Clinical trial NCT04102579
Conditions: Chorea, Huntington
Keywords: Huntington's Huntington Chorea Movement disorder Valbenazine HD Tetrabenazine VMAT2-Inhibitor
Sponsor: Neurocrine Biosciences
Start date: 2019-11-13; Completion date: 2021-10-26
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of valbenazine to treat chorea in participants with Huntington disease.

Detailed description:

Arms: arm 1: Capsule, administered orally once daily for 12 weeks. arm 2: Capsule, administered orally once daily for 12 weeks.
Interventions: intervention 1: Valbenazine intervention 2: Placebo
Intervention descriptions: intervention 1: vesicular monoamine transporter 2 (VMAT2) inhibitor intervention 2: non-active dosage form

Protocol documents:
Prot_000.pdf: 


Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
Clinical Protocol Amendment No. 5 Final Version 
12 April 2021 
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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)






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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 
12 April 2021 
Confidential 
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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). 


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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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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 


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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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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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Jun;67(6):361-70. 


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12 April 2021 
Confidential  
67 
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. 


Neurocrine Biosciences, Inc., Study No. NBI-98854-HD3005 
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12 April 2021 
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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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Clinical Protocol Amendment No. 5 Final Version 
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Confidential  
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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. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
PHASE 3 
 
Version:
1.0 
Date:
19 November 2021 
Based on Protocol:
Amendment No. 5 Final Version: 12 April 2021 
  
 
 
  
 
  
 
Study Drug:
NBI-98854 
Study Number:
NBI-98854-HD3005 
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 
Study Sponsor:
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Telephone:  
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
CONFIDENTIAL 
 
 
 


Neurocrine Biosciences, Inc. 
 
Study NBI-98854-HD3005  
Statistical Analysis Plan 
 
19 November 2021 
 
 
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SIGNATURE PAGE 
This document has been prepared by:  
 
 
 
Electronically Signed and Dated 
 
 
 
Neurocrine Biosciences, Inc. 
 
Signature 
 
Date 
 
 
 
 
 
 
 
This document has been reviewed by:  
 
 
 
Electronically Signed and Dated 
 
 
 
Neurocrine Biosciences, Inc. 
 
Signature 
 
Date 
 
 
 
 


Neurocrine Biosciences, Inc. 
 
Study NBI-98854-HD3005  
Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES ................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Randomization ............................................................................................................10 
3.2. 
Blinding ......................................................................................................................10 
3.3. 
Sample Size Considerations .......................................................................................10 
4. 
ENDPOINTS ..............................................................................................................12 
4.1. 
Primary Efficacy .........................................................................................................12 
4.2. 
Secondary Efficacy .....................................................................................................12 
4.3. 
Exploratory Efficacy ...................................................................................................12 
4.4. 
Safety Endpoints .........................................................................................................13 
4.5. 
Pharmacokinetics Endpoint ........................................................................................13 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ....................................14 
5.1. 
General Statistical Procedures ....................................................................................14 
5.2. 
Analysis Sets ...............................................................................................................14 
5.3. 
Baseline and Maintenance Definition .........................................................................15 
5.4. 
Derived and Transformed Data ..................................................................................15 
5.5. 
Study Day ...................................................................................................................15 
5.6. 
Handling of Missing Data ...........................................................................................16 
5.6.1. 
Missing Assessments ..................................................................................................16 
5.6.2. 
Missing Dates .............................................................................................................16 
5.6.2.1. 
First and Last Dose Dates ...........................................................................................16 
5.6.2.2. 
Start Date for Adverse Events and Start and Stop Dates for Prior and 
Concomitant Medications ...........................................................................................17 
5.7. 
Coding Dictionaries ....................................................................................................17 
5.8. 
Impact of COVID-19 ..................................................................................................17 
6. 
STUDY POPULATION .............................................................................................19 
6.1. 
Disposition ..................................................................................................................19 
6.2. 
Protocol Deviations ....................................................................................................19 
6.3. 
Demographic and Other Baseline Characteristics ......................................................20 
7. 
EFFICACY .................................................................................................................21 


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7.1. 
Multiple Comparisons and Multiplicity Adjustment ..................................................21 
7.2. 
Interim Analysis ..........................................................................................................21 
7.3. 
Primary Efficacy Endpoint .........................................................................................21 
7.3.1. 
Sensitivity Analysis of Primary Efficacy Variable .....................................................22 
7.3.2. 
Supplementary Analysis of Primary Efficacy Variable ..............................................24 
7.4. 
Secondary Efficacy Endpoints ....................................................................................24 
7.5. 
Other Efficacy Endpoints ...........................................................................................26 
7.5.1. 
Clinical Global Impression-Severity (CGI-S) ............................................................26 
7.5.2. 
Patient Global Impression-Severity (PGI-S) ..............................................................26 
7.5.3. 
Short Form 36 Health Survey (SF-36)........................................................................26 
7.5.4. 
Huntington Disease Health Index (HD-HI) ................................................................27 
7.5.5. 
EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) ............................................................27 
7.5.6. 
UHDRS Scores for Motor, Cognitive, Behavior, and Functional Capacity 
Assessment at Weeks 2 through 12 ............................................................................27 
7.5.7. 
Other UHDRS Scores including Functional Assessment and Independence 
Scale at Week 12 ........................................................................................................28 
7.5.8. 
Anosognosia Scale (AS) at Week 12 ..........................................................................28 
7.5.9. 
 ...............................28 
7.5.10. 
Examination of Subgroups .........................................................................................28 
8. 
PHARMACOKINETICS ...........................................................................................30 
9. 
SAFETY .....................................................................................................................31 
9.1. 
Study Drug Dosing and Compliance ..........................................................................31 
9.2. 
Adverse Events ...........................................................................................................31 
9.2.1. 
Adverse Events Leading to Premature Discontinuation of Study Drug .....................32 
9.2.2. 
Adverse Events Leading to Study Drug Dose Reductions .........................................32 
9.2.3. 
Deaths and Other Serious Adverse Events .................................................................32 
9.3. 
Laboratory Safety Parameters .....................................................................................32 
9.4. 
Vital Signs ..................................................................................................................34 
9.5. 
Body Weight ...............................................................................................................35 
9.6. 
Electrocardiogram (ECG) ...........................................................................................35 
9.7. 
Other Safety Endpoints ...............................................................................................36 
9.7.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................36 
9.7.2. 
UHDRS Motor Score (Items for Parkinsonism) .........................................................37 


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9.7.3. 
Barnes Akathisia Rating Scale (BARS) .....................................................................37 
9.7.4. 
Hospital Anxiety and Depression Scale (HADS) .......................................................38 
10. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS .................................39 
11. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................40 
12. 
REFERENCES ...........................................................................................................41 
 
