A Randomized, Placebo-controlled Trial to Evaluate the Long-term (ie, Maintenance) Efficacy of Oral Aripiprazole in the Treatment of Pediatric Subjects With Tourette's Disorder
Phase: PHASE4
Conditions: Tourette's Disorder (TD)
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

 
Official Title: 
A Randomized, Placebo-controlled Trial to Evaluate the Long-term (ie, 
Maintenance) Efficacy of Oral Aripiprazole in the Treatment of Pediatric 
Subjects with Tourette’s Disorder 
 
NCT Number: 
NCT03661983 
 
Document Date: 
 
Protocol Version 5.0: 04 March 2019 
 
 
 
 
 
 
 
 

Protocol 31-14-204
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Version 5.0, 04 Mar 2019
Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Investigational Medicinal Product
Aripiprazole (OPC-14597)
REVISED CLINICAL PROTOCOL
A Randomized, Placebo-controlled Trial to Evaluate the Long-term (ie, Maintenance) 
Efficacy of Oral Aripiprazole in the Treatment of Pediatric Subjects with Tourette’s 
Disorder
Protocol No. 31-14-204 
IND No. 116003/EudraCT No. 2018-002270-48
CONFIDENTIAL - PROPRIETARY INFORMATION
Clinical Development Phase: 
3b/4
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850
United States
Immediately Reportable Event 
PRA Safety Fax Line
North/South America: 
 or 
 
EAPA (Europe, Asia-Pacific and Africa): 
PRA Drug Safety Center Email Address
North/South America:
EAPA (Europe, Asia-Pacific and Africa):
Issue Date:
08 Jan 2016
Amendment 1:
30 Apr 2018
Amendment 2:
20 Jun 2018
Administrative Change 1:
14 Sep 2018
Administrative Change 2:
04 Mar 2019
Version No.:
5.0
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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: Abilify, 
Aripiprazole (OPC-14597)
Protocol No.: 31-14-204
IND No.: 116003
EudraCT No.:
2018-002270-48
Protocol Title:
A Randomized, Placebo-controlled Trial to Evaluate the 
Longer-term (ie, Maintenance) Efficacy of Oral Aripiprazole 
in the Treatment of Pediatric Subjects with Tourette’s Disorder
Clinical Phase/Trial 
Type:
Phase 3b/4, Therapeutic use 
Treatment Indication: Tics associated with Tourette’s disorder (TD) in children and 
adolescents 
Objective(s):
Primary: The primary objective of the trial is to evaluate the 
long-term efficacy of aripiprazole once-daily treatment with 
oral tablets in pediatric subjects with TD. 
Secondary: The secondary objective of the trial is to evaluate 
the safety and tolerability of aripiprazole once-daily treatment 
with oral tablets in pediatric subjects with a diagnosis of TD.
Trial Design:
This Phase 3b/4 trial is a randomized, double-blind, placebo-
controlled trial. The trial consists of 3 distinct phases:  a 
pretreatment phase, open-label stabilization phase, and a 
double-blind randomized withdrawal phase. The trial will be 
conducted on an outpatient basis. Screening assessments may 
occur during 1 or more visits (as needed), and must occur in 
the clinic. The baseline visit will occur in the clinic, as well as 
the open-label stabilization phase visits on Weeks 1, 2, 4, 8, 
12, 14,16, 18, and 20 and the double-blind, randomized 
withdrawal phase visits at Weeks 1, 2, 4, 8, and 12. All other 
visits will occur via telephone with direct patient visualization 
(except for open-label Week 3 which does not require direct 
patient visualization), web, in-clinic, or other acceptable means 
of contact.
The pretreatment phase consists of the screening period and a 
washout period (when applicable). This period ensures the 
subject meets the inclusion/exclusion criteria, that the 
appropriate washout periods of their current treatments are 
completed, and establishes a baseline for the efficacy and 
safety measures.
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The open-label stabilization phase will start with the baseline 
visit (Day 1). Doses will be titrated (based on 2 weight groups 
[< 50 kg or ≥ 50 kg]) during this phase to establish an optimal, 
stabilized aripiprazole dose for each subject. Dose adjustments 
are not permitted after the Week 8 visit. Starting at Week 2, 
subjects meeting the stabilization criteria (≥ 35% improvement 
[decrease] of Yale Global Tic Severity Scale [YGTSS] Total 
Tic Score [TTS]) who demonstrate a continued response as 
described (≥35% improvement [decrease] of YGTSS TTS) for 
12 consecutive weeks, inclusive, with no more than one 
excursion of response criteria will enter the double-blind 
randomized withdrawal phase. Stabilization can be achieved 
by Week 14 at the earliest. Excursions will not be permitted at
the end of the 12th consecutive week of stabilization (ie, the 
randomization visit).
Subjects entering the double-blind randomized withdrawal 
phase will be randomized 1:1:1 to the half-dose aripiprazole 
arm, full-dose aripiprazole arm, or placebo arm. 
Randomization will be stratified by region and weight group. 
Doses in the aripiprazole arms will be based on each subject’s 
stabilized dose from the open-label stabilization phase. 
Subjects will be monitored for relapse during the double-blind 
randomized withdrawal phase. Relapse is defined as a loss of 
≥50% of the improvement experienced during the open-label 
stabilization phase (ie, improvement at the last assessment of 
YGTSS before randomization) on the YGTSS TTS.
There will also be a safety follow-up period (30 + 3 days) after 
the last dose of investigational medicinal product (IMP) or 
after the clinical site is notified that the subject prematurely 
discontinued their IMP.
Subject Population:
The trial population will include pediatric subjects, 6 to 
17 years of age, meeting the current Diagnostic and Statistical 
Manual of Mental Disorders, fifth edition (DSM-5) diagnostic 
criteria for TD. It is anticipated that approximately 
228 subjects will be enrolled in the open-label stabilization 
phase in order to randomize approximately 114 subjects into 
the double-blind randomized withdrawal phase.
Inclusion/Exclusion 
Criteria:
Key Inclusion Criteria:
1) The subject is a male or female child or adolescent, 6 to 
17 years of age (inclusive) at the time of signing the 
informed consent/assent.
2) The subject meets current DSM-5 diagnostic criteria 
for TD, documented at screening and made by an 
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adequately trained clinician, as confirmed by the 
Kiddie Schedule for Affective Disorders and 
Schizophrenia - Present and Lifetime Version.
3) The subject has a TTS ≥ 20 on the YGTSS at screening 
and baseline (Day 1).
4) The subject, a caregiver, and the investigator must all 
agree that the presenting tic symptoms cause 
impairment in the subject’s normal routines, which 
include academic achievement, occupational 
functioning, social activities, and/or relationships.
5) Females of childbearing potential (all female subjects 
≥12 years of age and all female subjects < 12 years of 
age if menstruation has started) must have a negative 
pregnancy test and must not be pregnant or lactating.
6) Written informed consent must be obtained from the 
subject or a legally acceptable representative (eg, 
guardian or caregiver), in accordance with 
requirements of the trial site's institutional review 
board (IRB)/independent ethics committee (IEC) and 
local regulatory requirements, prior to the initiation of 
any protocol-required procedures.  In addition, the
subject, as required by the trial center's IRB/IEC, must 
provide informed assent at screening and as such must 
be able to understand that he or she can withdraw from 
the trial at any time.
7) Ability, in the opinion of the principal investigator, of 
the subject and the subject’s legally acceptable 
representative (eg, guardian) or caregiver(s) to 
understand the nature of the trial and follow protocol 
requirements, including the prescribed dosage 
regimens, tablet ingestion, and discontinuation of 
prohibited concomitant medications, to read and 
understand the written word in order to complete 
subject-reported outcomes measures, and to be reliably 
rated on assessment scales.
Key Exclusion Criteria:
1) The subject presents with a clinical presentation 
and/or history that is consistent with another 
neurologic condition that may have accompanying 
abnormal movements.
These include, but are not limited to, the following:
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
Transient tic disorder

Huntington's disease

Parkinson's disease

Sydenham's chorea

Wilson's disease

Mental retardation

Pervasive developmental disorder

Tardive dyskinesia

Traumatic brain injury

Stroke

Restless legs syndrome
2) The subject has a history of schizophrenia, bipolar 
disorder, or other psychotic disorder.
3) Subjects who receive psychostimulants for the 
treatment of attention-deficit hyperactivity disorder 
(ADHD) and who have developed and/or had 
exacerbations of the tic disorder after the initiation of 
stimulant treatment. (Note that subjects with ADHD 
who are treated with psychostimulants and have not 
developed new tics or a worsening of their current tics 
can be included if all other enrollment obligations are 
met).
4) The subject currently has a primary diagnosis that 
meets DSM-5 criteria for mood disorder.
5) The subject has severe obsessive-compulsive disease, 
as evidenced by a Children’s Yale-Brown Obsessive 
Compulsive Scale (CY-BOCS) score > 16.
6) The subject has taken aripiprazole within 1 month 
(30 days) of the screening visit.
7) The subject has a history of neuroleptic malignant 
syndrome.
8) Subject is a sexually active male or female of 
childbearing potential (FOCBP) (all female subjects 
≥12 years of age and all female subjects < 12 years of 
age if menstruation has started) who will not agree to 
practice 2 acceptable methods of birth control or who 
will not remain abstinent during the trial and for 30 or 
90 days following the last dose of IMP for females and 
males, respectively. Abstinence will be permitted if it is 
confirmed and documented at every trial visit.  
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9) The subject represents a significant risk of committing 
suicide based on history (suicide attempt in past 
1 year), routine psychiatric status examination, 
investigator’s judgment, or who has an answer of “yes” 
on any question other than 1-3 (current or over the last 
30 days) on the baseline/screening version of the 
Columbia-Suicide Severity Rating Scale (C-SSRS).
10) The subject has a body weight < 16 kg.
11) Subjects who have taken neuroleptic or antiparkinson 
drugs within 14 days prior to baseline.
12) Subjects requiring cognitive-behavioral therapy (CBT)
for TD during the trial period. CBT for other 
nonexclusionary disorders must remain consistent 
throughout the trial.
13) The subject has met DSM-5 criteria for any significant 
psychoactive substance use disorder within the past 
3 months.
14) A positive drug screen for cocaine, alcohol, or other 
drugs of abuse (excluding caffeine, nicotine, or 
prescribed psychostimulants for ADHD). Investigators 
can choose to repeat a positive drug screen one time 
during screening period after concurrence from the 
medical monitor.  A second positive test for any drug 
of abuse would be exclusionary.
15) Subject requiring medication not allowed per protocol.
16) Use of any cytochrome P450 (CYP)2D6 and CYP3A4 
inhibitors or CYP3A4 inducers within 14 days prior to 
baseline and for the duration of the trial.
17) Other nutritional or dietary supplements and 
nonprescription herbal preparations for TD (eg, 
cannabinoids, N-aceytlcysteine, omega-3 fatty acids, 
kava extracts, GABA supplements) within 7 days prior 
to baseline and for the duration of the trial, unless 
approved in advance by the medical monitor.
18) The inability to swallow tablets or tolerate oral 
medication.
19) Subject has participated in a clinical trial involving 
either study medication or interventional 
(non-medication) treatment for TD within the last 
60 days.
20) The following laboratory test results, vital signs and 
electrocardiogram (ECG) results are exclusionary:
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a) Platelets ≤75,000/mm3
b) Hemoglobin ≤9 g/dL
c) Neutrophils, absolute ≤1000/mm3
d) Aspartate aminotransferase > 3 × upper limit of
normal (ULN) as defined by the central laboratory
e) Alanine aminotransferase > 3 × ULN as defined by
the central laboratory
f)
Creatinine ≥2 mg/dL
g) Diastolic blood pressure > 105 mmHg
h) Corrected QT interval ≥450 msec (males) or
≥470 msec (females) using the corrected QT
interval for heart rate using Fridericia’s formula
Trial Site(s):
Approximately 70 sites worldwide will be used in this trial.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Once-daily oral aripiprazole will be administered every day, 
without regard to meals. 
Four dose strengths of an aripiprazole immediate release tablet 
formulation will be used in this trial: 2.0 mg, 5.0 mg, 10.0 mg, 
and 15.0 mg. Matching placebo tablets will be used in the 
double-blind randomized withdrawal phase. The 20.0 mg/day 
dose taken as two 10.0 mg tablets
During the open-label stabilization phase, all enrolled subjects 
will begin treatment at a 2.0 mg/day dose, with the dose 
titrated to 5.0 mg/day after 2 days. Subsequent dose 
adjustments in set increments will be based on the subject’s 
weight to achieve optimum control of tics up to the maximum 
recommended doses based on the United States (US) labeling.
Subjects will be allowed one down titration during the 
open-label stabilization phase. Dose adjustments, and a 
subsequent return to the highest dose, are not allowed after the 
Week 8 visit.
During the double-blind randomized withdrawal phase, 
subjects meeting the stabilization criteria will be randomized 
in a 1:1:1 ratio to the half-dose aripiprazole arm, full-dose 
aripiprazole arm, or placebo arm based on their stabilized dose 
in the open-label stabilization phase. All subjects will take 
2 tablets per day.
Trial Assessments:
Efficacy: YGTSS TTS, Clinical Global Impressions Scale for 
Tourette’s Syndrome (CGI-TS) Severity, CGI-TS 
Improvement.
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Safety: Adverse event (AE) reporting, clinical laboratory tests, 
12-lead ECG, vital signs, and physical examination.
In addition, the subject’s height, body weight, body mass index 
(BMI), waist circumference, serum prolactin (blinded),
glycosylated hemoglobin, and thyroid-stimulating hormone 
(TSH) will be monitored. The C-SSRS (children’s version) 
will be used to assess the risk of suicide events during the trial 
at every visit. Extrapyramidal symptoms (EPS) will be 
assessed using the following scales: Abnormal Involuntary 
Movement Scale (AIMS), Simpson-Angus Scale (SAS), and 
Barnes Akathisia Rating Scale (BARS).
Screening/Other: Screening evaluations include psychiatric, 
medical and medication history, CY-BOCS, urine drug and 
blood alcohol screen(s), and urine pregnancy tests.
Criteria for 
Evaluation:
Primary Endpoint: The primary efficacy endpoint is the time 
from randomization to relapse during the double-blind 
randomized withdrawal phase.
Exploratory Efficacy Endpoint: The other efficacy endpoints 
include the following:

Mean change from randomization to last visit (Week 12 for 
completers and withdrawal visit for discontinued subject) 
in YGTSS TTS score

Mean change from randomization to last visit (Week 12 for 
completers and withdrawal visit for discontinued subject) 
in Total YGTSS score

Mean change from randomization to last visit (Week 12 for 
completers and withdrawal visit for discontinued subject) 
in CGI-TS Severity score

CGI-TS Improvement score at last visit (Week 12 for 
completers and withdrawal visit for discontinued subject)
Safety Endpoints: Safety endpoints include the following:

AEs

Laboratory tests (hematology, serum chemistry [including 
prolactin (blinded), glycosylated hemoglobin, and TSH], 
urinalysis, and urine pregnancy tests)

