-blind, placebo-controlled treatment period. 
The relationship between subject clinical characteristics (including psychiatric diagnosis, age, 
gender, concomitant use of antipsychotic medications, and other parameters) and the persistence 
of effect of valbenazine during the double-blind, placebo-controlled treatment period will be 
evaluated using descriptive statistics and graphical methods. 
13.8. 
Health-Related Quality of Life and Disability Data 
The health-related quality of life and disability measures in this study are the EQ-5D-5L and the 
SDS, respectively.  Descriptive statistics will be presented for each of these measures by visit. 
13.9. 
Plasma Drug Exposure 
The plasma concentrations of valbenazine and the metabolite NBI-98782 (other metabolites may 
be evaluated) will be summarized with descriptive statistics by dose at each visit.  
Concentrations below the lower limit of quantification will be set equal to zero for all plasma 
concentration summaries. 
13.10. 
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 and percentage of subjects experiencing each event. 
TEAEs reported during the open-label treatment period will be summarized separately from 
TEAEs reported during the double-blind, placebo-controlled treatment period.  Summary tables   


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will be presented including all TEAEs, only TEAEs that are considered to be possibly or 
definitely related to study drug (for the open-label treatment period only), and TEAEs according 
to maximum intensity.   
Additional summaries will be presented for TEAEs leading to study drug dose reduction, early 
discontinuation from the study, SAEs, and deaths. 
Clinical laboratory, vital signs, ECG, C-SSRS, and BPRS 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. 
13.11. 
Software 
Statistical calculations and summaries will be generated using SAS software version 9.4 or later. 
13.12. 
Interim Analysis 
An interim analysis is not planned for this study. 
14. 
REGULATORY AND ETHICAL ISSUES 
14.1. 
General Legal References 
The study will be carried out according to the 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 
representatives at any time.  The investigator must agree to the inspection of study-related 
records by health authority representatives and/or NBI or its designee. 
14.2. 
Institutional Review Board 
The final approved protocol and the ICF will be reviewed by the IRB for the clinical site.  The 
committee’s decision concerning conduct of the study will be sent in writing to the investigator 
and a copy will be forwarded to NBI.  The investigator must agree to make any required progress 
reports to the IRB, as well as reports of SAEs, life-threatening problems, or death.  
14.3. 
Protocol Adherence and Amendments 
The protocol must be read thoroughly, and the instructions must be followed exactly.  Any 
changes in the protocol will require a formal amendment.  Such amendments will be agreed upon 
and approved in writing by the investigator and NBI.  The IRB will be notified of all 
amendments to the protocol.  Amendments to the protocol will not be implemented until written 
IRB approval has been received. 
14.4. 
Required Documents 
The investigator must provide to NBI or its representatives the following documents before the 
enrollment of any subject (originals should be kept by the investigator in the investigator’s 
regulatory document binder): 


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• Signed copy of the approved protocol. 
• Investigator’s Brochure acknowledgement page. 
• Completed and signed statement of investigator (Form FDA 1572). 
• Curriculum vitae and current medical license of the investigator and subinvestigators. 
• Financial disclosure information as required. 
• Letter of approval from the IRB for the protocol and consent form. 
• Copy of the IRB 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 informed consent before the performance of any study-related 
procedures. 
Each subject’s chart will include the signed ICF for study participation.  When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder. 
14.6. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include emails, telephone calls, and on-site visits.  During the on-site 
visits, the eCRFs will be reviewed for completeness and adherence to the protocol.  As part of 
the data audit, source documents will be made available for review by the study monitor.  The 
study monitor will also perform drug accountability checks and may periodically request review 
of the investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.  The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and respond to inquiries.  In addition, the investigator 
will permit inspection of the study files by authorized representatives of the regulatory agencies. 
14.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed to 
ensure that all procedures are in compliance with GCP and FDA Guidelines and according to 
national law.  Quality assurance audits may be performed at the discretion of NBI. 
14.8. 
Record Retention 
Federal regulations require that records of drug disposition, eCRFs, and all reports of this 
investigation shall be retained by the investigator for a minimum of 2 years after notification by 
NBI that the regulatory authorities have been notified of the study's termination, or 2 years after 


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approval of the marketing application.  If the investigator is unable to retain the study documents 
for the required amount of time, NBI must be informed of the individual who will be assuming 
this responsibility. 
14.9. 
Confidentiality 
NBI and the clinical site affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, all data will be identified only by an 
identification number and, where applicable, subject’s initials and birth date. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of NBI; it 
shall not be disclosed to others without written consent of NBI; and shall not be used except in 
the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To allow the 
use of the information derived from this clinical study and to ensure compliance with current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study material be delivered to the study site.  Subject entry should not begin until after 
the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred.  All personnel expected to be involved in the conduct 
of the study will undergo orientation to include review of study protocol, instructions for eCRF 
completion, AE reporting, and overall responsibilities including those for drug accountability 
and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow-up examination.  Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 


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16. 
REFERENCES 
Guy W. Ed. ECDEU Assessment Manual for Psychopharmacology, revised, 1976, US 
Department of Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD:  
National Institute of Mental Health – Abnormal Involuntary Movement Scale. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec;20(10):1727-36. 
Jeste DV, Palmer BW, Appelbaum PS, Golsham 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. 
Leon AC, Olfson M, Portera L, Farber L, Sheehan DV. Assessing psychiatric impairment in 
primary care with the Sheehan Disability Scale. Int J Psychiatry Med. 1997;27(2):93-105. 
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. 
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS). Psychological Reports. 
1962;10:799-812.  
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): recent developments in 
ascertainment and scaling. Psychopharmacol Bull. 1988;24:97-9. 

SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
 
NBI-98854-TD4002 
Statistical Analysis Plan 
 
02-AUG-2020 
 
1 
 
 
  
 
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 4 
 
VERSION: Final 
DATE OF PLAN: 
02-AUG-2020 
 
BASED ON: 
Protocol Amendment No. 2 Final Version Date:  14 May 2019 
Protocol Amendment No. 1 Final Version Date:  13 September 2018 
Original Final Version Date:  18 July 2018 
 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI-98854-TD4002 
STUDY TITLE: 
A Phase 4, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the 
Persistence of Effect and Safety of Valbenazine for the Treatment of Tardive Dyskinesia 
 
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. 




Neurocrine Biosciences, Inc. 
 
NBI-98854-TD4002 
Statistical Analysis Plan 
 
02-AUG-2020 
 
3 
 
 
  
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
INTRODUCTION ........................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
3.1. 
Study Objectives .........................................................................................................10 
3.1.1. 
Primary Objective .......................................................................................................10 
3.1.2. 
Secondary Objectives .................................................................................................10 
4. 
STUDY DESIGN .......................................................................................................11 
4.1. 
Summary of Study Design ..........................................................................................11 
4.2. 
Sample Size Considerations .......................................................................................12 
4.3. 
Randomization ............................................................................................................12 
4.4. 
Clinical Assessments ..................................................................................................12 
5. 
PLANNED ANALYSES ............................................................................................14 
5.1. 
Interim Analyses .........................................................................................................14 
5.2. 
Final Analyses ............................................................................................................14 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................15 
6.1. 
General Statistical Procedures ....................................................................................15 
6.2. 
Analysis Sets ...............................................................................................................15 
6.2.1. 
Definition of Analysis Sets .........................................................................................15 
6.2.1.1. 
Safety Analysis Set .....................................................................................................15 
6.2.1.2. 
Randomized Safety Analysis Set ................................................................................15 
6.2.1.3. 
Persistence of Effect Analysis Set ..............................................................................16 
6.2.1.4. 
Patient Reported Outcome Analysis Set .....................................................................16 
6.3. 
Baseline Definition .....................................................................................................16 
6.4. 
Derived and Transformed Data ..................................................................................16 
6.4.1. 
Study Day ...................................................................................................................16 
6.4.2. 
Change from Baseline .................................................................................................16 
6.4.3. 
Handling of Early Termination Visit Data .................................................................17 
6.5. 
Handling of Missing Data ...........................................................................................17 
6.5.1. 
Missing Outcome Data ...............................................................................................17 
6.5.2. 
Missing Dates .............................................................................................................17 


Neurocrine Biosciences, Inc. 
 
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Statistical Analysis Plan 
 
02-AUG-2020 
 
4 
 
 
  
 
6.5.2.1. 
First and Last Dose Dates ...........................................................................................17 
6.5.2.2. 
Missing Start Dates for Adverse Events and Prior and Concomitant 
Medications .................................................................................................................18 
7. 
STUDY POPULATION .............................................................................................20 
7.1. 
Protocol Deviations ....................................................................................................20 
7.2. 
Demographic and Baseline Characteristics ................................................................21 
7.3. 
Medical History and Medical Conditions Present at Entry ........................................21 
7.4. 
Study Drug Dosing, Compliance, and Dose Reductions ............................................21 
7.4.1. 
Compliance .................................................................................................................21 
7.4.2. 
Dose Reductions .........................................................................................................22 
8. 
PLASMA CONCENTRATION DATA .....................................................................23 
9. 
PERSISTENCE OF EFFECT OF VALBENAZINE .................................................24 
9.1. 
General Considerations ...............................................................................................24 
9.2. 
Abnormal Involuntary Movement Scale ....................................................................24 
9.2.1. 
AIMS Individual Items ...............................................................................................24 
9.2.2. 
AIMS Dyskinesia Total Score ....................................................................................24 
9.2.3. 
AIMS Responder Analysis .........................................................................................25 
9.3. 
AEs of TD and Discontinuations ................................................................................25 
9.4. 
Subgroup Analyses .....................................................................................................25 
10. 
HEALTH-RELATED QUALITY OF LIFE AND DISABILITY .............................27 
10.1. 
General Considerations ...............................................................................................27 
10.2. 
EuroQol 5 Dimensions 5 Levels .................................................................................27 
10.3. 
Sheehan Disability Scale ............................................................................................27 
11. 
SAFETY AND TOLERABILITY ..............................................................................29 
11.1. 
General Considerations ...............................................................................................29 
11.1.1. 
Format for By-Visit Summaries .................................................................................29 
11.1.2. 
Format for Adverse Events and Other Event-Based Summaries ................................29 
11.2. 
Adverse Events ...........................................................................................................29 
11.2.1. 
Adverse Events Resulting in Premature Discontinuation from Study........................30 
11.2.2. 
Adverse Events Resulting in Study Drug Dose Reductions .......................................30 
11.2.3. 
Deaths and Other Serious Adverse Events .................................................................30 
11.3. 
Clinical Laboratory Data ............................................................................................31 
11.4. 
Vital Signs ..................................................................................................................32 


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11.5. 
Body Weight ...............................................................................................................33 
11.6. 
Electrocardiogram .......................................................................................................33 
11.7. 
Columbia-Suicide Severity Rating Scale ....................................................................34 
11.8. 
Brief Psychiatric Rating Scale ....................................................................................35 
11.9. 
Prior and Concomitant Medications ...........................................................................35 
12. 
REFERENCES ...........................................................................................................37 
 