LIST OF TABLES 
Table 1: 
Analysis Visit Windows .............................................................................................15 
Table 2: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables ............34 
Table 3: 
Potentially Clinically Significant Criteria for Vital Signs Variables ..........................35 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................10 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
ANC 
Absolute neutrophil count 
AS 
Anosognosia Scale 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale  
BMI 
Body mass index 
CAG 
Cytosine Adenine Guanine  
CGI 
Clinical Global Impression 
CGI-C 
Clinical Global Impression-Change 
CGI-S 
Clinical Global Impression-Severity  
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019  
CRS-PSP 
Clinical Rating Scale for Progressive Supranuclear Palsy  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Levels 
ET 
Early termination 
FAS 
Full analysis set 
GGT 
Gamma-glutamyl transferase 
HADS 
Hospital Anxiety and Depression Scale  
HD 
Huntington Disease  
HD-HI 
Huntington Disease Health Index  
IPD 
Important protocol deviation 
IWRS 
Interactive web response system 
LS 
Least-squares  


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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Multiple imputation 
MMRM 
Mixed-effect model for repeated measures 
MoCA 
Montreal Cognitive Assessment 
NBI 
Neurocrine Biosciences, Inc. 
Neuro-QoL 
Quality of Life in Neurological Disorders  
PCS 
Potentially clinically significant 
PGI-C 
Patient Global Impression-Change 
PGI-S 
Patient Global Impression-Severity 
PK 
Pharmacokinetics  
PT 
Preferred term 
QTcF 
Corrected QT interval using Fredericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDQ 
Swallowing Disturbance Questionnaire  
SE 
Standard error 
SF-36 
Short Form 36 Health Survey  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TFC 
Total functional capacity  
TMC 
Total Maximal Chorea  
TMS 
Total Motor Score 
UHDRS  
Unified Huntington’s Disease Rating Scale  
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays that will be prepared to summarize the data from the Phase 3 Study NBI-98854-HD3005 
(HD3005 hereafter). 
This SAP was developed in accordance with International Council for Harmonization E9 
guidance. All decisions regarding the final analysis will be made prior to database lock and 
unblinding of the study data and will be documented in this SAP. Changes to the planned 
analyses described in this SAP will be statistically justified and described in the study report. 
Further information related to study design and methodology can be found in the study protocol. 
 


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2. 
STUDY OBJECTIVES 
Primary Study Objective:  
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. 
 
 
 
 
 


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3. 
STUDY DESIGN 
This is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, 
safety, and tolerability of once-daily 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.  
The study design schematic is shown in Figure 1. 
 
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. 
 
3.1. 
Randomization 
Approximately 120 adult male and female subjects with motor manifest HD and a genetic diagnosis 
of HD will be enrolled. Eligible subjects will be randomized 1:1 to either valbenazine or placebo on 
Day -1 (baseline) using an interactive web response system (IWRS).   
3.2. 
Blinding 
This study includes a 12-week double-blind placebo-controlled treatment period during which the 
subject, investigator, all study center personnel, and the sponsor (or designee) will be blinded to the 
subject’s treatment until the end of study. During the treatment period, all subjects will receive 
valbenazine or placebo as two capsules (identical in appearance) to be self-administered once daily. 
3.3. 
Sample Size Considerations 
A total sample size of 120 subjects (60 per treatment 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 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 
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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4. 
ENDPOINTS  
The efficacy, safety, pharmacokinetics (PK) and other endpoints are briefly described below. 
Detailed definitions and planned methods of analysis are provided in the following sections on 
efficacy (Section 7), pharmacokinetics (Section 8), and safety (Section 9).  
4.1. 
Primary Efficacy 
The primary efficacy endpoint is 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.   
4.2. 
Secondary Efficacy 
The secondary efficacy endpoints are: 
 CGI-C response status at Week 12  
 PGI-C response status at Week 12  
 The change from baseline (Day -1) to Week 12 in the Neuro-QoL Upper Extremity 
Function T-score  
 The change from baseline (Day -1) to Week 12 in the Neuro-QoL Lower Extremity 
Function T-score 
4.3. 
Exploratory Efficacy  
 Changes from the screening period baseline to each postbaseline study visit (Weeks 2 
through 12) in the TMC based on site assessments 
 Changes from the screening period baseline to maintenance (the average of the Week 
10 and Week 12 assessments) in the TMC based on video recording central rater 
assessments 
 CGI-C response statuses at Weeks 2 through 10 
 PGI-C response statuses at Weeks 2 through 10 
 The change from baseline to Weeks 4, 8, and 10 in the Neuro-QoL Upper Extremity 
Function T-score 
 The change from baseline to Weeks 4, 8, and 10 in the Neuro-QoL Lower Extremity 
Function T-score 
 Clinical Global Impression of Severity (CGI-S) at Weeks 2 through 12  
 Patient Global Impression of Severity (PGI-S) at Weeks 2 through 12 
 Short Form 36 Health Survey (SF-36) at Week 12 
 Huntington Disease Health Index (HD-HI) at Week 10 and Week 12 
 EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) at Week 10 and Week 12 


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Study NBI-98854-HD3005  
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 UHDRS scores for motor, behavior, and functional capacity assessment at Weeks 2 
through 12 
 Other UHDRS scores including functional assessment and independence scale at 
Week 12 
 Anosognosia Scale (AS) at Week 12 
 
 
 
4.4. 
Safety Endpoints  
 Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), severe 
TEAEs, AEs leading to study drug dose reduction, and AEs leading to 
discontinuation of study drug dosing  
 Clinical laboratory tests (including hematology and clinical chemistry) 
 Prolactin 
 Vital signs (including orthostatic blood pressure and pulse rate, respiratory rate, and 
oral body temperature) 
 12-lead Electrocardiogram (ECG)  
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 UHDRS motor assessment for parkinsonism (items rating retropulsion pull test, finger 
taps, pronate/supinate hands, rigidity-arms, and bradykinesia-body) 
 Barnes Akathisia Rating Scale (BARS) 
 Hospital Anxiety and Depression Scale (HADS) 
4.5. 
Pharmacokinetics Endpoint 
The PK endpoint is plasma concentrations of valbenazine and the metabolite (NBI-98782).  


