A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Chorea Associated With Huntington Disease
Phase: PHASE3
Conditions: Chorea, Huntington
Sponsor: Neurocrine Biosciences



Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
12 April 2021 
Confidential 
 
2 
 
SIGNATURES: 
I agree to conduct this study in accordance with the requirements of this Clinical Study Protocol 
and in accordance with the following: 
• Established principles of International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA) 
• Canada Food and Drugs Act and Regulations; Health Canada 
CLINICAL STUDY TITLE:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of 
Chorea Associated with Huntington Disease 
 
PROTOCOL No.: 
NBI-98854-HD3005 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Clinical Investigator Signature 
 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Clinical Investigator Name) 
 
CENTER:  
 
 
________________________________________________________ 
(Print Study Center Name)

Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
12 April 2021 
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2. 
SYNOPSIS 
Title of study:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, 
Safety, and Tolerability of Valbenazine for the Treatment of Chorea Associated with Huntington Disease 
Study number:  NBI-98854-HD3005 
Study site(s):  Approximately 55 study sites in the United States and Canada. 
Primary Study Objectives:  
• 
Evaluate the efficacy of valbenazine to reduce chorea associated with Huntington disease (HD) using 
the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score. 
Secondary Study Objectives:  
• 
Evaluate the efficacy of valbenazine to reduce chorea associated with HD using the Clinical Global 
Impression of Change (CGI-C), the Patient Global Impression of Change (PGI-C), and the Quality of 
Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function Short Form and the Neuro-
QoL Lower Extremity Function Short Form. 
• 
Evaluate the safety and tolerability of valbenazine in subjects with HD. 
 
 
 
Study design:  This is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of valbenazine in subjects with HD.  The study includes a 4-week screening period, an 
8-week dose-adjustment period, a 4-week maintenance period, and a final study visit 2 weeks following the 
final dose of study drug.  Approximately 120 adult male and female subjects with motor manifest HD and a 
genetic diagnosis of HD will be enrolled. 
If individual in-person study visits at the study site are not possible due to Corona Virus Disease 2019 
(COVID-19) related reasons (eg, subject is not able to travel to the site for safety reasons or as part of public 
health measures), remote visits may be conducted on a case-by-case basis at the judgment of the investigator 
and in consultation with the study medical monitor; once able, the subject is to return to in-person visits at the 
study site. Screening, baseline, and study visits at Weeks 10 and 12 must be performed at the study site; subjects 
who plan on entering Study NBI-98854-HD3006 the same day as Study NBI-98854-HD3005 Week 14 must 
have Week 14 follow-up performed at the study site. 
Before subjects can provide informed consent, the investigator (or designee) must determine whether the subject 
has the capacity to provide consent for study participation using the University of California, San Diego Brief 
Assessment of Capacity to Consent (UBACC).  Only subjects who are deemed to have the capacity to provide 
consent may sign the informed consent form (ICF).  All subjects must sign an ICF prior to the conduct of any 
study-related procedures.  Subjects will be screened for eligibility during a screening period, which will be up to 
4 weeks (28 days) prior to Day -1.  Screening visit must be performed at the study site.  Screening assessments 
may be repeated during the screening period if approved by the Study Medical Monitor.  A subject who has 
been deemed a screen failure may be rescreened if approved by the Study Medical Monitor; during rescreening, 
all procedures must be conducted with the exception of Cytosine Adenine Guanine repeat (provided the results 
are available from a prior screening period). 
Eligible subjects will be randomized 1:1 to either valbenazine or placebo treatment on Day -1 (baseline).  Study 
drug will be administered in a blinded fashion throughout the 12-week treatment period beginning on Day 1.  
The baseline visit must be performed at the study site.  The maximum doses during each week of the treatment 
period are shown in the table below. 
 

Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
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Dose Adjustment Period 
Maintenance 
Period 
Week 
1-2
3-4
5-6
7-8
9-12
Arm 1 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Arm 
2a 
Valbenazine 
40 mg 
Valbenazine 
60 mg 
Valbenazine 
80 mg 
Valbenazine 
80 mg 
Valbenazine 
80 mg 
a Doses reflect maximum daily doses during each week. 
During the dose-adjustment period, the investigator will increase a subject’s dose to the next dose level if, in the 
investigator’s opinion, the subject has tolerated the study drug at the current dose.  Doses will be adjusted in a 
blinded manner; subjects receiving placebo will undergo the dose-adjustment process but will continue to 
receive placebo.  Dose increases are allowed at visits at the end of Weeks 2, 4, and 6.  If the subject has not 
tolerated the current dose, the investigator may decrease the subject’s dose at any time during the dose 
adjustment period (the 40 mg dose can be decreased to 20 mg).  Doses are to be decreased 1 dose level at a time 
and subjects may have multiple dose decreases during the dose-adjustment period; subjects who are unable to 
tolerate the 20 mg dose should remain in the study but study drug dosing will be discontinued.  Subjects who 
have had a dose decrease may re-escalate during the dose adjustment period if the investigator considers that the 
dose increase would be reasonably tolerated.  
During the maintenance period (beginning after the Week 8 visit through the end of Week 12), the subject’s 
dose will be maintained.  If the subject cannot tolerate the maintenance dose, the investigator may reduce the 
subject’s dose a single time by 1 dose level (unless the subject is receiving 20 mg); if the subject cannot tolerate 
the lower dose, he/she should remain in the study but study drug dosing will be discontinued.  Study visits at 
Weeks 10 and 12 during the maintenance period must performed at the study site. 
During the dose-adjustment and maintenance periods, the investigator may assess that a dose level is not 
tolerated if a subject experiences an adverse event (AE) that is (1) deemed associated with the study drug, and 
(2) of either moderate or severe intensity, or a serious AE.
Follow-up assessments will be conducted at the end of Week 14 (2 weeks after the last dose of the study drug).  
Subjects who withdraw from the study should have an early termination visit, which has the same assessments 
as the Week 12 visit. 
If individual in-person study visits at the study site are not possible due to COVID-19 related reasons,study 
visits during the dose adjustment period, the early termination visit, and Week 14 follow-up visit may be 
performed remotely at the judgment of the investigator and in consultation with the study medical monitor. 
Study drug will be self-administered (in the presence of the subject’s caregiver, if applicable) once daily (qd) 
beginning on Day 1.  Study drug should be administered at approximately the same time each day during the 
study.  As much as possible, all study visits (including baseline and follow-up) should occur at approximately 
the same time to standardize the time of day for the assessment of efficacy, safety, and drug exposure.  Visits 
during the treatment period and the follow-up visit will have a window of ±3 days. 
An independent Data and Safety Monitoring Board (DSMB) will periodically review ongoing, unblinded 
clinical safety data to ensure the safety and well-being of the study subjects. 
Study population:  A total of approximately 120 male and female subjects, 18 to 75 years of age, inclusive, 
with genetically confirmed motor manifest HD will be enrolled.  Of the approximately 120 subjects enrolled in 
the main study, approximately 50 subjects will be enrolled in the exploratory substudy with wearable movement 
sensors. 
Duration of treatment and study participation:  The expected duration of study participation for each subject 
is approximately 18 weeks, including up to 4 weeks (28 days) of screening, a 12-week treatment period, and a 
follow-up visit 2 weeks after the final dose of study drug. 
Investigational product, dosage, and mode of administration:  Valbenazine will be supplied as orally 
administered capsules containing 20 or 40 mg of valbenazine (free base equivalents as the ditosylate salt).  
Subjects must swallow the capsules with approximately 4 ounces of water or other liquid, with or without food.  
The table below shows the doses and capsules that will be used in the study. 

Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
12 April 2021 
Confidential 
 
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Dose 
Valbenazine 
20 mg capsule 
Valbenazine 
40 mg capsule 
Placebo 
capsule 
Valbenazine 20 mg 
1 
-- 
1 
Valbenazine 40 mg 
2 
-- 
-- 
Valbenazine 60 mg 
1 
1 
-- 
Valbenazine 80 mg 
-- 
2 
-- 
Placebo 
-- 
-- 
2 
Reference therapy, dosage, and mode of administration:  Matching placebo capsules are identical in 
appearance and will be orally administered in a double-blind manner (2 placebo capsules) on an identical 
schedule as valbenazine.  Subjects must swallow the capsules with approximately 4 ounces of water or other 
liquid, with or without food. 
Criteria for evaluation: 
Efficacy: 
• 
UHDRS. 
o 
Motor only:  Total Maximal Chorea score, Total Motor Score 
o 
Full: Motor, Cognition, Behavior, Functional Assessment, Independence, Total Functional 
Capacity  
o 
Independent rating of chorea video recordings:  TMC score 
• 
PGI-C. 
• 
CGI-C. 
• 
Clinical Global Impression of Severity (CGI-S). 
• 
Patient Global Impression of Severity (PGI-S). 
• 
Neuro-QoL Upper Extremity Function Short Form. 
• 
Neuro-QoL Lower Extremity Function Short Form. 
• 
Short Form 36 Health Survey (SF-36). 
• 
Huntington Disease Health Index (HD-HI) 
• 
EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
• 
 
Pharmacokinetics: 
Blood samples for plasma drug and metabolite concentration analyses will be collected during the study. 
Safety:   
Safety and tolerability will be monitored throughout the study and will include the following assessments: 
• 
AEs. 
• 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis). 
• 
Prolactin 
• 
Vital signs (including orthostatic blood pressure and pulse). 
• 
Physical examinations. 
• 
12-lead electrocardiogram (ECG). 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
• 
UHDRS motor score (items for parkinsonism).  
• 
Barnes Akathisia Rating Scale (BARS). 
• 
Hospital Anxiety and Depression Scale (HADS). 

Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
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Other Assessment: 
• 
Anosognosia Scale (AS). 
Statistical methods:  The primary efficacy endpoint is the change from screening/baseline period baseline (the 
average of the screening and Day -1 assessments) to maintenance (the average of the Week 10 and Week 12 
assessments) in the TMC based on on-site assessments.  The primary analysis method for the TMC change from 
screening period baseline will be a mixed-effect model repeated measures (MMRM) analysis.  The valbenazine 
arm will be compared with the placebo arm using a 2-sided test with a 5% level of significance. 
Response based on the CGI-C and PGI-C scales defined as "much improved" or "very much improved" at 
Week 12 will be secondary efficacy endpoints.  The change from baseline (Day -1) to Week 12 in the Neuro-
QoL Lower Extremity Function and the Neuro-QoL Upper Extremity Function scores will also be secondary 
efficacy endpoints.  All other efficacy endpoints will be exploratory. 
Pharmacokinetic and safety data will be summarized using descriptive statistics. 

