Clinical trial NCT02405091
Conditions: Tardive Dyskinesia
Sponsor: Neurocrine Biosciences
Start date: 2015-03-01; Completion date: 2017-03-01
Enrollment: 167 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Phase 3, open-label, study to evaluate the safety and tolerability of NBI-98854 administered once daily (qd) for a total of 48 weeks of treatment. This study will enroll approximately 150 medically stable male and female subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder with neuroleptic-induced TD.

Detailed description:

Arms: arm 1: Fixed dose of NBI-98854 administered once daily for 48 weeks arm 2: Fixed dose of NBI-98854 administered once daily up to 48 weeks
Interventions: intervention 1: NBI-98854
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
 
Amendment No. 2 Final Version Date:  03 December 2015 
Amendment No. 1 Final Version Date:  21 May 2015 
Original Final Version Date:  25 November 2014 
 
 
 
A PHASE 3, OPEN-LABEL, SAFETY AND TOLERABILITY STUDY OF 
NBI-98854 FOR THE TREATMENT OF TARDIVE DYSKINESIA 
 
Study No.:  NBI-98854-1402 
 
Development Phase:  Phase 3 
 
 
Sponsor: 
Neurocrine Biosciences, Inc. 
 
12780 El Camino Real  
 
San Diego, CA  92130 
 
Telephone:  (858) 617-7600 
 
Facsimile:    (858) 617-7705 
 
 
 
 
 
 
CONFIDENTIAL 
This document is a confidential communication of Neurocrine Biosciences, Inc.  It 
is agreed that no unpublished information contained herein will be published or 
disclosed without prior approval from the Sponsor.  However, this document may 
be disclosed to an appropriate Institutional Review Board/Ethics Committee 
(IRB/EC) or authorized representatives of national regulatory authorities under the 
condition that they respect its confidential nature. 


SIGNATURES: 
I agree to conduct this study in accordance with the requirements of this Clinical Study 
Protocol and also in accordance with the following: 
• 
Established principles of Good Clinical Practice (GCP) (Harmonized) 
• 
United States (US) Code of Federal Regulations (CFR); US Food and Drug 
Administration (FDA) 
 
CLINICAL STUDY TITLE: 
A Phase 3, Open-Label, Safety and Tolerability Study of NBI-98854 for the Treatment of 
Tardive Dyskinesia 
PROTOCOL NO: 
 
 
NBI-98854-1402 
 
SITE:   
 
________________________________________________________ 
(Site Name) 
 
PRINCIPAL INVESTIGATOR:  
 
 
_________________________________________________________ 
(Principal Investigator Name) 
As Agreed:  
 
 
___________________ 
 
 
__________________________________ 
Date  
 
 
 
 
Principal Investigator 
 
 
 
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LIST OF PERSONNEL:   
 
Sponsor:  
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
 
 
Director, Clinical Programs: 
 
Telephone: 
 
 
Facsimile: 
 
Cell Phone: 
 
 
 
Medical Monitor:  
 
 
Telephone: 
 
Facsimile: 
 
Cell Phone: 
 
 
Serious Adverse Event Reporting: 
 
Telephone: 
 
 
Facsimile: 
 
E-mail: 
 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
1. 
STUDY SYNOPSIS ............................................................................................ 10 
2. 
LIST OF ABBREVIATIONS ............................................................................... 14 
3. 
ETHICS .............................................................................................................. 16 
4. 
INTRODUCTION ................................................................................................ 16 
4.1. 
Background ...................................................................................................... 16 
4.2. 
NBI-98854 ......................................................................................................... 17 
4.3. 
Study Rationale and Selection of Dose .......................................................... 19 
5. 
STUDY OBJECTIVES ........................................................................................ 20 
6. 
OVERVIEW OF STUDY DESIGN ...................................................................... 21 
6.1. 
Study Design .................................................................................................... 21 
6.1.1. 
Efficacy, Blood Sample Collections, and Safety Assessments for All 
Subjects .............................................................................................. 22 
6.1.2. 
Additional Safety Assessments for Subjects with Schizophrenia or 
Schizoaffective Disorder: ..................................................................... 23 
6.1.3. 
Additional Safety Assessments for Subjects with Mood Disorder: ........ 23 
7. 
STUDY POPULATION ....................................................................................... 25 
7.1. 
Inclusion Criteria .............................................................................................. 25 
7.2. 
Exclusion Criteria ............................................................................................ 27 
7.2.1. 
Exclusion Criteria for All Subjects ........................................................ 27 
7.2.2. 
Exclusion Criteria for Subjects with Clinical Diagnosis of 
Schizophrenia or Schizoaffective Disorder .......................................... 29 
7.2.3. 
Exclusion Criteria for Subjects with Clinical Diagnosis of Mood 
Disorder ............................................................................................... 29 
7.3. 
Subject Identification and Replacement......................................................... 29 
7.4. 
Randomization ................................................................................................. 29 
8. 
STUDY EVALUATIONS ..................................................................................... 29 
8.1. 
Schedule of Assessments ............................................................................... 29 
8.2. 
Screening Assessment .................................................................................... 35 
8.2.1. 
Brief Psychiatric Rating Scale (BPRS) ................................................. 35 
8.3. 
Efficacy Assessments ..................................................................................... 35 
8.3.1. 
Abnormal Involuntary Movements Scale (AIMS) .................................. 35 
8.3.1.1. 
AIMS Administration and Scoring .................................... 36 
8.3.1.2. 
AIMS Video Recording and Blinded, External AIMS 
Reviewer ......................................................................... 36 
8.3.1.3. 
Blinded, Central AIMS Video Raters ................................ 36 
8.3.2. 
Clinical Global Impression – Global Improvement of Tardive 
Dyskinesia (CGI-TD) ........................................................................... 37 
8.3.3. 
Patient Global Impression of Change (PGIC) ...................................... 37 
8.3.4. 
Tardive Dyskinesia Impact Scale (TDIS) and Assessment of Most 
Bothersome Movement in Tardive Dyskinesia (AMBMTD) .................. 37 
8.4. 
Pharmacokinetics Evaluations ....................................................................... 37 
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8.4.1. 
Blood Sample Collection...................................................................... 37 
8.5. 
Safety Assessments ........................................................................................ 38 
8.5.1. 
Safety Assessments for All Subjects.................................................... 38 
8.5.1.1. 
Medical History ................................................................ 38 
8.5.1.2. 
Physical Examination Including Neurological 
Assessment, Height, and Weight ..................................... 38 
8.5.1.3. 
Vital Sign Measurements ................................................. 39 
8.5.1.4. 
Twelve-lead Electrocardiogram ....................................... 39 
8.5.1.5. 
Laboratory Assessments ................................................. 39 
8.5.1.6. 
Assessment of Suicidal Ideation and Behavior – 
Columbia-Suicide Severity Rating Scale (C-SSRS) ......... 41 
8.5.1.7. 
Evaluation of Akathisia and Extrapyramidal Symptoms 
- Barnes Akathisia Rating Scale and Simpson-Angus 
Scale ............................................................................... 42 
8.5.2. 
Safety Assessments in Subjects with Schizophrenia or 
Schizoaffective Disorder ...................................................................... 42 
8.5.2.1. 
Symptoms of Schizophrenia – Positive and Negative 
Syndrome Scale (PANSS) for Schizophrenia .................. 42 
8.5.2.2. 
Calgary Depression Scale for Schizophrenia (CDSS) ..... 43 
8.5.3. 
Safety Assessments in Subjects with Mood Disorders ......................... 43 
8.5.3.1. 
Young Mania Rating Scale (YMRS) ................................ 43 
8.5.3.2. 
Montgomery-Asberg Depression Rating Scale 
(MADRS) using the Structured Interview Guide for the 
MADRS (SIGMA) ............................................................ 44 
8.6. 
Exploratory Assessments ............................................................................... 44 
8.6.1. 
Biomarker Analysis .............................................................................. 44 
8.7. 
Specific Study Phase Information .................................................................. 44 
8.7.1. 
Screening Period (Week -6 to -1) ........................................................ 45 
8.7.1.1. 
Informed Consent Process .............................................. 45 
8.7.1.2. 
Washout of Prohibited Medications ................................. 45 
8.7.1.3. 
Screening Procedures ..................................................... 45 
8.7.2. 
Baseline (Day -1) ................................................................................. 46 
8.7.3. 
Treatment Period ................................................................................. 48 
8.7.3.1. 
End of Weeks 4, 12, 24, and 36 ...................................... 48 
8.7.3.2. 
End of Week 8 ................................................................. 49 
8.7.3.3. 
End of Weeks 16, 20, 28, 32, 40, and 44 ......................... 51 
8.7.3.4. 
End of Week 48 ............................................................... 52 
8.7.4. 
Follow-up Visit - Final Study Visit (End of Week 52 or Early 
Termination) ........................................................................................ 53 
8.8. 
Study Duration ................................................................................................. 54 
8.9. 
Prohibitions and Restrictions ......................................................................... 54 
8.9.1. 
Prior and Concomitant Medication Restrictions ................................... 54 
8.9.2. 
General and Dietary Restrictions ......................................................... 56 
8.10. 
Withdrawal Criteria .......................................................................................... 56 
8.10.1. 
Reasons for Withdrawal....................................................................... 56 
8.10.2. 
Handling of Withdrawals ...................................................................... 57 
8.10.3. 
Sponsor’s Termination of Study ........................................................... 57 
9. 
STUDY DRUG .................................................................................................... 57 
9.1. 
Study Drug Supplies ........................................................................................ 57 
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9.2. 
Study Drug Storage ......................................................................................... 57 
9.3. 
Study Drug Packaging and Labeling .............................................................. 58 
9.4. 
Blinding ............................................................................................................ 58 
9.5. 
Study Drug Administration.............................................................................. 58 
9.6. 
Drug Compliance and Accountability ............................................................. 58 
9.7. 
Study Drug Return ........................................................................................... 59 
10. 
ADVERSE EVENTS ........................................................................................... 59 
10.1. 
Definition .......................................................................................................... 59 
10.1.1. 
Intensity of Adverse Events ................................................................. 60 
10.1.2. 
Relationship to Study Drug .................................................................. 60 
10.2. 
Recording Adverse Events.............................................................................. 61 
10.3. 
Post Study Follow-Up of Adverse Events ...................................................... 61 
10.4. 
Serious Adverse Events .................................................................................. 62 
10.4.1. 
Definition of a Serious Adverse Event .................................................. 62 
10.4.2. 
Managing Serious Adverse Events ...................................................... 62 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately 
Reportable Events ............................................................................... 63 
10.4.4. 
Expedited Safety Reports .................................................................... 63 
10.5. 
Pregnancy ........................................................................................................ 63 
11. 
DOCUMENTATION OF DATA ........................................................................... 64 
11.1. 
Case Report Form ............................................................................................ 64 
11.2. 
Data Capture, Review, and Validation ............................................................ 64 
11.3. 
Coding Dictionaries ......................................................................................... 65 
12. 
STATISTICAL AND ANALYTICAL PLAN ......................................................... 65 
12.1. 
Analysis Sets ................................................................................................... 65 
12.2. 
Sample Size ...................................................................................................... 65 
12.3. 
Handling of Missing Data ................................................................................ 65 
12.4. 
Enrollment and Disposition of Subjects ......................................................... 65 
12.5. 
Demographics Data and Baseline Characteristics ........................................ 65 
12.6. 
Study Drug Dosing .......................................................................................... 66 
12.7. 
Pharmacokinetic Data...................................................................................... 66 
12.8. 
Efficacy Data .................................................................................................... 66 
12.9. 
Safety Data ....................................................................................................... 66 
12.10. Interim Analyses .............................................................................................. 67 
12.11. Software ........................................................................................................... 67 
13. 
REGULATORY AND ETHICAL ISSUES ........................................................... 67 
13.1. 
General Legal References ............................................................................... 67 
13.2. 
Institutional Review Board .............................................................................. 67 
13.3. 
Protocol Adherence-Amendments ................................................................. 67 
13.4. 
Required Documents ....................................................................................... 67 
13.5. 
Informed Consent ............................................................................................ 68 
13.6. 
Study Monitoring ............................................................................................. 68 
13.7. 
Quality Assurance ........................................................................................... 68 
13.8. 
Record Retention ............................................................................................. 68 
13.9. 
Confidentiality .................................................................................................. 69 
14. 
STUDY COMMENCEMENT AND DISCONTINUATION .................................... 69 
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15.
REFERENCES ................................................................................................... 70
16.
SUPPLEMENTS ................................................................................................. 72
16.1. 
Neuroleptic-Induced Tardive Dyskinesia Diagnostic Criteria ....................... 72 
16.2. 
NBI-98854-1402 Dose Titration Algorithm ...................................................... 73 
16.3. 
Blinded Central AIMS Video Raters’ Consensus Scoring Process .............. 74 
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Page 
LIST OF TABLES 
Table 1.  
Schedule of Assessments for Subjects with Schizophrenia or 
Schizoaffective Disorder ....................................................................................... 31 
Table 2. 
Schedule of Assessments for Subjects with Mood Disorders ................................ 33 
Table 3. 
Estimated Total Blood Sample Volume ................................................................. 41 
Table 4. 
Intensity of Adverse Events................................................................................... 60 
Table 5. 
Relationship of Adverse Events to Study Drug ...................................................... 61 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schematic ....................................................................................... 24 
 