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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the study database. Analyses defined subsequent to locking the database will be 
considered post hoc analyses and will be applied as exploratory methodology. Any pertinent post 
hoc analyses will be statistically justified and described in the clinical study report. Statistical 
analysis will be conducted, and all tables, figures, and listings generated using SAS® software 
, unless stated otherwise. 
5.1. 
General Statistical Procedures 
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, standard deviation (SD) or standard error (SE), minimum, and maximum for continuous 
and ordinal categorical variables. Number and percentage of subjects will be summarized for 
categorical 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. All hypothesis tests will be tests of the null 
hypothesis of no difference between the groups being compared versus the two-sided alternative 
hypothesis that there is a difference. The level of significance (type I error) for declaring 
statistical significance will be 0.05. 
Summary statistics will be presented using the following decimal precision (ie, number of digits 
to the right of the decimal point): the minimum and maximum will have the same number of 
decimal places as the data; the mean, median, SD and SE will have one more decimal place than 
the data being summarized; and the sample size (N) will be reported as an integer. This rule may 
be modified if warranted, based on practical considerations.  
All available study data will be included in relevant data displays, including data for subjects 
with incomplete or missing values. Replacement of missing data values with imputed values will 
generally not be performed unless specified otherwise in relevant endpoint subsections. 
5.2. 
Analysis Sets 
The following 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 post baseline 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 (based on on-site assessments) during the 12-week double-blind treatment 
period.  
 The PK analysis set will include all randomized subjects who receive a dose of study 
drug and have at least one post-dose PK sample qualified. The PK analysis set will be 
used for summary of plasma concentration.    
Summaries of subject disposition, randomization by study site, analysis set inclusion/exclusion 
status, and IPDs will be based on all randomized subjects.  


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Efficacy summaries and demographics/baseline characteristics are based on FAS. The FAS 
consists of all randomized subjects analyzed according to the treatment group to which they were 
randomly assigned. 
All other summaries are based on safety analysis set. The safety analysis set consists of all 
randomized and treated subjects analyzed according to the treatment group to which they were 
randomly assigned unless they received the wrong treatment for the entire treatment period. 
5.3. 
Baseline and Maintenance Definition 
For efficacy analysis purpose, unless otherwise specified, the assessments collected at 
randomization visit will serve as the baseline value. If the randomization visit value is not 
available, then the last measurement collected prior to randomization will serve as baseline. For 
TMC analysis, the screening period baseline is defined as the average of the screening and 
Day -1 assessments. If one of the assessments is not available, the available assessment will 
serve as screening period baseline. The maintenance value is defined as the average of the Week 
10 and Week 12 assessments. If one of the assessments is not available, the available assessment 
will serve as the maintenance value. 
For other analyses, the assessments collected at Day -1 prior to study drug will serve as the 
baseline value for all assessments. If a Day -1 visit value is not available, then the last 
measurement collected prior to study drug will serve as baseline. 
5.4. 
Derived and Transformed Data 
Change from baseline is calculated as the post-baseline value minus the baseline value; a 
negative value will represent a decrease at the post-baseline visit. Percent change from baseline 
is calculated as (change from baseline/baseline value × 100).  If either the baseline or 
postbaseline value is missing, the change from baseline and/or percent change from baseline will 
also be missing. The percent change from baseline will also be missing if the baseline value is 
equal to zero. 
5.5. 
Study Day 
Study day is calculated relative to the first dose date. The visit number for each visit, including 
scheduled, unscheduled, repeat, and early termination/end of study visits, will be re-mapped 
based on the actual study day according to Table 1. If multiple measurements occur within the 
same visit window after mapping, the measurement that is closest to the target study day will be 
used for the summary tables where one observation per visit is needed, unless otherwise 
specified. Where there are ties between the earlier and later observation within the visit window, 
the earlier observation will be used. 
Table 1: 
Analysis Visit Windows 
Scheduled Visit 
Target Study Day 
Analysis Window 
(Study Day Range) 
Week 2 
14 
1-21 
Week 4 
28 
22-35 


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Scheduled Visit 
Target Study Day 
Analysis Window 
(Study Day Range) 
Week 6 
42 
36-49 
Week 8 
56 
50-63 
Week 10 
70 
64-77 
Week 12 
84 
78-91 
Week 14 
98 
92+ 
5.6. 
Handling of Missing Data 
5.6.1. 
Missing Assessments 
Missing values for assessments will generally not be replaced with imputed values except as 
noted in Section 5.5 for the ET visit data mapped to scheduled visits for data summary purposes. 
Any imputation methods used for the efficacy endpoints are further discussed in the section of 
efficacy (Section 7). 
5.6.2. 
Missing Dates  
5.6.2.1. 
First and Last Dose Dates 
Missing and incomplete (“partial”) dates for first and last dose dates will be imputed for the 
purpose of estimating exposure and defining treatment periods. Missing dates will not be 
imputed for subjects when the subject is known to have not taken at least one dose of study drug, 
as documented by the site in the dosing electronic case report form (eCRF).  
The imputation rules for first dose date are as follows: 
 If the date is completely missing or if both the day and month are missing, the date 
will be imputed as the randomization date 
 If only the day is missing, the date will be imputed as the randomization date if the 
month and year match the month and year of the randomization date; if the month or 
year occur after the randomization date, the missing day will be imputed as the first 
day of the month. 
If the date of the last dose of study drug is missing, then the last dose date will be imputed as the 
earliest of:  
 The Week 12 visit date,  
 The end of treatment date for subjects who discontinue on or before Week 12,  
 The last visit (up to Week 10) prior to discontinuation or the date of an unscheduled 
dose reduction, whichever occurs later. 


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5.6.2.2. 
Start Date for Adverse Events and Start and Stop Dates for Prior and 
Concomitant Medications 
Missing and incomplete (“partial”) dates for AEs and concomitant medications will be imputed 
for the purpose of estimating the time of the event or medication usage in relationship to study 
drug. Any data listings will display the original dates as reported in the database.   
To handle missing/partial start dates for adverse events, investigators will be asked to respond 
“Yes” or “No” on the eCRF as to whether the AE started after the subject took the first dose of 
study drug. An AE with a response of “Yes” will be classified as a TEAE. If the investigator’s 
response is missing, then the treatment emergent status will be derived based on the AE onset 
date and time relative to the date and time of the subject’s first dose of study drug.  
The missing and incomplete (“partial”) dates for AEs will be imputed using the following 
algorithm. For start date: missing day (impute the 1st of the month unless the same month and 
year as the study drug, otherwise impute the first dose date of study drug); missing day and 
month (impute 1st January, unless the same year as the study drug, otherwise impute the first 
dose date of study drug). There will be no imputation for AE stop dates. 
To handle missing/partial dates for prior and concomitant medications, the following algorithm 
will be employed to estimate the time of medication usage relative to study drug. For start date: 
missing day (impute the 1st of the month, if the same month and year as the study drug, otherwise 
impute the first dose date of study drug); missing day and month (impute 1st January, if the same 
year as the study drug, otherwise impute the first dose date of study drug). For stop date: missing 
day (impute the last day of the month if the same month and year as the study drug, otherwise 
impute the last dose date of study drug); missing day and month (impute 31st December, if the 
same year as the study drug, otherwise impute the last dose date of study drug). If any of the 
above imputations result in a start date that is later than an existing (not imputed) stop date for 
the event, the start date will be imputed as the stop date. If any of the above imputations result in 
a stop date that is earlier than an existing (not imputed) start date for the event, the stop date will 
be imputed as the start date. 
5.7. 
Coding Dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Prior and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
5.8. 
Impact of COVID-19 
Due to the global Coronavirus Disease 2019 (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 
January 2021]) and Health Canada (Management of Clinical Trials During the COVID-19 
Pandemic: Notice to Clinical Trial Sponsors [May 2021]), the following summaries will be 
conducted to evaluate the impact of the COVID-19 pandemic, including but not limited to: 
 A listing of all subjects affected by the COVID-19 pandemic will be generated. The 
listing will identify subjects that experience one of the following situations due to the 
COVID-19 pandemic (additional situations may be included): 