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Clinical Protocol Amendment No. 5 Final Version 
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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
4. 
ETHICS ......................................................................................................................16 
5. 
INTRODUCTION ......................................................................................................16 
5.1. 
Background .................................................................................................................16 
5.2. 
NBI-98854 ..................................................................................................................17 
5.3. 
Study and Dose Rationale ...........................................................................................18 
6. 
STUDY OBJECTIVES ..............................................................................................19 
7. 
STUDY DESIGN .......................................................................................................19 
8. 
STUDY POPULATION .............................................................................................23 
8.1. 
Subject Inclusion Criteria ...........................................................................................23 
8.2. 
Subject Exclusion Criteria ..........................................................................................24 
8.3. 
Subject Identification and Replacement of Subjects ..................................................26 
8.4. 
Randomization ............................................................................................................26 
9. 
STUDY EVALUATIONS ..........................................................................................26 
9.1. 
Schedule of Assessments ............................................................................................26 
9.2. 
Screening and Baseline Assessments .........................................................................29 
9.2.1. 
Cytosine Adenine Guanine Repeat .............................................................................29 
9.2.2. 
Genotyping .................................................................................................................29 
9.2.3. 
Swallowing Disturbance Questionnaire .....................................................................29 
9.2.4. 
Clinical Rating Scale for Progressive Supranuclear Palsy .........................................29 
9.2.5. 
Montreal Cognitive Assessment .................................................................................29 
9.3. 
Efficacy Assessments .................................................................................................29 
9.3.1. 
Unified Huntington’s Disease Rating Scale ...............................................................30 
9.3.1.1. 
Unified Huntington’s Disease Rating Scale Administrator ........................................30 
9.3.1.2. 
Unified Huntington’s Disease Rating Scale Video Recording ...................................30 
9.3.1.3. 
Blinded, Central Unified Huntington’s Disease Rating Scale Motor Video 
Raters ..........................................................................................................................30 

Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
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9.3.2. 
Patient Global Impression of Change .........................................................................31 
9.3.3. 
Clinical Global Impression of Change .......................................................................31 
9.3.4. 
Patient Global Impression of Severity ........................................................................31 
9.3.5. 
Clinical Global Impression of Severity ......................................................................31 
9.3.6. 
Short Form 36 Health Survey .....................................................................................31 
9.3.7. 
Quality of Life in Neurological Disorders ..................................................................32 
9.3.8. 
Huntington Disease Health Index ...............................................................................32 
9.3.9. 
EuroQol 5 Dimensions 5 Levels .................................................................................32 
 
 
9.4. 
Pharmacokinetic Assessments ....................................................................................34 
9.5. 
Safety Assessments .....................................................................................................34 
9.5.1. 
Data and Safety Monitoring Board .............................................................................34 
9.5.2. 
Vital Sign Measurements ............................................................................................34 
9.5.3. 
Medical History ..........................................................................................................35 
9.5.4. 
Physical Examination Including Height and Weight..................................................35 
9.5.5. 
Electrocardiogram .......................................................................................................35 
9.5.6. 
Clinical Laboratory Assessments ...............................................................................35 
9.5.7. 
Columbia-Suicide Severity Rating Scale ....................................................................36 
9.5.8. 
Barnes Akathisia Rating Scale ....................................................................................36 
9.5.9. 
Hospital Anxiety and Depression Scale .....................................................................37 
9.5.10. 
Unified Huntington’s Disease Rating Scale ...............................................................37 
9.6. 
Other Assessment .......................................................................................................37 
9.6.1. 
Anosognosia Scale ......................................................................................................37 
9.7. 
Specific Study Period Information .............................................................................37 
9.7.1. 
Screening Period (Weeks -4 to -1) ..............................................................................38 
9.7.2. 
Baseline (Day -1) ........................................................................................................39 
9.7.3. 
Dose-Adjustment Period (Weeks 2 to 8 [±3 days]) ....................................................41 
9.7.4. 
Maintenance Period (Weeks 10 and 12 [or early termination; ±3 days]) ...................42 
9.7.5. 
Follow-up Visit (Week 14 [±3 days] or 2 weeks following an early 
termination visit) .........................................................................................................43 
9.7.6. 
Unscheduled Visit(s) ..................................................................................................44 
9.8. 
Study Duration ............................................................................................................45 
9.9. 
Prohibitions and Restrictions ......................................................................................45 

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Clinical Protocol Amendment No. 5 Final Version 
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9.9.1. 
Prior and Concomitant Medications ...........................................................................45 
 
 
9.9.3. 
Other Restrictions .......................................................................................................46 
9.9.4. 
Caregiver Responsibilities ..........................................................................................46 
9.10. 
Discontinuation of Study Drug and Subject Withdrawal ...........................................47 
9.10.1. 
Discontinuation of Study Drug Dosing ......................................................................47 
9.10.2. 
Withdrawal from Study ..............................................................................................48 
9.10.3. 
Sponsor’s Termination or Suspension of Study .........................................................48 
10. 
STUDY DRUG ...........................................................................................................48 
10.1. 
Study Drug Supplies ...................................................................................................48 
10.1.1. 
Valbenazine ................................................................................................................48 
10.1.2. 
Placebo ........................................................................................................................49 
10.2. 
Study Drug Storage.....................................................................................................49 
10.3. 
Study Drug Packaging and Labeling ..........................................................................49 
10.4. 
Blinding ......................................................................................................................49 
10.5. 
Study Drug Preparation and Administration ..............................................................50 
10.6. 
Study Drug Compliance and Accountability ..............................................................50 
10.7. 
Study Drug Return ......................................................................................................50 
11. 
ADVERSE EVENTS..................................................................................................51 
11.1. 
Definition ....................................................................................................................51 
11.1.1. 
Intensity of Adverse Events ........................................................................................52 
11.1.2. 
Relationship to Study Drug ........................................................................................52 
11.2. 
Recording Adverse Events .........................................................................................52 
11.3. 
Poststudy Follow-Up of Adverse Events ....................................................................53 
11.4. 
Serious Adverse Events ..............................................................................................53 
11.4.1. 
Definition of a Serious Adverse Event .......................................................................53 
11.4.2. 
Managing Serious Adverse Events .............................................................................54 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................54 
11.4.4. 
Expedited Safety Reports ...........................................................................................54 
11.5. 
Pregnancy ...................................................................................................................55 
12. 
DOCUMENTATION OF DATA ...............................................................................55 
12.1. 
Case Report Forms .....................................................................................................55 

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12.2. 
Data Capture, Review, and Validation .......................................................................56 
12.3. 
Coding Dictionaries ....................................................................................................56 
13. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................57 
13.1. 
Overview.....................................................................................................................57 
13.2. 
Analysis Sets ...............................................................................................................57 
13.3. 
Sample Size Determination ........................................................................................57 
13.4. 
Handling of Missing Data ...........................................................................................57 
13.5. 
Disposition of Subjects ...............................................................................................57 
13.6. 
Important Protocol Deviations ....................................................................................58 
13.7. 
Demographics and Baseline Subject Characteristics ..................................................58 
13.8. 
Study Drug Dosing and Compliance ..........................................................................58 
13.9. 
Pharmacokinetics ........................................................................................................58 
13.10. 
Efficacy Data ..............................................................................................................58 
13.10.1. 
Primary Efficacy Endpoint .........................................................................................58 
13.10.2. 
Secondary Efficacy Endpoints ....................................................................................59 
13.10.3. 
Procedure to Control for Multiple Comparisons ........................................................60 
13.10.4. 
Exploratory Endpoints ................................................................................................60 
13.11. 
Safety Data..................................................................................................................60 
13.12. 
Software ......................................................................................................................61 
13.13. 
Interim Analysis..........................................................................................................61 
14. 
REGULATORY AND ETHICAL ISSUES ...............................................................61 
14.1. 
General Legal References ...........................................................................................61 
14.2. 
Institutional Review Board/Independent Ethics Committee ......................................61 
14.3. 
Protocol Adherence – Amendments ...........................................................................61 
14.4. 
Required Documents ..................................................................................................62 
14.5. 
Informed Consent .......................................................................................................62 
14.6. 
Study Monitoring ........................................................................................................62 
14.7. 
Quality Assurance .......................................................................................................63 
14.8. 
Record Retention ........................................................................................................63 
14.9. 
Confidentiality ............................................................................................................63 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................63 
16. 
REFERENCES ...........................................................................................................65 

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APPENDIX A. GUIDANCE TO ADDRESS GLOBAL HEALTH EMERGENCIES 
AND POTENTIAL IMPACT ON THE CLINICAL STUDY ...................................67 
 
LIST OF TABLES 
Table 1: 
Maximum Allowable Doses During the Study ...........................................................20 
Table 2: 
Schedule of Assessments ............................................................................................27 
Table 3: 
Dosing Regimens and Number of Valbenazine Capsules ..........................................49 
Table 4: 
Intensity of Adverse Events ........................................................................................52 
Table 5: 
Relationship of Adverse Events to Study Drug ..........................................................52 
Table 6: 
Schedule of Remote Assessments for Subjects Impacted by COVID-19 ..................70 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................22 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AS 
Anosognosia Scale 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-∞ 
AUC from time 0 extrapolated to infinity 
β-hCG 
beta-human chorionic gonadotropin 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CAG 
Cytosine Adenine Guanine 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 
CRS-PSP 
Clinical Rating Scale for Progressive Supranuclear Palsy 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
CYP 
cytochrome P450 
DSMB 
Data and Safety Monitoring Board 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA K2 
dipotassium ethylenediaminetetraacetic acid 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HADS 
Hospital Anxiety and Depression Scale 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C antibody 
HD 
Huntington disease 
HD-HI 
Huntington Disease Health Index 
HIV-Ab 
human immunodeficiency virus antibody 
HSG 
Huntington Study Group 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IPDs 
important protocol deviations 

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IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LS 
least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effect model repeated measures 
MoCA 
Montreal Cognitive Assessment 
NBI 
Neurocrine Biosciences, Inc. 
Neuro-QoL 
Quality of Life in Neurological Disorders 
NOAEL 
no observed adverse effect level 
PCR 
polymerase chain reaction 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetics 
PM 
poor metabolizer 
PT 
Preferred Term 
qd 
once daily 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDQ 
Swallowing Disturbance Questionnaire 
SF-36 
Short Form 36 Health Survey 
SOC 
System Organ Class 
t½ 
apparent terminal half-life 
TBZ 
tetrabenazine 
TD 
tardive dyskinesia 
TEAEs 
Treatment-emergent adverse events 
TESAEs 
treatment-emergent serious adverse events 
TFC 
Total Functional Capacity 
tmax  
time to maximum plasma concentration 
TMC 
Total Maximal Chorea 
TS 
Tourette syndrome 
UBACC 
University of California, San Diego Brief Assessment of Capacity to Consent 
UHDRS 
Unified Huntington’s Disease Rating Scale 
ULN 
upper limit of normal 
US 
United States 
VMAT2 
vesicular monoamine transporter 2 
WBC 
white blood cell 
 

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4. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) standards 
that meet regulations relating to Good Clinical Practices (GCP).  These standards respect the 
following guidelines: 
• Good Clinical Practice:  Consolidated Guideline (International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use [ICH; current version]). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR 
parts 50, 54, 56, 312, and 314). 
• Canada Food and Drugs Act and Regulations (FDAR) Part C, Division 5:  Drugs for Clinical 
Trials Involving Human Subjects. 
• Guidance for Clinical Trial Sponsors:  Clinical Trial Applications, Effective March 2016, 
Health Canada Therapeutic Products Directorate, Health Products and Food Branch. 
The ethical requirements of Institutional Review Boards (IRBs)/Independent Ethics Committees 
and the informed consent forms (ICFs) are discussed in Section 14. 
5. 
INTRODUCTION 
5.1. 
Background 
Huntington disease (HD) is a genetic progressive neurodegenerative disease characterized 
clinically by chorea, cognitive dysfunction, and psychiatric symptoms.  Pathologically, HD is 
associated with brain atrophy characterized by loss of striatal medium spiny neurons and cortical 
pyramidal neurons.  Neurochemically, alterations in dopamine function and neurotransmission is 
observed in HD patients, with increased dopamine neurotransmission observed with early stage 
HD symptoms manifesting as hyperkinetic abnormal involuntary movements.  Later stage motor 
symptoms are primarily hypokinetic in nature (Frank, 2014; Cepeda et al., 2014). 
Patients with HD typically have onset of symptoms at approximately 30 to 50 years of age.  Five 
to 10% of cases are classified as juvenile onset, with patients becoming symptomatic before the 
age of 20.  The average lifespan after symptom onset is 15 to 20 years (Frank, 2014; 
Roos, 2010). 
One of the defining motor symptoms of HD is chorea, characterized as abnormal, abrupt, 
irregular, nonstereotyped movements (Thorley et al., 2018).  As HD progresses, chorea can 
increase in frequency and amplitude (Carlozzi et al., 2016).  Chorea is also associated with 
decreased quality of life (Carlozzi et al., 2016).  While there is no established treatment to delay 
onset or progression of HD, treatment of HD-associated chorea could benefit some patients 
through improved quality of life (Thorley et al., 2018). 
Valbenazine’s pharmacological activity is primarily derived from its highly selective and potent 
major metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ) (Grigoriadis et al., 2017).  
Valbenazine and [+]-α-HTBZ have relatively long half-lives of 15 to 22 hours, allowing for once 
daily dosing with consistent exposure to [+]-α-HTBZ, and more stable management of 
hyperkinetic movements. 

