A Phase 4, Single-Arm, Open-Label Study to Evaluate the Effectiveness of Valbenazine on Patient- and Clinician-Reported Outcomes in Subjects With Tardive Dyskinesia
Phase: PHASE4
Conditions: Schizophrenia, Schizoaffective Disorder, Bipolar Disorder, Major Depressive Disorder, Tardive Dyskinesia
Sponsor: Neurocrine Biosciences

Protocol Title 
A Phase 4, Single-Arm, Open-Label Study to Evaluate 
the Effectiveness of Valbenazine on Patient- and 
Clinician-Reported Outcomes in Subjects With Tardive 
Dyskinesia 
Protocol Identifier: 
NBI-98854-TD4020 
Phase: 
Phase 4 
Sponsor: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
United States 
Sponsor Medical Monitor: 
 
Telephone: 
  
Email: 
 
Serious Adverse Event 
Reporting 
Facsimile: 
+1 (888) 617-7551 or +1 (858) 617-7561
Email: 
cds@neurocrine.com
Protocol Amendment 
1.0 – 29 January 2024 
CONFIDENTIAL 
This document contains information that is of confidential, trade secret, and/or proprietary nature 
to Neurocrine Biosciences, Inc. It is intended for your confidential review and to provide you, your 
staff, and your reviewing Institutional Review Board/Independent Ethics Committee with 
information regarding the specific clinical study in which you are participating. You may not 
disclose the contents of this document to parties, other than those previously mentioned, without 
prior written permission from Neurocrine Biosciences, Inc.; provided that you shall be entitled to 
disclose it to authorized representatives of national regulatory authorities under the condition that 
they respect its confidential nature. 
NCT #: NCT05859698

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Study No. NBI-98854-TD4020 Clinical Protocol Amendment 1.0 
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PROTOCOL AMENDMENTS  
Protocol/Amendments 
Date 
Original Protocol 
05 December 2022 
Amendment 1.0 
29 January 2024 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENTS .......................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
1. 
SYNOPSIS .................................................................................................................11 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Background .................................................................................................................15 
2.2. 
Benefit/Risk Assessment for Valbenazine ..................................................................15 
3. 
OBJECTIVES .............................................................................................................18 
3.1. 
Primary .......................................................................................................................18 
3.2. 
Secondary ...................................................................................................................18 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Overall Study Design ..................................................................................................19 
4.1.1. 
Screening Period .........................................................................................................19 
4.1.2. 
Treatment Period ........................................................................................................19 
4.1.3. 
Safety Follow-Up Period ............................................................................................20 
4.2. 
Rationale for Dose Selection ......................................................................................20 
4.3. 
Primary Completion and End of Study Definitions ....................................................20 
5. 
STUDY POPULATION .............................................................................................22 
5.1. 
Inclusion Criteria ........................................................................................................22 
5.2. 
Exclusion Criteria .......................................................................................................24 
6. 
STUDY TREATMENT ..............................................................................................27 
6.1. 
General Information ....................................................................................................27 
6.2. 
Study Treatment Administration ................................................................................27 
6.2.1. 
Dosing Schedule .........................................................................................................27 
6.3. 
Study Treatment Storage and Compliance .................................................................29 
6.4. 
Study Treatment Accountability and Return ..............................................................29 
6.5. 
Blinding ......................................................................................................................29 
6.6. 
Procedures for Overdose .............................................................................................29 
7. 
SUBJECT RESTRICTIONS ......................................................................................31 

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7.1. 
Prior and Concomitant Medications ...........................................................................31 
7.2. 
Dietary and Other Restrictions ...................................................................................32 
7.3. 
Dosage Limitations in Specific Populations ...............................................................32 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL ........................................................................................................33 
8.1. 
Discontinuation of Study Treatment ...........................................................................33 
8.2. 
Withdrawal from Study ..............................................................................................34 
8.3. 
Sponsor’s Termination or Temporary Halt of Study or Study Site ............................35 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
9.1. 
Screening Assessments ...............................................................................................36 
9.1.1. 
Mini International Neuropsychiatric Interview for Psychotic Disorders ...................36 
9.1.2. 
Abnormal Involuntary Movement Scale ....................................................................36 
9.1.2.1. 
AIMS Individual Items ...............................................................................................36 
9.1.2.2. 
AIMS Dyskinesia Total Score ....................................................................................37 
9.1.2.3. 
Administration and Scoring of the AIMS ...................................................................37 
9.1.3. 
CYP2D6 Genotyping ..................................................................................................37 
9.2. 
Efficacy Assessments .................................................................................................37 
9.2.1. 
Tardive Dyskinesia Impact Scale ...............................................................................37 
9.2.2. 
Sheehan Disability Scale ............................................................................................38 
9.2.3. 
EQ-5D-5L and EQ-VAS .............................................................................................38 
9.2.4. 
Patient Global Impression of Change .........................................................................38 
9.2.5. 
Clinical Global Impression of Change - Tardive Dyskinesia .....................................38 
9.2.6. 
Clinical Global Impression of Severity - Tardive Dyskinesia ....................................39 
9.2.7. 
 .......................................................................39 
9.2.8. 
 ....................................................................................39 
9.2.9. 
Abnormal Involuntary Movement Scale ....................................................................40 
9.3. 
Safety Assessments .....................................................................................................40 
9.3.1. 
Vital Sign Measurements ............................................................................................40 
9.3.2. 
Medical History ..........................................................................................................40 
9.3.3. 
Physical Examination, including Height and Weight .................................................40 
9.3.4. 
Electrocardiogram .......................................................................................................40 
9.3.5. 
Clinical Laboratory Assessments ...............................................................................41 
9.3.6. 
Barnes Akathisia Rating Scale....................................................................................41 

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9.3.7. 
Modified Simpson-Angus Scale .................................................................................42 
9.3.8. 
Columbia-Suicide Severity Rating Scale ....................................................................42 
9.4. 
Pharmacokinetic Assessments ....................................................................................42 
9.5. 
Caregiver Assessments ...............................................................................................43 
9.5.1. 
 ..................................................43 
9.5.2. 
 
...................................................................................................................43 
9.6. 
Specific Study Period Information .............................................................................43 
9.6.1. 
Screening Period (Week -4 to Day -1) .......................................................................43 
9.6.1.1. 
Screen Failures and Rescreening ................................................................................44 
9.6.2. 
Study Treatment Period (Day 1 to End of Week 24) ..................................................44 
9.6.3. 
End of Study/Follow-Up Period (Week 26) ...............................................................45 
10. 
ADVERSE EVENTS..................................................................................................46 
10.1. 
Definition ....................................................................................................................46 
10.1.1. 
Intensity of Adverse Events ........................................................................................47 
10.1.2. 
Relationship to Study Treatment ................................................................................47 
10.2. 
Recording Adverse Events .........................................................................................48 
10.3. 
Poststudy Follow-Up of Adverse Events ....................................................................48 
10.4. 
Serious Adverse Events ..............................................................................................48 
10.4.1. 
Definition of a Serious Adverse Event .......................................................................48 
10.4.2. 
Managing Serious Adverse Events .............................................................................49 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................49 
10.4.4. 
Expedited Safety Reports ...........................................................................................50 
10.5. 
Urgent Safety Measures ..............................................................................................50 
10.6. 
Pregnancy ...................................................................................................................50 
11. 
STATISTICAL METHODS .......................................................................................52 
11.1. 
Statistical Hypothesis and Estimands .........................................................................52 
11.2. 
Sample Size Determination ........................................................................................52 
11.3. 
Analysis Sets ...............................................................................................................52 
11.4. 
Endpoints ....................................................................................................................53 
11.4.1. 
Primary .......................................................................................................................53 
11.4.2. 
Secondary ...................................................................................................................53 

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11.4.3. 
 ...........................................................................................................................53 
11.4.4. 
Safety ..........................................................................................................................53 
11.5. 
Statistical Analyses .....................................................................................................53 
11.5.1. 
Efficacy Analyses .......................................................................................................54 
11.5.1.1. 
Procedure to Control for Multiple Comparisons ........................................................54 
11.5.1.2. 
Primary Endpoints ......................................................................................................54 
11.5.1.3. 
Secondary Endpoints ..................................................................................................54 
11.5.2. 
Safety Analyses ..........................................................................................................54 
11.6. 
Interim Analyses .........................................................................................................54 
12. 
SUPPORTING DOCUMENTATION ........................................................................55 
12.1. 
Case Report Forms .....................................................................................................55 
12.2. 
Data Capture, Review, and Validation .......................................................................55 
12.3. 
Coding Dictionaries ....................................................................................................56 
12.4. 
Ethics ..........................................................................................................................56 
12.5. 
General Legal References ...........................................................................................56 
12.6. 
Institutional Review Board/Independent Ethics Committee ......................................56 
12.7. 
Protocol Adherence - Amendments ............................................................................56 
12.8. 
Required Documents ..................................................................................................57 
12.9. 
Informed Consent .......................................................................................................57 
12.9.1. 
Caregiver Consent ......................................................................................................57 
12.10. 
Study Monitoring ........................................................................................................57 
12.11. 
Quality Assurance .......................................................................................................58 
12.12. 
Record Retention ........................................................................................................58 
12.13. 
Confidentiality and Data Protection ...........................................................................58 
12.14. 
Publication and Disclosure Policy ..............................................................................58 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................60 
14. 
REFERENCES ...........................................................................................................61 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................63 
APPENDIX B. INVESTIGATOR SIGNATURE ......................................................................67 
APPENDIX C. SPONSOR APPROVAL SIGNATURE ............................................................68 
APPENDIX D. LIST OF STRONG CYP2D6 INHIBITORS, CYP3A4 INHIBITORS, 
AND CYP3A4 INDUCERS .......................................................................................69 
 

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LIST OF TABLES  
Table 1: 
Study Treatments ........................................................................................................27 
Table 2: 
Dosing Schedule .........................................................................................................28 
Table 3: 
Prohibited Concomitant Medications .........................................................................31 
Table 4: 
Intensity of Adverse Events ........................................................................................47 
Table 5: 
Relationship of Adverse Events to Study Treatment ..................................................47 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance and Medical 
Monitor .......................................................................................................................50 
Table 7: 
Analysis Sets ...............................................................................................................52 
Table 8: 
Schedule of Assessments ............................................................................................64 
Table 9: 
Strong CYP2D6 Inhibitors .........................................................................................69 
Table 10: Strong CYP3A4 Inhibitors .........................................................................................70 
Table 11: Strong CYP3A4 Inducers ...........................................................................................71 
 
LIST OF FIGURES  
Figure 1: 
Study Design Schematic .............................................................................................21 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATS 
Adjunctive treatment of schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
β-hCG 
β-human chorionic gonadotropin 
BMI 
Body mass index 
 
 
CFR 
Code of Federal Regulations 
CGI-TD-C 
Clinical Global Impression of Change – Tardive Dyskinesia 
CGI-TD-S 
Clinical Global Impression of Severity – Tardive Dyskinesia 
CI 
Confidence interval 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease-2019 
 
 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA K2 
Dipotassium ethylenediaminetetraacetic acid 
EQ-5D-5L 
5-level EQ-5D version 
EQ-VAS 
EQ-visual analogue scale 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HD 
Huntington disease 

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HRQOL 
Health-related quality of life 
ICD-10 
International Statistical Classification of Diseases and Related Health 
Problems, Tenth Edition 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
MDD 
Major depressive disorder 
MDMA 
3,4 methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
 
 
NBI 
Neurocrine Biosciences, Inc. 
PGI-C 
Patient Global Impression of Change 
PK 
Pharmacokinetic(s) 
Q1 
First quartile 
Q3 
Third quartile 
qd 
Once a day 
QOL 
Quality of life 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SE 
Standard error 
SDS 
Sheehan Disability Scale 
TD 
Tardive dyskinesia 
TDIS 
Tardive Dyskinesia Impact Scale 
TEAE 
Treatment-emergent adverse event 
TS 
Tourette syndrome 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 

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US 
United States 
VMAT2 
Vesicular monoamine transporter 2 
WBC 
White blood cell 
 
 

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1. 
SYNOPSIS  
Title of study: A Phase 4, Single-Arm, Open-Label Study to Evaluate the Effectiveness of 
Valbenazine on Patient- and Clinician-Reported Outcomes in Subjects With Tardive Dyskinesia 
Protocol number: NBI-98854-TD4020 
Phase of development: 4 
Study centers: This study will be conducted at approximately 30 study centers in the United States 
(US). 
Objectives 
Primary: 
The primary objective is to evaluate patient-reported change in impacts of tardive dyskinesia (TD), 
social and work impairment, and overall health in subjects with TD who are receiving valbenazine for 
up to 24 weeks. 
Secondary: 
The secondary objective is to evaluate clinician-reported change in TD severity and patient-reported 
change in TD symptoms for subjects with TD who are receiving valbenazine for up to 24 weeks. 
Study Design: 
This is a Phase 4, single-arm, open-label study to evaluate the effectiveness of valbenazine on 
patient- and clinician-reported outcomes assessing health-related quality of life (HRQOL), functioning, 
and treatment effect in subjects with TD who are receiving valbenazine for up to 24 weeks. 
Approximately 60 medically stable adult subjects (≥18 years of age) with schizophrenia, 
schizoaffective disorder, bipolar disorder, or major depressive disorder (MDD) who have 
neuroleptic-induced TD of at least mild severity, and who have awareness of and are experiencing at 
least mild distress from their abnormal movements will be enrolled. Enrolled subjects will receive 
valbenazine orally once a day (qd) at 40, 60, or 80 mg as described below. 
The study includes a Screening Period of up to 4 weeks, a 24-week Treatment Period, and a 2-week 
post-treatment Safety Follow-Up Period. 
Screening Period 
All subjects must sign an informed consent form (ICF) prior to the conduct of any study-related 
procedures. Subjects will be screened for eligibility for up to 4 weeks prior to Day 1 (baseline). 
After informed consent has been provided, subjects will undergo screening assessments to determine 
eligibility as outlined in the Schedule of Assessments (Table 8). The screening visit may be conducted 
anytime up to 28 days prior to first dose. 
The Screening Period may be extended by up to 14 days for certain unavoidable circumstances (such as 
the coronavirus disease-2019 [COVID-19] pandemic) with approval from Sponsor or designee. 
Subjects who do not meet entry criteria during the Screening Period may be considered for rescreening 
1 time with the approval of the Sponsor or designee. 
Treatment Period 
Subjects will return to the site on Day 1 for baseline assessments as outlined in the Schedule of 
Assessments (Table 8). Before the subject can begin study treatment on Day 1, the investigator must 
ensure that the subject continues to meet study entry criteria as specified in the study 
inclusion/exclusion criteria (Section 5). 