 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping ..........................17 
Table 3: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables ............32 
Table 4: 
Potentially Clinically Significant Criteria for Vital Signs Variables ..........................33 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical Classification 
BMI 
Body Mass Index  
BPRS 
Brief Psychiatric Rating Scale 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
Electronic Case Report Form 
eTMF 
Electronic Trial Master File 
ECG 
Electrocardiogram  
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
ET 
Early Termination 
GGT 
Gamma-glutamyl Transferase 
IPD 
Important Protocol Deviation 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect Model with Repeated Measures 
NBI 
Neurocrine Bioscience, Inc.  
PCS 
Potentially Clinically Significant  
PE 
Persistence of Effect 
PT 
Preferred Term 
PRO 
Patient Reported Outcome  
QTcF 
Fridericia’s Correction of QT Interval 
SAE  
Serious Adverse Event 


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SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event 
TD 
Tardive Dyskinesia  
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale  
WHO 
World Health Organization 
 


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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-TD4002. 
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 team to 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 persistence of effect of valbenazine in subjects with tardive dyskinesia 
(TD) who receive placebo in a double-blind, randomized withdrawal period following 
open-label treatment with valbenazine. 
3.1.2. 
Secondary Objectives 
The secondary objectives of this clinical study are:  
• To evaluate the relationship between subject clinical characteristics and persistence of 
effect of valbenazine during the double-blind, placebo-controlled treatment period. 
• To evaluate the effect of valbenazine on measures of quality of life and disability when 
administered once daily for up to 16 weeks. 
• To evaluate the safety and tolerability of valbenazine administered once daily for up to 
16 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 persistence 
of effect of valbenazine 40 mg and 80 mg. Approximately 120 medically stable male and female 
subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-
induced TD or mood disorder with neuroleptic-induced TD will be enrolled. 
The study includes an initial open-label treatment period for 8 weeks, followed by a double-
blind, placebo-controlled treatment period for 8 weeks, for a total of up to 16 weeks of treatment.  
A final study visit will be conducted at Week 20 or upon early termination.   
Eligible subjects will be enrolled in the study on Day 1. Valbenazine will be self-administered at 
home (in the presence of the subject’s caregiver, if applicable) beginning on Day 1; the subject 
will be directed to take their dose at about the same time each day. During the open-label 
treatment period, subjects will receive 40 mg for the first week followed by 80 mg for 7 weeks. 
At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo. Subjects 
randomized to valbenazine will continue with the same dose as the last dose they received during 
the open-label treatment period. Randomization will be stratified based on the use of 
concomitant antipsychotic medication; this will include up to 40 subjects who are not using 
antipsychotic medications (ie, have not used antipsychotic medication for at least 60 days prior 
to screening and have no plans for resuming antipsychotic treatment during the course of the 
study) and the remaining subjects will be using concomitant antipsychotic medications. 
At any time during treatment (open-label and placebo-controlled treatment periods), subjects 
who are unable to tolerate the 80 mg dose will have their dose decreased to 40 mg (during the 
double-blind, placebo-controlled treatment period, 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 will be discontinued from the study. 
A schematic of the study design is shown in Figure 1. 


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Figure 1: 
Study Design Schematic 
 
a During the open-label treatment period, subjects will receive 40 mg for the first week followed by 80 mg for  
7 weeks.  At any time during treatment, subjects who are unable to tolerate the 80 mg dose will have their dose 
decreased to 40 mg.  Subjects randomized to valbenazine will continue with the same dose as the last dose they 
received during the open-label treatment period. 
 
4.2. 
Sample Size Considerations 
Approximately 120 subjects will be enrolled in this study. The 1:1 randomization to placebo or 
valbenazine during the double-blind, placebo-controlled treatment period will therefore provide a 
sample size of approximately 60 subjects in the placebo arm. The standard deviation (SD) for the 
Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score change from the end of 
the open-label treatment period (end of Week 8) to visits during the double-blind, placebo-
controlled treatment period in the placebo treatment arm is estimated to be 4.0 based on results 
from the previously reported Phase 3 study NBI-98854-1304. With this SD and a sample size of 
60, the overall width of a two-sided 95% confidence interval (CI) for the AIMS dyskinesia total 
score mean change will be approximately 2.0. The width of the confidence interval will increase 
to approximately 2.2 if the placebo treatment arm sample size is 50 and to approximately 2.5 if 
the sample size is 40. 
4.3. 
Randomization 
At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo. Subjects 
randomized to valbenazine will continue with the same dose as the last dose they received during 
the open-label treatment period. Randomization will be stratified based on the use of 
concomitant antipsychotic medication (yes vs. no). 
4.4. 
Clinical Assessments 
Assessments of persistence of effect after randomization will be based on: 
• AIMS 
• Adverse events (AEs) of TD 
Screening
Period
Final Visit / 
Early Termination
Open-Label
Treatment Period
Double-Blind, Placebo-Controlled 
Treatment Period
Week
-6 to -1
1
8
16
20
4
12
Valbenazine
(40 or 80 mg)a
Valbenazine (40 or 80 mg)a,
or Placebo 


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• Discontinuation from study during the double-blind, placebo-controlled treatment 
period due to lack of efficacy 
Health-related quality of life and disability assessments include: 
• EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
• Sheehan Disability Scale (SDS) 
Safety assessments include: 
• AEs 
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
• Vital signs (including orthostatic blood pressures and pulse) 
• Physical examinations 
• 12-lead electrocardiograms (ECGs) 
• Suicidal ideation and behavior – evaluated using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
• Brief Psychiatric Rating Scale (BPRS) 
Blood samples for plasma valbenazine and metabolite concentration analyses are also collected. 
Subjects/caregivers will be asked to record and provide dosing times from the evening before the 
treatment period visits when these samples are collected. 
The schedule of assessments can be found in the protocol. 
 