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with the exception of Cytosine Adenine Guanine repeat (CAG; provided the results are available 
from a prior screening period).   
Eligible subjects will be randomized 1:1 to either valbenazine or placebo on Day -1 (baseline).  
Study drug will be administered in a blinded fashion throughout the 12-week treatment period 
beginning on Day 1.  The maximum doses during each week of the treatment period are shown 
in Table 1. 
Table 1: 
Maximum Allowable Doses During the Study 
 
Dose Adjustment Period 
Maintenance Period 
Week 
1-2 
3-4 
5-6 
7-8 
9-12 
Arm 1 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Arm 2a 
Valbenazine 40 mg 
Valbenazine 60 mg 
Valbenazine 80 mg 
Valbenazine 80 mg 
Valbenazine 80 mg 
a Doses reflect maximum daily doses during each week. 
During the dose-adjustment period, the investigator will increase a subject’s dose to the next 
dose level if, in the investigator’s opinion, the subject has tolerated the study drug at the current 
dose.  Doses will be adjusted in a blinded manner; subjects receiving placebo will undergo the 
dose-adjustment process but will continue to receive placebo.  Dose increases are allowed at 
visits at the end of Weeks 2, 4, and 6.  If the subject has not tolerated the current dose, the 
investigator may decrease the subject’s dose at any time during the dose adjustment period (the 
40 mg dose can be decreased to 20 mg).  Doses are to be decreased 1 dose level at a time and 
subjects may have multiple dose decreases during the dose-adjustment period; subjects who are 
unable to tolerate the 20 mg dose should remain in the study but study drug dosing will be 
discontinued.  Subjects who have had a dose decrease may re-escalate during the dose 
adjustment period if the investigator considers that the dose increase would be reasonably 
tolerated.   
During the maintenance period (beginning after the Week 8 visit through the end of Week 12), 
the subject’s dose will be maintained.  If the subject cannot tolerate the maintenance dose, the 
investigator may reduce the subject’s dose a single time by 1 dose level (unless the subject is 
receiving 20 mg); if the subject cannot tolerate the lower dose, he/she should remain in the study 
but study drug dosing will be discontinued.   
During the dose-adjustment and maintenance periods, the investigator may assess that a dose 
level is not tolerated if a subject experiences an adverse event (AE) that is (1) deemed associated 
with the study drug, and (2) of either moderate or severe intensity, or a serious AE. 
Follow-up assessments will be conducted at the end of Week 14 (2 weeks after the last dose of 
the study drug).  Subjects who withdraw from the study should have an early termination visit, 
which has the same assessments as the Week 12 visit.  
Study drug will be self-administered (in the presence of the subject’s caregiver, if applicable) 
once daily (qd) beginning on Day 1.  Study drug should be administered at approximately the 
same time each day during the study.  As much as possible, all study visits (including baseline 
and follow-up) should occur at approximately the same time to standardize the time of day for 
the assessment of efficacy, safety, and drug exposure.  Visits during the treatment period and the 
follow-up visit will have a window of ±3 days.   

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An independent Data and Safety Monitoring Board (DSMB) will periodically review ongoing, 
unblinded clinical safety data to ensure the safety and well-being of the study subjects.  The 
study design is shown in Figure 1. 

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Figure 1: 
Study Design Schematic 
 
a Doses represent maximum daily doses during each 2-week period. 
Early termination can happen at any time; the early termination assessments will be the same assessments as those performed at Week 12. 
 
Screening Period
Dose-Adjustment Period
Maintenance Period
Follow-up
Placebo
Valbenazine 40 mga
Valbenazine 60 mga
Valbenazine 80 mga
Valbenazine 80 mga
Screening
Randomization 
1:1
Week
Day -1 
(Baseline)
2
4
6
8
10
-4
12/early 
termination
14
Valbenazine 80 mga

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8. 
STUDY POPULATION 
This study will include approximately 120 male and female subjects.  Subjects must meet all 
inclusion criteria and no exclusion criteria in order to be enrolled. 
8.1. 
Subject Inclusion Criteria 
To participate in this study, subjects must meet the following criteria:  
1. Be a male or female aged 18 to 75 years, inclusive.  
2. Diagnosis of motor manifest HD at or before screening. 
3. Genetic diagnosis of HD with an expanded CAG repeat (≥37) in huntingtin (HTT) gene at or 
before Day -1 (baseline). 
4. Subjects must be ambulatory, but assist devices are permitted. 
5. TMC score ≥8 at screening and Day -1 (baseline).  
6. Total Functional Capacity (TFC) score ≥5 at screening.  Subjects with a TFC score between 
5 and 10 (inclusive) must have a reliable caregiver to ensure study drug administration and 
attendance at study visits. 
7. Subjects of childbearing potential must agree to use contraception consistently while 
participating in the study until 30 days (females) or 90 days (males) after the last dose of the 
study drug.  A female subject of childbearing potential is defined as a subject who is not 
surgically sterile (ie, bilateral oophorectomy, hysterectomy, or bilateral tubal ligation for at 
least 3 months prior to screening) and who has not been postmenopausal for at least 1 year 
prior to screening.  A male subject of childbearing potential is defined as a subject who has 
not been vasectomized for at least 3 months prior to screening. 
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom). 
• Vaginal sponge impregnated with spermicide used with condom. 
• Intrauterine device (IUD). 
• Hormonal contraception taken for at least 3 months prior to screening. 
The following subjects are not required to use contraception: 
• Male and female subjects not of childbearing potential. 
• Subjects who practice total abstinence from sexual intercourse as the preferred lifestyle 
(periodic abstinence is not acceptable). 
• Female subjects with male partners not of childbearing potential. 
8. Female subjects of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test result at screening and a negative urine pregnancy test 
at Day -1. 

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11. Have a positive human immunodeficiency virus antibody (HIV-Ab) test result or hepatitis B 
surface antigen (HBsAg) test result at screening.  Subjects with positive hepatitis C virus 
antibody (HCV) and confirmatory positive polymerase chain reaction (PCR) reflex test 
results at screening will be allowed to participate in the study provided that the subject is 
asymptomatic as assessed by the investigator and does not meet the liver function tests 
abnormalities for alanine transaminase (ALT), aspartate transaminase (AST), gamma-
glutamyl transferase (GGT), and total bilirubin in exclusion criterion 12.  
12. Have any of the following laboratory test abnormalities at screening: 
• Serum creatinine >1.5 times the upper limit of normal (ULN). 
• AST ≥2.5 × ULN 
• ALT ≥2.5 × ULN 
• GGT ≥3.0 × ULN 
• Total bilirubin >1.5 mg/dL 
13. Have any of the following hematologic abnormalities at screening: 
• Hemoglobin <10 g/dL 
• White blood cell (WBC) count <3.0 × 103/mm3 
• Platelet count <100,000/mm3 
14. Have a positive urine drug screen at screening (positive for amphetamines, barbiturates, 
phencyclidine, benzodiazepines, cocaine, or opiates), except for subjects who have a 
prescription for benzodiazepines or opiates.  
15. History of substance dependence or substance (drug) or alcohol abuse (nicotine and caffeine 
dependence are not exclusionary), as defined in the Diagnostic and Statistical Manual of 
Mental Disorders (eg, -IV or -5), within 1 year of screening. 
16. Have received any prohibited medication (see Section 9.9.1). 
17. Have received gene therapy at any time, or an investigational drug in the context of a clinical 
study within 30 days or 5 half-lives (if known), whichever is longer, of Day -1 or plan to use 
such investigational drug (other than the study drug) during this study.   
18. Have a blood loss ≥550 mL or have donated blood within 30 days prior to Day -1 (baseline). 
19. Have a history of previously established therapy with a VMAT2 inhibitor, in the judgment of 
the investigator and in consultation with a study medical monitor if needed.  Previous 
exposure to a VMAT2 inhibitor is allowable provided that discontinuation occurred >30 days 
prior to screening, prior to establishment of a therapeutic response, and was otherwise 
unrelated to efficacy or tolerability. 
20. 
 
 
 
 
 

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8.3. 
Subject Identification and Replacement of Subjects 
Subjects will be identified by their unique subject number.  The subject number will be noted on 
electronic case report forms (eCRFs), all source documentation, laboratory documents, and ECG 
tracings.  Subjects who discontinue from the study will not be replaced. 
8.4. 
Randomization 
The site must enter the subject’s screening data in the electronic data capture (EDC) system for 
the Study Medical Monitor (or designee) to review, confirm eligibility, and authorize the subject 
to proceed to Day -1 (baseline).  The investigator will review the screening and baseline 
eligibility criteria at Day -1 (baseline) and authorize the subject for randomization.  Eligible 
subjects will be randomized 1:1 to either valbenazine or placebo on Day -1 (baseline) using an 
interactive web response system (IWRS). 
9. 
STUDY EVALUATIONS 
9.1. 
Schedule of Assessments 
A schedule of assessments is shown in Table 2.  All visits below should be performed, if 
possible, at the study site.  Subjects will provide written informed consent before any 
study-related procedures are performed.  Subject-related events and activities including specific 
instructions, procedures, concomitant medications, dispensing of study drug, and descriptions of 
AEs should be recorded in the appropriate source documents and eCRFs. 
If individual in-person study visits at the study site are not possible due to COVID-19 related 
reasons (eg, subject is not able to travel to the site for safety reasons or as part of public health 
measures), remote visits may be conducted on a case-by-case basis at the judgment of the 
investigator and in consultation with the study medical monitor; once able, the subject is to 
return to in-person visits at the study site (see Appendix A).  Screening, baseline, and study visits 
at Weeks 10 and 12 must be performed at the study site. 
 

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Table 2: 
Schedule of Assessments 
Procedurea 
Screening Period 
Baseline 
Dose-Adjustment Period 
Maintenance Period 
Follow-up 
Weekb 
-4 to -1
Day -1 
Day 1 
2 
4 
6 
8 
10 
12/ET 
14c 
Visitb 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
UBACC/informed consentd 
X 
Treatment assignment scripte 
X 
X 
Inclusion/exclusion criteria 
X 
update 
Medical history 
X 
update 
Physical examination (including weight)f 
X 
X 
X 
X 
X 
X 
X 
X 
Heightf 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testh 
X (s) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
CAG repeat 
X 
Clinical laboratory testsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for prolactin 
X 
X 
X 
X 
Urine drug screenj 
X 
Genotype blood sample (
)k  
X 
Blood for PK assessmentsl 
X 
X 
X 
X 
X 
X 
X 
X 
HADS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BARS 
X 
X 
X 
X 
X 
X 
X 
UHDRS (full) 
X 
X 
X 
UHDRS (motor, behavior, TFCm) 
X 
X 
X 
X 
X 
X 
Video recording UHDRS motor 
X  
X 
X 
X 
PGI-C and CGI-C 
X 
X 
X 
X 
X 
X 
X 
PGI-S and CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 
X 
X 
Neuro-QoLn 
X 
X 
X 
X 
X 
X 
HD-HI 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
MoCA 
X 
AS 
X 
X 
X 
SDQ and CRS-PSP 
X 
Randomization 
X 
Study drug dosing 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
X 
X 
X 
X 
X 
Study drug accountabilityp 
X 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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9.2. 
Screening and Baseline Assessments 
Screening and baseline visits must be performed at the study site. 
9.2.1. 
Cytosine Adenine Guanine Repeat 
A blood sample will be collected from subjects during screening to assess for CAG trinucleotide 
repeat expansion number in the HTT gene.  Blood will be collected in tubes containing 
dipotassium ethylenediaminetetraacetic acid (EDTA K2).  Instructions for processing samples 
will be provided by the central laboratory.  CAG repeat blood samples collected from subjects 
will be shipped to a central laboratory for analysis. 
Prior documentation of CAG repeat ≥37 from a validated laboratory is sufficient to confirm 
eligibility; however, a sample will still be collected at screening for all subjects to be assessed by 
the central laboratory. 
9.2.2. 
Genotyping 
A blood sample will be collected from randomized subjects for the analysis of 
 