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Valbenazine will be administered at 40 mg (minimum allowable dose), 60 mg, or 80 mg (maximum 
allowable dose) qd as described in Section 6.2.1. Briefly: 
• 
From Day 1 through Week 4, subjects will take valbenazine 40 mg qd. 
• 
After the end of Week 4 visit through Week 16, subjects will continue to take valbenazine 
40 mg qd or the dose may be adjusted to 60 or 80 mg qd. Dose adjustments may be performed 
based on individual treatment needs, response, and/or tolerability. 
• 
After the end of Week 16 visit through Week 24, subjects will take valbenazine 40, 60, or 
80 mg qd; the dose will be assigned by the investigator at the end of Week 16 visit based on 
individual treatment needs, response, and/or tolerability observed during Weeks 1 to 16. Dose 
adjustments are not expected from Week 17 through Week 24; however, dose decreases are 
permitted if needed for safety or tolerability. 
Subjects who are unable to tolerate the lowest dose (40 mg qd) at any time will be discontinued from 
study treatment and withdrawn from the study. 
Subjects will have onsite and virtual study visits at scheduled times throughout the 24-week Treatment 
Period as outlined in the Schedule of Assessments (Table 8); study assessments and procedures are 
described in Section 9. 
Safety Follow-Up Period 
A Safety Follow-Up Visit for each subject will be conducted 14 days after the final dose of study 
treatment (end of Week 26 [Visit 9]) (Table 8). 
Study population: 
Approximately 60 medically stable adult (≥18 years of age) subjects who: 
• 
Have a clinical diagnosis of: 
- 
Schizophrenia or schizoaffective disorder with neuroleptic-induced TD, or 
- 
Bipolar disorder with neuroleptic-induced TD, or 
- 
MDD with neuroleptic-induced TD 
• 
Have at least mild TD (defined by an Abnormal Involuntary Movement Scale [AIMS] Item 8 
score of ≥2 at screening) as assessed by an onsite rater and confirmed by an external reviewer 
using a video recording of the subject’s AIMS assessment at screening. This criterion must be 
reconfirmed at baseline (as assessed by the onsite AIMS rater only). 
• 
Have at least moderate dyskinetic movements in ≥1 body area (≥3 on AIMS) or at least mild 
dyskinetic movements in ≥2 body areas (≥2 on AIMS) at screening, as assessed by an onsite 
rater and confirmed by an external reviewer using a video recording of the subject’s AIMS 
assessment. This criterion must be reconfirmed at baseline (as assessed by the onsite AIMS 
rater only). 
• 
Have awareness of and are experiencing at least mild distress from their abnormal movements 
as defined by an AIMS Item 10 score of ≥2 at screening. 
To ensure adequate representation of patients with different background psychiatric disorders and 
ranges of TD severity, subjects with schizophrenia or schizoaffective disorder will not exceed 50% of 
the enrolled study population, and subjects with mild dyskinesia will not exceed 50% of the enrolled 
study population. 
Duration of study treatment and study participation: The expected duration of study participation 
for each subject is approximately 30 weeks, including a Screening Period of up to 4 weeks, a 24-week 
Treatment Period, and 2-week Safety Follow-Up Period. 

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Investigational product, dosage, and mode of administration: 
Valbenazine will be taken once daily with or without food. Valbenazine should be taken at 
approximately the same time each day during the study; it is recommended that subjects take 
valbenazine at the same time as their oral antipsychotic medication(s), if appropriate. 
Valbenazine will be formulated as 40, 60, and 80 mg capsules for oral administration at the following 
doses: 
• 
Day 1 through Week 4: 40 mg qd 
• 
After the end of Week 4 visit through Week 24: 40, 60, or 80 mg qd. 
The dosing schedule is summarized above; refer to Section 6.2.1 for details. 
Endpoints: 
Primary 
• 
Change from baseline in the Tardive Dyskinesia Impact Scale (TDIS) total score at Week 24 
• 
Change from baseline in the Sheehan Disability Scale (SDS) Items 1, 2, and 3 at Week 24 
• 
Change from baseline in the EQ-visual analogue scale (EQ-VAS) score at Week 24 
Secondary 
• 
Patient Global Impression of Change (PGI-C) score at Week 24 
• 
Change from baseline in the Clinical Global Impression of Severity – Tardive Dyskinesia 
(CGI-TD-S) score at Week 24 
• 
Change from baseline in the AIMS dyskinesia total score at Week 24 
Safety 
Safety endpoints include the occurrence of adverse events (AEs), observed and changes from baseline 
in clinical laboratory tests (hematology and clinical chemistry), vital sign measurements (including 
blood pressure and pulse rate), 12-lead electrocardiogram (ECG) parameters, and scores from the 
Columbia-Suicide Severity Rating Scale (C-SSRS), Barnes Akathisia Rating Scale (BARS), and 
modified Simpson-Angus Scale (SAS). 
Statistical methods: 
Summary of efficacy analyses 
Descriptive statistics (including both categorical variable statistics [using response categories] and 
continuous variable statistics [using numerical scores]) will be presented for the score or the change 
from baseline score, as appropriate, at the end of Weeks 4, 8, 16, and 24. Two-sided 95% confidence 
intervals (CIs) will be included in the descriptive statistics for changes from baseline. Descriptive 

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statistics (including CIs for changes from baseline) will also be presented by disease category 
(schizophrenia/schizoaffective disorder or MDD/bipolar disorder). 

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2. 
INTRODUCTION  
2.1. 
Background  
Tardive dyskinesia (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, TD most often develops after long-term 
neuroleptic drug use and often persists after discontinuation of such medications. The Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines chronic exposure to 
neuroleptics as a criterion for TD diagnosis. In addition to duration and amount of neuroleptic 
exposure, other risk factors for TD appear to include older age, schizophrenia, and cognitive 
impairment (Margolese et al., 2005). TD can be disabling, lead to bodily harm (eg, lip or tongue 
lacerations, falls), interfere with activities of daily living, and result in social isolation. 
The pathophysiology of TD is not fully understood; however, postsynaptic dopamine 
hypersensitivity in the striatum is the most prominent feature (Margolese et al., 2005). 
Dysregulation of dopaminergic systems is an integral component of several central nervous 
system (CNS) disorders, including other hyperkinetic movement disorders and conditions such 
as schizophrenia and bipolar disorder. The transporter protein vesicular monoamine transporter 2 
(VMAT2) plays an important role in presynaptic dopamine release, regulating monoamine 
uptake from the cytoplasm to the synaptic vesicle for storage and release. The differential 
expression of VMAT2 in human brain (versus endocrine tissue) makes agents that selectively 
target VMAT2 potentially useful for the treatment of CNS disorders (Weihe and Eiden, 2000). 
This study is being conducted to evaluate the potential of valbenazine to improve patient- and 
clinician-reported outcomes in subjects with TD. 
2.2. 
Benefit/Risk Assessment for Valbenazine  
Valbenazine (valbenazine tosylate, NBI-98854) is a selective, orally active VMAT2 inhibitor 
developed by Neurocrine Biosciences, Inc. (NBI). Valbenazine was approved by the United 
States (US) Food and Drug Administration (FDA) in April 2017 for the treatment of adults with 
TD under the trade name INGREZZA®. Valbenazine has also been evaluated in pediatric and 
adult subjects for the treatment of Tourette syndrome (TS) and is currently being evaluated for 
the treatment of chorea associated with Huntington disease (HD), the treatment of dyskinetic 
cerebral palsy (DCP), and the adjunctive treatment of schizophrenia (ATS). 
Valbenazine has been on the market for over 5 years for the treatment of adults with TD. A full 
development program of 20 clinical studies supporting the safety and effectiveness of 
valbenazine for the treatment of adults with TD included 3 placebo-controlled studies of patients 
with TD and underlying psychiatric conditions of schizophrenia/schizoaffective disorder and 
mood disorder (66% and 34% of subjects, respectively, in the Phase 3 study NBI-98854-1304). 
The valbenazine clinical program in TD enrolled more than 2000 subjects, of which 1547 unique 
subjects received at least 1 dose of valbenazine. Two additional studies in patients with TD have 
been conducted since approval. The cumulative postmarketing exposure to valbenazine as of the 
cutoff date of 10 April 2022 is estimated at 67,093 unique patient exposures with 
58,010 patient-years of exposure. 

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Clinical data from healthy individuals and subjects with TD in prior studies and in patients with 
TD in postmarketing experience with valbenazine indicate that the FDA-approved doses of 40, 
60, and 80 mg to be used in this study are generally well tolerated. 
The most common treatment-emergent adverse events (TEAEs) identified in the NBI-sponsored 
valbenazine clinical development program of adults with TD (in 3 placebo-controlled studies of 
6-week treatment duration) reported in ≥2% of subjects and at a higher percentage in valbenazine 
vs placebo include somnolence (10.9%; somnolence, fatigue, sedation), anticholinergic effects 
(5.4%; dry mouth, constipation, disturbance in attention, vision blurred, urinary retention), and 
balance disorders/fall (4.1%; fall, gait disturbance, dizziness, balance disorder). 
In the entire valbenazine clinical development program (NBI-sponsored completed and ongoing 
studies) as of 10 April 2022, treatment-emergent serious adverse events (SAEs) occurring in 3 or 
more valbenazine-treated subjects were schizophrenia, suicidal ideation, chronic obstructive 
pulmonary disease, depression, mental status changes, suicide attempt, syncope, abdominal pain, 
and schizoaffective disorder. 
Ten deaths have been reported in ongoing or completed valbenazine studies conducted by 
NBI: 8 occurred in subjects taking valbenazine and 2 in subjects taking placebo. All of the deaths 
occurred in adults and were considered not related or unlikely related to study treatment. 
No cardiovascular, laboratory, or vital sign–related safety risks have been identified. Increases in 
serum prolactin above normal laboratory ranges have been noted; mean changes in subjects who 
received placebo were considerably smaller. No increased risk of depression or suicidality has 
been observed. 
Hypersensitivity to valbenazine or any components of INGREZZA is a contraindication. A total 
of 6 hypersensitivity SAEs (5 in valbenazine-treated subjects and 1 in a placebo-treated subject) 
have been reported in clinical studies of valbenazine, including events of hypersensitivity, 
angioedema, rash, and Henoch-Schönlein purpura. Of these events, 3 were assessed as related to 
valbenazine (hypersensitivity, angioedema, and rash). A safety evaluation of these events 
supported a risk of developing hypersensitivity reactions with the use of valbenazine. 
Hypersensitivity reactions such as allergic dermatitis, angioedema, pruritis, urticaria, and rash 
have also been reported in the postmarketing setting. 
Valbenazine can cause somnolence and related events (including fatigue and sedation). 
Somnolence was the most commonly reported adverse reaction that occurred at a higher 
percentage in valbenazine-treated subjects compared with placebo-treated subjects in the 
3 placebo-controlled studies in subjects with TD, 1 placebo-controlled study in subjects with TS, 
and in 1 placebo-controlled study in subjects with HD. 
An exposure-response analysis of clinical data from 2 studies in healthy subjects revealed an 
increased QT interval corrected for heart rate using Fridericia’s formula (QTc) with higher 
plasma concentrations of the active metabolite. In subjects taking a strong cytochrome P450 
(CYP)2D6 or CYP3A4 inhibitor or in subjects who are CYP2D6 poor metabolizers, plasma 
concentrations of the active metabolite of valbenazine may be higher and QT prolongation 
clinically significant. 
Parkinsonism is a known risk with VMAT inhibitors. In the placebo-controlled clinical studies of 
valbenazine in subjects with TD, the incidence of Parkinson-like adverse events (AEs) was 3% 

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in subjects treated with valbenazine and <1% in placebo-treated subjects. Postmarketing safety 
reports have described Parkinson-like symptoms, some of which were severe and required 
hospitalization. 
Additional information about the known and expected benefits and risks of valbenazine is 
provided in the Investigator’s Brochure and in the INGREZZA Prescribing Information. 

