Conditions: Schizophrenia Bipolar I Disorder
Keywords: Aripiprazole Aripiprazole Intramuscular Depot Gluteal Muscle Long Acting Injection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 266
Healthy volunteers: no

Brief summary:
The purpose of this trial is to determine the safety and tolerability of multiple-dose administrations of aripiprazole, to establish the similarity of aripiprazole concentrations on the last day of the dosing interval following the final administration of aripiprazole into the gluteal muscle site, and to establish the similarity of aripiprazole exposure over the dosing interval following the administration of aripiprazole into the gluteal muscle site in adult participants with schizophrenia or bipolar I disorder.

Detailed description:

Arms:
arm 1: Participants with schizophrenia or bipolar I disorder received aripiprazole 2 month (2M) long-acting injection (LAI) 960 milligrams (mg) for a total of 4 injections administered every 56 days (± 2 days) over the course of 32 weeks. arm 2: Participants with schizophrenia or bipolar I disorder received aripiprazole IM 400 mg, for a total of 8 injections administered every 28 days (± 2 days) over the course of 32 weeks.

Interventions: intervention 1: Aripiprazole intervention 2: Aripiprazole
Intervention descriptions: intervention 1: Administered as an intramuscular (IM) depot injection. intervention 2: Administered as an IM depot injection.

Protocol document:
Prot_000.pdf: 
 
Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Aripiprazole (OPC-14597, Lu AF41155)
REVISED CLINICAL PROTOCOL
A Phase 1b, Open-label, Multiple-dose, Randomized, Parallel-arm, Safety, Tolerability, 
and Pharmacokinetic Trial of Aripiprazole Intramuscular Depot Administered in the 
Gluteal Muscle in Adult Subjects With Schizophrenia or Bipolar I Disorder
Protocol No. 031-201-00181
IND No. 134612
CONFIDENTIAL - PROPRIETARY INFORMATION
Drug Development Phase:
1b
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard 
Rockville, Maryland 20850, United States
Immediately Reportable Event:
Pharmaceutical Research Associates, Inc. 
(PRA Health Sciences)
Phone: PRA Safety Helpline:
+1-800-772-2215
Fax:     +1-888-772-6919 or
+1-434-951-3482
Email:  CHOSafety@prahs.com
Issue Date:
14 Dec 2018
Date of Amendment 1:
31 May 2019
Date of Amendment 2:
31 Jul 2019
Protocol Version Number:
3.0
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


Protocol 031-201-00181
Confidential -- Proprietary Information
2
Protocol Version 3.0, 31 Jul 2019
Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: 
Aripiprazole (OPC-14597)
Protocol No.: 031-201-00181
IND No.: 134612
Protocol Title:
A Phase 1b, Open-label, Multiple-dose, Randomized, 
Parallel-arm, Safety, Tolerability, and Pharmacokinetic Trial of 
Aripiprazole Intramuscular Depot Administered in the Gluteal 
Muscle in Adult Subjects With Schizophrenia or Bipolar I 
Disorder
Clinical Phase:
Phase 1b
Treatment 
Indication:
Schizophrenia and bipolar I disorder
Objectives:
Primary:

To determine the safety and tolerability of multiple-dose 
administrations of aripiprazole in adult subjects with 
schizophrenia or bipolar I disorder.

To establish the similarity of aripiprazole concentrations on 
the last day of the dosing interval following the final 
administration of aripiprazole into the gluteal muscle site in 
adult subjects with schizophrenia or bipolar I disorder. 

To establish the similarity of aripiprazole exposure over the 
dosing interval following the administration of aripiprazole 
into the gluteal muscle site in adult subjects with 
schizophrenia or bipolar I disorder.
Secondary:

To determine the pharmacokinetics (PK) of aripiprazole.

To determine aripiprazole concentrations 7 days (C7) and 
14 days (C14) after the first dose of aripiprazole for subjects 
enrolled to the robust sampling schedule.

To obtain information on the efficacy of aripiprazole over the 
course of 32 weeks.
Trial Design:
This is a phase 1b, open-label, multiple-dose, randomized, 
parallel-arm, multicenter trial. After a screening period of up to 
30 days, eligible subjects will be randomized (1:1) to receive 
multiple doses of either aripiprazole 2 month (2M) long-acting 
injectable (LAI) 960 mg (4 injections) or aripiprazole IM depot 
400 mg (8 injections) over the course of 32 weeks. Aripiprazole 
2M LAI 960 mg will be administered at 56-day (± 2 days) 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
2


Protocol 031-201-00181
Confidential -- Proprietary Information
3
Protocol Version 3.0, 31 Jul 2019
intervals and aripiprazole IM depot 400 mg will be administered 
at 28-day (± 2 days) intervals. A final visit will occur 
56 (± 2) days after the last dose of aripiprazole 2M LAI 960 mg 
or 28 (± 2) days after the last dose of aripiprazole IM depot 
400 mg.
Randomization to the 2 trial treatments will be stratified by the 
PK sampling schedule (robust or sparse) and disease type 
(schizophrenia or bipolar I disorder). Four to 6 trial sites will be 
designated as Robust Sampling Trial Sites; all other trial sites 
will be designated as Sparse Sampling Trial Sites. Up to 
76 subjects (38 per treatment group) will be enrolled to the robust 
sampling schedule and 182 subjects (91 per treatment group) will 
be enrolled to the sparse sampling schedule. If enrollment of the 
number of subjects required for the robust sampling schedule is 
completed, the Robust Sampling Trial Sites may enroll additional 
subjects to the sparse sampling schedule with approval from the 
sponsor.
Blood samples for PK analyses will be drawn from subjects at 
both Robust and Sparse Sampling Trial Sites after the first 
(Day 1) and fourth (Day 169) doses of investigational medicinal 
product (IMP) for subjects randomized to aripiprazole 2M LAI 
960 mg, and after the first (Day 1), seventh (Day 169), and eighth
(Day 197) doses of IMP for subjects randomized to aripiprazole 
IM depot 400 mg. 
Subjects enrolled to the robust sampling schedule who are 
randomized to aripiprazole 2M LAI 960 mg must be housed in 
the unit for 21 days after the first and fourth doses of IMP and 
will be outpatients for the rest of the trial. Subjects randomized to 
aripiprazole IM depot 400 mg will stay in the unit for 21 days 
after administration of the first, seventh, and eighth doses of IMP.
Subjects who are not able to accommodate the scheduled stays in 
the unit may be permitted to have some visits as outpatients with 
approval from the medical monitor. For any outpatient visit, an 
unscheduled C-SSRS will be performed.
Subjects enrolled to the sparse sampling schedule will be 
outpatients for administration of all doses of IMP; however, they 
may be housed in the unit for up to 21 days after administration 
of the first dose of IMP at the discretion of the investigator. 
Subjects who do not have a history of tolerating aripiprazole will 
receive 3 single 10-mg doses of oral aripiprazole on 
3 consecutive days (total of 30 mg) in addition to their current 
oral antipsychotic, mood stabilizer, and if applicable, 
antidepressant for at least 14 days prior to the first administration 
of IMP to establish tolerability. Subjects may be housed in the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
3


Protocol 031-201-00181
Confidential -- Proprietary Information
4
Protocol Version 3.0, 31 Jul 2019
unit during these 3 days at the investigator’s discretion.
At the time of administration of the first dose of IMP, subjects 
will begin a 7- to 14-day period (oral overlap) where they will 
transition from their current oral antipsychotic to include 
injections of IMP. Subjects currently stabilized on a non-
aripiprazole oral antipsychotic who are enrolled to a sparse 
sampling schedule will continue on their medication and subjects 
who are enrolled to a robust sampling schedule will switch to
10 to 20 mg oral aripiprazole (dose determined by the 
investigator).
During oral overlap, subjects will take their oral antipsychotic
medications concurrently with IMP for 7 days after the first
administration of aripiprazole 2M LAI 960 mg or 14 days after 
the first administration of aripiprazole IM depot 400 mg. Subjects 
stabilized on oral aripiprazole as their current antipsychotic 
medication will continue treatment concurrently with IMP at an 
adjusted dose for either 7 or 14 days. The oral antipsychotic will
be discontinued after 7 days of administration of aripiprazole 2M 
LAI 960 mg and after 14 days of administration of aripiprazole 
IM depot 400 mg.
There will be no oral overlap for subjects who are taking Abilify 
Maintena® as their current antipsychotic medication. Subjects 
will not be permitted entry to the trial if taking an LAI other than 
Abilify Maintena.
Subjects with a diagnosis of bipolar I disorder who are taking a 
mood stabilizer (lithium, valproate, lamotrigine) will be 
permitted to stay on their mood stabilizer over the course of the 
trial, and if applicable, to continue treatment with their 
antidepressant unless the medication is prohibited during the trial 
(fluoxetine, fluoxetine/olanzapine).
Subjects may resume treatment on their previous oral non-
aripiprazole antipsychotic after Day 28 if there is evidence of 
clinical deterioration based on the judgment of the investigator. If 
a decision is made that a subject may resume previous oral non-
aripiprazole antipsychotic medication, the investigator will 
continue to monitor the subject for safety and clinical stability.
Subject 
Population:
The trial population will include male and female subjects 
between the ages of 18 to 64 years of age, inclusive, with a 
current diagnosis of schizophrenia or bipolar I disorder as defined 
by the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria. Approximately 258 subjects 
(129 per treatment group) will be enrolled into the trial with the 
expectation that approximately 170 subjects (85 per treatment 
group) will complete the trial. An interim analysis may be 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
4


Protocol 031-201-00181
Confidential -- Proprietary Information
5
Protocol Version 3.0, 31 Jul 2019
conducted to ensure adequate power of the trial. Based on the 
possible sample size re-estimation in the proposed interim 
analysis, fewer subjects may be enrolled.
Inclusion/
Exclusion Criteria:
Key inclusion criteria:

Body mass index of 18 to 35 kg/m2.

Prior history of tolerating aripiprazole and/or Abilify 
Maintena per the investigator’s judgment. If the subject has 
not established tolerability, then assessment of oral 
aripiprazole tolerability will be completed within the 
screening period at least 14 days prior to the first 
administration of IMP (oral aripiprazole 10 mg/day for 
3 consecutive days prior to Day −15).

Subjects must be clinically stable (based on investigator 
judgment, subject/caregiver report, and/or documentation) for 
at least 2 months prior to screening, AND

On a stable dose of 1 of the following oral atypical 
antipsychotic medications for at least 2 months prior to 
screening: aripiprazole (sparse only), brexpiprazole, 
risperidone, olanzapine, quetiapine, paliperidone, 
cariprazine, lurasidone, ziprasidone, or asenapine; or 
Abilify Maintena (sparse only). Additionally, subjects 
with bipolar I disorder who are stabilized on their current 
medications for at least 2 months prior to screening may 
continue their mood stabilizer (lithium, valproic acid, 
lamotrigine) and antidepressant (citalopram, escitalopram, 
sertraline).

Other oral non-aripiprazole, antipsychotic medications 
may be allowed if approved by the medical monitor and 
sponsor; however, clozapine will not be allowed. 
(Subjects intended to enroll to the robust sites may not be 
taking oral aripiprazole or Abilify Maintena as their 
current atypical antipsychotic.)
Key exclusion criteria:

Use of any cytochrome P450 (CYP) 2D6 and CYP3A4 
inhibitors, or CYP3A4 inducers, within 14 days (fluoxetine or 
fluoxetine/olanzapine within 28 days) prior to dosing, for the 
duration of the trial, and 30 days after the last dose of IMP.

Subjects may not receive varenicline beyond screening. If a 
subject is receiving varenicline at screening, attempts should 
be made to discontinue the medication, if clinically feasible, 
to allow potential subjects to enter the trial.

Subjects who participated in any clinical trial involving an 
oral psychotropic medication within 1 month prior to the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
5


Protocol 031-201-00181
Confidential -- Proprietary Information
6
Protocol Version 3.0, 31 Jul 2019
administration of IMP, as well as subjects who participated in 
a clinical trial with an aripiprazole depot-containing
formulation of a psychotropic medication within the last 
1 year or a non-aripiprazole depot formulation within the last 
6 months.

Subjects enrolled to the robust sampling schedule must not
have taken oral aripiprazole for 30 days, or Abilify Maintena
for 1 year, prior to screening.

Subjects currently in an acute relapse of schizophrenia.

Subjects with a current DSM-5 diagnosis other than 
schizophrenia or bipolar I disorder, including schizoaffective 
disorder, major depressive disorder, delirium, dementia, 
amnestic, or other cognitive disorders. Also, subjects with 
borderline, paranoid, histrionic, or antisocial personality 
disorder.

Subjects who are considered treatment-resistant to 
antipsychotic medication (subjects need to have shown a 
previous response to an antipsychotic medication other than 
clozapine).

History of any significant drug allergy or known or suspected 
hypersensitivity, in particular to aripiprazole or other 
quinolinones.
Trial Site(s):
Approximately 20 trial sites in the United States. Of the 20 trial 
sites, 4 to 6 will be designated as Robust Sampling Trial Sites.
Investigational 
Medicinal
Product(s), Dose, 
Dosage Regimen, 
Treatment 
Duration, 
Formulation, 
Mode of 
Administration:
Subjects will be randomized (1:1) to receive multiple doses of:

Aripiprazole 2M LAI 960 mg (test) - 2-month injection (total 
of 4 injections), administered every 56 days (± 2 days), over 
the course of 32 weeks.

Aripiprazole IM depot 400 mg (reference) - 1-month
injection (total of 8 injections), administered every 28 days 
(± 2 days), over the course of 32 weeks.
Aripiprazole 2M LAI will be supplied as aripiprazole IM depot 
300 mg/mL ready-to-use single-dose vials and aripiprazole 
IM depot 400 mg will be supplied as single-dose lyophilized 
vials. Aripiprazole tablets for oral overlap will be provided from 
a commercial supply.
Trial Assessments:
Safety: Adverse events (AEs), vital signs, electrocardiograms 
(ECGs), clinical laboratory monitoring (serum chemistry, 
hematology, and urinalysis), physical examinations, 
extrapyramidal symptoms (EPS) (The Simpson-Angus 
Neurologic Rating Scale [SAS], Abnormal Involuntary 
Movement Scale [AIMS], and Barnes Akathisia Rating Scale 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
6


Protocol 031-201-00181
Confidential -- Proprietary Information
7
Protocol Version 3.0, 31 Jul 2019
[BARS]), Visual Analog Scale (VAS) scores for pain perception, 
Investigator’s Assessment of Most Recent Injection Site, and 
suicidality via the Columbia-Suicide Severity Rating Scale 
(C-SSRS).
Pharmacokinetics: Plasma concentrations of aripiprazole and its 
major metabolite, dehydro-aripiprazole, after administration of 
aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg
over the course of 32 weeks, and after 7 days or 14 days of oral 
overlap of 10 to 20 mg aripiprazole administered with 
aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg, 
respectively, starting on Day 1 (first day of dosing).
Efficacy: Positive and Negative Syndrome Scale (PANSS; 
schizophrenia subjects only), Clinical Global Impression -
Severity (CGI-S), Clinical Global Impression - Improvement 
(CGI-I), Subjective Well-being under Neuroleptic 
Treatment-Short Form (SWN-S), Montgomery-Asberg 
Depression Rating Scale (MADRS; bipolar subjects only), 
Young Mania Rating Scale (YMRS; bipolar subjects only), and 
Clinical Global Impression - Bipolar Version (CGI-BP; bipolar 
subjects only).
Screening/Other: Demography; documentation of medical and 
psychiatric history, birth control methods, and prior/concomitant 
medications; serum hepatitis and human immunodeficiency virus 
screen; urine drug and urine or breath alcohol screen; urine 
pregnancy test; follicle stimulating hormone test; prolactin 
assessment; measurements of height and weight, and calculation 
of body mass index; and blood sampling for pharmacogenomics 
testing and future biospecimen research.
Criteria for 
Evaluation:
Primary endpoints:

Safety and tolerability will be based on reported AEs, vital 
signs, ECGs, clinical laboratory monitoring (serum 
chemistry, hematology, and urinalysis), physical 
examinations, EPS (SAS, AIMS, and BARS), VAS scores for 
pain perception, Investigator’s Assessment of Most Recent 
Injection Site, and the C-SSRS. 

Plasma concentration of aripiprazole 56 days postdose (C56) 
for aripiprazole 2M LAI 960 mg after the fourth dose or 
plasma concentration of aripiprazole 28 days postdose (C28) 
for aripiprazole IM depot 400 mg after the eighth dose over 
the course of 32 weeks.

The area under the concentration-time curve of aripiprazole 
from time zero to 56 days postdose (AUC0-56) for 
aripiprazole 2M LAI 960 mg after the fourth dose or the area 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
7


Protocol 031-201-00181
Confidential -- Proprietary Information
8
Protocol Version 3.0, 31 Jul 2019
under the concentration-time curve of aripiprazole from time 
zero to 28 days postdose (AUC0-28) for aripiprazole IM depot 
400 mg after the seventh and eighth doses over the course of 
32 weeks, based on the PK data from subjects enrolled to the
robust sampling schedule.
Secondary endpoints:
The following PK parameters will be estimated for aripiprazole 
after the administration of aripiprazole 2M LAI 960 mg and 
aripiprazole IM depot 400 mg: 

Maximum (peak) plasma concentration of the drug (Cmax), 
and time to maximum (peak) plasma concentration (tmax) 
after the first and fourth doses of aripiprazole 2M LAI
960 mg.

AUC0-56 and C56 after the first dose of aripiprazole 2M LAI
960 mg.

AUC0-28 and C29-56 after the fourth dose of aripiprazole 
2M LAI 960 mg.

Peak-to-trough percent fluctuation (PTF%) after the fourth 
dose of aripiprazole 2M LAI 960 mg.

Cmax, and tmax after the first, seventh, and eighth doses of 
aripiprazole IM depot 400 mg.

AUC0-28 and C28 after the first dose of aripiprazole IM depot 
400 mg.

PTF% after the eighth dose of aripiprazole IM depot 400 mg.
Note: Cmax, tmax, AUC, and PTF% will be determined only from 
subjects enrolled to the robust sampling schedule; C56 and C28
will be determined from subjects enrolled to the sparse and 
robust sampling schedules.
After the first dose of IMP, the following PK parameters will be 
estimated for aripiprazole after aripiprazole 2M LAI 960 mg + 
10 to 20 mg oral aripiprazole for 7 days and aripiprazole 
IM depot 400 mg + 10 to 20 mg oral aripiprazole for 14 days 
(this endpoint is only for subjects enrolled to the robust sampling 
schedule): 

Plasma concentration of aripiprazole 7 days postdose (C7)

Plasma concentration of aripiprazole 14 days postdose (C14)
The efficacy of aripiprazole IM depot administration in the 
gluteal muscle will be assessed by the PANSS (schizophrenia 
subjects only), CGI-S, CGI-I, SWN-S, MADRS (bipolar subjects 
only), YMRS (bipolar subjects only), and CGI-BP (bipolar 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
8


Protocol 031-201-00181
Confidential -- Proprietary Information
9
Protocol Version 3.0, 31 Jul 2019
subjects only).
Statistical 
Methods:
Determination of sample size:
To establish the similarity in primary PK variables, the lower 
bound of the 90% confidence interval (CI) of the geometric 
means ratio (GMR) of C56 and AUC0-56 after the fourth dose of 
aripiprazole 2M LAI 960 mg to C28 after the eighth dose and the 
sum of AUC0-28 values after the seventh and eighth doses of 
aripiprazole IM depot 400 mg should be greater than 80%, 
respectively. It is estimated that a total of at least 100 subjects (ie, 
50 per group) completing the trial will have at least 80% power 
to ensure that the lower limit of the 90% CI of the GMR of C56
after the fourth dose of aripiprazole 2M LAI 960 mg (test) to C28
after the eighth dose of aripiprazole IM depot 400 mg (reference) 
is greater than 0.80, assuming the actual GMR of concentrations 
is 1.0 and the coefficient of variation (CV) is 46%.
Among these 100 subjects, 30 completers enrolled to the robust 
sampling schedule will provide at least 80% power to ensure that 
the lower limit of the 90% CI of the GMR of AUC0-56 of 
aripiprazole 2M LAI 960 mg (test) to the sum of AUC0-28 values 
of aripiprazole IM depot 400 mg (reference) after the seventh and 
eighth doses is greater than 0.80, assuming the actual GMR of 
concentrations is 1.15 and the CV is 40%.
 