.  Blood will be collected in tubes 
containing EDTA K2.  Instructions for processing samples will be provided by the central 
laboratory.  Genotyping blood samples collected from subjects will be shipped to a central 
laboratory for analysis. 
9.2.3. 
Swallowing Disturbance Questionnaire 
The SDQ is a 15-item instrument that assesses subjects’ difficulty in swallowing food on a scale 
from 0 (never) to 3 (very frequently).  The SDQ is a valid and reliable instrument to determine 
subjects’ ability to swallow (Cohen and Manor, 2011).  The SDQ will be administered at 
screening to determine eligibility for the study. 
9.2.4. 
Clinical Rating Scale for Progressive Supranuclear Palsy 
Subjects who score ≥11 on the SDQ during screening and, in the investigator’s judgement, may 
still be eligible for participation, will be asked to complete item 13 on the CRS-PSP.  Dysphagia 
is rated from 0 (none) to 4 (requires artificial measures) after the subject drinks 30 to 50 mL of 
water (Golbe and Ohman-Strickland, 2007).  Subjects who score ≤2 will be eligible for the study. 
9.2.5. 
Montreal Cognitive Assessment 
The Montreal Cognitive Assessment (MoCA) is an instrument to determine cognitive abilities 
including:  orientation, short-term memory, executive function, language abilities, abstraction, 
animal naming, attention, and a clock-drawing test (Nasreddine et al., 2005).  The maximum 
score on the instrument is 30 points.  The MoCA will be administered on Day -1 (baseline). 
9.3. 
Efficacy Assessments 
If individual in-person study visits at the study site are not possible due to COVID-19 related 
reasons (eg, subject is not able to travel to the site for safety reasons or as part of public health 
measures), remote visits may be conducted on a case-by-case basis at the judgment of the 

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investigator and in consultation with the study medical monitor; once able, the subject is to 
return to in-person visits at the study site (see Appendix A).   
9.3.1. 
Unified Huntington’s Disease Rating Scale 
The UHDRS is a tool developed by the Huntington Study Group (HSG) to assess the clinical 
features and course of HD.  The UHDRS has undergone extensive reliability and validity testing 
and has been used as a major outcome measure in controlled clinical trials (HSG, 1996).  The 
full UHDRS includes the following assessments:  motor, cognitive, behavioral, independence, 
function, and TFC.  The motor portion of the UHDRS consists of 15 items that measure the 
severity of the motor symptoms. 
The TMC is item 12 of the motor assessment and measures the chorea in 7 different body parts 
including the face, oral-buccal-lingual region, trunk and each limb independently.  The 
maximum score is 28. 
The full UHDRS will be administered Day -1 (baseline) and Weeks 12 (or early termination) and 
14.  The motor and behavior portions of the UHDRS will be administered at screening (including 
TFC), Weeks 2, 4, 6, 8, and 10.  The motor only portion of the UHDRS will be video recorded at 
screening, Day -1 (baseline), and Weeks 10 and 12 (or early termination). 
The motor and cognition portions of the UHDRS will not be administered at COVID-19 related 
remote visits. 
9.3.1.1. 
Unified Huntington’s Disease Rating Scale Administrator 
The UHDRS will be administered and scored by the investigator (or qualified designee).  If 
possible, the same person should administer the UHDRS for an individual subject at all 
timepoints. 
9.3.1.2. 
Unified Huntington’s Disease Rating Scale Video Recording 
Subjects will be video recorded for the duration of the UHDRS motor section according to 
standardized guidelines provided by NBI (or designee).  Video recordings will be uploaded to a 
secure, central server, and managed by a core laboratory.  Access to the dedicated central server 
will be limited and will require the user to provide a user identification and password to access 
the secure server and the subject’s video recording.  
9.3.1.3. 
Blinded, Central Unified Huntington’s Disease Rating Scale Motor Video Raters 
The UHDRS video recording files will be reviewed and scored by blinded, central UHDRS 
motor video raters.  A triple-blind consensus scoring will be conducted by these raters according 
to scoring guidelines developed by NBI.  NBI (or designee) will provide the blinded central 
UHDRS motor video raters digital-secure access to the subjects’ randomized UHDRS video 
recording files for review and scoring.  The central raters will score maximal chorea (0 to 4) on 
7 body regions (face, buccal-oral-lingual, trunk, right upper extremities, left upper extremities, 
right lower extremities, and left lower extremities).  The central raters will be blinded to the 
subjects’ study visits and treatment assignments.  Two blinded, central raters will review each 
UHDRS video file from beginning to end and must agree on the TMC score.  The central 

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UHDRS video raters will review and score the UHDRS video recordings conducted at screening, 
Day -1 (baseline), and Weeks 10 and 12 (or early termination).  
9.3.2. 
Patient Global Impression of Change  
Subjects will evaluate the change in their chorea symptoms since initiation of study drug dosing 
by choosing one of 7 responses (very much improved, much improved, minimally improved, not 
changed, minimally worse, much worse, and very much worse) on the PGI-C.   
The PGI-C will be completed by subjects at Weeks 2, 4, 6, 8, 10, 12 (or early termination), and 
14. 
9.3.3. 
Clinical Global Impression of Change 
The CGI-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 overall global improvement of chorea since the initiation of study 
drug dosing.  This scale is a modification 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 improvement over time 
from the clinician’s perspective (Guy, 1976). 
An investigator or qualified clinician designee (eg, psychologist or social worker) will rate the 
scale at the scheduled timepoints.  If possible, the same person should rate the CGI-C at all 
timepoints.  The CGI-C will be administered at Weeks 2, 4, 6, 8, 10, 12 (or early termination), 
and 14. 
This assessment will not be conducted at COVID-19 related remote visits. 
9.3.4. 
Patient Global Impression of Severity 
The Patient Global Impression of Severity (PGI-S) scale will be used to assess overall severity of 
chorea on a 5-point scale (range:  1=none to 5=very severe).  The PGI-S will be assessed by the 
subject on Day -1 (baseline) and at Weeks 2, 4, 6, 8, 10, 12 (or early termination), and 14. 
9.3.5. 
Clinical Global Impression of Severity 
The Clinical Global Impression of Severity (CGI-S) scale will be used to assess overall severity 
of chorea on a 7-point scale (range:  1=normal, not at all ill to 7=among the most extremely ill 
patient).  The CGI-S will be assessed by the investigator on Day -1 (baseline) and at Weeks 2, 4, 
6, 8, 10, 12 (or early termination), and 14. 
This assessment will not be conducted at COVID-19 related remote visits. 
9.3.6. 
Short Form 36 Health Survey 
The SF-36 is a 36-item, self-administered questionnaire.  It measures health on 8 dimensions:  
vitality, physical functioning, pain, general health perception, physical role limitations, 
emotional role functioning, social functioning, and mental health (Brazier et al., 1992).  The 
SF-36 has been shown to be a reliable and validated instrument (Brazier et al., 1992).  Version 2 
of the SF-36 will be used in this study. 

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The SF-36 will be administered on Day -1 (baseline) and Week 12 (or early termination). 
This assessment will not be conducted at a COVID-19 related remote early termination visit. 
9.3.7. 
Quality of Life in Neurological Disorders 
The Neuro-QoL is a collection of psychometrically sound, clinically relevant, health-related 
quality of life measurement tools for individuals with neurological conditions.  The Neuro-QoL 
has been demonstrated to be a reliable tool for assessing patient-reported physical functioning 
measures in subjects with HD (Carlozzi et al., 2017).  The Lower Extremity Function Short Form 
and the Upper Extremity Function Short Form each comprise 8 questions about physical 
abilities, rated from 1 (unable to do) to 5 (without any difficulty). 
Both the Upper Extremity Function Short Form and the Lower Extremity Function Short Form 
will be administered on Day -1 (baseline), and Weeks 4, 8, 10, 12 (or early termination), and 14.  
9.3.8. 
Huntington Disease Health Index 
The Huntington Disease Health Index (HD-HI) (Glidden et al., 2017) is a disease-specific patient 
reported outcome measure designed to evaluate patient disease burden in therapeutic trials.  The 
HD-HI comprises 13 subscales that measure 13 individual areas of HD patient health. Together, 
each of the subscales can be utilized to generate an estimate of a HD patient’s overall disease 
burden.  Each question in the instrument was selected based on its high relevance to the HD 
population, its ability to be consistently understood by patients and clinicians, its content 
validity, its face validity, and its potential responsiveness to measure therapeutic benefit of 
disease progression during clinical trials. 
This instrument is a questionnaire that is completed by the subject (with assistance, as 
necessary).  In standard use, the instrument is handed to a subject who is asked to read the 
directions and complete the instrument, using a pen, by checking the most appropriate box next 
to each question. 
Upon completion of the HD-HI, 14 scores are generated: a subject receives a score for each of 
the 13 subscales and a total instrument score.  The total instrument score is a composite of the 
13 subscales.  The score for each subscale and the total instrument ranges from 0 to 100 with 
100 representing the highest disease burden and a score of 0 representing no disease burden. 
The HD-HI will be administered on Day -1 (baseline) and Weeks 10 and 12 (or early 
termination). 
This assessment will not be conducted at COVID-19 related remote visits. 
9.3.9. 
EuroQol 5 Dimensions 5 Levels 
The EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) is a general, single index measure for 
describing and valuing health (Herdman et al., 2011).  It defines health in terms of 5 dimensions:  
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.  Each 
dimension has 5 levels:  no problems, slight problems, moderate problems, severe problems, and 
extreme problems.  The subject indicates his/her health state by checking the box next to the 
most appropriate statement.  The scores for the 5 dimensions can be combined into a 5-digit 

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9.5.3. 
Medical History 
A medical history will be taken at the screening visit and updated on Day -1 (baseline) and as 
needed throughout the study.  
9.5.4. 
Physical Examination Including Height and Weight 
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system.   
A complete physical examination including weight will be performed at screening, Day -1 
(baseline), and Weeks 2, 4, 6, 8, 12 (or early termination), and 14.  Height will be measured at 
screening only.  Height and weight will be measured with subjects not wearing shoes. Physical 
examination including weight will not be performed at COVID-19 related remote visits. 
9.5.5. 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicate (at least 1 minute apart and within 
approximately 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.  If needed, the investigator may 
consult with a local or central cardiologist to assist in the interpretation of an ECG.  Based on the 
review of these parameters, the investigator or designee will note if the ECG is Normal, 
Abnormal not Clinically Significant, or Abnormal Clinically Significant.  If the ECG is 
Abnormal Clinically Significant, the investigator or designee will provide a description of the 
abnormality recorded on the AE eCRF.  
The 12-lead ECG will be conducted at screening, Day -1 (baseline), and Weeks 2, 4, 6, 8, 10, 12 
(or early termination), and 14. 
9.5.6. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory or at a local 
laboratory as needed.  In addition, a urine pregnancy test will be performed by the study site on 
Day -1 (baseline) to confirm subject eligibility.  The central laboratory will provide instructions 
and supplies before study initiation and instructions will be included in a laboratory manual.  The 
laboratory test battery will include routine and screening laboratory tests.  Fasting is not required 
for the clinical laboratory assessments.  Select clinical laboratory assessments may be performed 
by a local lab (for re-testing or if the subject is not able to come to the study site); prior approval 
by the medical monitor is required. 
The following clinical safety laboratory assays will be performed: 
Hematology:  complete blood count including WBC count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, and platelet count, mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red 
cell distribution width (RDW), and mean platelet volume (MPV). 