 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
An interim analysis is not 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 statistics will be used to summarize the data from this study. The term “descriptive 
statistics” refers to the number of subjects, mean, median, SD, standard error of the mean (SEM), 
minimum, and maximum for numerical variables; and refers to the number and/or percentage of 
subjects for categorical variables. Two-sided 95% confidence intervals will be presented for 
selected variables. Additional descriptive statistics may be presented for selected variables.  
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.  
Some analyses may be combined in the same summary table. Graphical displays of the analyses 
described in this SAP may also be produced.  
6.2. 
Analysis Sets  
6.2.1. 
Definition of Analysis Sets 
For purposes of defining analysis sets, “enrolled subjects” refers to subjects enrolled into the 
study at the Day 1 visit (ie, are not screen failures) as specified by the subject enrollment 
electronic case report form (eCRF). 
6.2.1.1. 
Safety Analysis Set 
The safety analysis set will include all enrolled subjects who receive at least one dose of open-
label study drug and have any safety data collected after the first dose of study drug. The safety 
analysis set will be used for summaries of safety data during the open-label period and for all 
summaries of plasma concentration data. A single treatment group (Open-label Valbenazine) will 
generally be used for analyses of the open-label period. 
6.2.1.2. 
Randomized Safety Analysis Set 
The randomized safety analysis set will include all randomized subjects who receive at least one 
dose of randomized study drug and have any safety data collected after the first dose of 
randomized study drug. The randomized safety analysis set will be used for all summaries of 
safety data during the placebo-controlled period. Data from the preceding open-label period may 
be included in by-visit summaries. Subjects will be grouped by randomized treatment. 


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6.2.1.3. 
Persistence of Effect Analysis Set 
The persistence of effect (PE) analysis set will include all subjects who are randomized to a 
treatment group at Week 8, take at least one dose of randomized study drug and have at least one 
value for change from randomization baseline in the AIMS total score during the placebo-
controlled period. Treatment assignment for all summaries and analyses using the PE analysis set 
will be based on the randomization schedule. 
6.2.1.4. 
Patient Reported Outcome Analysis Set 
The patient reported outcome (PRO) analysis set will include all enrolled subjects who take at 
least one dose of study drug and have at least one health-related quality of life and/or disability 
assessment collected after baseline. Descriptions of the analysis groups are provided in 
Section 10.1. 
6.3. 
Baseline Definition 
Two definitions of baseline will be used: 
Study baseline: The assessments collected at the Day 1 study visit will serve as the study 
baseline value for all assessments. If a value is not available at the Day 1 visit, then the last 
measurement collected on or prior to the date of the first dose of open-label study drug will serve 
as study baseline. 
Randomization baseline: The assessments collected at the randomization visit (Week 8) will 
serve as the randomization baseline value for select assessments. If a value is not available at the 
randomization visit, then the last measurement collected after the first dose of open-label study 
drug and on or prior to the date of the first dose of randomized study drug will serve as 
randomization 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). 
Percent change from baseline is calculated as (change from baseline/baseline value * 100). 
If either the baseline or postbaseline value is missing, the change from baseline and the percent 
change from baseline will also be missing. The percent change from baseline will also be 
missing if the baseline value is equal to zero. 


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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 20 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.  
An ET visit will be mapped to the next scheduled study visit if it occurs within 14 days prior to 
and 13 days after the expected study day of the next scheduled visit (with the requirement that 
the scheduled visit prior to the ET visit was actually completed by the subject). ET visits 
occurring after the Week 16 visit will be mapped to the Week 20 follow-up visit if it occurs after 
day 125. 
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. 
Table 2 displays the allowable study day range for each scheduled visit for ET visit mapping 
purposes. 
Table 2: 
Allowable Study Day Range for Early Termination Visit Mapping 
Scheduled Visit 
Target Study Day 
Visit Window  
(Study Day Range) 
Week 4 
28 
14-41 
Week 8 
56 
42-69 
Week 12 
84 
70-97 
Week 16 
112 
98-125 
Week 20 
140 
>125 
 
6.5. 
Handling of Missing Data 
6.5.1. 
Missing Outcome Data 
Unless otherwise specified, missing values will not be imputed for descriptive statistics.  
For persistence of effect summaries based on the AIMS dyskinesia total score, the missing 
values for change from randomization baseline will be handled in a linear mixed-effect model 
with repeated measures (MMRM), where the values are assumed to be missing at random. 
Missing data for other selected endpoints will be imputed using last observation carried forward 
(LOCF). 
6.5.2. 
Missing Dates 
6.5.2.1. 
First and Last Dose Dates  
Missing and incomplete (“partial”) dates for first and last dose dates will be imputed for the 
purpose of estimating exposure and defining treatment periods. Missing dates will not be 


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imputed for subjects when the subject is known to have not taken at least one dose of study drug, 
as documented by the site in the dosing eCRF.  
The imputation rules for first open-label dose date are as follows: 
• If the date is completely missing or if both the day and month are missing, the date will 
be imputed as the date when the first study drug kit was assigned; 
• If only the day is missing, the date will be imputed as the date when the first study drug 
kit was assigned if the month and year match the month and year of the kit assignment 
date; if the month and year occur after the kit assignment date, the missing day will be 
imputed as the first day of the month. 
A similar logic will be used for the first dose of randomized study drug, using the kit dispensed 
at the time of randomization. 
If the date of the last dose of study drug is missing, then the last dose date will be imputed as the 
earliest of:  
• the Week 16 visit date,  
• study discontinuation date for subjects who discontinue before Week 16,  
• the date when the last study drug kit(s) was assigned + the number of doses dispensed 
with the kit(s).  
6.5.2.2. 
Missing Start Dates for Adverse Events and Prior and Concomitant Medications 
Missing and incomplete 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 of the AE start date 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 AE start 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 concomitant medication start date is in the same month and year as the first 