 
To ensure adequate power of the trial, an interim analysis may be 
conducted by the Interim Analysis Review Committee (IARC). 
The final sample size could be increased as per recommendation 
of the IARC.
Assuming a dropout rate of 34%, approximately 152 to 
258 subjects will be enrolled to have 100 to 170 completers based 
on the recommendation of the proposed interim analysis.
Primary endpoint analyses:
Safety assessments including AEs, vital signs, ECGs, clinical 
laboratory monitoring (serum chemistry, hematology, and 
urinalysis), physical examinations, EPS (SAS, AIMS, and 
BARS), VAS scores for pain perception, Investigator’s 
Assessment of Most Recent Injection Site, and suicidality via the 
C-SSRS will be summarized for the safety sample by treatment 
group. The mean change from baseline will be provided for vital 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
9


Protocol 031-201-00181
Confidential -- Proprietary Information
10
Protocol Version 3.0, 31 Jul 2019
signs, ECGs, clinical laboratory, and EPS assessments by visit,
treatment group, and disease type. The incidence of clinically 
relevant abnormalities in vital sign, ECGs, and clinical laboratory 
results will be summarized descriptively by visit, treatment 
group, and disease type.
Plasma concentrations of aripiprazole will be analyzed using 
noncompartmental methods. The following PK parameters will 
be estimated and summarized descriptively for aripiprazole: C56
and AUC0-56 of aripiprazole 2M LAI 960 mg after the fourth 
dose, C28 of aripiprazole IM depot 400 mg after the eighth dose, 
and AUC0-28 values of aripiprazole IM depot 400 mg after the 
seventh and eighth doses over the course of 32 weeks. The 
90% CI of GMR of C56 of aripiprazole after the fourth injection 
of aripiprazole 2M LAI 960 mg (test) to C28 after the eighth 
injection of aripiprazole IM depot 400 mg (reference) will be 
provided. An analysis of variance will be performed on the 
natural-log transformed PK parameters using the MIXED 
procedure in the Statistical Analysis System (SAS). The 
mixed-effects linear model will include treatment group, disease 
type (if applicable), and PK sampling schedule as fixed effects 
and subject as a random effect. The least squares means for the 
2 treatment groups, their difference, and the 90% CI for their 
difference will be derived. The antilog of the confidence limits 
will provide the 90% CI for the GMR of the 2 treatments. For 
subjects enrolled to the robust sampling schedule, the values of 
AUC0-28 after the seventh and eighth dose of aripiprazole IM 
depot 400 mg (reference) will be summed up before analyzing by 
the same method together with AUC0-56 after the fourth injection 
of aripiprazole 2M LAI 960 mg (test). Only subjects who receive 
a fourth dose of aripiprazole 2M LAI 960 mg or a seventh and/or
eighth dose of aripiprazole IM depot 400 mg and have C56, C28, 
and AUC0-28 values, and AUC0-56 values determined for the 
respective treatments will be included in the analysis.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10


Protocol 031-201-00181
Confidential -- Proprietary Information
11
Protocol Version 3.0, 31 Jul 2019
Secondary endpoint analyses:
The secondary PK endpoints will be summarized descriptively.
The Cmax, area under the concentration-time curve (AUC), tmax, 
and PTF% will be summarized based on samples from subjects 
enrolled to the robust sampling schedule; whereas C28 and C56
after the first injection will be summarized based on samples 
from subjects enrolled to the robust and sparse sampling 
schedules.
Efficacy assessments including the PANSS (schizophrenia 
subjects only), CGI-S, CGI-I, SWN-S, MADRS (bipolar subjects 
only), YMRS (bipolar subjects only), and CGI-BP (bipolar 
subjects only) will be summarized for the efficacy sample at each 
visit by treatment group and disease type, if applicable. These 
analyses will be performed for both the last observation carried 
forward and observed case data. In addition, the linear 
mixed-effects model will be used to explore the effect of the 
treatment and change from baseline over time, as applicable.
Trial Duration:
The trial will consist of a screening period of up to 30 days and a 
treatment period of 169 (± 2) days with a follow-up period of 
56 (± 2) days after administration of the final dose for the 
aripiprazole 2M LAI 960 mg treatment group, or a treatment 
period of 197 days with a follow-up period of 28 (± 2) days after 
administration of the final dose for the aripiprazole IM depot 
400 mg treatment group. Individual participation for both 
treatment groups will be approximately 255 (± 2) days.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
11


Protocol 031-201-00181
Confidential -- Proprietary Information
12
Protocol Version 3.0, 31 Jul 2019
Table of Contents
Title Page ........................................................................................................1
Protocol Synopsis...........................................................................................2
Table of Contents.........................................................................................12
List of In-text Tables ...................................................................................17
List of In-text Figures..................................................................................18
List of Appendices........................................................................................19
List of Abbreviations and Definitions of Terms .......................................20
1
Introduction ........................................................................................22
1.1.1
Pharmacodynamics.........................................................................................22
1.1.2
Safety Pharmacology......................................................................................22
1.1.3
Pharmacokinetics............................................................................................23
1.1.4
Toxicology......................................................................................................23
1.1.5
Aripiprazole 2 Month Long-Acting Injectable Formulation ..........................24
1.2
Clinical Data......................................................................................................26
1.3
Pharmacokinetics...............................................................................................27
1.4
Risks and Benefits.............................................................................................29
2
Trial Rationale and Objectives..........................................................31
2.1
Trial Rationale...................................................................................................31
2.2
Dosing Rationale...............................................................................................31
2.3
Trial Objectives.................................................................................................32
2.3.1
Primary Objectives .........................................................................................32
2.3.2
Secondary Objectives .....................................................................................32
3
Trial Design.........................................................................................32
3.1
Type/Design of Trial .........................................................................................32
3.2
Trial Treatments ................................................................................................35
3.2.1
Investigational Medicinal Product..................................................................35
3.2.2
Tolerability Testing ........................................................................................36
3.2.3
Oral Overlap ...................................................................................................36
3.2.4
Concurrent Antipsychotic Treatment .............................................................37
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
12


Protocol 031-201-00181
Confidential -- Proprietary Information
13
Protocol Version 3.0, 31 Jul 2019
3.3
Trial Population.................................................................................................38
3.4
Eligibility Criteria..............................................................................................39
3.4.1
Informed Consent ...........................................................................................39
3.4.2
Inclusion Criteria ............................................................................................40
3.4.3
Exclusion Criteria...........................................................................................40
3.5
Endpoints...........................................................................................................43
3.5.1
Primary Endpoints ..........................................................................................43
3.5.1.1
Safety...........................................................................................................43
3.5.1.2
Pharmacokinetic..........................................................................................43
3.5.2
Secondary Endpoints ......................................................................................43
3.5.2.1
Pharmacokinetic..........................................................................................43
3.5.2.2
Efficacy.......................................................................................................44
3.6
Measures to Minimize/Avoid Bias....................................................................44
3.6.1
Randomization................................................................................................44
3.6.2
Blinding ..........................................................................................................44
3.7
Trial Procedures ................................................................................................44
3.7.1
General Inpatient Procedures..........................................................................55
3.7.2
Dietary Requirements .....................................................................................55
3.7.3
Schedule of Assessments................................................................................55
3.7.4
Prior and Concomitant Medications...............................................................77
3.7.5
Efficacy Assessments .....................................................................................77
3.7.5.1
Positive and Negative Syndrome Scale Rating Criteria..............................77
3.7.5.2
Clinical Global Impression - Severity.........................................................78
3.7.5.3
Clinical Global Impression - Improvement Scale.......................................78
3.7.5.4
Subjective Well-being under Neuroleptic Treatment-Short Form..............78
3.7.5.5
Montgomery-Asberg Depression Rating Scale...........................................78
3.7.5.6
Young Mania Rating Scale .........................................................................79
3.7.5.7
Clinical Global Impression - Bipolar Version ............................................79
3.7.6
Safety Assessments.........................................................................................79
3.7.6.1
Adverse Events............................................................................................79
3.7.6.2
Clinical Laboratory Assessments................................................................79
3.7.6.3
Physical Examination and Vital Sign Assessments ....................................81
3.7.6.4
Electrocardiogram Assessments..................................................................82
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
13


Protocol 031-201-00181
Confidential -- Proprietary Information
14
Protocol Version 3.0, 31 Jul 2019
3.7.6.5
Columbia-Suicide Severity Rating Scale....................................................82
3.7.6.6
Other Safety Assessments...........................................................................82
3.7.6.6.1
Extrapyramidal Symptoms ......................................................................82
3.7.6.6.1.1
Simpson-Angus Scale..........................................................................83
3.7.6.6.1.2
Abnormal Involuntary Movement Scale..............................................83
3.7.6.6.1.3
Barnes Akathisia Rating Scale.............................................................83
3.7.6.6.2
Pain Perception - Visual Analog Scale....................................................84
3.7.6.6.3
Investigator’s Assessment of Injection Site ............................................84
3.7.7
Pharmacokinetic Assessments........................................................................84
3.7.7.1
Pharmacokinetic Assessments ....................................................................84
3.7.7.1.1
Pharmacokinetic Blood Plasma Samples ................................................84
3.7.8
Genetic Assessments ......................................................................................85
3.7.8.1
Deoxyribonucleic Acid Blood Samples for Pharmacogenomic 
Testing.........................................................................................................85
3.7.10
End of Trial.....................................................................................................86
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................86
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................86
3.8.2
Individual Site.................................................................................................86
3.8.3
Individual Subject Discontinuation ................................................................86
3.8.3.1
Treatment Discontinuation..........................................................................86
3.8.3.2
Documenting Reasons for Discontinuation ................................................86
3.8.3.3
Withdrawal of Consent ...............................................................................87
3.9
Screen Failures ..................................................................................................88
3.10
Definition of Completed Subjects.....................................................................88
3.11
Definition of Subjects Lost to Follow-up..........................................................88
3.12
Subject Compliance...........................................................................................88
3.13
Protocol Deviations...........................................................................................88
4
Restrictions..........................................................................................89
4.1
Prohibited Medications......................................................................................89
4.2
Restricted Medications......................................................................................90
4.3
Nontherapy Precautions and Restrictions..........................................................91
5
Reporting of Adverse Events.............................................................91
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
14


Protocol 031-201-00181
Confidential -- Proprietary Information
15
Protocol Version 3.0, 31 Jul 2019
5.1
Definitions.........................................................................................................91
5.2
Eliciting and Reporting Adverse Events ...........................................................93
5.3
Immediately Reportable Events ........................................................................94
5.4
Potential Serious Hepatotoxicity.......................................................................94
5.5
Pregnancy..........................................................................................................94
5.6
Procedure for Breaking the Blind......................................................................96
5.7
Follow-up of Adverse Events............................................................................96
5.7.1
Follow-up of Nonserious Adverse Events......................................................96
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................96
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Last Scheduled Contact .........................97
6
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis................................................................................................97
6.1
Pharmacokinetic Methods.................................................................................97
6.2
Pharmacodynamic Methods ..............................................................................97
6.3
Pharmacokinetic/Pharmacodynamic Methods ..................................................97
6.4
Pharmacogenomic Methods ..............................................................................98
7
Statistical Analysis..............................................................................98
7.1
Determination of Sample Size...........................................................................98
7.1.1
Interim Analysis/Sample Size Re-estimation.................................................98
7.2
Datasets for Analysis.........................................................................................99
7.3
Handling of Missing Data ...............................................................................100
7.4
Primary and Secondary Endpoint Analyses ....................................................100
7.4.1
Primary Endpoint Analyses ..........................................................................100
7.4.2
Secondary Endpoint Analyses ......................................................................101
7.5
Analysis of Demographic and Baseline Characteristics..................................102
7.6
Safety Analysis................................................................................................102
7.6.1
Adverse Events .............................................................................................102
7.6.2
Clinical Laboratory Data ..............................................................................103
7.6.3
Physical Examination and Vital Signs Data .................................................103
7.6.4
Electrocardiogram Data................................................................................103
7.6.5
Other Safety Data .........................................................................................103
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
15


Protocol 031-201-00181
Confidential -- Proprietary Information
16
Protocol Version 3.0, 31 Jul 2019
7.6.5.1
Columbia-Suicide Severity Rating Scale..................................................103
7.6.5.2
Extrapyramidal Symptoms Rating Scales.................................................104
7.6.5.3
Visual Analog Scale Scores for Pain Perception ......................................104
7.6.5.4
Investigator’s Assessment of the Injection Site ........................................104
7.7
Pharmacodynamic Analysis ............................................................................104
8
Management of Investigational Medicinal Product......................104
8.1
Packaging and Labeling ..................................................................................104
8.2
Storage.............................................................................................................104
8.3
Accountability .................................................................................................105
8.4
Returns and Destruction..................................................................................105
8.5
Reporting of Product Quality Complaints.......................................................105
8.5.1
Eliciting and Reporting Product Quality Complaints...................................105
8.5.2
Information Required for Reporting Product Quality Complaints...............106
8.5.3
Return Process for Product Quality Complaints...........................................106
8.5.4
Assessment/Evaluation.................................................................................106
8.6
Investigational Medicinal Product Reserve Sample Requirements ................106
9
Records Management.......................................................................107
9.1
Source Documents...........................................................................................107
9.2
Data Collection................................................................................................107
9.3
File Management at the Trial Site...................................................................109
9.4
Record Retention at the Trial Site...................................................................109
10
Quality Control and Quality Assurance.........................................110
10.1
Monitoring.......................................................................................................110
10.2
Auditing...........................................................................................................110
10.3
Protocol Deviations.........................................................................................110
11
Ethics and Responsibility.................................................................111
12
Confidentiality ..................................................................................112
13
Amendment Policy............................................................................112
14
Publication Authorship Requirements...........................................113
15
References..........................................................................................113
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
16


Protocol 031-201-00181
Confidential -- Proprietary Information
17
Protocol Version 3.0, 31 Jul 2019
List of In-text Tables
Table 1.1.5-1
Mean Pharmacokinetic Parameters in Male Rats Treated 
Intramuscularly With Abilify Maintena or RTU Formulation ......24
Table 3.2.1-1
Needle Size for IM Depot Injection...............................................35
Table 3.2.3-1
Scenarios for Initiation of Oral Aripiprazole Overlap During 
the First 2 Weeks After the Initiation of IMP................................37
Table 3.2.3-2
Dose Adjustment for Initiation of Oral Overlap for Subjects 
Currently Stabilized on Oral Aripiprazole.....................................37
Table 3.4.2-1
Inclusion Criteria ...........................................................................40
Table 3.4.3-1
Exclusion Criteria ..........................................................................41
Table 3.7-1
Schedule of Assessments: Sparse Sampling..................................46
Table 3.7-2
Schedule of Assessments: Robust Sampling .................................50
Table 3.7.3-1
Screening Assessments and Procedures.........................................57
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities....................58
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities...................67
Table 3.7.6.2-1
Clinical Laboratory Assessments...................................................80
Table 4.1-1
Example List of CYP3A4 and CYP2D6 Inhibitors and 
CYP3A4 Inducers Prohibited During the Trial .............................90
Table 4.2-1
Medications Restricted During the Trial........................................91
Table 7.1.1-1
Sample Size Re-estimation ............................................................99
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
17


Protocol 031-201-00181
Confidential -- Proprietary Information
18
Protocol Version 3.0, 31 Jul 2019
List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................34
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
18


Protocol 031-201-00181
Confidential -- Proprietary Information
19
Protocol Version 3.0, 31 Jul 2019
List of Appendices
Appendix 1
Names of Sponsor Personnel .......................................................115
Appendix 4
Protocol Amendment 1 ................................................................120
Appendix 5
Protocol Amendment 2 ................................................................122
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
19


Protocol 031-201-00181
Confidential -- Proprietary Information
20
Protocol Version 3.0, 31 Jul 2019
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
2M
2 month
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT 
Alanine aminotransferase
anti-HCV
Hepatitis C antibodies
AST 
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC∞
Area under the concentration-time curve from time zero to infinity
AUC0-28
Area under the concentration-time curve of aripiprazole from time zero
to 28 days postdose
AUC0-56
Area under the concentration-time curve of aripiprazole from time zero
to 56 days postdose
AUC0-84
Area under the concentration-time curve from time zero to 84 days
postdose
AUCt
Area under the concentration-time curve from time zero to time t
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
CGI-BP
Clinical Global Impression - Bipolar Version
CGI-I
Clinical Global Impression - Improvement
CGI-S
Clinical Global Impression - Severity
C7
Plasma concentration of aripiprazole 7 days postdose
C14
Plasma concentration of aripiprazole 14 days postdose
C28
Plasma concentration of aripiprazole 28 days postdose
C56
Plasma concentration of aripiprazole 56 days postdose
CI
Confidence interval
Cmax
Maximum (peak) plasma concentration of the drug
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Score
CV
Coefficient of variation
CYP
Cytochrome P450
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
Dx
Dopamine receptor where x is the receptor type number
ECG
Electrocardiogram
eCRF
Electronic case report form
EPS
Extrapyramidal symptoms
ET
Early termination
FDA
(United States) Food and Drug Administration
FOCBP
Females of childbearing potential
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GMR
Geometric mean ratio
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
20


Protocol 031-201-00181
Confidential -- Proprietary Information
21
Protocol Version 3.0, 31 Jul 2019
Abbreviation
Definition
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
5-HTxx
5-hydroxytryptamine receptor where xx denotes the receptor type 
number
IARC
Interim Analysis Review Committee
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IM
Intramuscular
IMP
Investigational medicinal product
IND
Investigational new drug
IRB
Institutional review board
IRE
Immediately reportable event
K2EDTA
Dipotassium ethylenediaminetetraacetic acid
LAI
Long-acting injection
LOCF
Last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
NDA
New Drug Application
OC
Observed case
OPC
Otsuka Pharmaceutical Co.
PANSS
Positive and Negative Syndrome Scale
PK
Pharmacokinetic
PQC
Product quality complaint
PTF%
Peak-to-trough percent fluctuation
QTcF
Corrected QT interval using Fridericia’s formula
RTU
Ready-to-use
SAE
Serious adverse event
SAS
The Simpson-Angus Neurologic Rating Scale; Statistical Analysis 
System
SD
Standard deviation
SWN-S
Subject Well-being under Neuroleptic Treatment-Short Form
t1/2
Terminal phase elimination half-life
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
ULN
Upper limit of normal
US
United States
VAS
Visual Analog Scale
YMRS
Young Mania Rating Scale 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21


Protocol 031-201-00181
Confidential -- Proprietary Information
22
Protocol Version 3.0, 31 Jul 2019
1
Introduction
Aripiprazole (OPC-14597, Lu AF41155) is a dopamine serotonin system stabilizer, for 
which efficacy is thought to be mediated through a combination of partial agonism at 
dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A
receptors.
Abilify Maintena®, an extended-release suspension for once monthly intramuscular (IM)
injection, is indicated for the treatment of schizophrenia at a dose of 400 mg once 
monthly (deltoid or gluteal IM administration).1 In addition, Abilify Maintena was 
approved by the United States (US) Food and Drug Administration (FDA) on 27 Jul 2017 
for the maintenance monotherapy treatment of bipolar I disorder in adults (Supplemental 
New Drug Application [NDA] 202971 S-010 submitted 28 Sep 2016).
This trial will examine the safety, tolerability, and pharmacokinetics (PK) of multiple 
doses of aripiprazole 2 month (2M) long-acting injectable (LAI) 960 mg injected in the 
gluteal muscle in adult subjects with schizophrenia or bipolar I disorder over the course 
of 32 weeks. The aripiprazole 2M LAI 960 mg formulation is an extended-release 
presentation intended for dosing every 2 months. The extension of the dosing interval for 
aripiprazole 2M LAI 960 mg is primarily through an increase in the dose while 
maintaining minimum aripiprazole concentrations that are comparable to aripiprazole 
IM depot 400 mg after multiple doses.
Please refer to the Investigator’s Brochure (IB) for more detailed information on 
nonclinical data and clinical data for aripiprazole.1 A brief summary is included below.
 
 
 
 
 
 
 
 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
22


Protocol 031-201-00181
Confidential -- Proprietary Information
23
Protocol Version 3.0, 31 Jul 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
23






Protocol 031-201-00181
Confidential -- Proprietary Information
26
Protocol Version 3.0, 31 Jul 2019
 
 
 
 
 
 
 
 
 
1.2
Clinical Data
As of 01 Jun 2018, approximately 3591 adult subjects have been exposed to Abilify 
Maintena in all clinical trials and the safety has been well established. The Abilify 
Maintena safety profile is similar to that of the Abilify oral tablets, with the exception of 
injection site reactions, which is an IM depot-specific adverse event (AE); however, the 
injection site pain does not represent a particular safety concern.1
The efficacy of Abilify Maintena for the treatment of schizophrenia was established in:

A phase 3, short-term (12-week), randomized, double-blind, placebo-controlled trial 
in acutely relapsed adult subjects with schizophrenia (Trial 31-12-291)

A phase 3, long-term (52-week), double-blind, placebo-controlled, 
randomized-withdrawal trial in adult subjects with schizophrenia (Trial 31-07-246)

A phase 3, long-term (38-week), randomized, double-blind, active-controlled trial in 
adult subjects with schizophrenia (Trial 31-07-247)
In Trial 31-12-291, the primary endpoint was the change from baseline in Positive and 
Negative Syndrome Scale (PANSS) total score to Week 10. The key secondary endpoint 
was the change from baseline in Clinical Global Impression - Severity (CGI-S) 
assessment scale to Week 10. Abilify Maintena was superior to placebo in improving the 
PANSS total score at the end of Week 10 (least squares mean change from 
baseline = −26.8 for Abilify Maintena [400 to 300 mg] and least squares mean change 
from baseline = −11.7 for placebo). Abilify Maintena also showed improvement in 
symptoms represented by the CGI-S score mean change from baseline to Week 10.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26


Protocol 031-201-00181
Confidential -- Proprietary Information
27
Protocol Version 3.0, 31 Jul 2019
For Trial 31-07-246, in addition to the PANSS and CGI-S, clinical ratings during this 
trial included the Clinical Global Impression-Improvement scale and CGI-S of Suicide 
scale. The primary efficacy endpoint was time from randomization to relapse. The trial 
was terminated early because maintenance of efficacy was demonstrated at a preplanned 
interim analysis. The final analysis demonstrated a statistically significantly longer time 
to relapse in subjects randomized to the Abilify Maintena group compared to 
placebo-treated subjects. In the placebo group 39.6% of the subjects had progressed to 
impending relapse, while in the Abilify Maintena group impending relapse occurred in 
10% of the subjects. The key secondary efficacy endpoint, percentage of subjects meeting 
the relapse criteria, was statistically significantly lower in subjects randomized to the 
Abilify Maintena group (10%) than in the placebo group (40%).
In addition to the above, efficacy was demonstrated in Trial 31-07-247 for registration of 
Abilify Maintena in the European Union. The results of analysis of the primary efficacy 
endpoint, the estimated proportion of subjects experiencing impending relapse by the end 
of Week 26 showed that Abilify Maintena 400 mg/300 mg is noninferior to Abilify oral 
tablets 10 to 30 mg. The estimated relapse rate by the end of Week 26 was 7.12% for 
Abilify Maintena and 7.76% for Abilify oral tablets 10 to 30 mg. Further, the 
noninferiority of Abilify Maintena compared to Abilify oral tablets 10 to 30 mg was 
supported by the results of the analysis of the PANSS.
The efficacy and safety of Abilify Maintena for the treatment of bipolar I disorder was 
established in a phase 3, 52-week, randomized, double-blind, placebo-controlled trial 
(Trial 31-08-250). The primary efficacy endpoint was the time to recurrence of any mood 
episode, as measured in subjects with bipolar I disorder who had maintained stability on 
aripiprazole IM depot for at least 8 weeks. The time to recurrence of any mood episode 
was statistically significantly delayed with aripiprazole IM depot treatment compared 
with placebo treatment (log-rank test p < 0.0001). Aripiprazole IM depot treatment 
significantly reduced the risk of recurrence of any mood episode over 1 year compared 
with placebo treatment by approximately half (hazard ratio = 0.451 [Cox proportional 
hazard model]; 95% confidence interval [CI], 0.299 - 0.678). The proportion of subjects 
who met the criteria for recurrence of any mood episode was significantly lower with 
aripiprazole IM depot treatment compared with placebo treatment (26.5% versus 51.1%, 
Cochran-Mantel-Haenszel test p < 0.0001).
1.3
Pharmacokinetics 
Abilify Maintena activity is presumably primarily due to the parent drug, aripiprazole, 
and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
27