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Clinical Chemistry:  sodium, potassium, calcium, magnesium, phosphorus, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate 
dehydrogenase, AST, ALT, GGT, creatine kinase, total bilirubin, total cholesterol, triglycerides, 
total protein, and glucose. 
Prolactin:  Serum prolactin samples will be shipped to a central laboratory for analysis.  Prolactin 
results will remain blinded to investigators, subjects, and sponsor until database lock.  The 
DSMB may review unblinded prolactin data during the course of the study. 
Urinalysis:  specific gravity, nitrite, ketones, protein, urobilinogen, glucose, bilirubin, leukocyte 
esterase, occult blood, and pH; microscopic examination of sediment will be performed only if 
the results of the urinalysis dipstick evaluation are positive for nitrite, protein, leukocyte esterase, 
or blood. 
The following additional laboratory tests will be performed: 
Serology:  Blood will be collected for HIV-Ab, HBsAg, and HCV-Ab and reflex PCR testing at 
screening. 
Urine Drug Screen:  The urine drug screen will test for amphetamines, barbiturates, 
benzodiazepines, cocaine, phencyclidine, and opiates.  The urine drug screen will be collected at 
screening by the study site and analyzed by a central laboratory. 
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 
urine pregnancy tests will be performed at subsequent visits. 
9.5.7. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(Posner et al., 2011).  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.  Subjects with any lifetime suicidal behavior or suicidal ideation of type 4 (active 
suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation 
with specific plan and intent) in the 3 months before screening based on the C-SSRS should be 
excluded (see exclusion criterion #10). 
The C-SSRS will be administered and scored by the investigator or qualified study site personnel 
at screening, Day -1 (baseline), and Weeks 2, 4, 6, 8, 10, 12 (or early termination), and 14. 
9.5.8. 
Barnes Akathisia Rating Scale 
The Barnes Akathisia Rating Scale (BARS) is a validated four-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, subjects’ awareness of restlessness and 
related distress), together with a global assessment of akathisia.  Global assessment is made on a 

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scale of 0 to 5 (0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked 
akathisia; 5=severe akathisia).   
The BARS will be administered on Day -1 (baseline) and Weeks 2, 4, 6, 8, 10, and 12 (or early 
termination). 
This assessment will not be conducted at COVID-19 related remote visits. 
9.5.9. 
Hospital Anxiety and Depression Scale 
The HADS is a commonly used instrument to determine the levels of anxiety and depression that 
a person is experiencing.  The HADS is a 14-item scale; 7 of the items relate to anxiety and 7 
relate to depression (Zigmond and Snaith, 1983).  Each item is answered on a 4-point (0 to 3) 
response category so the possible scores range from 0 to 21 for anxiety and 0 to 21 for 
depression.  The HADS has been validated as a measure of depression and anxiety 
(Barczak et al., 1988).  
The HADS will be administered at screening, Day -1 (baseline), and Weeks 2, 4, 6, 8, 10, 12 (or 
early termination), and 14. 
9.5.10. 
Unified Huntington’s Disease Rating Scale 
A subset of the UHDRS Motor Assessment (items rating retropulsion pull test, finger taps, 
pronate/supinate hands, rigidity-arms, and bradykinesia-body) will be used to assess for 
parkinsonism at each visit. 
This assessment will not be conducted at COVID-19 related remote visits. 
9.6. 
Other Assessment 
9.6.1. 
Anosognosia Scale 
The Anosognosia Scale (AS) is an instrument to screen for anosognosia in daily practice and is 
specific for HD (Deckel and Morrison, 1996).  This scale requires subjects and investigators to 
rate the subject’s ability to perform tasks relative to individuals of the subject’s age and 
education on a five-point scale, rating 8 items. 
The AS will be completed at the study site by both the subject and the investigator (or designee) 
at Day -1 (baseline) and Weeks 12 (or early termination) and 14.  This assessment will not be 
performed at COVID-19 related remote visits. 
9.7. 
Specific Study Period Information 
After signing the ICF, subjects will undergo screening procedures within 4 weeks (28 days) of 
Day -1. 
If individual in-person study visits at the study site are not possible due to COVID-19 related 
reasons (eg, subject is not able to travel to the site for safety reasons or as part of public health 
measures), remote visits may be conducted on a case-by-case basis at the judgment of the 
investigator and in consultation with the study medical monitor; once able, the subject is to 
return to in-person visits at the study site (see Appendix A).  Screening, baseline, and study visits 

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• To return to the study site in approximately 2 weeks for their next study visit having 
taken their daily dose of study drug.  
• To return all used and unused study drug and packaging at the next study visit. 
9.7.3. 
Dose-Adjustment Period (Weeks 2 to 8 [±3 days]) 
All visits should be conducted at the study site.  Due to COVID-19, in the event a subject is 
unable to attend an in-person visit, a select subset of assessments may be conducted at a remote 
visit (see Appendix A). 
The following study evaluations and tasks will be performed at the study site: 
• Perform a physical examination (including weight). 
• Collect vital signs. 
• Perform 12-lead ECG in triplicate (at least 1 minute apart and within approximately 
15 minutes). 
• Perform a urine pregnancy test only for female subjects of childbearing potential. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect blood sample for prolactin (Week 8 only). 
• Collect urine sample for urinalysis. 
• Collect blood sample for PK assessment. 
• Administer the HADS. 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BARS. 
• Administer the UHDRS (motor and behavior portions only). 
• Administer the Neuro-QoL Upper Extremity Function Short Form and the Lower 
Extremity Function Short Form (Weeks 4 and 8 only). 
• Administer the PGI-C. 
• Administer the CGI-C. 
• Administer the CGI-S. 
• Administer the PGI-S. 
• Dispense study drug. 
• Perform compliance check by counting the capsules returned. 
• Record concomitant medications. 
• AE monitoring. 

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9.7.4. 
Maintenance Period (Weeks 10 and 12 [or early termination; ±3 days]) 
All visits should be conducted at the study site.  Due to COVID-19, in the event a subject is 
unable to attend an in-person visit, the early termination visit may performed remotely (see 
Appendix A). 
The following study evaluations and tasks will be performed at the study site: 
• Perform a physical examination (including weight) (Week 12 [or early termination] 
only). 
• Collect vital signs. 
• Perform 12-lead ECG in triplicate (at least 1 minute apart and within approximately 
15 minutes). 
• Perform a urine pregnancy test only for female subjects of childbearing potential. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect blood sample for prolactin (Week 12 [or early termination] only). 
• Collect urine sample for urinalysis. 
• Collect blood sample for PK assessment. 
• Administer the HADS. 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the BARS. 
• Administer the full UHDRS (motor and behavior portions only at Week 10, full 
UHDRS at Week 12), including video recording of the motor portion only. 
• Administer the Neuro-QoL Upper Extremity Function Short Form and the Lower 
Extremity Function Short Form. 
• Administer the PGI-C. 
• Administer the CGI-C. 
• Administer the CGI-S. 
• Administer the PGI-S. 
• Administer the SF-36 (Week 12 [or early termination] only). 
• Administer the HD-HI. 
• Administer the EQ-5D-5L. 
• Administer the AS (Week 12 only). 
• Dispense study drug (Week 10 only). 
• Perform compliance check by counting the capsules returned. 

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• Collect urine sample for urinalysis. 
• Collect blood sample for PK assessment. 
• Administer the HADS. 
• Administer the C-SSRS (Since Last Visit version). 
• Administer the full UHDRS.  
• Administer the Neuro-QoL Upper Extremity Function Short Form and the Lower 
Extremity Function Short Form. 
• Administer the PGI-C. 
• Administer the CGI-C. 
• Administer the CGI-S. 
• Administer the PGI-S. 
• Administer the AS. 
• Record concomitant medications. 
• AE monitoring. 
9.7.6. 
Unscheduled Visit(s) 
All visits should be conducted at the study site.  Due to COVID-19, in the event a subject is 
unable to attend an in-person visit, unscheduled visits may be performed remotely (see 
Appendix A).   
For unscheduled visit(s) needed during the course of the study that are due to AEs (including 
clinically significant laboratory abnormalities) or other safety or tolerability concerns (including 
dose decreases), the following study evaluations and tasks may be performed at the investigator’s 
discretion: 
• Perform a physical examination (including weight). 
• Collect vital signs. 
• Perform 12-lead ECG in triplicate (at least 1 minute apart and within approximately 
15 minutes). 
• Perform a urine pregnancy test only for female subjects of childbearing potential. 
• Collect blood sample for hematology and clinical chemistry. 
• Collect urine sample for urinalysis. 
• Collect a blood sample for PK assessment (for unscheduled visits due to AEs within 
48 hours of the most recent study drug dose). 
• Administer the HADS. 
• Administer the C-SSRS (Since Last Visit version). 

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• Administer the BARS. 
• Administer the motor and behavior portion only of the UHDRS.  
• Record concomitant medications. 
• AE monitoring. 
9.8. 
Study Duration 
The expected duration of study participation for each subject is approximately 18 weeks, 
including up to 4 weeks (28 Days) of screening, a 12-week treatment period, and a follow-up 
visit 2 weeks after the final dose of study drug. 
9.9. 
Prohibitions and Restrictions 
9.9.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter (OTC) medications, including dietary and herbal 
supplements, taken by subjects during the 30 days before screening and during the study will be 
entered on the Prior and Concomitant Medications eCRF. 
Medications that may prolong the QT interval:  valbenazine may prolong the QT interval. 
Caution should be used when valbenazine is coadministered with medications known to prolong 
the QT interval. 
Medications to treat medical conditions:  All coexistent diseases or conditions will be treated 
in accordance with prevailing medical practice.  Benzodiazepines and opiates must be at a stable 
dose (ie, no as-needed use) for 2 weeks before Day -1 (baseline).  Antidepressant therapy must 
be at a stable dose (ie, no prn use) for 8 weeks before Day -1 (baseline).  Investigators should 
document doses of current medication using medical or pharmacy records, confirmation with the 
subject’s caregivers (if applicable), or through reliable subject-reported information (eg, provide 
a list of medications and doses). 
Prohibited medications:  The following medications are prohibited from 30 days prior to 
Day -1 (baseline) until the final study visit (or early termination) as described below (unless 
otherwise stated): 
• Antipsychotics or other dopamine receptor blockers:  antipsychotics (eg, risperidone, 
olanzapine, quetiapine, aripiprazole, ziprasidone,  chlorpromazine, haloperidol, fluphenazine, 
clozapine) and dopamine receptor blockers (eg, metoclopramide, domperidone) are 
prohibited. 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenytoin, phenobarbital, rifabutin, 
rifampin, primidone, St. John's Wort) are prohibited. 
• Dopamine agonists and precursors:  Dopamine receptor agonists (eg, ropinirole) and 
precursors (eg, carbidopa/levodopa) are prohibited.  
• MAOIs:  All MAOIs (eg, isocarboxazid, phenelzine, selegiline, tranylcypromine) are 
prohibited. 

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9.10. 
Discontinuation of Study Drug and Subject Withdrawal 
Subjects can discontinue study drug or withdraw their consent to participate in the study at any 
time.  The investigator must discontinue study drug dosing or withdraw any subject from the 
study if a subject requests study drug dosing to be discontinued or to be withdrawn from the 
study, respectively.  All subjects prematurely discontinuing study drug dosing should continue 
study participation to be followed for safety and efficacy outcomes. 
9.10.1. 
Discontinuation of Study Drug Dosing 
If a subject prematurely discontinues study drug dosing, the investigator will record the reason 
for discontinuation on the relevant eCRF.  Such subjects will not be automatically withdrawn 
from the study and should continue participation in the study.  The investigator and subject 
should discuss a plan for continued participation.  Data for any outcome measures, particularly 
the primary and secondary endpoints, as well as safety follow-up, are important to collect.  For 
any subsequent study visits after study drug is prematurely discontinued, subjects will not be 
required to undergo PK sampling, 
 
.  If medically indicated, treatment with medication listed under Section 9.9.1 is no 
longer prohibited after study drug discontinuation.  Subjects must wait a minimum of 2 weeks 
after discontinuation of study drug dosing before starting any symptomatic drug treatment for 
chorea. 
The investigator must discontinue study drug dosing if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable, despite 
attempts to decrease the dose. 
• If the subject is unable to tolerate the lowest allowable study dose (20 mg).   
• QTcF value >500 msec (cardiologist verified) on any ECG tracing.  
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation 
with specific plan and intent) based on the C-SSRS. 
• Subject is confirmed to be pregnant. 
The investigator or NBI may discontinue study drug dosing for other reasons as described below.   
• Subject develops a clinically significant laboratory (eg, ALT or AST ≥2.5 times ULN) or 
ECG abnormality. 
• Subject requires a medication that is prohibited by the protocol. 
It is crucial to obtain follow-up data for any subject who discontinues study drug dosing because 
of an AE, abnormal laboratory test, vital sign measurement, physical examination, or ECG 
finding.  In any case, every effort must be made to undertake safety follow-up procedures. 