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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 concomitant medication start 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 
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) each analysis set (Section 6.2.1) will be provided. The number and percentage of 
subjects excluded from each analysis set by reason for exclusion will also be provided.  
A summary of subject disposition will be prepared that displays the number of subjects who 
were enrolled, who received at least one dose of study drug, who were randomized to each 
treatment group, who were randomized and completed the placebo-controlled withdrawal period, 
who were randomized and completed the follow-up period, and who were not randomized and 
discontinued study participation. The number of subjects who discontinued from the study will 
also be displayed by reason for discontinuation. 
The analysis set and subject disposition summaries will be based on all enrolled subjects and will 
include the following analysis groups:  
• subjects enrolled but not randomized;  
• subjects randomized to placebo;  
• subjects randomized to valbenazine;  
• all subjects. 
A listing of randomized subjects will also be provided and will include subject ID, informed 
consent date, enrollment date, randomization date, concomitant antipsychotic use (yes vs. no), 
and randomized treatment group. 
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. 
7.1. 
Protocol Deviations 
Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into 
the study electronic Trial Master File (eTMF) system and used to identify important protocol 
deviations (IPDs). 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. This committee will 
review a listing of all protocol deviations reported in the study database and determine which 
deviations are IPDs.  
A summary of the number and percentage of subjects with IPDs by deviation category will be 
provided using all enrolled subjects. The following analysis groups will be used: subjects 
enrolled but not randomized; subjects randomized to placebo; subjects randomized to 
valbenazine; all subjects.  
All major protocol deviations entered into the study eTMF will be presented in a data listing. 
Any IPDs will be flagged in the listing.  


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7.2. 
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. Summaries 
will be presented for each of the analysis sets described in Section 6.2.1. An additional “All 
Subjects” column will be included, where appropriate.  
Demographics include: 
• Age (years) 
• Sex 
• Ethnicity 
• Race 
Study baseline subject characteristics include: 
• Primary clinical diagnosis (schizophrenia or schizoaffective disorder with 
neuroleptic-induced TD; mood disorder with neuroleptic-induced TD) 
• 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 
baseline weight; kg/m2) 
• CYP2D6 genotype status 
• AIMS dyskinesia total score 
• Concomitant antipsychotic use (yes vs. no; as indicated by the investigator in IWRS 
and included for randomized analysis groups only) 
7.3. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized in frequency tables (number and percentage of subjects) by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT), with SOCs and PTs within each SOC sorted alphabetically. Separate 
summaries will be presented for the safety analysis set and the randomized safety analysis set. 
The randomized safety analysis set will be presented by treatment and will include an additional 
“All Subjects” column. 
7.4. 
Study Drug Dosing, Compliance, and Dose Reductions 
7.4.1. 
Compliance 
Subjects will bring all unused study drug and empty study drug packaging material to the center 
at each study visit for drug accountability and reconciliation by study center personnel. A 


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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 who are dosing compliant at each visit will be 
summarized using the safety analysis set (through Week 8) and the randomized safety analysis 
set (Week 8 through Week 16). 
7.4.2. 
Dose Reductions 
Subjects will receive 40 mg for the first week of treatment and 80 mg until the end of Week 8 in 
subjects randomized to receive placebo and until the end of Week 16 in subjects randomized to 
remain on valbenazine. 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 a dose reduction at any time during the open-label 
treatment period will be presented using the safety analysis set. The number and percentage of 
subjects with a dose reduction at any time during the placebo-controlled treatment period will be 
presented by treatment group using the randomized safety analysis set.  


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8. 
PLASMA CONCENTRATION DATA 
The plasma concentrations of valbenazine (NBI-98854) and its metabolite NBI-98782 will be 
summarized with descriptive statistics by visit and by the last 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. 
In addition to the descriptive statistics noted in Section 6.1, the following 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 (%). 
The safety analysis set will be used for all plasma concentration summaries. Data for subjects 
receiving placebo at the visit will not be included.  


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9. 
PERSISTENCE OF EFFECT OF VALBENAZINE 
9.1. 
General Considerations 
Unless otherwise specified, the PE analysis set will be used for all analyses described in this 
section. Results will be displayed by randomized treatment group (Randomized Valbenazine vs 
Randomized Placebo). 
9.2. 
Abnormal Involuntary Movement Scale 
The severity of TD will be assessed using the AIMS. The AIMS examination will be 
administered by the investigator (or designee) in accordance with the AIMS administration 
procedure. The AIMS administration will be video recorded (approximately 10 minutes) 
following standardized guidelines. The investigator (or designee) will score items 8-10 and items 
11-12 (binary dental status items). Items 1-7 will be scored by two blinded Central AIMS Video 
Raters using consensus scoring. 
9.2.1. 
AIMS Individual Items 
The score for Items 1 through 7 ranges from 0 (no dyskinesia) to 4 (severe dyskinesia) and 
includes facial and oral movements (Items 1 to 4), extremity movements (Items 5 to 6), and trunk 
movements (Item 7). Items 8, 9 and 10 rate global judgments: Items 8 (severity of abnormal 
movements) and 9 (incapacitation due to abnormal movements) range from 0 (none, normal) to 4 
(severe) and Item 10 being scored based only on the subject’s report of his/her awareness of 
abnormal movements from 0 (no awareness) to 4 (aware, severe distress). Items 11 and 12 are 
yes/no questions concerning problems with teeth and/or dentures. 
Descriptive statistics of the individual AIMS items 1 through 10 will be presented for study 
baseline, randomization baseline and for each study visit occurring thereafter. Change from 
randomization baseline will be presented for the post-randomization visits.  
9.2.2. 
AIMS Dyskinesia Total Score 
The AIMS dyskinesia total score is defined as the sum of the scores of AIMS items 1 through 7. 
If any of the seven items have a missing value, the total score for that subject/visit will be set 
equal to missing. The AIMS dyskinesia total score can therefore range from 0 to 28, with higher 
scores indicating greater severity. 
The change from randomization baseline in AIMS dyskinesia total score during the placebo-
controlled treatment period will be analyzed using a linear mixed-effect model of repeated 
measures (MMRM) that includes the fixed effects of treatment, visit, treatment-by-visit, 
concomitant antipsychotic use (yes vs. no), and study baseline AIMS dyskinesia total score as a 
covariate. Within-subject variability will be accounted for using a random effect with an 
unstructured covariance matrix. The least squares (LS) mean for each treatment group and the 
associated 95% confidence interval (CI) will be presented for each visit. The primary 
measurement of persistence of effect will be based off the CI for the LS mean change from 
randomization baseline in the placebo group at Week 16. 
Descriptive statistics of the AIMS dyskinesia total score will be presented for study baseline, 
randomization baseline and for each study visit occurring thereafter. Descriptive statistics for 