Protocol 031-201-00181
Confidential -- Proprietary Information
28
Protocol Version 3.0, 31 Jul 2019
shown to have affinities for D2 receptors similar to the parent drug and represents about 
29% of the parent drug exposure in plasma.
The plasma aripiprazole concentrations after single- and multiple-dose administration of 
Abilify Maintena are well established. The aripiprazole 2-month RTU formulation at the 
960 mg dose is expected to provide plasma concentrations of aripiprazole within the 
concentration range of Abilify Maintena.
Aripiprazole absorption into the systemic circulation is slow and prolonged following 
Abilify Maintena administration due to low solubility of aripiprazole particles. The 
average absorption half-life of aripiprazole from Abilify Maintena is 28 days. The 
absorption of aripiprazole from Abilify Maintena was complete relative to the 
IM standard (immediate-release) formulation. The dose-adjusted Cmax values for the 
depot formulation were approximately 5% of Cmax from the IM standard formulation. 
Following a single-dose administration of Abilify Maintena in the deltoid and gluteal 
muscle, the extent of absorption (area under the concentration-time curve [AUC]) was 
similar for both injection sites, but the rate of absorption (Cmax) was higher following 
administration to the deltoid muscle.
Based on results from trials with oral administration of aripiprazole, aripiprazole is 
widely distributed throughout the body with an apparent volume of distribution of 
4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, 
aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, 
binding primarily to albumin.
Elimination of aripiprazole is mainly through hepatic metabolism involving 2 cytochrome 
P450 (CYP) isozymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate of 
CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 
enzymes. Aripiprazole also does not undergo direct glucuronidation.
Following a single oral dose of [14C]-labeled aripiprazole, approximately 27% of the 
administered radioactivity was recovered in the urine and approximately 60% in the 
feces. Less than 1% of unchanged aripiprazole was excreted in the urine and 
approximately 18% was recovered unchanged in the feces.
Based on a population PK evaluation of Abilify Maintena, the total body clearance of 
aripiprazole was 3.71 L/h in extensive metabolizers of CYP2D6 and approximately 
1.88 L/h (approximately 50% lower) in poor metabolizers of CYP2D6.1
In the recently completed
 single-dose administration of 780 mg or 
1200 mg aripiprazole LAI to the gluteal muscle resulted in, respectively, a roughly 2-and 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
28


Protocol 031-201-00181
Confidential -- Proprietary Information
29
Protocol Version 3.0, 31 Jul 2019
3-fold increase in aripiprazole Cmax and exposure (area under the concentration-time 
curve from time zero to infinity [AUC∞] and area under the concentration-time curve 
from time zero to time t [AUCt]) than previously observed following single-dose 
administration of 400 mg Abilify Maintena to the gluteal muscle. The ratio of 
dehydro-aripiprazole to aripiprazole for mean AUC∞after administration of 780 mg or 
1200 mg aripiprazole LAI (0.34 and 0.31, respectively) was similar to that observed 
following administration of 400 mg Abilify Maintena (0.28). Administration of 780 mg 
or 1200 mg aripiprazole LAI resulted in a slightly less than proportional increase in 
aripiprazole and dehydro-aripiprazole Cmax and a slightly more than dose proportional 
increase in exposure (AUCt and AUC∞) based on mean values corrected for dose. 
Administration of 780 mg aripiprazole LAI resulted in shorter median tmax values for 
aripiprazole (25.1 days versus 41.0 days) and dehydro-aripiprazole (29.6 days versus
55.0 days) when compared to the 1200 mg dose. Following administration of 780 mg or 
1200 mg aripiprazole 2M LAI, the mean terminal phase elimination half-life (t1/2) values 
for aripiprazole (22.1 days and 20.0 days, respectively) and dehydro-aripiprazole 
(25.5 days and 22.9 days, respectively) were comparable, and similar to the median t1/2
following administration of 400 mg Abilify Maintena (24.0 days). A consistent increase 
in aripiprazole concentrations followed by a decline and a secondary peak in 
concentrations were observed following administration of 780 mg or 1200 mg 
aripiprazole LAI to the gluteal muscle based on examination of mean, median, and 
individual concentration-time profiles.
1.4
Risks and Benefits
Abilify Maintena is marketed worldwide and is approved for schizophrenia and bipolar I
disorder. To date, no unexpected safety concerns have been reported. The most 
frequently observed adverse reactions for approved indications are weight increased and 
akathisia.
Based on a 12-week, double-blind, placebo-controlled trial of Abilify Maintena in adult 
subjects with schizophrenia, the most commonly observed adverse reactions associated 
with the use of Abilify Maintena (incidence of 5% or greater and aripiprazole incidence 
at least twice that for placebo) were increased weight (16.8% versus 7.0%), akathisia 
(11.4% versus 3.5%), injection site pain (5.4% versus 0.6%), and sedation (5.4% versus 
1.2%).
Based on a double-blind, placebo-controlled, randomized withdrawal (maintenance) trial, 
the most commonly observed adverse drug reactions that were associated with the use of 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
29


Protocol 031-201-00181
Confidential -- Proprietary Information
30
Protocol Version 3.0, 31 Jul 2019
Abilify Maintena (incidence of 5% or greater and aripiprazole incidence greater than 
placebo) were weight increased (22.7%) and akathisia (20.5%).
Other commonly reported adverse reactions (reported in 2% or more of Abilify 
Maintena-treated subjects and at a greater proportion than in the placebo group) during 
the trials included the following:

Eye disorders: vision blurred

Gastrointestinal disorders: constipation, dry mouth, diarrhea, vomiting, and 
abdominal discomfort

Infections and infestations: upper respiratory tract infection

Investigations: decreased weight, blood creatine phosphokinase increased

Metabolism and nutrition disorders: increased appetite

Musculoskeletal and connective tissue disorders: arthralgia, back pain, myalgia, and 
musculoskeletal pain

Nervous system disorders: dizziness somnolence, sedation, bradykinesis, and tremor

Psychiatric disorder: anxiety and depression

Respiratory, thoracic, and mediastinal: nasal congestion

Reproductive system and breast disorders: erectile dysfunction
In addition to the above, the list of adverse reactions associated with the use of Abilify 
Maintena or other antipsychotic/atypical antipsychotic drugs includes the following:

Neuroleptic malignant syndrome

Tardive dyskinesia

Metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and 
weight gain

Orthostatic hypotension

Falls

Sleep apnea

Leukopenia, neutropenia, and agranulocytosis

Impairment of judgment, thinking, or motor skills

Disruption of the body’s ability to reduce core body temperature

Esophageal dysmotility and aspiration

Hypersensitivity reactions

Pathological gambling

Hypersexuality

Impulse control disorders
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
30




Protocol 031-201-00181
Confidential -- Proprietary Information
32
Protocol Version 3.0, 31 Jul 2019
aripiprazole is predicted to be reached by the fourth administration of aripiprazole 
2M LAI 960 mg. Therefore, 4 administrations of aripiprazole 2M LAI 960 mg in the 
gluteal site were chosen for this trial. A total of 8 administrations of Abilify Maintena
(aripiprazole IM depot 400 mg) were chosen to match the treatment duration of subjects 
receiving aripiprazole 2M LAI 960 mg.
2.3
Trial Objectives
2.3.1
Primary Objectives
The primary objectives of this trial are:

To determine the safety and tolerability of multiple-dose administrations of 
aripiprazole in adult subjects with schizophrenia or bipolar I disorder.

To establish the similarity of aripiprazole concentrations on the last day of the dosing 
interval following the final administration of aripiprazole into the gluteal muscle site 
in adult subjects with schizophrenia or bipolar I disorder.

To establish the similarity of aripiprazole exposure over the dosing interval following 
the administration of aripiprazole into the gluteal muscle site in adult subjects with 
schizophrenia or bipolar I disorder.
2.3.2
Secondary Objectives
The secondary objectives of this trial are:

To determine the PK of aripiprazole.

To determine aripiprazole concentrations 7 days (C7) and 14 days (C14) after the first 
dose of aripiprazole for subjects enrolled to the robust sampling schedule.

To obtain information on the efficacy of aripiprazole over the course of 32 weeks.
3
Trial Design
3.1
Type/Design of Trial
This is a phase 1b, open-label, multiple-dose, randomized, parallel-arm, multicenter
(approximately 20 trial sites) trial in adult subjects with schizophrenia or bipolar I 
disorder. After a screening period of up to 30 days, eligible subjects will be randomized 
(1:1) to receive multiple doses of either aripiprazole 2M LAI 960 mg (4 injections) or 
aripiprazole IM depot 400 mg (8 injections) over the course of 32 weeks. Aripiprazole 
2M LAI 960 mg will be administered at 56-day (± 2 days) intervals and aripiprazole 
IM depot 400 mg will be administered at 28-day (± 2 days) intervals. A final visit will 
occur 56 (± 2) days after the last dose of aripiprazole 2M LAI 960 mg or 28 (± 2) days 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
32


Protocol 031-201-00181
Confidential -- Proprietary Information
33
Protocol Version 3.0, 31 Jul 2019
after the last dose of aripiprazole IM depot 400 mg. A schematic of the trial design is 
provided in Figure 3.1-1.
Randomization to the 2 trial treatments will be stratified by the PK sampling schedule
(robust or sparse) and disease type (schizophrenia or bipolar I disorder). Four to 6 trial 
sites will be designated as Robust Sampling Trial Sites; all other trial sites will be 
designated as Sparse Sampling Trial Sites. Up to 76 subjects (38 per treatment group) 
will be enrolled to the robust sampling schedule and 182 subjects (91 per treatment 
group) will be enrolled to the sparse sampling schedule. If enrollment of the number of 
subjects required for the robust sampling schedule is completed, the Robust Sampling 
Trial Sites may enroll additional subjects to the sparse sampling schedule with approval 
from the sponsor. An interim analysis may be conducted to ensure adequate power of the 
trial Section 7.1.1. Based on the possible sample size re-estimation in the proposed 
interim analysis, fewer subjects may be enrolled.
Blood samples for PK analyses will be drawn from subjects at both Robust and Sparse 
Sampling Trial Sites after the first dose (Day 1) and fourth (final) dose (Day 169) of 
investigational medicinal product (IMP) for subjects randomized to aripiprazole 2M LAI 
960 mg, and after the first dose (Day 1), seventh dose (Day 169), and eighth (final) dose 
(Day 197) of IMP for subjects randomized to aripiprazole IM depot 400 mg. 
Subjects enrolled to the robust sampling schedule who are randomized to aripiprazole 2M 
LAI 960 mg must be housed in the unit for 21 days after the first and fourth doses of 
IMP, and will be outpatients for the rest of the trial. Subjects randomized to aripiprazole 
IM depot 400 mg will stay in the unit for 21 days after administration of the first, 
seventh, and eighth doses of IMP. Subjects who are not able to accommodate the 
scheduled stays in the unit may be permitted to have some visits as outpatients with 
approval from the medical monitor. For any outpatient visit, an unscheduled C-SSRS will 
be performed.
Subjects enrolled to the sparse sampling schedule will be outpatients for administration of 
all doses of IMP; however, they may be housed in the unit for up to 21 days after
administration of the first dose of IMP at the discretion of the investigator. 
Subjects who do not have a history of tolerating aripiprazole will undergo testing to 
determine tolerability prior to enrollment. Details of tolerability testing are provided in 
Section 3.2.2.
At the time of administration of the first dose of IMP, subjects will begin a 7- to 14- day 
period (oral overlap) where they will transition from their current oral antipsychotic to 
include injections of IMP. Details of the oral overlap period are provided in Section 3.2.3. 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
33




Protocol 031-201-00181
Confidential -- Proprietary Information
35
Protocol Version 3.0, 31 Jul 2019
3.2
Trial Treatments
3.2.1
Investigational Medicinal Product
The test IMP (aripiprazole 2M LAI) administered in this trial will be supplied as 
aripiprazole IM depot 300 mg/mL RTU single-dose vials. The reference IMP will be 
aripiprazole IM depot 400 mg single-dose lyophilized vials. 
 
 
 
 
 
Subjects will be randomized (1:1) to receive multiple doses of:

Aripiprazole 2M LAI 960 mg (test) - 2-month injection (total of 4 injections), 
administered every 56 days (± 2 days) over the course of 32 weeks.

Aripiprazole IM depot 400 mg (reference) - 1-month injection (total of 8 injections), 
administered every 28 days (± 2 days) over the course of 32 weeks.
The IMP will be administered as a single injection in the gluteal muscle for a total of 
4 (960 mg/injection) or 8 (400 mg/injection) injections. Due to possible safety and 
tolerability issues, a one-time dose reduction is allowed as outlined below:

Aripiprazole 2M LAI 960 mg: a dose decrease to 660 mg. If the subject has had a 
decrease to 660 mg, a one-time increase back to 960 mg is then allowed. 

Aripiprazole IM depot 400 mg: a dose decrease to 300 mg. If the subject has had a 
decrease to 300 mg, a one-time increase back to 400 mg is then allowed. 
Syringes and needles will be provided for the injection of IMP. Needles are selected 
based on the subject’s body weight recorded on Day 1 and on each subsequent visit, as 
specified in Table 3.2.1-1. Care must be taken to avoid inadvertent injection into a blood 
vessel, as per administration instructions. Detailed instructions on dose preparation and 
administration will be included in the site manual.
Table 3.2.1-1
Needle Size for IM Depot Injection
Day 1 Body Weight
Needle Type
< 200 lb
22 gauge, 1.5 inch
≥200 lb
21 gauge, 2.0 inch
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
35


Protocol 031-201-00181
Confidential -- Proprietary Information
36
Protocol Version 3.0, 31 Jul 2019
3.2.2
Tolerability Testing
Subjects who do not have a history of tolerating aripiprazole will receive 3 single 10-mg
doses of oral aripiprazole on 3 consecutive days (total of 30 mg) in addition to their 
current oral antipsychotic, mood stabilizer, and if applicable, antidepressant for at least
14 days prior to the first administration of IMP to establish tolerability. Subjects may be 
housed in the unit during these 3 days at the investigator’s discretion. 
3.2.3
Oral Overlap
At the time of administration of the first dose of IMP, subjects will begin a 7- to 14-day 
period (oral overlap) where they will transition from their current oral antipsychotic to 
include injections of IMP, according to the scenarios described in Table 3.2.3-1.
Subjects currently stabilized on a non-aripiprazole oral antipsychotic who are enrolled to 
a sparse sampling schedule will continue on their medication and subjects who are 
enrolled to a robust sampling schedule will switch to 10 to 20 mg oral aripiprazole (dose 
determined by the investigator). Subjects will take their oral antipsychotic medications
concurrently with IMP for 7 days after the first administration of aripiprazole 2M LAI 
960 mg or 14 days after the first administration of aripiprazole IM depot 400 mg. The 
oral antipsychotic will be discontinued after 7 days of administration of aripiprazole 2M 
LAI 960 mg and after 14 days of administration of aripiprazole IM depot 400 mg.
For subjects currently stabilized on oral aripiprazole, the recommended supplemental oral 
aripiprazole dose will be reduced to 10 mg/day with the first dose of IMP for subjects
with a previous dose of 10 to 20 mg/day or to 15 mg/day for subjects with a previous 
dose of > 20 to 30 mg/day (Table 3.2.3-2).
There will be no oral overlap for subjects who are taking Abilify Maintena® as their 
current antipsychotic medication. Subjects who are on Abilify Maintena as their current 
antipsychotic cannot be enrolled until their next scheduled dose is required as specified in 
the label, and they cannot receive IMP any earlier than 26 days after the last Abilify 
Maintena injection. In this scenario, the investigator should carefully consider the 
screening period and the timing of randomization in relation to the first dose of IMP and 
previous dose of Abilify Maintena.
Given the addition of a second antipsychotic, investigators should consider reducing the 
dose of the current oral antipsychotic, mood stabilizer, or antidepressant medications to 
the mid to lower range of the recommended dose range described in the labeling.
Aripiprazole tablets for oral overlap will be provided from a commercial supply.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
36


Protocol 031-201-00181
Confidential -- Proprietary Information
37
Protocol Version 3.0, 31 Jul 2019
Table 3.2.3-1
Scenarios for Initiation of Oral Aripiprazole Overlap During 
the First 2 Weeks After the Initiation of IMP
Treatment
PK Sampling 
Schedule
Current Antipsychotic Medicationa
Abilify 
Maintenab
300 or 400 mg 
Oral 
Aripiprazolec
Non-aripiprazole Oral 
Antipyschotic
Aripiprazole 
2M LAI 
960 mg
Sparse
No oral 
overlap
7-day oral overlap 
with adjusted dose
Continue current antipsychotic 
for 7 days
Robustd
Not applicable 
Not applicable 
(Switch to) Oral aripiprazole 
10 to 20 mg: 7-day oral 
overlap
Aripiprazole 
IM depot 
400 mg
Sparse
No oral 
overlap
14-day oral overlap 
with adjusted dose
Continue current antipsychotic 
for 14 days
Robustd
Not applicable 
Not applicable 
(Switch to) Oral aripiprazole 
10 to 20 mg: 14-day oral 
overlap
aSubjects with bipolar I disorder who are taking a mood stabilizer will be permitted to stay on their 
mood stabilizer over the course of the trial, and if taking an antidepressant, to continue treatment with 
their antidepressant unless it is unless the medication is prohibited during the trial (eg, fluoxetine, 
fluoxetine/olanzapine; Table 4.1-1).
bSubjects on an LAI other than Abilify Maintena are excluded from the trial. Subjects on Abilify 
Maintena as their current antipsychotic medication cannot enroll to the robust sampling schedule.
cFor subjects who are taking oral aripiprazole 10 to 20 mg as their current antipsychotic, the dose will 
be reduced for the overlap period (Table 3.2.3-2).
dIn order to be enrolled to the robust sampling schedule, subjects must have demonstrated prior 
tolerability to aripiprazole, must be stabilized on an existing non-aripiprazole antipsychotic, and must 
switch to oral aripiprazole on Day 1 for 7 or 14 days depending on the assigned IMP treatment.
Table 3.2.3-2
Dose Adjustment for Initiation of Oral Overlap for Subjects 
Currently Stabilized on Oral Aripiprazole
Current Dose of Oral Aripiprazole
Adjusted Dose of Oral Aripiprazole
10 - 20 mg
10 mg
> 20 - 30 mg
15 mg
3.2.4
Concurrent Antipsychotic Treatment
During the trial, concurrent antipsychotic treatment will be managed as follows:

Subjects with a diagnosis of bipolar I disorder who are taking a mood stabilizer 
(lithium, valproate, lamotrigine) will be permitted to stay on their mood stabilizer
over the course of the trial, and if applicable, to continue treatment with their 
antidepressant (citalopram, escitalopram, sertraline) unless the medication is 
prohibited during the trial (eg, (fluoxetine, fluoxetine/olanzapine; Table 4.1-1).

Subjects may resume treatment on their previous oral non-aripiprazole antipsychotic 
medication after Day 28 if there is evidence of clinical deterioration based on the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
37


Protocol 031-201-00181
Confidential -- Proprietary Information
38
Protocol Version 3.0, 31 Jul 2019
judgment of the investigator. If a decision is made that a subject may resume previous 
oral non-aripiprazole antipsychotic medication, the investigator will continue to 
monitor the subject for safety and clinical stability.
3.3
Trial Population
The trial population will include male and female subjects between the ages of 18 to 
64 years of age, inclusive, with a current diagnosis of schizophrenia or bipolar I disorder 
as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) criteria. Approximately 258 subjects (129 per treatment group) will be enrolled 
into the trial with the expectation that approximately 170 subjects (85 per treatment 
group) will complete the trial. An interim analysis may be conducted to ensure adequate 
power of the trial. Based on the possible sample size re-estimation in the proposed 
interim analysis, fewer subjects may be enrolled. 
Subjects entering the trial must have demonstrated prior tolerability to aripiprazole. In 
addition, subjects must be clinically stable (based on investigator judgment, 
subject/caregiver report, and/or documentation) for at least 2 months prior to screening 
AND must be on a stable dose of 1 of the following oral atypical antipsychotic 
medications for at least 2 months prior to screening: aripiprazole, brexpiprazole, 
risperidone, olanzapine, quetiapine, paliperidone, cariprazine, lurasidone, ziprasidone, or 
asenapine. Other oral non-aripiprazole, antipsychotic medications may be allowed if 
approved by the medical monitor and sponsor; however, clozapine will not be allowed. 
Additionally, subjects with bipolar I disorder, who are stabilized on their current 
medications for at least 2 months prior to screening may continue their mood stabilizer 
(lithium, valproic acid, lamotrigine) and antidepressant (citalopram, escitalopram, 
sertraline). 
Subjects who are on Abilify Maintena as their current antipsychotic cannot be enrolled 
until their next scheduled dose is required as specified in the label, and they cannot
receive IMP any earlier than 26 days after the last Abilify Maintena injection. In this 
scenario, the investigator should carefully consider the screening period and the timing of 
randomization in relation to the first dose of IMP and previous dose of Abilify Maintena.
Subjects taking oral aripiprazole or Abilify Maintena as their current antipsychotic 
medication cannot be enrolled to the robust sampling schedule (ie, subjects at these trial 
sites will not enter the screening period if they are taking oral aripiprazole or Abilify 
Maintena).
At screening, subjects will be assigned a unique identification (ID) number (subject 
identifier) upon signing the informed consent form (ICF). Subjects who meet the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
38


Protocol 031-201-00181
Confidential -- Proprietary Information
39
Protocol Version 3.0, 31 Jul 2019
inclusion criteria and do not fulfill any of the exclusion criteria will be eligible for the 
trial and will be enrolled as needed.
The trial sites will maintain a list identifying all subjects by their ID number and initials.
Recruitment of replacement subjects for noncompleters will be at the discretion of the 
sponsor. Noncompleters are defined as subjects who do not attend their last scheduled 
visit for PK sampling (Section 3.10).
3.4
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, either by the 
investigator or by the medical monitor.
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally
acceptable representative, as applicable for local laws) and documented using an 
electronic informed consent system. The ICF will be approved by the same institutional 
review board (IRB) that approves this protocol.
Each ICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline6 and local regulatory requirements. The investigator 
will ensure that the sponsor reviews and authorizes any site-specific ICF used in the trial
before submission to the IRB.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented prior to initiation of any procedures that are performed solely for the purpose 
of determining eligibility for research, 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.
Prospective trial participants will be provided with controlled access to the electronic ICF 
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 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. Any other parties required by the IRB (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 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
39


Protocol 031-201-00181
Confidential -- Proprietary Information
40
Protocol Version 3.0, 31 Jul 2019
Guideline and local regulatory requirements/guidelines. These signatures cannot be 
altered, removed, or copied.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
As part of the main ICF, subjects will also provide informed consent for 
phamacogenomic sampling. 
 