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1. 
STUDY SYNOPSIS 
Title: 
A Phase 3, Open-Label, Safety and Tolerability Study of NBI-98854 for the 
Treatment of Tardive Dyskinesia 
Protocol Number: 
NBI-98854-1402 
Development Phase: 
Phase 3 
Study Sites: 
Approximately 50 study sites in North America and Puerto Rico. 
Study Objectives: 
To evaluate the safety and tolerability of NBI-98854 (titrated from 40 to 80 mg) 
administered once daily for up to 12 months for the treatment of Tardive 
Dyskinesia (TD). 
Overview of Study 
Design: 
This is a Phase 3, open-label, fixed-dose titration study to evaluate the safety 
and tolerability of NBI-98854 (titrated from 40 mg to 80 mg) administered once 
daily (qd) for a total of 48 weeks of treatment.  This study will enroll 
approximately 180 medically stable male and female subjects with clinical 
diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced 
TD or mood disorder with neuroleptic-induced TD. 
All subjects must sign an informed consent form (ICF) prior to the conduct of 
any study related procedures, including washout of medications disallowed in 
the study.  Before subjects can provide informed consent, the investigator (or 
designee) must determine whether the subject has the capacity to provide 
consent for study participation using the University of California, San Diego 
Brief Assessment of Capacity to Consent (UBACC).  Only subjects who are 
deemed to have the capacity to provide consent may sign the ICF.  Subjects 
will also be asked to sign an optional release form to allow their Abnormal 
Involuntary Movement Scale (AIMS) video recordings to be used for 
educational purposes.  Subjects will be screened for eligibility for up to 6 weeks 
prior to Day -1 (baseline visit). 
On Day -1, eligible subjects will receive a supply of NBI-98854 40 mg qd for the 
first 4 weeks of the treatment period.  Beginning on Day 1, study drug will be 
self-administered at home (in the presence of their caregiver, if applicable) in 
the morning between 0700-1000 hours.   
At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg 
or continue with the subject’s current dose.  A dose escalation will be allowed at 
the end of Week 4 if (1) the investigator or designee’s assessment of the 
Clinical Global Impression – Tardive Dyskinesia (CGI-TD) is “minimally 
improved”, “not changed”, “minimally worse”, “much worse”, or “very much 
worse”, and (2) the safety and tolerability of the current dose is acceptable as 
determined by a physician.  The subject will then continue at the 80 mg dose 
until the end of the treatment period (end of Week 48). 
At any time after a dose escalation, the investigator may decrease the dose to 
40 mg if the subject is unable to tolerate the dose increase.  The subject will 
then continue at the 40 mg dose until the end of the treatment period (end of 
Week 48).  Subjects who are unable to tolerate the starting dose of 40 mg or 
the resumption of 40 mg will be discontinued from the study. 
Subjects will return to the study site every 4 weeks for study assessments and 
dispensation of the study drug.  These visits will occur in the afternoon between 
1200-1700 hours at the end of Weeks 4, 8, 12, 24, 36, 48 and 52 (or early 
termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 
32, 40 and 44.   
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The study site will call the subjects weekly to remind them to take their study 
medication daily.  Subjects who do not want to continue in the study will be 
terminated and will be asked to return for an early termination visit 
approximately 4 weeks after receiving the last dose.  Follow-up assessments 
will be performed at the end of Week 52 (4 weeks after the last dose) or early 
termination. 
Efficacy, safety, and pharmacokinetics (PK) will be assessed at scheduled 
times throughout the study.  The treatment period visits (end of Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, and 48) and the follow-up visit (end of Week 52) 
will have a visit window of ±6 days.  
Study Population: 
Approximately 180 medically stable adult male and female subjects with clinical 
diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced 
TD or mood disorder with neuroleptic-induced TD will be enrolled.  Of the 
approximately 180 subjects to be enrolled, approximately 60% may have 
schizophrenia or schizoaffective disorder.  The subjects must be 18 to 85 years 
of age (inclusive) and have moderate or severe symptoms of TD as assessed 
by a blinded, external AIMS reviewer, based on the subject’s AIMS video 
recording conducted at screening.  Subjects must be psychiatrically stable as 
determined clinically by the investigator, including a BPRS score of <50 at 
screening. 
Approximately 50 subjects who participated in and completed any NBI-98854 
Phase 2 study, and were compliant with the study procedures, will be allowed to 
participate in this study. 
Duration of Treatment 
and Study 
Participation: 
The expected duration of study participation for each subject is approximately 
58 weeks, including up to 6 weeks of screening, a 48-week treatment period, 
and a 4-week follow-up period. 
Test Product, Dose, 
and Mode of 
Administration: 
NBI-98854 
will 
be 
supplied 
as 
capsules 
containing 
40 
mg 
of  
NBI-98854 ditosylate (dose is of free base).  The doses that will be used in this 
study are: 40 mg qd taken as one NBI-98854 40 mg capsule and 80 mg qd 
taken as two NBI-98854 40 mg capsules.  The subjects will swallow the 
capsules with at least 4 oz. of water and can take study drug with or without 
food. 
Reference Therapy 
Not applicable. 
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Efficacy 
Assessments: 
The AIMS will be administered and scored by the investigator (or designee) on 
Day -1 (the day prior to dosing), during the treatment period (end of Weeks 4, 8, 
12, 24, 36, and 48), and at the follow-up visit (end of Week 52) or early 
termination.  The AIMS will also be conducted at screening to assess the global 
severity of TD for study eligibility.  At specified timepoints, the AIMS will be 
video recorded for approximately 10 minutes. 
The AIMS will be assessed in accordance with the AIMS administration 
procedure and scoring guidelines provided by the sponsor (or designee).  At 
screening, Day -1, end of Week 8, and at the follow-up visit (end of Week 52) or 
early termination, the AIMS administration will be video recorded following 
standardized guidelines and the video recordings will be uploaded to a secure 
central server.   
- 
At screening, a blinded, external AIMS reviewer will access the central 
server to view the recording and evaluate the subject’s global TD severity 
(based on AIMS item 8) and the investigator (or designee) will score AIMS 
items 1-12.  
- 
On Day -1, at the end of Week 8, and at the follow-up visit (end of Week 52) 
or early termination, the AIMS recordings will be reviewed by blinded, 
central AIMS video raters who will score AIMS items 1-7, using a triple-blind 
consensus scoring process.  
The CGI-TD will be used to rate the investigator’s (or designee’s) assessment 
of the overall global improvement of TD symptoms since initiation of NBI-98854 
dosing, and will be administered during the treatment period (end of Weeks 4, 
8, 12, 24, 36, and 48) and at the follow-up visit (end of Week 52) or early 
termination. 
The Tardive Dyskinesia Impact Scale (TDIS) and Assessment of Most 
Bothersome Movement in TD (AMBMTD) will be used to evaluate the 
impairment and disability associated with dyskinesia and  to rate the subject’s 
most bothersome movement, respectively.  The TDIS and AMBMTD will be 
completed by the subject at screening, on Day -1 (the day prior to dosing), 
during the treatment period (end of Weeks 4, 8, 12, 24, 36, and 48), and at the 
follow-up visit (end of Week 52) or early termination. 
The Patient Global Impression of Change (PGIC) will be used to evaluate the 
change in TD symptoms since initiation of the study drug. The PGIC will be 
completed by the subjects during the treatment period (end of Weeks 4, 8, 12, 
24, 36, and 48) and at the follow-up visit (end of Week 52) or early termination.  
Plasma Drug 
Exposure: 
Blood samples to evaluate plasma concentrations of NBI-98854, the active 
metabolite NBI-98782 and possibly other metabolites will be collected during 
the treatment period (end of Weeks 4, 8, 12, 24, 36, and 48), and at the 
follow-up visit (end of Week 52) or at early termination. 
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Safety Assessments: 
Safety and tolerability will be monitored throughout the study and will include 
the following assessments:  
All subjects: 
• 
AEs 
• 
Clinical laboratory tests (hematology, clinical chemistry, prolactin, and 
urinalysis). 
• 
Vital signs (including orthostatic blood pressures and pulse) 
• 
Physical examinations 
• 
12-lead electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior - evaluated using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) 
• 
Drug-induced akathisia and extrapyramidal symptoms – evaluated 
using the Barnes Akathisia Rating Scale (BARS) and Simpson-Angus 
Scale (SAS) 
Specific to underlying disease category: 
• 
Depressive symptoms – Calgary Depression Scale for Schizophrenia 
(CDSS) in subjects who have schizophrenia or schizoaffective disorder 
and Montgomery-Asberg Depression Rating Scale (MADRS) conducted 
using the Structured Interview Guide for the MADRS (SIGMA) in 
subjects who have mood disorder. 
• 
Schizophrenia symptoms – Positive and Negative Syndrome Scale 
(PANSS), only in subjects who have schizophrenia or schizoaffective 
disorder. 
• 
Mania – evaluated using the Young Mania Rating Scale (YMRS) only in 
subjects who have mood disorder.  
Exploratory 
Assessments: 
Plasma samples will be collected for an exploratory assessment of biomarkers 
associated with the metabolic profile of NBI-98854; however, the data collected 
will not be reported in this study. 
Data Analysis: 
Efficacy endpoints as well as safety, PK, and PD data will be summarized by 
treatment and timepoint (as appropriate) using descriptive statistics. 
The efficacy measures in this study include the AIMS as scored by the blinded 
central AIMS video raters, CGI-TD, PGIC, TDIS, and AMBMTD.  The AIMS as 
scored by the investigators (or designee) will be evaluated as an exploratory 
measure.   
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2. 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale  
ALT 
Alanine aminotransferase  
AMBMTD 
Assessment of Most Bothersome Movement in Tardive Dyskinesia 
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration versus time curve 
β-hCG 
β-human chorionic gonadotropin  
BARS 
Barnes Akathisia Rating Scale  
BMI 
Body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CDSS 
Calgary Depression Scale for Schizophrenia 
CFR 
Code of Federal Regulations 
CGI-TD 
Clinical Global Impression of Change – Tardive Dyskinesia 
CK 
Creatine kinase 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DHTBZ 
Dihydrotetrabenazine 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EPS, EPSE 
Extrapyramidal symptoms or side effects 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-Ab 
Human immunodeficiency virus antibody 
ICF 
Informed Consent Form 
IRB 
Institutional review board 
IUD 
Intrauterine device 
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IV 
intravenous 
IWRS 
Interactive Web Response System 
K2EDTA  
Dipotassium ethylenediaminetetraacetic acid 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No Observed Adverse Effect Level 
OTC 
Over the counter 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic(s) 
PGIC 
Patient Global Impression of Change 
QTcF 
Fridericia’s correction of QT interval  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SIGMA 
Structured Interview Guide for the Montgomery and Asberg 
Depression Rating Scale 
SST 
Serum separator tube 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TD 
Tardive dyskinesia 
TDIS 
Tardive Dyskinesia Impact Scale 
UBACC 
University of California, San Diego Brief Assessment of Capacity to 
Consent 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
US 
United States 
VMAT2 
Vesicular monoamine transporter 2 
WBC 
White blood cell 
YMRS 
Young Mania Rating Scale 
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3. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) 
standards that meet regulations relating to Good Clinical Practice (GCP).  These 
standards respect the following guidelines: 
• Good Clinical Practice:  Consolidated Guideline (International Conference on 
Harmonisation of Technical Requirements for the Registration of Pharmaceuticals 
for Human Use, May 1996). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies 
(21 CFR parts 11, 50, 54, 56, 312, and 314). 
The ethical requirements of Institutional Review Boards (IRBs)/ Ethics Committees 
(ECs) and Informed Consent Forms (ICFs) are discussed in Section 13, Regulatory and 
Ethical Issues 
4. 
INTRODUCTION  
4.1. 
Background  
Tardive dyskinesia (TD) is a neurological condition characterized by involuntary 
movements of the orofacial region (ie, tongue, lips, jaw, face) and choreoathetoid 
movements in the limbs and trunk.  Tardive dyskinesia develops with long-term 
neuroleptic drug use and often persists after discontinuation of the offending 
medication.  Only a small proportion of patients who are treated with dopamine receptor 
blocking drugs develop this syndrome.  While isolated case reports of TD after short-
term exposure exist, most often TD emerges after long-term neuroleptic treatment over 
months to years.  The Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition (DSM-IV) defines chronic exposure (treatment for 3 months or greater) to 
neuroleptics as the basis for TD diagnosis.  In addition to duration and amount of 
neuroleptic exposure, other risk factors for TD appear to include older age, 
schizophrenia and cognitive impairment (Margolese et al., 2005).  While often of mild 
intensity, moderate to severe TD can be disabling.  Most patients with mild TD are 
unaware of their involuntary movements and do not seek treatment (Macpherson and 
Collis, 1992).  Severe TD can also cause great bodily harm (eg, lip or tongue 
lacerations, falls), interference with activities of daily living, and social isolation. 
The pathophysiology of TD is not fully understood; however, post-synaptic dopamine 
hypersensitivity in the striatum is the most prominent feature (Margolese et al., 2005). 
Dysregulation of dopaminergic systems is an integral component of several central 
nervous system (CNS) disorders, including other hyperkinetic movement disorders and 
conditions such as schizophrenia and bipolar disorder.  The transporter protein 
vesicular monoamine transporter 2 (VMAT2) plays an important role in presynaptic 
dopamine release, regulating monoamine uptake from the cytoplasm to the synaptic 
vesicle for storage and release.  The differential expression of VMAT2 in human brain 
(versus endocrine tissue) makes agents that selectively target VMAT2 potentially useful 
for the treatment of CNS disorders (Weihe and Eiden, 2000). 
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Tetrabenazine, a VMAT2 inhibitor and monoamine depletor, was recently approved for 
the treatment of chorea associated with Huntington’s disease.  Use of tetrabenazine for 
the treatment of TD and a variety of hyperkinetic movement disorders has also been 
described (Ondo et al, 1999; Jankovic and Beach, 1997).  The beneficial pharmacologic 
effects of tetrabenazine on the targeted hyperkinetic involuntary movements have been 
documented, as well as the adverse effects associated with excessive monoamine 
reduction, such as sedation, depression, akathisia and parkinsonism.  The occurrence 
of these adverse effects with tetrabenazine have resulted in the need for individualized 
dosing, dose titration, and management of treatment-related side effects. 
The requirement for dose titration with tetrabenazine may be due to its extensive and 
variable metabolism.  Upon absorption, tetrabenazine is rapidly reduced to 
dihydrotetrabenazine (DHTBZ) which is a mixture of the stereoisomers (±)α-DHTBZ and 
(±)β-DHTBZ.  Since (+)α-DHTBZ is an VMAT2 inhibitor, with potency comparable to 
tetrabenazine, and since very low exposures of tetrabenazine are observed upon its 
oral administration, the therapeutic efficacy of tetrabenazine appears to be derived from 
(+)α-DHTBZ (Kilbourn et al., 1995; Mehvar et al., 1987; Xenazine® Package Insert, 
2011).  Metabolism of tetrabenazine to (±)α-DHTBZ and (±)β-DHTBZ is highly variable 
between patients and these stereoisomers of DHTBZ exhibit wide-ranging 
pharmacology (ie, binding to off-target protein receptors).  This represents a source of 
added risk to the patient and complication for the physician in terms of actively 
managing a patient’s dosing regimen.  Orally administered NBI-98854 may provide an 
advantage by delivering the potent and selective VMAT2 inhibitor (+)α−DHTBZ 
(NBI-98782), in a consistent and controlled manner minimizing excessive monoamine 
reduction and off-target effects. 
4.2. 
NBI-98854 
NBI-98854 is an orally active valine ester prodrug of a VMAT2 inhibitor (NBI-98782) and 
is currently under development at Neurocrine Biosciences Inc. (NBI) for the treatment of 
neuroleptic-induced TD, Tourette Syndrome (TS) and other involuntary movement 
disorders.  NBI-98782 ([+]α−dihydrotetrabenazine) is the most potent and selective of 
the four stereoisomers of dihydrotetrabenazine formed upon reduction of tetrabenazine 
(Xenazine® Package Insert, 2011), a Food and Drug Administration (FDA) approved 
drug for the treatment of Huntington’s chorea.  NBI-98854 was designed to deliver  
NBI-98782 in a controlled fashion with reduced peak plasma concentrations and 
pharmacokinetic (PK) variability that should limit off-target binding and allow for an 
improved safety profile in human subjects.   
The intravenous (IV) and oral PK of NBI-98854 has been studied in mice, rats, 
monkeys, dogs, and humans.  In animals, orally administered NBI-98854 is rapidly 
absorbed and relatively slowly converted to the active moiety NBI-98782, such that 
animals are exposed to both the prodrug and the active drug.  This is in contrast to 
other prodrug esters that are typically rapidly absorbed and immediately converted to 
the active drug.  Dose-dependent increases in exposure to both the prodrug and active 
moiety were seen in animal studies.  NBI-98854 appears to cause little or no 
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cytochrome P450 (CYP) enzyme inhibition or induction at pharmacologically relevant 
concentrations.  Metabolism of NBI-98854 is characterized by esterase-dependent 
conversion of NBI-98854 to NBI-98782, and CYP3A4/5-dependent mono-oxidation of 
NBI-98854.  The elimination of NBI-98782 is in part catalyzed by CYP2D6.  Repeat 
dose nonclinical toxicology studies conducted in mice, rats, and dogs (up to 9 months 
duration) have revealed no adverse effects at doses of 60 mg/kg/day in the mouse,  
3 mg/kg/day in the rat and 15 mg/kg/day in the dog.  Radiolabeled absorption, 
metabolism, distribution, and excretion studies have confirmed that all abundant human 
circulating metabolites were identified as circulating metabolites in both rat and dog 
providing justification for the use of these species for pivotal toxicology studies in the 
safety assessment of NBI-98854.  Additionally, cardiovascular, pulmonary, and CNS 
safety pharmacology studies have also been conducted, where the no observed 
adverse effect level (NOAEL) was equal to or exceeded the 15 mg/kg level seen in 
repeat dose toxicology studies.  NBI-98854 had a modest negative effect on rat fertility 
at 10 mg/kg/day (NOAEL of 3 mg/kg/day). The NOAEL for embryo/fetal development in 
rats and rabbits was 15 mg/kg/day and 50 mg/kg/day, respectively. There was no 
evidence of teratogenicity in the rat or rabbits.  Finally, NBI-98854 was negative in 
in vitro mutagenicity assays (namely, Ames and chromosomal aberration) and an in vivo 
rat micronucleus test. 
Twelve clinical studies with NBI-98854 have been completed to date; eight Phase 1 
clinical studies in healthy male and female subjects, including elderly, non-elderly, and 
hepatically impaired adults; and four Phase 2 studies in subjects with TD and a clinical 
diagnosis 
of 
schizophrenia 
or 
schizoaffective 
disorder, 
mood 
disorder, 
or 
gastrointestinal (GI) disorder.  The Phase 1 studies have evaluated the PK of  
NBI-98854 administered as an oral solution or capsule formulation, pharmacodynamic 
assessments including serum prolactin and cognitive performance, and safety 
measures including evaluation of cardiovascular risk using triplicate 12-lead 
electrocardiogram (ECG) and 24-hour Holter monitoring.  The Phase 2 studies have 
included an evaluation of efficacy in the treatment of symptoms of TD using the 
Abnormal Involuntary Movement Scale (AIMS). 
Clinical PK data indicate that when administered orally under fasted conditions,  
NBI-98854 appeared to be rapidly absorbed with maximum plasma concentration (Cmax) 
being reached within 1 hour.  The active metabolite NBI-98782 was formed gradually 
with maximum plasma concentration being reached 4 to 10 hours after dosing.  Plasma 
concentrations for both NBI-98854 and NBI-98782 appeared to decline after reaching 
maximal concentration and both exhibited an apparent terminal half-life of 
approximately 20 hours in non-elderly adult subjects and 23 to 28 hours in elderly 
subjects.  Preliminary data from healthy volunteer studies suggest that coadministration 
of NBI-98854 with strong CYP3A4 and CYP2D6 inhibitors is expected to increase the 
Cmax and area under the plasma concentration versus time curve (AUC) of NBI-98782 
by approximately 2-fold.  A similar approximately 2-fold increase in NBI-98782 was 
observed when NBI-98854 is given to subjects with moderate or severe hepatic 
impairment. 
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NBI-98854 has been generally well tolerated in single doses up to 300 mg and in 
multiple doses of up to 100 mg.  Treatment-emergent adverse events (TEAEs) 
consistent with the pharmacological effects of monoamine reduction (eg, fatigue, 
insomnia, nervousness) occurred at a lower incidence in the NBI-98854 100 mg dose 
compared to the 50 mg dose in the Phase 2 studies.  Most TEAEs were transient and 
considered mild or moderate in intensity.  Thirteen treatment-emergent serious adverse 
events (SAEs) among 10 subjects have been reported.  No SAEs have been assessed 
by the investigator as possibly related to study drug.  No cardiovascular, laboratory, or 
vital sign-related safety signals have been identified.  Increases in serum prolactin 
above normal laboratory ranges have been noted, but there have been no TEAEs 
associated with hyperprolactinemia.  In general, depression, drug-induced akathisia, 
and drug induced parkinsonism did not worsen during treatment with NBI-98854. 
Results from a small, open-label Phase 2 study in 6 subjects with schizophrenia or 
schizoaffective disorder and TD indicated improvement in abnormal involuntary 
movements as measured by the AIMS after 12 consecutive days of NBI-98854 dosing 
(4 days each at 12.5 mg, 25 mg, and 50 mg).  Findings from a second Phase 2 study 
conducted in this patient population, a placebo-controlled crossover study in  
37 subjects, indicated a greater improvement in the AIMS score after 14 days of 
treatment with NBI-98854 50 mg compared to placebo.  Preliminary results from two 
more recently completed Phase 2b studies indicated an improvement in the AIMS score 
after 6 weeks of continuous dosing with either NBI-98854 50 mg once daily, continuous 
dosing at NBI-98854 100 mg once daily for 2 weeks followed by continuous dosing at 
NBI-98854 50 mg once daily for 4 weeks (NBI-98854-1201) or 6 weeks of titrated doses 
from 25 mg up to 75 mg NBI-98854 once daily (NBI-98854-1202).  Preliminary results 
from an open-label safety extension with dosing out to 12 weeks (NBI-98854-1201) 
continued to show benefit in subjects continuing on with NBI-98854 50 mg daily dosing 
and also in subjects originally assigned to placebo who went on to receive NBI-98854 
50 mg once daily for the 6 weeks of open-label treatment period.  Results from the  
6-week dose-titration study (NBI-98854-1202) showed a statistically significant 
reduction in the AIMS dyskinesia total score in the NBI-98854 group compared to 
placebo.  A statistically significant higher responder rate (ie, ≥50% improvement in 
AIMS dyskinesia total score from baseline) was also observed in the NBI-98854 group 
compared to placebo. 
4.3. 
Study Rationale and Selection of Dose  
The present study is a Phase 3, open-label, fixed-dose titration study of NBI-98854 
(titrated from 40 mg to 80 mg) in medically stable subjects with schizophrenia or 
schizoaffective disorder or mood disorder and TD.  Subjects will be required to have 
moderate or severe TD as determined by a blinded, external AIMS reviewer to assure 
appropriate subject inclusion.  This study is designed to evaluate the safety and 
tolerability of NBI-98854 administered for up to 48 weeks for the treatment of TD.  
In the current study, all subjects will receive NBI-98854 for 48 weeks.  Subjects will 
receive a starting dose of NBI-98854 40 mg once daily for 4 weeks.  After 4 weeks, 
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subjects may be eligible for a dose escalation to NBI-98854 80 mg provided that (1) the 
investigator or designee’s assessment of the subject’s Clinical Global Impression of 
Change – Tardive Dyskinesia (CGI-TD) is “minimally improved”, “not changed”, 
“minimally worse”, “much worse” or “very much worse”, and (2) the safety and 
tolerability of the current dose is acceptable as determined by a physician.  The 
investigator will increase the dose for any subject meeting both criteria and may 
decrease the dose to the previous dose at any time for a subject who is unable to 
tolerate the dose increase; subjects who have had a dose reduction will continue at that 
dose until the end of Week 48 (refer to the schematic in Section 16.2).  Subjects will be 
discontinued from the study if they are unable to tolerate the starting dose (40 mg), or 
resumption of the starting dose.  This fixed dose titration design, based on Phase 2 
data, maximizes the proportion of subjects receiving an adequate dose for robust 
clinical response (eg, ≥50% reduction in dyskinesia) along with good tolerability. It is 
anticipated that approximately 30% of subjects will complete on the 40 mg dose and 
approximately 70% of subjects on the 80 mg dose. 
Rationale for Dose Selection 
Clinical data from TD subjects administered repeated doses of NBI-98854 from 12.5 mg 
to 100 mg per day indicate that NBI-98854 is generally well tolerated and associated 
with dose-related efficacy.  Exposure-response analysis indicates that a steady state 
Cmax of 20 to 40 ng/mL NBI-98782 is an appropriate plasma concentration range for 
efficacy.   
NBI-98854 doses of 40 mg and 80 mg are associated with exposure to the active 
metabolite, NBI-98782, in the target range of 20 to 40 ng/mL when administered initially 
as 40 mg once daily and adjusted upward to 80 mg if dyskinesia persists after several 
weeks of treatment.  These doses have been selected as a simple and practical method 
to provide exposure associated with acceptable tolerability and robust efficacy. Doses 
below 40 mg are well tolerated but offer dyskinesia reduction comparable to placebo. 
Doses above 80 mg afford little incremental benefit but increase the risk of adverse 
events (AEs) reflecting extension of VMAT2 pharmacology. Because many patient-
specific factors appear to influence tolerability and efficacy, clinicians would be guided 
to start all patients at the lower of two doses.  Preliminary analysis of Phase 2 data 
suggests that these patient-specific factors include body weight, CYP2D6 genotype, 
concomitant medications, comorbid medical conditions and a number of other clinical 
variables.   
5. 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and tolerability of NBI-98854 (titrated 
from 40 mg to 80 mg) administered once daily for up to 48 weeks. 
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6. 
OVERVIEW OF STUDY DESIGN 
Subjects will provide written informed consent before any study-related procedures, 
including washout of disallowed medications, are performed as described in  
Section 6.1. 
6.1. 
Study Design 
This is a Phase 3, open-label, dose-titration study to evaluate the safety and tolerability 
of NBI-98854 (titrated from 40 mg to 80 mg) administered once daily (qd) for a total of 
48 weeks of treatment.  Approximately 180 medically stable male and female subjects 
with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic 
induced TD or mood disorder with neuroleptic induced TD will be enrolled.  Of the 
approximately 180 subjects, approximately 60% may have schizophrenia or 
schizoaffective disorder. 
All subjects must sign an ICF prior to the conduct of any study related procedures, 
including washout of medications disallowed in the study.  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). A copy of the 
UBACC is located in Appendix 17.1.  During the initial step of consent process, the ICF 
will be reviewed with the subject.  The UBACC will then be administered.  Only subjects 
who are deemed to have the capacity to provide consent may sign the ICF. Subjects 
may also be asked to sign an optional release form to allow their AIMS video recordings 
to be used for educational purposes.  After providing informed consent, the subjects will 
be screened for eligibility for up to 6 weeks prior to Day -1 (baseline visit) (Week -6 to 
Day -1). 
On Day -1, eligible subjects will receive a supply of NBI-98854 40 mg qd for the first 
4 weeks of the treatment period.  Beginning on Day 1, study drug will be self-
administered at home (in the presence of their caregiver, if applicable) in the morning 
between 0700 and 1000 hours.   
At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg or 
continue with the subject’s current dose.  A dose escalation will be allowed at the end of 
Week 4 if (1) the investigator or designee’s assessment of the CGI-TD is “minimally 
improved”, “not changed”, “minimally worse”, “much worse”, or “very much worse”, and 
(2) the safety and tolerability of the current dose is acceptable as determined by a 
physician.   The subject will then continue at the 80 mg dose until the end of the 
treatment period (end of Week 48). 
At any time after a dose escalation, the investigator may decrease the dose to 40 mg if 
the subject is unable to tolerate the dose increase.  The subject will then continue at the 
40 mg dose until the end of the treatment period (end of Week 48).  Subjects who are 
unable to tolerate the starting dose of 40 mg, or the resumption of 40 mg, will be 
discontinued from the study (refer to the schematic in Section 16.2).  
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Subjects will return to the study site every 4 weeks in the afternoon for study 
assessments and dispensation of the study drug.  These visits will occur in the 
afternoon between 1200-1700 hours at the end of Weeks 4, 8, 12, 24, 36, 48 and 52 (or 
early termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 32, 
40 and 44.  The study site will call subjects weekly to remind them to take their study 
medication daily.  Subjects who do not want to continue in the study will be terminated 
and will be asked to return for an early termination visit approximately 4 weeks after 
receiving the last dose.  Follow-up assessments will be performed at the end of 
Week 52 (4 weeks after the last dose) or early termination. 
Efficacy, safety, and PK will be assessed at scheduled times throughout the study.  The 
treatment period visits (end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48) 
and the follow-up visit (end of Week 52) will have a visit window of ±6 days. 
A schematic of the study design is provided in Figure 1. 
6.1.1. Efficacy, Blood Sample Collections, and Safety Assessments for All 
Subjects 
Efficacy assessments will be performed using the AIMS, the CGI-TD, the Patient Global 
Impression of Change (PGIC), the Tardive Dyskinesia Impact Scale (TDIS), and the 
Assessment of Most Bothersome Movement in Tardive Dyskinesia (AMBMTD).  The 
AIMS will be administered at screening, on Day -1 (the day prior to dosing), during the 
treatment period (end of Weeks 4, 8, 12, 24, 36, and 48), and at the follow-up visit (end 
of Week 52) or early termination.  The AIMS will be administered and scored by the 
investigator (or designee) in accordance with the AIMS administration procedure and 
scoring guidelines provided by the sponsor (or designee).  At screening, Day -1, end of 
Week 8, and at the follow-up visit (end of Week 52) or early termination, the AIMS 
assessment will be video recorded (approximately 10 minutes) following standardized 
guidelines and the video recording will be uploaded to a secure central server.  At 
screening, a blinded, external AIMS reviewer will access the central server to view the 
recoding and evaluate the subject’s global TD severity (based on AIMS item 8).  The 
subject must have moderate or severe TD as determined by the blinded, external 
reviewer to be eligible for study participation. The investigator or designee will score 
AIMS items 1-10 and complete AIMS items 11-12. The AIMS video recording conducted 
on Day -1, at the end of Week 8, and at the follow-up visit (end of Week 52) or early 
termination will be reviewed by blinded, central AIMS video raters who will score AIMS 
items 1-7 using a triple-blind consensus scoring process.  Refer to Sections 8.3.1.1, 
8.3.1.2 and 8.3.1.3 for details.  
The CGI-TD will be used to rate the investigator or designee’s assessment of the overall 
global improvement of TD symptoms since initiation of study drug dosing, and will be 
administered during the treatment period (end of Weeks 4, 8, 12, 24, 36, and 48) and at 
the follow-up visit (end of Week 52) or early termination.   
The PGIC will be used to evaluate the change in TD symptoms since initiation of study 
drug dosing, and will be completed by the subjects during the treatment period (end of 
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Weeks 4, 8, 12, 24, 36, and 48) and at the follow-up visit (end of Week 52) or early 
termination.  
A patient reported outcome, the TDIS and AMBMTD will be used to assess the 
impairment and disability associated with dyskinesia and to rate the subject’s most 
bothersome movement, respectively.  The TDIS will be completed by the subjects at 
screening, on Day -1 (the day prior to dosing), during the treatment period (end of 
Weeks 4, 8, 12, 24, 36, and 48), and at the follow-up visit (end of Week 52) or at early 
termination.  
The Brief Psychiatric Rating Scale (BPRS) will be performed at screening as an 
assessment of the severity of psychopathology to determine study eligibility. 
Blood samples for plasma drug concentration analysis will be collected during the study. 
A blood sample will be collected from enrolled subjects on Day -1 and analyzed to 
determine CYP2D6 status.  Plasma samples for an exploratory assessment of 
biomarkers associated with the metabolic profile of NBI-98854 will be collected during 
the study. 
Safety and tolerability assessments including AE monitoring, clinical laboratory tests 
(including hematology, clinical chemistry, prolactin, and urinalysis), vital sign 
measurements, PE, and 12-lead ECG will be conducted at scheduled times throughout 
the study.  Suicidal ideation and behavior will be evaluated using the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  The Barnes Akathisia Rating Scale (BARS) and the 
Simpson-Angus Scale (SAS) will be used to assess the presence and severity of drug-
induced akathisia and drug-induced extrapyramidal symptoms, respectively. 
6.1.2. Additional Safety Assessments for Subjects with Schizophrenia or 
Schizoaffective Disorder: 
Depressive symptoms will be evaluated using the Calgary Depression Scale for 
Schizophrenia (CDSS).  Psychiatric symptoms will be assessed using the Positive and 
Negative Syndrome Scale (PANSS). 
6.1.3. Additional Safety Assessments for Subjects with Mood Disorder: 
The Young Mania Rating Scale (YMRS) will be used to assess manic symptoms.  
Depressive symptoms will be evaluated with the Montgomery-Asberg Depression 
Rating Scale (MADRS) conducted using the Structured Interview Guide for MADRS 
(SIGMA). 
 
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Figure 1. Study Design Schematic 
Week 
1
4
AIMSa   
CGI-TD 
MADRS (SIGMA)c
Open-Label NBI-98854
Treatment Period
BARS, SAS
Prolactin  
16
Pharmacokinetics
AIMS = Abnormal Involuntary Movement Scale; AMBMTD = Assessment of Most Bothersome Movement in Tardive Dyskinesia; BARS = Barnes Akathisia Rating Scale; 
BPRS = Brief Psychiatric Rating Scale; CDSS = Columbia Depression Scale for Schizophrenia; CGI-TD = Clinical Global Impression - Tardive Dyskinesia; C-SSRS = Columbia 
Suicide Severity Rating Scale; MADRS (SIGMA) = Montgomery-Asberg Depression Rating Scale using the Structured Interview Guide for the MADRS; PANSS = Positive and 
Negative Syndrome Scale; PGIC = Patient Global Impression of Change; QD = once daily; SAS = Simpson-Angus Scale; TDIS = Tardive Dyskinesia Impact Scale; YMRS = Young 
Mania Rating Scale
a  AIMS will be administered and scored by the investigator (or designee). At screening, Day -1, end of Week 8, and at the follow-up visit (end of Week 52) or early termination, 
    the AIMS will be video recorded for approximately 10 minutes. At screening, a blinded, external AIMS reviewer will evaluate the severity of TD symptoms; eligible subjects must 
    have moderate or severe symptoms of TD. 
b  The TDIS and AMBMTD will be completed by the subject.
c  Assessments for subjects with Mood Disorder only.
d  Assessments for subjects with Schizophrenia or Schizoaffective Disorder only.
e  At Screening, only SAS will be administered.
Safety Assessments
Follow-up
TDIS/AMBMTDb
        -1
Day 
C-SSRS
YMRSc
Follow-up 
Period
PANSSd
CDSSd
Plasma for Biomarkers
8
Dosing (QD)   
40 mg 
NBI-
98854
40 mg or 80 mg NBI-98854
24
36
40
12
20
28
32
44
48
52
Screening 
Screening 
            