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 Discontinued study drug or withdrew from study 
 Presumed or confirmed diagnosis of COVID-19 
 Had at least one COVID-19 pandemic-related major protocol deviation 
 Missed at least one study visit or assessment  
 Had at least one assessment collected in a non-standard way (eg, remotely) 
 Had at least one study drug interruption  
 A table and/or listing will summarize the COVID-19 pandemic-related reasons for 
treatment and study discontinuation. 
 A table and listing will summarize the COVID-19 pandemic-related major protocol 
deviations.  
 A table will summarize assessments affected by the COVID-19 pandemic (eg, 
missing, partial, collected remotely). 
 Adverse events of diagnosed or presumed COVID-19 infections will be included in 
the standard summaries of TEAEs and SAEs.  
 The impact of the COVID-19 pandemic on the primary efficacy endpoint (and 
secondary endpoints, where appropriate) will be performed.  


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6. 
STUDY POPULATION 
6.1. 
Disposition 
The summary of subject enrollment and disposition will include:  
 The total number of subjects who provided informed consent and were screened 
 The following categories will be presented by treatment group and overall. The 
number of subjects randomized will serve as the denominator to calculate 
percentages. 
 Randomized subjects 
 Randomized but not treated subjects 
 Full Analysis Set 
 Safety Analysis Set 
 Completed the dose-adjustment period (ie, up to Week 8) 
 Completed the dose maintenance period (ie, up to Week 12) 
 Completed study drug dosing 
 Completed study 
 Discontinued study drug prematurely, including reasons for discontinuation. 
Discontinuation of study drug due to COVID-19 will also be summarized. 
 Discontinued study, including reasons for discontinuation. 
A separate summary of randomization by study site will be presented.  This summary will 
display the number of subjects randomized to each treatment group by site. 
6.2. 
Protocol Deviations 
Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into 
the clinical trial management system. Prior to database lock, all major protocol deviations that 
have been entered into the clinical trial management system will be exported to a file and 
integrated into the study data.  
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being. An assessment of IPDs will be performed prior to database 
lock and unblinding of the randomized treatment assignments. This study team will review a 
listing of all protocol deviations reported in the study database and determine which deviations 
are IPDs.  
A summary of the number and percentage of subjects with IPDs by deviation category and 
treatment group will be provided. 
All major protocol deviations will be presented in a data listing and any that are classified as 
IPDs will be flagged in the listing. 


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The COVID-19 pandemic-related major protocol deviations will be summarized and listed. 
 
6.3. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics data will be summarized using descriptive statistics for 
continuous variables, and frequency counts and percentages for categorical variables. Results 
will be presented by treatment group and overall based on Full Analysis Set.  
Demographics include: 
 Age (years) 
 Age categories (<65 years versus ≥65 years) 
 Sex 
 Ethnicity 
 Race 
 Country (US and Canada) 
Baseline subject characteristics include, but not limited to: 
 Height (measured at screening, cm) 
 Weight (presented in kilograms) 
 Body mass index (BMI; measured at screening; kg/m2) 
 CAG repeat length 
 
 phenotype status 
 Montreal Cognitive Assessment (MoCA) 
 Swallowing Disturbance Questionnaire (SDQ) 
 Baseline TMC based on site assessments 
 Baseline CGI-S categories (<4, >=4) 
 Baseline PGI-S categories (<3, >=3) 


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7. 
EFFICACY 
The efficacy endpoints and planned analysis methods are described below. Unless otherwise 
specified, the Full Analysis Set will be used for all efficacy analyses, and descriptive statistics 
presented by treatment group (valbenazine vs. placebo) according to the study visit.  
7.1. 
Multiple Comparisons and Multiplicity Adjustment 
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. 
7.2. 
Interim Analysis 
No interim analysis is planned for this study.  
7.3. 
Primary Efficacy Endpoint 
The UHDRS is a tool developed by the Huntington Study Group (HSG) to assess the clinical 
features and course of HD.  The full UHDRS includes the following assessments:  motor, 
cognitive, behavioral, independence, function, and total functional capacity (TFC).   
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 primary estimator is the mean treatment 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) in the TMC score based on on-site assessments to maintenance (the 
average of the Week 10 and Week 12 assessments), in all randomized subjects, regardless of 
adherence to study drug. The primary analysis will be based on observed TMC scores. For 


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sensitivity analysis, subjects who are missing TMC scores at treatment visits will have their data 
imputed using observed data from other subjects through a multiple imputation procedure. 
Changes from the screening period baseline to each postbaseline study visit (Weeks 2 through 
12) and changes from the screening period baseline to maintenance (the average of the Week 10 
and Week 12 assessments) in the TMC based on video recording central rater assessments 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 
the screening period 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 comparing treatment groups at the individual postbaseline 
visits will also be reported in the summary tables.  
An example of the SAS® software code is provided below:  
 
 
 
   
 
 
 
 
 
 
  
          
 
  
 
 
7.3.1. 
Sensitivity Analysis of Primary Efficacy Variable 
The following sensitivity analyses will be performed for the primary endpoint with differing 
assumptions to explore the robustness of inferences from the main estimator: 
 Multiple imputation (MI) analysis assuming data are missing at random (MAR): This 
methodology will structure data based on missing data patterns. The method will be 
based on a missingness pattern having a monotone structure, ie, if among the 
observations over time one data value is missing, all other values after this missing 
value will also be treated as missing. For subjects with intermittent missing values, 
before performing MI, a monotone missingness pattern will be generated by imputing 