 
 
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
Male and female subjects between 18 and 64 years, inclusive.
2.
A current diagnosis of schizophrenia or bipolar I disorder, as defined by DSM-5 criteria.
3.
Body mass index of 18 to 35 kg/m2.
4.
Good physical health as determined by no clinically significant deviation from normal, in the 
opinion of the investigator, in medical history, clinical laboratory determination, ECGs, or physical 
examinations.
5.
Ability to provide written informed consent and/or consent obtained from a legally acceptable 
representative (as required by the IRB), prior to the initiation of any protocol-required procedures.
6.
Prior history of tolerating aripiprazole and/or Abilify Maintena per the investigator’s judgment. If 
the subject has not established tolerability, then assessment of oral aripiprazole tolerability will be 
completed within the screening period at least 14 days prior to the first administration of IMP (oral 
aripiprazole 10 mg/day for 3 consecutive days prior to Day −15).
7.
Subjects must be clinically stable (based on investigator judgment, subject/caregiver report, and/or 
documentation) for at least 2 months prior to screening AND 

On a stable dose of 1 of the following oral atypical antipsychotic medication for at least 
2 months prior to screening: aripiprazole (sparse only), brexpiprazole, risperidone, olanzapine, 
quetiapine, paliperidone, cariprazine, lurasidone, ziprasidone, or asenapine; or Abilify Maintena 
(sparse only). Additionally, subjects with bipolar I disorder who are stabilized on their current 
medications for at least 2 months prior to screening may continue their mood stabilizer (lithium, 
valproic acid, lamotrigine) and antidepressant (citalopram, escitalopram, sertraline).

Other oral non-aripiprazole, antipsychotic medications may be allowed if approved by the 
medical monitor and sponsor; however, clozapine will not be allowed. (Subjects intended to 
enroll to the robust sites may not be taking oral aripiprazole or Abilify Maintena as their current 
atypical antipsychotic.)
8.
Able to understand the nature of trial and follow protocol requirements and procedures.
AEs = adverse events; ECG = electrocardiogram.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
40


Protocol 031-201-00181
Confidential -- Proprietary Information
41
Protocol Version 3.0, 31 Jul 2019
Table 3.4.3-1
Exclusion Criteria
1.
Sexually active males who will not commit to utilizing 2 of the approved birth control methods or 
who will not remain abstinent during the trial and for 180 days following the last dose of IMP, or 
have not had an orchiectomy, or sexually active FOCBP who will not commit to utilizing 2 of the 
approved birth control methods or who will not remain abstinent during the trial and for 150 days 
following the last dose of IMP. 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, intrauterine device, birth control pill, birth control 
depot injections, implant, condom or sponge with spermicide. 
Note: FOCBP are defined as all women unless they have had an oophorectomy or hysterectomy or 
have been postmenopausal for 12 consecutive months.
2.
Subjects who have:

Met DSM-5 criteria for substance use disorder within the past 180 days.

A positive drug screen for drugs of abuse (excluding nicotine, alcohol, and marijuana). See 
note below for exceptions.
Note: For those who test positive for alcohol and/or marijuana, and for those who test positive for 
a drug of abuse for which they have a prescription, the investigator must provide sufficient written 
rationale and discuss with the medical monitor before attaining clearance to proceed with 
enrollment. This rationale must include the following: 1) rationale/indication for use, 2) review of 
patterns of use and frequency of use, and 3) justification to support compliance with the protocol 
for the intended duration of treatment (eg, based on investigator conversation with the subject).
3.
Use of any CYP2D6 and CYP3A4 inhibitors, or CYP3A4 inducers, within 14 days (fluoxetine or 
fluoxetine/olanzapine within 28 days) prior to dosing, for the duration of the trial, and 30 days 
after the last dose of IMP.
4.
Subjects may not receive varenicline beyond screening. If a subject is receiving varenicline at 
screening, attempts should be made to discontinue the medication, if clinically feasible, to allow 
potential subjects to enter the trial.
5.
Subjects enrolled to the robust sampling schedule must not have taken oral aripiprazole for 
30 days or Abilify Maintena for 1 year, prior to screening.
6.
Females who are pregnant, breast-feeding, lactating, and/or have a positive pregnancy test result 
prior to receiving IMP. A negative serum pregnancy test must be confirmed prior to the first dose 
of IMP for all female subjects.
7.
Subjects who participated in any clinical trial involving an oral psychotropic medication within 
1 month prior to the administration of IMP, as well as subjects who participated in a clinical trial 
with an aripiprazole depot-containing formulation of a psychotropic medication within the last 
1 year or a non-aripiprazole depot formulation within the last 6 months.
8.
Any major surgery within 30 days prior to enrollment or scheduled/elective surgery during the 
trial.
9.
Evidence of organ dysfunction or any clinically significant deviation from normal in the physical, 
electrocardiographic, or clinical laboratory examinations.
10.
Subjects who have a significant risk of committing suicide based on history, routine psychiatric 
status examination, investigator’s judgment, or who have an answer of “yes” on questions 4 or 5 
(current or over the last 6 months) on the baseline version of the C-SSRS.
11.
Subjects currently in an acute relapse of schizophrenia.
12.
Subjects with a current DSM-5 diagnosis other than schizophrenia or bipolar I disorder, including 
schizoaffective disorder, major depressive disorder, delirium, dementia, amnestic, or other 
cognitive disorders. Also, subjects with borderline, paranoid, histrionic, or antisocial personality 
disorder.
13.
Subjects who are considered treatment-resistant to an atypical antipsychotic medication (subjects 
need to have shown a previous response to an antipsychotic medication other than clozapine).
14.
Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive 
dyskinesia as assessed by the investigator.
15.
Any other sound medical reason as determined by the clinical investigator.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
41


Protocol 031-201-00181
Confidential -- Proprietary Information
42
Protocol Version 3.0, 31 Jul 2019
Table 3.4.3-1
Exclusion Criteria
16.
History of any significant drug allergy or known or suspected hypersensitivity, in particular to 
aripiprazole or other quinolinones.
17.
History of or current hepatitis or acquired immunodeficiency syndrome or carriers of HBsAg or 
anti-HCV, and/or HIV antibodies.
18.
Subjects deemed intolerant of receiving injections.
19.
Subjects who have had electroconvulsive therapy within 2 months of administration of IMP.
20.
The following laboratory test, vital sign, and ECG results are exclusionary:
1) Platelets ≤75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) AST > 3x upper limit of normal
5) ALT > 3x upper limit of normal
6) Creatinine ≥ 2 mg/dL
7) Diastolic blood pressure > 105 mmHg
8) QTcF ≥ 450 msec in males or ≥ 470 msec in females, on 2 of 3 time points of triplicate ECGs 
performed
anti-HCV = hepatitis C antibodies; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
C-SSRS = Columbia-Suicide Severity Rating Scale; FOCBP = females of childbearing potential; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; QTcF = corrected QT 
interval using Fridericia’s formula; ULN = upper limit of normal.
Subjects excluded for a positive drug screen for drugs of abuse are not eligible to be 
rescreened for participation in the trial. For those who test positive for alcohol and/or 
marijuana, and for those who test positive for a drug of abuse for which they have a 
prescription, the investigator must provide sufficient written rationale and discuss with 
the medical monitor before attaining clearance to proceed with enrollment. This rationale 
must include the following: 1) rationale/indication for use, 2) review of patterns of use 
and frequency of use, and 3) justification to support compliance with the protocol for the 
intended duration of treatment (eg, based on investigator conversation with the subject).
Subjects excluded for other reasons may be rescreened at any time if the exclusion 
characteristic has changed. In the event that the subject is rescreened, a new ICF must be 
signed, a new screening number assigned, and all screening procedures repeated.
Rescreening of subjects is described in Section 3.9.
Electrocardiogram or laboratory outcomes that emerge over the course of the trial that 
would have been deemed exclusionary during the screening period should be reviewed 
and discussed with the medical monitor. For this discussion, the investigator is asked to 
provide an assessment of risk associated with continuation in the trial, and a 
recommendation for follow-up.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
42


Protocol 031-201-00181
Confidential -- Proprietary Information
43
Protocol Version 3.0, 31 Jul 2019
3.5
Endpoints
3.5.1
Primary Endpoints
3.5.1.1
Safety
Safety and tolerability will be based on reported AEs, vital signs, electrocardiograms 
(ECGs), clinical laboratory monitoring (serum chemistry, hematology, and urinalysis), 
physical examinations, extrapyramidal symptoms (EPS) (the Simpson-Angus Neurologic 
Rating Scale [SAS], Abnormal Involuntary Movement Scale [AIMS], and Barnes 
Akathisia Rating Scale [BARS]), Visual Analog Scale (VAS) scores for pain perception, 
Investigator’s Assessment of Most Recent Injection Site, and suicidality via the 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
3.5.1.2
Pharmacokinetic
The primary PK parameters to be estimated for aripiprazole are as follows:

Plasma concentration of aripiprazole 56 days postdose (C56) of aripiprazole 2M LAI 
960 mg after the fourth dose and plasma concentration of aripiprazole 28 days 
postdose (C28) of aripiprazole IM depot 400 mg after the eighth dose over the course 
of 32 weeks.

AUC0-56 for aripiprazole 2M LAI 960 mg after the fourth dose or AUC0-28 for 
aripiprazole IM depot 400 mg after the seventh and eighth doses over the course of 
32 weeks, based on the PK data from subjects enrolled to the robust sampling 
schedule.
3.5.2
Secondary Endpoints
3.5.2.1
Pharmacokinetic
The following PK parameters will be estimated for aripiprazole after the administration 
of aripiprazole 2M LAI 960 mg and aripiprazole IM depot 400 mg: 

Cmax and tmax after the first and fourth doses of aripiprazole 2M LAI 960 mg.

AUC0-56 and C56 after the first dose of aripiprazole 2M LAI 960 mg.

AUC0-28 and AUC29-56 after the fourth dose of aripiprazole 2M LAI 960 mg.

Peak-to-trough percent fluctuation (PTF%) after the fourth dose of aripiprazole 
2M LAI 960 mg.

Cmax and tmax after the first, seventh, and eighth doses of aripiprazole IM depot 
400 mg.

AUC0-28 and C28 after the first dose of aripiprazole IM depot 400 mg.

PTF% after the eighth dose of aripiprazole IM depot 400 mg.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
43


Protocol 031-201-00181
Confidential -- Proprietary Information
44
Protocol Version 3.0, 31 Jul 2019
Note: Cmax, tmax, AUC, and PTF% will be determined only from subjects enrolled to the
robust sampling schedule; C56 and C28 will be determined from subjects enrolled to the
sparse and robust sampling schedule.
After the first dose of IMP, the following PK parameters will be estimated for 
aripiprazole after administration of aripiprazole 2M LAI 960 mg + oral aripiprazole 10 to 
20 mg for 7 days and aripiprazole IM depot 400 mg + oral aripiprazole 10 to 20 mg for 
14 days (this endpoint is only for subjects enrolled to the robust sampling schedule):

Plasma concentration of aripiprazole 7 days postdose (C7)

Plasma concentration of aripiprazole 14 days postdose (C14)
3.5.2.2
Efficacy
The efficacy of aripiprazole IM depot administration in the gluteal muscle will be 
assessed by the PANSS (schizophrenia subjects only), CGI-S, Clinical Global Impression 
- Improvement (CGI-I), Subjective Well-being under Neuroleptic Treatment-Short Form 
(SWN-S), Montgomery-Asberg Depression Rating Scale (MADRS; bipolar subjects 
only), Young Mania Rating Scale (YMRS; bipolar subjects only), and Clinical Global 
Impression - Bipolar Version (CGI-BP; bipolar subjects only).
3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
Randomization avoids systematic differences between groups with respect to known or 
unknown baseline variables that could affect outcome. After a screening period of up to 
30 days, eligible subjects will be randomized (1:1) to receive multiple doses of either 
aripiprazole 2M LAI 960 mg (4 injections) or aripiprazole IM depot 400 mg 
(8 injections) over the course of 32 weeks. Aripiprazole 2M LAI 960 mg will be 
administered at 56-day (± 2 days) intervals and aripiprazole IM depot 400 mg will be 
administered at 28-day (± 2 days) intervals.
Randomization to the 2 trial treatments will be stratified by the PK sampling schedule
(robust or sparse) and disease type (schizophrenia or bipolar I disorder).
3.6.2
Blinding
Not applicable; this is an open-label trial.
3.7
Trial Procedures
The trial will consist of a screening period of up to 30 days and a treatment period of 
169 (± 2) days with a follow-up period of 56 (± 2) days after administration of the final 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
44


Protocol 031-201-00181
Confidential -- Proprietary Information
45
Protocol Version 3.0, 31 Jul 2019
dose for the aripiprazole 2M LAI 960 mg treatment group, or a treatment period of 
197 (± 2) days with a follow-up period of 28 (± 2) days after administration of the final 
dose for the aripiprazole IM depot 400 mg treatment group. Individual participation for 
both treatment groups will be approximately 255 (± 2) days.
Subjects will provide signed informed consent prior to performing any trial procedures.
Screening procedures will be performed Day −30 to −1 to determine eligibility to 
participate in the trial.
Subjects who meet the inclusion criteria and do not fulfill any of the exclusion criteria 
will return to the trial site for check-in on Day −1 or Day 1. Predose assessments and 
administration of IMP will be performed on Day 1. After the predose assessments, 
subjects will be randomized (1:1) to receive multiple doses of either aripiprazole 2M LAI 
960 mg (4 injections) or aripiprazole IM depot 400 mg (8 injections) over the course of 
32 weeks. Aripiprazole 2M LAI 960 mg will be administered in 56-day (± 2 days) 
intervals and aripiprazole IM depot 400 mg injections will be administered in 28-day 
(± 2 days) intervals.
All visits may occur within ± 2 days of the target visit date for subjects enrolled to the
sparse sampling schedule and for subjects enrolled to the robust sampling schedule after 
discharge from the clinical unit. All subjects must return to the clinical trial site for 
scheduled doses, assessments, and PK sample collections. A final visit will occur
56 (± 2) days after the last dose of aripiprazole 2M LAI 960 mg or 28 (± 2) days after the 
last dose of aripiprazole IM depot 400 mg.
Trial assessments are summarized by visit in Table 3.7-1 for subjects enrolled to the
sparse sampling schedule and in Table 3.7-2 for subjects enrolled to the robust sampling 
schedule.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
45


Protocol 031-201-00181
Confidential -- Proprietary Information
46
Protocol Version 3.0, 31 Jul 2019
Table 3.7-1
Schedule of Assessments: Sparse Sampling
Screening
Check-ina
Days ± 2
Day −30 
to −1
Day 1
8
15
22 
29 
36b
43b
50b
57 
85
113
141
169
176b
183b
190b
197
204 
211 
218
225/
ET
Informed consent
X
Confirmation of current 
diagnosis of schizophrenia or 
bipolar I disorder by DSM-5
X
Inclusion/exclusion criteria
X
X
Demographic information
X
Medical and psychiatric 
history
X
X
Discontinue prohibited 
medication/taper off restricted 
medication
X
Document birth control 
methods
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer IMP tolerability 
dose
X
Admit to trial site clinic
Xa,c
Xd
Discharge from trial site clinic
Xc
Xd
Outpatient visits to trial site
clinic
X
X
X
X
X
X
X
X
X
X
X
Serum hepatitis and HIV 
screen
X
Urine drug screen and urine or 
breath alcohol screen
X
X
Urine pregnancy teste
X
X
X
X
X
X
X
X
X
X
FSHf
X
Hematology, clinical 
chemistry, and urinalysis
X
X
X
X
Serum prolactin assessment
X
X
X
Physical examination
X
X
X
Day 15
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
46


Protocol 031-201-00181
Confidential -- Proprietary Information
47
Protocol Version 3.0, 31 Jul 2019
Table 3.7-1
Schedule of Assessments: Sparse Sampling
Screening
Check-ina
Days ± 2
Day −30 
to −1
Day 1
8
15
22 
29 
36b
43b
50b
57 
85
113
141
169
176b
183b
190b
197
204 
211 
218
225/
ET
Height and BMI
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Day 15
X
X
X
X
C-SSRSh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EPS assessments (SAS, AIMS, 
and BARS)
X
X
X
X
X
X
X
X
X
X
X
PANSS (schizophrenia 
subjects only), CGI-S, and 
SWN-Sj
X
X
X
X
X
X
X
X
CGI-I
X
X
MADRS, YMRS, and CGI-BP 
(all 3 are in bipolar subjects 
only)j
X
X
X
X
X
X
X
X
Randomization
X
Record adjustment of current 
oral antipsychotic, mood 
stabilizer, or antidepressant
therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
VAS (perceived pain at 
injection site)k
X
Xi
X
Xi
X
Xi
X
Xi
Investigator’s assessment of 
injection sitek
X
Xi
X
Xi
X
Xi
X
Xi
Administer IMP: aripiprazole 
2M LAI 960 mg
X
X
X
X
Administer IMP: aripiprazole 
IM depot 400 mg
X
X
X
X
X
X
X
X
PK blood draw
Xl,m
Xn
Xb,n
Xi,l,m
Xn
Xl,m
Xb,n
Xi,l,m
Xl,m
Xb,n
Xi,l,m
Xl,m
Xn
Xb,n
Xi,l,m
Xn
Xn
CYP2D6 pharmacogenomics 
blood draw
X
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
47




Protocol 031-201-00181
Confidential -- Proprietary Information
49
Protocol Version 3.0, 31 Jul 2019
kCompleted approximately 30 minutes prior to injection and 1 hour (± 15 minutes) postdose.
lPredose samples are collected up to 2 hours prior to dosing.
mPostdose samples are collected at 4, 8, and 12 hours after dosing.
nPK samples on non-dosing days should be obtained between 8 AM and 2 PM on the specified trial day. For outpatients, the non-dosing day must be within
± 2 days of the specified day. 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
49


Protocol 031-201-00181
Confidential -- Proprietary Information
50
Protocol Version 3.0, 31 Jul 2019
Table 3.7-2
Schedule of Assessments: Robust Sampling
Screening
Check-
ina
Days (Clinical Unit)
Days ± 2 (Outpatient)
Days (Clinical Unit)
Days ± 2 (Outpatient)
Day 
± 2
Day −30 to 
−1
Day 1
2
3
5
8
10
13
15
18
22
29 
36b
43b
50b
57 
85
113
141
169
170
171
173
176
178
181
183
186
190 
197
198c
199c
201c
206c
209c
214c
204
211 
218
225/ 
ET
Informed consent
X
Confirmation of 
current diagnosis of 
schizophrenia or 
bipolar I disorder by 
DSM-5
X
Inclusion/exclusion 
criteria
X
X
Demographic 
information
X
Medical and 
psychiatric history
X
X
Discontinue prohibited 
medication/taper off 
restricted medication
X
Document birth control 
methods
X
X
X
X
X
X
X
X
X
X
X
Day 
190
X
X
X
X
Administer IMP 
tolerability dose
X
Admit to trial site
clinic
Xa,d
X
X
Xc
Discharge from trial 
site clinic
Xd
X
X
Day 
190
Xc
Day 
218
Outpatient visits to 
trial site clinic
X
X
X
X
X
X
X
Xb
Xb
X
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
50


Protocol 031-201-00181
Confidential -- Proprietary Information
51
Protocol Version 3.0, 31 Jul 2019
Table 3.7-2
Schedule of Assessments: Robust Sampling
Screening
Check-
ina
Days (Clinical Unit)
Days ± 2 (Outpatient)
Days (Clinical Unit)
Days ± 2 (Outpatient)
Day 
± 2
Day −30 to 
−1
Day 1
2
3
5
8
10
13
15
18
22
29 
36b
43b
50b
57 
85
113
141
169
170
171
173
176
178
181
183
186
190 
197
198c
199c
201c
206c
209c
214c
204
211 
218
225/ 
ET
Serum hepatitis and 
HIV screen
X
Urine drug screen and 
urine or breath alcohol 
screen
X
X
Urine pregnancy teste
X
X
X
X
X
X
X
X
X
X
FSHf
X
Hematology, clinical 
chemistry, and 
urinalysis
X
X
X
X
Serum prolactin
assessment
X
X
X
Physical examination
X
X
X
X
X
X
Weight 
X
X
X
X
X
X
X
X
X
X
Height and BMI
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
C-SSRSh
X
X
X
X
X
X
X
X
X
X
Xb
Day 
190
X
X
Days 
204b, 
211b,
218b,c
X
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
51


Protocol 031-201-00181
Confidential -- Proprietary Information
52
Protocol Version 3.0, 31 Jul 2019
Table 3.7-2
Schedule of Assessments: Robust Sampling
Screening
Check-
ina
Days (Clinical Unit)
Days ± 2 (Outpatient)
Days (Clinical Unit)
Days ± 2 (Outpatient)
Day 
± 2
Day −30 to 
−1
Day 1
2
3
5
8
10
13
15
18
22
29 
36b
43b
50b
57 
85
113
141
169
170
171
173
176
178
181
183
186
190 
197
198c
199c
201c
206c
209c
214c
204
211 
218
225/ 
ET
EPS assessments
(SAS, AIMS, and 
BARS)
X
X
X
X
X
X
X
X
X
X
X
X
X
PANSS (schizophrenia 
subjects only), CGI-S, 
and SWN-Si
X
X
X
X
X
X
X
X
CGI-I
X
X
MADRS, YMRS, and 
CGI-BP (bipolar 
subjects only)i
X
X
X
X
X
X
X
X
Randomization
X
Record adjusted
current oral 
antipsychotic, mood 
stabilizer, or 
antidepressant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
VAS (perceived pain at 
injection site)j
X
Xc
X
Xc
X
Xc
X
Xc
Investigator’s 
assessment of injection 
sitej
X
Xc
X
Xc
X
Xc
X
Xc
Administer IMP: 
aripiprazole 2M LAI 
960 mg
X
X
X
X
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
52