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9.10.2. 
Withdrawal from 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 early termination assessments performed.  If a subject withdraws prematurely 
and an in-person visit cannot be conducted for any reason, including COVID-19, the subject will 
be asked to participate in the visit via telephone (see Appendix A).  A safety follow-up call 
approximately 14 days after discontinuation of study drug should be performed. 
Reasons for a subject’s withdrawal from study are: 
• The subject is lost to follow-up. 
• Sponsor decision. 
• Investigator decision.  
• Subject death. 
• Withdrawal of consent for the study. 
9.10.3. 
Sponsor’s Termination or Suspension of Study 
The Sponsor or designee reserves the right to close a study site, terminate or suspend the entire 
study, or terminate or suspend the study at individual sites, at any time for any reason. If the 
study is prematurely terminated or suspended, 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 suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate therapy and/or 
follow-up. 
10. 
STUDY DRUG 
10.1. 
Study Drug Supplies 
10.1.1. 
Valbenazine 
NBI or its designee will provide the study site with a supply of study drug sufficient for the 
completion of the treatment period of the study.   
Valbenazine will be supplied as orally administered capsules containing 20 or 40 mg of 
valbenazine (free base equivalents as the ditosylate salt).  Subjects must swallow the capsules 
(2 capsules) with approximately 4 ounces of water or other liquid, with or without food.  The 
dosing regimens and valbenazine capsules that will be used in this study are shown in Table 3. 

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Table 3: 
Dosing Regimens and Number of Valbenazine Capsules 
Dose 
Valbenazine 
20 mg capsule 
Valbenazine 
40 mg capsule 
Placebo 
capsule 
Valbenazine 20 mg 
1 
-- 
1 
Valbenazine 40 mg 
2 
-- 
-- 
Valbenazine 60 mg 
1 
1 
-- 
Valbenazine 80 mg 
-- 
2 
-- 
Placebo 
-- 
-- 
2 
10.1.2. 
Placebo 
Matching placebo capsules are identical in appearance to valbenazine and will be orally 
administered in a double-blind manner (2 placebo capsules) on an identical schedule as 
valbenazine.  Subjects must swallow the capsules with approximately 4 ounces of water or other 
liquid, with or without food. 
10.2. 
Study Drug Storage 
All capsules must be stored at controlled room temperature (
). 
Study drug must be stored and inventoried according to applicable state and federal regulations 
and study procedures. 
10.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice (GMP) and GCP.  The study drugs will be sent to designated staff at the study site who 
must complete and return a drug supply confirmation to NBI or its designee verifying the receipt 
of the drug.  Study drug will be labeled in accordance with federal and local regulations, as 
applicable. 
Study drug will be supplied as capsules in child-resistant blistercard dispensers; each blistercard 
contains enough study drug for 14 days of dosing plus 3 extra dose days.  The blistercards will 
contain capsules of valbenazine or placebo. 
10.4. 
Blinding 
This study includes a 12-week double-blind placebo-controlled treatment period during which 
the subject, investigator, all study site personnel, and the sponsor (or designee) will be blinded to 
the subject’s treatment.  During this treatment period, all subjects will receive valbenazine or 
placebo as two capsules (identical in appearance) to be self-administered once daily. Clinical 
trial material supply chain personnel who are not involved in decisions regarding subject’s study 
treatment will not be blinded. 
The randomization code will be broken for an individual subject only if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 

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identity of the subject’s treatment assignment, or for regulatory reporting requirements.  After 
the randomization code is broken because of a pregnancy, the subject will be informed of her 
treatment assignment.  In the case of a medical emergency in which knowledge of the identity of 
the study treatment is important for subject management, the investigator has the responsibility 
to decide whether to break the blind; treatment assignments would be unblinded using IWRS. It 
is recommended that the investigator contact the Study Medical Monitor (or designee; refer to 
Section 11.4.3 for contact information) before unblinding if it would not result in unnecessary 
delay to the immediate medical management of the subject. Documentation of the unblinding 
must be maintained.  
Members of the DSMB and individuals who generate the DSMB reports will be unblinded 
throughout the study. 
10.5. 
Study Drug Preparation and Administration 
Study drug will be self-administered (in the presence of the subject’s caregiver, if applicable) 
once daily (qd) starting on Day 1.  Study drug should be administered at approximately the same 
time each day during the study.  If a subject forgets or is unable to take the study drug during this 
time period, the subject should take his or her daily dose of study drug as soon as possible but no 
later than 2400 hours.  The subject will need to skip the dose for that day if he or she is unable to 
take the study drug before 2400 hours.  Subjects or their caregivers will record the date and time 
of study drug dosing each day on the form provided as part of the study drug packaging. 
10.6. 
Study Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty drug packaging material to the site at 
specified study visits for drug accountability and reconciliation by study site personnel.  A 
compliance check will be performed by counting the capsules returned at each study visit.  In the 
case where a subject is unable to return used and unused study drug to the study site, the subject 
may ship them directly to the study site at the instruction of the investigator. 
The quantity of study drug dispensed, used, and returned will be recorded on a dispensing log or 
otherwise documented.  The quantity of study drug lost or destroyed must also be accounted for 
and documented.  The designated pharmacist or qualified personnel will be responsible for 
maintaining accurate records of the quantity and dates of all study drug supplies received, 
dispensed, and returned.   
10.7. 
Study Drug Return 
Written documentation to account for study drug and study drug materials is mandatory; all 
unused study drug and study drug materials must be kept in a secure location for final 
accountability and reconciliation.  Returned study drug and study drug material must be 
accounted for on a study drug return form provided by NBI or designee.  The investigator must 
provide a written explanation for any destroyed or missing study drug or study drug materials on 
the study drug return form. 

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Returns will be shipped to the Sponsor or its designee according to instructions provided by the 
Sponsor or its designee and according to applicable local and national regulations and study 
procedures unless alternate disposition of the study treatment is approved by the Sponsor. 
All returned study drug and study drug materials should be stored, inventoried, reconciled, and 
returned according to applicable state and federal regulations and study procedures. 
11. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject has signed the 
ICF until the subject’s final study visit (or upon early termination).  
11.1. 
Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of conditions present at the start of the study; (2) intercurrent illness; and (3) drug interaction. 
Subject deterioration due to HD beyond what would otherwise be expected due to the natural 
history of the disease should be reported as an AE. 
If at any time after baseline the subject’s response to the suicidal ideation section of the C-SSRS 
is worse than the baseline assessment, it will be documented as an AE.  All suicidal behaviors 
will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
drug, must be documented in the subject’s medical records, in accordance with the investigator’s 
normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for duration, intensity, 
frequency, seriousness, outcome, other actions taken, and relationship to the study drug.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before drug administration, unless it 
unexpectedly progresses, or increases in severity following drug administration.  
• Treatment failure or lack of efficacy. 
• Pregnancy. 

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11.1.1. 
Intensity of Adverse Events 
AEs must be graded for intensity.  An intensity category of mild, moderate, or severe, as defined 
in Table 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 adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities 
of daily living. 
Moderate 
An adverse event that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
Severe 
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
11.1.2. 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the criteria outlined in Table 5.  An AE is deemed associated with the use of the 
study drug “if there is a reasonable possibility that the drug caused the AE” (otherwise referred 
to as a suspected adverse reaction).  Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the AE (Title 21 CFR 312.32 [a]). 
Table 5: 
Relationship of Adverse Events to Study Drug 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the drug or in 
which the drug level has been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is confirmed by improvement on 
stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure. 
Possible 
An adverse event in which there is reasonable possibility that the drug caused the event.  
Reasonable possibility means there is evidence to suggest a causal relationship between the 
drug and the adverse event. 
Unlikely 
A reaction that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or suspected response pattern to the suspected drug; but that could 
reasonably be explained by known characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
11.2. 
Recording Adverse Events 
Each AE will be documented on the AE eCRF.  The investigator (or designee) will provide 
information on dates of onset and resolution, intensity, seriousness, frequency, action(s) taken, 
changes in study drug usage, relationship to study drug, and outcome.   

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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 and NBI Drug Safety and 
Pharmacovigilance (DSPV): 
• SAE, including death. 
• Pregnancy.  
• Treatment unblinding for any reason. 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) based on the C-SSRS. 
11.3. 
Poststudy Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up. 
AEs ongoing at the final visit or at early termination will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes or resolves or until the 
subject is lost to follow-up.  The investigator is responsible for ensuring that follow-up includes 
any supplemental investigations as may be indicated to elucidate the nature and/or causality of 
the AE.  This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals, as is practical. 
11.4. 
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 becomes aware 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 11.4.3. 
11.4.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcome: 
• Death. 
• A life-threatening AE.  Life-threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred.  It does 
not mean that hypothetically the event might have caused death if it occurred in a more 
serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization for 
elective treatment or a pre-existing condition that did not worsen during the clinical 
investigation is not considered an AE.  Hospitalization or nursing home admission for the 
purpose of caregiver respite is not considered an AE.  Complications that occur during 

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hospitalization are AEs, and if a complication prolongs hospitalization, the event is 
considered serious.  Treatment in a hospital emergency room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization.  These events may be considered serious when, based on appropriate medical 
judgment, they may jeopardize the health of the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed.  Any other event thought by the 
investigator to be serious should also be reported, following the reporting requirements 
detailed in this section.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
11.4.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible.  The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject.  The subject will remain under observation as long as 
medically indicated.  Appropriate laboratory studies will be conducted until all parameters return 
to normal or are otherwise explained or stable.  The subject will be followed until the SAE 
resolves or until the subject is medically stabilized.  The investigator (or designee) will notify the 
Study Medical Monitor and NBI DSPV Department (and the IRB/IEC, if necessary) immediately 
(within 24 hours) of the SAE and the outcome of the SAE as described in Section 11.4.3. 
11.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
SAEs and other immediately reportable events (defined in Section 11.2) must be reported within 
24 hours of first knowledge of the event by study personnel to the Study Medical Monitor and 
NBI DSPV Department.  Reports of SAEs and pregnancies must be followed by a fax or email of 
the SAE or Pregnancy Form.  It is important that the investigator provides his or her assessment 
of relationship to study drug at the time of the initial SAE report. 
For SAEs and other immediately reportable events, contact DSPV and Study Medical Monitor: 
DSPV telephone:
 
DSPV facsimile: 
 
DSPV e-mail: 
 
Study Medical Monitor:  
Telephone: 
 
 
 
 
 
 
Cell phone: 
 
11.4.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 11.1.2) that is considered both serious and unexpected within 

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The site investigator or an authorized member of the site 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 and acceptability by NBI (or designee).  NBI (or designee) will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify eCRF 
entries.  The site investigator will review the eCRFs for completeness and accuracy and enter his 
or her electronic signature on the eCRF page(s) as applicable as evidence thereof after each study 
visit. 
The CRO will provide NBI (or designee) and the study sites with access to the study EDC 
system 
 for the duration of the study through a password-protected 
method of internet access.  Such access will be removed from study sites at the end of the site’s 
participation in the study.  Data from the EDC system will be archived on appropriate data media 
and provided to the site investigator at that time as a durable record of the site’s eCRF data.  
Although not required, the site investigator may make paper printouts from that media.  All 
subject eCRF data will also be provided to NBI via an agreed transfer method and in an agreed 
format. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI (or designee) and/or health authority representatives at any time.  The site 
investigator will agree to the inspection of study-related records by health authority 
representatives and/or NBI (or designee). 
12.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
After completion of the entry process, automated (computer-generated) logic checks will run in 
order to identify items such as inconsistent study dates.  In addition, manual review/checks may 
be performed.  NBI (or designee) may also request specific reports and/or listings in order to 
perform manual review of the data.  Any inconsistencies/errors/omissions identified will be sent 
to the study site (via an electronic query) for the necessary corrections to be made to the eCRF.  
Any discrepancies will be corrected or explained online by authorized study site personnel.  
Once entered and saved in an eCRF, data immediately become part of the study database and are 
available to NBI (or designee). 
12.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA), per NBI.  Prior and concomitant medications will be coded 
using the chosen version of the World Health Organization Drug Dictionary, per NBI. 