Vital signs

ECGs
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
AIMS

BARS

SAS

C-SSRS

Body weight

BMI

Waist circumference
Statistical Methods:
The planned sample size for the randomization phase is 
114 subjects (ie, 38 subjects per treatment group). Assuming 
the proportion of randomized subjects experiencing relapse 
during the double-blind randomized withdrawal phase will be 
65% in the placebo group and 34% in each of the 2 
aripiprazole dose groups, 114 subjects will provide 
approximately 80% power to detect a hazard ratio of 0.4 for 
relapse (either aripiprazole dose group versus placebo) at the 
alpha level of 0.05 (2-sided). Under the above assumptions, a 
total of 51 relapse events are expected to be observed during 
the randomization phase. However, subject enrollment will 
stop when 51 relapse events have accrued or 114 subjects have 
been randomized, whichever occurs earlier.
Sample size will allow one interim analysis (IA) at 
approximately 70% of events accrual time point. The 
O’Brian-Fleming boundaries were used for sample size 
calculation of the IA so that the IA will be conducted after 36 
relapse events are observed. The two-sided alpha levels for the 
IA is 0.016, and the alpha left for the final analysis will be 
0.045.  
In order to randomize 114 subjects, approximately 
228 subjects need to enter the open-label stabilization phase 
assuming the stabilization rate is 50%.
The primary endpoint is time from randomization to relapse 
during the double-blind randomized withdrawal phase.
Subjects who complete or discontinue from the double-blind
randomized withdrawal phase without relapses will be 
considered as censored observations. The hazard ratio and its 
95% confidence interval (CI) will be estimated from the Cox 
proportional hazard model with treatment as a factor. The 
p- value from the log rank test will be presented to compare 
survival (subjects free of relapse) distributions, 
ie, Kaplan-Meier curves, between the treatment groups.
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Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 3 years and 
4 months including an estimated 30 month recruitment period.
Individual participation for subjects who complete the trial can 
range from a minimum of approximately 30 weeks to a 
maximum of 42 weeks.
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Table of Contents 
Protocol Synopsis...........................................................................................2
Table of Contents.........................................................................................11
List of In-text Tables ...................................................................................16
List of In-text Figures..................................................................................17
List of Appendices........................................................................................18
List of Abbreviations and Definitions of Terms .......................................19
1
Introduction ........................................................................................21
1.1
Nonclinical Data................................................................................................22
1.2
Clinical Data......................................................................................................22
1.2.1
Trial 31-12-293...............................................................................................22
1.2.2
Trial 31-12-294...............................................................................................23
1.3
Known and Potential Risks and Benefits ..........................................................24
2
Trial Rationale and Objectives..........................................................24
2.1
Trial Rationale...................................................................................................24
2.2
Dosing Rationale...............................................................................................25
2.3
Trial Objectives.................................................................................................25
2.3.1
Primary ...........................................................................................................25
2.3.2
Secondary .......................................................................................................25
3
Trial Design.........................................................................................25
3.1
Type/Design of Trial .........................................................................................25
3.2
Trial Treatments ................................................................................................30
3.2.1
Open-label Stabilization Phase.......................................................................30
3.2.2
Double-blind Randomized Withdrawal Phase................................................32
3.3
Trial Population.................................................................................................32
3.3.1
Number of Subjects and Description of Population .......................................32
3.3.2
Subject Selection and Numbering ..................................................................32
3.4
Eligibility Criteria..............................................................................................32
3.4.1
Informed Consent/Informed Assent ...............................................................32
3.4.2
Inclusion Criteria ............................................................................................34
3.4.3
Exclusion Criteria...........................................................................................35
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3.5
Endpoints...........................................................................................................37
3.5.1
Efficacy Endpoints..........................................................................................37
3.5.1.1
Primary Endpoint ........................................................................................37
3.5.1.2
Secondary Endpoint ....................................................................................37
3.5.1.3
Exploratory Efficacy Endpoint(s) ...............................................................37
3.5.2
Safety Endpoint(s) ..........................................................................................37
3.6
Measures to Minimize/Avoid Bias....................................................................38
3.6.1
Randomization................................................................................................38
3.6.2
Blinding ..........................................................................................................38
3.7
Trial Procedures ................................................................................................38
3.7.1
Schedule of Assessments................................................................................48
3.7.1.1
Pretreatment Phase: Screening and Washout Period ..................................48
3.7.1.2
Baseline Visit (Day 1).................................................................................50
3.7.1.3
Open-label Stabilization Phase Titration Visit (Week 1)............................51
3.7.1.4
Open-label Stabilization Phase Stabilization Visits....................................52
3.7.1.5
Open-label Stabilization Phase Contact (Week 3)......................................53
3.7.1.6
Open-label Stabilization Phase /Randomization/Early Termination ..........54
3.7.1.6.1
Randomization.........................................................................................55
3.7.1.6.2
Open-label Stabilization Phase/Early Termination .................................56
3.7.1.7
Double-blind Randomized Withdrawal Phase Visits..................................57
3.7.1.8
Double-blind Randomized Withdrawal Phase Week 12 or Early 
Termination.................................................................................................58
3.7.1.9
Post-treatment Follow-up Period ................................................................59
3.7.2
Efficacy Assessments .....................................................................................59
3.7.2.1
Yale Global Tic Severity Scale...................................................................59
3.7.2.2
Clinical Global Impression Scale for Tourette’s Syndrome .......................60
3.7.3
Safety Assessments.........................................................................................60
3.7.3.1
Adverse Events............................................................................................60
3.7.3.2
Clinical Laboratory Assessments................................................................60
3.7.3.3
Physical Examination and Vital Signs........................................................62
3.7.3.3.1
Physical Examination..............................................................................62
3.7.3.3.2
Vital Signs ...............................................................................................63
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3.7.3.3.3
Body Weight, Height, and Waist Circumference....................................63
3.7.3.4
Electrocardiogram Assessments..................................................................64
3.7.3.5
Other Safety Assessments...........................................................................64
3.7.3.5.1
Extrapyramidal Symptoms ......................................................................64
3.7.3.5.1.1
Simpson-Angus Scale..........................................................................64
3.7.3.5.1.2
Abnormal Involuntary Movement Scale..............................................65
3.7.3.5.1.3
Barnes Akathisia Rating Scale.............................................................65
3.7.3.5.2
Suicidality................................................................................................65
3.7.3.5.3
Children’s Yale-Brown Obsessive Compulsive Scale ............................66
3.7.4
Prior and Concomitant Medications...............................................................66
3.7.5
End of Trial.....................................................................................................66
3.7.6
Interim Analysis Review Committee..............................................................66
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................67
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................67
3.8.2
Individual Site.................................................................................................67
3.8.3
Individual Subject Discontinuation ................................................................67
3.8.3.1
Treatment Interruption ................................................................................67
3.8.3.2
Treatment Discontinuation..........................................................................67
3.8.3.3
Documenting Reasons for Treatment Interruption/Discontinuation...........68
3.8.3.4
Withdrawal of Consent ...............................................................................68
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................69
3.9
Screen Failures ..................................................................................................70
3.10
Definition of Completed Subjects.....................................................................70
3.11
Definition of Subjects Lost to Follow-up..........................................................70
3.12
Subject Compliance...........................................................................................71
3.13
Protocol Deviations...........................................................................................71
4
Restrictions..........................................................................................71
4.1
Prohibited Medications......................................................................................71
4.2
Other Restrictions..............................................................................................73
4.2.1
Restricted Therapies and Precautions.............................................................73
4.2.2
Nontherapy Precautions and Restrictions.......................................................73
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4.2.2.1
Precautions..................................................................................................73
4.2.2.2
Restrictions..................................................................................................73
5
Reporting of Adverse Events.............................................................73
5.1
Definitions.........................................................................................................73
5.2
Eliciting and Reporting Adverse Events ...........................................................75
5.3
Immediately Reportable Events ........................................................................76
5.4
Potential Serious Hepatotoxicity.......................................................................76
5.5
Pregnancy..........................................................................................................76
5.6
Procedure for Breaking the Blind......................................................................78
5.7
Follow-up of Adverse Events............................................................................78
5.7.1
Follow-up of Nonserious Adverse Events......................................................79
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................79
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................79
6
Pharmacokinetic Analysis..................................................................80
7
Statistical Analysis..............................................................................80
7.1
Sample Size.......................................................................................................80
7.2
Datasets for Analysis.........................................................................................80
7.3
Handling of Missing Data .................................................................................81
7.4
Primary and Secondary Endpoint Analyses ......................................................81
7.4.1
Primary Endpoint Analysis.............................................................................81
7.4.2
Secondary Endpoint Analysis.........................................................................82
7.4.3
Exploratory Efficacy Endpoint Analysis........................................................83
7.4.3.1
Open-label Stabilization Phase ...................................................................83
7.4.3.2
Double-blind Randomized Withdrawal Phase............................................83
7.4.4
Interim Analysis..............................................................................................84
7.5
Analysis of Demographic and Baseline Characteristics....................................84
7.6
Safety Analysis..................................................................................................85
7.6.1
Adverse Events ...............................................................................................85
7.6.1.1
Open-label Stabilization Phase ...................................................................85
7.6.1.2
Double-blind Randomized Withdrawal Phase............................................85
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7.6.2
Clinical Laboratory Data ................................................................................85
7.6.3
Physical Examination, Vital Signs, Body Weight, and Waist 
Circumference Data........................................................................................86
7.6.4
Electrocardiogram Data..................................................................................86
7.6.5
Other Safety Data ...........................................................................................86
7.6.5.1
Extrapyramidal Symptoms..........................................................................86
7.6.5.2
Suicidality ...................................................................................................87
8
Management of Investigational Medicinal Product........................87
8.1
Packaging and Labeling ....................................................................................87
8.2
Storage...............................................................................................................87
8.3
Accountability ...................................................................................................87
8.4
Returns and Destruction....................................................................................88
8.5
Reporting of Product Quality Complaints.........................................................88
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................88
8.5.2
Information Required for Reporting Purposes ...............................................89
8.5.3
Return Process ................................................................................................89
8.5.4
Assessment/Evaluation...................................................................................89
9
Records Management.........................................................................89
9.1
Source Documents.............................................................................................89
9.2
Data Collection..................................................................................................90
9.3
File Management at the Trial Site.....................................................................91
9.4
Records Retention at the Trial Site....................................................................91
10
Quality Control and Quality Assurance...........................................92
10.1
Monitoring.........................................................................................................92
10.2
Auditing.............................................................................................................92
11
Ethics and Responsibility...................................................................92
12
Confidentiality ....................................................................................93
13
Amendment Policy..............................................................................93
14
Publication Authorship Requirements.............................................94
15
References............................................................................................95
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List of In-text Tables
Table 3.2.1-1
US Labeling Information...............................................................30
Table 3.2.1-2
Open-label Stabilization Phase Dosing Schedule..........................31
Table 3.2.2-1
Double-blind Randomized Withdrawal Phase Doses....................32
Table 3.4.2-1
Inclusion Criteria ...........................................................................34
Table 3.4.3-1
Exclusion Criteria ..........................................................................35
Table 3.7-1
Schedule of Assessments - Screening and Open-label 
Stabilization Phase.........................................................................40
Table 3.7-2
Schedule of Assessments - Double-blind Randomized 
Withdrawal Phase ..........................................................................45
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................62
Table 7.4.1-1
Boundaries for Rejection of Null Hypothesis for Interim and 
Final Analysis ................................................................................82
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................29
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List of Appendices
Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
................................................................................97
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................98
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .........................................................................99
Appendix 4
Protocol Amendment(s)/Administrative Change(s) ....................100
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADHD
Attention-deficit hyperactivity disorder
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CBT
Cognitive-behavioral therapy
CGI-TS
Clinical Global Impressions Scale for Tourette’s Syndrome
CNS
Central nervous system
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CY-BOCS
Children’s Yale-Brown Obsessive Compulsive Scale
CYP
Cytochrome P450
D2
Dopamine D2
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
Electrocardiogram
ET
Early termination
EOP
End of phase
EU
European Union
FDA
(United States) Food and Drug Administration
FOCBP
Female of childbearing potential
GCP
Good Clinical Practice
5-HT
Serotonin type receptor
IA
Interim analysis
IAF
Informed assent form
IARC
Interim analysis review committee
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent ethics committee
IMP
Investigational medicinal product
IRB
Institutional review board
IRE
Immediately reportable event
IRT
Interactive response technology
K-SADS-PL
Kiddie Schedule for Affective Disorders and Schizophrenia - Present and 
Lifetime Version
LDH
Lactate dehydrogenase
MNAR
Missing not at random
OCD
Obsessive-compulsive disorder
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OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PK
Pharmacokinetics
PQC
Product quality complaint
QTcF
Corrected QT interval for heart rate using Fridericia’s formula
RBC
Red blood cell
SAE
Serious adverse event
SAS
Simpson-Angus Scale
SNRI
Selective norepinephrine reuptake inhibitor
SSRI
Selective serotonin reuptake inhibitor
T3
Triiodthyronine
T4
Thyroxine
TD
Tourette’s disorder
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
TTS
Total Tic Score
US 
United States 
ULN
Upper limit of normal
WBC
White blood cell
YGTSS
Yale Global Tic Severity Scale
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1
Introduction
Abilify(aripiprazole) is approved for the treatment of schizophrenia and acute manic or 
mixed episodes associated with bipolar I disorder in adults in the United States (US), the 
European Union (EU), Canada, and several other countries, and as adjunctive treatment 
in adult patients with major depressive disorder in the US, Canada, and Japan. Abilify is 
also approved in the US, EU, and Canada as an adjunctive therapy to either lithium or 
valproate for the acute treatment of manic and mixed episodes associated with bipolar I 
disorder in adult patients, and these approved claims have been extrapolated to children 
and adolescents in the US. In addition, Abilify is approved for the treatment of 
schizophrenia in adolescents in the US (ages 13 - 17 years), Canada (ages 15 - 17 years),
and EU (ages ≥15 years), for the treatment of bipolar I disorder in children and
adolescents in the US (ages 10 - 17 years), and Canada (ages 13  -17 years), for the 
treatment of severe manic episodes in bipolar I disorder in the EU (ages ≥13 years), and 
for the treatment of irritability associated with autistic disorder in the US in children and 
adolescents 6 to17 years of age. Aripiprazole is currently approved for treatment of 
Tourette’s disorder (TD) in children and adolescents (6 - 18 years) in the US, the 
Republic of Korea, Philippines, Thailand, Indonesia, Taiwan, and Egypt.
Tourette’s disorder is a neuropsychiatric condition that is characterized by the appearance 
of tics that can be simple or complex in nature. A tic is a sudden, rapid, recurrent, 
nonrhythmic, stereotyped motor movement or vocalization. Tics associated with TD
become most prominent in early childhood and worsen progressively, showing the 
greatest tic severity at 10 years of age.1 Depending on the number, severity, and type of 
tics a patient experiences, TD can have a significant adverse effect on social functioning 
and self-esteem during formative years that are important for social development.2,3
Although the precise etiology of TD remains unknown, disturbances in serotonergic 
and/or dopaminergic pathways have been implicated because of the close association 
between TD and other disorders that involve imbalances in serotonin and/or dopamine 
(eg, obsessive-compulsive disease and attention-deficit hyperactivity disorder 
[ADHD]).4,5 Aripiprazole, which exhibits partial agonism (agonism/antagonism) at 
dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2 
receptors, may therefore be of benefit for patients with TD. Previous TD trials 
demonstrated the efficacy of aripiprazole over an 8-week period. This trial is part of the 
post-marketing commitment to evaluate the longer-term efficacy of aripiprazole.
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1.1
Nonclinical Data
The mechanism of action of aripiprazole differs from that of most currently marketed 
typical and atypical neuroleptics. It has been proposed that aripiprazole’s effectiveness in 
schizophrenia is mediated through a combination of partial agonism 
(agonism/antagonism) at dopamine D2 and serotonin 5-HT1A receptors and antagonism at 
serotonin 5-HT2 receptors. Aripiprazole has the properties of an agonist in an animal 
model of dopaminergic hypoactivity and the properties of an antagonist in animal models 
of dopaminergic hyperactivity. Aripiprazole exhibits high affinity for dopamine D2 and 
D3 and serotonin 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4, 
serotonin 5-HT2C and 5-HT7, alpha1-adrenergic, and histamine H1 receptors, and the 
serotonin reuptake site. Aripiprazole also displays 5-HT1A partial agonist and 5-HT2A
antagonist activity in nonclinical studies.
Please refer to the Investigator’s Brochure (IB) for more detailed information.6
1.2
Clinical Data
Information about relevant clinical studies in the pediatric population is presented below. 
Please refer to the IB for more detailed information.6
1.2.1
Trial 31-12-293
The primary purpose of this phase 3, multicenter, randomized, double-blind, placebo-
controlled, outpatient trial was to compare the efficacy of aripiprazole with placebo in the 
treatment of tics in children and adolescents (ages 7 - 17 years) with a diagnosis of TD
over 8 weeks of treatment. The secondary purpose was to evaluate the safety and 
tolerability of aripiprazole once-daily treatment (5 - 20 mg/day) with oral tablets.
Efficacy was demonstrated by the statistically significant results achieved for the primary 
(Yale Global Tic Severity Scale [YGTSS] Total Tic Score [TTS]) and key secondary 
(Clinical Global Impressions Scale for Tourette’s Syndrome [CGI-TS] Change Score) 
endpoints, as well as other secondary endpoints of the total YGTSS score, Clinical 
Global Impressions Scale [CGI]-Severity Score, and response rate (for the high-dose 
aripiprazole group). The primary efficacy analysis demonstrated that both low and high 
doses of aripiprazole were superior to placebo in the treatment of tics based on the 
YGTSS TTS score (p = 0.0020 for low-dose and p < 0.0001 for high-dose aripiprazole 
after multiplicity adjustment). The key secondary efficacy analysis also showed that both 
low- and high-doses of aripiprazole were superior to placebo in CGI improvement 
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(p = 0.0002 for low-dose and p = 0.0002 for high-dose aripiprazole after multiplicity 
adjustment).
The results of this trial demonstrated that the efficacy of aripiprazole as a treatment of 
tics associated with TD was robust. The results also demonstrated that the onset of 
efficacy started as early as 1 week after the initiation of treatment. Further, the efficacy of 
aripiprazole was demonstrated across a variety of demographic subgroups (age, region, 
race, and baseline YGTSS TTS). Importantly, the results are consistent with and confirm 
the evidence of efficacy seen in other trials, most notably Trial 031-KOA-0703, a 
double-blind, placebo-controlled trial in children and adolescents conducted in Korea.7
The results are also consistent with the findings from a number of open-label and case 
studies in children and adolescents with TD reported in the published literature.7,8,9,10,11
In aggregate, more than 500 children between 6 and 18 years of age were treated with 
aripiprazole from 2 weeks to 24 months in these trials. The literature indicated a 
significant reduction in the frequency and severity of tics, as assessed by the YGTSS, 
following treatment with aripiprazole. Overall, the average reduction in the total tic score 
was 47.1%; this reduction is consistent with the findings in Trial 31-12-293. In addition, 
the aripiprazole safety data reported in these trials did not differ from the side-effect 
profile that has been previously reported.
1.2.2
Trial 31-12-294
The primary purpose of this phase 3, multicenter, open-label trial was to evaluate the 
long-term safety and tolerability of aripiprazole once-daily treatment with oral tablets in 
children and adolescents (7 - 17 years of age) with a diagnosis of TD. The secondary 
purpose was to evaluate the efficacy of once-daily aripiprazole in the suppression of tics 
in children and adolescents with a diagnosis of TD, as measured by change from baseline 
to Week 52 on the TTS of the YGTSS.
Subjects who successfully completed Trial 31-12-293 were eligible to enter this 
extension trial, provided that continuation of treatment was clinically warranted, as 
judged by the investigator, and there had been no significant protocol violations or 
clinically relevant AEs that would preclude their inclusion in the trial.
Aripiprazole was generally well tolerated in this trial. The safety and tolerability of 
aripiprazole, as demonstrated in this trial, was reflected in no subjects experiencing a 
fatal serious adverse event (SAE), 4 subjects experiencing nonfatal SAEs (none deemed 
related to investigational medicinal product [IMP]), and 10 subjects experiencing 
treatment-emergent adverse events (TEAEs) leading to IMP discontinuation (5 subjects 
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for the event of weight increased). In addition, 40.0% and 31.8% of subjects overall 
experienced mild and moderate TEAEs, respectively, with 4.5% of subjects experiencing 
severe TEAEs. Fifty-six subjects (50.9%) had TEAEs that the investigator considered 
potentially related to IMP, with the events of weight increased, somnolence, and fatigue 
accounting for 45 of these subjects.
The efficacy analyses demonstrated that once-daily aripiprazole, as shown in the parent 
Trial 31-12-293, is effective in the treatment of tics associated with TD in children and 
adolescents (aged 7 - 18 years). In addition, these analyses demonstrated that subjects not 
currently taking aripiprazole, versus subjects with prior exposure (ie, subjects who 
received aripiprazole in Trial 31-12-293), yielded greater improvement in TD symptoms 
as measured by YGTSS TTS, CGI-TS change and severity scores, and total YGTSS 
score.
In summary, the data from this 52-week extension trial of subjects who participated in the 
parent Trial 31-12-293 demonstrated a favorable safety and tolerability profile of 
aripiprazole once-daily treatment in children and adolescents and its efficacy in the 
suppression of tics in this population. 
1.3
Known and Potential Risks and Benefits
As of 01 Jun 2017, approximately 2300 children and adolescents with schizophrenia, 
bipolar disorder, autistic disorder, conduct disorder, or TD have been treated with 
once-daily or once-weekly oral aripiprazole in clinical trials.6
Commonly observed adverse reactions associated with the use of aripiprazole in pediatric 
patients with TD (incidence of 5% or greater and aripiprazole incidence at least twice that 
for placebo) are sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, and 
increased appetite.12
Additional safety and prescribing information can be found in the product label, which is 
attached to the IB.6
2
Trial Rationale and Objectives
2.1
Trial Rationale
The goal of this trial is to evaluate the longer-term efficacy of aripiprazole in pediatric 
subjects (6 - 17 years) for the treatment of TD. The trial has a pretreatment phase, up to a
20-week open-label stabilization phase, a 12-week double-blind randomized withdrawal 
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phase, and a 1 month follow-up period after the last dose of IMP or after the clinical site 
is notified that the subject discontinued the IMP. The proposed age range for the 
population in this trial is 6 to 17 years, inclusive. These age ranges are based on 
published data indicating that tics associated with TD show the greatest severity at 
10 years of age. Previous TD trials demonstrated the efficacy of aripiprazole over an 
8-week period. This trial is part of the US Food and Drug Administration (FDA) 
post-marketing commitment to evaluate the longer-term efficacy of aripiprazole.
2.2
Dosing Rationale
Based on the approved labeling aripiprazole in the US for TD, the 5 to 20 mg once-daily 
tablets are expected to result in safe, tolerable, and efficacious aripiprazole 
concentrations.12 The goal of this trial is obtain long-term efficacy, safety, and 
tolerability data in a controlled condition of a once-daily aripiprazole formulation in 
children and adolescents with TD. Additionally, this trial will evaluate if the long-term 
therapeutic benefit is maintained with a lower dose of aripiprazole.
2.3
Trial Objectives
2.3.1
Primary
The primary objective of the trial is to evaluate the long-term efficacy of aripiprazole 
once-daily treatment with oral tablets in pediatric subjects with TD. 
2.3.2
Secondary
The secondary objective of the trial is to evaluate the safety and tolerability of 
aripiprazole once-daily treatment with oral tablets in pediatric subjects with a diagnosis 
of TD.
3
Trial Design
3.1
Type/Design of Trial
This phase 3b/4 trial is a randomized, double-blind, placebo-controlled trial to evaluate 
the long-term efficacy of oral aripiprazole in the treatment of pediatric subjects with TD. 
Subjects will be recruited at approximately 70 sites globally. The trial consists of 
3 distinct phases: a pretreatment phase, an open-label stabilization phase, and a 
double-blind randomized withdrawal phase. Screening assessments may occur during 
1 or more visits (as needed), and must occur in the clinic. The baseline visit will occur in 
the clinic, as well the open-label stabilization phase visits on Weeks 1, 2, 4, 8, 12, 14, 16, 
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18, and 20 and the double-blind, randomized withdrawal phase visits at Weeks 1, 2, 4, 8, 
and 12. All other visits will occur via telephone with direct patient visualization (except 
for open-label Week 3 which does not require direct patient visualization), web, in-clinic, 
or other acceptable means of contact.
The pretreatment phase consists of the screening period and a washout period (when 
applicable). This period ensures the subject meets the inclusion/exclusion criteria, that the 
appropriate washout periods are completed, and establishes a baseline for efficacy and 
safety measures.
The open-label stabilization phase will start with the baseline visit (Day 1). Doses will be 
titrated (based on 2 weight groups [< 50 kg or ≥ 50 kg]) during this phase to establish an 
optimal, stabilized aripiprazole dose for each subject. Dose adjustments are not permitted 
after the Week 8 visit. Starting at Week 2, subjects meeting the stabilization criteria 
(≥35% improvement [decrease] of YGTSS TTS) who demonstrate a continued response 
as described (≥35% improvement [decrease] of YGTSS TTS) for 12 consecutive weeks, 
inclusive; with no more than one excursion of response criteria will enter the 
double-blind randomized withdrawal phase. Excursions are defined by loss of 
stabilization (< 35%) in YGTSS TTS. If a subject misses a visit, it will be considered an 
excursion, but if they miss a dose, it will not be considered an excursion. Stabilization 
can be achieved by Week 14 at the earliest. Excursions will not be permitted at the end of 
the 12th consecutive week of stabilization (ie, the randomization visit).
Subjects entering the double-blind randomized withdrawal phase will be randomized 
1:1:1 to the half-dose arm, full-dose arm, or placebo arm. Doses in the aripiprazole arms 
will be based on the subject’s stabilized dose during the single-blind stabilization phase. 
Subjects will be monitored for relapse during the double-blind randomized withdrawal 
phase. Relapse is defined as a loss of ≥50% of the improvement experienced during the 
open-label stabilization phase (ie, improvement at the last assessment of YGTSS before 
randomization) on the YGTSS TTS. If a subject meets relapse criteria, they should be 
discontinued and treated according to the schedule of assessments.
There will also be a safety follow-up period (30 + 3 days) after the last dose of IMP or 
after the clinical site is notified that the subject prematurely discontinued their IMP.
During the pretreatment phase, modifications to a subject’s pre-existing treatment are not 
to be made for the explicit purpose of entering this trial, but should be done only where 
deemed clinically appropriate by the investigator. Tapering rates for washout of 
medications are at the discretion of the investigator and are to be determined on an 
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individual basis, with consideration to the subject’s clinical condition, dose, and known 
pharmacokinetics (PK) of the medication being tapered, as long as the protocol-mandated 
discontinuation timeframe is met. The exception is a long-acting depot medication, which 
cannot be tapered and would be discontinued after the informed consent/assent is 
obtained.
All psychotropic medications and any medications used to treat tics must be discontinued 
for at least 2 weeks (14 days) prior to the baseline visit, with the exception of 
psychostimulant medications such as, but not limited to, Vyvanse, Adderall, Concerta, 
Metadate CR, Ritalin LA, Focalin, and Focalin XR, prescribed for the treatment of 
symptoms of ADHD, which are permitted during the trial. Use of psychostimulant 
medications is only permitted if the subject does not develop and/or have an exacerbation 
of the tic disorder after the initiation of treatment with the psychostimulant. In addition, 
the dose of any psychostimulant must have been stable for at least 4 weeks prior to 
screening. All selective serotonin reuptake inhibitors (SSRIs)/selective norepinephrine 
reuptake inhibitors (SNRIs) must be discontinued at least 4 weeks (28 days) prior to the 
baseline visit. In addition, once-weekly formulation of neuroleptics must be discontinued 
at least 4 weeks (28 days) prior to the baseline visit; long-acting (depot) neuroleptics 
must be discontinued for at least 1 full cycle (2 weeks to 1 month, depending on the drug)
plus 2 weeks prior to the baseline visit. Clonidine, guanfacine, guanabenz, atomoxetine 
and carbamazepine are prohibited during the trial and must be discontinued for at least 
2 weeks prior to baseline. Subjects must have discontinued aripiprazole treatment at least 
30 days prior to the screening visit. Subjects not in need of medication washout may 
proceed to the trial baseline visit after the inclusion/exclusion criteria have been met.
During the open-label stabilization phase, visits will occur at Week 1 (± 2 days) for the 
titration visit and at Weeks 2, 3, and 4 (± 2 days) and Weeks 6, 8, 10, 12, 14, 16, 18, and 
20 (± 3 days) for the stabilization visits, at which time efficacy and safety measures will 
be collected. Starting at Week 2, subjects meeting the stabilization criterion (≥ 35% 
improvement [decrease] of YGTSS TTS) who demonstrate a continued response as 
described (≥35% improvement [decrease] of YGTSS TTS) for 12 consecutive weeks, 
inclusive, with no more than one excursion of response criteria will enter the 
double-blind randomized withdrawal phase. Excursions will not be permitted at the end 
of the 12th consecutive week of stabilization (ie, the randomization visit). At Week 8, 
subjects will be discontinued if they no longer have the opportunity to achieve 12 weeks 
of response in the open-label stabilization phase (eg, the subject has not achieved a 
response).
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Upon entering the double-blind randomized withdrawal phase, subjects will be 
randomized to aripiprazole full dose, aripiprazole half dose, or placebo. Subjects will 
have trial visits at Weeks 1, 2, 3, and 4 (± 2 days) and Weeks 6, 8, 10, and 12 (± 3 days), 
at which time efficacy and safety measures will be collected. Subjects will be followed 
up for safety for 30 days after the last dose of IMP or after the clinical site is notified that 
the subject discontinued the IMP. The trial schematic is presented in Figure 3.1-1.
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Figure 3.1-1
Trial Design Schematic 
aWeek 3 Visit will consist of a phone call to assess safety and tolerability. If dose adjustments are required, the subject will have an in-clinic visit for IMP 
dispensing. 
.
Visits Weeks 1, 2, 3a, and 4 
(± 2 days); 6, 8, 10, 12, 14, 16, 
18, and 20 (± 3 days)
Open-label 
Stabilization Phase
Double-blind Randomized 
Withdrawal Phase
Follow-up Period
30 (+ 3) days after last 
dose
12 Weeks 
Weeks 1 to 14 (min)
Weeks 1 to 20 (max)
Pretreatment 
Phase
Days −42 to −3
Visits Weeks 1, 2, 3, 4
(± 2 days); 6, 8, 10, and 12
(± 3 days)
1 or more visits
as needed
Stabilize on oral 
aripiprazole
5 to 20 mg/day
Stabilization criteria:
35% reduction in 
YGTSS-TTS
Meets Entry Criteria
Washout completed
Starting at Week 2, subjects 
meeting the stabilization 
criteria for 12 consecutive 
weeks will be eligible for 
randomization
30 (+ 3) days after last dose
Follow-up will consist of 
telephone contact to assess 
any AEs experienced since 
the last trial visit and 
information on ongoing AEs 
and SAEs and recording of 
concomitant medications.
Full-dose
R
Screening and 
Washout of 
prohibited 
medications
= Randomized (1:1:1 ratio) 
R
Half-dose
Placebo
Fixed dose of 
aripiprazole
Follow-up Call
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3.2
Trial Treatments
Four dose strengths of an aripiprazole immediate release tablet formulation will be used 
in this trial: 2.0 mg, 5.0 mg, 10.0 mg, 15.0 mg. Matching placebo tablets will be used in 
the double-blind randomized withdrawal phase.
Once-daily oral aripiprazole will be administered at approximately the same time every 
day beginning at baseline. Doses may be taken without regard to meals. 
3.2.1
Open-label Stabilization Phase
All enrolled subjects will begin treatment at a 2.0 mg/day dose, with the dose titrated to 
5.0 mg/day after 2 days. Subsequent dose adjustments in set increments will be based on 
the subject’s weight at baseline to achieve optimum control of tics up to the maximum 
recommended doses based on the US labeling, presented in Table 3.2.1-1.
Table 3.2.1-1
US Labeling Information
Weight Group
Dosing Adjustments
Target Doses for 
Stabilization
Maximum Dose
< 50 kg
5 mg and 10 mg
5 mg and 10 mg
10 mg/day
≥50 kg
5 mg, 10 mg, and 20 mg
10 mg and 20 mg
20 mg/day
The dose titration schedule per weight group is provided in Table 3.2.1-2. Subjects with 
body weight < 50 kg must remain on a minimum stable dose of 5.0 mg or maximum 
10.0 mg for a minimum of 12 weeks. Subjects with body weight ≥ 50 kg must achieve a 
dose of 10.0 mg no later than Week 4 and remain on a stable dose of 10.0 mg or 20.0 mg 
for a minimum of 12 weeks. For the remainder of the 12 week period, subjects can 
remain of 10.0 mg or titrate to 20.0 mg as long as efficacy is stable. In order to be titrated 
from 10.0 mg to 20.0 mg, subject must remain on a dose of 15.0 mg for 1 week (ie, at 
least 4 days) prior to being titrated to 20.0 mg. If a subject is titrated to 20.0 mg and 
subsequently requires down-titration, their dose will be reduced to 10.0 mg. If the dose is 
up-titrated again, the dose must increase from 10.0 mg to 20.0 mg without a 15.0 mg 
step.
Subjects will be allowed one down titration (only to the minimum dose to achieve 
stabilization) and a return to the prior maximum dose during the open-label stabilization 
phase. Up-titration can only occur at scheduled visits, but down-titration may occur at 
either scheduled or unscheduled visits. Dose adjustments, and a subsequent return to the 
higher dose, are not allowed after the Week 8 visit. If a subject experiences an AE or 
tolerability issues after the Week 8 visit that require the dose to be down-titrated, 
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regardless of dose level, they must be discontinued. Subjects who meet the YGTSS TTS 
criteria for stability and remain on a stable dose of IMP for 12 weeks may be randomized 
into the double-blind phase of the trial prior to the Week 20/EOP visit.
Table 3.2.1-2
Open-label Stabilization Phase Dosing Schedule
Body 
Weight
Day 1 
(Baseline)
Week 1
Week 2
Week 4
Week 8a
Weeks 12 to 
20a
< 50 kg
2.0 mg 
starting 
dose, 
increased
to 5.0 mg 
after 2 days
5.0 mg or 
increase to 
10.0 mg
5.0 mg or 
increase to 
10.0 mg
5.0 mg or 
increase to 
10.0 mg
5.0 mg or 
increase to 
10.0 mg
5.0 mg or 
10.0 mg
≥ 50 kg
2.0 mg 
starting 
dose, 
increased 
to 5.0 mg 
after 2 days
5.0 mg or 
increase to 
10.0 mg
5.0 mg or 
increase to 
10.0 mg or 
20.0 mg (via 
15.0 mg
step)b
10.0 mg or 
increase to 
20.0 mgb
10.0 mg or 
20.0 mgb
10.0 mg or 
20.0 mg
aA one-time down-titration and a return to the previous dose is allowed at or before Week 8. No dose 
adjustments are permitted after the Week 8 visit.
bSubjects that will be titrated from 10.0 mg to 20.0 mg must remain on a dose of 15.0 mg for 1 week (ie, 
at least 4 days) prior to being titrated to 20.0 mg.
An emergency dose reduction blister card will be distributed between trial visits where 
there is a requested dose titration. The blister card will have sufficient tablets for 
7 ± 2 days. If the subject is advised to reduce the IMP due to tolerability issues, the 
subject will return for an in-clinic visit within 1 week after initiating the dose reduction 
blister card.   
Starting at Week 2, subjects meeting the stabilization criteria (≥ 35% improvement 
[decrease] of YGTSS TTS) who demonstrate a continued response as described (≥35% 
improvement [decrease] of YGTSS TTS) for 12 consecutive weeks, inclusive, with no 
more than one excursion of response criteria, will enter the double-blind randomized 
withdrawal phase. Excursions will not be permitted at the end of the 12th consecutive 
week of stabilization (ie, the randomization visit). Subjects who experience a second 
excursion of response criteria should continue in the open-label stabilization phase until 
they achieve response criteria again, and maintain their response for 12 consecutive 
weeks with no more than one excursion. Subjects should be discontinued if they no 
longer have the opportunity to achieve 12 weeks of response in the open-label 
stabilization phase (eg, the subject has not achieved response by the Week 8 visit).
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3.2.2
Double-blind Randomized Withdrawal Phase
Subjects meeting the stabilization criteria will be randomized in a 1:1:1 ratio to the 
half-dose arm, full-dose arm, or placebo arm based on their stabilized dose in the 
open-label stabilization phase. Weight-based dosing will be determined using the body 
weight measurement from the open-label stabilization phase baseline. See Table 3.2.2-1
for the dosing schedule.
All subjects will take 2 tablets once daily. The 20.0 mg/day dose taken as two 10-mg 
tablets. No dose adjustments will be allowed in the double-blind randomized withdrawal 
phase.
Table 3.2.2-1
Double-blind Randomized Withdrawal Phase Doses
Weight Group
Stabilized Dose
Double-blind Randomized Withdrawal Phase Doses
Full-dose Arm
Half-dose Arm
Placebo Arm
< 50kg
5 mg
5 mg
2 mg
Matching placebo
10 mg
10 mg
5 mg
Matching placebo
≥50 kg
10 mg
10 mg
5 mg
Matching placebo
20 mg
20 mg
10 mg
Matching placebo
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The trial population will include pediatric subjects, 6 to 17 years of age, meeting the 
current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
diagnostic criteria for TD. It is anticipated that approximately 228 subjects will be 
enrolled in the open-label stabilization phase from approximately 60 sites worldwide in 
order to randomize approximately 114 subjects into the double-blind randomized 
withdrawal phase.
3.3.2
Subject Selection and Numbering
All subjects will be given a unique 5 digit subject screening identification number
preceded by an S (SXXXXX).
3.4
Eligibility Criteria
3.4.1
Informed Consent/Informed Assent
Written informed consent will be freely obtained from all subjects (or their guardian or 
legally acceptable representative, as applicable for local laws). Consent and assent will be 
documented on a written informed consent form (ICF) and informed assent form (IAF). 
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The ICF/IAF will be approved by the same institutional review board/independent ethics 
committee (IRB/IEC) that approves this protocol. Subjects who are too young to sign an 
ICF either via wet signature or electronic signature (e-signature) will provide informed 
assent per local law, and the subject must be able to understand that he or she can 
withdraw from the trial at any time and for any reason.
Each ICF/IAF will comply with the International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline13 and local regulatory requirements. The 
investigator will ensure that the sponsor reviews and authorizes any written site-specific 
ICF/IAF used in the trial before submission to the IRB/IEC. Age-appropriate assent 
documents will be created and subjects who are able will be required to reconsent or 
assent as appropriate if they matriculate from one age group to another. Subjects who 
become legal adults during the trial will be required to provide written informed consent 
as soon as they reach legal age.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, ICF/IAF must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and/or his/her parent/legal guardian or legally 
acceptable representative, as applicable by the investigator (or a qualified designee), and 
it has been documented that the subject and his/her parent/legal guardian or legally 
acceptable representative has had the opportunity to ask questions, the IRB/IEC-approved 
written ICF/IAF will be signed and dated by the subject, the subject’s legally acceptable 
representative (eg, guardian) and the person obtaining consent (investigator or designee), 
as well as by any other parties required by the IRB/IEC. The subject will receive a copy 
of the signed ICF/IAF; the original shall be kept on file by the investigator.
At sites where the electronic ICF application is used, prospective trial participants will be 
provided with controlled access to the application by trial site staff. When the trial site 
staff and the participant agree that the participant has enough information to make an 
informed decision to participate, the participant will electronically sign the ICF or assent 
form in the electronic ICF application and an electronic date and timestamp will be 
applied to the signature. The subject will be given a printed, signed copy of the ICF and 
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assent form. Any other parties required by the IRB/IEC (trial site staff, witnesses, or 
legally authorized representative) are also required to sign electronically and these 
signatures will be stored with the electronic ICF in accordance with the ICH GCP 
Guideline and local regulatory requirements/guidelines. These signatures cannot be 
altered, removed, or copied. At sites where the electronic ICF application is not used, 
paper consent and assent forms will be signed after trial site staff and the participant 
agree that the participant has enough information to make an informed decision to 
participate. Any other parties required to provide signatures will also sign the paper 
forms, and the forms will be stored in accordance with the ICH GCP Guideline and local 
regulatory requirements/guidelines.
Subjects and his/her parent/legal guardian or legally acceptable representative may be 
asked to sign additional ICF/IAFs if the protocol is amended to significantly add or 
change procedures.
Subjects who are not started on treatment after the ICF/IAF is signed are permitted to be 
rescreened under the conditions specified in Section 3.9 (Screen Failures). In the event 
that the subject is rescreened for trial participation, a new ICF/IAF must be signed.
If a subject is legally emancipated, informed consent must be sought directly from the 
subject. Subjects who turn age 18 (or the age of adulthood as specified by local laws or 
regulations) during the trial must sign a new ICF at that time.
In addition to the English version of the ICF/IAF, the documents may also be translated 
into local languages for use in this trial. Translation with back-translation for 
confirmation will be utilized to ensure accuracy.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
The subject is a male or female child or adolescent, 6 to 17 years of age (inclusive) at the time of 
signing the informed consent/assent.
2.
The subject meets current DSM-5 diagnostic criteria for TD, documented at screening and made by 
an adequately trained clinician, as confirmed by the K-SADS-PL.
3.
The subject has a TTS 20 on the YGTSS at screening and baseline (Day 1).
4.
The subject, a caregiver, and the investigator must all agree that the presenting tic symptoms cause 
impairment in the subject’s normal routines, which include academic achievement, occupational 
functioning, social activities, and/or relationships.
5.
Females of childbearing potential (all female subjects ≥ 12 years of age and all female subjects 
< 12 years of age if menstruation has started) must have a negative pregnancy test and must not be 
pregnant or lactating.
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Table 3.4.2-1
Inclusion Criteria
6.
Written informed consent must be obtained from the subject or a legally acceptable representative 
(eg, guardian or caregiver), in accordance with the trial site’s IRB/IEC and local regulatory 
requirements, prior to the initiation of any protocol-required procedures. In addition, the subject, as 
required by the trial site’s IRB/IEC, must provide informed assent at screening and as such must be 
able to understand that he or she can withdraw from the trial at any time.
7.
Ability, in the opinion of the principal investigator, of the subject and the subject’s legally 
acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and 
follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and 
discontinuation of prohibited concomitant medications, to read and understand the written word in 
order to complete subject-reported outcomes measures, and to be reliably rated on assessment 
scales.
K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime 
Version.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
The subject presents with a clinical presentation and/or history that is consistent with another 
neurologic condition that may have accompanying abnormal movements.
These include, but are not limited to, the following:

Transient tic disorder

Huntington's disease

Parkinson's disease

Sydenham's chorea

Wilson's disease

Mental retardation

Pervasive developmental disorder

Tardive dyskinesia

Traumatic brain injury

Stroke

Restless legs syndrome
2.
The subject has a history of schizophrenia, bipolar disorder, or other psychotic disorder.
3.
The subject has received psychostimulants for the treatment of ADHD and has developed and/or 
had exacerbations of the tic disorder after the initiation of stimulant treatment. (Note that subjects 
with ADHD who are treated with psychostimulants and have not developed new tics or a 
worsening of their current tics can be included if all other enrollment obligations are met).
4.
The subject currently has a primary diagnosis that meets DSM-5 criteria for a mood disorder.
5.
The subject has severe OCD, as evidenced by a CY-BOCS score > 16.
6.
The subject has taken aripiprazole within 1 month (30 days) of the screening visit.
7.
The subject has a history of neuroleptic malignant syndrome.
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Table 3.4.3-1
Exclusion Criteria
8.
The subject is a sexually active male or FOCBP (all female subjects ≥12 years of age and all 
female subjects < 12 years of age if menstruation has started) who will not agree to practice 2
acceptable methods of birth control or who will not remain abstinent during the trial and for 30 or 
90 days following the last dose of IMP for females and males, respectively. Abstinence will be 
permitted if it is confirmed and documented at every trial visit. If employing birth control, 2 of the 
following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm with spermicide, 
intrauterine device, birth control pill, birth control depot injections, implant, condom with 
spermicide, or sponge with spermicide.
9.
The subject represents a significant risk of committing suicide based on history (suicide attempt in 
past 1 year), routine psychiatric status examination, investigator’s judgment, or who have an 
answer of “yes” on any question other than 1-3 (current or over the last 30 days) on the 
baseline/screening version of the C-SSRS.
10.
The subject has a body weight < 16 kg.
11.
Subjects who have taken neuroleptic or antiparkinson drugs within 14 days prior to baseline.
12.
Subjects requiring CBT for TD during the trial period. CBT for other nonexclusionary disorders 
must remain consistent throughout the trial.
13.
The subject has met DSM-5 criteria for any significant psychoactive substance use disorder within 
the past 3 months.
14.
A positive drug screen for cocaine, alcohol, or other drugs of abuse (excluding caffeine, nicotine, or 
prescribed psychostimulants for ADHD). Investigators can choose to repeat a positive drug screen 
one time during screening period after concurrence from the medical monitor. A second positive 
test for any drug of abuse would be exclusionary.
15.
Subject requiring medication not allowed per protocol.
16.
Use of any CYP2D6 and CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to baseline 
and for the duration of the trial.
17.
Other nutritional or dietary supplements and nonprescription herbal preparations for TD (eg, 
cannabinoids, N-aceytlcysteine , omega-3 fatty acids, kava extracts, GABA supplements) within 
7 days prior to baseline and for the duration of the trial, unless approved in advance by the medical 
monitor.
18.
The inability to swallow tablets or tolerate oral medication.
19.
Subject has participated in a clinical trial involving either study medication or interventional 
(non-medication) treatment for TD within the last 60 days.
20.
The following laboratory test results, vital signs and ECG results are exclusionary:
a) Platelets 75,000/mm3
b) Hemoglobin 9 g/dL
c) Neutrophils, absolute 1000/mm3
d) AST > 3 ULN as defined by the central laboratory
e) ALT > 3 ULN as defined by the central laboratory
f) Creatinine 2 mg/dL
g) Diastolic blood pressure > 105 mmHg
h) QTc 450 msec (males) or ≥ 470 msec (females) using the QTcF correction.
NOTE: In addition, subjects should be excluded if they have any other abnormal laboratory tests, 
vital sign results, or ECG findings which in the investigator’s judgment is medically significant and 
would impact the safety of the subject or the interpretation of the trial results. Criteria are provided 
in Appendix 1, Appendix 2, and Appendix 3 to assist investigators in their assessments of results 
that may be potentially medically significant, depending on the subject’s medical history and 
clinical presentation. Abnormal results for laboratory parameters or vital signs should be repeated 
once to ensure reproducibility of the abnormality before excluding a subject based on the criteria 
noted above. Based on the QTcF correction, a subject will be excluded if the correction exceeds 
450 msec (males) or ≥ 470 msec (females).
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ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBT = cognitive-behavioral 
therapy; CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale; CYP = cytochrome 
P450; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
FOCBP = female of childbearing potential; OCD = obsessive-compulsive disorder; QTc = corrected 
QT interval; QTcF = corrected QT interval for heart rate using Fridericia’s formula; ULN = upper 
limit of normal.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
3.5
Endpoints
3.5.1
Efficacy Endpoints
3.5.1.1
Primary Endpoint
The primary efficacy endpoint is the time from randomization to relapse during the 
double-blind randomized withdrawal phase.
3.5.1.2
Secondary Endpoint
Not applicable.
3.5.1.3
Exploratory Efficacy Endpoint(s)
The other efficacy endpoints include the following:

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in YGTSS TTS score

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in Total YGTSS score

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in CGI-TS Severity score

CGI-TS Improvement score at last visit (Week 12 for completers and withdrawal visit 
for discontinued subject)
3.5.2
Safety Endpoint(s)
Safety endpoints include the following:

Adverse events (AEs)

Laboratory tests (hematology, serum chemistry [including prolactin (blinded), 
glycosylated hemoglobin, and thyroid-stimulating hormone (TSH)], urinalysis, and 
urine pregnancy tests)

Vital signs

Electrocardiograms (ECGs)
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
Abnormal Involuntary Movement Scale (AIMS)

Barnes Akathisia Rating Scale (BARS)

Simpson-Angus Scale (SAS)

Columbia-Suicide Severity Rating Scale (C-SSRS)

Body weight

Body mass index (BMI)

Waist circumference
3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
Subjects will be randomly assigned in a 1:1:1 ratio via interactive response technology 
(IRT) to the half-dose aripiprazole arm, full-dose aripiprazole arm, or placebo arm. The 
randomization will be stratified by region and weight group, where region is classified as 
North America (including USA and Canada) vs. Rest of the World and weight group is 
classified as low weight (body weight at Baseline < 50 kg) vs. high weight (body weight 
at Baseline ≥ 50 kg). Computer-generated randomization codes will be prepared by a 
sponsor's independent biostatistician.
3.6.2
Blinding
Placebo tablets are identical in appearance to active IMP and all dose strength 
aripiprazole tablets are visually indistinguishable.
Except in cases of emergency unblinding, subjects, investigational site personnel, Otsuka 
Pharmaceutical Development & Commercialization, Inc. (OPDC) employees, and all 
other trial personnel will remain blinded to the identity of the treatment assignments until 
every subject has completed trial treatment and the database has been locked. 
3.7
Trial Procedures
The duration of this trial from first subject enrolled to last subject completed is estimated 
to be approximately 3 years and 4 months including an estimated 30-month recruitment 
period.
Individual participation for subjects who complete the trial can range from a minimum of 
approximately 30 weeks to approximately 42 weeks. Length of participation will vary,
depending on the screening duration (3 - 42 days). 
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However, the trial may be terminated early based on the result of a planned interim 
analysis (IA).
During the open-label stabilization phase, visits will occur at Week 1 (± 2 days) for the 
titration visit and at Weeks 2, 3, and 4 (± 2 days) and Weeks 6, 8, 10, 12, 14, 16, 18, and 
20 (± 3 days). Upon entering the double-blind randomized withdrawal phase, subjects 
will be randomized to aripiprazole full dose, aripiprazole half dose, or placebo. Subjects 
will have trial visits at Weeks 1, 2, 3, and 4 (± 2 days) and Weeks 6, 8, 10, and 12 
(± 3 days).
Screening assessments may occur during 1 or more visits (as needed), and must occur in 
the clinic. The baseline visit will occur in the clinic, as well the open-label stabilization 
phase visits on Weeks 1, 2, 4, 8, 12, 14, 16, 18, and 20 and the double-blind, randomized 
withdrawal phase visits at Weeks 1, 2, 4, 8, and 12. All other visits will occur via 
telephone with direct patient visualization (except for open-label Week 3 which does not 
require direct patient visualization), web, in-clinic, or other acceptable means of contact.
Trial assessment time points are summarized by phase in Table 3.7-1 (Pretreatment and 
Open-label Stabilization Phase) and Table 3.7-2 (Double-blind Randomized Withdrawal 
Phase).
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Table 3.7-1
Schedule of Assessments - Screening and Open-label Stabilization Phase
Assessments/Procedures
Screening and 
Washout 
Period
(Days −42
to −3)
Open-label Stabilization Phase Visits - Week (Day)a
Baseline
(Day 1)
1
(8
± 2)
2
(15
± 2)
3
(22
± 2)
4
(29
± 2)
6
(43
± 3)
8
(57
± 3)
10
(71
± 3)
12
(85
± 3)
14
(99
± 3)
16
(113
± 3 )
18
(127
± 3 )
20 (141
± 3 )/
EOP or 
ETb
Screening/Eligibility
Informed Consent/Assentc
X
Confirmation of diagnosis 
of TD by DSM-5d
X
K-SADS-PLe
X
CY-BOCSf
X
Inclusion/exclusion
criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
Record current 
psychotropic therapyg
X
X
X
X
X
X
X
X
X
X
X
X
X
Washout of prohibited 
medications, including 
psychotropicsg
X
Trial Assessments
YGTSSf
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-TS Severityf
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-TS Improvementf
X
X
X
X
X
X
X
X
X
X
X
C-SSRS (children’s
version)f,h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 3.7-1
Schedule of Assessments - Screening and Open-label Stabilization Phase
Assessments/Procedures
Screening and 
Washout 
Period
(Days −42
to −3)
Open-label Stabilization Phase Visits - Week (Day)a
Baseline
(Day 1)
1
(8
± 2)
2
(15
± 2)
3
(22
± 2)
4
(29
± 2)
6
(43
± 3)
8
(57
± 3)
10
(71
± 3)
12
(85
± 3)
14
(99
± 3)
16
(113
± 3 )
18
(127
± 3 )
20 (141
± 3 )/
EOP or 
ETb
Physical examination
X
Xi
X
Height
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGk
X
Xi
X
Clinical laboratory tests 
(hematology, serum 
chemistry, and urinalysis)l
X
Xi
X
Glycosylated hemoglobin, 
prolactin 
(blinded),TSHl,m
X
Xi
X
Urine pregnancy testn
X
X
X
X
X
X
X
Documentation of birth 
control statuso
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine drug and blood 
alcohol screenp
X
X
X
SASf
X
X
X
X
AIMSf
X
X
X
X
BARSf
X
X
X
X
Adverse Eventsq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 3.7-1
Schedule of Assessments - Screening and Open-label Stabilization Phase
Assessments/Procedures
Screening and 
Washout 
Period
(Days −42
to −3)
Open-label Stabilization Phase Visits - Week (Day)a
Baseline
(Day 1)
1
(8
± 2)
2
(15
± 2)
3
(22
± 2)
4
(29
± 2)
6
(43
± 3)
8
(57
± 3)
10
(71
± 3)
12
(85
± 3)
14
(99
± 3)
16
(113
± 3 )
18
(127
± 3 )
20 (141
± 3 )/
EOP or 
ETb
Prior and Concomitant 
Medicationsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Management
Dispense IMP
X
X
X
X
Xs
Xs
Xs
Xt
Assess eligibility for 
treatment
X
X
Assess stabilization 
criteria
X
X
X
X
X
X
X
X
X
X
Randomization of stable 
subjects
Xu
Xu
Xu
Xt
Drug accountability
X
X
X
X
X
X
X
X
Phone call to assess if 
titration is needed in-
clinic
X
D = day; EOP = end of phase; IRE = immediately reportable event; K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia - Present and 
Lifetime Version.
aThe subject will return to the clinic for visits at Weeks 2 (± 2 days), 4 (± 2 days), 8 (± 3 days), 12 (± 3 days), 14 (± 3 days), 16 (± 3 days), and 18 (± 3 days). 
The Week 20 (± 3 days)/EOP visit will also occur in the clinic. All other visits during the open-label stabilization phase will occur via telephone with direct 
patient visualization (except for open-label Week 3 which does not require direct patient visualization), web, in-clinic, or other acceptable means of contact. 
bThe End of Phase visit must serve as the baseline for double-blind randomized withdrawal phase; therefore, all evaluations noted for “Week 20 (141)/EOP or 
early termination (ET)” must be performed on the day of randomization prior to the first dose of double-blind IMP. Please note that randomization must 
occur on the same day that the subject receives double-blind IMP for double-blind randomized withdrawal phase. For subjects who meet the 12-week (eg, 6 
bi-weekly-visits) stabilization requirement at a visit that coincides with IMP dispensing, the “Week 20 (141)/ EOP or ET” evaluations will be performed 
instead of the evaluations noted for the individual trial visit. Once these evaluations are completed, the subject will be randomized and dispensed double-
blind IMP.  
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cInformed consent/assent must be obtained from all legally acceptable representatives/subjects prior to initiation of any trial-related procedures.
dCurrent diagnosis of TD should be made and documented at screening by an adequately qualified clinician.
eK-SADS-PL: This assessment must be performed by certified personnel.
fBenztropine (up to 4 mg/day) is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 3 mg/day lorazepam equivalents) are not to be 
administered 4 hours prior to rating scales.
gTapering rates for washout medications are at the discretion of the investigator and are to be determined on an individual basis, with consideration to subject 
state, dose, and known PK of the medication being tapered, as long as the protocol-mandated discontinuation timeframe is met. The exception is a 
long-acting depot medication, which cannot be tapered and will be discontinued after informed consent/assent is obtained. See Section 4.1 for additional 
details.
hThe C-SSRS (children’s version) will be completed for all subjects at screening and at all subsequent visits.
iET procedures performed only on subjects not starting to meet stability at the open-label stabilization phase Week 8 visit and subjects not maintaining 
stability by the open-label stabilization phase Week 20 visit. These subjects will be discontinued from the trial.
jVital signs include systolic and diastolic blood pressure and heart rate and will be performed at all in-clinic visits. Orthostatic assessments of blood pressure 
and heart rate will be made after the subject has been sitting for at least 5 minutes and again after the subject has been standing for approximately 
2 minutes, but not more than 3 minutes. If a remote visit is converted to an in-clinic visit, vital signs will be recorded. Vital signs will not be collected for 
remote visits that are not converted to occur in-clinic.
kA standard 12-lead ECG will be performed at rest after the subject has been lying down for approximately 5 minutes. ECGs will be evaluated at the 
investigational site to determine the subject’s eligibility and to monitor safety. Based on the QTcF, a subject will be excluded if the correction is 450 
msec (males) or ≥ 470 msec (females). Subjects with clinically significant ECG findings at screening may enter the open-label stabilization phase only after 
the screening ECG is repeated and determined by the investigator prior to treatment to have no abnormality(ies) that are clinically significant.
lSubjects should fast for a minimum of 8 hours prior to blood draws for all laboratory assessments. If nonfasting blood samples are obtained initially for 
determining eligibility for the trial, a fasting blood sample should be drawn prior at or prior to the baseline visit (prior to the first dose of open-label drug).  
Subjects with clinically significant abnormal laboratory test results at screening may enter the open-label stabilization phase only after repeated laboratory 
test results are received and determined by the investigator prior to treatment to have no abnormality(ies) that are clinically significant.
mIf the observed TSH level is outside of the normal range, tests of triiodthyronine (T3) and thyroxine (T4) levels will be assessed.
nA urine pregnancy test will be performed at screening on all female subjects ≥ 12 years of age and all female subjects < 12 years of age if menstruation has 
started. Subjects with a positive result will be excluded from the trial. Urine pregnancy tests can be performed at any point during the trial if pregnancy is 
suspected. All positive urine pregnancy test results must be confirmed by a serum test. Subjects who are taking IMP and have a positive urine and serum 
pregnancy test must discontinue treatment, be withdrawn from the trial, and an immediately reportable event (IRE) form should be completed.
oAbstinence will be permitted if it is confirmed and documented at every trial visit.
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pA urine drug screen and a blood alcohol test, is required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator. Subjects who have 2 positive drug screens for any drug of abuse (with the exception of caffeine, nicotine, or prescribed 
psychostimulants for ADHD) at any time during the trial must be discontinued from the trial.  
qAdverse events will be recorded starting at the time the ICF/IAF is signed.
rA complete history of use of central nervous system (CNS)-active compounds other than neuroleptics will be recorded, as will all other medications taken 
within 30 days of starting IMP. In addition, all prescription and nonprescription medications taken during the trial will be recorded as concomitant 
medications.
sOnly subjects starting to meet stability (eg, ≥ 35% improvement [decrease] of YGTSS TTS) by the open-label stabilization phase Week 8 visit will be 
allowed to continue in the open-label stabilization phase and have IMP dispensed. Any subject not starting to show stability by the open-label stabilization 
phase Week 8 visit will be discontinued from the trial and will undergo ET procedures.
tOnly subjects who have met stability criteria for 12 consecutive weeks with no more than 1 excursion of the stabilization criterion at the open-label 
stabilization phase Week 20 visit and who will continue into the double-blind randomized withdrawal phase and have IMP dispensed.
uSubjects meeting stability for 12 consecutive weeks with no more than 1 excursion of the stabilization criterion will continue into the double-blind 
randomized withdrawal phase with IMP being dispensed. Excursions are not permitted at the end of the 12th consecutive week of stabilization (ie, the 
randomization visit).
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Table 3.7-2
Schedule of Assessments - Double-blind Randomized Withdrawal Phase
Assessments/Procedures
Double-blind Randomized Withdrawal Phasea
Follow-up 
Period 
30 Days 
(+ 3 days)
Week 1
(± 2 days)
Week 2
(± 2 days)
Week 3
(± 2 days)
Week 4
(± 2 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Week 10
(± 3 days)
Week 12 
(± 3 days)/ 
ET
Trial Assessments
Record current psychotropic 
therapy
X
X
X
X
X
X
X
X
X
YGTSSb
X
X
X
X
X
X
X
X
CGI-TS Severityb
X
X
X
X
X
X
X
X
CGI-TS Improvementb
X
X
X
X
X
X
X
X
C-SSRS (children’s version)b
X
X
X
X
X
X
X
X
Physical examination
X
Height
X
Body weight
X
X
Waist circumference
X
X
Vital signsc
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
Clinical laboratory tests 
(hematology, serum chemistry, 
urinalysis)e
X
X
Glycosylated hemoglobin, 
prolactin (blinded), TSHe,f
X
X
Urine pregnancy testg
X
X
X
X
Documentation of birth control 
statush
X
X
X
X
X
X
X
X
Urine drug and blood alcohol 
screeni
X
X
SASb
X
X
X
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Table 3.7-2
Schedule of Assessments - Double-blind Randomized Withdrawal Phase
Assessments/Procedures
Double-blind Randomized Withdrawal Phasea
Follow-up 
Period 
30 Days 
(+ 3 days)
Week 1
(± 2 days)
Week 2
(± 2 days)
Week 3
(± 2 days)
Week 4
(± 2 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Week 10
(± 3 days)
Week 12 
(± 3 days)/ 
ET
AIMSb
X
X
X
BARSb
X
X
X
Adverse Eventsj
X
X
X
X
X
X
X
X
X
Prior and Concomitant 
Medicationsk
X
X
X
X
X
X
X
X
X
Trial Management
Dispense IMP
X
X
X
X
Drug accountability
X
X
X
X
X
aAfter randomization, the subject will return to the clinic for weekly then bi-weekly visits at Weeks 1 (± 2 days), 2 (± 2 days), 4 (± 2 days), and 8 (± 3 days) 
during the double blind randomized withdrawal phase. Visits at Weeks 3 (± 2 days), 6 (± 3 days), and 10 (± 3 days) will occur via telephone with direct 
patient visualization, web, in-clinic, or other acceptable means of contact. If the subject terminates early from the trial, the end-of-treatment visit procedures 
should be completed.
bBenztropine (up to 4 mg/day) is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 3 mg/day lorazepam equivalents) are not to be 
administered 4 hours prior to rating scales.
cVital signs include systolic and diastolic blood pressure and heart rate and will be performed at all in-clinic visits. Orthostatic assessments of blood pressure 
and heart rate will be made after the subject has been sitting for at least 5 minutes and again after the subject has been standing for approximately 
2 minutes, but not more than 3 minutes. If a remote visit is converted to an in-clinic visit, vital signs will be recorded. Vital signs will not be collected for 
remote visits that are not converted to occur in-clinic.
dA standard 12-lead ECG will be performed at rest after the subject has been lying down for approximately 5 minutes. ECGs will be evaluated at the 
investigational site to monitor safety.  
eSubjects should fast for a minimum of 8 hours prior to blood draws for all laboratory assessments.  
fIf the observed TSH level is outside of the normal range, tests of triiodthyronine (T3) and thyroxine (T4) levels will be assessed.
gUrine pregnancy tests can be performed at any point during the trial if pregnancy is suspected. All positive urine pregnancy test results must be confirmed by 
a serum test. Treated subjects with a positive urine and serum pregnancy test must discontinue treatment, be withdrawn from the trial, and an IRE form 
should be completed.
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hAbstinence will be permitted if it is confirmed and documented at every trial visit.
iA urine drug screen and a urine blood test can be conducted at any time during the trial at the discretion of the investigator. Subjects who have 2 positive drug 
screens for any drug of abuse (with the exception of caffeine, nicotine, or prescribed psychostimulants for ADHD) at any time during the trial must be 
discontinued.  
jAdverse events will be recorded starting at the time the ICF/IAF is signed.
kAll prescription and nonprescription medications taken during the trial will be recorded as concomitant medications.
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3.7.1
Schedule of Assessments
3.7.1.1
Pretreatment Phase: Screening and Washout Period
This phase includes both a screening and washout period. Screening and washout (if 
required) will take place between Days −42 and −3 prior to enrollment. Screening 
assessments may occur during 1 or more visits (as needed), and must occur in the clinic.  
The following procedures will be conducted during the screening period for all subjects:
1) Subjects and the subject’s legally acceptable representative (eg, guardian) will 
sign an ICF/IAF to participate in this trial prior to initiation of any trial-related 
procedures. After signing the ICF/IAF, subjects will be assigned a unique
subject screening identification number through the eConsent system that is 
transferred to both the eSource and IRT.
2) Trial personnel will enter subject data into eSource to register all trial visits 
(screening visit only).
3) The DSM-5 diagnosis of TD will be confirmed and documented by an 
adequately trained clinician.
4) After TD is documented, the investigator (or qualified designee) will administer 
the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and 
Lifetime Version (K-SADS-PL) to confirm the diagnosis. The K-SADS-PL 
must be administered by an adequately trained clinician.
5) Completion of the Children’s Yale-Brown Obsessive Compulsive Scale 
(CY-BOCS).  Subject must have a score ≤16 to qualify for the trial.
6) An assessment of all inclusion and exclusion criteria will be made to determine 
the subject’s eligibility for the trial.
7) Demographic data and full medical and psychiatric history will be recorded.
8) Current psychotropic therapy will be recorded. 
9) A complete history of use of central nervous system (CNS)-active compounds 
other than neuroleptics will be recorded, including details (eg, drug name, dose, 
and frequency), as will all other medications taken within 30 days of starting 
IMP. In addition, all prescription and nonprescription medications taken during 
the screening period will be recorded as concomitant medications.
10) The YGTSS and CGI-TS Severity will be performed to assess symptoms 
associated with TD. Subjects are required to have a TTS 20 on the YGTSS at 
screening and baseline in order to be included in the trial.
11) Completion of the C-SSRS (children’s version).
12) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to 
rating scales.
13) A complete physical examination will be performed. 
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14) Body weight, height, and waist circumference will be measured. Subjects with 
body weight < 16 kg will be excluded from the trial.
15) Vital signs including systolic and diastolic blood pressure and heart rate will be 
measured. Orthostatic assessments of blood pressure and heart rate will be made 
after the subject has been sitting for at least 5 minutes and again after the subject 
has been standing for approximately 2 minutes, but not more than 3 minutes.
16) A standard 12-lead ECG will be performed at rest after the subject has been 
lying down for approximately 5 minutes. ECGs will be evaluated at the 
investigational site to determine the subject’s eligibility. Based on the corrected 
QT interval for heart rate using Fridericia’s formula (QTcF), a subject will be 
excluded if the correction is 450 msec (males) or ≥ 470 msec (females). 
Subjects with clinically significant ECG findings at screening may enter the 
open-label stabilization phase only after the screening ECG is repeated and 
determined by the investigator prior to treatment to have no abnormality(ies) 
that are clinically significant.
17) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
levels; prolactin samples will remain blinded). Subjects should fast for a 
minimum of 8 hours prior to blood draws for all laboratory assessments; 
however, a subject should provide informed consent for the trial prior to being 
asked to fast for blood draws. If nonfasting blood samples are obtained initially 
for determining eligibility for the trial, a fasting blood sample should be drawn 
at or prior to the baseline visit (prior to the first dose of open-label drug). 
Subjects with clinically significant abnormal laboratory test results at screening 
may enter the open-label stabilization phase only after repeated laboratory test 
results are received and determined by the investigator prior to treatment to 
have no abnormality(ies) that are clinically significant. If the observed TSH 
level is outside the normal range, a test of T3 and T4 levels will be performed.
18) Urine will be collected for urinalysis and urine screen(s) for drugs of abuse and 
a blood sample will be taken for alcohol.
19) A urine pregnancy test will be done on females of childbearing potential 
(FOCBP). Subjects with a positive result will be excluded from the trial. If 
positive, a follow-up serum pregnancy test will be performed and the subject 
will not be assigned to treatment.
20) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. Abstinence is permitted if it is confirmed and 
documented at every visit.
21) AEs will be recorded starting at the time the ICF/IAF is signed.
Subject who satisfy eligibility criteria and do not require washout from prohibited 
medications can enter the open-label stabilization phase directly.  
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Subjects who require medication washout will undergo the following procedures during 
the washout period:
1) Washout from prohibited medications, including psychotropics, will begin, if 
applicable. Tapering rates for washout medications are at the discretion of the 
investigator and are to be determined on an individual basis, with consideration 
to subject state, dose, and known PK of the medication being tapered, as long as 
the protocol-mandated discontinuation timeframe is met. The exception is a 
long-acting depot medication, which cannot be tapered and would be 
discontinued after the informed consent is obtained. All psychotropic 
medications and any medications used to treat tics must be discontinued for at 
least 2 weeks (14 days) prior to the baseline visit, with the exception of 
psychostimulant medications such as, but not limited to, Vyvanse, Adderall, 
Concerta, Metadate CR, Ritalin LA, Focalin, and Focalin XR, prescribed for the 
treatment of symptoms of ADHD, which are permitted during the trial. Use of 
psychostimulant medications is only permitted if the subject did not develop 
and/or have an exacerbation of the tic disorder after the initiation of treatment 
with the psychostimulant. In addition, the dose of any psychostimulant must 
have been stable for at least 4 weeks prior to screening.  All SSRIs/SNRIs must 
be discontinued at least 4 weeks (28 days) prior to the baseline visit. In addition, 
long-acting (depot) neuroleptics must be discontinued for at least 1 full cycle 
(2 weeks to 1 month, depending on the drug) plus 2 weeks prior to the baseline 
visit. Clonidine, guanfacine, guanabenz, atomoxetine and carbamazepine are 
prohibited during the trial and must be discontinued for at least 2 weeks prior to 
the baseline visit. Subjects must have discontinued aripiprazole treatment at 
least 30 days prior to the screening visit. Subjects not in need of medication 
washout may proceed to the trial baseline visit after the inclusion/exclusion 
criteria have been met.
2) AEs will be recorded starting at the time the ICF/IAF is signed.
3) All prescription and nonprescription medications taken during the washout 
period will be recorded as concomitant medications.
3.7.1.2
Baseline Visit (Day 1)
If the subject is found to be eligible for the trial during the screening period and has either 
completed or does not require the washout of previous designated medications, the 
subject will return to clinic for the baseline (Day 1) visit of the open-label stabilization 
phase. The following procedures are to be completed prior to dosing:
1) Subject eligibility will be confirmed.
2) Current psychotropic therapy will be recorded.  
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3) The YGTSS and CGI-TS severity will be performed to assess symptoms 
associated with TD. Subjects are required to have a TTS 20 on the YGTSS at 
screening and baseline in order to be included in the trial.
4) Completion of the C-SSRS (children’s version).
5) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to 
rating scales.
6) Height, body weight, and waist circumference will be measured.
7) Vital signs include systolic and diastolic blood pressure and heart rate will be 
measured. Orthostatic assessments of blood pressure and heart rate will be made 
after the subject has been sitting for at least 5 minutes and again after the subject 
has been standing for approximately 2 minutes, but not more than 3 minutes.
8) A urine pregnancy test will be done on all FOCBP. If the results of the test are 
positive, then a serum pregnancy test will be completed.  
9) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. Abstinence is permitted if it is confirmed and 
documented at every visit. 
10) AEs and concomitant medications will be recorded.
Confirmation that all inclusion and exclusion criteria were evaluated to ensure subject 
eligibility was met. If the subject still meets all inclusion/exclusion criteria, the following 
tasks will be completed:
1) Subjects will be dispensed IMP and administered the first dose while in the 
clinic. Subjects will take each daily dose of IMP at approximately the same time 
each day. The date and time of the first dose will be recorded in the eSource.
2) The investigator will schedule the Week 1 visit for within 7 days ± 2 days.
3.7.1.3
Open-label Stabilization Phase Titration Visit (Week 1)
The subject will return to the clinic at Week 1 (± 2 days) during the open-label 
stabilization phase. The following procedures are to be completed:
1) Current psychotropic therapy will be recorded
2) The YGTSS and CGI-TS (both the severity and improvement scales) will be 
performed to assess symptoms associated with TD. 
3) Completion of the C-SSRS (children’s version).
4) Vital signs including systolic and diastolic blood pressure and heart rate will be 
measured. Orthostatic assessments of blood pressure and heart rate will be made 
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after the subject has been sitting for at least 5 minutes and again after the subject 
has been standing for approximately 2 minutes, but not more than 3 minutes.
5) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. Abstinence is permitted if it is confirmed and 
documented at every visit. 
6) AEs and concomitant medications will be recorded.
7) The subject will be dispensed once-daily IMP. The subject will be dosed in the 
clinic unless the evening dosing is preferred. Subjects will be instructed to 
return unused IMP at the next scheduled office visit.  
8) Drug accountability records will be completed.
3.7.1.4
Open-label Stabilization Phase Stabilization Visits
The subject will return to the clinic for visits at Weeks 2 (± 2 days) and 4 (± 2 days) and 
visits at Weeks 8 (± 3 days), 12 (± 3 days), 14 (± 3 days), 16 (± 3 days), and 18 (± 3) days
to start assessment of stability. The Week 20 (± 3 days)/EOP visit will also occur in the 
clinic. All other visits during the open-label stabilization phase (ie, Weeks 3, 6, and 10)
will occur via telephone with direct patient visualization (except for Week 3 which does 
not require direct patient visualization), web, in-clinic, or other acceptable means of 
contact. The following procedures are to be completed at each visit:
1) Current psychotropic therapy will be recorded at all open-label visits EXCEPT 
for Week 3.
2) The YGTSS and CGI-TS (both the severity and improvement scales) will be 
performed to assess symptoms associated with TD at all open-label visits 
EXCEPT for Week 3. 
3) Completion of the C-SSRS (children’s version).
4) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed at all open-label visits EXCEPT for Week 3. 
Abstinence is permitted if it is confirmed and documented at every visit. 
5) AEs and concomitant medications will be recorded.
6) Stability will be assessed at all open-label visits EXCEPT for Week 3.
The following procedures will be performed at the Weeks 2 (± 2 days), 4 (± 2 days), 
8 (± 2 days), 12 (± 3 days), 14 (± 3 days), 16 (± 3 days), and 18 (± 3 days) visits only:
1) Vital signs including systolic and diastolic blood pressure and heart rate will be 
measured. Orthostatic assessments of blood pressure and heart rate will be made 
after the subject has been sitting for at least 5 minutes and again after the subject 
has been standing for approximately 2 minutes, but not more than 3 minutes. If 
visits on Weeks 3, 6, and/or 10 are converted to in-clinic visits, vital signs will 
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be recorded. Vital signs will not be collected for remote visits that are not 
converted to occur in-clinic.
2) The subject will be dispensed once daily IMP. The subject will be dosed in the 
clinic unless the evening dosing is preferred. Subjects will be instructed to 
return unused IMP at the next scheduled office visit.
3) Drug accountability records will be completed.
The following procedures will be performed at the Weeks 4 (± 2 days), 8 (± 3 days), 
12 (± 3 days), and 16 (± 3 days) visits only:
1) Body weight and waist circumference will be measured.
2) A urine pregnancy test will be done on all FOCBP, but can be done at any visit 
is pregnancy is suspected.  
The following procedures will be performed at the Week 8 (± 3 days) visit only:
1) A complete physical examination will be performed. 
2) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to rating 
scales.
3) A standard 12-lead ECG will be performed at rest after the subject has been lying 
down for approximately 5 minutes. 
4) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
levels; prolactin samples to remain blinded).  If the observed TSH level is outside 
the normal range, a test of T3 and T4 levels will be performed.
5) Urine will be collected for urinalysis and urine screen(s) for drugs of abuse and a 
blood sample will be taken for alcohol.
The following procedure will be performed at the Weeks 8 (± 3 days) and 16 (± 3 days) 
visits only:
1) Height will be measured.
3.7.1.5
Open-label Stabilization Phase Contact (Week 3)
The Week 3 (± 2 days) contact will consist of telephone contact to assess any AEs 
experienced since the last trial visit and information on ongoing AEs and serious TEAEs 
and recording of concomitant medications, including current psychotropic therapy.  
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If the investigator feels that a dose titration is required the subject will return to the clinic 
for IMP dispensing. The following procedures are to be completed at this visit:
1) Current psychotropic therapy will be recorded.
2) Completion of the C-SSRS (children’s version).
3) AEs and concomitant medications will be recorded.
4) If visit is converted to an in-clinic visit, vital signs will be recorded. Vital signs 
including systolic and diastolic blood pressure and heart rate will be measured. 
Orthostatic assessments of blood pressure and heart rate will be made after the 
subject has been sitting for at least 5 minutes and again after the subject has 
been standing for approximately 2 minutes, but not more than 3 minutes.
3.7.1.6
Open-label Stabilization Phase /Randomization/Early 
Termination
Subjects should be randomized at the visit where they meet the protocol-specified 
stabilization criteria; the visit where stabilization is confirmed will revert to the EOP 
visit. However, if for some reason subject was not randomized, if the subject still meets 
eligibility criteria at the next visit they can be randomized at that time. In those instances, 
the earlier assessment should be completed according to that week's required 
assessments, and not as an EOP visit. 
The subject will return to the clinic for a visit at Week 20 (± 3 days) during the open-
label stabilization phase. Investigators must perform the open-label stabilization phase 
assessments to determine if the subject has maintained the stabilization criteria for entry 
into the double-blind randomized withdrawal phase. The EOP visit must serve as the 
baseline for double-blind randomized withdrawal phase; therefore, all evaluations noted 
for Week 20/EOP or ET must be performed on the day of randomization prior to the first 
dose of double-blind IMP. Randomization (Section 3.7.1.6.1) must occur on the same day 
that the subject receives double-blind IMP for double-blind randomized withdrawal 
phase. 
The following procedures are to be completed at the Week 20/EOP visit:
1) Current psychotropic therapy will be recorded.
2) The YGTSS and CGI-TS (severity and improvement assessments) will be 
performed to assess symptoms associated with TD. 
3) Completion of the C-SSRS (children’s version).
4) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. Abstinence is permitted if it is confirmed and 
documented at every visit. 
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5) AEs and concomitant medications will be recorded.
6) Drug accountability records will be completed.
7) Stability will be assessed.
8) A complete physical examination will be performed.
9) Height, body weight, and waist circumference will be measured.
10) A urine pregnancy test will be done on FOCBP.  
11) Urine drug and blood alcohol screens will be done.
12) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to 
rating scales.
13) Vital sign measurements (systolic and diastolic blood pressure and heart rate) 
will be recorded. Orthostatic assessments of blood pressure and heart rate will 
be made after the subject has been sitting for at least 5 minutes and again after 
the subject has been standing for approximately 2 minutes, but not more than 3 
minutes.
Subjects that have not maintained stability for 12 consecutive weeks in the open-label 
stabilization phase can continue the bi-weekly visits to assess stability. Subjects should 
be discontinued (see Section 3.7.1.6.2) if they no longer have the opportunity to achieve 
12 weeks of stability in the open-label stabilization phase (eg, the subject has not 
achieved response by Week 8). The following procedures are to be completed at each 
visit:
1) The subject will be dispensed once-daily IMP, if continuing in the trial. The 
subject will be dosed in the clinic unless the evening dosing is preferred. 
Subjects will be instructed to return unused IMP at the next scheduled office 
visit. For details regarding those subjects who are discontinued from the trial, 
refer to Section 3.7.1.6.2.  
3.7.1.6.1
Randomization
Subjects that have maintained stability for 12 consecutive weeks with no more than 
1 excursion of the stabilization criterion will enter the double-blind randomized 
withdrawal phase. The following randomization procedures will be completed at this 
visit:
1) A standard 12-lead ECG will be performed at rest after the subject has been 
lying down for approximately 5 minutes.  
2) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
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levels; prolactin samples to remain blinded).  If the observed TSH level is 
outside the normal range, a test of T3 and T4 levels will be performed.
3) Urine will be collected for urinalysis.
4) Subjects should be dispensed IMP and administered the first dose while in the 
clinic unless evening dose is preferred. Subjects will take each daily dose of 
IMP at approximately the same time each day. All other assessments should be 
completed prior to the administration of IMP.
5) The investigator will schedule the visit for the double-blind randomized 
withdrawal phase Week 1 visit for within 7 days ± 2 days.
3.7.1.6.2
Open-label Stabilization Phase/Early Termination
Subjects who have never met stability criteria by the Week 8 visit, or subjects who have 
not met stability criteria for 12 consecutive weeks (with 1 excursion permitted) by Week 
20 will be discontinued from the trial after completion of ET procedures. Subjects who 
discontinue early should also complete the 30-day follow-up visit as described in 
Section 3.7.1.9. For subjects who discontinue early, attempts should be made to complete 
ALL evaluations, particularly efficacy assessments (ie, YGTSS and CGI-TS), for the 
open-label stabilization phase visit/ET visit prior to the administration of any new 
psychotropic medications. However, if the subject receives a new antipsychotic prior to 
ET procedures, no efficacy assessments should be done. Any prohibited medications 
started before the end of the trial assessments should be documented as a protocol
deviation in the source notes. The following additional ET activities and assessments will 
occur at the open-label stabilization phase visit (or at ET visit, if applicable):
1) A complete physical examination will be performed.
2) Height, body weight, and waist circumference will be measured.
3) A standard 12-lead ECG will be performed at rest after the subject has been 
lying down for approximately 5 minutes. 
4) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
levels; prolactin samples to remain blinded). If the observed TSH level is 
outside the normal range, a test of T3 and T4 levels will be performed.
5) Urine will be collected for urinalysis.
6) A urine pregnancy test will be done on all FOCBP.  
7) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed.
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3.7.1.7
Double-blind Randomized Withdrawal Phase Visits
After randomization, the subject will return to the clinic for weekly then bi-weekly visits 
at Weeks 1 (± 2 days), 2 (± 2 days), 4 (± 2 days), and 8 (± 3 days) during the 
double-blind randomized withdrawal phase. Visits at Weeks 3 (± 2 days), 6 (± 3 days), 
and 10 (± 3 days) will occur via telephone with direct patient visualization, web, 
in-clinic, or other acceptable means of contact. If the subject terminates early from the 
trial, the end-of-treatment visit procedures should be completed. 
The following procedures are to be completed at each visit:
1) Current psychotropic therapy will be recorded.
2) The YGTSS and CGI-TS (both the severity and improvement scales) will be 
performed to assess symptoms associated with TD. 
3) Completion of the C-SSRS (children’s version).
4) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. Abstinence is permitted if it is confirmed and 
documented at every visit. 
5) AEs and concomitant medications will be recorded.
The following procedures will be performed at the Weeks 1 (± 2 days), 2 (± 2 days), 
4 (± 2 days), and 8 (± 3 days) visits only:
1) Vital signs including systolic and diastolic blood pressure and heart rate will be 
measured. Orthostatic assessments of blood pressure and heart rate will be made 
after the subject has been sitting for at least 5 minutes and again after the subject 
has been standing for approximately 2 minutes, but not more than 3 minutes. If 
visits on Weeks 3, 6, and/or 10 are converted to in-clinic visits, vital signs will 
be recorded. Vital signs will not be collected for remote visits that are not 
converted to occur in-clinic.
2) The subject will be dispensed once-daily IMP. The subject will be dosed in the 
clinic unless the evening dosing is preferred.  They will be instructed to return 
the medication at the next scheduled office visit.
3) Drug accountability records will be completed.
The following procedures will be performed at the Week 2 (± 2 days), 4 (± 2 days), and 8 
(± 3 days) visits only:
1) A urine pregnancy test will be done on all FOCBP.  
The following procedures will be performed at the Week 1 (± 2 days) and 4 (± 2 days) 
visits only:
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1) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to rating 
scales.
The following procedures will be performed at the Week 4 (± 2 days) visit only:
1) Body weight and waist circumference will be measured.
2) A standard 12-lead ECG will be performed at rest after the subject has been lying 
down for approximately 5 minutes. 
3) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
levels; prolactin samples to remain blinded). If the observed TSH level is outside 
the normal range, a test of T3 and T4 levels will be performed.
4) Urine will be collected for urinalysis and urine screen(s) for drugs of abuse and a 
blood sample will be taken for alcohol.
3.7.1.8
Double-blind Randomized Withdrawal Phase Week 12 or Early 
Termination
One day before the Week 12 (± 3 days) visit of the double-blind randomized withdrawal 
phase, subjects will take their final dose of double-blind IMP. The subject will return to
the clinic for the final trial visit at the double-blind randomized withdrawal phase 
Week 12 visit. If the subject terminates early from the trial, the end-of-treatment visit 
procedures should be completed. For subjects who discontinue early, attempts should be 
made to complete ALL evaluations, particularly efficacy assessments (YGTSS, CGI, 
etc.), for the Week 12/ET visit prior to the administration of any new psychotropic 
medications. However, if the subject receives a new psychotropic medication prior to ET 
procedures, no efficacy assessments should be done. Any prohibited medications started 
before the end of the trial assessments should be documented as a protocol deviation in 
the source notes. 
The following procedures are to be completed:
1) Current psychotropic therapy will be recorded.
2) The YGTSS and CGI-TS (both the severity and improvement scales) will be 
performed to assess symptoms associated with TD. 
3) Completion of the C-SSRS (children’s version).
4) The SAS, BARS, and AIMS will be administered. Benztropine (up to 4 mg/day) 
is not to be administered 12 hours prior to rating scales. Benzodiazepines (up to 
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3 mg/day lorazepam equivalents) are not to be administered 4 hours prior to 
rating scales.
5) A complete physical examination will be performed.
6) Height, body weight, and waist circumference will be measured.
7) Vital sign measurements (systolic and diastolic blood pressure and heart rate) 
will be recorded. Orthostatic assessments of blood pressure and heart rate will 
be made after the subject has been sitting for at least 5 minutes and again after 
the subject has been standing for approximately 2 minutes, but not more than 3 
minutes.
8) A standard 12-lead ECG will be performed at rest after the subject has been 
lying down for approximately 5 minutes. 
9) Fasting blood samples will be collected for clinical laboratory tests (hematology 
and serum chemistry, including TSH, glycosylated hemoglobin, and prolactin 
levels; prolactin samples to remain blinded). If the observed TSH level is 
outside the normal range, a test of T3 and T4 levels will be performed.
10) Urine will be collected for urinalysis and may be collected for a urine screen(s) 
for drugs of abuse (can be conducted at any time during the trial at the 
investigator’s discretion).
11) A urine pregnancy test will be done on all FOCBP. 
12) For all FOCBP and sexually active males, documentation of birth control 
methods will be completed. 
13) AEs and concomitant medications will be recorded.
14) Drug accountability will be assessed.
3.7.1.9
Post-treatment Follow-up Period
All subjects (completers and subjects who receive at least 1 dose of IMP and discontinue 
the trial for any reason) will be followed up for safety reasons 30 days (+ 3 days) after the 
last trial visit. Follow-up will consist of telephone contact to assess any AEs experienced 
since the last trial visit and information on ongoing AEs and serious TEAEs and 
recording of concomitant medications, including current psychotropic therapy.
3.7.2
Efficacy Assessments
3.7.2.1
Yale Global Tic Severity Scale 
The YGTSS1 is a semi-structured clinical interview designed to measure current tic 
severity. This scale consists of a tic inventory, with 5 separate rating scales to rate the 
severity of symptoms, and an impairment ranking. Ratings are made along 5 different 
dimensions on a scale of 0 to 5 for motor and vocal tics, each including number, 
frequency, intensity, complexity, and interference. Summation of these scores (ie, 0-50) 
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provides a TTS that will be the primary outcome measure.  The YGTSS ranking of 
impairment, with a maximum of 50 points, is based on the impact of the tic disorder on 
areas of self-esteem, family life, social acceptance, and school scores. This is a fully 
validated scale in adults and has become a standard instrument for the evaluation of the 
severity of TD in children.
3.7.2.2
Clinical Global Impression Scale for Tourette’s Syndrome
The severity of illness and efficacy of IMP for each subject will be rated using the 
CGI-TS scale.14 To assess CGI-TS severity, the rater or investigator will answer the 
following question: “Considering your total clinical experience with this particular 
population, how mentally ill is the patient at this time?” However, the evaluation of 
illness will be limited to manifestations of TD only. Response choices include:  0 = not 
assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 
4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely 
ill patients.  
The rater or investigator will rate the subject’s total improvement whether or not it is due 
to drug treatment. All responses will be compared to the subject’s condition at baseline 
(Day 1). Response choices include:  0 = not assessed, 1 = very much improved, 2 = much 
improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much 
worse, and 7 = very much worse.  
3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.3.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up labs, if needed). Reports from 
the central laboratory should be filed with the source documents for each subject.  The 
central laboratory will provide laboratory results to the sponsor electronically.
Samples for serum chemistry, hematology, and urinalysis will be obtained at the visits 
designated in Table 3.7-1 and Table 3.7-2. Additional urine and blood samples may be 
collected for further evaluation of safety as warranted by the investigator’s judgment. 
Subjects should be fasting for a minimum of 8 hours prior to any blood draws for all 
laboratory assessments. If nonfasting blood samples are obtained initially for determining 
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eligibility for the trial, a fasting blood sample should be drawn at or prior to the baseline 
visit (prior to the first dose of open-label drug). Microsampling procedures may be used 
for obtaining blood samples for clinical laboratory analysis in order to minimize the 
amount of blood drawn from subjects. The laboratory tests to be evaluated in this trial are 
listed in Table 3.7.3.2-1.
A urine pregnancy test will be performed at screening on all female subjects ≥ 12 years of 
age and all female subjects < 12 years of age if menstruation has started. Subjects with a 
positive result at screening will be excluded from the trial. In addition, urine and/or serum 
pregnancy tests can be performed at any point during the trial for female subjects
≥12 years of age and female subjects < 12 years of age if menstruation has started, if 
pregnancy is suspected. Any positive urine pregnancy test result will be confirmed by a 
serum pregnancy test. Treated subjects with a positive urine and serum pregnancy test 
must discontinue treatment, be withdrawn from the trial, and an immediately reportable 
event (IRE) form should be completed. 
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance. If one or 
more values are questionable, the test(s) may be repeated. If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor. In addition, follow-up unscheduled laboratory tests should be 
performed for clinically significant abnormalities. Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care.
Subjects will be excluded from the trial if they have any other abnormal laboratory test 
result at screening that, in the investigator’s judgment, is medically significant in that it 
would impact the safety of the subject or the interpretation of the trial results. The 
following laboratory test results are exclusionary:
1) Platelets 75,000/mm3
2) Hemoglobin 9 g/dL
3) Neutrophils, absolute 1000/mm3
4) Aspartate aminotransferase (AST) > 3 upper limit of normal (ULN) as defined 
by the central laboratory
5) Alanine aminotransferase (ALT) > 3 ULN as defined by the central laboratory
6) Creatinine 2 mg/dL
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Appendix 2 is included to assist investigators in their assessments of results that may be 
of potential clinical relevance, depending on the subject’s medical history and clinical 
presentation.
Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
Hematocrit
Hemoglobin
Platelet count
Red blood cell count
White blood cell count with differential 
Serum Chemistry:
Alkaline phosphatase 
ALT
AST
Total bilirubin 
Blood urea nitrogen
Calcium
Chloride
Cholesterol (total, low-density lipoprotein, and 
high-density lipoprotein)
Creatinine
Creatinine phosphokinase
Gamma glutamyl transferase 
Glucose
Glycosylated hemoglobin
Lactate dehydrogenase
Phosphorus, inorganic
Potassium
Total protein 
Sodium
Triglycerides
Uric acid
Urinalysis:
Blood
Glucose
Ketones
Microscopic exam (performed only if any part of 
the urinalysis is not negative)
pH
Protein
Specific gravity
Additional Tests:
Prolactinb
Serum pregnancy, for confirmation of positive urine 
tests
TSHa
Urine drug (including alcohol) screen
Urine pregnancy (FOCBP)
aIf the observed TSH level is outside of the normal range, tests of triiodthyronine (T3) and thyroxine 
(T4) levels will be assessed.
bThe blinded prolactin results will be reviewed by the designated unblinded medical  monitor.
3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
A complete physical examination at the visits designated in Table 3.7-1 and Table 3.7-2.  
The principal investigator or his/her appointed designee is primarily responsible for 
performing the physical examination. If the appointed designee is to perform the physical 
examination, he/she must be permitted by local regulations and his/her name must be 
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included on the US FDA Form 1572. Whenever possible, the same individual should 
perform all physical examinations. Any condition present at the post-treatment physical 
examination that was not present at the baseline examination should be documented as an 
AE and followed to a satisfactory conclusion. A complete physical examination is an 
integral part of study safety assessments and includes a urogenital assessment. A 
urogenital assessment should be performed on all trial subjects according to local medical 
standards as applied to other body systems. For the purposes of this trial, at a minimum, a 
screening urogenital exam is required, which could have been performed up to one 
calendar year prior to the date of the ICF being signed, or can be performed during the 
screening period. The urogenital examination may be performed by the subject’s primary 
care provider or pediatrician as long as the source records are obtained and the findings 
documented. Post-baseline, medically relevant questions about the urogenital body 
system must be asked of the subject at all protocol-required physical exams, with answers 
documented accordingly in the source. The extent and scope of any part of the physical 
examination is to be left to the discretion of the investigator as deemed appropriate for 
each subject.
3.7.3.3.2
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure and heart rate 
and will be performed at all in-clinic visits. If a remote visit is converted to an in-clinic 
visit, vital signs will be recorded. Vital signs will not be collected for remote visits that 
are not converted to occur in-clinic.
3.7.3.3.3
Body Weight, Height, and Waist Circumference
Height will be measured with a stadiometer, measuring stick, or tape at the visits 
designated in Table 3.7-1 and Table 3.7-2. Body weight will be measured at the visits 
designated in Table 3.7-1 and Table 3.7-2. Waist circumference will be measured with a 
measuring tape at the visits designated in Table 3.7-1 and Table 3.7-2. The following 
guidelines will aid in the standardization of these measurements:

The same scale should be used to weigh a given subject each time.

Scales should be calibrated and reliable; scales should be at zero just prior to 
each subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no 
shoes or heavy overgarments).

Weight and waist circumference should be recorded before a subject’s meal 
and at approximately the same time at each visit.
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
The waist circumference measurement will be accomplished by locating the 
upper hip bone and the top of the right iliac crest and placing a weighted 
measuring tape in a horizontal plane around the abdomen at the level of the 
crest. Before reading the tape measure, the assessor should assure that the tape 
is snug, but does not compress the skin, and is parallel to the floor. The 
measurement is to be made at the end of a normal exhalation.15
Utilizing the programing, the BMI (kg/m2) will be calculated from the height and the 
weight at the current (or closest preceding) visit using one of the following formulae, as 
appropriate: Weight (kg) (Height [m])2 or Weight (lb) (Height [in])2 x 703.
3.7.3.4
Electrocardiogram Assessments
A standard 12-lead ECG will be recorded at the visits designated in Table 3.7-1 and 
Table 3.7-2. It will be done at rest, with the subject lying down for approximately 5 
minutes before the ECG is obtained. A central ECG service will be utilized for reading all 
ECGs in order to standardize interpretations for the safety analysis. The ECG will be 
evaluated at the investigational site to determine the subject’s eligibility and to monitor 
safety during the trial. The principal investigator or qualified designee will review, sign, 
and date each ECG reading, noting whether or not any abnormal results are of clinical 
significance. The ECG will be repeated if any results are considered to be clinically 
significant.  
Based on the QTcF correction, a subject will be excluded from the trial if the correction 
is 450 msec (males) or ≥ 470 msec (females). Subjects with clinically significant ECG 
findings at screening may enter the open-label stabilization phase only after the screening 
ECG is repeated and determined by the investigator prior to treatment to have no 
abnormalities that are clinically significant.
3.7.3.5
Other Safety Assessments
3.7.3.5.1
Extrapyramidal Symptoms
3.7.3.5.1.1
Simpson-Angus Scale
The SAS16 consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia). Each item will be rated on a 5-point scale, with a score of 1 
representing absence of symptoms, and a score of 5 representing a severe condition. The 
SAS Total Score is the sum of the scores for all 10 items.
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3.7.3.5.1.2
Abnormal Involuntary Movement Scale
The AIMS14 assessment consists of 10 items describing symptoms of dyskinesia. Facial 
and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (eg, in the 
waiting room), and the investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10). Each item will be rated on a 5-point scale, with a score 
of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 
indicating a severe condition (for item 10, awareness/severe distress).  For this scale, the 
subject is to be sitting on a hard, firm chair. In addition, the AIMS includes 2 yes/no 
questions that address the subject’s dental status.
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 through 6, extremity movements; and 
item 7, trunk movements).
3.7.3.5.1.3
Barnes Akathisia Rating Scale
The BARS17 consists of 4 items related to akathisia: objective observation of akathisia by 
the investigator, subjective feelings of restlessness by the subject, subject distress due to 
akathisia, and global evaluation of akathisia. The first 3 items will be rated on a 4-point 
scale, with a score of 0 representing absence of symptoms and a score of 3 representing a 
severe condition. The global clinical evaluation will be made on a 6-point scale, with 0 
representing absence of symptoms and a score of 5 representing severe akathisia. To 
complete this scale, subjects will be observed while they are seated and then standing for 
a minimum of 2 minutes in each position. Symptoms observed in other situations (eg, 
while engaged in neutral conversation or engaged in activity on the ward) may also be 
rated. Subjective phenomena are to be elicited by direct questioning.
The BARS Global Score is from the global clinical assessment of akathisia from the 
panel BARS in the eSource.
3.7.3.5.2
Suicidality
Suicidality will be monitored throughout the trial using the C-SSRS (children’s version) 
at every clinic visit. The C-SSRS scale consists of a baseline evaluation that assesses the 
lifetime experience of the subject with suicide events and suicidal ideation and a 
postbaseline/“Since Last Visit” evaluation that focuses on suicidality since the last trial 
visit. The baseline C-SSRS form will be completed at the screening visit. The “Since Last 
Visit” C-SSRS form will be completed at all subsequent visits. If a subject’s C-SSRS 
results indicate active suicidal ideation and a plan/intent, then the results should be 
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discussed with the medical monitor, when the situation allows it, and the subject may be 
discontinued from the trial at the discretion of the investigator. Appropriate medical 
interventions and measures should be undertaken in such cases by the investigator.
3.7.3.5.3
Children’s Yale-Brown Obsessive Compulsive Scale
The CY-BOCS18 is a semi-structured interview used with children and adolescents ages 
6 to 17 years to rate the severity and type of symptoms in subjects with OCD. In general, 
the items depend on the subject's report; however, the final rating is based on the clinical 
judgment of the interviewer, and should include additional information supplied by 
others. The characteristics of obsessions and compulsions are rated for the week prior to 
the interview. The total CY-BOCS score is the sum of items 1 through 10 (excluding lb 
and 6b); whereas, the obsession and compulsion subtotals are the sums of items 1 through 
5 (excluding lb) and 10 (excluding 6b; respectively).
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent through the end of the evaluation period 
(defined as the time period during which subjects are evaluated for primary and/or 
secondary objectives) on the eSource. The investigator will record all medications and 
therapies taken by the subject for treatment of an AE or which caused an AE until the end 
of the trial (defined as the last date of contact or date of final contact attempt) on the 
eSource.
3.7.5
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource page for the last subject completing or 
withdrawing from the trial.
3.7.6
Interim Analysis Review Committee 
This trial will utilize an independent Interim Analysis Review Committee (IARC). The 
IARC will be responsible for reviewing efficacy data during the IA and will make trial 
recommendations (Section 7.4.4). The details of the IARC structure and its roles and 
responsibilities will be documented in an IARC charter.
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3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements. One IA is planned (Section 7.4.4) so that the trial can be 
terminated if the null hypothesis on the comparison between aripiprazole full dose and 
placebo is rejected at the IA time point.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP. The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Interruption
In this approximately year-long trial, it is expected that subjects may have one or more 
treatment interruptions during the open-label stabilization phase or double-blind 
randomized withdrawal phase. If a subject’s IMP treatment must be interrupted for 
medical or surgical reasons; liver test abnormalities; use of a prohibited concomitant 
medication; or other reasons (eg, hospital admission for an invasive procedure, a 
major medical condition, surgery; dental work, or a temporary situation that prevents 
subject compliance with the IMP administration schedule), the subject’s IMP should be 
resumed as early as the situation allows (see Section 3.8.3.4). If > 3 doses of IMP are 
missed in a row, a discussion should occur with the medical monitor to determine if the 
subject should be discontinued from the trial as a result of the treatment interruption.
3.8.3.2
Treatment Discontinuation
After randomization, a subject may stop treatment permanently for a variety of reasons.  
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
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3.8.3.3
Documenting Reasons for Treatment 
Interruption/Discontinuation
A subject may temporarily interrupt or discontinue IMP for a number of reasons 
including those listed below:

Reasons related to an AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAE 

Other potentially IMP-related safety concerns or AEs

Death

Reasons unrelated to medical condition (provide detail and review AE history with 
subject)

Withdrawal of informed consent (complete written withdrawal of consent form)

Lost to follow-up

Pregnancy (see Section 5.5)

Termination of all or part of the trial by the sponsor

Tolerability issues requiring down-titration of IMP after the Week 8 visit

Subject meets the criteria for relapse (ie, a loss of ≥ 50% of the improvement 
experienced during the open-label stabilization phase (ie, improvement at the last 
assessment of YGTSS before randomization) on the YGTSS TTS)
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 3.8.3.1 and/or Section 3.8.3.2 must be
followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
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withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up (these methods of follow-up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol-specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail,
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1 and Section 3.8.3.2). A subject may, however, indicate 
that further trial participation is creating a burden on their work or social schedule. 
Therefore, the investigator should follow the procedures outlined in Section 3.8.3.3 to 
determine if the subject can continue participation in the trial if modifications to his/her 
treatment and/or schedule of assessments can be accommodated. Only subjects who 
withdraw their permission for all of the above degrees of follow-up are considered to 
have completely withdrawn their consent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss with the subject their options of continuing in 
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the trial, preferably on therapy. The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent.  
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF/IAF), but who is not randomized or
assigned trial treatment.
For the purposes of this trial, treatment begins with the first dose of IMP in the open-label 
stabilization phase. If a subject fails to qualify for the trial during screening, he/she is 
permitted to be rescreened at a later date. However, a new ICF/IAF must be signed prior 
to reinitiating screening procedures. Subjects are permitted to be rescreened only once.  
Rescreened subjects will be assigned a new screening number.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete the Week 12 visit of the double-blind randomized 
withdrawal phase will be defined as trial completers. Protocol-specified post-treatment 
follow-up contacts will not qualify as the “last scheduled visit.” Subjects who are not 
completers are defined as those who “discontinued the trial.”
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the double-blind randomized withdrawal 
phase Week 12 visit, who do not have a known reason for discontinuation (eg, withdrew 
consent or AE), and for whom a survival status at the end of the trial cannot be 
determined will be classified as “lost to follow-up” as the reason for discontinuation. 
Survival status can be determined from a variety of sources, either by obtaining 
acceptable documentation for death (ie, death certificate, medical records, public records, 
statement by a family member or primary care physician) or acceptable documentation 
for life (ie, direct contact with the subject, medical records, successful telephone contact 
with the subject, statement by a family member or primary care physician, or public 
records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
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the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance 
The date of each IMP administration will be recorded in the eSource. Information 
regarding any missed or inappropriately administered doses will also be documented in
the eSource.
Accountability and compliance verification should be documented in the subject's trial 
records. Subjects must be counseled on the importance of taking the IMP as directed at 
all trial visits. If poor compliance continues (eg, multiple missed doses resulting in < 80% 
overall compliance at any point in the trial), discontinuation from the trial should be 
considered. This decision will be documented by the investigator in consultation with the 
medical monitor.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone. The investigator and sponsor will come as quickly 
as possible to a joint decision regarding the subject’s continuation in the trial. This 
decision will be documented by the investigator and the sponsor, and reviewed by the site 
monitor.
4
Restrictions
4.1
Prohibited Medications
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs). All trial personnel should be familiar with the content of the IB6 for aripiprazole in 
order to manage the subject’s condition adequately and select appropriate concomitant 
medications, if needed. The investigator should carefully assess the potential for 
interaction with aripiprazole before prescribing any concomitant medications.
All psychotropic medications and any medication for the treatment of tics must be
discontinued for at least 2 weeks (14 days) prior to the baseline visit, with the exception 
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of psychostimulant medications such as, but not limited to, Vyvanse, Adderall, Concerta, 
Metadate CR, Ritalin LA, Focalin, and Focalin XR, prescribed for the treatment of 
symptoms of ADHD, which are permitted during the trial. The use of psychostimulant 
medications is only permitted if the subject did not develop and/or have an exacerbation 
of the tic disorder after the initiation of treatment with the psychostimulant. The dose of 
any psychostimulant must have been stable for at least 4 weeks prior to screening. All 
SSRIs/SNRIs must be discontinued at least 4 weeks (28 days) prior to the baseline visit. 
In addition, long-acting (depot) neuroleptics must be discontinued for at least 1 full cycle 
(2 weeks to 1 month, depending on the drug) plus 2 weeks prior to the baseline visit. 
Other nutritional or dietary supplement and nonprescription herbal preparation for TD 
(eg, cannabinoids, N-acetylcysteine, omega-3 fatty acids, kava extracts, GABA 
supplements) are not permitted within 7 days prior to baseline and for the duration of the 
trial.
Clonidine, guanfacine, guanabenz, atomoxetine, and carbamazepine are prohibited during 
the trial and must be discontinued for at least 2 weeks prior to the baseline visit. Subjects 
must have discontinued aripiprazole treatment at least 30 days prior to the screening visit.  
The use of cytochrome P450 (CYP)3A4 or CYP2D6 inhibitors and CYP3A4 inducers is 
not permitted during the trial, as they may affect the PK of aripiprazole. Examples of 
inhibitors include, but are not limited to amiodarone, celecoxib, chlorpheniramine, 
cimetidine, clarithromycin, clemastine, diltiazem, erythromycin, itraconazole, 
ketoconazole, methadone, nefazodone, pyrilamine, quinidine, rifampin, terbinafine, 
tripelennamine, verapamil and human immunodeficiency virus protease inhibitors 
(eg, amprenavir, indinavir, nelfinavir, ritonavir and saquinavir). Examples of inducers 
include, but are not limited to, carbamazepine, dexamethasone, phenobarbital, phenytoin, 
and nonnucleoside reverse transcriptase inhibitors (eg, efavirenz and nevirapine). The 
medical monitor should be consulted for any questions regarding the potential for PK 
interactions with concomitant medications used by subjects during the trial.
Other guidelines for use of concomitant medications during the trial include the 
following:

Treatment of extrapyramidal symptoms: Benztropine (up to 4 mg/day) is not to be 
administered 12 hours prior to rating scales or benzodiazepines (up to 3 mg/day 
lorazepam equivalents) are not to be administered 4 hours prior to rating scales.