Protocol 031-201-00181
Confidential -- Proprietary Information
54
Protocol Version 3.0, 31 Jul 2019
cSubjects who receive aripiprazole IM depot 400 mg. These subjects will stay in the unit for 21 days after administration of the first (Day 1), seventh 
(Day 169), and eighth (Day 197) doses of IMP. Subjects who are not able to accommodate the scheduled stays in the unit may be permitted to have some 
visits as outpatients with approval from the medical monitor. For any outpatient visit, an unscheduled C-SSRS will be performed.
dIf tolerability to aripiprazole must be established, there will be a 3-day assessment of oral aripiprazole tolerability during the screening period. At the 
discretion of the investigator, subjects may be housed in the unit for the assessment. Subjects having tolerability assessed as outpatients must be contacted 
by the site each day during the assessment period.
eFemale subjects of childbearing potential only. If the urine pregnancy test is positive, the result should be confirmed with a serum pregnancy test.
fPerimenopausal and postmenopausal female subjects only.
gVital signs will include systolic and diastolic blood pressure, heart rate, and body temperature. Vital signs will be obtained prior to PK blood draws and 
ECGs at the nominal time points, where applicable. At each time point, blood pressure (systolic and diastolic) and heart rate will be taken after subjects 
have been in the supine position for at least 5 minutes and again after subjects have been standing for 2 minutes, but not more than 3 minutes. Body 
temperature will be taken with the subject in the supine position (ie, only once).
hThe Baseline/Screening version of the C-SSRS will be administered at the screening visit and the Since Last Visit version of the C-SSRS will be 
administered at all other time points.
iAll efficacy assessments will be performed prior to PK blood draws and dosing, where applicable.
jCompleted approximately 30 minutes prior to injection and 1 hour (± 15 minutes) postdose.
kPredose samples are collected up to 2 hours prior to dosing.
lPostdose samples are collected at 4, 8, and 12 hours after dosing.
mPK samples on non-dosing days should be obtained between 8 AM and 2 PM on the specified trial day. For outpatients, the non-dosing day must be within
± 2 days of the specified day. 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
54


Protocol 031-201-00181
Confidential -- Proprietary Information
55
Protocol Version 3.0, 31 Jul 2019
3.7.1
General Inpatient Procedures
Subjects enrolled to the robust sampling schedule who receive aripiprazole 2M LAI 
960 mg must be housed in the clinical unit for 21 days after the first (Day 1) and last 
administration of investigational medicinal product (IMP), and will be outpatients for the 
rest of the trial. Subjects who receive aripiprazole IM depot 400 mg will stay in the unit 
for 21 days after administration of the first (Day 1), seventh (Day 169), and eighth 
(Day 197) doses of IMP. Subjects who are not able to accommodate the scheduled stays 
in the unit may be permitted to have some visits as outpatients with approval of the 
medical monitor. For any outpatient visit, an unscheduled C-SSRS will be performed.
Subjects enrolled to the sparse sampling schedule will be outpatients for all 
administrations of IMP but, at the discretion of the investigator, may be housed in the 
unit for up to 21 days after the first administration of IMP (Section 3.1). Subjects staying 
in the clinical unit may check in to the clinical unit on Day −1; however, all predose 
assessments will be performed on Day 1 prior to the administration of IMP.
While housed in the clinical unit, standard meals consisting of breakfast, lunch, dinner, 
and an evening snack will be provided at times that do not interfere with trial activities 
and assessments. There are no restrictions on food or water intake prior to administration 
of aripiprazole IM depot. Food and water will be permitted ad libitum according to the 
clinical unit’s standard operating procedures.
Subjects will be required to present to the clinical trial site for efficacy and safety 
assessments and collection of PK samples on the days specified in Table 3.7-1 for 
subjects enrolled to the sparse sampling schedule and in Table 3.7-2 for subjects enrolled 
to the robust sampling schedule.
3.7.2
Dietary Requirements
With the exception of alcohol consumption, which is prohibited (Section 4), there are no 
other dietary restrictions in this trial.
3.7.3
Schedule of Assessments
Subjects are to continue their current oral antipsychotic, mood stabilizer, or 
antidepressant medications as specified in Section 3.1.
At each time point for vital signs, blood pressure (systolic and diastolic) and heart rate 
will be taken after subjects have been in the supine position for at least 5 minutes and 
again after subjects have been standing for 2 minutes, but not more than 3 minutes. Body 
temperature will be taken with the subject in the supine position (ie, only once). The ECG
will be recorded after the subject has been supine and at rest for ≥10 minutes prior to the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
55


Protocol 031-201-00181
Confidential -- Proprietary Information
56
Protocol Version 3.0, 31 Jul 2019
first ECG and subjects will remain supine through the final ECG. Vital signs will be 
obtained prior to PK blood draws and ECGs at the nominal time points, where applicable,
and ECGs will be collected prior to PK blood draws at the nominal time points, where 
applicable. If a PK blood sample cannot be drawn at the designated postdose times, a 
window of ± 15 minutes for each blood draw is acceptable, with the exact time recorded.
All efficacy assessments will be performed prior to PK blood draws and dosing, where 
applicable.
After predose assessments on Day 1, subjects will be randomized 1:1 to receive multiple
doses of aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg over the course of 
32 weeks.
Whenever a serious adverse event (SAE) occurs, blood samples should be collected as 
early as is feasible to measure the plasma concentrations of aripiprazole.
Assessments performed at the screening visit are summarized in Table 3.7.3-1.
Assessments are summarized by trial day in Table 3.7.3-2 for subjects enrolled to the 
sparse sampling schedule and in Table 3.7.3-3 for subjects enrolled to the robust 
sampling schedule. Trial visits that are 2 days apart should be done in relation to the last 
dosing (ie, the ± 2-day window does not apply).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
56


Protocol 031-201-00181
Confidential -- Proprietary Information
57
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-1
Screening Assessments and Procedures
Days −30 to −1
Subjects will be screened within the 30-day period prior to Day 1. Screening procedures will consist of the following:

Review trial procedures and information regarding the nature of the trial and obtain informed consent prior to any trial-related procedures.

Confirm that subject is stable on current oral antipsychotic, mood stabilizer, or antidepressant medications as deemed by the investigator.

Confirm current diagnosis of schizophrenia or bipolar I disorder, as defined by DSM-5 criteria.

Review inclusion and exclusion criteria.

Collect demographic information.

Document medical and psychiatric history.

Document birth control methods.

Record current oral antipsychotic, mood stabilizer, or antidepressant medications (or Abilify Maintena, if applicable).

Discontinue prohibited medications or taper off restricted medications as per Section 4 (if applicable).

Record concomitant medications and review for prohibited or restricted medications. All medications taken within 30 days prior to starting IMP will be 
recorded.

Record AEs.

Perform a physical examination.

Measure height and weight and calculate BMI.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect samples for serum hepatitis and HIV screen.

Perform a urine drug screen and a urine or breath alcohol screen.

Perform a urine pregnancy test (FOCBP only).

Collect a sample for FSH testing (perimenopausal and postmenopausal female subjects only).

Collect clinical laboratory samples for hematology, clinical chemistry, prolactin assessment, and urinalysis.

Administer the Baseline/Screening version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
For subjects who do not have a history of tolerating aripiprazole:

Administer 3 single 10-mg doses of oral aripiprazole on 3 consecutive days (total of 30 mg) at least 14 days prior to the administration of IMP. Subjects may 
be housed in the unit during these 3 days at the investigator’s discretion. Subjects having tolerability assessed as outpatients must be contacted by the site 
each day during the assessment period. Subjects will continue to take their current oral antipsychotic, mood stabilizer, or antidepressant therapy 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
57


Protocol 031-201-00181
Confidential -- Proprietary Information
58
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-1
Screening Assessments and Procedures
during this period. The subjects’ antipsychotic, mood stabilizer, or antidepressant treatment should not be discontinued but dose adjustments are allowed as 
determined by the investigator.
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities
Day 1 ± 2 days (outpatient, all subjects)
Predose:  

Admit subjects to the trial site clinic (if the subject has not been admitted on Day −1). Subjects may be housed in the clinical unit for up to 21 days following 
the first administration of IMP, if the investigator deems it necessary. Subjects will be discharged on Day 22.

Confirm that the subject is stable on current oral antipsychotic, mood stabilizer, or antidepressant medications, as deemed by the investigator.

Review inclusion and exclusion criteria.

Update medical and psychiatric history (if applicable).

Document birth control methods.

Record current oral antipsychotic, mood stabilizer, or antidepressant medications (or Abilify Maintena, if applicable).

Record prior and concomitant medications and review for prohibited or restricted medications.

Assess and record AEs.

Adjust current oral antipsychotic, mood stabilizer, or antidepressant medications.

Subjects will continue their current oral antipsychotic, mood stabilizer, or antidepressant medications for the first 7 days following aripiprazole 2M LAI 
960 mg and the first 14 days following aripiprazole IM depot 400 mg. For this reason, investigators should consider reducing the dose of the oral 
antipsychotic, mood stabilizer, or antidepressant medications to the mid to lower range of the recommended dose range described in the labeling. Subjects 
who are outpatients during the 7- to 14-day oral overlap period must be contacted by the site every day during this period.

Perform a urine drug screen and a urine or breath alcohol screen.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight (choice of needle size for IM dosing will be based upon this weight).

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect clinical laboratory samples for hematology, clinical chemistry, prolactin assessment, and urinalysis.

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
58


Protocol 031-201-00181
Confidential -- Proprietary Information
59
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Draw blood for CYP2D6 pharmacogenomics.

Randomize to aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg.

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (aripiprazole IM depot 400 mg or aripiprazole 2M LAI 960 mg).
.Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.

Draw a PK blood sample at 4, 8, and 12 hours postdose.
Day 8 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Subjects assigned to aripiprazole 2M LAI 960 mg will discontinue taking 10 to 20 mg oral aripiprazole and/or current oral antipsychotic (as applicable) 
until the end of the trial. Subjects may resume treatment on their previous oral non-aripiprazole antipsychotic after Day 28, if there is evidence of clinical 
deterioration based on the judgment of the investigator.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Draw a PK blood sample between 8 AM and 2 PM.
Days 15 and 22 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a physical examination (Day 15 only).

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Administer a 12-lead safety ECG in triplicate (5 minutes apart; Day 15 only).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
59


Protocol 031-201-00181
Confidential -- Proprietary Information
60
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Assess EPS (SAS, AIMS, and BARS).

Draw a PK blood sample between 8 AM and 2 PM.

Discharge subjects housed in the clinical unit for an optional stay after completing all activities (Day 22).
Day 29 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect clinical laboratory samples for hematology, clinical chemistry, prolactin assessment, and urinalysis.

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
60


Protocol 031-201-00181
Confidential -- Proprietary Information
61
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities
Days 36, 43, and 50 ± 2 days (outpatient, subjects receiving aripiprazole 2M LAI 960 mg)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Draw a PK blood sample between 8 AM and 2 PM.
Day 57 ± 2 days (outpatient, all subjects)
Predose:

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Administer the Since Last Visit version of the C-SSRS. 

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale, CGI-I scale, and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site completed approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 85 ± 2 days (outpatient, all subjects)

Document birth control methods.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
61


Protocol 031-201-00181
Confidential -- Proprietary Information
62
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 113 ± 2 days (outpatient, all subjects)
Predose:

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Administer the Since Last Visit version of the C-SSRS.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
62


Protocol 031-201-00181
Confidential -- Proprietary Information
63
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (aripiprazole IM depot 400 mg or aripiprazole 2M LAI 960 mg). 
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 141 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
63


Protocol 031-201-00181
Confidential -- Proprietary Information
64
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 169 ± 2 days (outpatient, all subjects)
Predose:

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (aripiprazole IM depot 400 mg or aripiprazole 2M LAI 960 mg). 
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.

Draw a PK blood sample at 4, 8, and 12 hours postdose.
Days 176, 183, and 190 ± 2 days (outpatient, subjects receiving aripiprazole 2M LAI 960 mg)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
64


Protocol 031-201-00181
Confidential -- Proprietary Information
65
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Draw a PK blood sample between 8 AM and 2 PM.
Day 197 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight and calculate BMI.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
Subjects who receive aripiprazole 2M LAI 960 mg only:

Draw a PK blood sample between 8 AM and 2 PM.
Subjects who receive aripiprazole IM depot 400 mg only:
Predose:

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Draw a PK blood sample within 2 hours prior to dosing.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1-hour (± 15 minutes) postdose.

Draw a PK blood sample 4, 8, and 12 hours postdose.
Days 204, 211, and 218 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record prior and concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
65


Protocol 031-201-00181
Confidential -- Proprietary Information
66
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-2
Sparse Sampling Schedule Trial Days and Activities

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Draw a PK blood sample between 8 AM and 2 PM.
Day 225/Early Termination ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect hematology, clinical chemistry, and urinalysis clinical laboratory samples.

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample between 8 AM and 2 PM.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
66


Protocol 031-201-00181
Confidential -- Proprietary Information
67
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities
Day 1
Predose:

Admit subjects to the trial site clinic (if the subject has not been admitted on Day −1). Subjects must be housed in the clinical unit for 21 days following the 
first administration of aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg (Section 3.1).

Confirm that the subject is stable on current oral antipsychotic, mood stabilizer or antidepressant medications, as deemed by the investigator.

Review inclusion and exclusion criteria.

Update medical and psychiatric history (if applicable).

Subjects will switch from their current oral antipsychotic to 10 to 20 mg of oral aripiprazole (dose determined by the investigator) for 7 days after the first
administration of aripiprazole 2M LAI 960 mg and for 14 days after the first administration of aripiprazole IM depot 400 mg. Subjects who are outpatients 
during the 7- to 14-day oral overlap period must be contacted by the site every day during this period.

Document birth control methods.

Record prior and concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant medications.

Assess and record AEs.

Perform a urine drug screen and a urine or breath alcohol screen.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure height and weight (choice of needle size for IM dosing will be based upon this weight); calculate BMI.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature) prior to dosing.

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect clinical laboratory samples for hematology, clinical chemistry, prolactin assessment, and urinalysis.

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Randomize subjects to aripiprazole 2M LAI 960 mg or aripiprazole IM depot 400 mg.

Draw a PK blood sample within 2 hours prior to dosing.

Collect pharmacogenomics blood sample to determine the CYP2D6 metabolizer status.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (subjects randomized to aripiprazole IM depot 400 mg and subjects randomized to aripiprazole 2M LAI 960 mg). 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
67


Protocol 031-201-00181
Confidential -- Proprietary Information
68
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.

Draw a PK blood sample 4, 8, and 12 hours postdose.
Days 2, 3, and 5 (inpatient, all subjects)

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Draw a PK blood sample between 8 AM and 2 PM.
Day 8 (inpatient, all subjects)

Subjects assigned to aripiprazole 2M LAI 960 mg will discontinue taking 10 to 20 mg oral aripiprazole and/or current oral antipsychotic (as applicable) 
until the end of the trial. Subjects may resume treatment on their previous oral non-aripiprazole antipsychotic after Day 28, if there is evidence of clinical 
deterioration based on the judgment of the investigator.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Assess EPS (SAS, AIMS, and BARS).

Draw a PK blood sample between 8 AM and 2 PM.
Days 10 and 13 (inpatient, all subjects)

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Draw a PK blood sample between 8 AM and 2 PM.
Days 15, 18, and 22 (inpatient, all subjects)

Subjects assigned to aripiprazole IM depot 400 mg will discontinue taking 10 to 20 mg oral aripiprazole and/or current oral antipsychotic (as applicable) 
from Day 15 until the end of the trial. Subjects may resume treatment on their previous oral non-aripiprazole antipsychotic after Day 28, if there is evidence 
of clinical deterioration based on the judgment of the investigator.

Document birth control methods (Day 22 only). 

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
68


Protocol 031-201-00181
Confidential -- Proprietary Information
69
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Assess and record AEs.

Perform a physical examination (Day 15 only).

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart; Day 15 only).

Administer the Since Last Visit version of the C-SSRS (Day 22 only; predose).

Assess EPS (SAS, AIMS, and BARS) (Days 15 and 22 only).

Draw a PK blood sample between 8 AM and 2 PM.

Discharge subjects from clinical unit after completing all activities (Day 22).
Day 29 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect clinical laboratory samples for hematology, clinical chemistry, prolactin assessment, and urinalysis.

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
69


Protocol 031-201-00181
Confidential -- Proprietary Information
70
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Days 36, 43, and 50 ± 2 days (outpatient, subjects receiving aripiprazole 2M LAI 960 mg)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS.

Draw a PK blood sample between 8 AM and 2 PM.
Day 57 ± 2 days (outpatient, all subjects)
Predose:

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Administer the Since Last Visit version of the C-SSRS (predose). 

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
70


Protocol 031-201-00181
Confidential -- Proprietary Information
71
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 85 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation that the injection site is appropriate by the investigator 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 113 ± 2 days (outpatient, all subjects)
Predose:

Document birth control methods. 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
71


Protocol 031-201-00181
Confidential -- Proprietary Information
72
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs. Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart). 

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (subjects randomized to aripiprazole IM repot 400 mg and subjects randomized to aripiprazole 2M LAI 960 mg).
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (±15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.
Day 141 ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS (predose).

Assess EPS (SAS, AIMS, and BARS) (predose).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
72


Protocol 031-201-00181
Confidential -- Proprietary Information
73
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities
For subjects who receive aripiprazole 2M LAI 960 mg:

Draw a PK blood sample between 8 AM and 2 PM.
For subjects who receive aripiprazole IM depot 400 mg:
Predose:

Draw a PK blood sample within 2 hours prior to dosing.

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP.
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 1 hour (±15 minutes) postdose.
Assessment of the injection site by the investigator completed approximately 1 hour (±15 minutes) postdose.
Day 169 (inpatient, all subjects)
Predose:

Admit subjects to the trial site clinic. Subjects must be housed in the clinical unit for 21 days following administration of aripiprazole 2M LAI 960 mg or 
aripiprazole IM depot 400 mg (Section 3.1). Subjects will be discharged on Day 190.

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS prior to dosing.

Assess EPS (SAS, AIMS, and BARS).

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS prior to dosing.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
73


Protocol 031-201-00181
Confidential -- Proprietary Information
74
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample (within 2 hours prior to dosing).

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Administer IMP (subjects randomized to aripiprazole IM repot 400 mg and subjects randomized to aripiprazole 2M LAI 960 mg).
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1 hour (± 15 minutes) postdose.

Draw a PK blood sample at 4, 8, and 12 hours postdose.
Days 170, 171, 173, 176, 178, 181, 183, 186, and 190 (inpatient, all subjects)

Document birth control methods (Day 190 only).

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer the Since Last Visit version of the C-SSRS for subjects randomized to aripiprazole 2M LAI 960 mg only (Day 190).

Draw a PK blood sample between 8 AM and 2 PM.

Discharge subjects from clinical unit after completing all activities (Day 190).
Day 197 (inpatient, subjects receiving aripiprazole IM depot 400 mg)
Day 197 ± 2 days (outpatient, subjects receiving aripiprazole 2M LAI 960 mg)
Subjects receiving aripiprazole IM depot 400 mg:

Admit subjects to the trial site clinic. Subjects must be housed in the clinical unit for 21 days following the administration of aripiprazole IM depot 400 mg 
(Section 3.1). Subjects will be discharged from the unit on Day 218.
All subjects:

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature). 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
74


Protocol 031-201-00181
Confidential -- Proprietary Information
75
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Administer the Since Last Visit version of the C-SSRS (predose).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).
Subjects who receive aripiprazole 2M LAI 960 mg only:

Draw a PK blood sample between 8 AM and 2 PM.
Subjects who receive aripiprazole IM depot 400 mg only:
Predose:

Assessment and confirmation by the investigator that the injection site is appropriate 30 minutes prior to IMP injection.

Have subjects complete a VAS of the level of perceived pain at the injection site approximately 30 minutes prior to IMP injection.

Draw a PK blood sample within 2 hours prior to dosing.

Administer IMP. 
Postdose:

Have subjects complete a VAS of the level of perceived pain at the injection site 1 hour (± 15 minutes) postdose.

Assessment of the injection site by the investigator completed approximately 1-hour (± 15 minutes) postdose.

Draw a PK blood sample at 4, 8, and 12 hours postdose.
Days 198, 199, 201, 206, 209, 214 (inpatient, subjects receiving aripiprazole IM depot 400 mg)
No visits for subjects receiving aripiprazole 2M LAI 960 mg 

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Draw a PK blood sample between 8 AM and 2 PM.
Days 204, 211, and 218 (inpatient, subjects receiving aripiprazole IM depot 400 mg)
± 2 days (outpatient, subjects receiving aripiprazole 2M LAI 960 mg)

Document birth control methods (outpatients: all days; inpatients: Day 218 only).

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant therapy.

Assess and record AEs.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
75


Protocol 031-201-00181
Confidential -- Proprietary Information
76
Protocol Version 3.0, 31 Jul 2019
Table 3.7.3-3
Robust Sampling Schedule Trial Days and Activities

Administer the Since Last Visit version of the C-SSRS to subjects randomized to aripiprazole IM Depot 400 mg only on Day 218.

Administer the Since Last Visit version of the C-SSRS to subjects randomized to aripiprazole 2M LAI 960 mg on each outpatient Days 204, 211, and 218.

Draw a PK blood sample between 8 AM and 2 PM.

Discharge subjects randomized to aripiprazole IM Depot 400 mg from the clinical unit after completing all activities (Day 218).
Day 225/Early Termination ± 2 days (outpatient, all subjects)

Document birth control methods.