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3. 
OBJECTIVES  
3.1. 
Primary  
The primary objective is to evaluate patient-reported change in impacts of TD, social and work 
impairment, and overall health in subjects with TD who are receiving valbenazine for up to 
24 weeks. 
3.2. 
Secondary  
The secondary objective is to evaluate clinician-reported change in TD severity and patient-
reported change in TD symptoms for subjects with TD who are receiving valbenazine for up to 
24 weeks. 

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4. 
STUDY DESIGN  
4.1. 
Overall Study Design  
This is a Phase 4, single-arm, open-label study to evaluate the effectiveness of valbenazine on 
patient- and clinician-reported outcomes assessing health-related quality of life (HRQOL), 
functioning, and treatment effect in subjects with TD who are receiving valbenazine for up to 
24 weeks. 
Approximately 60 medically stable adult subjects (≥18 years of age) with schizophrenia, 
schizoaffective disorder, bipolar disorder, or major depressive disorder (MDD) who have 
neuroleptic-induced TD of at least mild severity and who have awareness of and are 
experiencing at least mild distress from their abnormal movements will be enrolled. To ensure 
adequate representation of patients with different background psychiatric disorders and ranges of 
TD severity, subjects with schizophrenia or schizoaffective disorder will not exceed 50% of the 
enrolled study population, and subjects with mild dyskinesia will not exceed 50% of the enrolled 
study population. 
Enrolled subjects will receive valbenazine orally once a day (qd) at 40, 60, or 80 mg during the 
study as described in Section 6.2.1. 
The study includes a Screening Period of up to 4 weeks, a 24-week Treatment Period, and a 
2-week post-treatment Safety Follow-Up Period. 
A schematic of the study design is shown in Figure 1. 
4.1.1. 
Screening Period  
All subjects must sign an informed consent form (ICF) prior to the conduct of any study-related 
procedures. Subjects will be screened for eligibility up to 4 weeks prior to Day 1 (baseline). 
After informed consent has been provided, subjects will undergo screening assessments to 
determine eligibility as outlined in the Schedule of Assessments (Table 8). The screening visit 
may be conducted anytime up to 28 days prior to first dose. 
The Screening Period may be extended by up to 14 days for certain unavoidable circumstances 
(such as the coronavirus disease-2019 [COVID-19] pandemic) with approval from Sponsor or 
designee. 
Subjects who do not meet entry criteria during the Screening Period may be considered for 
rescreening 1 time with the approval of the Sponsor or designee. 
4.1.2. 
Treatment Period  
Subjects will return to the site on Day 1 for baseline assessments as outlined in the Schedule of 
Assessments (Table 8). Before the subject can begin study treatment on Day 1, the investigator 
must ensure that the subject continues to meet study entry criteria as specified in the study 
inclusion/exclusion criteria (Section 5). 

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Valbenazine will be administered at doses(s) of 40 mg (minimum allowable dose), 60 mg, or 
80 mg (maximum allowable dose) qd as described in Section 6.2.1. Briefly: 
• From Day 1 through Week 4, subjects will take valbenazine 40 mg qd. 
• After the end of Week 4 visit through Week 16, subjects will continue to take 
valbenazine 40 mg qd or the dose may be adjusted to 60 or 80 mg qd. Dose 
adjustments may be performed based on individual treatment needs, response, and/or 
tolerability. 
• After the end of Week 16 visit through Week 24, subjects will take valbenazine 40, 
60, or 80 mg qd; the dose will be assigned by the investigator at the end of Week 16 
visit based on individual treatment needs, response, and/or tolerability observed 
during Weeks 1 to 16. Dose adjustments are not expected from Week 17 through 
Week 24; however, dose decreases are permitted if needed for safety or tolerability. 
Subjects who are unable to tolerate the lowest dose (40 mg qd) at any time will be discontinued 
from study treatment and withdrawn from the study. 
Subjects will have onsite and virtual study visits at scheduled times throughout the 24-week 
Treatment Period as outlined in the Schedule of Assessments (Table 8); study assessments and 
procedures are described in Section 9. 
4.1.3. 
Safety Follow-Up Period  
A Safety Follow-Up Visit for each subject will be conducted 14 days after the final dose of study 
treatment (end of Week 26 [Visit 9]) (Table 8). 
4.2. 
Rationale for Dose Selection  
The FDA-approved INGREZZA® dose range for the treatment of adults with TD will be used in 
this study. The visit schedule has been selected to be consistent with a frequency commonly used 
in clinical practice and based on patient convenience. The dose may be adjusted (as described in 
Section 6.2.1) at onsite office visits. 
4.3. 
Primary Completion and End of Study Definitions  
Primary Completion: The primary completion date is defined as the date when the last subject 
is assessed or receives an intervention for the final collection of data used for the primary 
endpoints, whether the study concluded as planned or was terminated early. The planned primary 
completion date for this study is the date when the last subject has completed the assessments for 
the end of Week 24 visit. If the study is terminated early, then the primary completion date will 
be the date of the last visit for the last subject in the study. 
End of Study: The end of study is defined as the date of the last visit shown in the Schedule of 
Assessments for the last subject in the study globally.

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Figure 1: 
Study Design Schematic  
 
D=study day; EOW=end of study week; qd=once a day; W=study week 
a The Screening Period may be extended by up to 14 days for certain unavoidable circumstances (such as the COVID-19 pandemic) with approval from Sponsor 
or designee. Subjects who do not meet entry criteria during the Screening Period may be considered for rescreening 1 time with the approval of the Sponsor or 
designee.  
b From the end of Week 4 visit until the end of Week 16 visit, dose adjustments may be performed based on individual treatment needs, response, and/or 
tolerability; refer to Section 6.2.1 for additional details. 
c From Week 17 until the end of Week 24, dose adjustments are not expected; however, dose decreases are permitted if needed for safety or tolerability. Refer to 
Section 6.2.1 for additional details. 
d These are virtual visits (ie, telephone contacts). Tolerability and adherence will be assessed to determine whether an unscheduled onsite visit is needed. 

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5. 
STUDY POPULATION  
Subjects must fulfill all inclusion and exclusion criteria to participate in the study. 
5.1. 
Inclusion Criteria  
Subjects must meet all of the following inclusion criteria: 
1. Completed informed consent. 
2. At least 18 years of age. 
3. Have one of the following clinical diagnoses for at least 3 months prior to screening: 
• Schizophrenia or schizoaffective disorder as defined by the DSM-5 
• Bipolar disorder as defined by the DSM-5 
• MDD as defined by the DSM-5 
This criterion will be satisfied if the clinical evaluation from the investigator supports the 
diagnosis and if the subject is able to meet one of the following criteria: 
• Provide a medical record of the diagnosis or confirmation by a letter from a treating 
physician 
• Provide a reliable self- or caregiver-reported medical history with confirmation by 
prescription or pharmacy records of medications taken for the disorder 
If the subject is unable to meet either of these criteria, then the investigator must confirm the 
psychiatric diagnosis based on an evaluation using the Mini International Neuropsychiatric 
Interview (MINI) using the applicable module. 
4. Have a clinical diagnosis of neuroleptic-induced TD as defined by the DSM-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. 
5. Have at least mild TD, defined by an Abnormal Involuntary Movement Scale (AIMS) Item 8 
score of ≥2 at screening, as assessed by an onsite rater and confirmed by an external reviewer 
using a video recording of the subject’s AIMS assessment at screening. This criterion must 
be reconfirmed at baseline as assessed by the onsite AIMS rater only. 
6. Have at least moderate dyskinetic movements as assessed by an onsite rater and confirmed 
by an external reviewer using a video recording of the subject’s AIMS assessment in ≥1 body 
area (≥3 on AIMS) or at least mild dyskinetic movements in ≥2 body areas (≥2 on AIMS) at 
screening. This criterion must be reconfirmed at baseline as assessed by the onsite AIMS 
rater only. 
7. Have awareness of abnormal movements and at least mild distress associated with them as 
defined by an AIMS Item 10 score of ≥2 at screening and baseline. 

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8. Medication(s) for schizophrenia or schizoaffective disorder, bipolar disorder, or MDD and 
other protocol-allowed concurrent medications must meet all of the following criteria: 
• Be at a stable dose for a minimum of 30 days before Day 1: 
− No changes to the dose and frequency of ongoing medications 
− No new or discontinued medications 
• Expected to remain stable during the study 
Benzodiazepines must be at a stable dose equal to or less than the equivalent of 3 mg/day of 
lorazepam for 2 weeks before screening. Barbiturates and opiates must be at a stable dose for 
a minimum of 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). 
9. Subjects must be outpatients and have a stable psychiatric status as clinically determined by 
the investigator. 
10. A body mass index (BMI) of 18.0 to 42.0 kg/m2, inclusive (BMI is defined as the subject's 
weight in kilograms divided by the square of the subject’s height in meters). 
11. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening and 
urine pregnancy test on Day 1 (baseline), for females of childbearing potential. 
12. Female subjects of childbearing potential must agree to use contraception consistently from 
screening until 30 days after the last dose of study treatment or the final study visit, 
whichever is longer. 
Women are considered to not be of childbearing potential if they are either postmenopausal 
(defined as no menses for 12 months without an alternative medical cause and confirmed by 
elevated follicle-stimulating hormone [FSH] consistent with a postmenopausal range) or if 
they have undergone permanent sterilization procedure, such as hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy. 
Highly effective methods of contraception are required for women of childbearing potential: 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) in place for 
at least 3 months before screening. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (which may be oral, intravaginal, or transdermal) initiated 
and used in accordance with medical direction for at least 1 month (with no missed 
doses) before screening. 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(which may be oral, injected, or implanted) initiated and used in accordance with 
medical direction at least 1 month (with no missed doses) before screening. 
• Bilateral tubal occlusion. 
• Total abstinence from sexual intercourse (periodic abstinence is not acceptable). 

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− Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. 
• Sexual partner(s) who had been successfully vasectomized at least 3 months prior to 
screening. 
13. Male subjects must agree to use effective barrier contraception consistently from screening 
until 30 days after last dose of study treatment or final study visit, whichever is longer. 
The acceptable methods of contraception for male subjects are: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film) 
• Vasectomy (successful procedure) at least 3 months prior to screening 
• Total abstinence from sexual intercourse (periodic abstinence is not acceptable) 
− Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. 
14. In the opinion of the investigator, the subject is expected to complete the clinical study as 
designed. 
15. Willing and able to comply with all study procedures and restrictions. 
16. Have adequate hearing, vision, reading, and language skills to perform the procedures 
specified in the protocol. 
5.2. 
Exclusion Criteria  
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Pregnant or breastfeeding or plans to become pregnant during the study. This criterion must 
be reconfirmed before the first dose of study treatment on Day 1. 
2. Known hypersensitivity to any component of the formulation of valbenazine. 
3. Have comorbid Parkinsonism (drug-induced or otherwise) as assessed by the investigator or 
exhibit more than a minimal level of extrapyramidal signs/symptoms, as documented by a 
score on the modified Simpson-Angus Scale (SAS) (excluding Items 8 and 10) >6 at 
screening or Day 1 (baseline). 
4. 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. 
5. Have a Barnes Akathisia Rating Scale (BARS) global clinical assessment score ≥2 at 
screening or Day 1 (baseline). 
6. 
 
7. Have a significant risk of suicidal or violent behavior. Subjects with any suicidal behavior or 
suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific 

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plan) or type 5 (active suicidal ideation with specific plan and intent) based on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) in the 3 months prior to screening (using 
Baseline/Screening version) or Day 1 (baseline) (using Since Last Visit version) will be 
excluded. 
8. Diagnosis of moderate or severe substance use disorder (with the exception of nicotine or 
caffeine dependence) within the 6 months before screening based on the MINI. 
9. Positive urine drug screen (UDS) for disallowed substances, including amphetamines; 
cocaine; methadone; methamphetamine; MDMA; phencyclidine; or nonprescribed 
benzodiazepines, opiates, or barbiturates. If a subject is taking a benzodiazepine at screening, 
they must be on a stable dose equal to or less than the equivalent of 3 mg/day of lorazepam 
for 2 weeks before screening. If subject is taking prescribed barbiturates or opiates, they must 
be at a stable dose for a minimum of 2 weeks before Day 1. 
Note: Subjects testing positive for cannabinoids at screening may be eligible for participation 
in the study if all of the following criteria are met: 
• The subject does not meet the diagnostic criteria for moderate or severe substance use 
disorder within the 6 months before screening based on the MINI 
(exclusion criterion #8) 
• Based on the investigator’s clinical assessment, the subject’s marijuana use is limited 
to ≤3 times per week and is not expected to interfere with their ability to adhere to 
study procedures 
• Marijuana is legal per local law 
10. Have an active, clinically significant unstable medical condition within 1 month (30 days) 
prior to Day 1 (baseline) in the judgement of the investigator, or have any laboratory value 
outside the normal range that is considered by the investigator to be clinically significant at 
the screening visit. 
11. Have any known history of long QT syndrome or cardiac arrhythmia, including uncontrolled 
bradyarrhythmia and heart failure (class IV). 
12. Have a triplicate average electrocardiogram (ECG) corrected QT interval using Fridericia’s 
formula (QTcF) of >450 msec (male subjects) or >470 msec (female subjects) or the 
presence of any clinically significant cardiac abnormality during the Screening Period. 
13. Have a history of severe hepatic impairment or elevation of any of the following laboratory 
tests: 
• Serum creatinine >1.5 × the upper limit of normal (ULN) 
• Serum aspartate aminotransferase (AST) ≥3.0 × ULN 
• Serum alanine aminotransferase (ALT) ≥3.0 × ULN 
• Gamma-glutamyl transferase (GGT) ≥3.0 × ULN 
• Serum total bilirubin >2.0 × ULN. Subjects with a documented diagnosis of Gilbert 
syndrome are not required to meet the bilirubin criteria. 