Treatment of allergy symptoms: Nonsedating antihistamines are permitted.
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
Treatment of cold/flu symptoms: Medications containing ingredients that have CNS 
effects should be limited to short-term use and discontinued as soon as the 
symptom(s) resolve.

Treatment of gastroesophageal reflux disease: The use of cimetidine is prohibited.  
All other medications for the treatment of gastroesophageal reflux disease are 
permitted.

Treatment of hypertension: Medications that are CYP3A4 or CYP2D6 inducers or 
inhibitors (eg, verapamil) are prohibited.

Treatment of diabetes: No additional guidelines.

Treatment of infection: No additional guidelines.
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
If there is a need for cognitive-behavioral therapy (CBT) for TD during the trial period, 
the subject will be excluded from trial participation. No CBT for TD will be allowed 
during the duration of the trial. CBT for other nonexclusionary disorders must remain 
consistent throughout the trial.
4.2.2
Nontherapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator. An elective procedure (minor surgery, dental surgery, orthopedic 
surgery, etc.) that might require hospitalization or anesthesia should be deferred until 
after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
Subjects will be instructed to refrain from drinking alcoholic beverages or using illicit 
drugs during participation in the trial. The investigator may request a urine drug screen or 
a blood alcohol test at any time during the trial if there is a suspicion of illicit drug or 
alcohol use.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
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relationship with this treatment. AEs would not include information recorded as medical 
history at screening for preplanned procedures for which the underlying condition was 
known and no worsening occurred. An adverse reaction is any untoward and unintended 
response to an IMP-related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred. It does not include an 
event that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible 
the reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, 
those required for reasons of convenience or other non-medical need) are 
not considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):  

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4).
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
Pregnancies are also defined as IREs. Although normal pregnancy is not an 
AE, it will mandate IMP discontinuation and must be reported on an IRE form 
to the sponsor. Pregnancy will only be documented on the AE eSource page if 
there is an abnormality or complication.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available. This review will be 
documented by the investigator’s dated signature on the laboratory report. For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests. If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eSource. The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs. To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question: “How have you 
felt since your last visit?” All AEs (serious and nonserious) reported by the subject must 
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be recorded on the source documents and eSource documentation provided by the 
sponsor. Serious AE collection is to begin after a subject has signed the ICF.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3. Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, serious hepatotoxicity, or confirmed pregnancy, by telephone, 
fax, or e-mail to the sponsor using the contact information on the cover page of this 
protocol. An IRE form must be completed and sent by e-mail, fax, or overnight courier to 
the sponsor. (Please note that the IRE form is NOT the AE eSource.)
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eCRF.
5.5
Pregnancy
For purposes of this pediatric trial, FOCBP are considered all female subjects ≥12 years 
of age and all female subjects < 12 years of age, if menstruation has started.
For FOCBP and for males who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(eg, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP. Two of the following precautions must be used:
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vasectomy, tubal ligation, vaginal diaphragm with spermicide, intrauterine device, birth 
control pills, birth control depot injection, birth control implant, condom with spermicide, 
or sponge with spermicide. Any single method of birth control, including vasectomy and 
tubal ligation, may fail, leading to pregnancy. The contraceptive method will be 
documented at each trial visit. Abstinence will be permitted, if it is documented at every 
trial visit.
Before enrolling FOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all FOCBP. The topics should generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, FOCBP must be advised of the importance of avoiding
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject and the subject’s legally acceptable representative (eg, guardian)
must sign an ICF/IAF stating that the above-mentioned risk factors and the consequences 
were discussed with them.
A urine pregnancy test for human chorionic gonadotropin (hCG) will be performed at 
screening on all female subjects ≥12 years of age and all female subjects < 12 years of 
age, if menstruation has started. If a urine test is performed and is positive, the 
investigator will follow-up with a confirmatory serum test.
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
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discontinuation may be considered for life-threatening conditions only after consultations 
with the Clinical Safety and Pharmacovigilance department (see the cover page of this 
protocol for contact information).
The investigator must immediately notify the sponsor of any pregnancy associated with
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor. The sponsor will forward Pregnancy 
Surveillance Form(s) for monitoring the outcome of the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of 6 months from the date of 
birth.
5.6
Procedure for Breaking the Blind 
The investigator is encouraged to contact the sponsor/contract research organization 
(CRO) medical advisor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergency 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor). The 
investigator must contact the sponsor/CRO medical advisor by telephone or e-mail with 
an explanation of the need for opening the treatment assignment code within 24 hours of 
opening the code. If the blind is broken, the Clinical Safety and Pharmacovigilance 
department must be notified immediately (see the cover page of this protocol for contact 
information). Documentation of breaking the blind should be recorded in the subject’s 
medical record with the date and time the blind was broken and the names of the 
personnel involved. Once the blind is broken for a subject, that subject may not reinitiate 
treatment with the IMP.
5.7
Follow-up of Adverse Events 
For this trial, information on all AEs will be followed for up 30 (+ 3) days after the last 
dose of IMP has been administered.
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5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eSource. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history and occupation).
5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs up to 30 (+ 3) days after 
the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eSource page. If updated information (eg, 
resolved status) on SAE or IRE status becomes available after a subject’s last scheduled 
contact (up to last in-clinic visit for the entire trial), this must be reported to the sponsor 
and recorded on the AE eSource, according to the appropriate reporting procedures. The 
investigator will follow SAEs until the events are resolved, stabilized, or the subject is 
lost to follow-up or has died. Resolution means that the subject has returned to the 
baseline state of health and stabilized means that the investigator does not expect any 
further improvement or worsening of the subject’s condition. The investigator will 
continue to report any significant follow-up information to the sponsor up to the point the 
event has resolved or stabilized, or the subject is lost to follow-up or has died.
5.7.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring after Last Scheduled 
Contact
Any new SAEs reported to the investigator which occur after the last scheduled contact
and are determined by the investigator to be reasonably associated with the use of the 
IMP, should be reported to the sponsor. This may include SAEs or IREs that are captured 
on follow-up telephone contact or at any other time point after the defined trial period.
The investigator should follow SAEs or IREs identified after the defined trial period and
continue to report any significant follow-up information to the sponsor until the events 
are resolved or stabilized, or the subject is lost to follow-up or has died.
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6
Pharmacokinetic Analysis
No PK analysis is planned.
7
Statistical Analysis
7.1
Sample Size
The planned sample size for the double-blind randomized withdrawal phase is 
114 subjects (ie, 38 subjects per treatment group). Assuming the proportion of 
randomized subjects experiencing relapse during the double-blind randomized 
withdrawal phase will be 65% in the placebo group and 34% in each of the 2 aripiprazole 
dose groups, 114 subjects will provide approximately 80% power to detect a hazard ratio 
of 0.4 for release (either aripiprazole dose group versus placebo) at the alpha level of 0.05 
(2-sided). Under the above assumptions, a total of 51 relapse events are expected to be 
observed during the randomization phase. However, subject enrollment will stop when 
51 relapse events have accrued or 114 subjects have been randomized, whichever occurs 
earlier.
The sample size will allow one IA at approximately 70% of events accrual time point. 
The O’Brian-Fleming boundaries were used for sample size calculation of the interim 
analysis so that the interim analysis will be conducted when 36 relapse events occur.19
The 2-sides alpha levels for the IA is 0.016, and the alpha left for the final analysis will 
be 0.045.
In order to randomize 114 subjects, approximately 228 subjects will need to enter the 
open-label stabilization phase of the trial, assuming that the stabilization rate is 50%.
7.2
Datasets for Analysis
The following analysis datasets are defined for this trial:

Open-label Safety Sample: The Open-label Safety Sample includes all subjects that 
are administered at least one dose of IMP during the open-label stabilization phase.

Intent to treat (ITT) Sample: All subjects who are randomized and receive at least one 
dose of randomized IMP will be included in this dataset and analyzed according to 
the treatment group they are randomized to. The ITT Sample will serve as the 
primary efficacy dataset for all efficacy endpoints in the double-blind randomized 
withdrawal phase. 
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
Randomized Safety Sample: All subjects who receive at least one dose of randomized 
IMP during the double-blind randomized withdrawal phase will be included and 
analyzed according to the treatment actually received. 
7.3
Handling of Missing Data
The primary endpoint is time from randomization to relapse during the double-blind 
randomized withdrawal phase. Subjects who complete or discontinue from the 
randomization phase without relapses will be considered as non-informative censoring in 
the primary analysis of the primary endpoint. Non-informative censoring means the 
dropout reason for subject who drops out of the trial without relapse is unrelated to 
efficacy. However, as the possibility of potential informative censoring in the randomized 
phase cannot be ruled out, sensitivity analyses of the primary endpoint will be performed 
under the assumption of informative censoring. Details of such sensitivity analyses will 
be provided in the statistical analysis plan (SAP). 
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary endpoint is time from randomization to relapse during the double-blind 
randomized withdrawal phase. Subjects who complete or discontinue from the 
randomization phase without relapses will be considered as censored observations. The 
primary objective of the trial is to evaluate the long-term efficacy of aripiprazole 
once-daily treatment in pediatric subjects with TD. This will be accomplished by 
comparing the long-term efficacy of aripiprazole full-dose and half-dose with that of 
placebo with regard to time to relapse. Hazard ratio and its 95% confidence interval (CI) 
will be estimated from the Cox proportional hazard model with treatment as a factor.  The 
p-value from the log rank test will be presented to compare survival (subjects free of 
relapse) distributions, ie, Kaplan-Meier (KM) curves, between the treatment groups.
Analyses of the primary endpoint will use the data of subjects from the ITT Sample.
The statistical comparison will be performed by the log-rank test comparing each 
aripiprazole treatment groups with placebo at an overall nominal significance level of 
0.05 (two-sided) following a group sequential procedure described as follows. One IA is 
planned at approximately 70% of events accrual time point using the O’Brian-Fleming 
boundaries for rejection of the null hypothesis, as detailed in Table 7.4.1-1.
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Table 7.4.1-1
Boundaries for Rejection of Null Hypothesis for Interim and 
Final Analysis
Analysis
Number of Events
Two-sides Alpha Levela
Interim analysis (70%)
36
0.016
Final analysis (100%)
51
0.045
aObtained using East 6.4 sample size software.
As there are 2 comparisons of the primary endpoint (one for aripiprazole full-dose vs 
placebo and the other for aripiprazole half-dose vs placebo), Type I error rate will be 
controlled for the primary endpoint at the alpha level specified in Table 7.4.1-1 using a 
fixed sequence procedure in the order of the full-dose and then the half-dose
comparisons. That is, one must reject the null hypothesis of the comparison of
aripiprazole full-dose to placebo at the level of 0.016 for interim analysis and 0.045 for 
final analysis (two-sided) in order to proceed to test the hypothesis of the comparison of 
aripiprazole half-dose to placebo at the level of 0.016 for interim analysis and 0.045 for 
final analysis (two-sided).
As a secondary analysis of the primary endpoint, the proportion of subjects experiencing 
relapse during the double-blind randomized withdrawal phase will be compared between 
each of the aripiprazole dose groups to placebo. The proportion of relapsed subjects will 
be computed as 1 minus the KM estimate of the proportions of subjects free of relapses 
during the double-blind randomized withdrawal phase. Group difference in the
proportion of relapsed subjects will be tested using 2-sided Z test with standard error 
computed from the Greenwood formula. Point estimate of the group difference and its 
95% CI will also be provided
Sensitivity analyses will be conducted to assess the sensitivity of the primary efficacy 
analysis results to the potential informative censoring which will be detailed in the SAP.
Subgroup analyses may be conducted for the primary endpoint based on subject baseline 
YGTSS TTS score, sex, and age if specific subgroups have reasonable sample sizes to 
permit such analyses.
7.4.2
Secondary Endpoint Analysis
Not applicable.
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7.4.3
Exploratory Efficacy Endpoint Analysis
7.4.3.1
Open-label Stabilization Phase
Descriptive statistics will be provided for the scores of each efficacy scale assessed 
during the open-label stabilization phase and their change from trial baseline for the 
Open-label Safety Sample. For CGI-TS Improvement score, only its observed value at
each visit will be summarized.  
7.4.3.2
Double-blind Randomized Withdrawal Phase
Exploratory efficacy endpoints during the double-blind randomized withdrawal phase 
include:

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in YGTSS TTS score

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in Total YGTSS score

Mean change from randomization to last visit (Week 12 for completers and 
withdrawal visit for discontinued subject) in CGI-TS Severity score

CGI-TS Improvement score at last visit (Week 12 for completers and withdrawal visit 
for discontinued subject)
For the above endpoints except the CGI-TS Improvement score, randomization baseline 
is defined as the assessment taken at the last visit of the open-label stabilization phase 
prior to the first dose of the randomized IMP. 
Variables in the form of change from randomization baseline will be analyzed using 
mixed model repeated measures (MMRM) under the assumption of missing at random 
(MAR). The time variable is scheduled visits, which will be treated as a categorical 
repeated factor. The MMRM model will include terms of treatment, visit, and treatment 
by visit interactions as fixed categorical effects, baseline as well as baseline by visit 
interactions as covariates, and a single unstructured covariance matrix assumed for all 
treatment arms in the model. Restricted maximum likelihood estimates of the treatment 
difference, their 2-sided 95% CIs and p-values (using Kenward-Roger degrees of 
freedom) from the MMRM inference will be provided. 
The change from randomization baseline to Week 12 of the double-blind randomized 
withdrawal phase in the above variables will also be analyzed using analysis of 
covariance (ANCOVA) with missing data being imputed by last observation carried 
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forward. The ANCOVA model will include treatment as a factor and baseline value as a 
covariate. 
To evaluate the sensitivity of the results to missing data that are potentially missing not at 
random (MNAR), sensitivity analyses will be conducted with multiple imputations for 
missing data under the assumption of MNAR, which will be detailed in the SAP.
CGI-TS Improvement score from postbaseline visits will be analyzed in a similar fashion 
to those change from baseline variables except that there will not be adjustment for 
baseline value in the analyses of CGI-TS Improvement score.
7.4.4
Interim Analysis
One IA is planned for the assessment of efficacy. The analysis will be performed 
following a group sequential approach at approximately 70% of events accrual time point 
and will include all randomized subjects. Subjects who withdraw early from the trial, or 
who are still in the trial at the end of trial without relapse, will be considered as censored 
observations. The O’Brian-Fleming boundaries will be used for the IA so that the IA will 
be conducted when 36 impending relapse events are available. The 2-sided alpha level for 
the IA is 0.016 and the alpha left for the final analysis will be 0.045 as specified in Table 
7.4.1-1. Additionally, a 95% CI for the hazard ratio (either aripiprazole or placebo) will 
be provided using the Cox proportional hazard model with term of treatment in the 
model.
If the null hypothesis on comparison between aripiprazole full dose and placebo is 
rejected at the IA time point, the trial will be terminated. An IA plan will be developed to 
document the details of the stopping rules, data flow and other logistical considerations 
relating to the IA.
7.5
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by descriptive statistics 
including tabulations of mean, median, range, and SD for continuous variables, and 
tabulations of frequency distributions for categorical variables. These summary statistics 
will be provided for the Open-label Safety Sample as well as by treatment groups for the 
ITT Sample.
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7.6
Safety Analysis
7.6.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  
7.6.1.1
Open-label Stabilization Phase
The incidence of the following events during the open-label stabilization phase will be 
summarized for the Open-label Safety Sample:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
7.6.1.2
Double-blind Randomized Withdrawal Phase
The incidence of the following events during randomized withdrawal phase will be 
summarized for the Randomized Safety Sample:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Data
The incidence of potentially clinically relevant values from clinical laboratory tests will 
be provided for the open-label stabilization phase and by treatment group for the 
randomized withdrawal phase with the safety samples appropriate to each phase. In 
addition, change from baseline in clinical laboratory values will be descriptively 
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summarized by visit for the Open-label Safety Sample and also by treatment group for 
the Randomized Safety Sample.
7.6.3
Physical Examination, Vital Signs, Body Weight, and Waist 
Circumference Data
The incidence of potentially clinically relevant vital sign abnormalities and body weight 
change will be reported for the open-label stabilization phase and by treatment group for 
the double-blind randomized withdrawal phase with the safety samples appropriate to 
each phase. Vital sign parameters, body weight, and waist circumference will also be 
evaluated by their changes from trial baseline for the Open-label Safety Sample and by 
change from randomization baseline for each treatment group for the Randomized Safety 
Sample. The BMI values will be calculated based on height and weight measurements 
and its results will be summarized by change from baseline similarly to body weight.
Physical examination data will be listed.
7.6.4
Electrocardiogram Data 
ECG parameters will be evaluated by tabulating the incidence of their clinically relevant 
changes and by summarizing their changes from the appropriate baseline. Results will be 
summarized for the open-label stabilization phase and by treatment group for the 
randomized withdrawal phase with the safety samples appropriate to each phase.  
For the analysis of QT and QTc data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values. The following 
QT corrections will be used:
1) QTcF is the length of the QT interval corrected for heart rate by the Fridericia
formula: QTcF = QT/(RR)0.33
2) QTcN is the length of the QT interval corrected for heart rate by the FDA
Neuropharm Division formula: QTcN = QT/(RR)0.37
7.6.5
Other Safety Data
7.6.5.1
Extrapyramidal Symptoms
Extrapyramidal Symptom scales including SAS, AIMS, and BARS scores will be 
evaluated by descriptively summarizing their changes from appropriate baseline for the 
Open-label Safety Sample and by treatment group for the Randomized Safety Sample. 
Results will be presented by visit.
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7.6.5.2
Suicidality
The incidence of suicidality, suicidal behavior and suicidal ideation will be calculated 
from the potential suicide events recorded on the C-SSRS (children’s version) for the 
single-blind stabilization phase and double-blind randomized withdrawal phase with the 
safety samples appropriate to each phase.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the Aripiprazole IB.6
8.1
Packaging and Labeling
Trial medication will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent. The IR tablet is an 
immediate-release oral formulation in 4 dose strengths (ie, 2.0, 5.0, 10.0, and 
15.0 mg/tablet).  Matching placebo tablets will be used in the double-blind randomized 
withdrawal phase.
The IMP will be labeled to clearly disclose the subject ID, compound ID, trial number, 
sponsor’s name and address, instructions for use, route of administration, and appropriate 
precautionary statements and other information required by local regulatory authorities.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to investigators and their designees. Neither the investigators nor any designees may 
provide IMP to any subject not participating in this protocol. The IMP will be stored 
according to the storage conditions indicated on the clinical label(s).
The clinical site staff will maintain a temperature log in the drug storage area recording 
the temperature at least once each working day. Temperature excursions, outside of the 
specific conditions for the IMP (as noted on the label), will be immediately reported to 
the sponsor.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned.
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8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially-used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial sites. The IMP may only be destroyed by the trial site(s) [if applicable], if 
approved by the sponsor and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 
container. Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return or destruction [if applicable] of used IMP 
containers, unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint is any written, electronic, or verbal communication by a 
healthcare professional, consumer, subject, medical representative, Competent Authority, 
regulatory agency, partner, affiliate or other third party that alleges deficiencies or 
dissatisfaction related to identity, quality, labeling, packaging, reliability, safety, 
durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all product quality complaints (PQCs) identified 
through any means from the receipt of the IMP from the sponsor, or sponsor’s designee, 
through and including reconciliation and up to destruction, including subject dosing. The 
investigator or designee must notify the sponsor (or sponsor’s designee) by e-mail or 
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telephone within 24 hours of becoming aware of the PQC according to the procedure 
outlined below.