-6
e
BPRS
PGIC
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7. 
STUDY POPULATION 
This study will be conducted in approximately 180 medically stable adult male or female 
subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with 
neuroleptic induced TD or mood disorder with neuroleptic induced TD.  Of the 
approximately 180 subjects to be enrolled, approximately 60% may have schizophrenia 
or schizoaffective disorder.  Subjects must have moderate to severe TD as assessed at 
screening by a blinded external reviewer.  Approximately 50 subjects who participated 
in and completed any NBI-98854 Phase 2 study, and were compliant with the study 
procedures, will be allowed to participate in this study.  Subjects must meet all the 
inclusion criteria and none of the exclusion criteria in order to qualify for the study.  
7.1. 
Inclusion Criteria 
To participate in this study, subjects must: 
1. 
Be male or female, aged 18 to 85 years (both inclusive). 
2. 
Subjects of childbearing potential must agree to use hormonal or two forms of 
nonhormonal contraception (dual contraception) consistently during the screening, 
treatment and follow-up periods of the study.   
Acceptable methods of contraception include the following: 
• Condom with spermicide (cream, spray, foam, gel, suppository, or polymer 
film). 
• Diaphragm with spermicide (with or without condom). 
• Cervical cap with spermicide (with or without condom).  
• Vaginal sponge impregnated with spermicide used with a condom. 
• Intrauterine device (IUD). 
• Hormonal contraception being taken for at least 3 months prior to screening.  
The following subjects are not required to use contraception:  
• Subjects who practice total abstinence from sexual intercourse as the 
preferred lifestyle (periodic abstinence is not acceptable).   
• Female subjects with partners or male subjects who had been vasectomized 
at least 3 months prior to screening. 
• Female subjects who have been postmenopausal for at least 1 year prior to 
screening. 
• Female subjects who are surgically sterile (ie, bilateral oophorectomy, 
hysterectomy or bilateral tubal ligation) at least 3 months prior to screening. 
3. 
Female subjects who have not been postmenopausal for at least 1 year must have 
a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at 
screening and a urine pregnancy test on Day -1. 
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4. 
Have one of the following clinical diagnoses for at least 3 months prior to 
screening: 
• Schizophrenia or Schizoaffective Disorder as defined in the in the Diagnostic 
and Statistical Manual of Mental Disorders, (DSM, eg, DSM-IV).   
• Mood Disorder as defined in the DSM (eg, DSM-IV). 
This criterion will be satisfied if the subject is able to provide a medical record of 
the diagnosis or reliable self-reported medical history and medications taken for 
the disorder.  If the subject is unable to provide a medical record or reliable self-
reported medical record, the investigator must confirm the psychiatric diagnosis 
based on an evaluation using the Mini International Neuropsychiatric Interview 
(MINI) (applicable module must be used to assess underlying disease). 
5. 
Have a clinical diagnosis of neuroleptic-induced TD as defined in the DSM 
(eg, DSM-IV code 333.82; refer to Section 16.1) for at least 3 months prior to 
screening.  This criterion will be satisfied if the subject is able to provide a medical 
record of the TD diagnosis or the investigator can confirm the TD diagnosis based 
on physical examination, and reliable self-reported medical history and medication 
use that show evidence of involuntary movements associated with dopamine 
antagonist/antipsychotic medication exposure that are clearly distinct from the 
typical parkinsonism associated with extrapyramidal symptoms or side effects 
(EPS or EPSE). 
6. 
Have moderate or severe TD (AIMS Item 8, severity of abnormal movement 
overall) as assessed by a blinded, external AIMS reviewer using a video recording 
of the subject’s AIMS assessment administered at the study site by the  
investigator (or designee) at screening. 
7. 
Maintenance medication(s) for schizophrenia or schizoaffective disorder, mood 
disorders, and other protocol allowed concurrent medications should be at a stable 
dose (including no changes to the dose and frequency of ongoing medications and 
no discontinuation of medications for a minimum of 30 days before screening).  
Exceptions may be allowed if discussed with and approved by NBI’s medical 
monitor (or designee) prior to Day -1.  If an exception is approved, the subject must 
be on a stable dose for 30 days prior to Day -1.  Benzodiazepines must be at a 
stable dose for 2 weeks before screening.  This criterion will be satisfied if the 
investigator can confirm prior and current medications and doses through reliable 
subject-reported information (eg, subject provides a list of medications and doses).   
8. 
Subjects with a diagnosis of schizophrenia or schizoaffective disorder who are not 
using antipsychotic medication must have a stable psychiatric status as clinically 
determined by the investigator.  Subjects with a diagnosis of bipolar disorder must 
be on stable dose of mood stabilizer(s) (eg, lithium, valproate, olanzapine) for a 
minimum of 30 days before screening.  Exceptions may be allowed as mentioned 
in inclusion criterion #7.  The use of carbamazepine is permitted if discussed with 
and approved by NBI’s medical monitor (or designee) prior to Day -1. 
9. 
Be in good general health and expected to complete the clinical study as designed. 
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10. Have a body mass index (BMI) of 18 to 38 kg/m2 (inclusive) at screening.  Subjects 
with BMI that is out of the specified range will require discussion with and approval 
by NBI’s medical monitor (or designee) prior to Day -1.  (BMI is defined as the 
subject’s weight in kg divided by the square of the subject’s height in meters). 
11. Have adequate hearing, vision, and language skills to perform the procedures 
specified in the protocol. 
12. Have voluntarily provided informed consent and have signed an ICF indicating that 
the purpose of the study has been explained, and are willing and able to adhere to 
the study regimen and study procedures described in the ICF.  Subjects must also 
have been deemed capable of providing consent to study participation using the 
UBACC prior to signing the ICF. 
13. Have a negative urine drug screen (UDS) (negative for amphetamines, 
barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids) at 
screening (central laboratory results) and Day -1 (UDS kit results conducted at the 
study site) except for any subject receiving a stable dose of benzodiazepines or 
opiates.  Subjects with positive cannabinoid results may be allowed to participate 
in the study provided that the subject is given thorough counseling and agrees to 
refrain from using cannabinoids for the duration of his/her study participation. 
14. Have a negative alcohol breath test at screening and Day -1. 
15. Be willing to provide authorization for access to personal health information in 
conjunction with US Health Insurance Portability and Accountability Act (HIPAA). 
7.2. 
Exclusion Criteria 
7.2.1. Exclusion Criteria for All Subjects 
Subjects will be excluded from the study if they: 
1. 
Have an active, clinically significant unstable medical condition within 1 month 
(30 days) prior to screening. 
2. 
Have comorbid abnormal involuntary movement(s) (eg, parkinsonism, akathisia, 
truncal dystonia) that is more prominent than TD as assessed by a blinded, 
external AIMS reviewer using video recording of the AIMS administration at 
screening. 
3. 
Have a SAS score ≥3 on two or more items at screening or Day -1, excluding 
Items 8 and 10. 
4. 
Have a known history of substance dependence or substance (drug) or alcohol 
abuse within the 3 months before Day -1 (nicotine and caffeine dependence are 
not exclusionary), as defined in the DSM (eg, DSM-IV). 
5. 
Have BPRS total score of ≥50 at screening. 
6. 
Have a significant risk of suicidal or violent behavior.  Subjects with any suicidal 
behavior or suicidal ideation of type 4 (active suicidal ideation with some intent to 
act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
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intent) based on the C-SSRS in the 3 months before screening (using 
Baseline/Screening version) and on Day -1 (using Since Last Visit version) will be 
excluded.  
7. 
Have a known history of neuroleptic malignant syndrome. 
8. 
Have a known history of long QT syndrome or cardiac tachy-arrhythmia. 
9. 
Have a screening or Day -1 average triplicate ECG QT interval corrected for heart 
rate using Fridericia’s correction of QT interval (QTcF) of >450 msec (males) or 
>470 msec (females) or the presence of any clinically significant cardiac 
abnormality. 
10. Receive any excluded concomitant medication (refer to Section 8.9.1); subjects 
receiving medications known to prolong the QT interval must be discussed with 
and approved by NBI’s medical monitor (or designee) on a case-by-case basis 
prior to Day -1. 
11. Have any of the following laboratory test abnormalities at screening: 
• serum creatinine >1.5 times upper limit of normal (ULN). 
• Aspartate aminotransferase (AST) ≥2.5 times ULN. 
• Alanine aminotransferase (ALT) ≥2.5 times ULN. 
• Gamma-glutamyl transferase (GGT) ≥3.0 times ULN.  Subjects with GGT 
≥3.0 times ULN will require discussion with and approval by NBI’s medical 
monitor or designee prior to Day -1 in order to participate in the study. 
• Total bilirubin >1.5 mg/dL.  
12. Have a hematologic malignancy or solid tumor diagnosed within 3 years prior to 
screening, with the exception of localized skin cancer or carcinoma in situ of the 
cervix. 
13. Have any of the following hematologic abnormalities at screening:  
• hemoglobin <10 g/dL. 
• white blood cell (WBC) count <3.0 x 103/mm3. 
• platelet count <100,000/mm3. 
14. Have other biochemistry or hematology results not within the laboratory’s 
reference range and deemed by the investigator to be clinically significant. 
15. Have a positive human immunodeficiency virus antibody (HIV-Ab) test result or 
hepatitis B surface antigen (HBsAg) test result at screening.  Subject with positive 
hepatitis C virus antibody (HCV-Ab) and confirmatory positive polymerase chain 
reaction (PCR) reflex test results at screening will be allowed to participate in the 
study provided that the subject is asymptomatic as assessed by the investigator 
and does not meet the liver function tests abnormalities (ALT, AST, GGT, and total 
bilirubin) exclusionary criterion  #11. 
16. Have received an investigational drug within 30 days before screening or plan to 
use an investigational drug (other than NBI-98854) during the study. 
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17. Have a blood loss ≥550 mL or donated blood within 30 days before Day -1. 
18. Have an allergy, hypersensitivity, or intolerance to tetrabenazine. 
19. Are currently participating or had participated in the NBI-98854-1304 study. 
20. Are currently pregnant or breastfeeding. 
7.2.2. Exclusion Criteria for Subjects with Clinical Diagnosis of Schizophrenia or 
Schizoaffective Disorder 
In addition to the exclusion criteria for all subjects, the following criteria must not be met 
for subjects with schizophrenia or schizoaffective disorder. 
21. Have CDSS total score of ≥10 at screening or Day -1. 
22. Have a PANSS total score of ≥70 at Day -1. 
7.2.3. Exclusion Criteria for Subjects with Clinical Diagnosis of Mood Disorder 
In addition to the exclusion criteria for all subjects, the following criteria must not be met 
for subjects with mood disorder. 
23. Have YMRS total score of >10 at screening or Day -1.  
24. Have been hospitalized for bipolar disorder or major depressive disorder within 
6 months of screening. 
25. Have had mood episodes (hypomania, mania, depressive, etc.) within 2 months of 
screening and Day -1. 
26. Have history of rapid cycling (>4 mood episodes per year) or ultra-rapid (>4 mood 
episodes per month). 
27. Have MADRS (SIGMA) total score of >13 at screening or Day -1. 
7.3. 
Subject Identification and Replacement 
Subjects will be identified by their unique subject number (combination of site number 
and subject number) and initials (first, middle, last).  Subject initials and subject number 
will be noted on the electronic case report forms (eCRFs), laboratory documents, and 
ECG tracings.  Subjects who discontinue the study will not be replaced. 
7.4. 
Randomization 
Subjects will not be randomized in this study.  
8. 
STUDY EVALUATIONS 
8.1. 
Schedule of Assessments 
Schedules of assessments that summarize the frequency and timing of all assessments 
for subjects with schizophrenia or schizoaffective disorder or subjects with mood 
disorders are provided in Table 1 and Table 2, respectively.  No protocol-related 
procedures, including the cessation of prohibited concomitant medications, should be 
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performed before subjects provide written informed consent.  Subject-related events 
and activities including specific procedures, concomitant medications, dispensing of 
study drug, and descriptions of AEs should be recorded in the appropriate source 
documents and eCRFs. 
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Table 1.  Schedule of Assessments for Subjects with Schizophrenia or Schizoaffective Disorder 
Procedurea 
Screening 
Period 
Baseline 
Open-Label  NBI-98854 Treatment Period 
Follow-up 
/ ET 
Weekb 
-6  TO -1 
DAY -1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52c 
Visitb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent / UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X (S) 
X (S,U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screeng  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotype blood sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum prolactin 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma for biomarkers 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PK plasma sampleh 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
AIMSi 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
TDIS and AMBMTDj 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CGI-TD  
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
SAS 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CDSS 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PANSS 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
NBI-98854 dosing at homek 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense NBI-98854l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NBI-98854 accountabilitym 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and footnotes appear on the next page. 
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Definitions: AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; AMBMTD=Assessment of Most Bothersome Movement in Tardive 
Dyskinesia; BARS=Barnes Akathisia Rating Scale; BPRS=Brief Psychiatric Rating Scale; CDSS=Calgary Depression Scale for Schizophrenia;  
CGI-TD=Clinical Global Impression-Tardive Dyskinesia; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early 
termination; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus antibody; HIV-Ab=human immnunodeficiency virus antibody; 
PANSS=Positive and Negative Syndrome Scale; PGIC=Patient Global Impression of Change; PK=pharmacokinetic; s=serum; SAS=Simpson-Angus 
Scale; TDIS=Tardive Dyskinesia Impact Scale; u=urine; UBACC=University of California, San Diego Brief Assessment of Capacity to Consent. 
a. Study assessments will be conducted at approximately the same time in the afternoon (between 1200-1700 hours) at screening, Day -1, at the end of 
Weeks 4, 8, 12, 24, 36, 48 and 52 (or early termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 32, 40 and 44. 
b. Day -1 visit is the day of baseline assessments.  Day 1 is the first day of dosing; NBI-98854 will be self-administered at home and subjects are not 
required to come to the study site.  The study visits after Day -1 will have a visit window of ±6 days. 
c. Final study visit for subjects who complete the study (or early termination). 
d. A standard 12-lead ECG will be conducted after the subject has rested supine for at least 5 minutes.  The ECG parameters that will be assessed 
include HR, QT, QTcF, and PR intervals, and QRS duration based on the ECG machine readings (QTcF may be calculated). 
e. Pregnancy tests are only required for women who are not postmenopausal for at least 1 year prior to screening.  Serum pregnancy tests will be 
conducted at screening and Day -1.  A urine pregnancy test will be conducted at Day -1 and all subsequent visits.  The urine pregnancy test result on 
Day -1 will be used to confirm eligibility. 
f. Clinical laboratory tests include hematology, chemistry and urinalysis.  All blood samples will be obtained under non-fasted conditions. 
g. Urine drug screen will be analyzed at Screening and Day -1 by the central lab.  In addition, a UDS kit provided by the central lab will used at the site to 
confirm eligibility on Day -1. 
h. Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
i. The AIMS will be administered and scored at the site by the investigator (or designee).  The AIMS will be video recorded for approximately 10 minutes 
at screening, Day -1, end of Week 8, and at the follow-up visit (end of Week 52 or early termination).  At screening, a blinded AIMS reviewer will view 
the video and evaluate the TD symptom severity (see inclusion #6) to determine subject eligibility. 
j. TDIS and AMBMTD will be completed by the subjects. 
k. Subjects will self-administer NBI-98854 daily (in the morning at approximately the same time) at home in the presence of their caregiver (if applicable). 
Subject or caregiver will record daily the date and time of dosing on the drug packaging form provided. A representative from the study site will call the 
subjects weekly to remind them to take NBI-98854 daily. 
l. Subjects will receive a 4-week supply (two kits) of NBI-98854 at Day -1 and will need to return to study site every 4 weeks to obtain a 4-week supply of 
NBI-98854.  
m. At the end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 subjects will return all used and unused NBI-98854, and a compliance check will be 
performed by counting the capsules returned at the visit. 
 
 
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Table 2. 
Schedule of Assessments for Subjects with Mood Disorders 
 
Procedurea 
Screening 
Period 
Baseline 
Open-Label NBI-98854 Treatment Period 
Follow-up / 
ET 
Weekb 
-6  TO -1 
DAY -1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52c 
Visitb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent / UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X (S) 
X (S,U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screeng  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotype blood sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum prolactin 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma for biomarkers 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PK plasma sampleh 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
AIMSi 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
TDIS and AMBMTDj 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CGI-TD  
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
SAS 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
MADRS (SIGMA) 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
YMRS 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
NBI-98854 dosing at homek 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense NBI-98854l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NBI-98854 accountabilitym 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and footnotes appear on the next page. 
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Clinical Study Protocol Amendment No. 2 Final Version
 
Confidential
03 December 2015
Page 33 of 137


Definitions: AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; AMBMTD=Assessment of Most Bothersome Movement in Tardive 
Dyskinesia; BARS=Barnes Akathisia Rating Scale; BPRS=Brief Psychiatric Rating Scale; CGI-TD=Clinical Global Impression-Tardive Dyskinesia;  
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=Electrocardiogram; ET=Early Termination; HBsAg=Hepatitis B Surface Antigen;  
HCV-Ab=Hepatitis C Virus Antibody; HIV-Ab=Human Immnunodeficiency Virus Antibody; MADRS (SIGMA)=Montgomery-Asberg Depression Rating 
Scale using the Structured Interview Guide for the MADRS; PGIC=Patient Global Impression of Chance; PK=Pharmacokinetic; s=serum; SAS=Simpson-
Angus Scale; TDIS=Tardive Dyskinesia Impact Scale; u=urine; UBACC=University of California, San Diego Brief Assessment of Capacity to Consent; 
YMRS=Young Mania Rating Scale. 
a. Study assessments will be conducted at approximately the same time in the afternoon (between 1200-1700 hours) at screening, Day -1, at the 
end of Weeks 4, 8, 12, 24, 36, 48 and 52 (or early termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 32, 40 and 44. 
b. Day -1 visit is the day of baseline assessments.  Day 1 is the first day of dosing; NBI-98854 will be self-administered at home and subjects are 
not required to come to the study site.  The study visits after Day -1 will have a visit window of ±6 days. 
c. Final study visit for subjects who complete the study (or early termination). 
d. A standard 12-lead ECG will be conducted after the subject has rested supine for at least 5 minutes.  The ECG parameters that will be 
assessed include HR, QT, QTcF, and PR intervals, and QRS duration based on the ECG machine readings (QTcF may be calculated). 
e. Pregnancy tests are only required for women who are not postmenopausal for at least 1 year prior to screening.  Serum pregnancy tests will be 
conducted at screening and Day -1.  A urine pregnancy test will be conducted at Day -1 and all subsequent visits.  The urine pregnancy test 
result on Day -1 will be used to confirm eligibility. 
f. Clinical laboratory tests include hematology, chemistry and urinalysis. All blood samples will be obtained under non-fasted conditions. 
g. Urine drug screen will be analyzed at Screening and Day -1 by the central lab. In addition, a UDS kit provided by the central lab will used at the 
site to confirm eligibility on Day -1. 
h. Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
i. The AIMS administered and scored at the site by the investigator (or designee).  At screening, Day -1, end of Week 8, and t the follow-up visit 
(end of Week 52 or early termination), the AIMS will be video recorded for approximately 10 minutes.  At screening, a blinded AIMS reviewer 
will view the video and evaluate the TD symptom severity (see inclusion #6) to determine subject eligibility. 
j.  TDIS and AMBMTD will be completed by the subjects. 
k. Subjects will self-administer NBI-98854 daily (in the morning at approximately the same time) at home in the presence of their caregiver (if 
applicable).  Subject or caregiver will record daily the date and time of dosing on the drug packaging form provided.  A representative from the 
study site will call the subjects weekly to remind them to take their study medication daily. 
l. Subjects will receive a 4-week supply (two kits) of NBI-98854 at Day -1 and will need to return to study site every 4 weeks to obtain a 4-week 
supply of NBI-98854. 
m. At the end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 subjects will return all used and unused NBI-98854, and a compliance check 
will be performed by counting the capsules returned at the visit. 
 
 
 
 
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Page 34 of 137


8.2. 
Screening Assessment 
8.2.1. Brief Psychiatric Rating Scale (BPRS) 
The BPRS is a clinician-rated tool designed to assess the severity of psychopathology 
in patients with schizophrenia and other psychotic disorders (Overall and Gorham, 
1962, 1988).  The BPRS includes 18 items that address somatic concern, anxiety, 
emotional withdrawal, conceptual disorganization, guilt feelings, tension, mannerisms 
and posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory 
behaviors, motor retardation, uncooperativeness, unusual though content, blunted 
affect, excitement, and disorientation.   
The severity of each of the 18 items of the BPRS is rated on a scale of 1 (not present) 
to 7 (extremely severe) (score range: 18 to 126). Higher scores represent greater 
symptom severity.   
The investigator or other qualified site personnel will administer and score the scale at 
screening, and subjects must have a BPRS total score <50 to be eligible for study 
participation (see exclusion criterion #5).  A copy of the BPRS is provided in 
Appendix 17.2. 
8.3. 
Efficacy Assessments 
8.3.1. Abnormal Involuntary Movements Scale (AIMS) 
The severity of TD will be assessed using the AIMS rating scale.  This scale was 
developed by the Psychopharmacology Research Branch of the National Institute of 
Mental Health (Guy, 1976a).  The AIMS rates a total of 10 items with 9 items rating 
involuntary movement from 0 (no dyskinesia) to 4 (severe dyskinesia).  Items 1 through 
7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and 
trunk movements (Item 7).  The AIMS dyskinesia total score for Items 1-7 ranges from 
0 to 28; a higher score reflects increased severity.  Items 8, 9 and 10 rate global 
judgments with item 10 being rated based only on subject’s report of his/her awareness 
of abnormal movements from 0 (no awareness) to 4 (aware, severe distress).  Items 
11-12 are yes-no questions concerning problems with teeth and/or dentures.  A copy of 
the AIMS is located in Appendix 17.3. 
The AIMS will be administered at the study site and conducted according to an AIMS 
administration procedure provided by the sponsor or designee.  The AIMS will be 
administered and scored by the investigator (or designee) using the AIMS scoring 
descriptors provided by NBI (see Section 8.3.1.1).  Subjects will be video recorded 
according to standardized guidelines for the duration of the AIMS structured 
examination at screening, Day -1, end of Week 8, and at the follow-up visit (end of 
Week 52) or early termination.  In order to qualify for the study, subjects must have 
moderate or severe TD at screening as determined by a blinded, external AIMS 
reviewer based on the AIMS video recording (see inclusion criterion #6 and 
Section 8.3.1.2).  The investigator (or designee) will score AIMS items 1-10 and 
complete AIMS items 11-12. 
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The AIMS will be administered at screening, Day -1, during the treatment period (end of 
Weeks 4, 8, 12, 24, 36, and 48) and at the follow-up visit (end of Week 52) or at early 
termination.  At each timepoint, the AIMS will be administered in the afternoon, between 
1200-1700 hours.   
8.3.1.1. 
AIMS Administration and Scoring  
During the study, the AIMS will be administered at the study site by the investigator (or 
designee) according to the AIMS administration procedure.  AIMS items 1-10 will be 
scored and items 11-12 will be completed by the investigator (or designee) 
administering the AIMS, based on the AIMS scoring descriptors provided by NBI (see 
Appendix 17.3).  If possible, the same person should administer and score the AIMS 
assessment for an individual subject at all timepoints.   
8.3.1.2. 
AIMS Video Recording and Blinded, External AIMS Reviewer 
At screening, Day -1, end of Week 8, and at the follow-up visit (end of Week 52) or early 
termination, subjects will be video recorded for the duration of the AIMS administration 
(approximately 10 minutes) according to standardized guidelines provided by the 
sponsor or designee.  Video recordings will be uploaded to a secure, central AIMS 
server within approximately 24 hours of the AIMS administration.  Access to the 
dedicated central AIMS server will be limited and will require the user to provide a user 
identification and password to access the secured server and the subject’s AIMS video 
recording.  The screening AIMS video recording uploaded to the server will be viewed 
by the blinded, external AIMS reviewer and the sponsor-designated representatives.  
The blinded external AIMS reviewer will review the video recordings for the following 
purposes: (1) determine if the subject has moderate or severe TD at screening (see 
inclusion criterion #6), and (2) determine if the AIMS was administered according to the 
AIMS administration procedure and video recorded according to the standardized 
guidelines (additional timepoints may be reviewed if warranted).  In addition, the study 
center will be asked to submit the original uncompressed AIMS video recording to a 
core laboratory using an encrypted (password protected) device (eg, flash drive). 
8.3.1.3. 
Blinded, Central AIMS Video Raters 
The AIMS video recording files for Day -1, end of Week 8, and at the follow-up visit (end 
of Week 52) or early termination will be reviewed and scored by blinded, central AIMS 
video raters.  A blinded consensus scoring will be conducted by these raters according 
to scoring guidelines developed by NBI (see Section 16.3).  NBI (or designee) will 
provide the blinded central AIMS video raters an external hard drive containing subjects’ 
randomized AIMS video recording files to review and score.  The central raters will be 
blinded to the subjects study visits and study drug dose. Two blinded, central raters will 
together review each AIMS video file from beginning to end and must agree on the 
score (0 to 4) for AIMS items 1-7.  The central AIMS video raters will review and score 
the AIMS video recordings conducted on Day -1 (baseline), at the end of Week 8, and 
at the follow-up visit (end of Week 52) or early termination. 
 
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8.3.2. Clinical Global Impression – Global Improvement of Tardive Dyskinesia 
(CGI-TD) 
The CGI-TD, 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 TD since the 
initiation of 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, 1976b).   
The investigator or qualified clinician designee (eg, psychologist or social worker) will 
rate the scale at the scheduled times.  If possible, the same person should rate the 
CGI-TD at all timepoints.  The CGI-TD is one of the assessments that will be used by 
the investigator to determine if a subject is eligible for dose escalation at the end of 
Week 4.  A dose escalation will be allowed at the end of Week 4 if (1) the investigator or 
designee’s assessment of the CGI-TD is “minimally improved”, “not changed”, 
“minimally worse”, “much worse”, or “very much worse”, and (2) the safety and 
tolerability of the current dose is acceptable as determined by a physician.   
The CGI-TD will be administered during the treatment period (end of Weeks 4, 8, 12, 
24, 36, and 48), and at the follow-up visit (end of Week 52) or at early termination.  A 
copy of the CGI-TD is located in Appendix 17.4.  
8.3.3. Patient Global Impression of Change (PGIC) 
Subjects will evaluate the change in their TD symptoms since the initiation of study drug 
dosing choosing one of 7 responses (very much improved, much improved, minimally 
improved, not changed, minimally worse, much worse, and very much worse).  The 
PGIC will be completed by the subjects during the treatment period (end of Weeks 4, 8, 
12, 24, 36, and 48), and at the follow-up visit (end of Week 52) or at early termination A 
copy of the PGIC is located in Appendix 17.5. 
 