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13. 
STATISTICAL AND ANALYTICAL PLAN 
13.1. 
Overview 
Descriptive and inferential statistical methods will be used to evaluate and summarize the data 
from this study. The term “descriptive statistics” refers to the number of subjects (n), mean, 
median, SD, SEM, minimum, and maximum for continuous and ordinal categorical variables; 
and refers to the number and percentage of subjects for categorical variables.  Additional 
descriptive statistics may be presented for selected variables.  The term “inferential statistics” 
refers to hypothesis tests which will be performed to assess differences between the valbenazine 
treatment group and the placebo treatment group for selected efficacy variables. 
The analysis plan provided in this protocol represents a brief description of the planned analyses.  
The comprehensive statistical analysis plan (SAP) will be generated prior to final study database 
lock. 
13.2. 
Analysis Sets 
Two primary analysis sets will be defined for this study.  The safety analysis set will include all 
subjects who are randomized to a treatment group, take at least one dose of study drug, and have 
any postbaseline safety data.  The full analysis set (FAS) will include all subjects who are 
randomized to a treatment group and who have at least one evaluable TMC change from baseline 
score during the 12-week double-blind treatment period.  Additional analysis sets may be 
specified in the SAP. 
13.3. 
Sample Size Determination 
A total sample size of 120 subjects (60 per group) will provide >95% power to detect a 
difference between the valbenazine and placebo treatment groups in the change from the 
screening period baseline (the average of the screening and Day -1 assessments) to maintenance 
(the average of the Week 10 and Week 12 assessments) in the TMC based on on-site 
assessments, using a two-sample t-test with a two-sided Type I error of 0.05.  This assumes a 
difference in means of 2.4 with a common SD of 3.3.  The specified treatment effect is 
attenuated to account for up to 4 (6.7%) subjects per treatment group who prematurely 
discontinue study drug dosing. 
The above sample size and power estimates were obtained from 
 
. 
13.4. 
Handling of Missing Data 
Methods for handling missing data for the primary and secondary efficacy endpoints are 
discussed in Section 13.10.  Any additional methods or details for the handling of missing data 
will be described in the SAP. 
13.5. 
Disposition of Subjects 
The summary of subject enrollment and disposition will display the number of subjects who 
were randomized to each treatment group, who completed the dose-adjustment period (ie, up to 
Week 8), who competed the dose maintenance period (ie, up to Week 12), and who completed 

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the study.  The number of subjects who discontinued study drug dosing early or did not complete 
the study will also be summarized, both overall and by reason.  Additional summaries may also 
be included. 
A separate summary of randomization by study site will be presented.  This summary will 
display the number of subjects randomized to each treatment group by site. 
13.6. 
Important Protocol Deviations 
A summary of the number and percentage of subjects with important protocol deviations (IPDs) 
by deviation category and by treatment group will be provided for all randomized subjects. 
13.7. 
Demographics and Baseline Subject Characteristics 
Demographic data (age, sex, race, and ethnicity) and baseline characteristics (including, but not 
limited to:  height, weight, BMI, 
 genotype status, and baseline values for the TMC 
score) will be summarized with descriptive statistics.  Medical history will be summarized 
according to MedDRA System Organ Class (SOC) and Preferred Term (PT). 
13.8. 
Study Drug Dosing and Compliance 
The number and percentage of subjects who are dose compliant (at least 80% of expected 
number of doses taken) will be summarized with descriptive statistics by visit (Weeks 2, 4, 6, 8, 
10, and 12). 
The number and percentage of subjects with dose adjustments will be summarized. 
13.9. 
Pharmacokinetics 
The plasma concentrations of valbenazine and the metabolite NBI-98782 will be summarized 
with descriptive statistics by visit (Day -1 and Weeks 2, 4, 6, 8, 10, 12, and 14) and dose (last 
dose received prior to blood sample being drawn).  Concentrations below the lower limit of 
quantification will be set equal to zero for all plasma concentration summaries. 
13.10. 
Efficacy Data 
The efficacy measures in this study include the UHDRS, PGI-C, CGI-C, PGI-S, CGI-S, SF-36, 
Neuro-QoL, EQ-5D-5L, HD-HI, 
.  Several 
derived variables based on these measures (eg, the SF-36 Physical Component Summary) will be 
summarized with descriptive statistics. Selected variables will include inferential statistics.  
Unless otherwise specified, the FAS will be used as the primary analysis set for all efficacy 
measures.  Regardless of adherence to study drug at the time of the assessment, all collected data 
will generally be included in the analyses.  The SAP will provide a full description of the derived 
variables and analyses that will be summarized for these efficacy measures. 
13.10.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint for this study is the change from the screening period baseline 
(the average of the screening and Day -1 assessments) to maintenance (the average of the 

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Week 10 and Week 12 assessments) in the TMC based on on-site assessments.  Changes from 
the screening period baseline to each postbaseline study visit (Weeks 2 through 12) are 
exploratory efficacy endpoints. 
Descriptive statistics will be presented by treatment group for the TMC observed values, and 
changes from the screening period baseline at each visit and at maintenance.  The changes from 
baseline to each postbaseline visit during the treatment period will be analyzed using a mixed-
effect model repeated measures (MMRM) analysis.  The model will include the screening period 
baseline TMC as a covariate, and treatment group, visit, treatment group-by-visit interaction, and 
baseline-by-visit interaction as fixed effects.  Subject will be included as a random effect.  
Treatment group comparisons of the valbenazine treatment group vs. placebo at maintenance and 
each visit will be performed by constructing linear contrasts (or equivalent programming code) 
for differences between treatment group least-squares (LS) means.  The LS means and 
differences in LS means will be presented in summary tables, along with the associated 95% 
confidence intervals.  The treatment difference for the primary endpoint (maintenance) will be 
considered statistically significant if the two-sided p value is <0.05.  Nominal (raw) two-sided 
p values for testing the significance of the treatment differences at the individual postbaseline 
visits will also be reported in the summary tables. 
Any additional supportive or sensitivity analyses of the TMC change from screening period 
baseline to maintenance will be described in the SAP. 
13.10.2. 
Secondary Efficacy Endpoints 
CGI-C Responder Endpoint 
CGI-C response status at Week 12 will be a secondary efficacy endpoint.  Subjects whose CGI-C 
score is either a 1 ("very much improved") or a 2 ("much improved") will be classified as 
responders. Response statuses at Weeks 2 through 10 are exploratory efficacy endpoints. 
Descriptive statistics will be presented by treatment group for the number and percentage of 
subjects classified as responders at each postbaseline visit.  Analyses comparing the valbenazine 
treatment group to placebo will be performed using the Fisher exact test.  Missing data at 
Week 12 will be imputed using non-responder imputation.  Nominal two-sided p values for 
testing the significance of treatment group will be reported in summary tables; however, 
interpretation of the p value for the treatment group comparison at Week 12 will be based on a 
procedure which controls for multiple comparisons (Section 13.10.3). 
PGI-C Responder Endpoint 
PGI-C response status at Week 12 will be a secondary efficacy endpoint.  The definition of 
response and analyses will be identical to those described for the CGI-C responder endpoint. 
Neuro-QoL Upper Extremity Function 
The change from baseline (Day -1) to Week 12 in the Neuro-QoL Upper Extremity Function 
T-score will also be a secondary endpoint.  Change from baseline to Weeks 4, 8, and 10 are 
exploratory efficacy endpoints.  
Descriptive statistics will be presented by treatment group for the observed values and changes 
from baseline at each visit.  The changes from baseline to each postbaseline visit during the 

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treatment period will be analyzed using MMRM.  The MMRM model will be similar to the 
model described above for the TMC analysis, with the exception that the covariate in the model 
will be the baseline value (Day -1) of the Neuro-QoL Upper Extremity Function T-score, and 
only visits where Neuro-QoL is scheduled to be collected will be included.  Nominal two-sided p 
values for testing the significance of treatment group differences and associated 95% confidence 
intervals will be reported in summary tables; however, interpretation of the p value for the 
treatment group comparison at Week 12 will be based on a procedure which controls for multiple 
comparisons (Section 13.10.3). 
Neuro-QoL Lower Extremity Function 
The change from baseline (Day -1) to Week 12 in the Neuro-QoL Lower Extremity Function 
T-score will also be a secondary endpoint.  The analyses will be identical to those described for 
the Neuro-QoL Upper Extremity Function. 
13.10.3. 
Procedure to Control for Multiple Comparisons  
A fixed-sequence testing procedure will be used to control the family-wise error rate for the 
primary and secondary efficacy endpoints.  Testing of hypotheses at each step of the procedure 
commences only if all null hypotheses of the prior steps were rejected.  The fixed-sequence 
testing procedure will consist of performing the hypothesis tests in the following prespecified 
order: 
1. Primary endpoint:  TMC change from screening period baseline to maintenance 
(valbenazine versus placebo treatment group). 
2. Secondary endpoint:  CGI-C response at Week 12 (valbenazine versus placebo treatment 
group).  
3. Secondary endpoint:  PGI-C response at Week 12 (valbenazine versus placebo treatment 
group). 
4. Secondary endpoint:  Neuro-QoL Upper Extremity Function change from baseline to 
Week 12 (valbenazine versus placebo treatment group). 
5. Secondary endpoint:  Neuro-QoL Lower Extremity Function change from baseline to 
Week 12 (valbenazine versus placebo treatment group). 
Each step in the sequential testing procedure uses a local two-sided 0.05 level of significance for 
the null hypothesis being tested.  The null hypothesis at each step of the procedure can only be 
rejected if all null hypotheses in prior steps were rejected. 
13.10.4. 
Exploratory Endpoints 
Endpoints not described in the preceding paragraphs are considered exploratory endpoints.  
Details regarding the definitions and analyses of these endpoints will be provided in the SAP. 
13.11. 
Safety Data 
Treatment-emergent adverse events (TEAEs), categorized by MedDRA SOC and/or PT will be 
summarized in frequency tables.  The TEAE summary tables will include the number and 

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percentage of unique subjects experiencing each event.  Summary tables will be presented for all 
TEAEs, severe TEAEs, TEAEs leading to study drug dose reduction, TEAEs leading to early 
discontinuation of study drug dosing, and SAEs. 
An AE overview summary table will be provided which summarizes the number and percentage 
of subjects with any TEAE, any TEAE leading to study drug dose reduction, any TEAE leading 
to discontinuation of study drug dosing, any SAE, and any TEAE resulting in death.  The 
summary table will also include the maximum TEAE intensity (mild, moderate, severe) reported 
for each subject. 
Clinical laboratory, vital signs, ECG, C-SSRS, UHDRS motor score (items for parkinsonism), 
BARS, and HADS data will be summarized with descriptive statistics.  Potentially clinically 
significant (PCS) values for selected clinical laboratory and vital signs variables will be 
summarized.  Prior and concomitant medications will be summarized according to WHO Drug 
Anatomical Therapeutic Chemical Classification (ATC) categories. 
13.12. 
Software 
Statistical calculations and summaries will be generated using 
. 
13.13. 
Interim Analysis 
An interim analysis is not planned for this study. 
14. 
REGULATORY AND ETHICAL ISSUES 
14.1. 
General Legal References 
The study will be carried out according to provisions of the US CFR, the US FDA, Canada Food 
and Drugs Act and Regulations, Health Canada, and the ICH Guidelines for GCP.  All clinical 
work conducted under this protocol is subject to GCP regulations.  This includes an inspection 
by NBI or its representative, health authority, or IRB/IEC representatives at any time.  The 
investigator must agree to the inspection of study-related records by health authority 
representatives and/or NBI or its designee. 
14.2. 
Institutional Review Board/Independent Ethics Committee 
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study site.  The 
committee’s decision concerning conduct of the study will be sent in writing to the investigator 
and a copy will be forwarded to NBI.  The investigator must agree to make any required progress 
reports to the IRB/IEC, as well as reports of SAEs, life-threatening problems, or death. 
14.3. 
Protocol Adherence – Amendments 
The protocol must be read thoroughly, and the instructions must be followed exactly.  Any 
changes in the protocol will require a formal amendment.  Such amendments will be agreed upon 
and approved in writing by the investigator and NBI.  The IRB/IEC will be notified of all 