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14. Any of the following laboratory abnormalities at screening: 
• Hemoglobin <10 g/dL 
• White blood cell (WBC) count <3.0 × 103/mm3 
• Platelet count <100,000/mm3 
• Absolute neutrophil count <1.0 × 103/mm3 
15. Have a hematologic malignancy or solid tumor diagnosed within 3 years before screening or 
not in remission, with the exception of localized skin cancer or carcinoma in situ of the 
cervix that has been excised. 
16. Have any known history of neuroleptic malignant syndrome. 
17. Are currently taking any of the prohibited medications listed in Section 7.1 or have received 
any of these medications within 30 days (unless otherwise stated in Section 7.1) before the 
screening visit. 
18. Has previously participated in this study; has used any active investigational drug in the 
context of a clinical study within 30 days or 5 half-lives before screening, whichever is 
longer; or has participated in 3 or more clinical studies within 12 months before screening. 
This criterion does not pertain to participation in an investigational vaccine clinical study, 
which is allowed if completed more than 30 days before screening. Eligibility based on this 
criterion must be reconfirmed before the first dose of study treatment on Day 1. 
19. Prior (within 1 month of screening) or concomitant use of any VMAT2 inhibitor 
(ie, valbenazine, reserpine, tetrabenazine, deutetrabenazine) or a history of intolerance to 
VMAT2 inhibitors. 
20. In the investigator’s opinion, the subject is not capable of adhering to the protocol 
requirements or considered unsuitable for participation (eg, the subject lacks a stable 
residence, is known to have difficulty complying with treatment or medical procedures, is 
known to provide inaccurate medical information, or is known to attempt participation in 
clinical studies inappropriately). 

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6. 
STUDY TREATMENT  
6.1. 
General Information  
Study treatments are summarized in Table 1. 
Table 1: 
Study Treatments  
Treatment 
Active (Valbenazine) 
Treatment administration 
Valbenazine will be orally self-administered by subjects once per day. 
Unit dose strength 
40 mg, 60 mg, or 80 mg per capsule 
Dose level 
Day 1 through Week 4: 40 mg 
After the end of Week 4 visit through Week 24: 40 mg, 60 mg, or 
80 mg. The dosing schedule is provided in Section 6.2.1. 
Dose formulation 
Valbenazine capsules 
Route of administration 
Oral 
Sourcing 
Provided centrally by Sponsor 
Packaging and labeling 
Bottles containing 35 doses (1 capsule per dose). Study treatment 
labeling will be in accordance with applicable regulatory requirements. 
 
6.2. 
Study Treatment Administration  
Subjects will be instructed to take 1 capsule a day with or without food. Valbenazine should be 
taken at approximately the same time each day during the study; it is recommended that subjects 
take valbenazine at the same time as their oral antipsychotic medication(s), if appropriate. If a 
subject forgets or is unable to take the study treatment on a given day, the subject should not take 
more than 1 dose within the same day and should resume normal dosing the following day. 
Subjects will take their first dose of valbenazine on Day 1. The dosing schedule is summarized in 
Section 6.2.1. 
6.2.1. 
Dosing Schedule  
Subjects will receive valbenazine 40 mg qd for the first 4 weeks of the Treatment Period (Day 1 
through Week 4). 
At each onsite study visit between the end of Week 4 (Visit 4) through the end of Week 16 
(Visit 7), inclusive, the investigator should escalate the subject’s dose to 60 or 80 mg qd if the 
dose escalation criteria below are met; otherwise, the subject should continue receiving their 
current dose. Dose increases are only permitted at scheduled onsite study visits. 
If the subject is unable to tolerate their current dose between Week 5 and the end of Week 16 
visit (Visit 7), the investigator can decrease the subject’s dose. At onsite visits during this same 
timeframe, the investigator may increase the dose again if the dose escalation criteria are met. 

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At the virtual (ie, telephone) study visits, the investigator will assess tolerability and adherence to 
determine whether an unscheduled onsite visit is needed. Unscheduled onsite visits may be used 
to decrease the subject’s dose if needed for tolerability.  
Dose escalation criteria 
All of the following criteria must be met prior to dose escalation: 
• The investigator or designee’s assessment of the Clinical Global Impression of 
Severity – Tardive Dyskinesia (CGI-TD-S) is ≥3 (ie, “mildly ill”, “moderately ill”, 
“markedly ill”, “severely ill”, or “among the most extremely ill patients”), or if the 
subject remains distressed by the presence of TD. 
• The safety and tolerability of the current dose permits a dose increase as determined 
by the investigator. 
• The subject does not meet the criteria for dosage limitations outlined in Section 7.3. 
After the end of Week 16 visit through Week 24, subjects will take valbenazine 40, 60, or 
80 mg qd; the dose will be assigned by the investigator at the end of Week 16 visit based on 
individual treatment needs, response, and/or tolerability observed during Weeks 1 to 16. After 
the end of Week 16 visit through Week 24, it is expected that the dose will remain stable with no 
dosing changes. However, dose decreases are permitted if needed for safety or tolerability. 
Subjects who are unable to tolerate the lowest dose (40 mg qd) at any time will be discontinued 
from study treatment, withdrawn from the study, and assessed as described in Section 8.2. 
The dosing schedule is summarized in Table 2. 
Table 2: 
Dosing Schedule  
Study 
Week 
D1 
(Baseline) 
EOW2 
EOW4 
EOW6 
EOW8 
EOW16 
EOW24/ 
ET 
EOW26/ 
Safety 
Follow-Up 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
Dose (qd) 
40 mg 
40 mg 
40, 60, 
or 80 
mga 
40, 60, 
or 80 mg 
40, 60, or 
80 mga 
40, 60, or 
80 mga,b 
None 
None 
Type of 
Visit 
Onsite 
Virtualc 
Onsite 
Virtualc 
Onsite 
Onsite 
Onsite 
Onsite 
Dispense 
Study 
Treatmentd 
X 
 
X 
 
X 
X 
 
 
D=study day; EOW=end of study week; ET=early termination; qd=once a day 
a From the end of Week 4 visit to the end of Week 16 visit, dose adjustments may be performed based on individual 
treatment needs, response, and/or tolerability. The investigator should escalate the subject’s dose up to 80 mg qd if 
the dose escalation criteria are met or continue with the current dose; dose increases are only permitted at 
scheduled onsite study visits. From Week 5 until the end of Week 16 visit, the investigator can decrease the 
subject’s dose if the subject is unable to tolerate their current dose. At onsite visits during this same timeframe, the 
investigator may increase the dose again if the dose escalation criteria are met. 
b From Week 17 to the end of Week 24, it is expected that the dose will remain stable with no dosing changes. 
However, dose decreases are permitted if needed for safety or tolerability. 

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c The virtual visits (ie, telephone contacts) will be used to assess tolerability and adherence to determine whether an 
unscheduled onsite visit is needed. 
d After the end of Week 4, if the investigator determines that a dose decrease is needed at an unscheduled onsite 
visit, then the subject will return all unused study treatment and receive a bottle of valbenazine at the new dose at 
this visit. 
 
6.3. 
Study Treatment Storage and Compliance  
The designated personnel is responsible for maintaining records of the quantity and dates of all 
study treatment supplies received, dispensed, returned, lost, and destroyed, according to 
applicable regulations and study procedures. Study treatment should be stored in a locked area 
accessible only to the designated pharmacist or qualified personnel. A detailed description of 
how study treatment should be dispensed, stored, and reconstituted, and any stability changes 
will be provided in the Pharmacy Manual. 
6.4. 
Study Treatment Accountability and Return  
Subjects will bring all unused study treatment and empty packaging material to the center at 
specified study visits for study treatment accountability and reconciliation by study center 
personnel. If the investigator determines that a dose decrease is needed at an unscheduled onsite 
visit, then the subject will return all unused study treatment and receive a bottle of valbenazine at 
the new dose at this visit. A compliance check will be performed by counting the capsules 
returned at each scheduled or unscheduled study visit. 
The quantity of study treatment dispensed, used, and returned will be recorded on a dispensing 
log or otherwise documented. The quantity of study treatment lost or destroyed must also be 
accounted for and documented. The designated pharmacist or qualified personnel will be 
responsible for maintaining accurate records of the quantity and dates of all study treatment 
supplies received, dispensed, and returned. 
If unused study treatment is not returned to the Sponsor or designee, alternative disposition of 
study treatment must be documented and follow local laws and regulations. 
6.5. 
Blinding  
This is an open-label study during which the subject/caregiver, investigator, all study center 
personnel, and the Sponsor or designee will be unblinded to the subject’s study treatment 
assignment (valbenazine). 
6.6. 
Procedures for Overdose  
Any dose of study treatment administered in excess of the protocol-specified dose will be 
considered an overdose. 
In the event of a suspected overdose, the investigator and/or treating physician should: 
1. Closely monitor the subject for any AE/SAE and laboratory abnormalities and follow the 
AE reporting process. The study Medical Monitor (or designee) should be contacted for 

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AEs related to an overdose or questions regarding clinical evaluation or management 
related to an overdose. 
2. Document the quantity of the excess dose(s) as well as the date(s) on which additional 
dose(s) were taken, if this information is available. 
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment, as necessary. Decisions regarding study discontinuation, dose interruptions, or dose 
modifications will be made by the investigator in consultation with the Medical Monitor (or 
designee) based on the clinical evaluation of the subject. 

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7. 
SUBJECT RESTRICTIONS  
7.1. 
Prior and Concomitant Medications  
All prescription and over-the-counter medications, dietary supplements (including vitamins), and 
herbal supplements taken by the subject within 30 days before screening will be recorded on the 
Prior and Concomitant Medications page of the electronic case report form (eCRF). All 
medications taken for indications of schizophrenia/schizoaffective disorder, bipolar disorder, 
MDD, extrapyramidal side effects, and TD within the last 2 years will also be entered on the 
appropriate eCRF. Any additions, deletions, or changes in the dose of these medications will be 
entered on the eCRF with indication, dose, route, and dates of drug administration. 
Medications to treat psychiatric and medical conditions: All coexistent diseases or conditions 
should be treated in accordance with prevailing medical practice. All medications should be on a 
stable treatment regimen (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 equal to or less than the equivalent of 3 mg/day of 
lorazepam for 2 weeks before screening. Barbiturates and opiates must be at a stable dose for a 
minimum of 2 weeks before Day 1. 
Investigators should confirm prior and current medications and doses through reliable 
subject-reported information (eg, subject provides a list of medications and doses). 
Prohibited medications: The medication classes listed in Table 3 are prohibited for all subjects 
from 30 days before the screening visit (unless otherwise stated) until the final study visit (or 
early termination [ET]). 
Medically appropriate episodic use of opioids, benzodiazepines, or hypnotics for acute medical 
conditions (eg, tooth extraction, insomnia) is permitted. Otherwise, as needed use of the 
following medication classes is prohibited: anticholinergics, benzodiazepines, opiates, hypnotics, 
antipsychotics, mood stabilizers, antidepressants, tricyclic antidepressants, and strong CYP3A4 
or CYP2D6 inhibitors. A list of strong CYP2D6 and CYP3A4 inhibitors is provided in 
Appendix D. 
Table 3: 
Prohibited Concomitant Medications  
Medication Classes 
Example Medications 
Antiemetics 
Metoclopramide, prochlorperazine, promethazine 
Botulinum toxina 
Botulinum toxin injections 
CYP3A4 strong inducersb 
Phenytoin, phenobarbital, rifabutin, rifampin, primidone, St. John's Wort, 
carbamazepine 
Dopamine agonists and precursors 
Ropinirole, pramipexole, carbidopa/levodopa 
MAOIs 
Isocarboxazid, phenelzine, selegiline, tranylcypromine 
Stimulants 
Amphetamine, methylphenidate, ephedrine 
VMAT2 inhibitors 
Deutetrabenazine, tetrabenazine, reserpine 
CYP=cytochrome P450; MAOI=monoamine oxidase inhibitors; VMAT2=vesicular monoamine transporter 2 
a Botulinum toxin injections are prohibited from 90 days prior to screening. 
b A list of strong CYP3A4 inducers is provided in Appendix D. 