8.3.4. Tardive Dyskinesia Impact Scale (TDIS) and Assessment of Most 
Bothersome Movement in Tardive Dyskinesia (AMBMTD) 
The TDIS and AMBMTD, patient reported outcomes, will be used to assess the 
impairment and disability associated with dyskinesia and the subject’s most bothersome 
TD movement.  The TDIS and AMBMTD will be completed by the subjects at screening, 
Day -1, during the treatment period (end of Weeks 4, 8, 12, 24, 36, and 48), and at the 
follow-up visit (end of Week 52) or at early termination.  Copies of the TDIS and 
AMBMTD are provided in Appendix 17.6. 
8.4. 
Pharmacokinetics Evaluations 
8.4.1. Blood Sample Collection  
Blood samples to determine plasma concentrations of NBI-98854 and its active 
metabolite NBI-98782 (other metabolites may also be evaluated) will be collected during 
the treatment period (end of Weeks 4, 8, 12, 24, 36, and 48), and at the follow-up visit 
(end of Week 52) or at early termination.  Samples will be collected in the afternoon 
between 1200-1700 hours.  The exact time of collection will be recorded on the e-CRF. 
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For each plasma sample, approximately 2 mL of blood will be collected in tubes 
containing dipotassium ethylenediaminetetraacetic acid (K2 EDTA).  Once obtained, the 
samples should be thoroughly mixed.  If the sample is not centrifuged immediately, the 
collection tube will be placed upright in a test tube rack and kept on crushed ice.  Within 
1 hour of collection, samples will be centrifuged at approximately 2,000 g for 
10 minutes, preferably under refrigerated conditions (2 to 8°C).  The separated plasma 
will be aspirated using a disposable pipette and then transferred in approximately equal 
volumes into two vials.  The vials will be stoppered and labeled with the study barcode, 
subject number, primary or back-up sample designation (PK A and PK B, respectively), 
and nominal study date.  The samples will be stored at approximately -20°C within 
approximately 15 minutes of centrifugation.  The date and actual 24-hour clock time of 
each collection will be recorded on the eCRF.  The duplicate plasma sample at each 
timepoint will be stored and used as backup.  These samples (including a manifest with 
additional information) will be shipped to a central laboratory for analysis preferably on 
the day of collection to be stored at approximately -70°C.  Plasma samples remaining at 
the end of the study may be used for exploratory assessments. 
8.5. 
Safety Assessments 
8.5.1. Safety Assessments for All Subjects 
Concomitant medication use and AEs will be monitored throughout the study as 
described in Sections 8.9.1 and 10, respectively.  Additional safety assessments are 
described in the following sections. 
Any abnormal vital sign measurement, clinical laboratory test, or ECG parameter 
deemed clinically significant by the investigator will be repeated as needed, including 
test results obtained at the follow-up visit or at early termination, until the value returns 
to baseline (or within normal limits), or the investigator deems the abnormality to be of 
no clinical significance.  If the investigator determines that a subject has a clinically 
significant finding of treatment-emergent depression, suicidal ideation, psychiatric 
symptoms (based upon the C-SSRS, CDSS, MADRS (SIGMA), PANSS, YMRS, or 
clinical assessment), the finding will be documented as an AE, and appropriate 
psychiatric evaluation and intervention will provided. 
8.5.1.1. 
Medical History 
A general medical history will be obtained at screening and will be updated upon entry 
into the study on Day -1.  
The subject’s psychiatric history will be documented and will include the subject’s age at 
first diagnosis of schizophrenia or schizoaffective disorder or mood disorder, and age at 
TD diagnosis. If necessary, subject age at onset can be estimated by the investigator 
based upon available clinical information. 
8.5.1.2. 
Physical Examination Including Neurological Assessment, Height, and Weight 
A complete physical examination will consist of an assessment of the following: general 
appearance; skin and mucosa; head, eyes, ears, nose, throat; lymph nodes; 
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chest/lungs; cardiovascular; abdomen; extremities; musculoskeletal; and neurological 
system.  
A physical examination including weight will be conducted at screening, Day -1, during 
the treatment period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), and 
at the follow-up visit (end of Week 52) or at early termination.  Height will be recorded at 
screening only.  Weight will be recorded with subjects wearing ordinary indoor clothing 
without shoes.  Height and weight will be used to calculate the BMI (kg/m2). 
8.5.1.3. 
Vital Sign Measurements 
Vital sign measurements, including orthostatic systolic and diastolic blood pressure, 
orthostatic pulse rate, respiratory rate (recorded only supine) and oral body temperature 
will be measured.  Blood pressure will be measured using a calibrated automatic blood 
pressure cuff after the subject has been supine for at least 5 minutes and after 
approximately 2 minutes of standing.  Pulse rate will be measured at the wrist for 
30 seconds. 
Vital sign measurements will be obtained before any scheduled blood sample collection 
at screening, Day -1, during the treatment period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48), and at the follow-up visit (end of Week 52) or at early 
termination. 
8.5.1.4. 
Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be conducted in triplicate (1 to 3 minutes apart) after the 
subject has rested supine for at least 5 minutes.  The ECG parameters to be assessed 
include heart rate, PR interval, QRS duration, QT interval, and QTcF interval (machine 
readings or calculated).  Additionally, the occurrence of de- and re-polarization and 
rhythm disorders or other abnormalities will be assessed.  Based on review of these 
parameters, the investigator or designee will note if the ECG is Normal, Abnormal not 
Clinically Significant, or Abnormal Clinically Significant. 
The ECGs will be interpreted by the investigator, and if needed, the findings will be 
confirmed by a cardiologist or internist.  Any medically important changes in ECG 
parameters compared with baseline (Day -1) will be documented on the AE eCRF.  
The 12-lead ECG will be conducted at screening, Day -1, during the treatment period 
(end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), and at the follow-up visit 
(end of Week 52) or at early termination. 
8.5.1.5. 
Laboratory Assessments 
All clinical laboratory tests will be analyzed by a central laboratory, which will provide 
instructions and supplies to the study staff before study initiation.  The laboratory test 
battery will include routine and screening laboratory tests.  Results from samples 
collected a screening will be reviewed by the investigator or qualified designee on  
Day -1 to confirm each subject’s eligibility. 
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The routine laboratory tests (hematology and chemistry) and a urinalysis will be 
performed under non-fasted conditions at screening, Day -1, during the  treatment 
period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), and at the follow-
up visit (end of Week 52) or at early termination. 
The routine safety laboratory panel will include: 
Hematology:  complete blood count, including WBC count with differential, red blood 
count, hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin, mean 
corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution 
width, and mean platelet volume.  A sample for hemoglobin A1c (HbA1c) will also be 
collected (approximately 4 mL in K2 EDTA). 
Clinical Chemistry: sodium, potassium, calcium, magnesium, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate 
dehydrogenase, AST, ALT, GGT, creatine kinase (CK), total bilirubin, total cholesterol, 
triglycerides, total protein, and glucose.  
Urinalysis:  ketones, protein, glucose, leukocyte esterase, occult blood, and pH by 
dipstick; microscopic examination of sediment will be performed only if the results of the 
urinalysis dipstick evaluation are positive for glucose, protein, leukocyte esterase, or 
blood. 
The following additional laboratory tests will be assessed: 
Alcohol:  An alcohol breathalyzer test will be conducted at screening and Day -1. This 
test may be randomly performed at any time during the study at the investigator’s 
discretion. 
Serology:  At screening, samples will be collected from all subjects for HBsAg, HCV-Ab, 
and HIV-Ab testing.  The results of the anti-HIV Ab testing will be retained by the study 
site under confidential restriction. 
UDS: Drug screening for amphetamines, barbiturates, benzodiazepines, phencyclidine, 
cocaine, opiates, and cannabinoids will be performed at screening and Day -1 and may 
be randomly performed at any time during the study at the investigator’s discretion.  In 
addition, a UDS will be conducted at the study site using a UDS kit provided by the 
central laboratory and the results will be used to confirm eligibility on Day -1.  Subjects 
with a positive cannabinoid result may be allowed to participate in the study provided 
that the subject is given thorough counseling and agrees to refrain from using 
cannabinoids for the duration of his/her study participation.  Subjects arriving at the 
study site clearly intoxicated will not be allowed to participate.  Subjects receiving a 
chronic and stable dose of a benzodiazepine or opioids are allowed into the study (refer 
to Section 8.9.1). 
Prolactin: Blood samples to determine serum prolactin concentration will be collected at 
Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), and at the 
follow-up visit (end of Week 52) or at early termination.  Approximately 5 mL of blood 
will be collected into a serum separator tube (SST).    
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Pregnancy Test:  Pregnancy tests will be performed throughout the study for female 
subjects who are not postmenopausal for at least 1 year.  A serum (β-hCG) pregnancy 
test will be performed at screening and Day -1.  A urine pregnancy test will be 
performed at Day -1, during the treatment period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48), and at the follow-up visit (end of Week 52) or at early 
termination.   
For any abnormal tests deemed clinically significant, repeat analysis will be performed 
until the cause of the abnormality is determined or until the value returns to baseline (or 
within normal limits), or the investigator deems the abnormality to be of no clinical 
significance.  
The estimated maximum total blood volume collected from each subject during the 
entire study is shown in Table 3. 
Table 3. 
Estimated Total Blood Sample Volume  
Assessment 
No of Samples 
Required 
Approximate 
Volume (mL) 
Approximate Total 
Volume (mL) 
Clinical Chemistry   
15 
5 
75 
Hematology 
15 
4 
60 
HbA1c 
15 
4 
60 
Serology 
1 
10 
10 
Genotyping  
1 
4 
4 
Prolactin 
7 
5  
35 
Pharmacokinetics 
7 
2 
14 
Biomarkers 
7 
2 
14 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
272 
HbA1c= hemoglobin A1c. 
8.5.1.6. 
Assessment of Suicidal Ideation and Behavior – Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and 
behavior (http://www.cssrs.columbia.edu).  There are versions of the questionnaire 
designed for use at screening (Baseline/Screening version) and at baseline (Day -1) 
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 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 in the 3 months before 
screening and based on since last visit on Day -1should be excluded (see exclusion 
criterion #6).  A copy of the C-SSRS (Screening/Baseline and Since Last Visit versions) 
is provided in Appendix 17.7. 
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The C-SSRS will be administered and scored by the investigator or other qualified site 
personnel who have completed C-SSRS certification.  The C-SSRS will be administered 
at screening, Day -1, during the treatment period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48), and at  the follow-up visit (end of Week 52) or at early 
termination.  The “Screening/Baseline” version of the scale will be used to evaluate 
subject eligibility at screening and the ‘Since Last Visit’ version will be used at all other 
timepoints. 
If at any time after baseline (Day -1) the subject’s response to the suicidal ideation 
section of the C-SSRS is worse than the baseline (Day -1) assessment, it will be 
documented as an AE.  All suicidal behaviors will be documented as an AE.  
Appropriate psychiatric evaluation and intervention will be provided for any treatment-
emergent suicidal behavior or clinically significant suicidal ideation. 
8.5.1.7. 
Evaluation of Akathisia and Extrapyramidal Symptoms - Barnes Akathisia 
Rating Scale and Simpson-Angus Scale 
The 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 scale of 0 to 5 (0=absent; 1=questionable; 2=mild 
akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia).  A copy of 
the BARS in included in Appendix 17.8.   
The SAS is a validated 10-item scale to evaluate the presence and severity of drug-
induced parkinsonism and other extrapyramidal symptoms (Simpson and Angus, 1970).  
The 10 items focus on clinician-assessed rigidity and each item is rated on a 0 to 4 
scale of increasing severity with definitions given for each anchor point.  The SAS will 
also be used as a screening tool; subjects will be excluded if they have a score ≥3 on 
two or more items at screening or Day -1, excluding Items 8 and 10 (see exclusion 
criterion #3).  A copy of the SAS in included in Appendix 17.9. 
The investigator or other qualified site personnel will administer and score the BARS 
and SAS at Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), 
and at the follow-up visit (end of Week 52) or at early termination.  The SAS is also 
administered and scored at screening.  If possible, the same person should administer 
and score these scales at all timepoints. 
8.5.2. Safety Assessments in Subjects with Schizophrenia or Schizoaffective 
Disorder 
8.5.2.1. 
Symptoms of Schizophrenia – Positive and Negative Syndrome Scale 
(PANSS) for Schizophrenia 
The PANSS is a validated clinical instrument used for measuring symptom reduction in 
patients with schizophrenia (Kay et al., 1987).  The scale is divided into three sections 
with seven items designed to evaluate positive symptoms (symptoms of the disease 
which manifest as the presence of traits), seven items designed to evaluate negative 
symptoms (symptoms that manifest as the absence of traits), and 16 items which 
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address general psychopathology.  Each item is scored on a 7-point severity scale 
(0=absent; 1=minimal; 2=mild; 3=moderate; 4=moderate severe; 5=severe; 6=extreme).  
The scale also includes three supplementary items that constitute an aggression risk 
profile; however, these items will not be scored as they are not applicable to the study.  
Subjects with schizophrenia or schizoaffective disorder must have a PANSS total score 
of <70 at Day -1 to be eligible for enrollment (see exclusion criterion #22).  A copy of the 
PANSS questions and rating criteria is provided in Appendix 17.10. 
The PANSS will be administered and scored by the investigator or other qualified site 
personnel at Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), 
and at the follow-up visit (end of Week 52) or at early termination.  
8.5.2.2. 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is a validated nine-item scale to assess depressive symptoms in patients 
with schizophrenia (Addington et al., 1990).  All nine items are scored on a scale of 0 to 
3 (0=absent; 1=mild; 2=moderate; 3=severe) and the CDSS depression total score is 
obtained by adding each of the item scores.  The CDSS will be used to evaluate 
depressive symptoms throughout the study.  The CDSS will also be used as a 
screening tool; subjects with schizophrenia or schizoaffective disorder must have a 
score <10 at screening and Day -1 (see exclusion criterion #21).  A copy of the CDSS is 
provided in Appendix 17.11. 
The investigator or other qualified site personnel will administer and score the scale at 
screening, Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), 
and at the follow-up visit (end of Week 52) or at early termination. If possible, the same 
person should administer and score the scale at all timepoints.  At each timepoint, the 
subject will be instructed to provide responses to the CDSS based on feelings and 
experiences during the 2 weeks prior to the study visit.   
8.5.3. Safety Assessments in Subjects with Mood Disorders 
8.5.3.1. 
Young Mania Rating Scale (YMRS) 
The YMRS is a validated rating scale to assess manic symptoms over time in patients 
with mania (Young et al., 1978).  The scale consists of 11 items; seven items are scored 
on a five-point scale (0 to 4) and four items graded on a nine-point scale (0 to 8).  
Anchor points vary by item, but increasing number value indicates increasing severity of 
described abnormality for each item.  It is possible to score half points between the 
provided scale points where appropriate.  Scoring is based on the subject’s report of his 
or her clinical condition during the past 7 days prior to the study visit as well as clinical 
observations made during the course of the interview.  The YMRS will be used to 
evaluate mania in subjects with mood disorder throughout the study and will also be 
used as a screening tool.  Subjects must have an YMRS score ≤10 at screening and 
Day -1 to be eligible for enrollment (see exclusion criterion # 23). A copy of the YMRS is 
provided in Appendix 17.12. 
The investigator or other qualified site personnel will administer and score the scale at 
screening, Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), 
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and at the follow-up visit (end of Week 52) or at early termination. If possible, the same 
person should administer and score the scale at all timepoints. 
8.5.3.2. 
Montgomery-Asberg Depression Rating Scale (MADRS) using the Structured 
Interview Guide for the MADRS (SIGMA) 
The MADRS is a validated rating scale designed to measure changes in the severity of 
depressive symptoms (Montgomery and Asberg, 1979).  The MADRS consists of 
10 items scored on a seven-point scale (0 to 6) with increasing number value indicating 
increasing severity for each item with anchor points provided at two-point intervals.  
Scoring is based on a structured clinical interview following the Structured Interview 
Guide for the MADRS (SIGMA; Williams and Kobak, 2008).  Subjects must have a 
MADRS (SIGMA) score ≤13 at screening and Day -1 to be eligible for enrollment (see 
exclusion criterion # 27). A copy of the SIGMA is provided in Appendix 17.13. 
The investigator or other qualified site personnel will administer and score the scale at 
screening, Day -1, during the treatment period (end of Weeks 4, 12, 24, 36, and 48), 
and at the follow-up visit (end of Week 52) or at early termination. If possible, the same 
person should administer and score the scale at all timepoints.  At each timepoint, the 
subject will be instructed to provide responses based on feelings and experiences 
during the previous 7 days. 
8.6. 
Exploratory Assessments 
8.6.1. Biomarker Analysis 
Blood samples will be collected during the study for an exploratory assessment of 
biomarkers associated with the metabolic profile of NBI-98854.  Data collected as part 
of this exploratory analysis will not be reported as part of the study results. 
For each sample, approximately 2 mL of blood will be collected in tubes containing 
K2 EDTA.  Once obtained, the samples should be thoroughly mixed.  If the sample is not 
centrifuged immediately, the collection tube will be placed upright in a test tube rack and 
kept on crushed ice.  Within 1-hour of collection, samples will be centrifuged at 
approximately 1,000 g for 10 minutes, preferably under refrigerated conditions (2 to 
8°C).  The separated plasma will be aspirated using a disposable pipette and then 
transferred in approximately equal volumes into two vials.  The vials will be stoppered 
and labeled with the study barcode, subject number, primary or backup sample 
designation (BIO A and BIO B, respectively), and nominal study day.  The samples will 
be stored at approximately -20°C within approximately 15 minutes of centrifugation.  
These samples will be shipped to a central laboratory to be stored at 
approximately -70°C.  
Blood samples will be collected on Day -1, during the treatment period (end of Weeks 4, 
12, 24, 36, and 48), and at the follow-up visit (end of Week 52) or at early termination.  
8.7. 
Specific Study Phase Information 
The procedures to be conducted at each study visit are listed in the following sections.  
Assessments are to be performed for all subjects regardless of underlying disease 
diagnosis unless otherwise specified.  Study visits during the treatment period (end of 
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Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), and at the follow-up visit (end of 
Week 52) or at early termination will have a visit window of ±6 days. 
8.7.1. Screening Period (Week -6 to -1) 
8.7.1.1. 
Informed Consent Process 
The ICF will be reviewed with subjects.  The UBACC will then be administered (Jeste et 
al., 2007).  A copy of the UBACC is provided in Appendix 17.1.  Only subjects who are 
deemed to have the capacity to provide consent may sign the ICF.  The ICF must be 
signed prior to the start of any screening procedures.  Subjects may also be asked to 
sign an optional release form to allow video recordings of their AIMS assessments to be 
used for educational purposes.  Subjects may refuse to sign the release form with no 
effect on their study eligibility. 
8.7.1.2. 
Washout of Prohibited Medications 
Subjects should discontinue prohibited medications as described in Section 8.9.1 before 
undergoing screening procedures.  Subjects must sign an ICF (subjects must be 
deemed capable of providing consent using the UBACC as described in 
Section 8.7.1.1) before any changes in their medication may be made.   
8.7.1.3. 
Screening Procedures 
After subjects have signed the ICF (subjects have been deemed to have the capacity to 
consent to study participation using the UBACC prior to ICF signing), they will undergo 
screening procedures within 6 weeks prior to enrollment on Day -1.  The 6-week 
screening period begins with the subject’s first screening assessment (eg, AIMS, 
physical examination, vital signs, ECG, clinical laboratory assessments) and not from 
when the subject signs the ICF, collection of the screening medical history or 
medications, or pretreatment AEs (unless collected on the same day as the screening 
assessments).   The screening assessments will be performed in the afternoon between 
1200-1700 hours.   
During the first part of the screening visit, the AIMS (Items 1-12) assessments will be 
administered and scored by the investigator (or designee).  The structured examination 
will be video recorded (approximately 10 minutes) and uploaded to the central AIMS 
server within approximately 24 hours.  A blinded, external AIMS reviewer will review the 
video recording to determine study eligibility based on the assessment of global severity 
of TD (Item 8). In addition, the original uncompressed AIMS video recording files will be 
sent to a core laboratory using an encrypted (password protected) device.  
After the AIMS assessment, the following study procedures and assessments will be 
performed: 
• Inclusion/exclusion criteria. 
• Medical history, including medical and psychiatric conditions, demographic 
information, and alcohol use. 
• Physical examination including neurological assessment. 
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• Height and weight, and perform BMI calculation. 
• Vital sign measurements including orthostatic systolic and diastolic blood pressures, 
orthostatic pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
• A breathalyzer test for alcohol. 
• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Serology testing (HBsAg, HCV-AB, and HIV-Ab). 
• Serum (β-hCG) pregnancy test for female subjects who are not postmenopausal for 
>1 year. 
• Urine sample for urinalysis and UDS. 
• Subject to complete the TDIS and AMBMTD. 
• Administer C-SSRS (baseline/screening version). 
• Administer SAS. 
• Administer BPRS. 
• Administer CDSS (subjects with schizophrenia or schizoaffective disorder only). 
• Administer YMRS and MADRS (SIGMA) (subjects with mood disorders only). 
• Record all medications, including over the counter (OTC) medications, herbal 
remedies, homeopathic preparations, and health and dietary supplements taken by 
the subject within the previous 30 days and all medications taken for indications of 
schizophrenia/schizoaffective disorder, mood disorder, EPSE, and TD within the last 
2 years (recorded from the time of ICF signing). 
• AE monitoring (recorded from the time of ICF signing).   
All screening procedures must be completed and results evaluated by the investigator 
before the baseline procedures are performed on Day -1.  The assessment of the global 
TD symptom severity from the blinded, external AIMS reviewer must be available prior 
to the Day -1 visit to determine study eligibility. 
8.7.2. Baseline (Day -1) 
Subjects will return to the study site in the afternoon on Day -1 between 
1200-1700 hours.  During the first part of the study visit, the AIMS (Items 1-12) will be 
administered and scored by the investigator (or designee).  The structured examination 
will be video recorded (approximately 10 minutes) and uploaded to the central AIMS 
server within approximately 24 hours).  In addition, the original uncompressed AIMS 
video recording files will be sent to a core laboratory using an encrypted (password 
protected) device. 
After the AIMS assessment, the following study procedures and assessments will be 
performed: 
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• 
Inclusion/exclusion criteria and medical history update. 
• 
Physical examination, including weight measurement and a neurological 
assessment.  
• 
Vital sign measurements, including orthostatic systolic and diastolic blood 
pressures, orthostatic pulse rate, respiratory rate, and body temperature. 
• 
12-lead ECG in triplicate.  
• 
A breathalyzer test for alcohol. 
• 
Venous blood sample for clinical laboratory tests including routine assessments 
(hematology and clinical chemistry). 
• 
Venous blood for serum prolactin. 
• 
Venous blood sample for biomarkers. 
• 
Venous blood sample for CYP2D6 genotype status. 
• 
Urine sample for urinalysis and UDS.  In addition, the site will need to conduct 
UDS using the UDS kit provided by the central laboratory to confirm eligibility.  
• 
Urine and serum (β-hCG) pregnancy tests for female subjects who are not 
postmenopausal for >1 year. 
• 
Subject to complete the TDIS and AMBMTD. 
• 
Administer C-SSRS (since last visit version). 
• 
Administer SAS and BARS. 
• 
Administer CDSS and PANSS (subjects with schizophrenia or schizoaffective 
disorder only). 
• 
Administer YMRS and MADRS (SIGMA) (subjects with mood disorders only). 
• 
Record prior medications. 
• 
AE monitoring. 
The site will access the Interactive Web Response System (IWRS) to obtain an 
identification number for a kit containing a 4-week supply of the study drug to be 
dispensed to eligible subjects.   
At this visit, subjects will be instructed: 
• To take study drug (in the presence of their caregiver, if applicable) each morning at 
approximately the same time every day (between 0700-1000 hours).  The subjects 
may take the study drug with or without food and must swallow it with at least 4 oz. 
of water. A representative from the study site will conduct weekly telephone call to 
remind the subject take the study medication daily as instructed. 
• To record the date and time of each dose on the labels provided on the study drug 
kit packaging form. 
• To contact the study site immediately without waiting for the next study visit to report 
AEs or before starting any new medication.   
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• To return to the study site in approximately 4 weeks for their next study visit having 
taken their daily dose of study drug at home.  
• To return all used and unused study drug and packaging at the next study visit. 
8.7.3. 
 Treatment Period 
8.7.3.1. 
End of Weeks 4, 12, 24, and 36 
Subjects will return to the study site in the afternoon between 1200-1700 hours at the 
end of Weeks 4, 12, 24 and 36. During the first part of the study visit, the following 
assessments will be performed in the order listed:   
• The AIMS (Items 1-12) will be administered and scored by the investigator (or 
designee).   
• The CGI-TD will be assessed by the investigator (or qualified designee). At the end 
of Week 4, a dose escalation may be allowed based on the CGI-TD assessment and 
the subject’s safety and tolerability of the current dose (refer to Dose Titration 
Assessment below).   
After the AIMS and CGI-TD assessments are conducted, the following study procedures 
and assessments will be performed: 
• Physical 
examination 
including 
weight 
measurement 
and 
a 
neurological 
assessment. 
• Vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Venous blood sample for plasma drug concentration. 
• Venous blood sample for serum prolactin. 
• Venous blood sample for biomarkers. 
• Urine sample for urinalysis. 
• Urine sample for pregnancy test (female subjects who are not postmenopausal for 
>1 year). 
• Subject to complete the PGIC, TDIS, and AMBMTD. 
• Administer C-SSRS (since last visit version). 
• Administer SAS and BARS. 
• Administer CDSS and PANSS (subjects with schizophrenia or schizoaffective 
disorder only). 
• Administer YMRS and MADRS (SIGMA) (subjects with mood disorders only). 
• AE monitoring. 
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• Record concomitant medications. 
• Study drug accountability. 
Dose Titration Assessment 
At the end of Week 4, a dose escalation may be allowed if (1) the subject’s CGI-TD is 
“minimally improved”, “not changed”, ”minimally worse”, “much worse”, or “very much 
worse” as determined by the investigator or designee, and (2) the safety and tolerability 
of the current dose is acceptable as determined by a physician.  Based these criteria, 
the investigator will choose one of the following dosing options (also refer to the dose 
titration algorithm in Section 16.2): 
• Dose escalation:  The dose of NBI-98854 will be escalated from 40 mg qd to 80 mg 
qd.  
• Maintenance of current dose. 
The investigator may decrease the dose to 40 mg at any time after the end of Week 4 
(including between scheduled study visits) for any subject who is unable to tolerate the 
80 mg dose.  These subjects will receive 40 mg for the remainder of the treatment 
period. 
Once a determination of dose escalation, maintenance, or reduction (for subjects who 
had their dose escalated to 80 mg at the end of Week 4) is made, the IWRS will be 
accessed to obtain an identification number for a kit containing a 4-week supply of study 
drug to be dispensed to the subject.  The investigator will inform the subject that a dose 
reduction to 40 mg is allowed if the subject is unable to tolerate the 80 mg dose.   
At these visits, subjects will be reminded: 
• To take study drug (in the presence of their caregiver, if applicable) each morning at 
approximately the same time every day (between 0700-1000 hours).  The subjects 
may take the study drug with or without food and must swallow it with at least 4 oz. 
of water. A representative from the study site will conduct weekly telephone calls to 
remind the subject take the study medication daily as instructed. 
• To record the date and time of each dose on the labels provided on the study drug 
packaging form. 
• To contact the study site immediately without waiting for the next study visit to report 
AEs or before starting any new medication.   
• To return to the study site in approximately 4 weeks for their next study visit having 
taken their daily dose of study drug at home.  
8.7.3.2. 
End of Week 8 
Subjects will return to the study site in the afternoon between 1200-1700 hours at the 
end of Week 8.  During the first part of the study visit, the following assessments will be 
performed in the order listed:   
• The AIMS (Items 1-12) will be administered and scored by the investigator (or 
designee).  The structured examination will be video recorded (approximately 
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10 minutes) and uploaded to the central AIMS server within approximately 24 hours.  
In addition, the original uncompressed AIMS video recording files will be sent to a 
core laboratory using an encrypted (password protected) device. 
• The CGI-TD will be assessed by the investigator (or qualified designee).   
After the AIMS and CGI-TD assessments are conducted, the following study procedures 
and assessments will be performed: 
• Physical 
examination 
including 
weight 
measurement 
and 
a 
neurological 
assessment. 
• Vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Venous blood sample for plasma drug concentration. 
• Urine sample for urinalysis. 
• Urine sample for pregnancy test (female subjects who are not postmenopausal for 
>1 year). 
• Subject to complete the PGIC, TDIS, and AMBMTD. 
• Administer C-SSRS (since last visit version). 
• AE monitoring. 
• Record concomitant medications. 
• Study drug accountability. 
The investigator may decrease the dose to 40 mg at any time after the end of Week 4 
(including between scheduled study visits) for any subject who is unable to tolerate the 
80 mg dose.  These subjects will receive 40 mg for the remainder of the treatment 
period or will be discontinued from the study if they are unable to tolerate the 40 mg 
dose. 
Once a determination of maintenance or reduction is made, the IWRS will be accessed 
to obtain an identification number for a kit containing a 4-week supply of study drug to 
be dispensed to the subject.   
At this visit, subjects will be instructed: 
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• To take study drug (in the presence of their caregiver, if applicable) each morning at 
approximately the same time every day (between 0700-1000 hours).  The subjects 
may take the study drug with or without food and must swallow it with at least 4 oz. 
of water. A representative from the study site will conduct weekly telephone call to 
remind the subject take the study medication daily as instructed. 
• To record the date and time of each dose on the labels provided on the study drug 
kit packaging form. 
• To contact the study site immediately without waiting for the next study visit to report 
AEs or before starting any new medication.   
• To return to the study site in approximately 4 weeks for their next study visit having 
taken their daily dose of study drug at home.  
• To return all used and unused study drug and packaging at the next study visit. 
8.7.3.3. 
End of Weeks 16, 20, 28, 32, 40, and 44 
Subjects will return to the study site at any time before 1700 hours at the end of Weeks 
16, 20, 28, 32, 40, and 44 and the following assessments will be performed:   
• Physical 
examination 
including 
weight 
measurement 
and 
a 
neurological 
assessment. 
• Vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Urine sample for pregnancy test (female subjects who are not postmenopausal for 
>1 year). 
• Urine sample for urinalysis. 
• Administer C-SSRS (since last visit version). 
• AE monitoring. 
• Record concomitant medications. 
• Study drug accountability. 
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The investigator may decrease the dose to 40 mg at any time after the end of Week 4 
(including between scheduled study visits) for any subject who is unable to tolerate the 
80 mg dose.  These subjects will receive 40 mg for the remainder of the treatment 
period or will be discontinued from the study if they are unable to tolerate the 40 mg 
dose. 
Once a determination of maintenance or reduction is made, the IWRS will be accessed 
to obtain an identification number for a kit containing a 4-week supply of study drug to 
be dispensed to the subject.   
At these visits, subjects will be reminded: 
• To take study drug (in the presence of their caregiver, if applicable) each morning at 
approximately the same time every day (between 0700-1000 hours). The subjects 
may take the study drug with or without food and must swallow it with at least 4 oz. 
of water.  A representative from the study site will conduct weekly telephone calls to 
remind the subject take the study medication daily as instructed. 
• To record the date and time of each dose on the labels provided on the study drug 
packaging form. 
• To contact the study site immediately without waiting for the next study visit to report 
AEs or before starting any new medication.   
• To return to the study site in approximately 4 weeks for their next study visit having 
taken their daily dose of study drug at home.  
• To return all used and unused study drug and packaging at the next study visit. 
8.7.3.4. 
End of Week 48 
Subjects will return to the study site in the afternoon between 1200-1700 hours at the 
end of Week 48. During the first part of the study visit, the following assessments will be 
performed in the order listed:   
• The AIMS (Items 1-12) will be administered and scored by the investigator (or 
designee).  
• The CGI-TD will be administered by the investigator (or designee). 
After the AIMS and CGI-TD assessments are conducted, the following study procedures 
and assessments will be performed: 
• Physical 
examination 
including 
weight 
measurement 
and 
a 
neurological 
assessment. 
• Vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Venous blood sample for plasma drug concentration. 
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• Venous blood sample for serum prolactin. 
• Venous blood sample for biomarkers. 
• Urine sample for urinalysis. 
• Urine sample for pregnancy test for female subjects who are not postmenopausal for 
>1 year. 
• Subject to complete the PGIC, TDIS, and AMBMTD. 
• Administer C-SSRS (since last visit version). 
• Administer BARS and SAS. 
• Administer CDSS and PANSS (subjects with schizophrenia or schizoaffective 
disorder only).  
• Administer YMRS and MADRS (SIGMA) (subjects with mood disorders only). 
• AE monitoring. 
• Record concomitant medications. 
• Study drug accountability. 
The end of Week 48 visit is the end of NBI-98854 treatment period.  After all 
assessments have been completed, subjects will be reminded: 
• To contact the study site immediately without waiting for the next study visit to report 
AEs or before starting any new medication. 
• To return approximately 4 weeks for the follow-up visit. 
8.7.4. Follow-up Visit - Final Study Visit (End of Week 52 or Early Termination) 
Subjects will return to the study site in the afternoon between 1200-1700 hours and the 
following assessments and procedures will be performed.  During the first part of the 
study visit, the following assessments will be performed in the order listed:   
• The AIMS (Items 1-12) will be administered and scored by the investigator (or 
designee).  The structured examination will be video recorded (approximately 
10 minutes) and uploaded to the central AIMS server within approximately 24 hours.  
In addition, the original uncompressed AIMS video recording files will be sent to a 
core laboratory using an encrypted (password protected) device. 
• The CGI-TD will be assessed by the investigator (or qualified designee) 
After the AIMS and CGI-TD assessments are conducted, the following study procedures 
and assessments will be performed: 
• Physical 
examination 
including 
weight 
measurement 
and 
a 
neurological 
assessment. 
• Vital signs, including orthostatic systolic and diastolic blood pressures, orthostatic 
pulse rate, respiratory rate, and body temperature. 
• 12-lead ECG in triplicate. 
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• Venous blood sample for clinical laboratory assessments (hematology and clinical 
chemistry). 
• Venous blood samples for plasma drug concentration. 
• Venous blood sample for serum prolactin. 
• Venous blood sample for biomarkers. 
• Urine sample for urinalysis. 
• Urine sample for pregnancy test for female subjects who are not postmenopausal for 
>1 year. 
• Subject to complete PGIC, TDIS, and AMBMTD. 
• Administer C-SSRS (since last visit version). 
• Administer BARS and SAS. 
• Administer CDSS and PANSS (subjects with schizophrenia or schizoaffective 
disorder only).  
• Administer YMRS and MADRS (SIGMA) (subjects with mood disorders only). 
• AE monitoring. 
• Record concomitant medications. 
After all assessments have been completed, subjects determined to be medically and 
psychiatrically stable by the investigator will be discharged from the study.  
8.8. 
Study Duration 
The expected duration of study participation for each subject is approximately 
58 weeks, including up to 6 weeks of screening period, a 48-week NBI-98854 treatment 
period, and a 4-week follow up period with a follow-up visit approximately 4 weeks after 
the last dose of study drug.   
8.9. 
Prohibitions and Restrictions 
8.9.1. Prior and Concomitant Medication Restrictions 
All prescription and OTC medications, including dietary and herbal supplements, taken 
by subjects during the 30 days before screening and during the study will be entered on 
the Prior and Concomitant Medications eCRF.  All medications taken for indications of 
schizophrenia/schizoaffective disorder, mood disorder, EPSE, and TD within the last 
2 years will also be entered on the Prior and Concomitant Medications eCRF.  Any 
additions, deletions, or changes in the dose of these medications will be entered on the 
eCRF with indication, dose, route, and dates of drug administration. 
Medications to treat psychiatric and medical conditions:  All coexistent diseases or 
conditions will be treated in accordance with prevailing medical practice.  All 
medications to treat the subject’s psychiatric and medical conditions should be on a 
stable treatment regimen (including no changes to the dose and frequency of ongoing 
medications and no discontinuation of medications) for a minimum of 30 days before 
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screening procedures.  Benzodiazepines must be at a stable dose for 2 weeks before 
screening.  Exceptions may be allowed if discussed with and approved by NBI’s medical 
monitor (or designee) prior to Day -1.  If an exception is approved, the subject must be 
on a stable dose for 30 days prior to Day -1 and the treatment regimens are expected to 
remain stable during the study.  Investigators should document doses of current 
medication through medical or pharmacy records, confirmation with the subject’s 
caregivers (if applicable), or through reliable subject-reported information (eg, provide a 
list of medications and doses).   
Washout of Prohibited Medications:  Subjects should discontinue prohibited 
medications for at least 30 days before undergoing screening procedures provided they 
sign an ICF before discontinuation.  An exemption may be granted if discussed and 
approved by NBI’s medical monitor (or designee).  If an exemption is granted, the 
subject must complete the 30-day washout prior to Day -1.  Discontinuation of the 
subject’s medication should be done under the guidance of the investigator and 
according to the prescribing information. 
Prohibited medications:  The following medications are prohibited from 30 days prior 
to screening until the follow-up visit (end of Week 52 or early termination): 
• Antiemetics:  Metoclopramide, prochlorperazine, and promethazine are prohibited. 
• Antihypertensives:  Reserpine (known to irreversibly bind to VMAT2) is prohibited. 
• Botulinum toxin:  Botulinum toxin injections are prohibited starting 90 days prior to 
screening and during the study. 
• CYP3A4 inducers:  Strong inducers of CYP3A4 (eg, phenobarbital, rifabutin, 
rifampin, primidone, phenytoin, St. John's Wort) are prohibited.  The use of 
carbamazepine is permitted if approved by NBI’s medical monitor (or designee) prior 
to Day -1. 
• Dopamine agonists and precursors:  Dopamine receptor agonists (eg, ropinirole) 
and precursors (eg, carbidopa/levodopa) are prohibited.  
• Monoamine Oxidase Inhibitors (MAOIs):  All MAOIs (eg, isocarboxazid, 
phenelzine, selegiline, tranylcypromine) are prohibited. 
• Stimulants: 
 