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amendments to the protocol.  Amendments to the protocol will not be implemented until written 
IRB/IEC approval has been received. 
Any changes in protocol conduct necessary to immediately assure subject safety may be 
immediately implemented without subsequent review by the IRB and notification to the FDA.  
These changes must be documented as protocol deviations (until protocol amendment is 
approved). 
14.4. 
Required Documents 
The investigator must provide NBI or its designee with the following documents before the 
enrollment of any subject (originals should be kept by the investigator in the investigator’s study 
regulatory document binder): 
• Signed copy of the protocol signature page. 
• Investigator’s Brochure acknowledgement page. 
• Completed and signed statement of investigator qualifications, as applicable. 
• Financial disclosure documentation as required. 
• Curriculum vitae and current medical license of the investigator and sub-investigators. 
• Letter of approval from the IRB/IEC for both protocol and consent form. 
• Copy of the IRB/IEC approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
14.5. 
Informed Consent 
All subjects will provide informed consent before the performance of any study-related 
procedures.  Initial consent at screening must be performed at the study site.  Due to COVID-19, 
instances of reconsent may be performed remotely (process described in Appendix A).   
Each subject’s chart will include the signed ICF for study participation.  When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study. 
14.6. 
Study Monitoring 
Throughout the course of the study, the project manager and study monitor will make contacts 
with the investigator.  This will include study site monitoring.  The eCRFs will be reviewed for 
completeness and adherence to the protocol.  As part of the data audit, source documents will be 
made available for review by the study monitor.  The study monitor will also perform drug 
accountability checks and may periodically request review of the investigator study file to ensure 
completeness of documentation in all respects of clinical study conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.  The investigator or 
appointed delegate will receive the study monitor during on-site visits, provide appropriate 

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documentation electronically for remote visits, will cooperate in providing the documents for 
inspection, and will respond to inquiries.  In addition, the investigator will permit inspection of 
the study files by authorized representatives of the regulatory agencies. 
14.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s, HSG’s, and 
 standard operating 
procedures designed to ensure that all procedures are in compliance with GCP and FDA 
Guidelines, Health Canada Guidelines, and according to national law.  Quality assurance audits 
may be performed at the discretion of NBI. 
14.8. 
Record Retention 
Study records should be retained in compliance with the federal regulations and those of the 
study site. 
NBI 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, NBI must be informed of the individual 
who will be assuming this responsibility. 
14.9. 
Confidentiality 
NBI or its designee, and the study site affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy.  Throughout this study, all data will be identified only by 
an identification number. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of NBI; it 
shall not be disclosed to others without written consent of NBI; and shall not be used except in 
the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To allow the 
use of the information derived from this clinical study and to ensure compliance to current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
15. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study material be delivered to the study site.  Subject entry should not begin until after 
the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred.  All personnel expected to be involved in the conduct 
of the study will undergo orientation to include review of the study protocol, instructions for 
eCRF completion, AE reporting, and overall responsibilities including those for drug 
accountability and study file maintenance. 

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If the study is discontinued, all subjects should undergo a complete follow-up examination.  Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 

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16. 
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APPENDIX A. GUIDANCE TO ADDRESS GLOBAL HEALTH 
EMERGENCIES AND POTENTIAL IMPACT ON THE 
CLINICAL STUDY 
Due to the global COVID-19 pandemic and in alignment with guidance put forth by the US Food 
and Drug Administration (FDA; Conduct of Clinical Trials of Medical Products During the 
COVID-19 Public Health Emergency [March 2020, updated December 2020]) and Health 
Canada (Management of Clinical Trials During the COVID-19 Pandemic: Notice to Clinical 
Trial Sponsors [September 2020]), the following revisions have been made in the event that a 
subject is unable to attend an in-person visit (eg, subject is unable to travel to the site for safety 
reasons or as part of public health measures).  Remote visits are to be conducted on a 
case-by-case basis at the judgement of the investigator and in consultation with the study medical 
monitor; once able, the subject is to return to in-person visits at the study site. 
Informed Consent 
In the situation where reconsent is necessary (eg, updated ICF, protocol amendments, etc.) and 
the subject is unable to print the informed consent document provided electronically by the 
investigator and an electronic signature process is not available, the investigator may consider 
using the following alternative process for obtaining and documenting informed consent.  This 
process is not applicable for initial ICF signing at the screening visit which must be performed at 
the study site. 
1. The investigator provides the subject with an electronic version of the informed consent 
document. 
2. The investigator arranges a telephone call with the subject, the investigator, a witness 
who is not otherwise connected with the study and, if desired and feasible, additional 
participants requested by the subject.  Alternatively, in lieu of having a witness present, 
the conversation may be recorded. 
3. To ensure that all subjects are treated consistently, a standard process should be used that 
will accomplish the following: 
• Identification of who is on the call. 
• Review of the informed consent document with the investigator and responses to any 
questions the subject may have. 
• Verbal confirmation by the subject that their questions have been answered and that 
they agree to participate in the study. 
4. Verbal confirmation by the subject that they signed and dated a blank piece of paper with 
a written statement that they voluntarily agree to participate in the study, noting both the 
protocol number and brief protocol title. 
5. After signing and dating the newly created document, the subject sends a photograph of 
the signed and dated statement by facsimile, text message, or email to the investigator.  
The subject may also return the document to the investigator by mail at a later date, or at 
a future study visit that may occur at the study site. 

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6. When using a witness, documentation in the study records includes a signed and dated 
attestation by the witness who participated on the call that the subject confirmed their 
agreement to participate in the study and signed the document referenced above. 
7. When using a recording in lieu of using a witness, documentation in the study records 
includes the recording of the conference call. 
8. After the signed and dated document is received by study staff, it should be appended to a 
copy of the consent document that was reviewed with the subject and retained in the 
study records as would normally be done for a signed informed consent document.  
Additionally, a note should be made in the study records explaining the reason why 
informed consent was obtained through an alternative method.  The case history for each 
subject must document that informed consent was obtained prior to participation in the 
study. 
Data Collection, Transfer, and Storage 
When an assessment is conducted remotely, the investigator will document the date of the 
assessment, the person who conducted the assessment, and the type of technology used.  Remote 
data acquisition, transmission, and storage will be secured, and the privacy of study subjects will 
be protected.  Any electronic platforms used to transmit data into study records will include 
automated audit trails. 
Communication during remote visits between the investigator, subject, and home health 
professional will be conducted by audio telephone call. 
Remote Study Visits and Assessments 
Study Visits 3 to 6 (Weeks 2 to 8) and Study Visit 9 (Week 14) have a window of ±3 days.  The 
following sequence of events must be completed within this visit window (see Table 6 for full 
list of assessments): 
1. Remote visit and dosing decision (approximately 1 day). 
a. Vitals, ECG, and urine and blood samples are collected. 
b. Patient-reported outcome (PRO) assessments (HADS, PGI-C, PGI-S, and 
Neuro-QoL) are completed. 
c. Investigator and/or qualified designee conducts telephone call with subject and home 
health professional to conduct the investigator assessments per Table 6. 
d. Home health professional reports vitals and ECG values to investigator via telephone 
call. 
e. Investigator reviews initial data obtained over telephone call and makes dosing 
decision based on tolerability. 
2. Shipment of study drug kit directly to subject (at least 1 full day). 
3. Subject receives study drug kit.  Investigator confirms dosing decision after full 
assessment of data obtained at remote visit. 
4. Subject begins dosing from the new study drug kit, as instructed by the investigator. 

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It is the responsibility of the investigator, not the home health professional, to assess the data 
obtained during the remote visit. 
The investigator should make all attempts to prevent any gaps in dosing. 
Table 6 presents the visits and assessments that may be conducted remotely.  Assessments will 
be conducted by a home health professional, the subject, and the investigator and/or qualified 
designee as indicated below. 

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Table 6: 
Schedule of Remote Assessments for Subjects Impacted by COVID-19 
Procedurea 
Performed by 
Dose-Adjustment Period 
Follow-up 
ET 
Unscheduledb 
Weekc 
Day 1 
2 
4 
6 
8 
14d 
NA 
NA 
 
Visitc 
-- 
3 
4 
5 
6 
9 
NA 
NA 
Vital signs 
Home health professionale 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
Home health professionale 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testg 
Home health professionale 
 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X 
Clinical laboratory testsh 
Home health professionale 
 
X 
X 
X 
X 
X 
X 
X 
Blood sample for prolactin 
Home health professionale 
 
 
 
 
X 
X 
X 
 
Blood for PK assessmentsi 
Home health professionale 
 
X 
X 
X 
X 
X  
X  
X 
Study drug accountabilityj 
Home health professionale 
 
X 
X 
X 
X 
 
 
 
HADS 
Subjectk 
 
X 
X 
X 
X 
X 
X 
X 
PGI-C 
Subjectk 
 
X 
X 
X 
X 
X 
X 
 
PGI-S 
Subjectk 
 
X 
X 
X 
X 
X 
X 
 
Neuro-QoLl 
Subjectk 
 
 
X 
 
X 
X 
X 
 
C-SSRS 
Investigatorm 
 
X 
X 
X 
X 
X 
X 
X 
UHDRS (full, excluding motor and cognition) 
Investigatorm 
 
 
 
 
 
X 
X 
 
UHDRS (behavior) 
Investigatorm 
 
X 
X 
X 
X 
 
 
X 
AE monitoring 
Investigatorm 
 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
Investigatorm 
 
X 
X 
X 
X 
X 
X 
X 
Ship study drug 
Study siten 
 
X 
X 
X 
X 
 
 
 
Study drug dosingo 
Subjectj 
X 
X 
X 
X 
X 
 
 
 
AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; HADS=Hospital Anxiety and 
Depression Scale; NA=not applicable; Neuro-QoL=Quality of Life in Neurological Disorders; PGI-C=Patient Global Impression of Change; PGI-S=Patient 
Global Impression of Severity; PK=pharmacokinetic; QTcF=corrected QT interval using Fridericia’s formula; s=serum; TFC=Total Functional Capacity; 
u=urine; UHDRS=Unified Huntington’s Disease Rating Scale. 
a As much as possible, all remote study visits should occur at approximately the same time of day to standardize the time of day for the assessment of 
efficacy, safety, and drug exposure. 
b Assessments during unscheduled visits may be performed at the investigator’s discretion. 
c Day 1 is the first day of dosing; study drug will be self-administered.  Study visits 3 to 6 and study visit 9 (end of Weeks 2, 4, 6, 8 and 14) have a visit 
window of ±3 days. 
d Final study visit (±3 days) for subjects who complete the study; subjects who withdraw from the study should complete an early termination visit (ie, 
assessments listed for the Week 12 visit).  Subjects may discontinue study drug dosing, but should continue participation in the study. 
e Home health professional will be responsible for obtaining vital signs, ECG, pregnancy test, clinical laboratory tests, blood samples for prolactin and PK 
assessments, and recording study drug accountability. 
f A standard 12-lead ECG will be conducted in triplicate (at least 1 minute apart and within approximately 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). 
g Pregnancy tests are required for women of childbearing potential. 
h Clinical laboratory tests include hematology, clinical chemistry, and urinalysis.  All blood samples will be obtained under non-fasted conditions. 

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i Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
j Subjects will return all used and unused study drug and a compliance check will be performed by counting the capsules returned at each study visit. 
k Subject will be provided HADS, PGI-C, PGI-S, and Neuro-QoL questionnaires to be self-administered. 
l The Neuro-QoL assessments will include both the Upper Extremity Function Short Form and the Lower Extremity Function Short Form. 
m UHDRS, C-SSRS, AEs, and prior and concomitant medications will be assessed by the investigator or qualified designee via a telephone call with subject. 
n Study site will ship study drug kit directly to subject. 
o Subject will take study drug at home at approximately the same time of day each day.