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Restricted concomitant medications: Benzodiazepines, opioids, and hypnotics are not 
permitted within 4 hours before the start of any assessment related to the primary, secondary, or 
other endpoints (Sections 11.4.1 to 11.4.3) on Day 1 (baseline; Visit 2) through the end of 
Week 24 (Visit 8) (or the ET visit). 
Digoxin: Concomitant use of valbenazine with digoxin increases digoxin levels, which may 
increase the risk of adverse reactions. When digoxin is coadministered with valbenazine, digoxin 
levels should be monitored and the dosage of digoxin adjusted if necessary. 
7.2. 
Dietary and Other Restrictions  
There are no dietary restrictions. 
On the day of study visits, subjects may not use marijuana or alcohol until all assessments have 
been completed. If a subject appears intoxicated at a study visit, efficacy assessments should not 
be performed that day and the site should reschedule these assessments to the next day (or within 
the window defined in the Schedule of Assessments (Table 8). 
Subjects should adhere to the following prohibitions and restrictions during the study in order to 
be eligible to participate: 
• Male subjects must agree to refrain from donating sperm during the study and for 
30 days after the last dose of the study treatment. 
• Not to participate in an investigational drug study for at least 30 days after the last 
dose of study treatment or 30 days after study completion, whichever is longer. 
7.3. 
Dosage Limitations in Specific Populations  
Subjects in the following populations will receive a maximum dose of 40 mg valbenazine 
throughout the study: 
• Subjects with moderate hepatic impairment 
• Subjects who are known CYP2D6 poor metabolizers. 
− In the situation where CYP2D6 metabolizer status cannot be determined from the 
study laboratory testing, management of these subjects should be discussed with 
the study Medical Monitor (or designee) prior to the initiation of study treatment 
(before Visit 2). 
• Subjects who are receiving strong CYP2D6 inhibitors or strong CYP3A4 inhibitors at 
screening or Day 1 and expected to continue throughout the study. The investigator 
should discuss subject management with the Medical Monitor (or designee) for any 
subjects who start or stop receiving systemic strong CYP2D6 or strong CYP3A4 
inhibitors during the study. A list of strong CYP2D6 and CYP3A4 inhibitors is 
provided in Appendix D. 

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8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL  
At any time during the study, subjects can discontinue study treatment or withdraw their consent 
to participate in the study. The investigator must discontinue study treatment or withdraw any 
subject from the study at their request. 
Subjects who discontinue study treatment will be withdrawn from the study. 
8.1. 
Discontinuation of Study Treatment  
If a subject prematurely discontinues study treatment, the investigator will record the reason for 
discontinuation on the relevant eCRF. 
Subjects who are unable to tolerate the lowest dose (40 mg qd) at any time will be permanently 
discontinued from study treatment. 
Subjects permanently discontinuing study treatment should be assessed as described in 
Section 8.2 and then withdrawn from the study. 
Reasons for discontinuation from study treatment include, but are not limited to: 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Site termination by the Sponsor 
• Study termination by the Sponsor 
• AE 
• Pregnancy 
• Lack of efficacy 
• Protocol deviation 
The investigator must discontinue study treatment 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 lowest allowable dose (40 mg) 
• QTcF of >500 msec (cardiologist verified) on any ECG tracing 
• If the subject is confirmed to be pregnant 
• Withdrawal of consent/assent for study treatment administration by 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 

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The investigator or Sponsor may discontinue study treatment for other reasons as described 
below. These should be discussed on a case-by-case basis with the Sponsor medical monitor 
(or designee) prior to withdrawing the subject from the study. 
• Have any of the following laboratory abnormalities: 
− ALT or AST ≥5 × ULN and considered possibly or definitely treatment-related 
− GGT ≥3.0 × ULN 
− Serum total bilirubin >2.0 × ULN 
− Serum creatinine value >1.5 × ULN 
• Requires a medication that is prohibited by the protocol 
• Is noncompliant with the dosing regimen (<80% dosing compliance) as verified by 
study treatment accountability (ie, counting the capsules returned at each study visit) 
Every effort should be taken to obtain follow-up data for any subject who discontinues study 
treatment because of an AE, abnormal laboratory test, vital sign measurement, physical 
examination, or ECG finding. 
8.2. 
Withdrawal from Study  
Subjects who discontinue study treatment will be withdrawn from the study. 
If a subject prematurely withdraws from the study, the investigator will record the reason for 
withdrawal on the relevant eCRF. All subjects who withdraw from the study prematurely will be 
asked to have all ET assessments performed and, unless consent has been withdrawn, will be 
asked to come back approximately 2 weeks after their last dose for a follow-up visit. If a 
subject’s last dose of study treatment was >2 weeks before the ET visit, no additional visit is 
needed. 
Reasons for withdrawal from the study include, but are not limited to: 
• Withdrawal of consent by subject 
• AE 
• Death 
• Lost to follow-up 
• Site terminated by Sponsor 
• Study terminated by Sponsor 
• Protocol deviation 
• Investigator decision 

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8.3. 
Sponsor’s Termination or Temporary Halt of Study or Study Site  
The Sponsor or designee reserves the right to close a study site, terminate, or temporarily halt the 
entire study, or terminate or temporarily halt the study at individual sites, at any time for any 
reason. If the study is prematurely terminated or temporarily halted, the Sponsor shall promptly 
inform the investigators, the Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), the regulatory authorities, and any contract research organizations (CROs) used in the 
study of the reason for termination or temporary halt, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the subject and should assure appropriate 
therapy and/or follow-up. 

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9. 
STUDY ASSESSMENTS AND PROCEDURES  
A schedule of assessments is provided in Table 8 (Appendix A). No study procedures should be 
performed until after the subject has signed the ICF. Subject-related events and activities 
including specific instructions, procedures, concomitant medications, dispensing of study 
treatment, and descriptions of AEs should be recorded in the appropriate source documents and 
eCRFs. 
9.1. 
Screening Assessments  
9.1.1. 
Mini International Neuropsychiatric Interview for Psychotic Disorders  
The MINI is brief structured diagnostic interview for the major psychiatric disorders (including 
schizophrenia) in the revised DSM-5 and International Statistical Classification of Diseases and 
Related Health Problems, Tenth Edition (ICD-10) (Sheehan et al., 1998). Validation and 
reliability studies have been done comparing the MINI to other well-known psychiatric 
diagnostic interviews. The results of these studies show that the MINI has similar reliability and 
validity properties to these instruments, but it can be administered in a much shorter period of 
time and clinicians can use it after a brief training session (Sheehan et al., 1997; 
Lecrubier et al., 1997). 
The MINI should be administered by a healthcare professional with a clinically relevant 
qualification (eg, psychiatrist, psychiatric nurse, or psychologist) and documented experience 
assessing patients with schizophrenia, schizoaffective disorder, bipolar disorder, or MDD. Raters 
must be trained and certified for administration of MINI. 
If a subject is unable to confirm their psychiatric diagnosis (ie, schizophrenia or schizoaffective 
disorder, bipolar disorder, or MDD) as outlined in inclusion criterion #3, then the applicable 
module of the MINI will be used at screening to evaluate the presence of psychiatric disorders in 
order to assess the appropriateness of the subject for inclusion. 
The MINI will also be used to assess the presence of moderate or severe substance use disorder 
as outlined in exclusion criterion #8. 
9.1.2. 
Abnormal Involuntary Movement Scale  
The severity of TD will be assessed using the AIMS rating scale (Guy, 1976a). 
9.1.2.1. 
AIMS Individual Items  
The AIMS includes a total of 12 items and takes approximately 10 minutes to complete. 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) scores range from 0 (none, 
normal) to 4 (severe) and Item 10 is 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. 

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9.1.2.2. 
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. 
9.1.2.3. 
Administration and Scoring of the AIMS  
Administration and recording of the AIMS will be performed according to standardized 
guidelines to reduce variability across subjects, time points, and sites. 
Specific time points for collection are provided in Table 8. At each scheduled assessment, the 
AIMS should be the first procedure to be administered. If possible, the same person should 
administer the AIMS for a given subject at all time points. 
The AIMS assessment will be video recorded at the screening visit only. 
9.1.2.3.1. Onsite AIMS Rater  
An onsite AIMS rater (ie, the study investigator or designee) will score AIMS Items 1 to 10 and 
complete AIMS Items 11 to 12. Every effort should be made to have the same person rate the 
AIMS for a given subject throughout the study. 
9.1.2.3.2. External AIMS Reviewer  
An external AIMS reviewer will independently review AIMS Items 1 to 8 using a video 
recording of the AIMS assessment at screening. This assessment will be performed to confirm 
the TD severity required for study entry as outlined in inclusion criteria #5 and #6. Although the 
onsite rater will score the AIMS at screening, only the external AIMS reviewer’s assessment will 
be used to determine study eligibility with respect to inclusion criteria #5 and #6. 
The reviewer will be blinded to all other information about the subject. 
9.1.3. 
CYP2D6 Genotyping  
Blood samples for analysis of CYP2D6 metabolizer status (ie, poor, intermediate, normal, or 
ultrarapid metabolizer) will be collected during screening (Table 8). The CYP2D6 genotype 
status will be used to inform the pharmacokinetic (PK) assessment results but will not inform 
study participation. Management of subjects identified as CYP2D6 poor metabolizers and those 
who CYP2D6 metabolizer status cannot be determined are discussed in Section 7.3. 
9.2. 
Efficacy Assessments  
9.2.1. 
Tardive Dyskinesia Impact Scale  
The Tardive Dyskinesia Impact Scale (TDIS) is a disease specific patient-reported outcome 
under development by NBI that assesses the impact of impairment and disability associated with 
dyskinesia (Stull et al., 2021a; Stull et al., 2021b; data on file). It defines impact of TD in terms 
of 6 dimensions: Mouth/Throat Function (3 items), Dexterity (2 items), Mobility (2 items), 
Emotional (2 items), Pain (1 item), and Social (1 item). Each item measures the impact of 

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dyskinetic movements in terms of difficulty or frequency over the last 7 days on a 5-point scale, 
with scores ranging from 0 to 4. Response options for the difficulty items range from not at 
all (0) to extremely (4); those for the frequency items range from never (0) to all of the time (4). 
The TDIS total score is the sum of the scores of TDIS Items 1 to 11. Scores can range from 0 to 
44, with higher scores representing greater TD impact. 
Specific time points for collection are provided in Table 8. 
9.2.2. 
Sheehan Disability Scale  
The Sheehan Disability Scale (SDS) is a brief, validated, patient-reported 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 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 3 items. 
Specific time points for collection are provided in Table 8. 
9.2.3. 
EQ-5D-5L and EQ-VAS  
The 5-level EQ-5D version (EQ-5D-5L) is a general, single index, validated patient-reported 
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 
100 hash-marked, vertical EQ-visual analogue scale (EQ-VAS). The endpoints are labeled 
‘The best health you can imagine’ and ‘The worst health you can imagine.’ 
Specific time points for collection are provided in Table 8. 
9.2.4. 
Patient Global Impression of Change  
In the Patient Global Impression of Change-Tardive Dyskinesia (PGI-C), subjects will rate the 
change in their TD symptoms from the initiation of study treatment dosing by choosing one of 7 
responses (very much improved, much improved, minimally improved, not changed, minimally 
worse, much worse, and very much worse). 
Specific time points for collection are provided in Table 8. 
9.2.5. 
Clinical Global Impression of Change - Tardive Dyskinesia  
The Clinical Global Impression of Change – Tardive Dyskinesia (CGI-TD-C), which is based on 
a 7-point scale (range: 1=very much improved to 7=very much worse), will be used to rate the 

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overall global change in TD since the initiation of study treatment dosing. This scale is an 
adaptation of a scale developed by the Psychopharmacology Research Branch of the National 
Institute of Mental Health to rate the subject’s overall improvement in clinical disorder and 
provides a global evaluation of change over time from the clinician’s perspective (Guy, 1976b). 
The investigator or qualified clinician designee (eg, psychologist or social worker) will rate the 
scale at the scheduled time points. If possible, the same person should rate the CGI-TD-C at all 
visits. 
Specific time points for collection are provided in Table 8. 
9.2.6. 
Clinical Global Impression of Severity - Tardive Dyskinesia  
The CGI-TD-S, which is based on a 7-point scale (range; 1=normal, not at all ill to 7=among the 
most extremely ill patient), will be used to rate the overall global severity of TD. This scale is a 
modification of a scale developed by the Psychopharmacology Research Branch of the National 
Institute of Mental Health (Guy, 1976b). The investigator or qualified study site personnel will 
rate the scale at the scheduled times. If possible, the same person should rate the CGI-TD-S at all 
visits. 
• The investigator or designee’s assessment of the Clinical Global Impression of 
Severity – Tardive Dyskinesia (CGI-TD-S) is ≥3 (ie, “mildly ill”, “moderately ill”, 
“markedly ill”, “severely ill”, or “among the most extremely ill patients”), or if the 
subject remains distressed by the presence of TD. 
Specific time points for collection are provided in Table 8. 
9.2.7. 
  
9.2.8. 
  