Stimulants 
(eg, 
amphetamine, 
methylphenidate, 
ephedrine, 
pseudoephedrine, phenylephrine, and phenylpropanolamine) are prohibited. 
• VMAT2 Inhibitors:  VMAT2 inhibitor medications (eg, tetrabenazine, reserpine) are 
prohibited, except for NBI-98854. 
• Drugs known to increase the QT interval:  The use of medication known to 
increase the QT interval may be allowed if approved by the Sponsor.  QTcF must be 
≤450 msec for males or ≤470 msec for females at screening and baseline.  
Some of the medications that may increase the QT interval include the following: 
o Antipsychotics:  chlorpromazine, thioridazine and ziprasidone  
o Antidepressants: citalopram 
o Antibiotics: azithromycin, clarithromycin, erythromycin, moxifloxacin  
o Antiarrhythmics: quinidine, procainamide, amiodarone, sotalol 
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• As needed (prn) use:  As needed use of the following medications is strictly 
prohibited: anticholinergics, benzodiazepines, antipsychotics, mood stabilizers, 
antidepressants, CYP3A4 inhibitors and inducers, and CYP2D6 inhibitors.  
Allowed as needed use:  As needed use of over-the-counter and prescription 
medications is allowed to treat headaches, pain, respiratory symptoms, acute allergic 
symptoms, and allergies.  
Medications recommended for insomnia include eszopiclone 7.5 mg, zaleplon 10 mg, 
zolpidem 5 mg for female subjects and 10 mg for male subjects, or Silenor 3 or 6 mg at 
night as needed.  
8.9.2. General and Dietary Restrictions 
Subjects must agree to adhere to the following prohibitions and restrictions during the 
study in order to be eligible to participate: 
• Return to the study site at baseline (Day -1), for visits during the NBI-98854 
treatment period (end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48) and 
at the follow-up visit (end of Week 52) or at early termination.   
• Not to use any prohibited concomitant medication (Refer to Section 8.9.1). 
• Subjects must limit alcohol use to less than 7 drinks per week during the course of 
the study. 
• Not to donate blood during the study, including the screening period, and for 
4 weeks after completion of the study. 
• Not to participate in an investigational drug study for at least 30 days after the last 
dose of study drug or 30 days after study completion, whichever is longer.  
8.10. 
Withdrawal Criteria 
8.10.1. Reasons for Withdrawal 
Subjects are free to discontinue their participation in the study at any time and without 
prejudice to further treatment.  The investigator must withdraw any subject from the 
study who requests to be withdrawn. 
The investigator must withdraw the subject from the study if the subject experiences any 
of the following: 
• If the type, frequency, or severity of any AE become unacceptable/intolerable. 
• If the subject is unable to tolerate the starting dose or resumption of the previous 
dose.   
• QTcF value >500 msec or subject has a clinically significant ECG change. 
• 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. 
• Does not follow guidelines specified in the protocol. 
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• Is lost to follow-up. 
• Does not continue to meet entry criteria.  
• Subject is confirmed to be pregnant. 
The investigator or NBI may withdraw the subject from the study for other reasons as 
described below.  These should be discussed on a case-by-case basis with the NBI 
medical monitor (or designee) prior to withdrawing the subject from the study. 
• ALT or AST ≥2.5 times ULN or GGT ≥3.0 times ULN or total bilirubin value exceeds 
2.0 times ULN or serum creatinine value exceeds 1.5 times ULN. 
• Requires a medication that is prohibited by the protocol (refer to Section 8.9.1). 
• Is non-compliant with the dosing regimen (<80% dosing compliance) as verified by 
drug accountability (Refer to Section 9.6). 
8.10.2. Handling of Withdrawals 
If a subject prematurely withdraws from the study, either at his/her request or at the 
investigator’s discretion, the investigator will record the reason for withdrawal on the 
relevant eCRF.  All subjects who withdraw from the study prematurely must have all 
early termination assessments performed. 
It is crucial to obtain follow-up data for any subject withdrawn because of an AE, 
abnormal laboratory test, vital sign measurement, physical examination or ECG finding.  
In any case, every effort must be made to undertake safety follow-up procedures. 
8.10.3. Sponsor’s Termination of Study 
Neurocrine Biosciences, Inc. reserves the right to discontinue the study at any time for 
any reason.  Such a termination must be implemented by the investigator, if instructed 
to do so by NBI, in a time frame that is compatible with the subjects’ well-being. 
9. 
STUDY DRUG 
9.1. 
Study Drug Supplies 
Neurocrine Biosciences, Inc. or its designee will provide the clinical site with a supply of 
study drug sufficient for the completion of the treatment period of the study together with 
the respective certificates of analysis.   
Neurocrine Biosciences, Inc. or its designee will provide study drug as NBI-98854 
40 mg capsules.  The NBI-98854 40 mg capsule is a white, opaque, HPMC No. 3 size 
capsule containing 40 mg of NBI-98854 (dose is of the free base) and is formulated 
using 
 shells. 
9.2. 
Study Drug Storage 
NBI-98854 capsules must be stored at controlled room temperature (20˚C to 25˚C or 
68˚F to 77˚F) under the conditions specified in the Investigator’s Brochure and in a 
locked area accessible only to the pharmacist (or designee) until dispensing.  
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Excursions outside this range will be allowed provided they meet the following 
conditions: 
• Storage between refrigerated conditions (2˚C or 36˚F) and CRT (25˚C or 77˚F) for 
an unspecified length of time. 
• Storage at temperatures above 25˚C (77˚F) but no more than 30˚C (86˚F) for up to 
3 months. 
• Storage at temperatures above 30˚C (86˚F) but no more than 40˚C (104˚F) for up to 
24 hours. 
9.3. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be performed according to Good 
Manufacturing Practice and Good Clinical Practice rules.  The study drugs will be sent 
to an authorized staff at the study site.  The authorized study staff member must confirm 
receipt of the study drug to NBI or its designee via the IWRS. 
Study drug will be supplied as capsules in child-resistant blistercard dispensers; each 
blistercard contains enough study drugs for 28 days of dosing plus 6 extra dose days.  
The blistercards will contain capsules of NBI-98854 40 mg.  
Each blistercard dispenser will be labeled with a single-panel label and secured with 
tamper evident seals.  Label text will include but is not limited to the protocol number, 
batch number, dosage form, route of administration, study drug kit number, Sponsor 
name and address, storage condition and the statement “Caution – New Drug: Limited 
by Federal (or US) Law to Investigational Use”. 
9.4. 
Blinding 
This study is an open label study. 
9.5. 
Study Drug Administration 
Subjects will self-administer study drug (in the presence of their caregiver, if applicable) 
in the morning at approximately the same time (between 0700-1000 hours). Subjects 
may take the study drug with or without food and must swallow it with at least 4 oz. of 
water every day during the 48-week treatment period.  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 1800 hours.  The subject will need to 
skip the dose for that day if he or she is unable to take the study drug before 
1800 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. 
9.6. 
Drug Compliance and Accountability 
Subjects will bring all unused study drug and empty drug packaging material to the 
study site at each study visit for drug accountability and reconciliation by study site 
personnel.  A compliance check will be performed by counting the capsules returned at 
each study visit. A representative from the study site will call the subjects weekly to 
remind them to take their study medication daily. 
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The quantity of study drug dispensed, used, and returned will be recorded on a 
dispensing log or otherwise documented.  The quantity of study drug lost or destroyed, 
must also be accounted for and documented.  The designated pharmacist or qualified 
personnel will be responsible for maintaining accurate records of the quantity and dates 
of all study drug supplies received, dispensed, and returned.   
9.7. 
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 the designee.  
The investigator must provide a written explanation for any destroyed or missing study 
drug or study drug materials. 
Returns will be shipped to NBI or its designee at the completion of the study according 
to instructions provided by NBI or its designee. Study drug return forms must be 
completed for the shipment of returns and sent with the study drug and study drug 
materials.  One copy of the study drug return form will be retained in the investigator’s 
study file.   
All returned study drug and study drug materials should be stored, inventoried, 
reconciled, and returned according to applicable state and federal regulations and study 
procedures.  
10. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from 
laboratory findings, or identified by other means, will be recorded from the time the 
subject signed the ICF until the subject’s final study visit (end of Week 52 or early 
termination).  
10.1. 
Definition 
An AE is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  During the study, clinically significant 
adverse changes in clinical status, ECGs, laboratory values (not associated with an AE 
or concurrent medical condition), or physical examinations are considered AEs.  Any 
subject complaint associated with such an abnormal finding will also be reported as an 
AE. 
Adverse events include, but are not limited to:  (1) a worsening or change in nature, 
severity, or frequency of conditions present at the start of the study; (2) subject 
deterioration due to primary illness; (3) intercurrent illness; and (4) drug interaction. 
If at any time after the baseline visit (Day -1) 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.  
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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. 
• Recurrence of TD symptoms, unless worsened from baseline. 
• Pregnancy. 
10.1.1. Intensity of Adverse Events 
Adverse events must be graded for intensity.  An intensity category of mild, moderate, 
or severe, as defined in Table 4, must be entered on the AE eCRF.  It should be noted 
that the term “severe” used to grade intensity is not synonymous with the term “serious.” 
Table 4. 
Intensity of Adverse Events  
Grade  
Intensity 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
10.1.2. 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 
adverse event. (Title 21 CFR 312.32 [a]). 
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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. 
 
 
10.2. 
Recording Adverse Events 
For enrolled subjects, each AE will be listed as a separate entry on an AE eCRF.  
Screen failure subjects will have AE information noted in the source documentation.  
The investigator or designee will provide information on dates and times of onset and 
resolution, intensity, seriousness, frequency, action(s) taken, changes in study drug 
usage, relationship to study drug, and outcome. 
The following categories of medical events that could occur during participation in a 
clinical study must be reported within 24 hours to NBI or its designee: 
• Serious adverse event, including death (refer to Section 10.4). 
• Pregnancy (Refer to Section 10.5). 
• Events of 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.  
10.3. 
Post Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, 
or isolated clinically significant laboratory findings must be followed until the event 
resolves, the condition stabilizes, the event is otherwise explained, or the subject is lost 
to follow-up.  If resolved, a resolution date should be documented on the eCRF.   
Adverse events ongoing at the final study visit or early termination will be followed for as 
long as necessary to adequately evaluate the subject’s safety or until the event 
stabilizes or resolves or until the subject is lost to follow-up.  The investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as may 
be indicated to elucidate the nature and/or causality of the AE.  This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals, as is practical. 
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10.4. 
Serious Adverse Events 
All SAEs will be recorded from the time the subject has signed the ICF until the final 
study visit or 30 days after the last dose of study drug, whichever is longer in duration.  
10.4.1. Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcome: 
• Death. 
• A life-threatening adverse event.  Life-threatening means that the subject was, in the 
view of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred.  It does not mean that hypothetically the event might have caused death if 
it occurred in a more serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization 
for elective treatment or a pre-existing condition that did not worsen during the 
clinical investigation is not considered an AE.  Hospitalization or nursing home 
admission for the purpose of caregiver respite is not considered an AE.  
Complications that occur during hospitalization are AEs, and if a complication 
prolongs hospitalization, the event is considered serious.  Treatment in a hospital 
emergency room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization.  These events may be considered serious when, based on 
appropriate medical judgment, they may jeopardize the health of the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed.  
Any other event thought by the investigator to be serious should also be reported, 
following the reporting requirements detailed in this section.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
10.4.2. Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a 
physician as soon as possible.  The physician in attendance will do whatever is 
medically needed for the safety and well-being of the subject.  The subject will remain 
under observation as long as medically indicated.  Appropriate laboratory tests 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 Medical Monitor (and the IRB, if 
necessary) immediately (within 24 hours) of the SAE and the outcome of the SAE. 
If within the time of informed consent until 30 days after the last dose of study drug (or 
final study visit, whichever is longer in duration) an investigator becomes aware of an 
SAE, then the event must be documented and reported as described in Section 10.4.3. 
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10.4.3. Reporting Serious Adverse Events and Other Immediately Reportable 
Events 
Serious AEs and other immediately reportable events (as defined in Section 10.2) must 
be reported within 24 hours of first knowledge of the event by study personnel to the 
NBI Medical Monitor or NBI Clinical Drug Safety (CDS) Department.  Reports of SAEs 
or pregnancies should be followed by an email or fax of the SAE or Pregnancy Form.  It 
is important that the investigator provide his or her assessment of relationship to study 
drug at the time of the initial SAE report.  
For SAEs or Other Immediately Reportable Events, contact CDS: 
 
CDS telephone: 
 
 
CDS facsimile: 
 
 
CDS e-mail:  
 
 
NBI Medical Monitor: 
 
Telephone
 
 
 
 
 
 
 
Cell phone
 
10.4.4. Expedited Safety Reports 
Neurocrine Biosciences, Inc. or its representatives will submit an Expedited Safety 
Report for any suspected adverse reaction (as defined in Section 10.1.2) that is 
considered both serious and unexpected within 15 calendar days and for any 
unexpected fatal or life-threatening experience within 7 calendar days via telephone or 
facsimile; or according to country-specific regulations. 
Neurocrine Biosciences, Inc. or its representatives will send copies of each Safety 
Report submitted to regulatory authorities to the investigators.  The safety report must 
be submitted to the appropriate IRB as soon as possible.  Documentation of the 
submission to the IRB and receipt by the IRB (if applicable) must be retained for each 
safety report. 
10.5. 
Pregnancy 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  
However, all pregnancies in female subjects who received NBI-98854 will be followed to 
assess for congenital anomaly.  Subjects must be counseled at all visits to continue 
using two forms of nonhormonal contraception or hormonal contraception (see inclusion 
criterion #2 in Section 7.1) until the end of the follow-up visit (end of Week 52).  If at any 
time between the time the subject signs the ICF and the last study visit a subject 
believes she is pregnant, the subject will be instructed to stop taking the study 
medication and return to the study site within 24 hours and undergo a serum pregnancy 
test to confirm pregnancy.  
All confirmed pregnancies, in subjects who received study drug, must be immediately 
reported to NBI (Refer to Section 10.4.3 for contact information), and followed by email 
or fax of the pregnancy form to NBI CDS.  A first trimester ultrasound will be required for 
all confirmed pregnancies.  Pregnancies in subjects who received NBI-98854 will be 
followed until resolution (ie, termination [voluntary or spontaneous] or birth).  
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11. 
DOCUMENTATION OF DATA 
11.1. 
Case Report Form 
The CRF data for this study are being collected with an electronic data capture (EDC) 
system (
) provided by 
.  The EDC 
system and the study-specific eCRFs will comply with Title 21 CFR Part 11.  The 
documentation related to the validation of the EDC system is available through the 
vendor, 
, while the validation of the study-specific eCRFs will be conducted by 
NBI and the required documentation will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by authorized study personnel in the EDC system, with the exception of 
data captured in an electronic format, which will be loaded electronically into the 
appropriate eCRFs.  All data entered into the eCRF will be supported by source 
documentation.  The eCRF for each subject must be reviewed by the investigator and 
signed on the appropriate eCRF page(s).  This should be done as soon as possible 
after the subject completes the study. 
The investigator or an authorized member of the investigator's staff will make any 
necessary additions/corrections to the eCRF.  All change information, including the 
date, person performing the corrections, and reason for the change will be available via 
the electronic audit trail, which is part of the EDC system.  The eCRFs will be reviewed 
periodically for completeness, legibility, and acceptability by NBI (or designee).  NBI will 
also be allowed access to all source documents and medical records pertinent to the 
study in order to verify eCRF entries.  The principal investigator will review the eCRFs 
for completeness and accuracy and enter his or her electronic signature on the eCRFs 
as evidence thereof. 
 will provide access to the Neurocrine portal of the EDC system for the 
duration of the study through a password-protected method of internet access.  Such 
access will be removed from investigator sites at the end of the site's participation in the 
study.  Data from the EDC system will be archived on appropriate data media 
(CD-ROM, etc.) and provided to the investigator at that time as a durable record of the 
site's eCRF data.  Although not required, the investigator may make paper printouts 
from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This 
includes an inspection by NBI and/or health authority representatives at any time.  The 
Principal Investigator will agree to the inspection of study-related records by health 
authority representatives and/or NBI. 
11.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or 
designee).  Any discrepancies will be corrected on-line by an authorized site personnel.  
After completion of the entry process, automated (computer-generated) logic checks will 
run in order to identify items such as inconsistent study dates.  In addition, manual 
review/checks 
may 
be 
performed 
by 
NBI 
on 
the 
data. 
 
Any 
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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.  Once entered 
and saved in an eCRF, data immediately become part of the study database and are 
available to NBI. 
11.3. 
Coding Dictionaries 
Adverse events and medical history will be coded using the chosen version of the 
Medical Dictionary for Regulatory Activities (MedDRA).  Prior and concomitant 
medications will be coded using the chosen version of the World Health Organization 
Drug Dictionary (WHO Drug).   
12. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive statistical methods will be used to summarize the data from this study.  The 
term “descriptive statistics” refers to the number of subjects (n), mean, median, 
standard deviation (SD), standard error of the mean (SEM), minimum, and maximum for 
continuous variables; and refers to the number and/or percentage of subjects (or 
events) for categorical variables.  Data summaries will include tables, figures, and 
listings. 
12.1. 
Analysis Sets 
The safety analysis set will be the primary analysis set used for the summary of data for 
this study.  This analysis set will include all subjects who are dispensed study drug.  
Additional analysis sets may be specified in the expanded Statistical Analysis Plan 
(SAP). 
12.2. 
Sample Size 
The sample size calculation for this study is based on practical considerations and not 
on a statistical power calculation. 
12.3. 
Handling of Missing Data 
Conventions for the handling of missing data will be described in the SAP. 
12.4. 
Enrollment and Disposition of Subjects 
The summary of subject enrollment and disposition will display the number of subjects 
who received at least one dose of study drug, who completed the NBI-98854 treatment 
period, and who completed the study.  The number of subjects who did not complete 
the study will be summarized also, both overall and according to the reason for early 
discontinuation.  A separate summary of enrollment by study center will also be 
provided. 
12.5. 
Demographics Data and Baseline Characteristics 
Demographic data and subject baseline characteristics will be summarized with 
descriptive statistics.   
Medical history will be summarized in frequency tables (number and percentage of 
subjects) by MedDRA system organ class (SOC) and preferred term.  
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12.6. 
Study Drug Dosing 
The estimated number of doses of study drug taken during the 4-week intervals 
between consecutive scheduled visits during the treatment period will be summarized 
with descriptive statistics by visit.  The cumulative estimated number of doses taken 
through Week 48 will be summarized also.  Additionally, the number of subjects at each 
dose level (40 mg or 80 mg) will be summarized by visit along with the number of 
subjects who have a dose reduction. 
12.7. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and its active metabolite NBI-98782 (and 
other metabolites that may be evaluated) will be summarized with descriptive statistics 
by timepoint (Week 4, 8, 12, 24, 36, 48, and 52) and the most recent NBI-98854 dose 
(40 mg or 80 mg) received prior to that timepoint.  These summaries will also be 
generated separately for CYP2D6 poor metabolizers vs. non poor metabolizers.  
Concentrations below the lower limit of quantification will be set equal to zero for all 
plasma concentration summaries. 
12.8. 
Efficacy Data 
The efficacy measures in this study include the AIMS as scored by the blinded central 
AIMS video raters, CGI-TD, PGIC, TDIS, and AMBMTD.  The AIMS as scored by the 
investigators will be evaluated as an exploratory measure.  Descriptive statistics will be 
provided for various derived variables based on the efficacy measures at each 
measurement timepoint, both overall and by underlying disease category.  The efficacy 
variable of primary interest is the AIMS dyskinesia total score, which is calculated as the 
sum of items 1 through 7.  Descriptive statistics will be presented for the AIMS 
dyskinesia total score at each visit and for the changes from baseline (Day -1) at each 
visit after Day -1.  In addition, the percentage of AIMS responders (subjects with a 50% 
or greater reduction from baseline in the AIMS dyskinesia total score) will be 
summarized.  
12.9. 
Safety Data 
Treatment-emergent AEs (TEAEs), categorized by SOC and preferred term as defined 
by the MedDRA coding dictionary (Version 12.0), will be summarized overall and by 
NBI-98854 dose (with assignment to dose based on the last dose received prior to the 
AE onset).  Adverse events reported during the NBI-98854 treatment period and the 
posttreatment period will be summarized separately.  These TEAE tables will include 
the number of events, number of unique subjects experiencing each event, and 
percentage of subjects experiencing each event. 
Adverse events will be also be tabulated in terms of the number and percentage of 
subjects experiencing events by maximum intensity, and additional summaries will be 
presented which include only TEAEs that are considered to be possibly or definitely 
related to study drug.   
Separate summaries will be generated for AEs leading to premature discontinuation 
from the study, SAEs, and deaths. 
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Clinical laboratory tests (hematology and clinical chemistry), vital signs, ECG, physical 
examination, PANSS, CDSS, C-SSRS, BARS, SAS, YMRS, and MADRS (SIGMA) data 
at each study visit will be summarized overall and by NBI-98854 dose with descriptive 
statistics.  Prior and concomitant medications will be summarized also. 
12.10. Interim Analyses 
One or more interim data locks and analyses will be performed during the study for 
interim data review. 
12.11. Software 
Statistical calculations and summaries will be generated using 
 
. 
13. 
REGULATORY AND ETHICAL ISSUES 
13.1. 
General Legal References 
The study will be carried out according to the provision of the United States (US) CFR, 
the US FDA, and the International Conference on Harmonisation Guidelines for GCP.  
All clinical work conducted under this protocol is subject to GCP rules.  This includes an 
inspection by NBI or its representative, health authority or IRB representatives at any 
time.  The investigator must agree to the inspection of study-related records by health 
authority representatives and/or NBI or its designee. 
13.2. 
Institutional Review Board 
The final approved protocol and the ICF will be reviewed by the IRB for the clinical site.  
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to NBI.  The investigator must agree to make 
any required progress reports to the IRB, as well as reports of SAEs, life-threatening 
problems, or death.  
13.3. 
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 will be 
notified of all amendments to the protocol.  Amendments to the protocol will not be 
implemented until written IRB approval has been received.  
13.4. 
Required Documents 
The investigator must provide to NBI or its representatives the following documents 
before the enrollment of any subject (copies should be kept by the investigator in the 
investigator’s regulatory document binder): 
• Signed copy (original) of the approved protocol. 
• Completed and signed statement of investigator (Form FDA 1572 and/or Clinical 
Trial Site Form – as applicable ) 
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• Curriculum 
vitae 
and 
current 
medical 
license 
of 
the 
investigator 
and 
subinvestigators. 
• Financial disclosure information as required. 
• Letter of approval from the IRB for both protocol and consent form. 
• Copy of the IRB-approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided 
by a central laboratory. 
13.5. 
Informed Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. 
Each subject’s chart will include the signed ICF for study participation.  When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the 
signed ICF in this central study folder if not having done so during the study. 
13.6. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with 
the investigator.  This will include telephone calls and on-site visits. During the on-site 
visits, the eCRFs will be reviewed for completeness and adherence to the protocol.  As 
part of the data audit, source documents will be made available for review by the study 
monitor.  The study monitor will also perform drug accountability checks and may 
periodically request review of the investigator study file to ensure completeness of 
documentation in all respects of clinical study conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the 
study files after which the files should be secured for the appropriate time period.  The 
investigator or appointed delegate will receive the study monitor during these on-site 
visits, will cooperate in providing the documents for inspection, and respond to inquiries.  
In addition, the investigator will permit inspection of the study files by authorized 
representatives of the regulatory agencies. 
13.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures 
designed to ensure that all procedures are in compliance with GCP and FDA Guidelines 
and according to national law.  Quality assurance audits may be performed at the 
discretion of NBI. 
13.8. 
Record Retention 
Federal regulations require that records of drug disposition, CRFs, and all reports of this 
investigation shall be retained by the investigator for a minimum of 2 years after 
notification by NBI that the regulatory authorities have been notified of the study's 
termination, or 2 years after approval of the marketing application.  If the investigator is 
unable to retain the study documents for the required amount of time, NBI must be 
informed of the individual who will be assuming this responsibility. 
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13.9. 
Confidentiality 
Neurocrine Biosciences Inc. and the clinical site affirm and uphold the principle of the 
subject’s right to protection against invasion of privacy.  Throughout this study, all data 
will be identified only by an identification number and, where applicable, subject’s initials 
and birth date. 
All information concerning this study and which was not previously published is 
considered confidential information.  This confidential information shall remain the sole 
property of NBI; it shall not be disclosed to others without written consent of NBI; and 
shall not be used except in the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To 
allow the use of the information derived from this clinical study and to ensure 
compliance with current federal regulations, the investigator is obliged to furnish NBI 
with the complete test results and all data compiled in this study. 
14. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI or designee will 
arrange that all study material be delivered to the study site.  Subject entry should not 
begin until after the required regulatory documents are confirmed as received and the 
Investigator Meeting/Initiation Meeting has occurred.  All personnel expected to be 
involved in the conduct of the study will undergo orientation to include review of study 
protocol, instructions for eCRF completion, AE reporting, and overall responsibilities 
including those for drug accountability and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow-up 
examination.  Any clinically relevant finding, including laboratory values of potential 
clinical concern, and adverse experiences will be followed until they resolve or return to 
a clinically acceptable level. 
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15. 
REFERENCES  
Addington D, Addington J, Schissel B.  A depression rating scale for schizophrenics.  
Schizophren Res.  1990; 3(4):247-251. 
Barnes T.R.E.  A rating scale for drug-induced akathisia. Br J Psychiat. 1989; 
154:672-676. 
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, 1976a, US 
Department of Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD:  
National Institute of Mental Health – Abnormal Involuntary Movement Scale, p. 534-537.  
Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, 1976b, US 
Department of Health, Education, and Welfare. Pub. No. (ADM), 76-338, Rockville, MD:  
National Institute of Mental Health – Clinical Global Impression - Improvement, p. 
217-222.  
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement 
disorders. Neurology. 1997; 48(2):358-362. 
Jeste D, Palmer B, Appelbaum P, Golsham S, et al.  A New Brief Instrument for 
Assessing Decisional Capacity for Clinical Research.  Arch Gen Psychiatry. 2007; 
64(8):966-974. 
Kay SR, Fiszbein A, Opler LA.  The Positive and Negative Syndrome Scale (PANSS) 
for Schizophrenia.  Schizophrenia Bull. 1987; 13(2):261-276. 
Kilbourn 
M, 
Lee 
L, 
Vander 
Borght 
T, 
Jewett 
D, 
et 
al. 
 