Record concomitant medications and review for prohibited or restricted medications.

Record adjustment of current oral antipsychotic, mood stabilizer, or antidepressant medications.

Assess and record AEs.

Perform a urine pregnancy test (FOCBP only).

Perform a physical examination.

Measure weight.

Take vital signs (systolic and diastolic blood pressure, heart rate, and body temperature).

Administer a 12-lead safety ECG in triplicate (5 minutes apart).

Collect hematology, clinical chemistry, and urinalysis clinical laboratory samples.

Administer the Since Last Visit version of the C-SSRS.

Assess EPS (SAS, AIMS, and BARS).

Administer the PANSS (schizophrenia subjects only).

Administer CGI-S scale and SWN-S (all subjects).

Administer the MADRS, YMRS, and CGI-BP (bipolar subjects only).

Draw a PK blood sample between 8 AM and 2 PM.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
76


Protocol 031-201-00181
Confidential -- Proprietary Information
77
Protocol Version 3.0, 31 Jul 2019
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 electronic case report form (eCRF). 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 eCRF.
3.7.5
Efficacy Assessments
The efficacy assessments including PANSS (schizophrenia subjects only), CGI-S, CGI-I, 
SWN-S, MADRS (bipolar subjects only), YMRS (bipolar subjects only), and CGI-BP 
(bipolar subjects only) will be administered by trained trial site staff at the time points 
presented in the schedule of assessments (Table 3.7-1 for sparse sampling and 
Table 3.7-2 for robust sampling). All efficacy assessments will be performed prior to 
PK blood draws and dosing, where applicable.
3.7.5.1
Positive and Negative Syndrome Scale Rating Criteria
The PANSS consists of 3 subscales containing a total of 30 symptom constructs.7 For 
each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating 
the absence of symptoms and a score of 7 indicating extremely severe symptoms. The 
symptom constructs for each subscale are as follows:
1) Positive Subscale (7 positive symptom constructs: delusions, conceptual 
disorganization, hallucinatory behavior, excitement, grandiosity, 
suspiciousness/persecution, and hostility),
2) Negative Subscale (7 negative symptom constructs: blunted affect, emotional 
withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in 
abstract thinking, lack of spontaneity and flow of conversation, stereotyped 
thinking), and
3) General Psychopathology Subscale (16 symptom constructs: somatic concern, 
anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor 
retardation, uncooperativeness, unusual thought content, disorientation, poor 
attention, lack of judgment and insight, disturbance of volition, poor impulse 
control, preoccupation, and active social avoidance).
The PANSS will be administered using the Structured Clinical Interview (SCI) PANSS.8
Instructions for administering this instrument will be provided to the trial site. A copy of 
the PANSS assessment with complete rating criteria is required as source documentation. 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
77


Protocol 031-201-00181
Confidential -- Proprietary Information
78
Protocol Version 3.0, 31 Jul 2019
Direct entry of the PANSS item scores on the eCRF without verifiable source 
documentation is not acceptable.
3.7.5.2
Clinical Global Impression - Severity
The severity of illness for each subject will be rated using the CGI-S scale.9 To assess 
CGI-S, the rater or investigator will answer the following question: “Considering your 
total clinical experience with this particular population, how mentally ill is the subject at 
this time?” Response choices include: 0 = not assessed; 1 = normal, not ill at all; 
2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the most extremely ill subjects.
3.7.5.3
Clinical Global Impression - Improvement Scale
The improvement of illness for each subject will be rated using the CGI-I scale.9 To 
assess CGI-I, the rater or investigator will rate the subject’s total improvement whether or 
not it is due entirely to drug treatment. All responses will be compared with the subject’s 
condition at baseline. 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. Direct entry of the CGI-I score on the 
eCRF without verifiable source documentation is not acceptable.
3.7.5.4
Subjective Well-being under Neuroleptic Treatment-Short Form
The subject’s feeling of their own well-being will be assessed using the 20-question 
SWN-S.8 The SWN- S is a validated self-report instrument to evaluate the subject’s 
perception of well-being while receiving antipsychotic medication. Subjects will 
complete the questionnaire without discussing any of the items with others to avoid 
suggestive external manipulation. The questionnaire consists of 20 items and 5 subscales 
(mental functioning, social integration, emotional regulation, physical functioning, and 
self-control) whose items follow in random order. For items marked with a ‘+’, response 
choices and scoring are as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat 
= 4, much = 5, very much = 6. For items marked with a ‘-’, the scoring is reversed; 
response choices and scoring are as follows: not at all = 6, hardly at all = 5, a little = 4, 
somewhat = 3, much = 2, very much = 1.
3.7.5.5
Montgomery-Asberg Depression Rating Scale
The MADRS10 will be utilized as the primary assessment of a subject’s level of 
depressive symptoms and must be administered using a structured interview guide. 
Detailed instructions for administration of the structured interview guide will be 
provided. This scale consists of 10 items, each with 7 defined grades of severity.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
78


Protocol 031-201-00181
Confidential -- Proprietary Information
79
Protocol Version 3.0, 31 Jul 2019
3.7.5.6
Young Mania Rating Scale
The YMRS11 consists of 11 items assessing the core symptoms of mania and is based on 
the subject’s subjective report of his or her clinical condition. Additional information is 
based upon clinical observations made during the course of the clinical interview. Each 
item has 5 defined categories of severity with 4 items graded on a 0 to 8 scale (irritability, 
speech, content, and disruptive-aggressive behavior) and 7 items graded on a 0 to 4 scale.
3.7.5.7
Clinical Global Impression - Bipolar Version
The CGI-BP scale refers to the global impression of the subject with respect to bipolar I 
disorder.12 The scale rates the subject’s severity of illness (CGI-BP-Severity: mania,
depression, and overall bipolar illness) and change from preceding phase (CGI-BP
change from preceding phase: mania, depression, and overall bipolar illness) based on a
7-point scale. Severity of illness (CGI-BP-Severity) should be rated at visits as indicated 
in the schedule of assessments (Table 3.7-1 for sparse sampling and Table 3.7-2 for 
robust sampling). At each visit other than Day 1 (baseline), the change from preceding 
phase (CGI-BP change from preceding phase) will be judged with respect to the subject’s 
condition at baseline for that phase (ie, the last visit from the preceding phase).
3.7.6
Safety Assessments
3.7.6.1
Adverse Events
Refer to Section 5 for the methods and timing for assessing, recording, and analyzing 
AEs.
3.7.6.2
Clinical Laboratory Assessments
The tests listed in Table 3.7.6.2-1 will be collected at the time points presented in the 
schedule of assessments (Table 3.7-1 for sparse sampling and Table 3.7-2 for robust 
sampling) and processed in accordance with directions from the clinical chemistry 
laboratory.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
79




Protocol 031-201-00181
Confidential -- Proprietary Information
81
Protocol Version 3.0, 31 Jul 2019
urine drug screen will coincide with PK sampling following the occurrence of the SAE. 
The PK blood samples should be collected as early as is feasible to measure the plasma 
concentrations of aripiprazole.
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 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 labs should be performed on clinically significant 
abnormalities during the course of the trial. Unscheduled laboratory tests may be repeated 
at any time at the discretion of the investigator for appropriate medical care.
3.7.6.3
Physical Examination and Vital Sign Assessments
Complete physical examinations will be performed at the time points presented in the 
schedule of assessments (Table 3.7-1 for sparse sampling and Table 3.7-2 for robust 
sampling). The principal investigators or designees are primarily responsible for 
performing the physical examination. Whenever possible, the same individual should 
perform all physical examinations for any individual subject. If the appointed designee is 
to perform the physical examination, he/she must be permitted by local regulations and 
his/her name must be included on the FDA Form 1572 as principal investigator or 
sub-investigator and must be listed on the trial site delegation of authority form as 
performing this function. Any clinically significant condition present at a post-treatment 
physical examination that was not present at the baseline physical examination should be 
documented as an AE and followed to a satisfactory conclusion.
Body height and weight will also be measured during screening for calculation of body 
mass index (BMI) and weight will be measured as part of all subsequent physical 
examinations. For the measurement of height, the measurement will be made without 
shoes. For the measurement of weight, all efforts will be made to use the same scale for 
all measurements throughout the trial.
Vital signs will be taken at the time points presented in the schedule of assessments
(Table 3.7-1 for sparse sampling and Table 3.7-2 for robust sampling). Vital signs will be 
obtained prior to PK blood draws and ECGs at the nominal time points, where applicable. 
Vital signs will include systolic and diastolic blood pressure, heart rate, and body 
temperature. At each time point for vital signs, blood pressure (systolic and diastolic) and 
heart rate will be taken after subjects have been in the supine position for at least 
5 minutes and again after subjects have been standing for 2 minutes, but not more than 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
81


Protocol 031-201-00181
Confidential -- Proprietary Information
82
Protocol Version 3.0, 31 Jul 2019
3 minutes. Body temperature will be taken with the subject in the supine position (ie, 
only once).
3.7.6.4
Electrocardiogram Assessments
Standard 12-lead ECGs will be collected in triplicate (5 minutes apart) at the time points 
presented in the schedule of assessments (Table 3.7-1 for sparse sampling and 
Table 3.7-2 for robust sampling). Additional 12-lead ECGs may be obtained at the 
investigator’s discretion and should always be obtained in the event of an early 
termination (ET) of any cause. The ECGs will be collected prior to PK blood draws and 
after vital signs at the nominal time points, where applicable.
Standard 12-lead ECGs will be recorded after the subject has been supine and at rest 
for ≥10 minutes prior to the first ECG and subjects will remain supine through the final 
ECG. Heart rate, ventricular rate, RR interval, PR interval, QRS duration, and QT 
intervals will be recorded. The corrected QT interval using Fridericia’s formula (QTcF)
will be calculated. The 12-lead ECGs will be evaluated at the trial sites to determine the 
subject’s eligibility and to monitor safety during the trial. The principal investigators or 
designees (licensed physician) 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. The reviewers must be 
listed on FDA Form 1572 and the trial site delegation of responsibility form. 
Electrocardiogram data will be recorded electronically (ie, eCRFs) by the central ECG 
laboratory and by the trial site. Eligibility for the trial will be based on the central ECG 
report at the screening visit and the trial site’s local ECG reading at Day 1 predose.
3.7.6.5
Columbia-Suicide Severity Rating Scale
Suicidality will be monitored during the trial using the C-SSRS. The Baseline/Screening 
version and the Since Last Visit version of the C-SSRS will be completed by trained trial 
site staff at the time points presented in the schedule of assessments (Table 3.7-1 for 
sparse sampling and Table 3.7-2 for robust sampling). This scale consists of a baseline 
evaluation that assesses the lifetime experience of the subject with suicide events and 
suicidal ideation and a postbaseline evaluation that focuses on suicidality since the last 
assessment.
3.7.6.6
Other Safety Assessments
3.7.6.6.1
Extrapyramidal Symptoms
Extrapyramidal symptoms will be assessed by trained trial site staff using the SAS, 
AIMS, and BARS at the time points presented in the schedule of assessments
(Table 3.7-1 for sparse sampling and Table 3.7-2 for robust sampling).
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
82


Protocol 031-201-00181
Confidential -- Proprietary Information
83
Protocol Version 3.0, 31 Jul 2019
3.7.6.6.1.1
Simpson-Angus Scale
The SAS13 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.
3.7.6.6.1.2
Abnormal Involuntary Movement Scale
The AIMS9 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 investigators 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, aware/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).
3.7.6.6.1.3
Barnes Akathisia Rating Scale
The BARS14 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 eCRF.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
83


Protocol 031-201-00181
Confidential -- Proprietary Information
84
Protocol Version 3.0, 31 Jul 2019
3.7.6.6.2
Pain Perception - Visual Analog Scale
Subjects will assess the pain associated with the injection of IMP using the VAS. The 
VAS will be completed at the time points presented in the schedule of assessments
(Table 3.7-1 for sparse sampling and Table 3.7-2 for robust sampling).
3.7.6.6.3
Investigator’s Assessment of Injection Site
The investigators or designees will assess the injection site at the time points presented in 
the schedule of assessments (Table 3.7-1 for sparse sampling and Table 3.7-2 for robust 
sampling).
Whenever possible, the same individual should perform all assessments of the injection 
site for any individual subject.
3.7.7
Pharmacokinetic Assessments
3.7.7.1
Pharmacokinetic Assessments
3.7.7.1.1
Pharmacokinetic Blood Plasma Samples
To obtain a good distribution of PK sampling times, the trial sites will be divided into 
either sparse (majority of the sites) or robust (extensive) PK sampling trial sites. 
Blood will be collected for concentrations of aripiprazole and its major metabolite,
dehydro-aripiprazole, for the subjects who will receive aripiprazole 2M LAI 960 mg:

Sparse sampling schedule: Day 1 (predose [within 2 hours prior to dosing] and 4, 8, 
and 12 hours postdose), Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, 
Day 57 (predose), Day 85, Day 113 (predose), Day 141, Day 169 (predose [within 
2 hours prior to dosing] and 4, 8, and 12 hours postdose), Day 176, Day 183, 
Day 190, Day 197, Day 204, Day 211, Day 218, and Day 225/ET.

Robust sampling schedule: Day 1 (predose [within 2 hours prior to dosing] and 4, 8, 
and 12 hours postdose), Day 2, Day 3, Day 5, Day 8, Day 10, Day 13, Day 15, 
Day 18, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57 (predose), Day 85, 
Day 113 (predose), Day 141, Day 169 (predose [within 2 hours prior to dosing] and 4, 
8, and 12 hours postdose), Day 170, Day 171, Day 173, Day 176, Day 178, Day 181, 
Day 183, Day 186, Day 190, Day 197, Day 204, Day 211, Day 218, and Day 225/ET.
Blood will be collected for concentrations of aripiprazole and its major metabolite,
dehydro-aripiprazole, for the subjects who will receive aripiprazole IM depot 400 mg:

Sparse sampling schedule: Day 1 (predose [within 2 hours prior to dosing] and 4, 8, 
and 12 hours postdose), Day 8, Day 15, Day 22, Day 29 (predose), Day 57 (predose), 
Day 85 (predose), Day 113 (predose), Day 141 (predose), Day 169 (predose [within 
2 hours prior to dosing] and 4, 8, and 12 hours postdose), Day 197 (predose [within 
2 hours prior to dosing] and 4, 8, and 12 hours postdose), 204, 211, 218, and 225/ET.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
84


Protocol 031-201-00181
Confidential -- Proprietary Information
85
Protocol Version 3.0, 31 Jul 2019

Robust sampling schedule: Day 1 (predose [within 2 hours prior to dosing] and 4, 8, 
and 12 hours postdose), Day 2, Day 3, Day 5, Day 8, Day 10, Day 13, Day 15, 
Day 18, Day 22, Day 29 (predose), Day 57 (predose), Day 85 (predose), Day 113 
(predose), Day 141 (predose), Day 169 (predose [within 2 hours prior to dosing] and 
4, 8, and 12 hours postdose), Day 170, Day 171, Day 173, Day 176, Day 178, 
Day 181, Day 183, Day 186, Day 190, Day 197 (predose [within 2 hours prior to 
dosing] and 4, 8, and 12 hours postdose), 198, 199, 201, 204, 206, 209, 211, 214, 218, 
and 225/ET.
While predose samples must be collected on the specified day prior to dosing, other 
PK samples should be collected at any time between 8 AM and 2 PM on the specified 
days.
An additional PK sample will be collected from subjects who experience an SAE
immediately (at the earliest possible time point available) after the occurrence of the 
SAE.
All tubes must be labeled such that the protocol number, subject ID number, date of 
collection, and nominal sample postdose collection time can be verified. The labels must 
be approved by the bioanalytical scientist prior to use. It is important to note the exact 
time of the blood collection in the eCRF, not the scheduled PK collection time. The exact 
time of dosing will also be noted.
 
3.7.8
Genetic Assessments
3.7.8.1
Deoxyribonucleic Acid Blood Samples for Pharmacogenomic 
Testing
A pharmacogenomics sample will be collected on Day 1 prior to dosing.
The pharmacogenomics blood sample will be taken in order to collect deoxyribonucleic 
acid (DNA) for the determination of genotypes related to CYP2D6 drug metabolizing 
enzymes.
 
 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
85


Protocol 031-201-00181
Confidential -- Proprietary Information
86
Protocol Version 3.0, 31 Jul 2019
 
3.7.10
End of Trial
The end of trial date is defined as the last date of contact or the date of the final contact 
attempt from the post-treatment follow-up eCRF page for the last subject completing or 
withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
In the event of sponsor termination or suspension of the trial for any reason, prompt 
notification will be given to investigators, IRBs, and regulatory authorities in accordance 
with regulatory requirements.
3.8.2
Individual Site
The sponsor, investigator, or the IRB has the right to terminate the participation of a 
particular trial site, if necessary, due to lack of subject enrollment, noncompliance with 
the protocol, or if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP. The sponsor is to be 
notified promptly if the trial was terminated by the investigator or the IRB at the trial site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
After the first dose of IMP, a subject may discontinue from the trial for a variety of 
reasons. Treatment discontinuations may be initiated by a subject or may become 
medically necessary due to AEs, required treatment with a disallowed medication or 
therapy, or other reasons, as determined by the investigator. If a subject discontinues 
treatment, their participation in the trial will be discontinued. Discontinued subjects 
should be encouraged to complete all ET and follow-up assessments with ET assessments 
conducted as soon as possible after the subject is withdrawn.
3.8.3.2
Documenting Reasons for Discontinuation
All subjects have the right to withdraw and the investigator can discontinue a subject’s 
participation in the trial at any time if medically necessary. In addition, subjects meeting 
the following criteria must be withdrawn from the trial (only one reason for 
discontinuation [the main reason] can be recorded in the eCRF):

Death
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
86


Protocol 031-201-00181
Confidential -- Proprietary Information
87
Protocol Version 3.0, 31 Jul 2019

Disease relapse or disease progression

Failure to meet randomization criteria

Lost to follow-up

Non-compliance with IMP (if confirmed not related to an AE)

Physician decision (other than AE)

Pregnancy (see Section 5.5)

Site terminated by sponsor

Trial terminated by sponsor

Withdrawal of consent by parent/guardian (if confirmed not related to an AE)

Withdrawal of consent by subject (if confirmed not related to an AE)
If the subject 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 must be followed. Subjects may be replaced, if 
discontinuations/withdrawals occur, as described in Section 3.3.
3.8.3.3
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.
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 understood, documented, and 
managed to protect the rights of the subject and the integrity of the trial.
At any time, a subject may withdraw from the substudy 
 and may request that the
sponsor destroy their sample(s) by contacting the trial site. Should the subject choose to 
withdraw their consent to the storage and use of their sample(s), such sample(s) will not 
be used from that point on and will be promptly destroyed. Subjects will not lose any 
benefits, medical treatment, or legal rights which they are allowed if they request their 
sample(s) to be destroyed. Leaving the main trial does not mean that their sample(s) used 
for this substudy will automatically be destroyed. Subjects will have to make a request 
for their sample(s) to be destroyed after they leave the trial.
Subjects who withdraw should be encouraged to complete all ET and follow-up 
assessments with ET assessments conducted as soon as possible after the subject is 
withdrawn.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
87


Protocol 031-201-00181
Confidential -- Proprietary Information
88
Protocol Version 3.0, 31 Jul 2019
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), but who is not randomized or assigned 
trial treatment. In the case where a subject had a positive screen for stimulants or 
marijuana and was therefore excluded, the medical monitor should be contacted to 
determine if rescreening is an option. However, subjects excluded for any other reasons 
may be rescreened at any time if the exclusion characteristic has changed. In the event 
that the subject is rescreened, a new ICF must be signed, a new screening number 
assigned, and all screening procedures repeated. After 2 screening attempts, the medical 
monitor should be consulted to confirm whether or not the subject can be enrolled.
3.10
Definition of Completed Subjects
The evaluation period is defined as the time period during which subjects are evaluated 
for primary and secondary objectives of the trial irrespective of whether the subject is 
administered IMP. Subjects who are evaluated at the last scheduled visit (Day 225 for 
aripiprazole 2M LAI 960 mg and Day 197 for aripiprazole IM depot 400 mg) during the 
treatment phase will be defined as trial completers. 
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Day 225, or later, and who do not have a 
known reason for discontinuation (eg, withdrew consent or AE, etc.), except those who 
have completed the trial as defined in Section 3.10, will be classified as “lost to 
follow-up” as the reason for discontinuation.
The trial 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 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 actual time and dose of IMP administration will be recorded on the eCRF. 
Information regarding any inappropriately administered dose will also be documented on 
the eCRF.
3.13
Protocol Deviations
In the event of a major 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 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
88


Protocol 031-201-00181
Confidential -- Proprietary Information
89
Protocol Version 3.0, 31 Jul 2019
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone. The investigator, or designee, and sponsor will 
come to a joint decision as quickly as possible regarding the subject’s continuation in the 
trial. If the decision reached is to allow the subject to continue in the trial, this must be 
documented by the investigator and the sponsor, and approved or disapproved by the 
medical monitor.
4
Restrictions
4.1
Prohibited Medications
With the exception of the subject’s current atypical antipsychotic medication (and/or 
mood stabilizer or antidepressant for subjects with bipolar I disorder), any other 
psychotropics must be discontinued at least 14 days prior (with the exception of 
fluoxetine or fluoxetine/olanzapine, which need to be discontinued at least 28 days prior) 
to administration of IMP, and will not be allowed during the course of the trial (see 
Inclusion Criterion 7 in Table 3.4.2-1). Subjects on any LAI other than Abilify Maintena 
will be excluded from the trial. Other oral non-aripiprazole antipsychotic medications 
may be allowed if approved by the medical monitor and sponsor; however, clozapine and 
monoamine oxidase inhibitors (MAOIs) will not be allowed. Subjects may not receive 
varenicline beyond screening. If a subject is receiving varenicline at enrollment, attempts 
should be made to discontinue the medication if clinically feasible, to allow potential 
subjects to enter the trial.
Subjects must stop all other prohibited concomitant medications prior to dosing and for 
the duration of the trial. Subjects must wash out from antipsychotics that are known to 
cause corrected QT interval (QTc) prolongation, such as haloperidol, within 14 days prior 
to administration of IMP. Use of quetiapine or ziprasidone is permitted.
Inhibitors and inducers of CYP3A4 and inhibitors of CYP2D6 isozymes are not allowed 
within 14 days prior to dosing and for the duration of the trial, since these are the 
pathways in which aripiprazole is metabolized. An example list of CYP3A4 and 
CYP2D6 inhibitors and CYP3A4 inducers that are prohibited during the trial are listed in
Table 4.1-1.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
89