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9.2.9. 
Abnormal Involuntary Movement Scale  
Refer to Section 9.1.2 for details. 
9.3. 
Safety Assessments  
For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments 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 study treatment-
emergent suicidal behavior or clinically significant suicidal ideation. 
9.3.1. 
Vital Sign Measurements  
Vital signs will be measured for the following: systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature. Blood pressure and pulse rate 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 standing, if possible. Body temperature may be measured 
orally or at the forehead, ear, or rectum. 
Vital sign measurements will be obtained before any scheduled blood sample collection at 
screening and then at the time points specified in the Schedule of Assessments (Table 8). 
9.3.2. 
Medical History  
A medical history will be taken at the screening visit and updated on Day 1 (baseline) and as 
needed throughout the study. 
9.3.3. 
Physical Examination, including Height and Weight  
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system. The physical 
examination schedule is provided in Table 8. 
Height will be measured at screening only. Height and weight will be measured with subjects not 
wearing shoes; and weight will be measured with subjects not wearing outerwear (eg, jackets or 
coats). 
9.3.4. 
Electrocardiogram  
A standard 12-lead ECG will be conducted in triplicate (obtained at least 3 minutes apart and 
within a total time of 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 

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of these parameters, the investigator will note if the ECG is Normal, Abnormal not Clinically 
Significant, or Abnormal Clinically Significant. If the ECG is Abnormal Clinically Significant, 
the investigator will provide a description of the abnormality recorded on the AE eCRF. 
9.3.5. 
Clinical Laboratory Assessments  
All clinical laboratory assessments will be performed by a central laboratory. 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 following clinical safety laboratory 
assays will be performed: 
Hematology: complete blood count including WBC count with differential, red blood cell count, 
hemoglobin, hematocrit, and platelet count, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, mean corpuscular volume, red cell distribution width, mean platelet 
volume. 
Clinical Chemistry: sodium, potassium, calcium, magnesium, phosphorus, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate 
dehydrogenase, AST, ALT, GGT, creatine kinase, total bilirubin, total protein, and glucose. 
The following additional laboratory tests will be performed: 
Thyroid stimulating hormone: A thyroid stimulating hormone level will be measured at 
screening. 
Drug Screen: The UDS will test for amphetamines, barbiturates, cocaine, marijuana, methadone, 
methamphetamine, MDMA, phencyclidine, benzodiazepines, and opiates. The UDS will be 
performed at screening and may be repeated at any time at the investigator’s clinical judgment 
The UDS will be analyzed by the central laboratory. 
Prolactin: Serum prolactin samples will be shipped to a central laboratory for analysis. Prolactin 
results will remain blinded to investigators, subjects, CRO(s), and the Sponsor until database 
lock. 
Pregnancy Test: Pregnancy tests will be performed throughout the study for female subjects of 
childbearing potential. A serum β-hCG pregnancy test will be performed at screening and a urine 
pregnancy test (using a urine pregnancy kit provided by the central laboratory) will be performed 
at the time points indicated in Table 8. 
9.3.6. 
Barnes Akathisia Rating Scale  
The BARS is a validated 4-item scale to assess the presence and severity of drug-induced 
akathisia (Barnes, 1989). This scale includes both objective items (eg, observed restlessness) and 
subjective items (eg, subject’s awareness of restlessness and related distress), together with a 
global assessment of akathisia. Global assessment is made on a scale of 0 to 5 (0=absent; 
1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe 
akathisia). 
Specific time points for collection are provided in Table 8. The investigator or other qualified 
site personnel will administer and score the BARS. If possible, the same person should 
administer and score this scale at all time points. 

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9.3.7. 
Modified Simpson-Angus Scale  
The SAS is a clinician-administered rating scale that has been widely used to assess 
antipsychotic-induced parkinsonism in clinical practice and research settings 
(Simpson and Angus, 1970). The present study uses a modified 10-item version of the SAS (for 
the screening and Day 1 assessment of eligibility) in which “Leg Pendulousness” and “Head 
Dropping” items included in the original version have been replaced with “Head Rotation” and 
“Akathisia,” and has been used frequently in schizophrenia clinical trials 
(Moore and Furberg, 2017). Each item is rated using a 5-point scale (0-4); the modified SAS 
scores can range from 0 to 40. 
Specific time points for collection are provided in Table 8. The investigator or other qualified 
site personnel will administer and score the modified SAS. If possible, the same person should 
administer and score the scales at all time points. 
9.3.8. 
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 one or more screening 
questions will prompt additional questions that evaluate frequency and intensity of suicidal 
ideation and/or behavior. 
Of note, the Since Last Visit version of the C-SSRS will be administered at baseline and visits 
throughout the study, but the lookback period will be since the last C-SSRS assessment, not 
since the subject’s last visit. 
The C-SSRS will be administered and scored by the investigator or qualified study site 
personnel. If possible, the same person should administer and score the scale at all time points. 
Specific time points for collection are provided in Table 8.  
9.4. 
Pharmacokinetic Assessments  
Blood samples for determination of plasma concentrations of valbenazine and metabolites will 
be collected at the time points identified in the Schedule of Assessments (Table 8) or at ET. 
For each sample, approximately 2 mL of blood will be collected in tubes containing dipotassium 
ethylenediaminetetraacetic acid (EDTA K2). The exact time of sampling in hours and minutes 
will be recorded for all PK plasma samples. A PK sample should be collected from subjects who 
withdraw early. 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. 

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9.5. 
Caregiver Assessments  
9.5.1. 
  
9.5.2. 
 
  
9.6. 
Specific Study Period Information  
A complete list of study assessments to be performed at the study site during the study periods 
and study visits is provided in the Schedule of Assessments (Table 8). 
9.6.1. 
Screening Period (Week -4 to Day -1)  
The ICF will be reviewed with subjects and must be signed before the start of any screening 
procedures. 
After providing informed consent, subjects will undergo screening assessments (Table 8) that 
may be completed in 1 or more visits during the Screening Period of up to 4 weeks. The 
Screening Period may be extended by up to 14 days for certain unavoidable circumstances (such 
as the COVID-19 pandemic) with approval from the Sponsor or designee. 
The AIMS assessment should be the first procedure to be administered and will be video 
recorded at the screening visit. A single onsite AIMS rater will score AIMS Items 1 to 10 and 
complete AIMS Items 11 to 12. An external AIMS reviewer will independently review and 
confirm the subject’s TD severity using the video recording of the AIMS assessment at 

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screening; only the external AIMS reviewer’s assessment will be used to determine eligibility 
with respect to inclusion criteria #5 and #6. 
Vital signs should be collected prior to the collection of blood for clinical laboratory tests. 
If applicable, the subject’s caregiver should be asked to complete the optional caregiver 
assessments 
 during the Screening Period or on Day 1 and at the end of 
Week 24. 
Eligible subjects will return to the study site on Day 1 (Visit 2) for baseline assessments. 
9.6.1.1. 
Screen Failures and Rescreening  
Subjects who do not meet entry criteria during the Screening Period may be considered for 
rescreening 1 time with the approval of the Sponsor or designee. 
9.6.2. 
Study Treatment Period (Day 1 to End of Week 24)  
Subjects will return to the study site on Day 1 (Visit 2) for baseline assessments. Before the 
subject can begin study treatment, the investigator must ensure that the subject continues to meet 
study entry criteria as specified in Section 5. 
As described in Section 7.1, if the subject has taken any restricted concomitant medications 
within 4 hours of any onsite visit during the Treatment Period, then the site should delay or 
reschedule these study visit assessments within the window defined in the Schedule of 
Assessments (Table 8). 
At each visit, subjects will undergo assessments as outlined in Table 8. At each scheduled onsite 
visit, the AIMS should be the first procedure to be administered. The remaining key efficacy 
assessments (TDIS, SDS, EQ-5D-5L [including the EQ-VAS], PGI-C, CGI-TD-S, CGI-TD-C, 
 and 
 should be performed before any other study procedures or assessments. Key 
safety assessments include evaluation of vital signs, ECGs, clinical laboratory tests, physical 
examination, concomitant medications, and AEs. In addition, the following safety assessments 
will be administered: C-SSRS (Since Last Visit version), BARS, and modified SAS. The 
optional caregiver assessments, as described in Section 9.5, may be administered on Day 1 and at 
the end of Week 24. 
At each onsite study visit between the end of Week 4 (Visit 4) through the end of Week 16 
(Visit 7), inclusive, the investigator should adjust the subject’s dose as appropriate based on 
individual treatment needs, response, and/or tolerability as described in Section 6.2.1. Dose 
increases are only permitted at scheduled onsite study visits. No dose adjustments are permitted 
after the end of Week 16 visit. 
At the virtual study visits, the investigator will assess tolerability and adherence to determine 
whether an unscheduled onsite visit is needed. If an unscheduled onsite visit is needed, the 
following assessments are required: vital signs (blood pressure, pulse, and temperature), 
concomitant medications, AE monitoring, C-SSRS Since Last Visit Version, and study treatment 
accountability. 

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9.6.3. 
End of Study/Follow-Up Period (Week 26)  
Subjects will return to the study site 14 days after their last dose of study treatment for the Safety 
Follow-Up Visit (end of Week 26 [Visit 9]). Key safety assessments performed at this visit 
include evaluation of AEs and the C-SSRS (Table 8). 

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10. 
ADVERSE EVENTS  
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject has signed the 
ICF until the subject’s final study visit/contact (or upon ET). 
10.1. 
Definition  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that occurs after enrollment into the study and which does 
not necessarily have a causal relationship with the study 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, any of the following: 
• Worsening or change in nature, severity, or frequency of conditions present at the 
start of the study 
• Subject deterioration beyond what would be expected due to the primary illness 
• Intercurrent illness 
• Drug interaction 
All suicidal behaviors and clinically significant suicidal ideations will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms. Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
treatment, 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 treatment. 
The following are not considered AEs: 
• Continuous persistent disease/symptom present before study treatment administration, 
unless it unexpectedly progresses, or increases in severity following study treatment 
administration 
• Study treatment failure or lack of efficacy 
• Pregnancy 
• Overdose of either study treatment or concomitant medication without any clinical signs 
or symptoms 

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10.1.1. 
Intensity of Adverse Events  
Adverse events must be graded for intensity. An intensity category of mild, moderate, or severe, 
as defined in Table 4, must be entered on the AE eCRF. It should be noted that the term “severe” 
used to grade intensity is not synonymous with the term “serious.” 
Table 4: 
Intensity of Adverse Events  
Grade 
Intensity 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AE=adverse event 
10.1.2. 
Relationship to Study Treatment  
The investigator will document his/her opinion of the relationship of the AE to study treatment 
using the criteria outlined in Table 5. An AE is deemed associated with the use of the study 
treatment “if there is a reasonable possibility that the treatment caused the AE” (otherwise 
referred to as a suspected adverse reaction). Reasonable possibility means there is evidence to 
suggest a causal relationship between the study treatment and the AE (Title 21 Code of Federal 
Regulations [CFR] 312.32 [a]). 
 
Table 5: 
Relationship of Adverse Events to Study Treatment  
Relationship 
Description 
Definite 
The AE follows a reasonable temporal sequence from administration of the study 
treatment, abates upon discontinuation of the study treatment, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the study 
treatment is reintroduced. 
Possible 
The AE follows a reasonable temporal sequence from administration of the study 
treatment and cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental, or toxic factors, or other modes of therapy 
administered to the subject. There should be some evidence to support a causal 
relationship between the study treatment and the AE. 
Unlikely 
The temporal sequence between the AE and the study treatment is such that the 
study treatment is not likely to have any reasonable association with the AE or other 
plausible explanations exist for the AE (eg, disease, other drugs). 

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Relationship 
Description 
Not related 
The AE does not follow a reasonable temporal sequence from administration of the 
study treatment, may not abate upon discontinuation of the study treatment, does not 
follow a known or hypothesized cause-effect relationship, and (if applicable) may 
not reappear when the treatment is reintroduced, furthermore, there may exist a clear 
alternative medical explanation (eg, underlying disease state) or association with 
study procedure or study conduct. 
AE=adverse event 
 
10.2. 
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 only in the source document. The investigator (or 
designee) will provide information on dates of onset and resolution, intensity, seriousness, 
frequency, action(s) taken, changes in study treatment usage, relationship to study treatment, and 
outcome. 
10.3. 
Poststudy Follow-Up of Adverse Events  
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up. 
Adverse events ongoing at the final visit or at ET will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes, resolves, or the subject is 
lost to follow-up. The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the 
AE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals, as is practical. 
10.4. 
Serious Adverse Events  
All SAEs will be recorded from the time the subject has signed the ICF until the final study visit. 
Investigators are not obligated to actively seek SAEs after a subject has withdrawn from or 
completed the study. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been withdrawn from or has completed the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the Sponsor as described in Section 10.4.3. 
10.4.1. 
Definition of a Serious Adverse Event  
An SAE is any AE that results in any of the following outcome: 
• Death 
• A life-threatening AE. Life-threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred. It 

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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. 
10.4.2. 
Managing Serious Adverse Events  
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The physician in attendance will do whatever is medically needed for the safety 
and well-being of the subject. The subject will remain under observation as long as medically 
indicated. Appropriate laboratory studies will be conducted until all parameters return to normal 
or are otherwise explained or stable. The subject will be followed until the SAE resolves or until 
the subject is medically stabilized. 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
SAEs must be reported immediately and no later than 24 hours of knowledge of the event under 
any circumstances, and pregnancies must be reported within 24 hours of first knowledge of the 
event by study personnel to NBI Drug Safety and Pharmacovigilance (DSPV). Reports of SAEs 
and pregnancies must be followed by a fax or email of the SAE or Pregnancy Form (Table 6). It 
is important that the investigator provides his/her assessment of relationship to study treatment at 
the time of the initial SAE report. The investigator (or designee) will also notify the IRB/IEC, if 
necessary) of the SAE and the outcome of the SAE, as required by the IRB/IEC. 
Additionally, the following categories of medical events that could occur during participation in 
a clinical study must be reported within 24 hours to the study Medical Monitor (Table 6). 