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change from randomization baseline and change from study baseline will also be presented for 
the relevant postbaseline visits. The descriptive statistics for the change from randomization 
baseline will include a 2-sided 95% confidence interval for the mean.  
Mean (±SEM) values of the observed values at each visit will be summarized in a line graph by 
treatment group. A similar graph will be presented for the changes from randomization baseline 
for the post-randomization visit. The LS means (±SEM) from the MMRM analysis results will 
be summarized in a similar line graph.  
9.2.3. 
AIMS Responder Analysis 
An AIMS responder is defined, on a per-visit basis, as a subject whose AIMS dyskinesia total 
score is reduced by at least 50% from study baseline. Descriptive statistics will be presented by 
visit and treatment group for the number and percentage of subjects classified as AIMS 
responders. 
9.3. 
AEs of TD and Discontinuations 
Additional measures of persistence of effect that will be summarized include AEs of TD and 
early discontinuations from the study due to lack of efficacy during the double-blind, placebo-
controlled treatment period.  
The summary will include the number and percentage of subjects who:  
1) experience an AE of TD during the placebo-controlled treatment period; 
2) discontinue from the study due to lack of efficacy during the placebo-controlled treatment 
period;  
3) meet either of the previous criteria.  
An AE of TD is defined as AEs with a MedDRA preferred term of "Tardive dyskinesia" or 
"Dyskinesia".  
9.4. 
Subgroup Analyses 
The relationship between subject clinical characteristics and the persistence of effect of 
valbenazine during the double-blind, placebo-controlled treatment period will be evaluated.  
The following clinical characteristics will be investigated: 
• Primary psychiatric diagnosis (schizophrenia or schizoaffective disorder vs. mood 
disorder) 
• Age group (<45 years vs. ≥45 years; <65 years vs. ≥65 years) 
• Sex (male vs. female) 
• Concomitant use of antipsychotic medications (yes vs. no, as indicated by investigator in 
IWRS) 
• Treatment response status (yes vs. no, as indicated by AIMS Responder status 
[Section 9.2.3] at randomization baseline) 


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Each subgroup factor along with its 2-way and 3-way interactions with treatment group and visit 
will be added to the MMRM model specified for the AIMS dyskinesia total score in 
Section 9.2.2. The LS mean for each combination of treatment group and subgroup stratum and 
the associated 95% CIs will be presented by visit. Descriptive statistics for the observed AIMS 
dyskinesia total scores and changes from randomization will also be presented by visit and 
treatment for each stratum of the subgroups. The MMRM results will not be presented if a 
subgroup has <10 subjects in any treatment and subgroup stratum combination or if the model 
fails to converge.   
If needed to investigate a potential signal, descriptive statistics of the individual AIMS items or 
other assessments of persistence of effect may also be presented by subgroup. 


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10. 
HEALTH-RELATED QUALITY OF LIFE AND DISABILITY 
10.1. 
General Considerations 
The PRO analysis set will be used for all analyses described in this section. Study baseline will 
be used as baseline for all assessments. By-visit summaries will include the following analysis 
groups: 
• Open-Label Valbenazine – all subjects in the PRO analysis set. Data will be presented 
through Week 8. 
• Randomized Valbenazine – all subjects in the PRO analysis set who were randomized to 
valbenazine at Week 8. 
• Randomized Placebo – all subjects in the PRO analysis set who were randomized to 
placebo at Week 8.  
In addition to observed summaries, missing data at Week 8 and Week 16 will be imputed using 
LOCF: 
• Week 8: last postbaseline assessment collected during the open-label treatment period 
• Week 16: last post-randomization collected during the placebo-controlled treatment 
period 
10.2. 
EuroQol 5 Dimensions 5 Levels 
The EQ-5D-5L is a general, single index measure for describing and valuing health (Herdman et 
al, 2011).  
The first part assesses health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The subject indicates 
his/her health state by checking the box next to the most appropriate statement. The scores for 
the 5 dimensions can be combined into a 5-digit number that describes the patient’s health state. 
The health state index score will be calculated from the individual health profiles using the 
United States value set (Pickard et al, 2019) and ranges from -0.573 to 1.0, with higher scores 
indicating higher health utility.  
The second part of the questionnaire consists of a visual analogue scale (VAS) on which the 
patient rates his/her perceived health from 0 (the worst imaginable health) to 100 (the best 
imaginable health). 
The EQ-5D-5L health state index and VAS scores will be summarized with descriptive statistics 
at baseline and at each postbaseline visit. Both observed values and changes from baseline will 
be summarized. Frequency counts and percentages for the responses of the 5 individual 
dimensions will also be presented at baseline and at each scheduled postbaseline visit. 
10.3. 
Sheehan Disability Scale 
The SDS is a brief, validated measure of functional impairment in a number of psychiatric 
disorders to measure the effect of treatment on disability (Leon et al, 1997). It includes 3 self-