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for the intermittent missing values using the Markov Chain Monte Carlo (MCMC) 
method, which assumes a multivariate normal distribution among all variables 
included in the imputation model. The MI procedure using SAS® software will be 
employed for this purpose and this first MI step is planned to be repeated 1000 times, 
creating several different datasets with a monotone missing data structure. The 
imputation is based on the MAR assumption, ie, the missing data are assumed to 
follow the same model as the other subjects in their respective treatment arm.  
The following SAS® software code will be used to generate the monotone missing 
data pattern: 
 
 
 
   
 
 
 
 
After this step, the remaining missing data will be imputed using a method for 
monotone missingness, also based on the MAR assumption. Thus, for each created 
dataset with a monotone missing data pattern, the MI procedure using SAS® software 
will be employed to impute missing values based on a sequential procedure reflecting 
the monotone missing data pattern. Subjects with the first missing value occurring at 
Week 2 will have their missing Week 2 value replaced by an imputed value from a 
regression model with treatment group and screening period baseline TMC score as 
explanatory variables. In the next step, subjects with their Week 4 value missing will 
have their missing Week 4 value replaced by an imputed value from a regression 
model with treatment group, the screening period baseline value and the Week 2 
value as explanatory variables. A similar procedure will be used to replace the 
missing values at Week 6, Week 8, Week 10, and Week 12. 
The following SAS® software code will be used to perform the imputation with the 
MAR assumption: 
 
 
 
  
  
   
 
  
 
 
The imputed datasets generated with the approach described above contain only 
non-missing values and are used as input in the model for the sensitivity analysis of 
the primary endpoint. MMRM models similar to that described for the primary 
analysis will thus be run on each of the 1000 generated imputed datasets and the 
difference between the treatment groups at maintenance visit will be estimated. 


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Finally, the MIANALYZE procedure using SAS® software will be applied to 
combine the results from these analyses to derive an overall estimate of the treatment 
difference at the maintenance visit. In addition to the estimates, corresponding 95% 
CIs and p-values will be calculated. 
The following SAS® software code will be used to complete the three-step process: 
 
 
 
  
 
 
 MI analysis assuming data are not missing at random (MNAR): The trajectories of 
the subjects are assumed to follow the placebo group after the discontinuation (ie, 
control group-based assumption). The procedure aforementioned will be used to 
generate monotone missing data. After this, the missing data will be imputed 
sequentially for each visit (first Week 2, followed by Week 4, followed by Week 6, 
followed by Week 8, followed by Week 10, and followed by Week 12). Only data 
from the control group will be used for the imputation. The MNAR statement of the 
following type will be used to generate the imputation: 
 
 Tipping point analysis (MNAR): The tipping point assumption will be used, ie, after 
the first visit with missing data, the trajectories of the subjects in the valbenazine 
group are assumed to be worse by an amount of delta. After the MI using the MAR 
assumption, as defined previously, an amount of delta will be added to each imputed 
value in the valbenazine group. Successively harsher deltas will be imposed on the 
imputed values in the valbenazine group, starting with a TMC score increase 
(worsening) of 1. The delta is further increased in the steps of 1 (ie, +1, +2, +3, …) 
until the statistical significance is lost, ie, until the p-value becomes ≥0.05. For the 
control group, the MI using MAR assumption will be used. 
7.3.2. 
Supplementary Analysis of Primary Efficacy Variable 
The following supplementary analyses will be performed for the primary efficacy endpoint: 
 Completers analysis using all subjects in the Full Analysis Set with non-missing data 
for the primary endpoint at all scheduled post-baseline visits up to the Week 12 visit. 
 COVID-19 impact analysis excluding all subjects who discontinued study drug 
dosing prematurely due to COVID-19. 
7.4. 
Secondary Efficacy Endpoints 
The CGI-C requires a clinician to rate how much the subject’s HD has improved or worsened 
relative to baseline. A subject’s illness improvement status is rated as: 
 1=Very much improved 
 2=Much improved 


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 3=Minimally improved 
 4=No change 
 5=Minimally worse 
 6=Much worse 
 7=Very much worse 
Subjects whose CGI-C score is either a 1 ("very much improved") or a 2 ("much improved") will 
be classified as responders. Response status at Week 12 is a secondary endpoint; Weeks 2 through 
10 are exploratory efficacy endpoints. 
The PGI-C response status based on patient rating is defined similarly.  
For analysis of CGI-C and PCI-C response status at Week 12, the 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’s exact test.    Nominal two-sided p-values for comparing 
treatment groups will be reported in summary tables; however, determining statistical 
significance of the p-value for the treatment group comparison at Week 12 will be based on a 
procedure which controls for multiple comparisons.  
An example of the SAS® software code for Fisher’s exact test is provided below:  
 
 
 
 
  
 
 
A sensitivity analysis will be performed by imputing non-responder to subjects with missing data 
at Week 12. 
The change from baseline (Day -1) to Week 12 in the Neuro-QoL Upper and Lower Extremity 
Function T-score are secondary efficacy endpoints; the change from baseline to Weeks 4, 8, and 
10 are exploratory efficacy endpoints. 
For analysis of the change from baseline (Day -1) to Week 12 in the Neuro-QoL Upper and 
Lower Extremity Function T-score, the 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 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 corresponding baseline value (Day -1) of the Neuro-QoL 
Upper and Lower Extremity Function T-score respectively, and only visits where Neuro-QoL is 
scheduled to be collected will be included.  Nominal two-sided p-values for comparing treatment 
groups and the associated 95% confidence intervals will be reported in summary tables; 
however, determining statistical significance of the p-value for the treatment group comparison 
at Week 12 will be based on a procedure which controls for multiple comparisons. 


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Similar supplementary analyses, described in Section 7.3.2, will be performed for the secondary 
efficacy endpoints. 
7.5. 
Other Efficacy Endpoints 
The other efficacy endpoints will be summarized descriptively by treatment group and visit.  
7.5.1. 
Clinical Global Impression-Severity (CGI-S)  
The CGI scales are commonly used measures of symptom severity and treatment response.  
The CGI-S requires a clinician to rate the severity of the subject’s HD at the time of the 
assessment, relative to the clinician’s past experience with HD patients. The subject should be 
assessed on the severity of his or her HD at the time of rating as: 
 1=Normal, not at all ill 
 2=Borderline ill 
 3=Mildly ill 
 4=Moderately ill 
 5=Markedly ill 
 6=Severely ill 
 7=Among the most extremely ill patients 
Number and percentage of subjects by CGI-S categories will be summarized by treatment group 
and visit.  
In addition, the shift table for CGI-S categories from baseline to Week 12 will be presented.    
7.5.2. 
Patient Global Impression-Severity (PGI-S) 
Subjects will rate their improvement in their HD symptoms at the time of the assessment. The 
subject should be assessed on the severity of his or her HD at the time of rating as: 
 1=None 
 2=Mild 
 3=Moderate 
 4=Severe 
 5=Very Severe 
PGI-S categories will be analyzed similarly as that previously described for CGI-S. 
7.5.3. 
Short Form 36 Health Survey (SF-36) 
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.  