Binding 
of 
alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific. 
Eur J Pharmacol. 1995; 278 (3):249-252. 
Macpherson R, Collis R. Tardive dyskinesia.  Patients’ lack of awareness of movement 
disorder. Br J Psychiatry. 1992; Jan;160:110-112. 
Margolese H, Chouinard G, Kolivakis T, Beauclair L, Miller R.  Tardive Dyskinesia in the 
Era of Typical and Atypical Antipsychotics. Part 1: Pathophysiology and Mechanisms of 
Induction. Can J Psychiatry 2005; 50:541-547. 
Mehvar R, Jamali F, Watson MWB, Skelton D. Pharmacokinetics of tetrabenazine and 
its major metabolite in man and rat.  Drug Metab Dispos. 1987; 15(2):250-255. 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry. 1979; 134:382-389. 
Ondo WG, Hanna PA, Jankovic J.  Tetrabenazine treatment for tardive dyskinesia: 
assessment 
by 
randomized 
videotape 
protocol. 
Am 
J 
Psychiatry 
1999; 
156(8):1279-1281. 
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS). Psychological 
Reports. 1962; 10:799-812.  
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Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): Recent 
Developments in Ascertainment and Scaling.  Psychopharmacol Bull. 1988. 24:97-9. 
Simpson GM, Angus JWS.  A rating scale for extrapyramidal side effects. Acta Psychiat 
Scand. 1970; 212:11-19. 
Weihe E, Eiden LE.  Chemical neuroanatomy of the vesicular amine transporters. 
FASEB J. 2000; 14:2435–2449. 
Williams JBW, Kobak KA.  Development and reliability of a structured interview guide 
for the Montgomery-Asberg Depression Rating Scale (SIGMA).  Brit J Psychiat. 
2008;192:52-58. 
Xenazine® Package Insert, April 2012, Lundbeck Inc., Deerfield IL, USA. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity 
and sensitivity. Br J Psychiatry. 1978;133:429-435. 
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16. 
SUPPLEMENTS 
16.1. 
Neuroleptic-Induced Tardive Dyskinesia Diagnostic Criteria 
The DSM-IV provides following diagnostic criteria for neuroleptic-induced tardive 
dyskinesia (refer to DSM-IV 333.82): 
• A person who has taken neuroleptics for at least 3 months* develops at least two 
movements of at least mild intensity while taking a neuroleptic. 
• A person who has taken neuroleptics for at least 3 months* develops at least one 
movement of at least moderate intensity while taking a neuroleptic. 
• A person who has taken neuroleptics for at least 3 months* develops at least two 
movements of at least mild intensity within 4 weeks of the discontinuation of the 
neuroleptic. 
• A person who has taken neuroleptics for at least 3 months* develops at least one 
movement of at least moderate intensity within 4 weeks of the discontinuation of the 
neuroleptic. 
 
*1 month if older than 60 years 
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16.2. 
NBI-98854-1402 Dose Titration Algorithm 
At any time after the end of Week 4
Resumption to 40 mg dose for subjects who are unable to tolerate the dose
escalation to 80 mg dose.  Subjects will remain at this dose for the remainder of the
treatment period.
Discontinuation from the study
Subject who are unable to tolerate the starting dose (40 mg) or resumption of the
40 mg dose will be discontinued from the study.
CGI-TD assessed by
the Investigator
(or designee)
End of Week 4
CGI-TD assessment of
very much improved or
much improved
No dose escalation is
allowed.  Maintain
dose at 40 mg.
CGI-TD assessment of
minimally improved or not
changed or minimally
worse or much worse or
very much worse
Qualified physician to
assess tolerability
and safety
Escalate dose to 80 mg
Subject able to tolerate study drug
Maintain dose at 40 mg
Qualified physician’s assessment that
subject may not be able to tolerate a
dose increase
 
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16.3. 
Blinded Central AIMS Video Raters’ Consensus Scoring Process 
 
1. The blinded central AIMS video raters must be neurologists who are movement 
disorder experts. 
2. Each blinded central AIMS video rater will be assigned a unique rater ID number. 
3. The blinded central AIMS raters must complete practice review and consensus 
scoring of AIMS videos provided by the sponsor (using AIMS video files from 
subjects who are not participating in the current study) prior to scoring any study 
subjects’ AIMS videos. 
4. Each AIMS video file to be scored will be assigned a randomization number thereby 
blinding the central AIMS video raters to the subject’s study visits and dose. 
5. A face-to-face meeting will be set up for two blinded central AIMS video raters to 
meet at a mutual location. The sponsor (or designee) will provide the following 
materials at the meeting for the raters to review and score the AIMS video files: 
• HD TV 
• Laptop computer 
• External Hard Drive containing study subjects’ randomized AIMS video files. 
• AIMS paper Case Report Form (CRF). 
6. At the meeting, two blinded central AIMS video raters will together review each video 
file from beginning to end.  If required, the raters can review each video multiple 
times but must not re-review the video file after scores have been generated. 
7. The two blinded, central AIMS video raters will score AIMS Items 1-7.  Both must 
agree (have consensus) on a score (0 to 4) based on the following AIMS 
descriptors. 
 
Score 
Descriptors 
0 
No dyskinesia 
1 
Minimal or Slight dyskinesia:  Low amplitude, present during some but not 
most of the exam 
2 
Mild dyskinesia:  Low amplitude and present during most of exam (or moderate 
amplitude and present during some of exam) 
3 
Moderate dyskinesia:  Moderate amplitude and present during most of exam 
4 
Severe dyskinesia: Maximal amplitude and present during most of exam 
 
8. One of the blinded central AIMS video raters will enter the item scores on a paper 
CRF for each AIMS video file reviewed.  Both raters will complete the rater ID 
number, and sign and date each paper CRF in the space provided.  
9. The completed paper CRF will be collected by the sponsor to enter the AIMS scores 
into the study database. 
 
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17. 
APPENDICES 
 
 
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NBI-98854-1402 
 
24-Nov-2014 
Final 
 
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NBI-98854-1402 
 
24-Nov-2014 
Final 
 
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NBI-98854-1402 
 
24-Nov-2014 
Final 
 
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NBI-98854-1402 
 
24-Nov-2014 
Final 
 
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SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
1 
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 3 
 
VERSION 1.0 
DATE OF PLAN: 
05Apr2016 
 
 
STUDY DRUG: 
NBI-98854 
PROTOCOL NUMBER: 
NBI-98854-1402 
STUDY TITLE: 
A PHASE 3, OPEN-LABEL, SAFETY AND TOLERABILITY STUDY OF NBI-98854 
FOR THE TREATMENT OF TARDIVE DYSKINESIA 
SPONSOR: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA  92130 
Telephone:  (858) 617-7600 
 
 
 
 
CONFIDENTIAL 




Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
3 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................7 
LIST OF DEFINITIONS .................................................................................................................9 
1. 
INTRODUCTION ......................................................................................................11 
2. 
STUDY OBJECTIVES ..............................................................................................11 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Study Design Overview ..............................................................................................11 
3.2. 
Efficacy, Blood Sampling, and Safety Assessments for All Subjects ........................12 
3.3. 
Additional Safety Assessments for Subjects with Schizophrenia or 
Schizoaffective Disorder ............................................................................................13 
3.4. 
Additional Safety Assessments for Subjects with Mood Disorder .............................13 
4. 
STUDY ASSESSMENT SCHEDULES ....................................................................13 
5. 
STATISTICAL ANALYSES .....................................................................................18 
5.1. 
General Statistical Procedures ....................................................................................18 
5.2. 
Sample Size ................................................................................................................18 
5.3. 
Data Locks and Analyses ............................................................................................18 
5.3.1. 
Data Lock and Analysis 1 ...........................................................................................18 
5.3.2. 
Data Lock and Analysis 2 ...........................................................................................19 
5.3.3. 
Data Lock and Analysis 3 ...........................................................................................19 
5.4. 
Pooling of Sites ...........................................................................................................19 
5.5. 
Handling of Early Termination Visit Data .................................................................19 
5.6. 
Handling of Missing Data ...........................................................................................20 
5.6.1. 
Missing and incomplete dates .....................................................................................20 
5.7. 
Coding Dictionary ......................................................................................................21 
5.8. 
Analysis Sets ...............................................................................................................21 
5.9. 
Subject Enrollment and Disposition ...........................................................................21 
5.10. 
Important Protocol Deviations ....................................................................................22 
5.11. 
Demographics .............................................................................................................22 
5.12. 
Baseline Subject Characteristics .................................................................................22 
5.13. 
Medical History ..........................................................................................................23 
5.14. 
Study Drug Dosing .....................................................................................................23 
5.14.1. 
Number of Doses Taken .............................................................................................23 
5.14.2. 
Dosing Compliance ....................................................................................................23 


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NBI-98854-1402 Statistical Analysis Plan  
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5.15. 
Dose Titration at Week 4 ............................................................................................24 
5.16. 
Dose Reductions after Week 4 ...................................................................................24 
5.17. 
Pharmacokinetic Data .................................................................................................24 
5.18. 
Efficacy Data ..............................................................................................................25 
5.18.1. 
Efficacy Variables ......................................................................................................25 
5.18.2. 
AIMS ..........................................................................................................................25 
5.18.2.1. 
Individual AIMS Items Descriptive Statistics ............................................................25 
5.18.2.2. 
Individual AIMS Dyskinesia Total Score Descriptive Statistics ................................25 
5.18.2.3. 
AIMS Dyskinesia Total Score Graphs .......................................................................25 
5.18.2.4. 
AIMS Responder Analysis .........................................................................................25 
5.18.3. 
CGI-TD .......................................................................................................................26 
5.18.3.1. 
CGI-TD Scores ...........................................................................................................26 
5.18.3.2. 
CGI-TD Descriptive Statistics ....................................................................................26 
5.18.3.3. 
CGI-TD Score Graphs ................................................................................................26 
5.18.3.4. 
CGI-TD Responder Analysis ......................................................................................26 
5.18.4. 
PGIC ...........................................................................................................................27 
5.18.4.1. 
PGIC Scores ................................................................................................................27 
5.18.4.2. 
PGIC Descriptive Statistics ........................................................................................27 
5.18.4.3. 
PGIC Score Graphs .....................................................................................................27 
5.18.4.4. 
PGIC Responder Analysis ..........................................................................................27 
5.18.5. 
TDIS Total Score ........................................................................................................27 
5.18.5.1. 
TDIS Total Score Descriptive Statistics .....................................................................28 
5.18.5.2. 
TDIS Total Score Graphs ...........................................................................................28 
5.18.6. 
Assessment of Most Bothersome Movement .............................................................28 
5.19. 
Safety Data ..................................................................................................................28 
5.19.1. 
Adverse Events ...........................................................................................................28 
5.19.1.1. 
Treatment-Emergent Adverse Event Frequency Tables .............................................28 
5.19.1.2. 
Adverse Event Overall Summaries .............................................................................29 
5.19.1.3. 
Adverse Event Time to Onset and Duration ...............................................................29 
5.19.1.4. 
Adverse Events Resulting in a Study Drug Dose Reduction ......................................30 
5.19.1.5. 
Adverse Events Resulting in Premature Study Discontinuation ................................30 
5.19.1.6. 
Deaths and Other Serious Adverse Events .................................................................30 


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NBI-98854-1402 Statistical Analysis Plan  
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5.19.1.7. 
Adverse Event Graphs ................................................................................................31 
5.19.2. 
C-SSRS .......................................................................................................................31 
5.19.3. 
Barnes Akathisia Rating Scale ....................................................................................32 
5.19.4. 
Simpson-Angus Scale .................................................................................................33 
5.19.5. 
Positive and Negative Symptoms Scale (Subjects with Schizophrenia or 
Schizoaffective Disorder) ...........................................................................................33 
5.19.6. 
Calgary Depression Scale for Schizophrenia (Subjects with Schizophrenia or 
Schizoaffective Disorder) ...........................................................................................33 
5.19.7. 
Young Mania Rating Scale (Subjects with Mood Disorders) ....................................33 
5.19.8. 
Montgomery-Asberg Depression Rating Scale (Subjects with Mood 
Disorders) ...................................................................................................................34 
5.19.9. 
Physical Examination and Weight ..............................................................................34 
5.19.10. 
Vital Signs ..................................................................................................................34 
5.19.11. 
Electrocardiogram .......................................................................................................35 
5.19.12. 
Clinical Laboratory Data ............................................................................................36 
5.19.13. 
Prior and Concomitant Medications ...........................................................................38 
5.20. 
Additional Data Presentations ....................................................................................38 
5.20.1. 
Inclusion and Exclusion Criteria ................................................................................38 
5.20.2. 
Serology Test Results .................................................................................................38 
5.20.3. 
Pregnancy Test Results ...............................................................................................38 
5.20.4. 
Urine Drug Screen and Alcohol Breath Test ..............................................................38 
5.20.5. 
Plasma Sampling Timepoints for Exploratory Biomarker Assessments ....................39 
6. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS .................................39 
7. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................39 
8. 
REFERENCES ...........................................................................................................40 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
6 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments for Subjects with Schizophrenia or Schizoaffective 
Disorder ......................................................................................................................14 
Table 2: 
Schedule of Assessments for Subjects with Mood Disorder ......................................16 
Table 3: 
Allowable Study Day Range for Early Termination Visit Mapping ..........................19 
Table 4: 
Potentially Clinically Significant Criteria for Selected Vital Signs ...........................35 
Table 5: 
Potential Clinically Significant Criteria for Selected Clinical Laboratory 
Variables .....................................................................................................................37 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
7 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification 
BARS 
Barnes Akathisia Rating Scale  
BLQ 
Below the limit of quantification 
BPRS 
Brief Psychiatric Rating Scale 
CDSS 
Calgary Depression Scale for Schizophrenia 
CGI-TD 
Clinical Global Impression of Change –Tardive Dyskinesia 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP2D6 
Cytochrome P450 2D6 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EPS, EPSE 
Extrapyramidal symptoms or side effects 
ET 
Early termination 
FDA 
[United States] Food and Drug Administration 
GGT 
Gamma-glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C antibody 
HIV-Ab 
Human immunodeficiency virus antibody 
ICF 
Informed Consent Form 
IPD 
Important protocol deviation 
ITT 
Intent-to-treat 
LS 
Least squares 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
n, N 
Sample size (number of subjects) 
NBI 
Neurocrine Biosciences, Inc. 
NDA 
New Drug Application 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
8 
 
Abbreviation 
Term 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially clinically significant 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PT 
Preferred term 
qd 
Once daily 
QTcF 
Fridericia’s correction of QT interval  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
 
 statistical software 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SIGMA 
Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TD 
Tardive dyskinesia 
TDIS 
Tardive Dyskinesia Impact Scale 
UBACC 
University of California, San Diego Brief Assessment of Capacity to Consent 
UDS 
Urine drug screen 
WHO 
World Health Organization 
YMRS 
Young Mania Rating Scale 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
9 
 
LIST OF DEFINITIONS 
The following definitions are developed for the purpose of statistical analysis and data 
tabulation. 
 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related.  During the study, clinically significant 
adverse changes in clinical status, electrocardiograms (ECGs), 
laboratory values (not associated with an AE or concurrent medical 
condition), or physical examinations are considered AEs.  Any 
subject complaint associated with such an abnormal finding will 
also be reported as an AE. 
Adverse events include, but are not limited to:  (1) a worsening or 
change in nature, severity, or frequency of conditions present at the 
start of the study; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction 
Descriptive Statistics 
Number of subjects, mean, median, standard deviation, standard 
error of the mean, minimum and maximum for continuous 
measurements; number and percentage of subjects in each level of a 
categorical measurement. (Note:  additional descriptive statistics 
may be calculated for certain variables if warranted.) 
Life-Threatening 
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. 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that results in any of the 
following outcomes: 
• 
Death; 
• 
A life-threatening adverse event; 
• 
Inpatient hospitalization or prolongation of existing 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 above. 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
10 
 
Treatment-Emergent  
Adverse Event 
A Treatment-Emergent Adverse Event (TEAE) is any reaction, side 
effect, or other untoward event, regardless of relationship to study 
drug, that is newly reported or considered a worsening or change in 
nature, severity, or frequency of conditions present at the start of 
the study which occurs any time after first dose of study drug. 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
11 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed description of the tables, figures, and 
listings that will be prepared to summarize the data from the Phase 3 study described in 
Neurocrine Biosciences, Inc. (NBI) Protocol NBI-98854-1402. 
2. 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and tolerability of NBI-98854 (titrated from 
40 mg to 80 mg) administered once daily for up to 48 weeks. 
3. 
STUDY DESIGN 
3.1. 
Study Design Overview 
This is a Phase 3, open-label, dose-titration study to evaluate the safety and tolerability of NBI-
98854 (titrated from 40 mg to 80 mg) administered once daily (qd) for a total of 48 weeks of 
treatment.  Approximately 180 medically stable male and female subjects with clinical diagnoses 
of schizophrenia or schizoaffective disorder with neuroleptic-induced tardive dyskinesia (TD) or 
mood disorder with neuroleptic-induced TD will be enrolled.  Approximately 60% of the 
subjects enrolled may have schizophrenia or schizoaffective disorder. 
All subjects must sign an informed consent form (ICF) prior to the conduct of any study related 
procedures, including washout of medications disallowed in the study.  Before subjects can 
provide informed consent, the investigator (or designee) must determine whether the subject has 
the capacity to provide consent for study participation using the University of California, San 
Diego Brief Assessment of Capacity to Consent (UBACC).  Only subjects who are deemed to 
have the capacity to provide consent may sign the ICF.  After providing informed consent, the 
subjects will be screened for eligibility for up to 6 weeks prior to Day -1 (baseline visit) (Week -
6 to Day -1). 
On Day -1, eligible subjects will receive a supply of NBI-98854 40 mg qd for the first 4 weeks of 
the treatment period.  Beginning on Day 1, study drug will be self-administered at home (in the 
presence of their caregiver, if applicable) in the morning between 0700 and 1000 hours.   
At the end of Week 4, the investigator may escalate the subject’s dose to 80 mg or continue with 
the subject’s current dose.  A dose escalation will be allowed at Week 4 if (1) the investigator or 
designee’s assessment of the Clinical Global Impression of Change –Tardive Dyskinesia  (CGI-
TD) is “minimally improved”, “not changed”, “minimally worse”, “much worse”, or “very much 
worse”, and (2) the safety and tolerability of the current dose is acceptable as determined by a 
physician.   The subject will then continue at the 80 mg dose until the end of the treatment period 
(Week 48). 
At any time after a dose escalation, the investigator may decrease the dose to 40 mg if the subject 
is unable to tolerate the dose increase.  The subject will then continue at the 40 mg dose until the 
end of the treatment period (Week 48).  Subjects who are unable to tolerate the starting dose of 
40 mg, or the resumption of 40 mg, will be discontinued from the study.  


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
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Subjects will return to the study site every 4 weeks for study assessments and dispensation of the 
study drug.  These visits will occur in the afternoon between 1200-1700 hours at Weeks 4, 8, 12, 
24, 36, 48 and 52 (or early termination) and at any time before 1700 hours at Weeks 16, 20, 28, 
32, 40 and 44.  Subjects who do not want to continue in the study will be terminated and will be 
asked to return for an early termination visit approximately 4 weeks after receiving the last dose.  
Follow-up assessments will be performed at Week 52 (4 weeks after the last dose) or early 
termination. 
Efficacy, safety, and PK will be assessed at scheduled times throughout the study.  The treatment 
period visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48) and the follow-up visit 
(Week 52) will have a visit window of ±6 days.  
3.2. 
Efficacy, Blood Sampling, and Safety Assessments for All Subjects 
Efficacy assessments will be performed using the Abnormal Involuntary Movement Scale 
(AIMS), the CGI-TD, the Patient Global Impression of Change (PGIC), the Tardive Dyskinesia 
Impact Scale (TDIS), and the Assessment of Most Bothersome Movement in Tardive Dyskinesia 
(AMBMTD).  The AIMS will be administered at screening, on Day -1 (the day prior to dosing), 
during the treatment period (Weeks 4, 8, 12, 24, 36, and 48), and at the follow-up visit (Week 
52) or early termination.  The AIMS will be administered and scored by the investigator (or 
designee) in accordance with the AIMS administration procedure and scoring guidelines 
provided by the sponsor (or designee).  At screening, Day -1, Week 8, and the follow-up visit 
(Week 52) or early termination, the AIMS assessment will be video recorded (approximately 10 
minutes) following standardized guidelines and the video recording will be uploaded to a secure 
central server.  At screening, a blinded, external AIMS reviewer will access the central server to 
view the recording and evaluate the subject’s global TD severity (based on AIMS item 8).  The 
subject must have moderate or severe TD as determined by the blinded, external AIMS reviewer 
to be eligible for study participation. The investigator or designee will score AIMS items 1-10 
and complete AIMS items 11-12. The AIMS video recording conducted on Day -1, at Week 8, 
and at the follow-up visit (Week 52) or early termination will be reviewed by blinded, central 
AIMS video raters, who will score AIMS items 1-7 using a triple-blind consensus scoring 
process.    
The CGI-TD will be used to rate the investigator or designee’s assessment of the overall global 
improvement of TD symptoms since initiation of study drug dosing, and will be administered 
during the treatment period (Weeks 4, 8, 12, 24, 36, and 48) and at the follow-up visit (Week 52) 
or early termination.   
The PGIC will be used to evaluate the change in TD symptoms since initiation of study drug 
dosing, and will be completed by the subjects during the treatment period (Weeks 4, 8, 12, 24, 
36, and 48) and at the follow-up visit (Week 52) or early termination.  
A patient reported outcome, the TDIS and AMBMTD, will be used to assess the impairment and 
disability associated with dyskinesia and to rate the subject’s most bothersome movement, 
respectively.  The TDIS will be completed by the subjects at screening, on Day -1 (the day prior 
to dosing), during the treatment period (Weeks 4, 8, 12, 24, 36, and 48), and at the follow-up 
visit (Week 52) or at early termination.  