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rated items designed to measure how work, social life, and family life are impaired by current 
psychiatric symptoms. Each item includes an 11-point analog scale that uses visual-spatial, 
numeric, and verbal descriptive anchors to represent the degree of disruption from 0 (none at all) 
to 10 (extremely). It also assesses the number of days a subject was unable to work/attend school 
and the number of days a subject was underproductive in the past week.  
The SDS total score is the sum of the 3 impairment items and will only be calculated for subjects 
who rate all three items. 
The SDS individual items and total scores will be summarized with descriptive statistics at 
baseline and at each postbaseline visit. Both observed values and changes from baseline will be 
summarized.  


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11. 
SAFETY AND TOLERABILITY 
11.1. 
General Considerations 
11.1.1. 
Format for By-Visit Summaries  
Study baseline will be used as baseline for all safety assessments. Descriptive statistics of 
observed and change from baseline values will be presented at baseline and at each scheduled 
postbaseline visit through Week 20. Results will be displayed by the following analysis groups: 
• Open-Label Valbenazine – all subjects in the safety analysis set. Data will be presented 
through Week 8. 
• Randomized Valbenazine – all subjects in the randomized safety analysis set who were 
randomized to valbenzine.  
• Randomized Placebo – all subjects in the randomized safety analysis set who were 
randomized to placebo. 
11.1.2. 
Format for Adverse Events and Other Event-Based Summaries  
Adverse events and assessment-based abnormality summaries, such as potentially clinically 
significant (PCS) laboratory values or "Yes" responses in the C-SSRS items, will be displayed 
by treatment period as followed: 
Open-Label Treatment Period: includes AEs and events that begin after the first dose of study 
drug, excluding any events with a start date or assessment date after the first dose of randomized 
study drug. Results will be displayed in a single treatment group (Open-Label Valbenazine) 
using the safety analysis set. 
Placebo-Controlled Treatment Period: includes AEs and events that begin after the first dose of 
randomized study drug. Results will be displayed by randomized treatment group (Randomized 
Placebo or Randomized Valbenazine) using the randomized safety analysis set.  
11.2. 
Adverse Events 
Adverse events are recorded in the eCRF. Each AE will be coded to 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 
eCRF 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 relative to the date of 
the subject’s first dose of study drug. If the AE onset date is unknown, it will be assumed that the 
AE is a TEAE. TEAEs will be assigned to a treatment period based on the onset date. Missing or 
incomplete AE onset dates or study drug dosing dates will be imputed as described in 
Section 6.5.2. 


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The frequency tables will include the number and percentage of unique subjects experiencing 
each event at least once during the specified treatment period. Separate summaries will be 
presented for each treatment period defined in Section 11.1.2. 
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 (number of unique subjects) in the Valbenazine treatment group.  
• Frequency of TEAEs by PT, with PT sorted by decreasing frequency (number of unique 
subjects) in the Valbenazine treatment group. 
The number and percentage of subjects with severe TEAEs will also be summarized. These 
tables will include both SOC and PT, sorted 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 severe 
TEAE.  
AE overview summary tables will be provided for each treatment period which summarize the 
number and percentage of 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. 
The summary table will also include the maximum TEAE intensity (mild, moderate, severe) 
reported for each subject during the specified treatment period. 
11.2.1. 
Adverse Events Resulting in Premature Discontinuation from Study 
Summary tables of TEAEs resulting in premature discontinuation from study will be presented. 
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, last study drug dose level received prior to the onset date of the TEAE(s) leading to 
discontinuation, study day of the discontinuation, and other relevant information from the AE 
eCRF or subject characteristics.  
11.2.2. 
Adverse Events Resulting in Study Drug Dose Reductions 
Summary tables of TEAEs resulting in study drug dose reductions will be presented. 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.  
11.2.3. 
Deaths and Other Serious Adverse Events 
Summary tables of serious adverse events (SAEs) will be presented. The tables will include the 
frequency of SAEs presented by PT within SOC (presented in the same method as the primary 
TEAE table). 


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Separate listings of SAEs and fatal TEAEs will also be provided. Each listing will include 
subject ID, last study drug dose level received prior to the onset date of the SAE or fatal TEAE, 
study day of the SAE or fatal TEAE, and any additional relevant information from the AE eCRF 
or subject characteristics. 
11.3. 
Clinical Laboratory Data 
By-visit summaries 
The clinical chemistry and hematology data will be summarized with descriptive statistics at 
baseline and at each postbaseline visit as described in Section 11.1.1. Both observed values and 
changes from baseline will be summarized.  
Shift tables 
Shift tables will be presented for selected clinical laboratory variables based on the reference 
range-based categories of “Low,” “Normal,” or “High.” A clinical laboratory variable value will 
be assigned to one of these three categories according to the reference ranges provided by the 
central clinical laboratory.  
Shift tables will be presented by treatment period: 
• Shifts from baseline to Week 8 (or last available assessment in the open-label treatment 
period) using the safety analysis set. 
• Shifts from baseline to Week 16 (or last available assessment in the placebo-controlled 
period) using the randomized safety analysis set. 
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 at postbaseline. 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 
transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl 
transferase (GGT), total bilirubin, creatine kinase, creatinine, blood urea nitrogen (BUN), white 
blood cell count, absolute neutrophil count, hemoglobin, and platelet count. 
PCS values 
Summaries of sponsor-defined PCS values will be presented for selected laboratory variables. 
The analytes and criteria for identifying PCS laboratory values are provided in Table 3. 
The number and percentage of subjects with PCS laboratory values that are reported at any 
postbaseline visit (scheduled or unscheduled, including repeat values) will be summarized. 
Results will be presented for each of the treatment periods described in Section 11.1.2. 