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Observed values and change from baseline to Week 12 will be summarized descriptively for all 
dimension scores by treatment group. 
7.5.4. 
Huntington Disease Health Index (HD-HI) 
The Huntington Disease Health Index (HD-HI) 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. 
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. 
Observed values and change from baseline will be summarized descriptively for all subscales 
and the total instrument score by treatment group and visit. 
7.5.5. 
EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
The EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) is a general, single index measure for 
describing and valuing health.  It defines health in terms of 5 dimensions: Mobility, Self-Care, 
Usual Activities, Pain/Discomfort, and Anxiety/Depression.  Each dimension has 5 levels:  no 
problems, slight problems, moderate problems, severe problems, and extreme problems.  The 
subject indicates his/her health state by checking the box next to the most appropriate statement.  
The scores for the 5 dimensions can be combined into a 5-digit number that describes the 
patient’s health state.  Number and percentage of subjects in each of the 5 levels for each 
dimension at baseline and Weeks 10 and 12 will be summarized by treatment group. 
Subjects also rate their overall health on a 0 to 100 hash-marked, vertical visual analogue scale 
(EQ-VAS).  The endpoints are labeled ‘The best health you can imagine is at the 100’ and ‘The 
worst health you can imagine is at the 0’. EQ VAS score at each time point and change from 
baseline to Week 10 and Week 12 will be summarized by treatment group. 
Health states in the EQ-5D-5L can be converted into a single index value, where index values are 
presented in the country specific value sets. EQ-5D-5L value sets can be used to obtain the 
EQ5D-5L index values based on the crosswalk for the respective countries. Observed values and 
change from baseline in EQ-5D index score will be summarized by treatment group and visit.  
7.5.6. 
UHDRS Scores for Motor, Cognitive, Behavior, and Functional Capacity 
Assessment at Weeks 2 through 12 
The motor portion of the UHDRS consists of 15 items that measure the severity of the motor 
symptoms. Similarly, to the analysis of TMC as described in Section 7.3, the total motor score 
(TMS) will be summarized by treatment group and visit. 


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The cognitive portion of the UHDRS consists of 3 executive function tests to evaluate the 
cognitive performance. The score of individual tests will be summarized by treatment group and 
visit. 
The behavior portion of the UHDRS consists of 11 items (under four subscales: mood, behavior, 
psychosis, and obsessive) that measure the severity and frequency of behavior symptoms. The 
frequency and severity of each item is ranked on a 0 to 4 scale with higher scores indicating 
higher frequency or more severe behavioral symptoms, respectively. The sum of behavior 
frequency scores (11 total items, range 0-44), and the sum of behavior frequency-times-severity 
item scores (11 total item products, range 0-176) will be summarized. The behavior milestone 
questions (items 36 to 40) will be summarized by treatment group. 
The functional capacity portion of the UHDRS consists of 5 items. Similarly, to the analysis of 
TMC as described in Section 7.3, the individual items and total functional capacity score (TFC) 
will be summarized by treatment group and visit. 
7.5.7. 
Other UHDRS Scores including Functional Assessment and Independence Scale 
at Week 12 
The functional assessment portion of the UHDRS consists of 25 functional questions with binary 
outcomes (Yes = 1, No = 0). Total scores defined as the sum of the 25 questions at baseline and 
Weeks 12 will be summarized by treatment group.  
The independence scale of UHDRS will be summarized similarly. 
7.5.8. 
Anosognosia Scale (AS) at Week 12 
The Anosognosia Scale (AS) is an instrument to screen for anosognosia in daily practice and is 
specific for HD.  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. 
Observed values and change from baseline to Week 12 will be summarized for AS total score by 
treatment group for subjects and investigators ratings, respectively. 
 
 
 
 
 
  
7.5.10. 
Examination of Subgroups 
The following subgroups have been pre-planned and will be used to examine consistency of 
effect for the primary efficacy endpoint:   
 Demographics (age <65 years versus ≥65 years, sex, race) 
 Baseline CGI-S categories (<4 versus ≥4) 
 Baseline PGI-S categories (<3 versus ≥3) 


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If the categories are sparse in number of subjects (eg, <15), similar categories maybe combined 
for analysis. The MMRM model will be used similar to the model described above for the 
primary analysis of the TMC scores, with additional interaction between treatment groups and 
subgroup variables included in the model.  Nominal two-sided p-values for comparing treatment 
groups and the associated 95% confidence intervals will be reported in summary tables and p-
values for the interaction term between treatment groups and subgroup variables will be 
presented. 


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8. 
PHARMACOKINETICS 
The plasma concentrations of valbenazine and the metabolite NBI-98782 will be summarized 
with descriptive statistics, which will include the coefficient of variation (CV[%]), geometric 
mean, and geometric CV(%) by treatment group, dose (last dose received prior to blood sample 
being drawn), and visit (Day -1 and Weeks 2, 4, 6, 8, 10, 12, and 14) based on PK analysis set.  
Concentrations below the lower limit of quantification (valbenazine: 1.00 ng/mL and NBI-
98782: 0.10 ng/mL) will be set equal to zero for all plasma concentration summaries. 


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9. 
SAFETY  
The safety objective of the study is to characterize the safety profile of valbenazine as measured 
by TEAEs and SAEs, vital signs, clinical laboratory tests, prolactin, ECG and safety scales. All 
outputs for safety endpoints will be based on the safety analysis set. The analysis of the safety 
data will be based on descriptive statistics and presented by treatment group and the study visit 
unless otherwise noted. Safety data will not be subject to any imputation and will be summarized 
on an observed case basis. No formal hypothesis-testing analysis of safety data will be 
performed.  
9.1. 
Study Drug Dosing and Compliance 
The duration of exposure to study drug will be calculated as: last dose date – first dose date +1.  
Duration of exposure will be summarized with descriptive statistics by treatment group. The 
number of subjects at each dose level in maintenance period will be summarized. 
The number and percentage of subjects who are dose compliant (site evaluation of 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 by visit and 
treatment group. 
9.2. 
Adverse Events 
Adverse events are recorded in the eCRF. Each AE will be coded to SOC and PT using 
MedDRA (Version 24.0).   
A treatment-emergent adverse event (TEAE) is an AE not present prior to the initiation of study 
drug dosing or is an already present event that worsens either in intensity or frequency following 
the initiation of study drug dosing.  
The frequency tables will include the number and percentage of unique subjects experiencing 
each event at least once during the study. Unless otherwise specified, summary tables will 
include events with a start date on or after the date of the first dose of study drug and up to the 
last dose of study drug + 14 days.  
Two versions of the primary TEAE frequency tables will be presented: 
 Frequency of TEAEs by SOC and PT, with SOCs sorted alphabetically and PTs 
within each SOC sorted by decreasing frequency (number of unique subjects) in 
valbenazine treatment group; 
 Frequency of TEAEs by PT, with PT sorted by decreasing frequency (number of 
unique subjects) in valbenazine treatment group. 
Summary tables of severe TEAEs will be presented by treatment group. The number and 
percentage of subjects with a severe TEAE will be presented by PT within SOC (presented in the 
same method as the primary TEAE table). The first line of the table will display the number and 
percentage of subjects with at least one severe TEAE. 