Protocol 031-201-00181
Confidential -- Proprietary Information
90
Protocol Version 3.0, 31 Jul 2019
Table 4.1-1
Example List of CYP3A4 and CYP2D6 Inhibitors and 
CYP3A4 Inducers Prohibited During the Trial
CYP3A4 Inhibitors
Amiodarone
Fluvoxamine
Amprenavir
Indinavir
Aprepitant
Itraconazole
Chloramphenicol
Ketoconazole
Cimetidine
Nefazodone
Clarithromycin
Nelfinavir
Clotrimazole (if used orally)
Quinupristin/Dalfopristin 
Delavirdine
Ritonavir
Diltiazem
Saquinavir
Erythromycin
Troleandomycin
Fluconazole
Verapamil
CYP2D6 Inhibitors
Bupropion
Hydroxyzine
Celecoxib
Methadone
Chloroquine
Moclobemide
Chlorpheniramine
Paroxetine
Clemastine
Pyrilamine
Clomipramine
Quinidine
Diphenhydramine
Terbinafine
Fluoxetine
Tripelennamine
Halofantrine
CYP3A4 Inducers
Carbamazepine
Phenytoin
Dexamethasone
Primidone
Efavirenz
Rifampin
Nevirapine
St. John's wort
Phenobarbital
Troglitazone
Note: The above is not an exhaustive list and there may be additional CYP3A4 and CYP2D6 inhibitors 
and CYP3A4 inducers that are prohibited during the trial.
4.2
Restricted Medications
Benzodiazepine use is allowed up to a maximum of 6 mg/day lorazepam or equivalent, 
but not within 8 hours of any rating scales during the trial. The use of IM lorazepam is 
also permitted for emergent agitation, but only if deemed absolutely necessary by the 
investigator. The following guide should be used to determine approximate lorazepam 
equivalents: 1 mg lorazepam = 5 mg diazepam = 15 mg oxazepam = 15 mg clorazepate. 
Subjects must not be on more than one benzodiazepine beyond the screening visit.
If a subject is receiving 2 benzodiazepines at the screening visit (eg, lorazepam and 
oxazepam), attempts should be made to discontinue one of the benzodiazepines, if 
clinically warranted, to allow potential subjects to enter the trial. The second 
benzodiazepine should be tapered off over an appropriate amount of time within the 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
90


Protocol 031-201-00181
Confidential -- Proprietary Information
91
Protocol Version 3.0, 31 Jul 2019
30-day screening period to prevent side effects, and the subject should be maintained on 
the remaining benzodiazepine for at least 14 days prior to the administration of IMP. 
Benzodiazepine and non-benzodiazepine use is allowed during the trial as needed to 
manage AEs such as agitation, anxiety, sleep disturbance, and insomnia. Combined use 
of both drug classes (ie, benzodiazepines and non-benzodiazepine sleep aids) as treatment 
for insomnia is not allowed. Benzodiazepine use should be discontinued as soon as the 
AE for which it was initiated subsides, as per the investigator’s discretion, to avoid any 
withdrawal effects.
Medications that are restricted during the trial are listed in Table 4.2-1.
Table 4.2-1
Medications Restricted During the Trial
Medication
Screening
Treatment Period
Anticholinergicsa
≤4 mg/day benztropine or equivalent
≤4 mg/day benztropine or 
equivalent
Propranolol (for akathisia 
or tremor)b, c
Maximum 60 mg propranolol per 
day
Maximum 60 mg propranolol per 
day
Benzodiazepinesb
-
No more than one benzodiazepine 
and not in combination with other 
sleep aid medication
aAnticholinergics are not allowed within 12 hours of any rating scales during any phase of the trial.
bPropranolol is not allowed within 8 hours of any rating scales during any phase of the trial.
cSubjects receiving propranolol for heart disease may remain on stable, pretrial doses, as needed, 
throughout the trial, so long as the total dose does not exceed 60 mg/day.
4.3
Nontherapy Precautions and Restrictions
Subjects will be instructed to refrain from drinking alcoholic beverages or using illicit 
drugs during participation in the trial.
Electroconvulsive therapy must not be conducted within 2 months prior to administration 
of the IMP and is not allowed during the course of the trial.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as medical history at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
91


Protocol 031-201-00181
Confidential -- Proprietary Information
92
Protocol Version 3.0, 31 Jul 2019
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 than “adverse reaction”.
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 inpatient 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 nonmedical 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).

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 eCRF if there is a 
complication or abnormality in the newborn.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
92


Protocol 031-201-00181
Confidential -- Proprietary Information
93
Protocol Version 3.0, 31 Jul 2019
Clinical Laboratory Assessment 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 relevant) 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 clinically relevant by the investigator (eg, subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, 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 eCRF. The intensity of an AE 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 IMP:
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 reasonable relationship between the IMP 
and the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator will assess subjects for the occurrence of AEs from the time the ICF is 
signed until the end of the trial. For this trial, information on AEs will be followed for up 
to 28 days after the last dose of aripiprazole IM depot 400 mg has been administered and 
56 days after the last of aripiprazole 2M LAI 960 mg has been administered. To avoid 
bias in eliciting AEs, subjects should be asked the following nonleading question: “How 
are you feeling?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eCRFs 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 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
93


Protocol 031-201-00181
Confidential -- Proprietary Information
94
Protocol Version 3.0, 31 Jul 2019
AEs only if there are unusual or severe clinical features that were not present, not 
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 report any SAE, any AE related to occupational exposure, potential 
serious hepatotoxicity, or confirmed pregnancy immediately after either the investigator 
or trial site personnel become aware of the event. An IRE form should be completed and 
sent by fax, e-mail, or overnight courier, using the contact information on the title page of 
this protocol. (Please note that the IRE form is a specific form and is NOT the AE eCRF).
Subjects experiencing SAEs should be followed clinically as described in Section 5.7.2.
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 aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥3 times the upper limit of normal (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
Females of childbearing potential are women whose menstruation has started and who are 
not documented as sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or 
who have been postmenopausal for at least 12 months).
For men and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 150 after the last dose of IMP for a female subjects or 180 days after the 
last dose of IMP for a male subjects. Unless the subject is sterile (ie, women who have 
had a bilateral oophorectomy, have had a hysterectomy, or have been postmenopausal for 
at least 12 consecutive months; or men who have had a bilateral orchiectomy) or remains 
abstinent during the trial and for 150 days after the last dose of IMP for a female subject 
or 180 days after the last dose of IMP for a male subject, 2 of the following approved 
methods of birth control must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pills, birth control implant, birth control depot injection, condom with 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
94


Protocol 031-201-00181
Confidential -- Proprietary Information
95
Protocol Version 3.0, 31 Jul 2019
spermicide, sponge with spermicide, or occlusive cap (vaginal diaphragm or 
cervical/vault cap) with spermicide. Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive method 
will be documented in the eCRF. Male subjects must also agree not to donate sperm from 
trial screening through 180 days after the last dose of IMP.
Before enrolling men and women in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, men and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed.
A urine or serum pregnancy test for human chorionic gonadotropin will be performed on 
all FOCBP at screening and throughout the trial at the time points presented in the 
schedule of assessments (Table 3.7-1 for sparse sampling and Table 3.7-2 for robust 
sampling). 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). Male subjects 
should also be instructed to contact the investigator immediately, during the trial, if their 
partners suspect that 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 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
95


Protocol 031-201-00181
Confidential -- Proprietary Information
96
Protocol Version 3.0, 31 Jul 2019
discontinuation may be considered for life-threatening conditions only after consultations 
with the sponsor (see the title 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 at least 150 days after the last dose of IMP for a 
female subject or 180 days after the last dose of IMP for a male subject, and record the 
event on the IRE form and forward it to the sponsor. The sponsor will forward the 
Pregnancy Surveillance Form(s) to the investigator 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 the 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
Not applicable; this is an open-label trial.
5.7
Follow-up of Adverse Events
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 eCRF 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 eCRF. For any AE having been identified throughout the trial, during 
data 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). Subjects should be given 
appropriate medical treatment until the resolution of any AE.
5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs up to 28 days 
after the last dose of aripiprazole IM depot 400 mg is administered and 56 days after the 
last dose of aripiprazole 2M LAI 960 mg is administered.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
96


Protocol 031-201-00181
Confidential -- Proprietary Information
97
Protocol Version 3.0, 31 Jul 2019
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF 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 eCRF page, according to the appropriate reporting procedures. 
The investigator will follow SAEs until the events are resolved or stabilized, or the 
subject is lost to follow-up or has died. Resolution means 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 or IREs 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.
6
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis
6.1
Pharmacokinetic Methods
Plasma concentrations of aripiprazole and its major metabolite, dehydro-aripiprazole, will 
be analyzed using noncompartmental methods.
Pharmacokinetic data will be summarized using descriptive statistics (median, mean, 
standard deviation [SD], percent coefficient of variation [CV], minimum, and maximum) 
for each cohort. Pharmacokinetic data will also be presented in listings.
6.2
Pharmacodynamic Methods
No pharmacodynamic endpoints are to be evaluated.
6.3
Pharmacokinetic/Pharmacodynamic Methods
No PK/pharmacodynamic analysis is planned.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
97


Protocol 031-201-00181
Confidential -- Proprietary Information
98
Protocol Version 3.0, 31 Jul 2019
6.4
Pharmacogenomic Methods
No pharmacogenomic analysis is planned.
7
Statistical Analysis
7.1
Determination of Sample Size
To establish the similarity in primary PK variables, the lower bound of the 90% CI of the 
geometric means ratio (GMR) of C56 and AUC0-56 after the fourth dose of aripiprazole 
2M LAI 960 mg to C28 after the eighth dose and the sum of AUC0-28 values after the 
seventh and eighth doses of aripiprazole IM depot 400 mg should be greater than 80%, 
respectively. 
It is estimated that a total of at least 100 subjects (ie, 50 per group) completing the trial 
will have at least 80% power to ensure that the lower limit of the 90% CI of the GMR of 
C56 after the fourth dose of aripiprazole 2M LAI 960 mg (test) to C28 after the eighth 
dose of aripiprazole IM depot 400 mg (reference) is greater than 0.80, assuming that the 
actual GMR of concentrations is 1.0 and the CV is 46%. 
Among these 100 subjects, at least 30 completers enrolled to the robust sampling 
schedule will provide at least 80% power to ensure that the lower limit of the 90% CI of 
the GMR of AUC0-56 of aripiprazole 2M LAI 960 mg (test) to the sum of AUC0-28 values 
of aripiprazole IM depot 400 mg (reference) after the seventh and eighth doses is greater 
than 0.80, assuming the actual GMR of concentrations is 1.15 and the CV is 40%.
The assumption of CV used in the sample calculation is based on the PK data in the 
previous multiple-dose aripiprazole IM depot PK Trial 31-11-298.
To ensure adequate power of the trial, an interim analysis may be conducted by the 
Interim Analysis Review Committee (IARC). The final sample size could be increased as 
per recommendation of the IARC and as further described in Section 7.1.1.
Assuming a dropout rate of 34%, approximately 152 to 258 subjects will be enrolled to 
have 100 to 170 completers based on the recommendation of the proposed interim 
analysis.
7.1.1
Interim Analysis/Sample Size Re-estimation
An interim analysis of the PK data is planned during the trial and may be performed by 
an IARC on approximately 50 subjects (25 subjects per treatment group) completing the 
trial. In this case, completers will be defined as subjects who receive a final dose of IMP 
(both treatment groups) at the maximum dose. Out of the 50 subjects, approximately 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
98


Protocol 031-201-00181
Confidential -- Proprietary Information
99
Protocol Version 3.0, 31 Jul 2019
14 subjects (7 subjects per treatment group) will have been enrolled to the robust 
sampling schedule. Subjects will continue to be enrolled into the trial until either the 
interim analysis is complete and recommends no sample size increase or there are enough 
subjects enrolled to ensure 170 completers.
If the trial is stopped due to futility (as described by the interim analysis), randomized 
subjects will be terminated; however, if the interim analysis stops the trial for having 
enough conditional power, then all randomized subjects will continue until the last 
observation. Subjects in screening will be discontinued and no further randomization will 
occur.
An alpha level of 0.001 (1-sided) is allocated to estimate the sample size during this 
interim analysis. The corresponding final significance level is 0.049 (1-sided).
The sample size will be re-estimated only based on the conditional power determined at 
the interim analysis. The adaptive designs methodology published by Chen, DeMets, and 
Lan (2004)15 will be used to increase the sample size based on an interim estimate of the 
treatment effect size, possibly combined with other external information, without 
inflating the Type I error.
All the detailed calculations and re-estimation methods will be prespecified and included 
in the statistical analysis plan and interim analysis plan.
Table 7.1.1-1
Sample Size Re-estimation
Endpoints
Conditional Power
Interim Analysis
Recommendation
Outcome
AUC0-56 versus 
sum of AUC0-28
values
≥80%
No adaption to the planned 
sample size
30 completers
(15 per group)
< 80%
Increase sample size to up to 
50 completers
Up to 50 completers
(25 per group)
C56 versus C28
after the last 
scheduled 
injection
≥80%
No adaption to the planned 
sample size
100 completers
(50 per group)
≥30% and < 80%
Increase sample size to up to 
170 completers
Up to 170 completers
(85 per group)
< 30%
Stop the trial
7.2
Datasets for Analysis
The following datasets will be analyzed:

The randomized sample will include all subjects who are randomized.

The PK sample will consist of all dosed subjects who have evaluable aripiprazole 
PK parameters. For analysis of the primary PK endpoint, only the completers with 
available values of the primary endpoints after the last scheduled injection will be 
included.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
99


Protocol 031-201-00181
Confidential -- Proprietary Information
100
Protocol Version 3.0, 31 Jul 2019

The safety sample will include all randomized subjects who receive at least one dose 
of aripiprazole injection, regardless of any protocol violation.

The efficacy sample will include all randomized subjects who receive at least one 
dose of aripiprazole injection and have at least one efficacy assessment.
7.3
Handling of Missing Data
No data imputation will be done for missing data in the PK analysis. The last observation 
carried forward (LOCF) method is used to impute missing data of the safety EPS 
assessment scales and efficacy assessment scales at postbaseline visits. The observed case 
(OC) dataset corresponding to a visit consists of data from all subjects who are evaluated 
at that visit. In the LOCF dataset, missing data at a postbaseline visit are imputed with the 
value obtained at the nearest preceding visit, except that baseline values are not carried 
forward to impute missing values at a postbaseline visit.
In addition, for the safety endpoints other than the EPS assessment scales, the LOCF
method is also applicable for the values from the last visit for laboratory tests, vital sign 
parameters, ECG parameters, C-SSRS suicidality-related parameters, VAS for 
Subject-reported Rating of Pain at Most Recent Injection Site, and Investigator’s
Assessment of Most Recent Injection Site.
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Endpoint Analyses
Safety assessments including AEs, vital signs, ECGs, clinical laboratory monitoring 
(serum chemistry, hematology, and urinalysis), physical examinations, EPS (SAS, AIMS, 
and BARS), VAS scores for pain perception, Investigator’s Assessment of Most Recent 
Injection Site, and suicidality via the C-SSRS will be summarized for the safety sample 
by treatment group. The mean change from baseline will be provided for vital signs, 
ECGs, clinical laboratory, and EPS assessments by visit, treatment group, and disease 
type. The incidence of clinically relevant abnormalities in vital signs, ECGs, and clinical 
laboratory results will be summarized descriptively by visit, treatment group, and disease 
type.
Plasma concentrations of aripiprazole will be analyzed using noncompartmental methods.
The following PK parameters will be estimated and summarized descriptively for 
aripiprazole: C56 and AUC0-56 of aripiprazole 2M LAI 960 mg after the fourth dose, C28
of aripiprazole IM depot 400 mg after the eighth dose, and AUC0-28 of aripiprazole IM 
depot 400 mg after the seventh and eighth doses over the course of 32 weeks. The 90% 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
100


Protocol 031-201-00181
Confidential -- Proprietary Information
101
Protocol Version 3.0, 31 Jul 2019
CI of GMR of C56 of aripiprazole after the fourth injection of aripiprazole 2M LAI 960
mg (test) to C28 after the eighth injection of aripiprazole IM depot 400 mg (reference) 
will be provided. An analysis of variance will be performed on the natural-log 
transformed PK parameters using the MIXED procedure in the Statistical Analysis 
System (SAS). The mixed-effects linear model will include treatment group, disease type
(if applicable), and PK sampling schedule as fixed effects and subject as a random effect. 
The least squares means for the 2 treatment groups, their difference, and the 90% CI for 
their difference will be derived. The antilog of the confidence limits will provide the 
90% CI for the GMR of the 2 treatments. For subjects enrolled to the robust sampling 
schedule, the values of AUC0-28 after seventh and eighth doses of aripiprazole IM depot 
400 mg (reference) will be summed up before analyzing by the same method together 
with AUC0-56 after the fourth injection of aripiprazole 2M LAI 960 mg (test). Only 
subjects who receive a fourth dose of aripiprazole 2M LAI 960 mg or a seventh and/or 
eighth dose of aripiprazole IM depot 400 mg and have C56, C28, AUC0-28, and AUC0-56
values determined for the respective treatments will be included in the analysis.
7.4.2
Secondary Endpoint Analyses
Individual and summary tables, using descriptive statistics (N, median, mean, SD, CV, 
minimum, maximum) will be provided for the following aripiprazole PK endpoints:

Cmax and tmax after the first and fourth doses of aripiprazole 2M LAI 960 mg

AUC0-56 and C56 after the first dose of aripiprazole 2M LAI 960 mg

AUC0-28 and AUC29-56 after the fourth dose of aripiprazole 2M LAI 960 mg

PTF% after the fourth dose of aripiprazole 2M LAI 960 mg (for aripiprazole only)

Cmax and tmax after the first, seventh, and eighth doses of aripiprazole IM depot 
400 mg

AUC0-28 and C28 after the first dose of aripiprazole IM depot 400 mg

PTF% after the eighth dose of aripiprazole IM depot 400 mg (for aripiprazole only)

C7 and C14 after the first injection of aripiprazole 2M LAI 960 mg and aripiprazole 
IM depot 400 mg from subjects enrolled to the robust sampling schedule.
Values for Cmax, AUC, tmax, and PTF% will be summarized based on samples from 
subjects enrolled to the robust sampling schedule; whereas C28 and C56 after the first 
injection will be summarized based on samples from subjects enrolled to the robust and 
sparse sampling schedules.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
101


Protocol 031-201-00181
Confidential -- Proprietary Information
102
Protocol Version 3.0, 31 Jul 2019
Efficacy assessments including the PANSS (schizophrenia subjects only), CGI-S, CGI-I, 
SWN-S, MADRS (bipolar subjects only), YMRS (bipolar subjects only), and CGI-BP 
(bipolar subjects only) will be summarized for the efficacy sample at each visit by 
treatment group and disease type, if applicable. These analyses will be performed for 
both LOCF and OC data. In addition, the linear mixed-effects model will be used to 
explore the effect of the treatment and change from baseline over time, as applicable.
7.5
Analysis of Demographic and Baseline Characteristics
The randomized sample will be used for demographic and baseline characteristic 
analyses. Demographic characteristics (including age, weight, height, BMI, sex, race, and 
ethnicity) will be summarized using descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable) and reported 
by treatment group, by robust/sparse sampling schedule, and by disease type.
Disease characteristics at baseline and psychiatric history (age of first diagnosis for 
schizophrenia or bipolar I disorder and treatment given for previous episodes) will be
presented using descriptive statistics and reported for the randomized sample by 
treatment group, by robust/sparse sampling schedule, and by disease type.
7.6
Safety Analysis
7.6.1
Adverse Events
All AEs will be coded by system organ class and the Medical Dictionary for Regulatory 
Activities preferred term. A treatment-emergent adverse event (TEAE) is defined as an 
AE which starts after the first dose of IMP or an AE that continues from baseline and is
serious, IMP-related, or results in death, discontinuation, interruption or reduction of 
IMP. The incidence of the following events will be summarized by treatment group and 
by disease type:

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
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
102


Protocol 031-201-00181
Confidential -- Proprietary Information
103
Protocol Version 3.0, 31 Jul 2019
7.6.2
Clinical Laboratory Data
The potentially clinically relevant laboratory test abnormalities will be listed by subject 
and by test for the safety sample. The incidences of potentially clinically relevant 
laboratory tests abnormalities based on the observation from the scheduled and the 
unscheduled postbaseline visits will be tabulated by treatment group. Summary statistics 
(frequency, mean, standard deviation, minimum, and maximum) for the clinical 
laboratory measurements and changes from baseline will be presented by visit, treatment 
group, and disease type.
7.6.3
Physical Examination and Vital Signs Data
Physical examination data will be listed by subject.
The potential clinically relevant vital sign abnormalities will be listed by subject.
Incidences of clinically relevant vital signs abnormalities based on the observation from 
the scheduled visits and unscheduled postbaseline visits will be tabulated by treatment 
group. In addition, vital sign parameters and changes from baseline at each visit and the 
last visit will be summarized by treatment group and disease type.
7.6.4
Electrocardiogram Data
The potentially clinically relevant ECG abnormalities will be listed by subject. The 
incidences of abnormal ECGs of potentially clinical relevance based on the observation at 
the scheduled and the unscheduled post-baseline visits will be tabulated by treatment 
group. Descriptive statistics of change from baseline in ECG intervals of PR, QRS, RR, 
QT, and QTcF will be presented by visit, treatment group, and disease type.
7.6.5
Other Safety Data
7.6.5.1
Columbia-Suicide Severity Rating Scale
Suicidality data collected from the C-SSRS assessments will be summarized by treatment 
group and disease type in incidence of suicidality, suicidal behavior only, emergence of 
suicidal behavior, suicidal ideation only, emergence of suicidal ideation, emergence of 
serious suicidal ideation, and worsening of suicidal ideation at each visit and last visit in 
addition to the overall during the treatment phase.
Descriptive statistics of the incidence of suicidality and incidence of suicidality by type 
(suicidal behavior and suicidal ideation), as well as the mean changes of Suicidal Ideation 
Intensity total scores for the most severe ideation from baseline will be reported by visit,
treatment group, and disease type.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
103


Protocol 031-201-00181
Confidential -- Proprietary Information
104
Protocol Version 3.0, 31 Jul 2019
7.6.5.2
Extrapyramidal Symptoms Rating Scales
Descriptive statistics of the EPS rating scales for both LOCF and OC data and the mean 
changes of the scales from baseline will be reported by visit, treatment group, and disease 
type.
7.6.5.3
Visual Analog Scale Scores for Pain Perception
Descriptive statistics for VAS scores will be tabulated by treatment group and disease 
type at each injection. 
7.6.5.4
Investigator’s Assessment of the Injection Site
The Investigator’s Assessment of Most Recent Injection Site including pain, swelling, 
redness, and induration will be reported in 4-point categorical scale (absent, mild, 
moderate, and severe) by treatment group and disease type at each injection.
7.7
Pharmacodynamic Analysis
No pharmacodynamic analysis is planned.
8
Management of Investigational Medicinal Product
8.1
Packaging and Labeling
The IMP will be provided to the investigator(s) and the persons designated by the 
investigator(s) or institutions(s) by the sponsor or designated agent. Aripiprazole 2M LAI 
will be supplied as aripiprazole IM depot 300 mg/mL RTU single-dose vials and 
aripiprazole IM depot 400 mg will be supplied as single-dose lyophilized vials. 
Aripiprazole tablets for oral overlap will be provided from a commercial supply. Detailed 
preparation and administration instructions will be provided in the site manual.
Each vial and carton used during the dosing period will be labeled according to Title 21 
of the FDA Code of Federal Regulations.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the 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 trial site staff will maintain a temperature log in the drug storage area 
recording the temperature at least once each working day.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
104


Protocol 031-201-00181
Confidential -- Proprietary Information
105
Protocol Version 3.0, 31 Jul 2019
8.3
Accountability
The investigator, or designee, must maintain an inventory record of IMP received, 
dispensed, administered, destroyed, or returned.
8.4
Returns and Destruction
The IMP will be destroyed by the clinical trial site. The IMP may only be destroyed by 
the trial sites, if approved by the sponsor and if the IMP destruction meets all local 
regulations. The IMP accountability must be completed and verified by the assigned trial 
monitor prior to destruction. The trial sites may utilize qualified third party vendors for 
IMP destruction.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) 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 (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 PQCs identified through any means from the 
receipt of the IMP from 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 telephone 
immediately after of becoming aware of the PQC according to the procedure outlined 
below.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
105


Protocol 031-201-00181
Confidential -- Proprietary Information
106
Protocol Version 3.0, 31 Jul 2019
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms below.