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
13 
 
The Brief Psychiatric Rating Scale (BPRS) will be performed at screening as an assessment of 
the severity of psychopathology to determine study eligibility. 
Blood samples for plasma drug concentration analysis will be collected during the study. A 
blood sample will be collected from enrolled subjects on Day -1 and analyzed to determine 
CYP2D6 status.  Plasma samples for an exploratory assessment of biomarkers associated with 
the metabolic profile of NBI-98854 will be collected during the study. 
Safety and tolerability assessments including AE monitoring, clinical laboratory tests (including 
hematology, clinical chemistry, prolactin, and urinalysis), vital sign measurements, PE, and 12-
lead ECG will be conducted at scheduled times throughout the study.  Suicidal ideation and 
behavior will be evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS).  The 
Barnes Akathisia Rating Scale (BARS) and the Simpson-Angus Scale (SAS) will be used to 
assess the presence and severity of drug-induced akathisia and drug-induced extrapyramidal 
symptoms, respectively. 
3.3. 
Additional Safety Assessments for Subjects with Schizophrenia or 
Schizoaffective Disorder 
Depressive symptoms will be evaluated using the Calgary Depression Scale for Schizophrenia 
(CDSS).  Psychiatric symptoms will be assessed using the Positive and Negative Syndrome 
Scale (PANSS). 
3.4. 
Additional Safety Assessments for Subjects with Mood Disorder 
The Young Mania Rating Scale (YMRS) will be used to assess manic symptoms.  Depressive 
symptoms will be evaluated with the Montgomery-Asberg Depression Rating Scale (MADRS) 
conducted using the Structured Interview Guide for the MADRS (SIGMA). 
4. 
STUDY ASSESSMENT SCHEDULES 
The schedules of assessments for subjects with schizophrenia or schizoaffective disorder and 
subjects with mood disorder are shown in Table 1 and Table 2, respectively. 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
14 
 
Table 1: 
Schedule of Assessments for Subjects with Schizophrenia or Schizoaffective Disorder 
Procedurea 
Screening 
Period 
Baseline 
Open-Label  NBI-98854 Treatment Period 
Follow-up / 
ET 
Weekb 
-6  to -1 
Day -1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52c 
Visitb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent / UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X (S) 
X (S,U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screeng  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotype blood sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum prolactin 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma for biomarkers 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PK plasma sampleh 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
AIMSi 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
TDIS and AMBMTDj 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CGI-TD  
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
SAS 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CDSS 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PANSS 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
NBI-98854 dosing at homek 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense NBI-98854l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NBI-98854 accountabilitym 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and footnotes appear on the next page. 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
15 
 
 
 
Definitions: AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; AMBMTD=Assessment of Most Bothersome Movement in Tardive Dyskinesia; 
BARS=Barnes Akathisia Rating Scale; BPRS=Brief Psychiatric Rating Scale; CDSS=Calgary Depression Scale for Schizophrenia;  
CGI-TD=Clinical Global Impression-Tardive Dyskinesia; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; 
HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus antibody; HIV-Ab=human immnunodeficiency virus antibody; 
PANSS=Positive and Negative Syndrome Scale; PGIC=Patient Global Impression of Change; PK=pharmacokinetic; s=serum; SAS=Simpson-Angus Scale; TDIS=Tardive 
Dyskinesia Impact Scale; u=urine; UBACC=University of California, San Diego Brief Assessment of Capacity to Consent. 
a. Study assessments will be conducted at approximately the same time in the afternoon (between 1200-1700 hours) at screening, Day -1, at the end of Weeks 4, 8, 12, 24, 
36, 48 and 52 (or early termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 32, 40 and 44. 
b. Day -1 visit is the day of baseline assessments.  Day 1 is the first day of dosing; NBI-98854 will be self-administered at home and subjects are not required to come to 
the study site.  The study visits after Day -1 will have a visit window of ±6 days. 
c. Final study visit for subjects who complete the study (or early termination). 
d. A standard 12-lead ECG will be conducted after the subject has rested supine for at least 5 minutes.  The ECG parameters that will be assessed include HR, QT, QTcF, 
and PR intervals, and QRS duration based on the ECG machine readings (QTcF may be calculated). 
e. Pregnancy tests are only required for women who are not postmenopausal for at least 1 year prior to screening.  Serum pregnancy tests will be conducted at screening 
and Day -1.  A urine pregnancy test will be conducted at Day -1 and all subsequent visits.  The urine pregnancy test result on Day -1 will be used to confirm eligibility. 
f. Clinical laboratory tests include hematology, chemistry and urinalysis.  All blood samples will be obtained under non-fasted conditions. 
g. Urine drug screen will be analyzed at Screening and Day -1 by the central lab.  In addition, a UDS kit provided by the central lab will used at the site to confirm 
eligibility on Day -1. 
h. Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
i. The AIMS will be administered and scored at the site by the investigator (or designee).  The AIMS will be video recorded for approximately 10 minutes at screening, 
Day -1, end of Week 8, and at the follow-up visit (end of Week 52 or early termination).  At screening, a blinded AIMS reviewer will view the video and evaluate the 
TD symptom severity to determine subject eligibility. 
j. TDIS and AMBMTD will be completed by the subjects. 
k. Subjects will self-administer NBI-98854 daily (in the morning at approximately the same time) at home in the presence of their caregiver (if applicable). Subject or 
caregiver will record daily the date and time of dosing on the drug packaging form provided. A representative from the study site will call the subjects weekly to 
remind them to take NBI-98854 daily. 
l. Subjects will receive a 4-week supply (two kits) of NBI-98854 at Day -1 and will need to return to study site every 4 weeks to obtain a 4-week supply of NBI-98854.  
m. At the end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 subjects will return all used and unused NBI-98854, and a compliance check will be performed by counting the 
capsules returned at the visit 
 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
16 
 
Table 2: 
Schedule of Assessments for Subjects with Mood Disorder 
Procedurea 
Screening 
Period 
Baseline 
Open-Label NBI-98854 Treatment Period 
Follow-up / 
ET 
Weekb 
-6  to -1 
Day -1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52c 
Visitb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent / UBACC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
UPDATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X (S) 
X (S,U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
X (U) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screeng  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotype blood sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum prolactin 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma for biomarkers 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PK plasma sampleh 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
AIMSi 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
TDIS and AMBMTDj 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CGI-TD  
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
SAS 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
MADRS (SIGMA) 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
YMRS 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
NBI-98854 dosing at homek 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense NBI-98854l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NBI-98854 accountabilitym 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient clinic visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and footnotes appear on the next page. 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
17 
 
Definitions: AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; AMBMTD=Assessment of Most Bothersome Movement in Tardive Dyskinesia; 
BARS=Barnes 
Akathisia 
Rating 
Scale; 
BPRS=Brief 
Psychiatric 
Rating 
Scale; 
CGI-TD=Clinical 
Global 
Impression-Tardive 
Dyskinesia;  
C-SSRS=Columbia-Suicide 
Severity 
Rating 
Scale; 
ECG=Electrocardiogram; 
ET=Early 
Termination; 
HBsAg=Hepatitis 
B 
Surface 
Antigen;  
HCV-Ab=Hepatitis C Virus Antibody; HIV-Ab=Human Immnunodeficiency Virus Antibody; MADRS (SIGMA)=Montgomery-Asberg Depression Rating Scale using the 
Structured Interview Guide for the MADRS; PGIC=Patient Global Impression of Chance; PK=Pharmacokinetic; s=serum; SAS=Simpson-Angus Scale; TDIS=Tardive 
Dyskinesia Impact Scale; u=urine; UBACC=University of California, San Diego Brief Assessment of Capacity to Consent; YMRS=Young Mania Rating Scale. 
a. Study assessments will be conducted at approximately the same time in the afternoon (between 1200-1700 hours) at screening, Day -1, at the end of Weeks 4, 8, 
12, 24, 36, 48 and 52 (or early termination) and at any time before 1700 hours at the end of Week 16, 20, 28, 32, 40 and 44. 
b. Day -1 visit is the day of baseline assessments.  Day 1 is the first day of dosing; NBI-98854 will be self-administered at home and subjects are not required to 
come to the study site.  The study visits after Day -1 will have a visit window of ±6 days. 
c. Final study visit for subjects who complete the study (or early termination). 
d. A standard 12-lead ECG will be conducted after the subject has rested supine for at least 5 minutes.  The ECG parameters that will be assessed include HR, 
QT, QTcF, and PR intervals, and QRS duration based on the ECG machine readings (QTcF may be calculated). 
e. Pregnancy tests are only required for women who are not postmenopausal for at least 1 year prior to screening.  Serum pregnancy tests will be conducted at 
screening and Day -1.  A urine pregnancy test will be conducted at Day -1 and all subsequent visits.  The urine pregnancy test result on Day -1 will be used to 
confirm eligibility. 
f. Clinical laboratory tests include hematology, chemistry and urinalysis. All blood samples will be obtained under non-fasted conditions. 
g. Urine drug screen will be analyzed at Screening and Day -1 by the central lab. In addition, a UDS kit provided by the central lab will used at the site to confirm 
eligibility on Day -1. 
h. Subjects will be asked to record and provide dosing times on the days during the treatment period when blood PK samples are collected. 
i. The AIMS administered and scored at the site by the investigator (or designee).  At screening, Day -1, end of Week 8, and t the follow-up visit (end of Week 
52 or early termination), the AIMS will be video recorded for approximately 10 minutes.  At screening, a blinded AIMS reviewer will view the video and 
evaluate the TD symptom severity to determine subject eligibility. 
j. TDIS and AMBMTD will be completed by the subjects. 
k. Subjects will self-administer NBI-98854 daily (in the morning at approximately the same time) at home in the presence of their caregiver (if applicable).  
Subject or caregiver will record daily the date and time of dosing on the drug packaging form provided.  A representative from the study site will call the 
subjects weekly to remind them to take their study medication daily. 
l. Subjects will receive a 4-week supply (two kits) of NBI-98854 at Day -1 and will need to return to study site every 4 weeks to obtain a 4-week supply of NBI-
98854. 
m. At the end of Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 subjects will return all used and unused NBI-98854, and a compliance check will be performed by counting the 
capsules returned at the visit 
 


Neurocrine Biosciences, Inc. 
NBI-98854-1402 Statistical Analysis Plan  
18 
 
5. 
STATISTICAL ANALYSES 
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 post hoc 
analyses will be clearly identified in the clinical study report. 
5.1. 
General Statistical Procedures 
Descriptive statistical methods will be used to summarize the data from this study.  The term 
“descriptive statistics” refers to the number of subjects (n), mean, median, standard deviation 
(SD), standard error of the mean (SEM), minimum, and maximum for continuous variables; and 
refers to the number and/or percentage of subjects (or events) for categorical variables.     
Unless stated otherwise, each table of descriptive statistics and associated figures will summarize 
data according to the following “treatment groups”: 
 NBI-98854 40 mg (subjects who are not titrated to the 80 mg dose at Week 4) 
 NBI-98854 80 mg (subjects who are titrated to the 80 mg dose at Week 4 and remain on 
that dose) 
 NBI-98854 80/40 mg (subjects who are titrated to the 80 mg dose at Week 4 and 
subsequently have a dose reduction to 40 mg at any time in the study) 
 All subjects (this may also be referred to as “overall” in treatment groups specifications 
below) 
Note that subjects who discontinue from the study prior to the Week 4 titration visit will be 
included in the NBI-98854 40 mg treatment group. 
5.2. 
Sample Size  
The sample size for this study is based on practical considerations and not on a statistical power 
calculation.  
5.3. 
Data Locks and Analyses 
Three analyses of this study will be performed, each of which will involve locking study data for 
a defined subset of the overall study database for purposes of statistical analysis. The study data 
locking process will be carried out by the sponsor’s Clinical Data Management department in 
accordance with company standard operating procedures (SOPs).  
5.3.1. 
Data Lock and Analysis 1 
The first data lock will be performed prior to an analysis of the study data that will be included in 
a New Drug Application (NDA) to be submitted to the US Food and Drug Administration (FDA) 
for the use of NBI-98854 for the treatment of TD.  Data included in this analysis will be locked 
for any subject who has completed or early terminated from the study at the time of data cutoff.  
For subjects who are still participating in the study, all data for visits that occurred by the time of 
data cutoff (with the exception of ongoing adverse events, concomitant medications, and study 
drug dosing and accountability) will also be locked prior to performing the analysis.  


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5.3.2. 
Data Lock and Analysis 2 
The second data lock/analysis will occur at the time the safety update is prepared for the NDA 
referenced above in Section 5.3.1. The specific data to be locked for Analysis 2 will be 
determined at the time of Analysis 2, which will be performed by an external vendor. 
5.3.3. 
Data Lock and Analysis 3 
The third and final data lock/analysis will occur when all subjects have completed the study. All 
study data will be locked prior to this analysis. Analysis 3 will include all of the data reported 
during the study, and the results of this analysis will be presented in the final clinical study 
report. 
5.4. 
Pooling of Sites 
With exception of the summary of subject enrollment by site, study sites will be pooled in all 
tables and graphs, since the majority of sites in this study are expected to enroll fewer than five 
subjects.  
5.5. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject discontinues from the study prior to 
completing the scheduled Week 52 visit. According to the study protocol, subjects who 
discontinue early from the study are to be asked to schedule their ET visit to occur approximately 
4 weeks after their last dose of study drug; however, study experience to date indicates that only 
a small number of subjects are returning for a follow-up visit after their last dose, and the timing 
of this visit is variable. The ET visit mapping algorithm described below applies to only those 
subjects whose ET visit does not occur at a follow-up visit after the subjects have stopped dosing 
with study drug (ie, have not had study drug kits dispensed), with the exception of the Week 52 
visit (which occurs 4 weeks after a subject has completed the treatment period).    
For the purpose of data summarization, a visit window will be applied to account for ET visits.  
An ET visit will be mapped to Week 4 if it occurs within 7 days prior to and 6 days after the 
expected study day of the Week 4 visit. For scheduled study visits at Weeks 8 through 48, an ET 
visit will be mapped to the next scheduled study visit if it occurs within 14 days prior to and 13 
days after the expected study day of the visit. Early termination visit data which are not mapped 
to a scheduled visit will be displayed in applicable by-subject data listings but not included in by-
visit summaries.  
Table 3 displays the allowable study day range for each scheduled visit for ET visit mapping 
purposes. 
Table 3: 
Allowable Study Day Range for Early Termination Visit Mapping 
Scheduled Visit 
Target Study Day 
Time Interval 
(Study Day Range) 
Week 4 
28 
21-34 
Week 8 
56 
42-69 
Week 12 
84 
70-97 
Week 16 
112 
98-125 
Week 20 
140 
126-153 


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Scheduled Visit 
Target Study Day 
Time Interval 
(Study Day Range) 
Week 24 
168 
154-181 
Week 28 
196 
182-209 
Week 32 
224 
210-237 
Week 36 
252 
238-265 
Week 40 
280 
266-293 
Week 44 
308 
294-321 
Week 48 
336 
322-349 
Week 52 
364 
350+ 
 
5.6. 
Handling of Missing Data 
Missing values for outcome measures will not be replaced with imputed values except as noted 
above for the ET visit data mapped to scheduled visits for data summary purposes.  
Derived scale total scores (eg, the YMRS score), which are calculated as the sum of the scores of 
the individual scale items, will be set equal to missing if any of the individual scale item scores 
are missing.    
Special rules for handling missing and incomplete dates are described below. 
5.6.1. 
Missing and incomplete dates 
Missing and incomplete (“partial”) dates for AEs and concomitant medications will be imputed 
only for the purpose of estimating the time of the event or medication usage in relationship to 
study treatment periods (eg, NBI-98854 treatment period vs. follow-up period); however, all data 
listings will display the original dates as reported on the eCRF.     
The imputation rules for AE start dates are as follows: 
 If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug following dispensing of study drug on Day -1; 
 If only the day component is missing from the date, the date will be imputed as the date 
of the first dose of study drug if the date is in the same month and year as the first dose of 
study drug; otherwise, the missing day component will be imputed as the first day of the 
month; 
 If both the day and month components are missing from the date, the date will be 
imputed as the date of the first dose of study drug if the date is in the same year as the 
first dose; otherwise, the missing components will be imputed as 01 January; 
 If any of the above imputations result in a start date that is later than an existing complete 
(not imputed) end date for the event, the start date will be set equal to the end date. 
The imputation rules for concomitant medication start dates are as follows: 
 If the date is completely missing, the date will be imputed as 01 January in the year of the 
subject’s screening vital signs assessment; 


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 If only the day component is missing from the date, the date will be imputed as the date 
of  the first dose of study drug if the date is in the same month and year as the first dose 
of study drug; otherwise, the missing day component will be imputed as the first day of 
the month; 
 If both the day and month components are missing from the date, the date will be 
imputed as the date of the first dose of study drug if the date is in the same year as the 
first dose; otherwise, the missing components will be imputed as 01 January; 
 If any of the above imputations result in a start date which is later than an existing 
complete (not imputed) medication stop date, the start date will be set equal to the stop 
date. 
5.7. 
Coding Dictionary 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 12.0).  Prior and concomitant medications will be coded using the World 
Health Organization (WHO) Drug Dictionary. 
5.8. 
Analysis Sets 
The safety analysis set will be the single analysis set defined for this study.  The safety analysis 
set will include all subjects who are enrolled into the study and dispensed study drug, with the 
following two exclusions: (a) subjects who withdraw from the study and return all previously 
dispensed study drug with all doses present, and (b) subjects who have no postbaseline data 
collected.   
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) the safety analysis set will be provided for each treatment group.  The number and 
percentage of subjects excluded from the safety analysis set by reason for exclusion will also be 
provided. 
Summaries of subject enrollment and disposition, enrollment by study site, and analysis set 
inclusion/exclusion status will include all enrolled subjects.  All other summaries will be based 
on the safety analysis set. 
Individual subject listings of all available data will be provided for all enrolled subjects.   
5.9. 
Subject Enrollment and Disposition 
The summary of subject enrollment and disposition will display, by treatment group and overall 
(ie, “all subjects”),  the number and percentage of subjects who enrolled in the study, completed 
the study through at least Week 4, completed the study through at least Week 8, completed the 
study through at least Week 48 (end of the treatment period), and completed the study through 
Week 52 (the final study visit).  The table will also summarize, for each of the study timepoints 
listed in the previous sentence, the number and percentage of subjects who did not complete the 
study according to the reason for study discontinuation.    
Programming considerations related to the determination of subject completion status for each 
interim timepoint specified in the above paragraph (eg, Week 8) are as follows:  subjects who 
have a visit date in the study database for their scheduled Week XX visit (XX refers to any one 


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of the specified timepoints) or who have an ET visit which is mapped to the Week XX visit 
according to the algorithm described in Section 5.55 will be considered to have completed the 
study through this timepoint for the purpose of this summary. 
A separate summary of enrollment by study site will be presented.  This summary will display 
the number of subjects enrolled at each site, by treatment group and for all subjects, and will be 
presented by disease category (schizophrenia/schizoaffective disorder or mood disorder) as well 
as with both disease categories combined. 
5.10. 
Important Protocol Deviations 
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being.  An assessment of IPDs will be performed by a committee 
composed of NBI Clinical Development project team members.  Important protocol deviations 
may include, but are not limited to the following:   
 Failure to obtain informed consent from the subject prior to performing any study 
procedures 
 Deviations from key inclusion/exclusion criteria 
 Use of prohibited concomitant medications 
 Error in drug dispensing which results in a subject not receiving intended treatment 
 Significant deviation from protocol-specified dosing regimen 
The number and percentage of subjects with IPDs will be summarized by deviation category, 
treatment group, and for all subjects. 
5.11. 
Demographics 
Demographic data (age, gender, race, and ethnicity) will be summarized with descriptive 
statistics by treatment group and overall.   
5.12. 
Baseline Subject Characteristics 
The following baseline subject characteristics will be summarized with descriptive statistics by 
treatment group and overall: 
 Weight (at screening; in units of pounds and kilograms) 
 Height 
 Body mass index 
 CYP2D6 metabolizer genotype 
 Disease category (schizophrenia/schizoaffective disorder or mood disorder) 
 Age at diagnosis of schizophrenia/schizoaffective disorder 
 Age at diagnosis of mood disorder 
 Age at diagnosis of tardive dyskinesia 
 BPRS total score 
 AIMS dyskinesia total score at Day -1 (from central AIMS video raters) 


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5.13. 
Medical History 
Medical history will be summarized in frequency tables (number and percentage of subjects) by 
MedDRA System Organ Class (SOC) and Preferred Term (PT) for each treatment group and 
overall. 
5.14. 
Study Drug Dosing 
5.14.1. 
Number of Doses Taken 
The estimated number of doses of study drug taken by each subject between consecutive 
scheduled visits will be summarized with descriptive statistics for each treatment group and 
overall by visit.  The estimated total number of doses taken by each subject through Week 48 
will be summarized also. 
The estimated number of doses taken by each subject between visits will be calculated based on 
the difference between the number of capsules dispensed at the first visit and the number of 
capsules returned at the subsequent visit (note that the number of 80 mg doses is equal to the 
number of capsules of study drug divided by two and the number of 40 mg doses is equal to the 
number of capsules of study drug).  If an early termination visit occurs between scheduled visits, 
the early termination visit data will be used in the calculation. If a subject fails to return the study 
drug kit dispensed at the previous visit, it will be assumed that the number of doses taken by the 
subject is equal to the number of days between visits (inclusive of the day of the second visit).  If 
a subject is lost to follow-up between visits, they will be excluded from the summary statistics 
for all visits occurring after the last visit at which they were present. 
The estimated number of doses taken by a subject across all study visits is calculated as the sum 
of the number of doses taken between each pair of consecutive visits throughout the subject’s 
participation in the study (through Week 48 or the subject’s early termination visit if applicable). 
5.14.2. 
Dosing Compliance 
Estimated study drug dosing compliance is calculated as the ratio of the estimated number of 
doses taken (calculated as described above in Section 5.14.1) to the expected number of doses 
that should have been taken, and is expressed as a percentage.  A subject is classified as being 
dose compliant if their calculated value is 80% or greater.  The number and percentage of 
subjects who were dose compliant will be summarized by treatment group and overall by visit as 
well as across all visits through Week 48. 
The expected number of doses that should have been taken by a subject between or across visits 
is defined as the expected number of days the subject should have dosed with study drug during 
the interval of interest, based on the duration of the subject’s study participation during the 
interval (which may be shorter, for example, if the subject withdraws from the study).   
For dosing compliance between successive scheduled study visits, the expected number of days 
of dosing is calculated as the difference between the visit date of the second of the two visits and 
the study drug kit dispense date at the first of the two visits.  Note that the expected number of 
days of dosing cannot exceed the number of doses dispensed.  If an early termination visit occurs 
between scheduled visits, the early termination visit date will be used in the calculation.  If a 
subject fails to return the study drug kit(s) dispensed at the previous visit, the expected number 


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of days of dosing will be set equal to the number of days between visits (inclusive of the day of 
the second visit).  If a subject is lost to follow-up between scheduled visits, they will be excluded 
from the compliance calculations for all visits occurring after the last visit at which they were 
present. 
The dosing compliance calculation for the overall treatment period will follow the logic 
described above, with the expected number of days of dosing being equal to the difference 
between the Week 48 (or early termination) visit date and the Study Day -1 drug kit dispense 
date. The estimated number of doses taken by a subject across all visits is calculated as the sum 
of the number of doses taken between each pair of consecutive visits during the treatment period.  
If a subject is lost to follow-up prior to Week 48, their dosing compliance will be based on the 
last study visit at which they were present. 
5.15. 
Dose Titration at Week 4 
The number and percentage of subjects whose dose is (a) increased from 40 mg to 80 mg at 
Week 4 vs. (b) maintained at 40 mg, will be summarized.   
5.16. 
Dose Reductions after Week 4 
The dose reduction summary will present the number of subjects with a dose reduction (from 80 
mg to 40 mg) at each visit from Week 8 through Week 44.  Dose reductions at unscheduled visits 
will be included in the summary for the next scheduled visit (eg, dose reductions between Week 
8 and Week 12 will be counted in the Week 12 results).  If any subjects have a dose reduction 
after Week 44, a line for Week 48 will be added to the table with a clarifying footnote.    
In addition, the table will include the total number of subjects with a dose reduction at any time 
during the study.   
5.17. 
Pharmacokinetic Data 
The plasma concentrations of NBI-98854 and its active metabolite NBI-98782 will be 
summarized with descriptive statistics by visit (Weeks 4, 8, 12, 24, 36, 48, and 52) and the most 
recent NBI-98854 dose received by a subject prior to that visit.  Note that the Week 52 dose level 
will reflect the last dose received prior to the Week 48 visit.  These summaries will also be 
generated separately for CYP2D6 poor metabolizers vs. non-poor metabolizers.  Concentrations 
below the lower limit of quantification (BLQ) will be set equal to zero for all plasma 
concentration summaries. The lower limits of quantification are as follows:  (a) NBI-98854: 1.00 
ng/mL and (b) NBI-98782: 0.100 ng/mL. 
The following additional descriptive statistics will be included in the plasma concentration 
summary tables:  (a) the number of plasma concentration values greater than or equal to the 
lower limit of quantification, (b) the geometric mean, and (c) the geometric coefficient of 
variation (%). 
The descriptive statistics presented for the plasma concentration data will be rounded to three 
significant figures in all summary tables. 
Plasma concentrations of each PK analyte will be summarized graphically with box plots by 
NBI-98854 dose level at each visit. 


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5.18. 
Efficacy Data 
5.18.1. 
Efficacy Variables 
The primary efficacy variable for this study is the AIMS dyskinesia total score based on the 
central AIMS video rater assessments.  Secondary efficacy variables include the CGI-TD, PGIC, 
TDIS, and AMBMTD.  The AIMS dyskinesia total score based on the AIMS scoring performed 
at the study sites by the investigators (or designees) is considered as an exploratory variable.   
Descriptive statistics will be presented for each efficacy variable, with the exception of the 
AMBMTD, which will be presented only in a data listing.  For the AIMS data, both central 
AIMS video rater and investigator assessments will be summarized. 
5.18.2. 
AIMS 
5.18.2.1. Individual AIMS Items Descriptive Statistics 
Scores for the individual AIMS items 1 through 7 (as scored by both the central AIMS video 
raters and investigators) will be summarized with descriptive statistics by treatment group and 
visit.   Scores for AIMS items 8 through 10 (which are scored only by the investigators) will be 
summarized also.   
5.18.2.2. Individual AIMS Dyskinesia Total Score Descriptive Statistics 
The AIMS dyskinesia total score is defined as the sum of the scores of AIMS items 1 through 7. 
If any of the seven items has a missing value, the total score for that subject/visit will be set 
equal to missing. 
Descriptive statistics will be presented by treatment group for the AIMS dyskinesia total score 
observed values (ie, the raw data) at each visit (for the investigator data: screening, Day -1, and 
Weeks 4, 8, 12, 24, 36, 48, and 52; for the central AIMS video rater data: Day -1, Week 8, and 
Week 52) and for the changes from baseline (Day -1) at each postbaseline visit.  Two-sided 95% 
confidence intervals (CIs) will be included in the descriptive statistics for changes from baseline. 
Descriptive statistics (including CIs for changes from baseline) will be presented by disease 
category (schizophrenia/schizoaffective disorder or mood disorder) for the central AIMS video 
rater data only. 
5.18.2.3. AIMS Dyskinesia Total Score Graphs 
Mean (±SEM) values of the central AIMS video rater AIMS dyskinesia total score at each visit 
at which the AIMS is scored (from Day -1, Week 8, and Week 52) will be summarized in line 
graphs by treatment group.  A similar graph will be presented for the mean changes from 
baseline (Day -1).   
5.18.2.4. AIMS Responder Analysis 
An AIMS responder is defined, on a per-visit basis, as a subject whose AIMS dyskinesia total 
score is reduced by at least 50% from baseline (Day -1) at the specified postbaseline visit. The 
percentage of subjects classified as AIMS responders based on the central AIMS video rater data 
will be summarized for each treatment group at Weeks 8 and 52.   


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A bar graph displaying the percentage of subjects classified as AIMS responders at Weeks 8 and 
52 will be presented by treatment group. 
5.18.3. 
CGI-TD 
5.18.3.1. CGI-TD Scores 
Each of the seven CGI-TD response categories will be assigned a numerical score as follows: 
 Very much improved = 1 
 Much improved = 2 
 Minimally improved = 3 
 No change = 4 
 Minimally worse = 5 
 Much worse = 6 
 Very much worse = 7 
5.18.3.2. CGI-TD Descriptive Statistics 
Descriptive statistics (including both categorical variable statistics [using response categories] 
and continuous variable statistics [using numerical scores]) will be presented by treatment group 
for the CGI-TD data at Weeks 4, 8, 12, 24, 36, 48, and 52. 
Descriptive statistics for CGI-TD scores and response categories will be presented also by 
disease category (schizophrenia/schizoaffective disorder or mood disorder). 
5.18.3.3. CGI-TD Score Graphs 
Mean (±SEM) values of the CGI-TD score at Weeks 4, 8, 12, 24, 36, 48, and 52 will be 
summarized in line graphs by treatment group.   
5.18.3.4. CGI-TD Responder Analysis 
Two definitions of a CGI-TD responder will be used for this study.  For the first definition 
(“CGI-TD Responder 1”), a subject is classified as a responder if their CGI-TD score is either a 
“1” (“very much improved”) or a “2” (“much improved”).  For the second definition (“CGI-TD 
Responder 2”), a subject is classified as a responder if their CGI-TD score is either a “1”, a “2”, 
or a “3” (“minimally improved”).  Similar to the AIMS responder outcome measure described 
above, a CGI-TD responder is defined on a per-visit basis, based on the data reported at that 
visit.   
The number and percentage of subjects classified as CGI-TD responders will be summarized for 
each treatment group at Weeks 4, 8, 12, 24, 36, 48, and 52.  Each responder definition will be 
summarized separately.  
Descriptive statistics for the CGI-TD responder analysis will also be presented by disease 
category (schizophrenia/schizoaffective disorder or mood disorder). 
Bar graphs displaying the percentage of subjects classified as CGI-TD responders (using both 
definitions) will be presented by treatment group at Weeks 4, 8, 12, 24, 36, 48, and 52. 