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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) 
 
11.4. 
Vital Signs 
By-visit summaries 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics at baseline and at each 
postbaseline visit as described in Section 11.1.1. Both observed values and changes from 
baseline will be summarized.  
PCS values 
Summaries of sponsor-defined PCS values will be presented for systolic blood pressure, diastolic 
blood pressure, and heart rate. The criteria for identifying PCS vital signs values are provided in 
Table 4. Both supine and standing values will be included in the identification and summary of 
PCS values. 
The number and percentage of subjects with PCS vital signs values that are reported at any 
postbaseline visit (scheduled or unscheduled, including repeat values) will be summarized. 
Results will be presented for each of the treatment periods described in Section 11.1.2. 


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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 
 
11.5. 
Body Weight 
By-visit summaries 
The body weight data (in units of kilograms) will be summarized with descriptive statistics at 
baseline and at each postbaseline visit as described in Section 11.1.1. Both observed values and 
changes from baseline will be summarized.   
11.6. 
Electrocardiogram 
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and Fridericia’s correction of QT interval [QTcF]) measured at each visit will be 
averaged for the purpose of analysis. For the 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 for each replicate, the value that 
represents the greatest degree of abnormality will be used in all summary tables. If less than 3 
values are recorded at an assessment, then the average of the available value(s) for the 
quantitative variables and the greatest degree of abnormality values(s) for the interpretation 
variable will be used. 
The quantitative ECG variables will be summarized with descriptive statistics at baseline and at 
each postbaseline visit as described in Section 11.1.1. Both observed values and changes from 
baseline will be summarized. Frequency counts and percentages for the ECG interpretation 
variable categories will also be presented at baseline and at each scheduled postbaseline visit.  
Categorical summaries will be presented for the QT and QTcF interval data. For these 
summaries, a subject’s highest reported postbaseline value (including values reported at 
unscheduled visits) will be used to determine in which category(s) the subject will be counted. 
The averaged triplicate values will be used when determining each subject’s highest reported 
values. Results will be presented for each of the treatment periods described in Section 11.1.2 
and may include post-treatment assessments.  
For the first summary, the number and percentage of subjects whose highest reported QT or 
QTcF postbaseline value meets the following thresholds will be summarized: 
• Greater than 450 msec 


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• Greater than 480 msec 
• Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects whose 
largest QT or QTcF increase from their baseline value meets the following thresholds:  
• Greater than 30 msec 
• Greater than 60 msec 
11.7. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS data will be presented in the following summaries: 
• Screening/lifetime assessment  
• Screening/past 3 month assessment 
• Baseline (Day 1) assessment 
• Open-Label Treatment Period 
• Placebo-Controlled Treatment Period 
Definitions for the treatment periods are described in Section 11.1.2, and may include post-
treatment assessments. 
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category). These C-SSRS items and categories are as follows: 
• Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
• Suicidal Ideation Category: Any of items (1) through (5) 
• Suicidal Behavior Items 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(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 treatment period summaries, each subject’s C-SSRS responses for all postbaseline 
assessments during the specified treatment period will be evaluated, and a “Yes” response at any 
postbaseline assessment for a particular item or category during the specified treatment period 
will be considered as a “Yes” for that item or category for the subject. 


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In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline scores will be presented for each treatment period. 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, with the rows representing the study baseline score and the columns representing the 
maximum score recorded across all postbaseline assessments (including both scheduled and 
unscheduled visits) during the specified treatment period. Subjects missing either a baseline 
score or all postbaseline scores will not appear in the table.  
11.8. 
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. 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 BPRS total score will be summarized with descriptive statistics at baseline and at each 
postbaseline visit as described in Section 11.1.1. Both observed values and changes from 
baseline will be summarized.    
11.9. 
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 or more reporting periods based on the medication start and 
stop dates relative to study drug dosing dates.  
• Prestudy/screening: medications with a start date prior to open-label study drug 
dosing 
• During the open-label treatment period or posttreatment: medications ongoing at the 
time of first open-label study drug dosing or with a start date after first dose of open-
label study drug, excluding medications started after the first dose study drug in the 
placebo-controlled period  


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• During the placebo-controlled period or posttreatment: medications ongoing at the 
time of first dose of study drug in the placebo-controlled period or with a start date 
after the first dose of study drug in the placebo-controlled period. 
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 the reporting periods defined in the previous 
paragraph. A subject may take the same medication more than once or multiple medications for a 
subject may be classified under the same ATC level or preferred name. A subject is counted only 
once for each level of medication classification within a summary.  
 


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12. 
REFERENCES 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec;20(10):1727-36.  
Leon AC, Olfson M, Portera L, Farber L, Sheehan DV. Assessing psychiatric impairment in 
primary care with the Sheehan Disability Scale. Int J Psychiatry Med. 1997;27(2):93-105. 
Pickard S, Law E, Jiang R, Pullenayegum E, Shaw J, Xie F, Oppe F, Boye K, Chapman R, Gong 
C, Balch A, Busschbach J. United States Valuation of EQ-5D-5L Health States Using an 
International Protocol. VALUE HEALTH. 2019; 22(8):931–941