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An AE overview summary table will be provided which summarizes the number and percentage 
of subjects with any TEAE, any TEAE leading to dose reduction, any TEAE leading to study 
drug discontinuation, any serious TEAE, and any TEAE leading to death. The summary table 
will also include the maximum TEAE severity (mild, moderate, severe) reported for each 
subject. 
In addition, tables will be provided for post-treatment emergent events (AE start dates after last 
dose of study drug to the date of the last dose of study drug + 14 days) and non-treatment 
emergent AEs (AE start dates after last dose date + 14 days) separately. The events will be 
summarized by treatment group and presented by PT within SOC. 
9.2.1. 
Adverse Events Leading to Premature Discontinuation of Study Drug 
Summary tables of TEAEs leading to early discontinuation of study drug will be presented by 
treatment group. The number and percentage of subjects with a TEAE leading to study drug 
discontinuation will be presented by PT within SOC (presented in the same method as the 
primary TEAE table). More than one AE can contribute to study drug discontinuation per 
subject. The first line of the table will display the number and percentage of subjects with at least 
one TEAE leading to study drug discontinuation. 
A listing of TEAEs leading to premature study drug discontinuation will be provided which 
includes subject ID, treatment group, last treatment received prior to the onset time of the 
TEAE(s) leading to discontinuation, study day of the discontinuation, and other relevant 
information from the AE eCRF. Note that “last treatment received prior to the onset time of the 
TEAE[s] leading to discontinuation” reflects the actual dose level received prior to the AE. 
9.2.2. 
Adverse Events Leading to Study Drug Dose Reductions 
Summary tables of TEAEs leading to study drug dose reductions will be presented by treatment 
group. The number and percentage of subjects with a TEAE leading to a dose reduction will be 
presented by PT within SOC (presented in the same method as the primary TEAE table). More 
than one AE can contribute to a dose reduction per subject. The first line of the table will display 
the number and percentage of subjects with at least one TEAE leading to dose reduction.  
9.2.3. 
Deaths and Other Serious Adverse Events 
Summary tables of serious adverse events (SAEs) and deaths will be presented by treatment 
group. The tables will include the frequency of SAEs presented by PT within SOC (presented in 
the same method as the primary TEAE table). 
Separate listings of SAEs and fatal TEAEs will also be provided. Each listing will include 
subject ID, treatment group, last treatment received prior to the onset time of the SAE or fatal 
TEAE, study day of the SAE or fatal TEAE, and any additional relevant information from the 
AE eCRF. 
9.3. 
Laboratory Safety Parameters 
The following clinical safety laboratory parameters will be analyzed: 
Hematology:  complete blood count including WBC count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, and platelet count, and absolute neutrophil count (ANC). 


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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 will be summarized by visit and treatment group for each sex 
separately and combined. 
The hematology, clinical chemistry, and prolactin data will be summarized with descriptive 
statistics by treatment group at baseline and at each scheduled postbaseline visit through Week 
14. Both observed values and changes from baseline will be summarized.  
Shift tables will be presented for selected clinical laboratory variables based on the reference 
range-based categories of “Low,” “Normal,” or “High.” A clinical laboratory variable value will 
be assigned to one of these three categories according to the reference ranges provided by the 
central clinical laboratory. The shift tables will present the shift from baseline to Week 12 (using 
observed values). Each shift table will have three rows and three columns, with rows reflecting 
the reference range category at baseline, and columns reflecting the reference range category at 
postbaseline. A “Total” row and “Total” column will also be included. Subjects with a missing 
baseline value or who do not have postbaseline data will be excluded from the shift tables for 
that variable. The number and percentage of subjects in each shift category will be displayed in 
the table; percentages will be based on the number of subjects included in the table. 
Shift tables will be presented for the following clinical laboratory variables:  
 aspartate aminotransferase (AST),  
 alanine aminotransferase (ALT),  
 gamma-glutamyl transferase (GGT),  
 total bilirubin,  
 creatine kinase,  
 creatinine,  
 prolactin, 
 blood urea nitrogen (BUN),  
 white blood cell count (WBC),  
 absolute neutrophil count (ANC), 
 hemoglobin, and  
 platelet count. 
Summaries of sponsor-defined potentially clinically significant (PCS) values will be presented 
for the following clinical laboratory variables: ALT, AST, creatine kinase, GGT, total bilirubin, 
white blood cell count, ANC, creatinine, and BUN. The number and percentage of subjects with 
PCS values that are reported at any postbaseline visit (scheduled or unscheduled) will be 
summarized by treatment. The criteria for identifying PCS clinical laboratory values are 
provided in Table 2. 


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Table 2: 
Potentially Clinically Significant Criteria for Clinical Laboratory Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN  
AST 
>3 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
absolute neutrophil count 
≤1.5 x 1000/µL 
Creatinine 
>1.5 x baseline value or >1.5 x ULN 
BUN 
>30 mg/dL (>10.71 mmol/L) 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; GGT=gamma-
glutamyl transferase; PCS=potentially clinically significant; ULN=upper limit of normal 
Boxplots will be presented for the prolactin data by treatment group at each visit (baseline 
through Week 14). Separate plots will also be presented for each sex. 
Repeat clinical laboratory samples may be collected at any time during this study due to either 
missing or abnormal results. The general rule for summarizing these data is to include the 
original sample results in summary tables and graphs. Exceptions to this rule are: (1) all available 
lab values will be used in the PCS summaries and (2) if there are missing results from the 
original samples at screening, the results of a repeat screening sample will be substituted for the 
missing results in summary tables and graphs.  
9.4. 
Vital Signs 
The vital signs data, including orthostatic systolic and diastolic blood pressure (calculated as 
standing value minus supine value), orthostatic pulse rate, respiratory rate (recorded only 
supine), and oral body temperature, will be summarized with descriptive statistics by treatment 
group at baseline and at each scheduled postbaseline visit through Week 14. Both observed 
values and changes from baseline will be summarized.  
Summaries of sponsor-defined PCS values will be presented for systolic blood pressure, diastolic 
blood pressure, heart rate, orthostatic systolic blood pressure, orthostatic diastolic blood pressure, 
and orthostatic heart rate. The number and percentage of subjects with PCS values that are 
reported at any postbaseline visit (scheduled or unscheduled) will be summarized by treatment 
group. The criteria for identifying PCS vital signs values are provided in Table 3.   