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5.18.4. 
PGIC 
5.18.4.1. PGIC Scores 
Each of the seven PGIC response categories will be assigned a numerical score as follows: 
 Very much improved = 1 
 Much improved = 2 
 Minimally improved = 3 
 No change = 4 
 Minimally worse = 5 
 Much worse = 6 
 Very much worse = 7 
5.18.4.2. PGIC Descriptive Statistics 
Descriptive statistics (including both categorical variable statistics [using response categories] 
and continuous variable statistics [using numerical scores]) will be presented by treatment group 
for the PGIC data at Weeks 4, 8, 12, 24, 36, 48, and 52. 
Descriptive statistics for the PGIC scores and response categories will also be presented by 
disease category (schizophrenia/schizoaffective disorder or mood disorder). 
5.18.4.3. PGIC Score Graphs 
Mean (±SEM) values of the PGIC scores at Weeks 4, 8, 12, 24, 36, 48, and 52 will be 
summarized in line graphs by treatment group.   
5.18.4.4. PGIC Responder Analysis 
Two definitions of a PGIC responder will be used for this study.  For the first definition (“PGIC 
Responder 1”), a subject is classified as a responder if their PGIC score is either a “1” (“very 
much improved”) or a “2” (“much improved”).  For the second definition (“PGIC Responder 2”), 
a subject is classified as a responder if their PGIC score is either a “1”, a “2”, or a “3” 
(“minimally improved”).  Similar to the AIMS responder outcome measure described above, a 
PGIC responder is defined on a per-visit basis, based on the data reported at that visit.   
The number and percentage of subjects classified as PGIC responders will be summarized for 
each treatment group at Weeks 4, 8, 12, 24, 36, 48, and 52.  Each responder definition will be 
summarized separately.  
Descriptive statistics for the PGIC responder analysis will also be presented by disease category 
(schizophrenia/schizoaffective disorder or mood disorder). 
Bar graphs displaying the percentage of subjects classified as PGIC responders (using both 
definitions) will be presented by treatment group at Weeks 4, 8, 12, 24, 36, 48, and 52. 
5.18.5. 
TDIS Total Score 
The TDIS total score is defined as the sum of the scores of TDIS items 1 through 11.  If any of 
the 11 items have a missing value, the total score for that subject/visit will be set equal to 
missing. 


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5.18.5.1. TDIS Total Score Descriptive Statistics 
Descriptive statistics will be presented by treatment group for the TDIS total score observed 
values (ie, the raw data) at screening, Day -1, and Weeks 4, 8, 12, 24, 36, 48, and 52, and for the 
changes from baseline (Day -1) at each postbaseline visit.  Two-sided 95% confidence intervals 
(CIs) will be included in the descriptive statistics for changes from baseline. 
Descriptive statistics will also be presented by disease category (schizophrenia/schizoaffective 
disorder or mood disorder). 
5.18.5.2. TDIS Total Score Graphs 
Mean (±SEM) values of the TDIS total score at Day -1 and Weeks 4, 8, 12, 24, 36, 48, and 52 
will be summarized in line graphs by treatment group.  A similar graph will be presented for the 
mean changes from baseline (Day -1).   
5.18.6. 
Assessment of Most Bothersome Movement 
The assessment of AMBMTD will be presented in a data listing. 
5.19. 
Safety Data 
5.19.1. 
Adverse Events 
5.19.1.1. Treatment-Emergent Adverse Event Frequency Tables 
TEAEs, categorized by MedDRA (Version 12.0) SOC and PT, will be summarized with 
frequency tables.  Unless stated otherwise, the frequency tables will include the number of events 
reported, and the number and percentage of unique subjects experiencing each event one or more 
times during the study interval summarized in the table.  A description of each table is provided 
below.  Note that AEs with an onset date during screening (“pretreatment AEs”) will be 
presented only in a data listing. 
NBI-98854 Treatment Period through Week 4 Visit 
TEAEs with an onset date during the first four weeks of the NBI-98854 treatment period (after 
Day -1 through Week 4) will be summarized separately from TEAEs that occur after the Week 4 
visit, as all subjects receive the same dose of 40 mg during the first 4 weeks of treatment. These 
tables will therefore not be “by treatment” and will summarize data for all subjects as a single 
group. 
Tables will be presented which include all TEAES, only TEAEs considered to be possibly or 
definitely related to study drug, and TEAEs categorized according to the maximum intensity 
reported for a given subject. 
These TEAEs will also be presented by PT only (ie, not by SOC), with PTs sorted according to 
decreasing frequency of subjects reporting each event. 
NBI-98854 Treatment Period after Week 4 Visit 
TEAEs with an onset date during the NBI-98854 treatment period after Week 4 through Week 
48 will be summarized by treatment group.  This table will include a separate column for all 
subjects. 


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Similar tables will be presented including only TEAEs considered to be possibly or definitely 
related to study drug and categorizing TEAEs according to the maximum intensity reported for a 
given subject. 
These TEAEs will also be presented by PT only (ie, not by SOC), with PTs sorted according to 
decreasing frequency of subjects reporting each event based on the “all subjects” column.   
Posttreatment Period 
TEAEs with an onset date during the posttreatment period (after Week 48 through Week 52) will 
be summarized using the approach described above for the NBI-98854 treatment period after the 
Week 4 visit. 
NBI-98854 Treatment after Week 4 Visit Period and Posttreatment Period Combined 
TEAEs with an onset date at any time during the study after the Week 4 visit will be summarized 
using the approach described above for the NBI-98854 treatment period after the Week 4 visit. 
5.19.1.2. Adverse Event Overall Summaries 
Overall summary tables will be provided which summarize the number and percentage of 
subjects with any TEAE, any treatment-related TEAE (ie, possibly or definitely related per 
electronic case report form [eCRF]), any severe TEAE, any TEAE leading to study 
discontinuation, any serious TEAE, and any TEAE resulting in death.  An overall summary table 
will be presented for each of the study intervals described above in Section 5.19.1.1.    
These tables will summarize data by treatment group (with the exception of the summary for the 
first 4 weeks of treatment) and will also include an “all subjects” column. 
5.19.1.3. Adverse Event Time to Onset and Duration 
Descriptive statistics for TEAE time to onset and duration will be presented by treatment group 
(and for “all subjects”) for selected TEAEs associated with study drug pharmacology and for 
other common TEAEs.  TEAEs reported during the NBI-98854 treatment period at the Week 4 
visit or earlier will be summarized separately from TEAEs reported after the Week 4 visit, 
similar to the TEAE frequency tables described in Section 5.19.1.1.  Examples of PTs that may 
be included are as follows (note that additional PTs may be included and that PTs may be 
combined for summary purposes upon review of the study data): 
 Fatigue 
 Somnolence 
 Insomnia 
 Anxiety 
 Sedation 
Time to onset will be calculated for the first subject report of a given TEAE PT and summarized 
with standard descriptive statistics in units of days.  Duration (in units of days) will be calculated 
as the TEAE end date minus the TEAE start date +1 for each subject TEAE.  If a subject reports 
the same TEAE more than once, the duration will be calculated as the average of all of the 
durations for that TEAE PT.   If a TEAE is ongoing at the time a subject either completes the 
study or has an early termination visit, the TEAE end date will be set equal to the subject’s final 


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study visit date.  If a TEAE is missing an end date due to the interim nature of the data at the 
time of the first data lock and analysis (Section 5.3.1), the duration for that TEAE will be 
considered to be a missing value and will not be included in any statistical summaries.  Duration 
will be summarized with standard descriptive statistics. 
5.19.1.4. Adverse Events Resulting in a Study Drug Dose Reduction 
A summary of TEAEs resulting in a study drug dose reduction (from 80 mg to 40 mg) will be 
presented.  This summary table will display the PTs for the TEAEs resulting in a dose reduction, 
with the PTs sorted in order of decreasing frequency (based on number of subjects).  The first 
line of the table will display the total number of subjects with a dose reduction. 
A listing of TEAEs resulting in a study drug dose reduction will be included in the study report.  
This listing will include subject, study day of the dose reduction, and both the PT and reported 
term for all TEAEs that resulted in the dose reduction (note that the specific PTs resulting in a 
dose reduction are determined from the AE eCRF “action taken with study drug” field). 
5.19.1.5. Adverse Events Resulting in Premature Study Discontinuation 
Three summary tables of TEAEs resulting in premature study discontinuation will be presented.  
Tables will be presented for the following study periods: 
 NBI-98854 treatment period after Day -1 through Week 4 
 NBI-98854 treatment period after Week 4 through Week 48 
 Posttreatment period (after Week 48 through Week 52) 
These summary tables will include both the SOC and PT, with data summarized by treatment 
group (for study intervals after Week 4) and overall (all subjects).  Note that the onset date of the 
TEAE(s) resulting in study discontinuation will be the basis for determining the study period 
assignment. 
A listing of TEAEs resulting in premature study discontinuation at any time prior to the final 
scheduled visit at Week 52 will be presented in the study report following the tables described 
above.  The listing will include subject, treatment group, study period when the TEAE which 
resulted in study discontinuation occurred ( NBI-98854 treatment period after Day -1 through 
Week 4, NBI-98854 treatment period after Week 4 through Week 48, or posttreatment period), 
study day of the discontinuation, and both the PT and reported (verbatim) term for all TEAEs 
that resulted in the premature study discontinuation (note that this is determined from the AE 
eCRF “action taken” field). 
5.19.1.6. Deaths and Other Serious Adverse Events  
The frequency of SAEs will be summarized in tables using the approach described above in 
Section 5.19.1.5.  The table formats (which include both the SOC and PT) for the SAE tables 
will match those used for the TEAE discontinuation tables.   Deaths will be presented in a listing 
only.   
Listings of SAEs and deaths will be presented in the study report following the tables described 
in the previous paragraph.  These listings will include subject, treatment group, study period 
when the death or SAE occurred, study day of the death or SAE, and all other AE-specific 
information reported on the AE eCRF. 


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5.19.1.7. Adverse Event Graphs  
Horizontal bar graphs (known as “swimmer’s” plots) will be presented for the TEAE PTs listed 
above in Section 5.19.1.3 (fatigue, somnolence, insomnia, anxiety, and sedation).  A separate 
graph will be generated for each of these PTs.  The graph for each PT will display horizontal 
bars for each subject who reported that PT at least once during their participation in the study.  
The start and end dates of each individual TEAE report (where available) will be indicated on 
each bar, and a special symbol will be plotted at the end of the bar if the subject discontinued the 
study early due to the TEAE.  The length of the bar will represent the total duration of the 
subject’s participation in the study (the x-axis will be displayed in units of weeks).   Treatment 
will be color-coded for each bar. 
5.19.2. 
C-SSRS 
The C-SSRS data will be presented in the following summaries: 
 Screening/lifetime assessment by treatment group and for all subjects  
 Screening/past 3 months assessment by treatment group and for all subjects  
 Baseline (Day -1) assessment by treatment group and for all subjects  
 NBI-98854 treatment period assessments (Day 1 through Week 48) by treatment group 
and for all subjects 
 Posttreatment period assessments (after Week 48) by treatment group and for all subjects 
 All postbaseline assessments (Day 1 through Week 52) by treatment group and for all 
subjects   
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category).  These C-SSRS items and categories are as follows: 
 Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
 Suicidal Ideation Category:  Any of items (1) through (5) 
 Suicidal Behavior Items 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(10) 
Completed suicide 


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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 each subject, the C-SSRS responses for all assessments (including both scheduled and 
unscheduled visits) during a given study interval (eg, the NBI-98854 treatment period) will be 
evaluated, and a “Yes” response for any assessment will be considered as a “Yes” for the subject 
for that study interval.     
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline (Day -1) scores will be presented for the NBI-98854 treatment and 
posttreatment periods combined (ie, including all assessments after baseline).  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 and for all subjects, with the rows representing the baseline score 
and the columns representing the maximum score recorded during the study period of interest (at 
all visits, including unscheduled visits). Subjects missing either a baseline score or all 
postbaseline scores will not be summarized.  
A summary listing of individual subject data will be presented for the C-SSRS data and will be 
provided in the study report following the tables described above.  This summary will list 
subjects with a positive response for suicidal ideation, suicidal behavior, or self-injurious 
behavior without suicidal intent at any time during after Day -1.   The listing will be in the form 
of a table, with each row representing a subject visit (including treatment group and study day 
for that visit), and a column for each suicidal ideation item (1 – 5), each suicidal behavior item (6 
– 10), and a final column for self-injurious behavior without suicidal intent.  The cells of the 
table will be populated with “Y” or “N,” representing either a positive or negative response, 
respectively, for each item in the table (ie, for each column of the table). 
5.19.3. 
Barnes Akathisia Rating Scale 
The BARS total score is calculated as the sum of Items 1 through 3 of the BARS.  The BARS 
total score for a subject at a specific visit will be set equal to missing if any of these items have a 
missing value.  Both the BARS total score and the BARS global score (Item 4) will be 
summarized with descriptive statistics for observed values and changes from baseline (Day -1) 
by treatment group and for all subjects at Day -1 and Weeks 4, 12, 24, 36, 48, and 52.  
The BARS total score and global score mean values (±SEM) at each of the visits listed in the 
previous paragraph will be summarized by treatment group in line graphs. 


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5.19.4. 
Simpson-Angus Scale 
The SAS global score is calculated as the mean of the scores of the 10 individual items 
comprising the scale (note that the mean value can be calculated even if one or more of the 
individual items is missing).  The SAS global score observed values and changes from baseline 
(Day -1, or screening if the Day -1 value is missing) will be summarized with descriptive 
statistics by treatment group and for all subjects at screening, Day -1, and Weeks 4, 12, 24, 36, 
48, and 52.   
The SAS global score mean values (±SEM) at each visit listed in the previous paragraph (with 
the exception of screening) will be summarized by treatment group in line graphs. 
5.19.5. 
Positive and Negative Symptoms Scale (Subjects with Schizophrenia or 
Schizoaffective Disorder) 
The total score will be calculated for each of the three sections of the PANSS (positive 
symptoms, negative symptoms, and general psychopathology) as the sum of the individual item 
scores.  In addition, the composite scale will be calculated as the difference between the positive 
symptoms total score and the negative symptoms total score.  A total score will be set equal to 
missing if any of the individual items used in calculating the score has a missing value.   
Each of the total score variables and the composite scale (both observed values and changes from 
baseline [Day -1]) will be summarized with descriptive statistics by treatment group and for all 
subjects at Day -1 and Weeks 4, 12, 24, 36, 48, and 52. 
Mean values (±SEM) for each of the PANSS section total scores and the composite scale at each 
visit listed in the previous paragraph will be summarized by treatment group in line graphs.    
5.19.6. 
Calgary Depression Scale for Schizophrenia (Subjects with Schizophrenia or 
Schizoaffective Disorder) 
The CDSS total score is calculated as the sum of the 9 items that comprise the CDSS scale.  If 
any individual item has a missing value for a subject visit, the total score will be set equal to 
missing for that subject visit. 
The CDSS total score observed values and changes from baseline (Day -1, or screening if the 
Day -1 value is missing) will be summarized with descriptive statistics by treatment group and 
for all subjects at screening, Day -1, and Weeks 4, 12, 24, 36, 48, and 52. 
The CDSS total score mean values (±SEM) at each visit listed in the previous paragraph will be 
summarized by treatment group in line graphs. 
5.19.7. 
Young Mania Rating Scale (Subjects with Mood Disorders) 
The YMRS total score is calculated as the sum of the scores of the 11 individual items 
comprising the scale.  The YMRS total score at a subject visit will be set equal to missing if any 
of the 11 individual items have a missing value at that subject visit.  
The YMRS total score observed values and changes from baseline (Day -1, or screening if the 
Day -1 value is missing) will be summarized with descriptive statistics by treatment group and 
for all subjects at screening, Day -1, and Weeks 4, 12, 24, 36, 48, and 52.  


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The YMRS total score mean values (±SEM) at each visit listed in the previous paragraph will be 
summarized by treatment group in line graphs. 
5.19.8. 
Montgomery-Asberg Depression Rating Scale (Subjects with Mood Disorders) 
The MADRS total score is calculated as the sum of the scores of the 10 individual items 
comprising the scale.  The MADRS total score for a subject visit will be set equal to missing if 
any of the 10 individual items have a missing value at that subject visit.   
The MADRS total score observed values and changes from baseline (Day -1, or screening if the 
Day -1 value is missing) will be summarized with descriptive statistics by treatment group and 
for all subjects at screening, Day -1, and Weeks 4, 12, 24, 36, 48, and 52.   
The MADRS total score mean values (±SEM) at each visit listed in the previous paragraph will 
be summarized by treatment group in line graphs. 
5.19.9. 
Physical Examination and Weight 
Clinically significant physical examination findings will be presented by subject and visit in a 
listing.  The listing will include subject, treatment group, visit at which the finding was reported, 
study day of the visit, and the clinically significant finding.  
Body weight, which is measured during the physical examination, will be summarized in units of 
kilograms with descriptive statistics (both observed values and changes from baseline [Day -1, or 
screening if the Day -1 value is missing]), by treatment group and for all subjects at screening, 
Day -1, and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.   
5.19.10. 
Vital Signs 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics by treatment group and 
for all subjects at screening, Day -1, and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
52.  Both observed values and changes from baseline (Day -1, or screening if the Day -1 value is 
missing) will be summarized.    
Sponsor-defined potentially clinically significant (PCS) values for systolic blood pressure, 
diastolic blood pressure, and heart rate will be summarized by treatment group and for all 
subjects in frequency tables for each of the following treatment periods: 
 NBI-98854 treatment period (after Day -1 through Week 48) 
 Posttreatment period (after Week 48 through Week 52) 
The number and percentage of subjects with one or more PCS values during a given treatment 
period will be presented in the summary tables.  Note that data collected at both scheduled and 
unscheduled study visits will be included in this assessment.  The criteria for identifying PCS 
values are provided in Table 4. 


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Table 4: 
Potentially Clinically Significant Criteria for Selected Vital Signs 
Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Systolic Blood 
Pressure 
<90 mmHg 
 
≥20 mmHg 
>180 mmHg 
 
≥20 mmHg 
Diastolic Blood 
Pressure 
<50 mmHg 
 
≥10 mmHg 
>105 mmHg 
 
≥15 mmHg 
Heart Rate 
<50 bpm 
 
≥15 bpm 
>120 bpm 
 
≥15 bpm 
Note that both supine and standing values of blood pressures and heart rate will be included in 
the identification and summary of PCS values. 
A listing of all subjects with a PCS value during either of the two specified treatment periods 
will be presented following the summary tables in the study report.  This listing will include vital 
signs data at all study visits for each subject with one or more PCS values.  The listing will 
include subject, treatment group, visit, study day of visit, systolic blood pressure (supine and 
standing), diastolic blood pressure (supine and standing), and heart rate (supine and standing).  
Values that meet the PCS criteria will be flagged with an asterisk in the listing. 
5.19.11. 
Electrocardiogram 
The triplicate values of the quantitative ECG variables (heart rate, PR interval, QRS duration, 
QT interval, and Fridericia’s correction of QT interval [QTcF]) measured at each visit will be 
averaged for the purpose of analysis.  For the overall assessment categorical 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. 
The ECG variables will be summarized with descriptive statistics (frequency tables for the 
overall assessment categorical variable) by treatment group  and for all subjects at screening, 
Day -1, and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.  Both observed values and 
changes from baseline (Day -1, or screening if the Day -1 value is missing) will be summarized 
(for the overall categorical assessment, only observed values will be summarized). 
Categorical summaries will be presented for the QT and QTcF interval data for the NBI-98854 
treatment period and for the posttreatment period.  For each of these treatment periods, a 
subject’s highest reported value (including assessments at both scheduled and unscheduled study 
visits) will be used to determine in which category(s) the subject will be counted.   
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 (and for all subjects) whose highest reported QT/QTcF value in a given 
treatment period meets the following thresholds will be summarized: 
 Greater than 450 msec 
 Greater than 480 msec 


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 Greater than 500 msec 
The second categorical summary will display the number and percentage of subjects in each 
treatment group (and for all subjects) whose largest QT/QTcF increase from their baseline value 
in a given treatment period meets the following thresholds:  
 Greater than 30 msec 
 Greater than 60 msec 
5.19.12. 
Clinical Laboratory Data 
The hematology, clinical chemistry, and prolactin data will be summarized with descriptive 
statistics by treatment group and for all subjects.  The hematology and clinical chemistry data 
will be summarized at screening, Day -1, and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
and 52.  Both observed values and changes from baseline (Day -1, or screening if the Day -1 
value is missing) will be summarized.  The prolactin data will be summarized at Day -1 and 
Weeks 4, 12, 24, 36, 48, and 52 (both observed values and changes from Day -1).   
The prolactin data will be summarized for each gender separately, in addition to the summaries 
described above. 
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.   
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 one of two 
postbaseline visits:  Week 8 or Week 48.  Subjects with missing data for a clinical laboratory 
variable at either baseline or at the specified postbaseline visit will not be included in tables for 
that variable.  The shift tables will be presented for each treatment group and for all subjects. 
Shift tables will be displayed for the following clinical laboratory variables: AST, alanine 
aminotransferase (ALT), gamma-glutamyl transferase (GGT), total bilirubin, creatine kinase, 
creatinine, BUN, prolactin, hemoglobin A1c, white blood cell count, absolute neutrophil count, 
hemoglobin, and platelet count. 
Summaries of sponsor-defined PCS values will be presented for the following clinical laboratory 
variables:  ALT, AST, creatinine kinase, GGT, total bilirubin, white blood cell count, neutrophil 
count, creatinine, and BUN.  Similar to the PCS summaries for the vital signs data, these data 
will be summarized by treatment group and for all subjects in frequency tables for each of the 
two following treatment periods: 
 NBI-98854 treatment period (after Day -1 through Week 48) 
 Posttreatment period (after Week 48 through Week 52) 
The number and percentage of subjects with one or more PCS values during a given treatment 
period will be presented in the summary tables.  Note that data collected at both scheduled and 
unscheduled study visits will be included in this assessment.  The criteria for identifying PCS 
values are provided in Table 5. 


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Table 5: 
Potential Clinically Significant Criteria for Selected Clinical Laboratory 
Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 
AST 
>3 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
Absolute Neutrophil count 
<1.5 x 1000/µL 
Creatinine 
>1.5 x Day -1 value or > 1.5 x ULN 
BUN 
>30 mg/dL (> 10.71 mmol/L) 
 
A listing of all subjects with any PCS value in any of the two specified treatment periods will be 
presented following the summary tables in the study report. This listing will include the values of 
the clinical laboratory variables in Table 5 at all study visits for each subject with one or more 
PCS values. The listing will include subject, treatment group, visit, study day of visit, and all 
laboratory results for the analytes with a PCS value.  Values that meet the PCS criteria will be 
flagged with an asterisk in the listing. 
Scatter plots of selected variables will be created which display Week 8 values vs. baseline 
values.  Each plot will include a 45 degree (“y=x”) reference line.  The plots will be generated by 
treatment group and for all subjects for ALT, AST, creatine kinase, GGT, total bilirubin, and 
prolactin.   
Similar scatter plots of Week 48 values vs. baseline values will be presented by treatment group 
and for all subjects.  
The clinical laboratory data listings will include associated normal/reference ranges (if 
provided).  In addition, values outside the normal range will be flagged as “L” if below the lower 
limit of normal and as “H” if above the upper limit of normal.  There will also be a flag for 
clinical significance based on the investigator’s assessment of out-of-range values.  The 
urinalysis data will be presented in data listings only. 
Repeat clinical laboratory samples may be collected at any time during this study due to either 
missing or abnormal results.  The general rule of thumb for summarizing these data is to include 
the original sample results in summary tables and graphs.  One exception to this rule is when 
there are missing results from the original samples at screening – in this situation, the results of a 
repeat screening sample will be substituted for the missing results in summary tables and graphs.  
All sample results (original and repeat) will be included in data listings. 


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5.19.13. 
Prior and Concomitant Medications 
Prior medications (taken within 30 days of screening or within the previous two years for 
indications of schizophrenia/schizoaffective disorder, mood disorder, extrapyramidal symptoms 
or side effects [EPSE], and TD) and concomitant medications will be summarized by WHO 
Drug Anatomical Therapeutic Chemical Classification (ATC) Level 3 category (or Level 2 if 
there is not an applicable Level 3 category) and preferred name.   
Medications will be assigned to one or more study periods based on the medication start and stop 
dates relative to the study drug dosing.  For example, medications that were started and stopped 
prior to the date of the first dose of study drug will be assigned to the prestudy/screening period 
only, while medications started prior to the first dose of study drug and either stopped during the 
NBI-98854 treatment period or indicated as “ongoing” will be assigned to both the 
prestudy/screening and NBI-98854 treatment periods.  A given medication can therefore be 
assigned to one or more study periods in the tabular summaries, depending on its start and end 
dates. 
The number and percentage of subjects using medications in each WHO Drug ATC category 
(Level 3/preferred name) will be summarized by treatment group and for all subjects for each 
study period as described in the next paragraph.  A subject may take the same medication more 
than once or multiple medications for a subject may be classified under the same ATC level or 
preferred name.  A subject is counted only once for each level of medication classification within 
a summary. 
The summary of medications taken prestudy or during screening will be presented by treatment 
group and for all subjects.  Medications taken during the NBI-98854 treatment or posttreatment 
periods will also be summarized by treatment group and for all subjects. 
5.20. 
Additional Data Presentations 
5.20.1. 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria confirmation results will be presented in a data listing by subject. 
5.20.2. 
Serology Test Results 
Serology assessments (ie, Human immunodeficiency virus antibody [HIV-Ab], Hepatitis B 
surface antigen [HBsAg], and Hepatitis C antibody [HCV-Ab]) collected at screening will be 
reviewed at the study site to ensure the entry criteria are met.  The HBsAg and HCV-Ab test 
results will be presented in a listing by subject.  The results of the HIV-Ab test will not be listed, 
but will be kept on file at the study site. 
5.20.3. 
Pregnancy Test Results 
Serum and urine pregnancy test results will be presented in a listing by subject. 
5.20.4. 
Urine Drug Screen and Alcohol Breath Test 
Urine drug screen and alcohol breath test results will be presented in a listing by subject. 


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5.20.5. 
Plasma Sampling Timepoints for Exploratory Biomarker Assessments 
The plasma sampling timepoints for exploratory biomarker assessments will be presented in a 
listing by subject. 
6. 
DEVIATIONS FROM PROTOCOL PLANNED ANALYSIS 
The SAP includes a number of additional summaries not described in the study protocol.  In 
addition the definition of the safety analysis set is further refined in the SAP, and the treatment 
groups described in the SAP replace the “dose level” treatment categories mentioned in the study 
protocol. 
7. 
PERFORMANCE QUALIFICATION OF 
 
The analysis and summary of data from this study will be performed using 
 
).  All 
 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 
® log files.  In addition, tables, figures, listings, and statistical analysis output 
will be independently reviewed for completeness and accuracy. 


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8. 
REFERENCES 
None.