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• 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. 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance and Medical 
Monitor  
Drug Safety and Pharmacovigilance 
Facsimile 
Email 
 
+1 (888) 617-7551 or +1 (858) 617-7561 
cds@neurocrine.com 
Study Medical Monitor 
+1 (973) 659-6677 or +1 (512) 652-0191 
10.4.4. 
Expedited Safety Reports  
The Sponsor or its representatives will submit an Expedited Safety Report for any suspected 
adverse reaction (Section 10.1.2) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life-threatening experience within 7 calendar 
days to the applicable regulatory authority(ies); or according to country-specific regulations. 
The Sponsor or its representatives will send copies of each safety report submitted to regulatory 
authorities to the investigators. The safety report must be submitted to the appropriate IRB/IEC 
as soon as possible. Documentation of the submission to the IRB/IEC and receipt by the 
IRB/IEC (if applicable) must be retained for each safety report. 
10.5. 
Urgent Safety Measures  
If an event occurs that is related to the conduct of the study or the development of the study 
treatment, and this new event is likely to affect the safety of subjects, the Sponsor and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard. The Sponsor will work with the investigator to ensure the IRB/IEC and local 
regulatory authority is notified within 3 days or in accordance with applicable local laws and 
regulations. 
10.6. 
Pregnancy  
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met. However, all 
pregnancies in subjects who received valbenazine will be followed to assess for pregnancy 
outcome. Subjects of childbearing potential must be counseled at all visits to continue using 
contraception until 30 days after the last dose of study treatment or final study visit, whichever is 
longer (inclusion criteria #12 and #13, Section 5.1). If a female subject believes she is pregnant 
at any time between signing the ICF and the last study visit, she should return to the study center 
within 24 hours and undergo a serum pregnancy test. Female subjects confirmed to be pregnant 
will be discontinued from the study treatment and withdrawn from the study. 
All confirmed pregnancies in female subjects or in female partners of male subjects who 
received study treatment must be immediately reported to NBI (contact information is provided 
in Section 10.4.3), followed by fax or email of the pregnancy form to NBI DSPV. A first 
trimester ultrasound may be requested for all confirmed pregnancies. Pregnancies in subjects 

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who received valbenazine will be followed until resolution (ie, termination [voluntary or 
spontaneous] or birth). 
Male subjects with female partners who become pregnant during the study must notify the study 
center as soon as possible. The study center will ask to follow the subject’s partner’s pregnancy. 

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11. 
STATISTICAL METHODS  
This section represents a brief description of the planned primary analysis of the primary and 
secondary objectives. A comprehensive and detailed statistical analysis plan (SAP) will be 
generated and finalized prior to study database lock. The SAP will provide additional details 
regarding the methods of analysis summarized in this protocol, will describe analysis methods 
for other endpoints, will describe analyses to characterize the study conduct and population, and 
may describe sensitivity and supplementary analyses for selected endpoints. 
11.1. 
Statistical Hypothesis and Estimands  
Not applicable because this is a single-arm estimation study. 
11.2. 
Sample Size Determination  
The sample size for this open-label, single-arm study is not based on power calculations, but on 
clinical and logistical considerations. 
Assuming that 74% of subjects complete the Week 24 assessments, approximately 60 subjects 
will be enrolled to achieve a total of 44 subjects for the primary analysis. 
For example, for the primary endpoint of change from baseline in TDIS at Week 24, a sample 
size of 44 subjects will provide a 2-sided 95% confidence interval (CI) that extends 2.5 from the 
observed mean, assuming that the standard deviation (SD) is known to be 8.55 and the CI is 
based on the large sample Z statistic. In an NBI-sponsored open-label study of subjects with 
neuroleptic-induced TD and either schizophrenia/schizoaffective disorder or mood disorder who 
received valbenazine for 48 weeks (Study NBI-98854-1402 [KINECT 4]), the change from 
baseline at Week 24 in TDIS ranged from -6.3 to -11.1 depending on valbenazine dose and 
disease category, with an SD of approximately 8.55. 
11.3. 
Analysis Sets  
Statistical analysis sets are defined in Table 7. Additional analysis sets may be specified in the 
SAP. 
Table 7: 
Analysis Sets  
Population 
Description 
Full analysis set 
The full analysis set includes all enrolled subjects with relevant 
baseline and postbaseline data. Subjects will be analyzed 
regardless of adherence to study treatment administration. 
Safety analysis set 
The safety analysis set will include all enrolled subjects who take 
at least 1 dose of study treatment. 

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11.4. 
Endpoints  
11.4.1. 
Primary  
• Change from baseline in the TDIS total score at Week 24 
• Change from baseline in the SDS Items 1, 2, and 3 at Week 24 
• Change from baseline in the EQ-VAS score at Week 24 
11.4.2. 
Secondary  
• PGI-C score at Week 24 
• Change from baseline in the CGI-TD-S score at Week 24 
• Change from baseline in the AIMS dyskinesia total score at Week 24 
11.4.3. 
  
11.4.4. 
Safety  
Safety endpoints include the occurrence of AEs, observed and changes from baseline in clinical 
laboratory tests (hematology and clinical chemistry), vital sign measurements (including blood 
pressure and pulse rate), 12-lead ECG parameters, and scores from the C-SSRS, BARS, and 
modified SAS. 
11.5. 
Statistical Analyses  
Descriptive statistical methods will be used to summarize the data from this study. Descriptive 
statistics typically include the number of subjects (n), mean, SD or standard error (SE), median, 
first (Q1) and third (Q3) quartile, minimum, maximum, and CIs for continuous variables; and 
refers to the number and percentage of subjects for categorical variables. 

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11.5.1. 
Efficacy Analyses  
This section is a summary of the planned statistical methods for the primary analysis of the 
primary and secondary endpoints. Additional details of the analyses will be described in the 
SAP. 
11.5.1.1. Procedure to Control for Multiple Comparisons  
There are no planned inferential analyses of the data. 
11.5.1.2. Primary Endpoints  
Descriptive statistics (including both categorical variable statistics [using response categories (to 
be defined in SAP)] and continuous variable statistics [using numerical scores]) will be presented 
for change from baseline in the TDIS total score; SDS Items 1, 2, and 3 scores; and the EQ-VAS 
score at the end of Weeks 4, 8, 16, and 24. Two-sided 95% CIs will be included in the 
descriptive statistics for changes from baseline. 
Descriptive statistics (including CIs for changes from baseline) will also be presented by disease 
category (schizophrenia/schizoaffective disorder or MDD/bipolar disorder). 
11.5.1.3. Secondary Endpoints  
Descriptive statistics for the PGI-C score and change from baseline in the CGI-TD-S score and 
the AIMS dyskinesia total score will presented overall and by disease category 
(schizophrenia/schizoaffective disorder or MDD/bipolar disorder). Two-sided 95% CIs will be 
included in the descriptive statistics for changes from baseline.  
The AIMS dyskinesia total score is defined as the sum of the scores of AIMS items 1 to 7. If any 
of the seven items has a missing value, the total score for that subject/visit will be set equal to 
missing. 
11.5.2. 
Safety Analyses  
Safety data will be analyzed using the safety analysis set. The subject incidence of treatment-
emergent AEs will be tabulated for AEs, SAEs, fatal AEs, and AEs leading to discontinuation of 
study treatment. Descriptive statistics will be generated for additional safety data, including 
selected laboratory analytes, vital signs, ECG parameters, and scores from the C-SSRS, BARS, 
and modified SAS assessments, which will be further described in the SAP. 
11.6. 
Interim Analyses  
There is no planned interim analysis. 

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12. 
SUPPORTING DOCUMENTATION  
12.1. 
Case Report Forms  
The eCRF data for this study are being collected with an electronic data capture (EDC) system. 
The EDC system and the study-specific eCRFs will comply with US FDA Title 21 CFR Part 11 
and the applicable laws and regulations of the country in which the study is conducted. 
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 may be loaded electronically into the appropriate eCRFs. All data 
entered into the eCRF will be supported by source documentation. The investigator should 
review the eCRFs as soon as possible after the subject visit has occurred and electronically sign 
the eCRFs as soon as possible after the subject completes or discontinues from 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 the Sponsor (or designee). The Sponsor 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/her 
electronic signature on the eCRFs as evidence thereof. 
Access to the EDC system will be provided for the duration of the study through a password-
protected method of internet access. Such access will be removed from study centers at the end 
of the center’s participation in the study. Data from the EDC system will be archived on 
appropriate data media or uploaded to a secure location with restricted access, in order to provide 
the investigator with a durable record of the center’s eCRF data. 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
regulations. This includes an inspection by the Sponsor 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 the Sponsor. 
12.2. 
Data Capture, Review, and Validation  
Data entered in the EDC system will be verified against the source data by the Sponsor (or 
designee); the percentage of source data verification will be determined by risk assessment. Any 
discrepancies will be corrected online by authorized study center personnel. After data is entered 
into EDC, 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 the Sponsor 
(or designee) on the data. Any inconsistencies/errors/omissions identified will be sent to the 
study center (via an electronic query) for the necessary corrections to be made to the eCRF. Once 
entered and saved in an eCRF, data immediately become part of the study database and are 
available to the Sponsor. 

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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), per the Sponsor. Prior and concomitant medications will be 
coded using the chosen version of the World Health Organization Drug Dictionary, per the 
Sponsor. 
12.4. 
Ethics  
The Sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) GCP guidelines, and with the laws and regulations of the 
country in which the study is conducted. 
The investigator and/or Sponsor/CRO will submit this protocol and any related document(s) to 
be provided to the subject to an IRB/IEC and to the national competent (health) authority (as 
applicable). Approval documentation (as applicable) from both the IRB/IEC and the national 
competent (health) authority must be obtained before starting the study. 
12.5. 
General Legal References  
The study will be carried out according to provisions of the US CFR, the US FDA, the laws and 
regulations of the country in which the study is conducted, and the ICH Guidelines for GCP. All 
clinical work conducted under this protocol is subject to GCP regulations. This includes an 
inspection by the Sponsor or its representative, health authority, or IRB/IEC representatives at 
any time. The investigator must agree to the inspection of study-related records by health 
authority representatives and/or the Sponsor or its designee. 
12.6. 
Institutional Review Board/Independent Ethics Committee  
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study center. 
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to the Sponsor. The investigator must agree to make 
any required progress reports to the IRB/IEC, as well as reports of SAEs, life-threatening 
problems, or death. 
A list of members participating in the IRB/IEC meetings must be provided, including the names, 
qualifications, and functions of these members. If that is not possible, the attempts made to 
obtain this information along with an explanation as to why it cannot be obtained or disclosed 
must be documented in the study documentation. 
If a member of the site study personnel was present during an IRB/IEC meeting, it must be clear 
that this person did not vote. 
12.7. 
Protocol Adherence - Amendments  
The protocol must be read thoroughly, and the instructions must be followed exactly. Any 
changes in the protocol will require a formal amendment. Such amendments will be agreed upon 
and approved in writing by the investigator and the Sponsor. The IRB/IEC and local health 

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authorities will be notified of all amendments to the protocol in accordance with local 
regulations. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator and/or Sponsor/CRO to the IRB/IEC and to the 
national competent (health) authority in accordance with local procedures and regulations. 
12.8. 
Required Documents  
The investigator must provide the Sponsor or its designee with the following documents before 
the enrollment of any subject (originals should be kept by the investigator in the investigator’s 
study regulatory document binder): 
• Signed copy of the protocol signature page 
• Investigator’s Brochure acknowledgement page 
• Completed and signed statement of investigator qualifications, as applicable 
• Financial disclosure documentation as required 
• Curriculum vitae and current medical license of the investigator and subinvestigators 
• Letter of approval from the IRB/IEC for protocol and ICF 
• Copy of the IRB/IEC approved written ICF to be used 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory 
12.9. 
Informed Consent  
Subjects must provide informed consent. 
Each subject’s chart will include the signed ICF for study participation. When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file. Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study. 
12.9.1. 
Caregiver Consent  
Caregivers will be required to sign a consent form if completing the optional caregiver 
assessments 
 
12.10. 
Study Monitoring  
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator. This will include telephone calls and monitoring visits. During the monitoring 
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 treatment accountability checks and may periodically request review 
of the investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 

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Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and will respond to inquiries. In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
12.11. 
Quality Assurance  
The study will be conducted in accordance with the Sponsor’s standard operating procedures 
designed to ensure that all procedures are in compliance with GCP and the laws and regulations 
of the country in which the study is conducted. Quality assurance audits may be performed at the 
discretion of the Sponsor. 
12.12. 
Record Retention  
Study records should be retained in compliance with federal, national, and/or local regulations of 
the clinical site. 
The Sponsor may request these records to be retained for a longer period if required by 
applicable regulatory requirements or Sponsor contractual obligations. If the investigator is 
unable to retain the study documents for the required amount of time, the Sponsor must be 
informed of the individual who will be assuming this responsibility. 
12.13. 
Confidentiality and Data Protection  
The Sponsor or its designee, and the study center affirm and uphold the principle of the subject’s 
right to protection against invasion of privacy. Throughout this study, all data will be identified 
only by an identification number. Information technology systems used to collect, process, and 
store study-related data are secured by technical and organizational security measures designed 
to protect such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of the 
Sponsor; it shall not be disclosed to others without written consent of the Sponsor; 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 the Sponsor as deemed necessary. To 
allow the use of the information derived from this clinical study and to ensure compliance with 
the laws and regulations of the country in which the study is conducted, the investigator is 
obliged to provide the Sponsor with the complete test results and all data compiled in this study. 
12.14. 
Publication and Disclosure Policy  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. Authorship will be 

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determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements. 
The Sponsor will submit study results for posting on public registry(ies) as required for 
compliance with applicable laws and/or regulations in the region(s) where the study is being 
conducted. For the purposes of study results disclosure, study completion is defined as the date 
of the last visit or procedure for the last subject in the study globally. 