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Table 3: 
Potentially Clinically Significant Criteria for Vital Signs Variables 
Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease 
from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Systolic Blood Pressure 
 N/A 
 
≥20 mmHg 
>145 mmHg 
 
≥20 mmHg 
Diastolic Blood Pressure  N/A 
 
≥10 mmHg 
>90 mmHg 
 
≥10 mmHg 
Heart Rate 
<50 bpm 
 
≥15 bpm 
>120 bpm 
 
≥15 bpm 
Orthostatic Systolic 
Blood Pressure 
Decrease 
of 
≥20 mmHg 
 
 
Increase 
of 
≥20 mmHg 
 
 
Orthostatic Diastolic 
Blood Pressure 
Decrease 
of 
≥10 mmHg 
 
 
Increase 
of 
≥10 mmHg 
 
 
Orthostatic Heart Rate 
Decrease 
of 
≥15 bpm 
 
 
Increase 
of 
≥15 bpm 
 
 
PCS=potentially clinically significant 
Both supine and standing values of blood pressures and heart rate will be included in the 
identification and all vital sign values will be used for the summary of PCS values. 
9.5. 
Body Weight 
The body weight data (in units of kilograms) will be summarized with descriptive statistics by 
treatment group at baseline and at each scheduled postbaseline visit through Week 14. Both 
observed values and changes from baseline will be summarized.  
9.6. 
Electrocardiogram (ECG)  
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and corrected QT interval using Fridericia’s formula [QTcF]) measured at each visit 
will be averaged for the purpose of analysis. For the categorical ECG interpretation variable (the 
investigator’s assessment of the ECG as “Normal”, “Abnormal, not Clinically Significant”, or 
“Abnormal, Clinically Significant”), which is also reported in triplicate, the value that represents 
the greatest degree of abnormality will be used in all summary tables. If less than 3 values are 
recorded at an assessment, then the average/greatest abnormality of the available value(s) will be 
used. 
The quantitative ECG variables will be summarized with descriptive statistics by treatment group 
at baseline and at each scheduled postbaseline visit through Week 14. Both observed values and 
changes from baseline will be summarized. Frequency counts and percentages for the ECG 
interpretation variable categories will be summarized at each scheduled visit.  
Categorical summaries will be presented for the QT and QTcF interval data. For these 
summaries, a subject’s highest reported postbaseline value (including values reported at 
unscheduled visits) will be used to determine in which category(s) the subject will be counted. 
The averaged triplicate values will be used when determining each subject’s highest reported 
values. 


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Two categorical summaries will be presented for the QT and QTcF intervals (each interval will 
be summarized separately). For the first summary, the number and percentage of subjects in each 
treatment group whose highest reported QT or QTcF postbaseline value meets the following 
thresholds will be summarized: 
 Greater than 450 msec 
 Greater than 480 msec 
 Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects in each 
treatment group whose largest QT or QTcF increase from their baseline value meets the 
following thresholds:  
 Greater than 30 msec 
 Greater than 60 msec 
9.7. 
Other Safety Endpoints 
9.7.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation and 
behavior. The C-SSRS summary will display the number and percentage of subjects who report 
“Yes” to specific C-SSRS items or categories of items (a category is assigned a “Yes” value if a 
“Yes” is reported for any item in the category). These C-SSRS items and categories are as 
follows: 
 Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
 Suicidal Ideation Category: Any of items (1) through (5) 
 Suicidal Behavior Items (not reported for the Screening/past 1 year assessment) 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(10) 
Completed suicide 


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 Suicidal Behavior Category: Any of items (6) through (10) 
 Suicidal Ideation or Behavior Category: Any of items (1) through (10) 
For the “all postbaseline assessments” summary, each subject’s C-SSRS responses for all 
postbaseline assessments during the study will be evaluated, and a “Yes” response for any 
assessment will be considered as a “Yes” for the subject. 
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline scores will be presented. The shift table scores are defined as the 
following: 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Active suicidal ideation with any methods (not plan) without intent to act 
4 = Active suicidal ideation with some intent to act, without specific plan 
5 = Active suicidal ideation with specific plan and intent 
The shift tables will display the number and percentage of subjects within each cell of a 6 x 6 
table for each treatment group, with the rows representing the baseline score and the columns 
representing the maximum score recorded across all postbaseline assessments (including both 
scheduled and unscheduled visits). Subjects missing either a baseline score or all postbaseline 
scores will not appear in the table.  
9.7.2. 
UHDRS Motor Score (Items for Parkinsonism) 
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.  
Observed values and change from baseline in parkinsonism total motor scores will be 
summarized descriptively by treatment group and visit. 
9.7.3. 
Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Rating Scale (BARS) is a validated four-item scale to assess the presence 
and severity of drug-induced akathisia.  This scale includes both objective items (eg, observed 
restlessness) and subjective items (eg, subjects’ awareness of restlessness and related distress), 
together with a global assessment of akathisia. Objective akathisia, subjective awareness of 
restlessness and subjective distress related to restlessness are rated on a 4-point scale from 0 – 3 
and are summed yielding a total score ranging from 0 to 9.  Global assessment is made on a 6-
point scale of 0 to 5 (0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 
4=marked akathisia; 5=severe akathisia). 
The BARS total score will be summarized by treatment group and visit. The BARS global 
assessment of akathisia score summary will be presented for each treatment group. 


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9.7.4. 
Hospital Anxiety and Depression Scale (HADS) 
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.  Each item is answered on a 4-point (0 to 3) response categories 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. 
Observed values and change from baseline in HADS scores for anxiety and depression will be 
summarized descriptively by treatment group and visit. 


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10. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS 
The analyses described in this SAP are consistent with the protocol planned analyses.  The 
following assessments will be reviewed by study personnel but will not be included in tables, 
listings, or figures: medical history, prior and concomitant medications, serology, urinalysis, and 
pregnancy test results. 


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11. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS 
The analysis and summary of data from this study will be performed using SAS® 
 
. All SAS® programs used in the production of statistical analyses, tables, 
listings, and figures described in this SAP will undergo performance qualification (verification 
that the program produces the intended output) in accordance with department standard operating 
procedures. The performance qualification may include independent programming and/or peer 
review of the SAS® log files. In addition, tables, figures, listings, and statistical analysis output 
will be independently reviewed for completeness and accuracy. 


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12. 
REFERENCES  
None.