Online – Send information required for reporting purposes (listed below) to 

Phone - Rocky Mountain Call Center at 
 
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
complaint sample is available for return, return it in the product retrieval package, which
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to progress 
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notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
Source document and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records. These data will be collected 
into a system that is fully validated. Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms. Designated trial site staff will not be given access to the 
system until they have been appropriately trained. Information to be originally captured 
and reviewed electronically shall include details of the subject visit and the protocol-
required assessments performed as a part of these visits, medical history, AEs, and 
concomitant medications. Because this trial is using an electronic source record as the 
original point of data capture, there is no additional data entry step for the site for data 
collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start. Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change. Changes will be made by striking a 
single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
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Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess site operational capabilities and to perform other 
monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate. After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations.
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.  
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
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sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of eSource with source documents. The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor. The IRB/IEC will evaluate the ethical, scientific and 
medical appropriateness of the trial. Further, in preparing and using screens in eSource, 
the investigator, sub-investigator and their staff will take measures to ensure adequate 
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care in protecting subject privacy. To this end, a subject number and subject 
identification code will be used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject numbers in eSource. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB/IEC, as required by local 
regulations. Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s). Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial. A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
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When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; 
AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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15
References
1
Leckman JF, Zhang H, Vitale A, Lahnin F, Lynch K, Bondi C, et al. Course of tic 
severity in Tourette Syndrome: The first two decades. Pediatrics. 1998:102(Pt 1):14 
9.
2
Cutler D, Murphy T, Gilmour J, Heyman I. The quality of life of young people with 
Tourette syndrome. Child Care Health Dev. 2009;35:496-504.
3
Golder T. Tourette Syndrome: Information for school nurses.  J Sch Nurs. 2010 
Feb:26(1):11-7.
4
Steeves TD, Fox SH. Neurological basis of serotonin-dopamine antagonists in the 
treatment of Gilles de la Tourette syndrome. Prog Brain Res. 2008;172:495-513.
5
Wong DF, Brasic JR, Singer HS, Schretlen DJ, Kuwabara H, Zhou Y, et al. 
Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette 
syndrome:  Clues from an in vivo neurochemistry study with PET. 
Neuropsychopharmacology. 2008;33:1139-51.
6
Aripiprazole Investigator Brochure, Edition 21, 25 Aug 2017.
7
Yoo HK, Joung YS, Lee JS, Song DH, Lee YS, Kim JW, et al. A multicenter, 
randomized, double-blind, placebo-controlled study of aripiprazole in children and 
adolescents with Tourette's disorder. J Clin Psychiatry. 2013 Aug;74(8):e772-e780.
8
Budman C, Coffey BJ, Shechter R, Schrock M, Wieland N, Spirgel A, Simon E. 
Aripiprazole in children and adolescents with Tourette disorder with and without 
explosive outbursts. J Child Adolesc Psychopharmacol. 2008 Oct;18(5):509-15.
9
Cui YH, Zheng Y, Yang YP, Liu L, Li J. Effectiveness and tolerability of aripiprazole 
in children and adolescents with Tourette’s disorder: a pilot study in China. J Child 
Adolesc Pyschopharmacol. 2010 Aug;20(4):291-8.
10 Lyon GJ, Samar S, Jummani R, Hirsch S, Spirgel A, Goldman R, et al. Aripiprazole 
in children and adolescents with Tourette's disorder: an open-label safety and 
tolerability study. J Child Adolesc Psychopharmacol. 2009 Dec;19(6):623 33.
11 Ghanizadeh A. Systemic review of aripiprazole for the treatment of children and 
adolescents with tic disorders. Neurosciences. 2012 Jul;17(3):200-204.
12 Approved Abilify (aripiprazole) United States prescribing information, Dec 2014; 
Otsuka America Pharmaceutical, Inc, Rockville, MD.
13 International Conference on Harmonisation (ICH) [homepage on the Internet].  E6:  
Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2014 Dec 5].  
14 Guy W. ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW 
Publication No. ADM 76-338). Rockville, MD, US Department of Health, Education, 
and Welfare, 1976:218-22.
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15 The Practical Guide:  identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
and Blood Institute. North American Association for the Study of Obesity. NIH 
Publication. 
16 Simpson GM, Angus JWS.  A rating scale for extrapyramidal side effects.  Acta 
Psychiatr Scand.  1970;212:S11-S19.
17 Barnes TR.  A rating scale for drug-induced akathisia.  Br J Psychiatry.  
1989;154:672-6.
18 Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, et al. 
Children's Yale-Brown Obsessive Compulsive Scale: Reliability and validity. J Am 
Acad Child Adolesc Psychiatry. 1997;36:844-52.
19 O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35(3):549-56.
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Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 120 bpm
< 50 bpm
15 bpm increase
15 bpm decrease
Systolic Blood Pressureb
> 180 mmHg
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic Blood Pressureb
> 105 mmHg
< 50 mmHg
15 mmHg increase
15 mmHg decrease
Weight
-
7% increase
7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistrya
AST (SGOT)
3 x ULN
ALT (SGPT)
3 ULN
Alkaline phosphatase
3 ULN
LDH
3 ULN
BUN
30 mg/dL
Creatinine
2.0 mg/dL
Uric Acid
Male
10.5 mg/dL
Female
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
CPK
3 ULN
Prolactin
> ULN
Hematologya
Hematocrit
30 % and decrease of 3 percentage points from baseline
Hemoglobin
Male
11.5 g/dL
Female
9.5 g/dL
White blood count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
1.5 THOUS/µL
Platelet count
75,000/ mm3
Urinalysisa
Protein
Increase of 2 units
Glucose
Increase of 2 units
Casts
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Hb1Ac
7%
Potassium
3.0 mEq/L or 5.5 mEq/L
Sodium
120 mEq/L or 160 mEq/L
Phosphorous, inorganic
1.0 mg/dL
Magnesium, serum
0.7 mEq/L or 5.0 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose, Fasting, serum
115 mg/dL
Total Cholesterol, Fasting
240 mg/dL 
LDL Cholesterol, Fasting
160 mg/dL 
HDL Cholesterol, Fasting
30 mg/dL 
Triglycerides, Fasting
Male
160 mg/dL
Female
120 mg/dL
aAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).  
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Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rate
Tachycardia
120 bpm
increase of  15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 0.20 second
increase of  0.05 second
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 0.12 second
increase of 0.02 second
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post trial entry
ST/TMorphological
Myocardial Ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTc 
450 msec (males) 
≥ 470 msec (females)
10% increase
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle-branch block or right bundle-branch block.
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Appendix 4
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
30 Apr 2018
PURPOSE:
The purpose of amending the Protocol 31-14-204, issued 08 Jan 2016, was to:

Add a Week 10 visit to the double-blind phase.

Allow for remote visits (ie, telemedicine) for selected trial visits.

Decrease the number of SAS, AIMS, BARS assessments and vital signs 
measurements.

Add waist circumference.

Specify that the C-SSRS is the children’s version.

Add the option of microsampling for clinical laboratory tests.

Add language for eSource and ePlatform.

Add an IA.

Revise language regarding sample size calculation and primary endpoint analysis.

Clarify inclusion/exclusion criteria.

Delete OPDC contact information in the appendices.

Delete sample assessment scales in the appendices.

Update the protocol to conform to the Otsuka template and style guide.

Correct minor typographical errors.
BACKGROUND:
Changes to Protocol 31-14-204 were made to improve clarity and to update the protocol 
per feedback received from the FDA.
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MODIFICATIONS TO PROTOCOL:
Description of 
Change
Rationale for Change
Sections Affected by Change
Update of 
background 
information
Updated to include information from 
current Investigator’s Brochure 
(Edition 21).
Section 1.3 Known and Potential Risks and 
Benefits
Addition of a 
Week 10 visit 
during the 
double-blind 
phase
Per FDA recommendation.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Section 3.7. Trial Procedures
Addition of the 
option of 
telemedicine at 
select visits
To potentially improve subject 
participation by minimizing clinic 
visits.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Section 3.7. Trial Procedures
Decrease the 
number of SAS, 
AIMS, BARS 
assessments and 
vital signs 
measurements
To limit specific assessments to 
face-to-face visits.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Section 3.7. Trial Procedures
Add waist 
circumference
To add waist circumference whenever 
body weight is measured.
Protocol Synopsis
Section 3.5.2 Safety Endpoint(s)
Section 3.7. Trial Procedures
Section 7.6.3 Physical Examination, Vital 
Signs, and Body Weight
Specification 
that the C-SSRS 
is the children’s 
version
To specify that the children’s version of 
the C-SSRS will be used, as it is 
appropriate for this subject population.
Protocol Synopsis
Section 3.7. Trial Procedures
Section 7.6.5.2 Suicidality
Addition of 
eSource and 
ePlatform 
language
To update language to include eSource 
and ePlatform technology.
Section 3.4.1 Informed Consent
Section 9.2 Data Collection
Revision of 
sample size 
calculation
To allow one IA at approximately 70% 
of events accrual time point.
Protocol Synopsis
Section 7.1 Sample Size
Addition of an 
IA
To include one IA in the protocol.
Protocol Synopsis
Section 3.7.6 Interim Analysis Review 
Committee
Section 3.8 Stopping Rules, Withdrawal 
Criteria, and Procedures
7.4.4 Interim Analysis Review Committee
Revision of 
primary 
endpoint 
analysis
To include additional details about 
primary endpoint analysis.
Section 7.4.1 Primary Endpoint Analysis
Clarification of 
inclusion/
exclusion 
criteria
To clarify inclusion criterion regarding 
consent/assent, and exclusion criteria 
regarding substance abuse, herbal 
medications, and previous clinical trial 
experience. 
Protocol Synopsis
Section 3.4 Eligibility Criteria
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4.1 Protocol and Protocol Amendments
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Version 5.0, 04 Mar 2019
Description of 
Change
Rationale for Change
Sections Affected by Change
Deletion of 
OPDC contact 
information 
from the 
appendices
To eliminate the need to modify the 
protocol due to changes in OPDC 
personnel.
Appendix 1
Deletion of 
sample 
assessment 
scales in the 
appendices
It is no longer the Otsuka convention to 
include sample scales in protocol 
appendices.
Appendices 5 to 11
Revisions to 
adhere to the 
current Otsuka 
protocol 
template
To adhere to the current Otsuka 
protocol template.
Section 3.4.1 Informed Consent/Informed 
Assent
Section 3.7.4 Prior and Concomitant 
Medications
Section 5.4 Potential Serious Hepatotoxicity
Section 5.7 Follow-up of Adverse Events
Section 3.9 Screen Failures
Section 8.4 Returns and Destruction
Correction of 
minor 
typographical
errors
To adhere to Otsuka standards and style 
guide.
Throughout protocol
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this amendment showing all changes from the previous 
version will be produced and will be available upon final approval of this amendment.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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Protocol 31-14-204
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Version 5.0, 04 Mar 2019
Amendment Number:
2
Issue Date:
20 Jun 2018
PURPOSE:
The purpose of amending the Protocol 31-14-204, Amendment 1, issued 30 Apr 2018, 
was to:

Add the EudraCT number.

Increase the number of proposed sites.

Specify that randomization will be stratified by region and body weight.

Clarify exclusion criterion #17.

Remove the option for the screening visit to be conducted remotely.

Remove the option for remote visits during the open-label stabilization phase after 
the Week 12 visit.

Clarify dose titration and specify when and how dose adjustments are permitted.

Add language regarding relapse.

Specify conditions for the measurement of blood pressure.

Remove triplicate ECGs so that only one ECG is done.

Add details regarding C-SSRS results.

Add missing clinical laboratory assessments.

Correct minor typographical errors and add clarifications to text.
BACKGROUND:
Changes to Protocol 31-14-204 were made to improve clarity and consistency of the 
document.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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Version 5.0, 04 Mar 2019
MODIFICATIONS TO PROTOCOL:
Description of 
Change
Rationale for Change
Sections Affected by Change
Addition of 
EudraCT 
number
Per regulatory requirements
Title Page
Protocol Synopsis
Increase in the 
number of 
proposed sites
To increase the number of potential 
sites to 70 sites.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Addition of 
language 
regarding 
stratification of 
randomization
To specify that randomization will be 
stratified by region and body weight.
Protocol Synopsis
Section 3.6.1 Randomization
Clarification of 
exclusion 
criterion #17
To specify types of nutritional, dietary, 
and herbal supplements for TD that are 
prohibited.
Protocol Synopsis
Section 3.4.3 Exclusion Criteria
Section 4.1 Prohibited Medications
Removal of 
option for 
screening 
assessments to 
be done 
remotely
To ensure consistency of screening 
assessments.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Section 3.7. Trial Procedures
Removal of 
remote visits 
after Week 12
To ensure appropriate evaluation of 
subjects and dose titration.
Protocol Synopsis
Section 3.1 Type/Design of Trial
Section 3.7. Trial Procedures
Provide details 
regarding dose 
titration
To ensure appropriate weight-based 
dosing and titration steps.
Section 3.2 Trial Treatments
Section 3.8.3.3 Documenting Reasons for 
Treatment Interruption/Discontinuation
Addition of 
language 
regarding 
relapse 
To state that subjects who meet relapse 
criteria should be discontinued.
Section 3.1 Type/Design of Trial
Section 3.8.3.3 Documenting Reasons for 
Treatment Interruption/Discontinuation
Specify sitting 
and standing for 
blood pressure 
measurements
To ensure consistency of blood 
pressure measurements.
Section 3.7. Trial Procedures
Remove 
triplicate ECGs
To require only one ECG to be done 
per visit.
Section 3.4.2 Exclusion Criteria
Section 3.7. Trial Procedures
Section 7.6.4 Electrocardiogram Data
Specify 
procedures 
regarding 
C-SSRS results
To specify that the investigator should 
discuss C-SSRS results with the 
medical monitor if they show active 
suicidal ideation and a plan/intent 
Section 3.7.3.5.2 Suicidality
Addition of 
missing 
laboratory 
parameters
To align Table 3.7.3.2-1 with other 
Otsuka TD protocols.
Table 3.7.3.2-1 Clinical Laboratory 
Assessments
Correction of 
minor
typographical 
errors
To adhere to Otsuka standards and style 
guide.
Throughout protocol
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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Version 5.0, 04 Mar 2019
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this amendment showing all changes from the previous 
version will be produced and will be available upon final approval of this amendment.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 31-14-204
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Version 5.0, 04 Mar 2019
Administrative Change Number:
1
Issue Date:
14 Sep 2018
PURPOSE:
The purpose of this administrative change to the Protocol 31-14-204, Amendment 2, 
issued 20 Jun 2018, was to correct and/or clarify the language related to IRT registration 
of subjects, collection of vital signs, clinical laboratory tests, ECGs, and administration of 
the CY-BOCS and K-SADS-PL. 
BACKGROUND:
Changes to Protocol 31-14-204 were made to accurately describe the functioning of the 
ePlatform system, collection of vital signs, clinical laboratory tests, ECGs, and 
administration of the CY-BOCS and K-SADS-PL.
MODIFICATIONS TO PROTOCOL:

Deletion of the diagnostic supplement of the K-SADS-PL (Protocol Synopsis, 
Section 3.4.2: Inclusion Criteria, and Schedule of Assessments [Table 3.7-1 and 
section 3.7.1.1]).

Removal of “register subject in IRT” from the Schedule of Assessments (Tables 3.7-1 
and 3.7-2 and throughout Section 3.7.1).

Addition of a footnote to the Schedule of Assessments (Tables 3.7-1 and 3.7-2) to 
specify that vital signs will be collected at clinic visits only.

Deletion of insulin from the list of clinical laboratory tests (Table 3.7.3.2-1: Clinical 
Laboratory Assessments).

Addition of a statement regarding the central reading of ECGs (Section 3.7.3.4: 
Electrocardiogram Assessments).

Clarification regarding the CY-BOCS (Section 3.7.3.5.3: Children’s Yale-Brown 
Obsessive Compulsive Scale).

Correction of minor formatting issues.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this administrative change showing all changes from the
previous version of the protocol will be produced and will be available upon final 
approval of this administrative change.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Version 5.0, 04 Mar 2019
Administrative Change Number:
2
Issue Date:
04 Mar 2019
PURPOSE:
This administrative change will not affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the trial. The purpose of this administrative 
change to the Protocol 31-14-204, Amendment 2, Administrative Change 1, issued 
14 Sep 2018, was to correct discrepancies between the schedule of assessments and 
corresponding information regarding collection of vital signs, YGTSS and CGI-TS 
collection dates, AIMS, BARS, and SAS collection dates, and to clarify language 
regarding remote visits.
BACKGROUND:
This administrative change to the aripiprazole pediatric Tourette’s Disorder 
Protocol 31-14-204 is to clarify language related to two scales for disease severity and 
response to therapy, in order to limit risk of protocol deviations and inconsistencies in 
data collection. The administrative change will resolve language contradictions between 
the protocol and schedule of assessments facilitating continuity in conduct of this global 
study across all participating sites. 
1)
Clarify language regarding vitals assessments, to accommodate administration if 
clinically indicated. Reconcile any inconsistencies with intent of frequency and schedule 
of assessments.
2)
Resolve inconsistency in protocol relative to schedule of assessments, regarding 
administration of YGTSS and CGI-TS, which is to be collected at all open-label visits 
except at Week 3.
3)
Resolve contradiction in protocol language as it pertains to administration of 
AIMS, BARS, and SAS, which should only be conducted at Weeks 1 and 4. The current 
version (Amendment 2) may be misconstrued, implying administration at Weeks 1 and 2.
4)
Currently, Weeks 6 and 10 in the open-label phase and Weeks 3, 6, and 10 in the 
double-blind phase are listed as visits that can occur by telephone, web, in-clinic, or other 
acceptable means of contact. The YGTSS is a required assessment on open-label visits 
Week 6 and 10, and double-blind visits Weeks 3, 6, and 10 which can occur by 
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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Version 5.0, 04 Mar 2019
telephone, web, in-clinic, or other acceptable means of contact. YGTSS requires 
visualization of the subject and thus a clarification of this requirement for this scale will 
be added.
MODIFICATIONS TO PROTOCOL:

Definition of cycle length for long-acting (depot) neuroleptics added in Section 3.1, 
Section 3.7.1.1, and Section 4.1.

Inclusion of C-SSRS added to occur at Week 3 in Schedule of Assessments 
(Table 3.7-1) and Section 3.7.1.5.

Inclusion of vital signs at visits 3, 6, 10, 14 and 18 to the Schedule of Assessments 
(Table 3.7-1).

Inclusion of vital signs visits at Weeks 3, 6, and 10 to the Schedule of Assessments 
(Table 3.7-2).

Revision of footnotes in Schedule of Assessments (Tables 3.7-1 and 3.7-2), 
Section 3.7.1.4, Section 3.7.1.5, and Section 3.7.1.7 revised to add that if a remote 
visit is converted to an in-clinic visit, vital signs will be recorded. Vital signs will not 
be collected for remote visits that are not converted to occur in-clinic.

Section 3.7.1.4 revised to include Weeks 14 (± 3 days) and 18 (± 3 days) for the 
procedures of vital signs, IMP dispensing, and drug accountability to occur. 

Section 3.7.1.4. procedures for psychotropic therapy, YGTSS and CGI-TS, 
documentation of birth control methods, and stability assessments revised to include
“at all open-label visits EXCEPT for Week 3”.

Section 3.7.1.5 orthostatic assessment instructions added.

Section 3.7.1.6.1 randomization procedures updated to clarify subjects should be 
dispensed IMP and administered the first dose while in the clinical “unless evening 
dose is preferred”.

The SAS, BARS, and AIMS administer dates corrected in Section 3.7.1.7 to match 
the Schedule of Assessments and be performed at Week 1 (± 2 days).

“with direct patient visualization (except for open-label Week 3 which does not 
require direct patient visualization),” added to the text surrounding telephone visits 
for Section 3.1 Trial Design, Section 3.7.1 Trial Procedures, footnote under Schedule 
of Assessments (Table 3.7-1), and Section 3.7.1.4. Footnote under Schedule of 
Assessments (Table 3.7-2) and Section 3.7.1.4 added “with direct patient 
visualization”.

Correction of minor wording and formatting issues.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
A complete redline version of this administrative change showing all changes from the 
previous version of the protocol will be produced and will be available upon final 
approval of this administrative change.
Synoptic Clinical Study Report 31-14-204
4.1 Protocol and Protocol Amendments
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-14597, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where OPC-14597 will be tested prior to commencement of this trial. I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
Synoptic Clinical Study Report 31-14-204
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: Protocol 31-14-204 Administrative Change 2
Document Number: 0000000000
Document Version: 8.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
06-Mar-2019
19:17:03
Biostatistics Approval
04-Mar-2019
22:43:18
Synoptic Clinical Study Report 31-14-204
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