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13. 
STUDY COMMENCEMENT AND DISCONTINUATION  
Upon satisfactory receipt of all required regulatory documents, the Sponsor (or designee) will 
arrange that all study materials 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 the study protocol, instructions for eCRF 
completion, AE reporting, and overall responsibilities including those for treatment 
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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14. 
REFERENCES  
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Bates GE, Hashmi AK, Bressler T, Zajac J, Hesdorffer M, Taub RN. Approach to offering 
remote support to mesothelioma patients: the mesothelioma survivor project. Transl Lung Cancer 
Res. 2016;5(3):216-8. 
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, US Department of 
Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD: National Institute of 
Mental Health – Abnormal Involuntary Movement Scale, p. 534-7. 1976a. 
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, US Department of 
Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD:  National Institute of 
Mental Health – Clinical Global Impression - Improvement, p. 217-222b. 1976b. 
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;20(10):1727-36. 
INGREZZA Prescribing Information. https://www.neurocrine.com/assets/2022/08/INGREZZA-
Full-Prescribing-Information.pdf. Revised August 2022. Accessed on 12 September 2022. 
Jain R, Ayyagari R, Goldschmidt D, King S, Leo S. Cross-sectional assessment of tardive 
dyskinesia work productivity and activity impairment in patients and caregivers. Poster presented 
at the Annual Academy of Managed Care Pharmacy (AMCP) Nexus; October 11-14, 2022. 
Kalali A. Patient satisfaction with, and acceptability of, atypical antipsychotics. Curr Med Res 
Opin. 1999a;15(2):135-7. 
Kalali, AH. Evaluating patient satisfaction: a practical approach. Clear Perspectives. 1999b; 2(3) 
18-21. 
Lecrubier Y, Sheehan DV, Weiller E, et al. The Mini-International Neuropsychiatric Interview 
(MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. 
European Psychiat. 1997(12):224-31. 
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;50(9):541-7. 
Moore TJ, Furberg CD. The harms of antipsychotic drugs: evidence from key studies. Drug Saf. 
2017;40(1):3-14. 
 
 
 
 

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62 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-65.  
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The validity of the Mini International 
Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. Eur Psychiatry. 
1997;12:232-41. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 4-57. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-9. 
Stull DE, Bron M, Bean S, et al. Impacts of tardive dyskinesia (TD) symptoms on patients: 
analysis of a TD-specific patient-reported outcome. Poster presented virtually at the 25th annual 
International Congress of Parkinson’s Disease and Movement Disorders; September 17-21, 
2021a. 
Stull DE, Bron M, Bean S, et al. Reanalysis of a patient-reported outcome (Tardive Dyskinesia 
Impact Scale) shows positive results. Poster presented virtually at the 25th annual International 
Congress of Parkinson’s Disease and Movement Disorders; September 17-21, 2021b. 
 
 
 
Weihe E, Eiden LE. Chemical neuroanatomy of the vesicular amine transporters. FASEB J. 
2000;14(15):2435-49. 

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APPENDIX A. SCHEDULE OF ASSESSMENTS  

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Table 8: 
Schedule of Assessments  
Procedure 
Screening 
Perioda 
(≤4 weeks) 
Baseline 
Treatment Period 
(24 weeks) 
Safety 
Follow-Up 
(14 days 
after last 
dose) 
Study Week 
(Study Day) 
W-4 to D-1 
D1 
EOW2 
(D15) 
EOW4 
(D29) 
EOW6 
(D43) 
EOW8 
(D57) 
EOW16 
(D113) 
EOW24 
(D169)/ 
ET 
EOW26 
(D183) 
Visit Window 
N/A 
N/A 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Onsite Visit 
X 
X 
 
X 
 
X 
X 
X 
X 
Virtual Visit 
 
 
X 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
update 
 
 
 
 
 
 
 
Medical historyb 
X 
update 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medication history 
X 
update 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationc 
X 
 
 
 
 
 
 
X 
 
Vital signs (blood 
pressure, pulse, and 
body temperature) 
X 
X 
 
X 
 
X 
X 
X 
 
12-lead ECGd 
X 
 
 
 
 
 
 
X 
 
Pregnancy teste 
X (s) 
X (u) 
 
X (u) 
 
X (u) 
X (u) 
X (u) 
X (u) 
Serum prolactin 
X 
 
 
 
 
 
 
X 
 
FSH (postmenopausal 
women only) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory 
testsf 
X 
 
 
 
 
 
 
X 
 
Urine drug screeng 
X 
 
 
 
 
 
 
 
 
Blood sample for 
CYP2D6 genotyping 
X 
 
 
 
 
 
 
 
 
Blood sample for PK 
 
 
 
 
 
 
 
X 
 
AIMSh 
X (v)i 
X 
 
X 
 
X 
X 
X 
 
CGI-TD-Sj 
 
X 
 
X 
 
X 
X 
X 
 

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Procedure 
Screening 
Perioda 
(≤4 weeks) 
Baseline 
Treatment Period 
(24 weeks) 
Safety 
Follow-Up 
(14 days 
after last 
dose) 
Study Week 
(Study Day) 
W-4 to D-1 
D1 
EOW2 
(D15) 
EOW4 
(D29) 
EOW6 
(D43) 
EOW8 
(D57) 
EOW16 
(D113) 
EOW24 
(D169)/ 
ET 
EOW26 
(D183) 
Visit Window 
N/A 
N/A 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Onsite Visit 
X 
X 
 
X 
 
X 
X 
X 
X 
Virtual Visit 
 
 
X 
 
X 
 
 
 
 
CGI-TD-Cj 
 
 
 
X 
 
X 
X 
X 
 
PGI-Cj 
 
  
 
X 
 
X 
X 
X 
 
EQ-5D-5L and EQ-
VASj 
 
X 
 
X 
 
X 
X 
X 
 
TDISj 
 
X 
 
X 
 
X 
X 
X 
 
SDSj 
 
X 
 
X 
 
X 
X 
X 
 
C-SSRS 
Baseline/Screening 
Version 
X 
 
 
 
 
 
 
 
 
C-SSRS Since Last 
Visit Version 
 
X 
 
X 
 
X 
X 
X 
X 
BARS 
X 
X 
 
 
 
X 
 
X 
 
Modified SAS 
X 
X 
 
 
 
X 
 
X 
 
Study treatment 
dosing at homek 
 
 
X (D1 to D169) 
 
Dispense study 
treatmentl 
 
X 
 
X 
 
X 
X 
 
 
Study treatment 
accountabilitym 
 
 
 
X 
 
X  
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; 
 
CGI-TD-C=Clinical Global Impression of Change - Tardive Dyskinesia; CGI-TD-S=Clinical Global Impression of Severity – Tardive Dyskinesia; 
COVID-19=coronavirus disease 2019; 
; C-SSRS=Columbia-Suicide Severity Rating Scale; 
CYP=cytochrome P450; D=study day; ECG=electrocardiogram; EOW=end of study week; EQ-5D-5L=5-level EQ-5D version; EQ-VAS=EQ-visual 
analogue scale; ET=early termination; FSH=follicle-stimulating hormone; MDD=major depressive disorder; MINI=Mini International Neuropsychiatric 
Interview; 
; N/A=not applicable; PGI-C=Patient Global Impression of Change; PK=pharmacokinetic(s); 
qd=once a day; QTcF=corrected QT interval using Fridericia’s formula; (s)=serum; SDS=Sheehan Disability Scale; SAS=Simpson-Angus Scale; 
TDIS=Tardive Dyskinesia Impact Scale; (u)=urine; (v)=video recorded; W=study week; 
 
 
If an unscheduled onsite is needed, the following assessments are required: vital signs (blood pressure, pulse, and temperature), concomitant medications, AE 
monitoring, C-SSRS Since Last Visit Version, and study treatment accountability. 
a The Screening Period may be extended by up to 14 days for certain unavoidable circumstances (such as the COVID-19 pandemic) with approval from the 
Sponsor or designee. Subjects who do not meet entry criteria during the Screening Period may be considered for rescreening 1 time with the approval of the 
Sponsor or designee. 
b The MINI will be used to assess the presence of moderate or severe substance use disorder as outlined in exclusion criterion #8. If a subject is unable to 
confirm their psychiatric diagnosis (ie, schizophrenia or schizoaffective disorder, bipolar disorder, or MDD) as outlined in inclusion criterion #3, then the 
applicable module of the MINI will be used at screening to evaluate the presence of psychiatric disorders in order to assess the appropriateness of the 
subject for inclusion.  
c Height will be measured at screening only. Height and weight will be measured with subjects not wearing shoes; and weight will be measured with subjects 
not wearing outerwear (eg, jackets or coats). 
d A standard 12-lead ECG will be conducted in triplicate (obtained at least 3 minutes apart and within a total time of 15 minutes) after the subject has rested 
supine for at least 5 minutes. The ECG parameters that will be assessed include heart rate, QT, QTcF, and PR intervals, and QRS duration based on the 
ECG machine readings (QTcF may need to be calculated). 
e Pregnancy tests are required for females of childbearing potential; the urine pregnancy test result on Day 1 will be used to confirm eligibility. 
f Clinical laboratory tests include hematology, chemistry, and prolactin. All blood samples will be obtained under nonfasted conditions. 
g The urine drug screen will be performed at screening and may be repeated at any time at the investigator’s clinical judgment. 
h The AIMS examination will be administered by the investigator (or designee) in accordance with the AIMS administration procedure. At the specified 
visits, the AIMS administration will be video recorded (approximately 10 minutes) following standardized guidelines. If possible, the same person should 
administer the AIMS for an individual subject at all time points. At each scheduled assessment, the AIMS should be the first procedure to be administered. 
Each time the AIMS is administered, a single onsite AIMS rater (ie, the study investigator or designee) will score AIMS Items 1 to 10 and complete AIMS 
Items 11 to 12. 
i An external AIMS reviewer will assess the overall severity of dyskinesia based on a video recording of the screening visit. This assessment will be 
performed to confirm the TD severity required for study entry as outlined in inclusion criteria #5 and #6. 
j After the AIMS assessment has been completed, the TDIS, SDS, EQ-5D-5L [including the EQ-VAS], PGI-C, CGI-TD-S, CGI-TD-C, 
 
should be performed before any other study procedures or assessments. 
k On Days 1 to 169, valbenazine will be self-administered qd. Valbenazine can be taken with or without food and should be taken at approximately the same 
time every day. It is recommended that subjects take valbenazine at the same time as their oral antipsychotic medication(s), if appropriate 
l After the end of Week 4, if the investigator determines that a dose decrease is needed at an unscheduled onsite visit, then the subject will return all unused 
study treatment and receive a bottle of valbenazine at the new dose at this visit. 
m Subjects will return all unused study treatment, and a compliance check will be performed by counting the capsules returned at each study visit. 

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APPENDIX B. INVESTIGATOR SIGNATURE  
CLINICAL STUDY TITLE: A Phase 4, Single-Arm, Open-Label Study to Evaluate the 
Effectiveness of Valbenazine on Patient- and Clinician-Reported Outcomes in Subjects With 
Tardive Dyskinesia 
 
PROTOCOL No.: 
NBI-98854-TD4020 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
 
 
Date 
 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
 
STUDY CENTER: 
 
________________________________________________________ 
(Print Study Center Name) 

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APPENDIX C. SPONSOR APPROVAL SIGNATURE  
The undersigned has reviewed and approves the content of this document. 
 
 
 
 
 
 
 
 
 
 
 
Electronically signed and dated 
_________________________ 
_______________________  
__________ 
 
 
 
 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
 
 
 
 

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APPENDIX D. 
LIST OF STRONG CYP2D6 INHIBITORS, CYP3A4 INHIBITORS, 
AND CYP3A4 INDUCERS  
Table 9: 
Strong CYP2D6 Inhibitors  
Strong CYP2D6 Inhibitors 
bupropion 
fluoxetine 
paroxetine 
quinidine 
terbinafine 
Note: This list may not be all-inclusive. Refer to the following for the most recent list: 
• 
US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
• 
https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 
• 
https://go.drugbank.com/categories/DBCAT002701 

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Table 10: 
Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inhibitors 
boceprevir 
cobicistat 
danoprevir and ritonavira 
elvitegravir and ritonavira 
grapefruit juice 
indinavir and ritonavira 
itraconazole 
ketoconazole 
lopinavir and ritonavira 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)a 
posaconazole 
ritonavira 
saquinavir and ritonavira 
telaprevir 
tipranavir and ritonavira 
telithromycin 
troleandomycin 
voriconazole 
clarithromycin 
idelalisib 
nefazodone 
nelfinavir 
Note: This list may not be all-inclusive. Refer to the following for the most recent list: 
• 
US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
• 
https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 
• 
https://go.drugbank.com/categories/DBCAT002701 
a Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. 

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Table 11: 
Strong CYP3A4 Inducers 
Strong CYP3A4 Inducers 
apalutamide 
carbamazepine 
enzalutamide 
mitotane 
phenytoin 
rifampin 
St. John's wort 
rifabutin 
Note: This list may not be all-inclusive. Refer to the following for the most recent list: 
• 
US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
• 
https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 
• 
https://go.drugbank.com/categories/DBCAT002701 

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