E-mail - Send information required for reporting purposes (listed in Section 8.5.2) to 
OAPI-EQCProductComplaints@Otsuka-us.com

Phone - Rocky Mountain Call Center at 1-800-438-6055
8.5.2
Information Required for Reporting Product Quality Complaints
The following information is required for reporting purposes:

Description of complaint

Reporter ID (eg, subject, investigator, site information, etc)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, kit number, or bottle number)

Clinical protocol reference (number and trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process for Product Quality Complaints
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable.
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.
8.6
Investigational Medicinal Product Reserve Sample Requirements 
In order to comply with FDA regulations 21CRF320.38 and 320.63, the trial sites must 
maintain sufficient reserve samples of the IMP (test and reference listed drug) to conduct 
full analytical testing 5 times (5 X). This reserve sample requirement is applicable to each 
shipment of IMP received at the trial sites. Each shipment of IMP sent to the trial sites 
will contain IMP to be used for conduct of the trial, as well as 5 X reserve samples. The 
trial sites will randomly select the IMP containers to be used in the trial, and will 
designate the remaining containers as reserve samples. Procedures for selecting IMP for 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
106


Protocol 031-201-00181
Confidential -- Proprietary Information
107
Protocol Version 3.0, 31 Jul 2019
clinical trial use and for storing reserve samples are provided in the Study Operations 
Manual.  
The trial sites must store the reserve samples per the clinical label storage condition 
requirements for a period of at least 5 years after marketing approval, or, if marketing 
approval is not obtained, at least 5 years following the date of completion of the 
bioequivalence trial unless FDA representatives collect the reserve samples for testing.
Sites maybe elect to store samples at an off-site facility over the duration of storage 
requirements; in this case, the site continues to maintain responsibility for the reserve 
samples.
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 
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 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
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding visit or day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
107


Protocol 031-201-00181
Confidential -- Proprietary Information
108
Protocol Version 3.0, 31 Jul 2019

The signature (or initials) and date of all clinicians (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Source documents 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 (eSource) 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 trial 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.
Another exception will be safety laboratory or central ECG data, where the official 
source documentation will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source records will take place; however,
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
108


Protocol 031-201-00181
Confidential -- Proprietary Information
109
Protocol Version 3.0, 31 Jul 2019
ensure protocol adherence, to assess trial 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 trial site file will include all source documentation as well as completed eCRF data 
for all subjects screened or enrolled at the trial site. The investigator/institution will take 
measures to ensure confidentiality and prevent accidental or premature destruction of 
these documents.
9.4
Record Retention at the Trial Site
Federal FDA regulations require all investigators participating in clinical drug trials to 
maintain detailed clinical data for one of the following periods:

A period of at least 2 years following the date on which a NDA is approved by the 
FDA;

A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) providing an opportunity for the 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 or withdraws during the record retention 
period (eg, due to relocation or retirement or trial site closure), all trial-related records 
should be transferred to a mutually agreed-upon designee within a sponsor-specified 
timeframe. Notice of such transfer will be given to the sponsor in writing.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
109


Protocol 031-201-00181
Confidential -- Proprietary Information
110
Protocol Version 3.0, 31 Jul 2019
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, 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 (or sponsor designee’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 trial site clinical personnel will undergo initial and ongoing training 
for this particular trial, and this training will be clearly documented.
10.2
Auditing
The sponsor’s (or designee’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 eCRFs with source 
documents. The investigator agrees to participate with audits.
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs.
10.3
Protocol Deviations
Due to the complexity of clinical trial protocols and despite training and preventive 
efforts, deviations from the written protocol may occur and potentially result in harm to 
subjects, biased or inaccurate results, and possible rejection of all or part of the trial data. 
Per the ICH E3 guidance on the structure and content of clinical study reports, 
Section 10.2, protocol deviations should be summarized by site and grouped into 
different categories such as:

Major IMP dosing errors that may compromise subject safety or efficacy assessments.

Administration of an excluded concomitant medication during the course of the trial.
The FDA defines a protocol deviation/violation as an unplanned excursion from the 
protocol that is not implemented or intended as a systematic change.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
110


Protocol 031-201-00181
Confidential -- Proprietary Information
111
Protocol Version 3.0, 31 Jul 2019
Otsuka categorizes clinical protocol deviations as major versus minor. A major deviation 
is an intentional or accidental action or omission in a trial conduct that could potentially 
have a negative impact on the integrity of the trial’s primary scientific objectives or has a 
significant potential to have a negative impact on the safety or efficacy assessments of 
any trial subject. Major deviations are those that might significantly affect the 
completeness, accuracy, or reliability of the trial data or that might significantly affect a 
subject’s rights, safety, or well-being.
A minor deviation is an intentional or accidental action or omission during trial conduct 
in which the protocol is not strictly followed, but which has inconsequential impact on 
the integrity of the trial as a whole or the safety or efficacy analyses of an individual 
subject.
All protocol deviations will be categorized as major or minor according to the above 
definitions and only major deviations will be summarized in the CSR.
If the same protocol deviation occurs for multiple subjects, it must be recorded separately 
for each subject.
Investigators are expected to document potential protocol deviations as well as their 
medical assessment regarding continuation of the subject(s) due to the protocol deviation.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA, ICH GCP Guideline 
(E6), international ethical principles derived from the Declaration of Helsinki and 
Council for International Organizations of Medical Science guidelines, and applicable 
local laws and regulations. The trial sites will seek approval/favorable opinion by an IRB 
according to regional requirements, and the investigator will provide that documentation 
to the sponsor. The IRB will evaluate the ethical, scientific, and medical appropriateness 
of the trial. Further, in preparing and handling eCRFs, the investigator, sub-investigator, 
and their staff will take measures to ensure adequate care in protecting subject privacy. 
To this end, a subject number or subject identifier will be used to identify each subject.
Financial aspects, subject insurance, and publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
111


Protocol 031-201-00181
Confidential -- Proprietary Information
112
Protocol Version 3.0, 31 Jul 2019
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 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 identifiers in eCRFs. If further subject 
ID 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. Any permanent 
change to the protocol, whether an overall change or a change for specific trial sites, must 
be handled as a protocol amendment. Any amendment will be written by the sponsor. 
Each amendment will be submitted to the IRB, as required by local regulations. Except 
for “administrative” or “nonsubstantial” amendments, investigators will wait for IRB
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 notification within local applicable timelines. The sponsor 
will submit protocol amendments to the applicable regulatory agency within local 
applicable timelines.
When the IRB, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design 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, 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.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
112


Protocol 031-201-00181
Confidential -- Proprietary Information
113
Protocol Version 3.0, 31 Jul 2019
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.
15
References
1
Otsuka Pharmaceutical Development and Commercialization. Aripiprazole 
Investigator’s Brochure, Edition 22. Otsuka Report, issued 07 Aug 2018.
2
Hoshika Y. PK study for aripiprazole IM depot ready to use (RTU) injection. Otsuka 
Report No. 14075, 2015.
3
Shimomura Y. Single intramuscular dose irritation study of OPC-14597 suspension 
for depot injection (new component) in beagle dogs. Otsuka Study No. 035591, 
Otsuka Report No. 029243, 2013.
4
Shimomura Y. Fifty-two-week intermittent intramuscular dose irritation study of 
OPC-14597 suspension for depot injection (new component) in beagle dogs with 
16-week recovery test. Otsuka Study No. 035592, Otsuka Report No. 029614, 2013.
5
Shimomura Y. Fifty-two-week intermittent intramuscular dose irritation study of 
OPC-14597 suspension for depot injection (new component) in beagle dogs with 
26-week recovery test. Otsuka Study No. 035592, Otsuka Report No. 030649, 2014.
6
International Council on Harmonisation. Guideline for Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Council on Harmonisation; 1996.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
113


Protocol 031-201-00181
Confidential -- Proprietary Information
114
Protocol Version 3.0, 31 Jul 2019
7
Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) 
Rating Criteria. North Tonawanda, NY: Multi-Health Systems; 1999.
8
Naber D, Moritz S, Lambert M, Pajonk F, Holzbach R, Mass R, et al. Improvement of 
schizophrenic patients' subjective well-being under atypical antipsychotic drugs. 
Schizophr Res. 2001;50:79-88.
9
Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. US 
Department of Health, Education, and Welfare Publication (ADM) 76-338. Rockville, 
MD: National Institute of Mental Health; 1976.
10 Montgomery SA, Asberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389.
11 Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, 
validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
12 Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the 
Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. 
Psychiatry Res. 1997;73:159-171.
13 Simpson GM, Mahmoud RA, Lasser RA, Kujawa M, Bossie C, Turkoz I, et al. 
A 1-year double-blind study of 2 doses of long-acting risperidone in stable patients 
with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2006;67:1194-1203.
14 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 
1989;154:672-676.
15 Chen YHJ, DeMets DL, Lan KKG. Increasing the sample size when the unblinded 
interim results are promising. Stat Med. 2004;23:1023-1038.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
114


Protocol 031-201-00181
Confidential -- Proprietary Information
115
Protocol Version 3.0, 31 Jul 2019
Appendix 1
Names of Sponsor Personnel
Report IREs (SAEs, AEs related to occupational exposure, potential serious 
hepatotoxicity, and pregnancies) to:
Pharmaceutical Research Associates, Inc. (PRA Health Sciences)
Phone: PRA Safety Helpline: +1-800-772-2215
Fax:    +1-888-772-6919 or +1-434-951-3482
Email:  CHOSafety@prahs.com
For Medical Emergencies (use only if sponsor personnel listed above are unavailable): 
301-990-0030
Senior Director, Global Clinical Development
Phone:
Fax:
Stephen R. Zukin, MD
Medical Monitor
Phone:
Fax:
Director, Clinical Management
Phone:
Fax:
Suzanne Watkin
Associate Director, Clinical Management
Phone:
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
115




Protocol 031-201-00181
Confidential -- Proprietary Information
117
Protocol Version 3.0, 31 Jul 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
117


Protocol 031-201-00181
Confidential -- Proprietary Information
118
Protocol Version 3.0, 31 Jul 2019
 
 
 
 
 
 
 
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
118


Protocol 031-201-00181
Confidential -- Proprietary Information
119
Protocol Version 3.0, 31 Jul 2019
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 Research 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, aripiprazole (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) responsible 
for such matters in the clinical trial facility where aripiprazole (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-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 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 approval before implementation of any protocol 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 within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IRB 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 may involve 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
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
119


Protocol 031-201-00181
Confidential -- Proprietary Information
120
Protocol Version 3.0, 31 Jul 2019
Appendix 4
Protocol Amendment 1
Amendment 1 Approval Date:
31 May 2019
PURPOSE:
The purpose of amending Protocol 031-201-00181, issued 14 Dec 2018, was to extend 
the treatment period by 8 weeks for subjects randomized to aripiprazole IM depot 400 mg 
to include an additional dose for comparison of PK parameters over the same duration as 
subjects randomized to aripiprazole 2M LAI 960 mg. Additional measurements of plasma 
aripiprazole concentrations and AUC were added. Clarification of eligibility requirements 
related to current use of antipsychotic medications at screening and guidance for 
management of the use of these medications during the trial were also added. Minor edits 
were made throughout the document for clarification.
BACKGROUND:
Changes to Protocol 031-201-00181 were made in response to a recommendation by 
BfArM (Germany) for an additional dose of aripiprazole IM depot 400 mg to better align 
the treatment duration with aripiprazole 2M LAI 960 mg, and to compare PK parameters 
between aripiprazole IM depot 400 mg and aripiprazole 2M LAI 960 mg over the last 
8 weeks of treatment. Additional measurements of plasma aripiprazole concentrations 
and AUC were also requested.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Added an eighth dose (Day 197) for subjects randomized to aripiprazole IM depot 
400 mg. 

Added 10 days (198, 199, 201, 204, 206, 209, 211, 214, 218, and 225) for 
collection of PK samples following administration of the eighth dose of 
aripiprazole IM depot 400 mg to subjects enrolled to the robust sampling 
schedule.

Added 4 days (204, 211, 218, and 225) for collection of PK samples following 
administration of the eighth dose of aripiprazole IM depot 400 mg to subjects 
enrolled to the sparse sampling schedule.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
120


Protocol 031-201-00181
Confidential -- Proprietary Information
121
Protocol Version 3.0, 31 Jul 2019

Added collection of an additional 4 blood samples (predose and at 4, 8, and 
12 hours postdose) for PK analysis after administration of the eighth dose
(Day 197) for all subjects randomized to aripiprazole IM depot 400 mg. 

Added new PK parameters for plasma aripiprazole concentrations and AUC, 
which included a new secondary endpoint (AUC0-28 and AUC29-56 after the fourth 
dose of aripiprazole 2M LAI 960 mg).

Specified the antipsychotic, mood stabilizer, and antidepressant medications 
allowed at screening to determine eligibility to enroll in the trial and described 
eligibility requirements specific to enrollment to the robust sampling schedule.

Added guidelines for use of mood stabilizers and antidepressants by subjects with 
bipolar disorder during tolerability testing, oral overlap, and the treatment period.

Reduced the number of visits that the C-SSRS would be administered to subjects 
enrolled to the robust sampling schedule to align the frequency of these 
assessments with subjects enrolled to the sparse sampling schedule.

Added Section 8.6 Investigational Medicinal Product Reserve Sample 
Requirements.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
121


Protocol 031-201-00181
Confidential -- Proprietary Information
122
Protocol Version 3.0, 31 Jul 2019
Appendix 5
Protocol Amendment 2
Amendment 2 Approval Date:
31 Jul 2019
PURPOSE:
The purpose of amending Protocol 031-201-00181, issued 31 May 2019, was to add 
additional C-SSRS assessments on outpatient days. Minor administrative clarifications
were also made throughout the document.
BACKGROUND:
Changes to Protocol 031-201-00181 were made to add additional C-SSRS assessments 
on outpatient days to the schedule of assessments for both trial treatment arms 
aripiprazole IM Depot 400 mg and aripiprazole 2M LAI 960 mg sparse and robust 
sampling schedules. Administrative changes were also made to clarify that unscheduled 
C-SSRS assessments will be performed during any outpatient visits, including those that 
may occur within 21 days after aripiprazole 2M LAI 960 mg dosing for subjects enrolled 
to the robust sampling schedule, and to clarify that the trial will take place from Day -30 
to Day 225/ET for both treatment arms.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Clarified globally that subjects enrolled to the robust sampling schedule who are 
randomized to aripiprazole 2M LAI 960 mg and who are not able to
accommodate the scheduled stay of 21 days in the clinical unit may be permitted 
to have some visits as outpatients with approval from the medical monitor. In 
addition, for any outpatient visit, an unscheduled C-SSRS will be performed.

Clarified that the trial will take place from Day -30 to Day 225/ET for both 
treatment arms in Figure 3.1-1 Trial Design Schematic.

Added C-SSRS assessments on Days 8, 15, 22, 36, 43, 50, 176, 183, 190, 204, 
211, and 218 to Table 3.7-1 Schedule of Assessments: Sparse Sampling and 
Table 3.7.3-2 Sparse Sampling Schedule Trial Days and Activities.

Added C-SSRS assessments on Days 36, 43, 50, 204, 211, and 218 to Table 3.7-2 
Schedule of Assessments: Robust Sampling and Table 3.7.3-3 Robust Sampling 
Schedule Trial Days and Activities.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
122


Protocol 031-201-00181
Confidential -- Proprietary Information
123
Protocol Version 3.0, 31 Jul 2019
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
123


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: Protocol 031-201-00181 Amendment 2
Document Number: 
Document Version: 4.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Pharmacology
Approval
31-Jul-2019
21:36:47
Biostatistics Approval
31-Jul-2019
12:14:54
Clinical Approval
31-Jul-2019
21:00:56
Clinical Study Report 031-201-00181
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
124

SAP_001.pdf: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Aripiprazole (OPC-14597, Lu AF41155)
A Phase 1b, Open-label, Multiple-dose, Randomized, Parallel arm, Safety, Tolerability, 
and Pharmacokinetic Trial of Aripiprazole Intramuscular Depot Administered in the 
Gluteal Muscle in Adult Subjects with Schizophrenia or Bipolar I Disorder
Protocol No. 031-201-00181
IND: 134612
STATISTICAL ANALYSIS PLAN
Version 2.0
Date: 16 Jul 2020
Confidential
May not be used, divulged, published or otherwise disclosed without the consent of 
Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1


Protocol 031-201-00181
Statistical Analysis Plan
2 of 36
Version 2.0
Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Appendices..........................................................................................6
1
Introduction ..........................................................................................7
2
Trial Objectives.....................................................................................7
2.1
Primary Objectives............................................................................................. 7
2.2
Secondary Objectives......................................................................................... 7
3
Trial Design...........................................................................................7
4
Sample Size and Power Justification................................................10
5
Statistical Analysis Datasets ..............................................................10
5.1
Definition of Baseline and Last Visit............................................................... 10
5.2
Trial Week Windows........................................................................................ 11
5.3
Handling of Missing Data ................................................................................ 12
6
Primary and Secondary Outcome Variables...................................12
6.1
Primary Safety Variables.................................................................................. 12
6.2
Primary Pharmacokinetics Variables ............................................................... 13
6.3
Secondary Pharmacokinetics Variables ........................................................... 13
6.4
Secondary Efficacy Variables .......................................................................... 13
7
Summary of Trial Data......................................................................14
7.1
Subject Disposition........................................................................................... 14
7.2
Demographic and Baseline Characteristics...................................................... 14
7.3
Treatment Compliance ..................................................................................... 14
7.4
Prior and Concomitant Medications................................................................. 15
7.5
Protocol Deviations.......................................................................................... 15
8
Safety Analyses ...................................................................................16
8.1
Exposure to Trial Medication........................................................................... 16
8.2
Adverse Events................................................................................................. 16
8.3
Vital Signs........................................................................................................ 17
8.4
Physical Examinations ..................................................................................... 17
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
2


Protocol 031-201-00181
Statistical Analysis Plan
3 of 36
Version 2.0
8.5
Clinical Laboratory........................................................................................... 17
8.6
Electrocardiogram ............................................................................................ 19
8.7
Suicidality......................................................................................................... 20
8.8
EPS Scales........................................................................................................ 21
8.9
Injection Site Pain ............................................................................................ 22
8.10
Special Interest Adverse Events....................................................................... 22
9
Efficacy Analyses................................................................................22
10
Pharmacokinetics Analysis................................................................24
10.1
Primary Pharmacokinetics Endpoint Analyses ................................................ 24
10.2
Secondary Pharmacokinetics Endpoint Analyses ............................................ 25
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
3


Protocol 031-201-00181
Statistical Analysis Plan
4 of 36
Version 2.0
List of In-text Tables
Table 5.2-1
Time Window for Trial Weeks for Primary PK Variables C28 
and C56........................................................................................... 11
Table 5.2-2
Time Window for Mapping Trial Week for Efficacy 
Variables ....................................................................................... 11
Table 5.2-3
Time Window for Mapping Trial Week for Safety Variables...... 12
Table 8.5-1
Criteria for Treatment-emergent Relevant Changes in Lipids 
Parameters and Glucose................................................................ 18
Table 8.7-1
Mapping C-SSRS to C-CASA...................................................... 21
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
4


Protocol 031-201-00181
Statistical Analysis Plan
5 of 36
Version 2.0
List of In-text Figures
Figure 3-1
Trial Design Schematic................................................................... 9
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
5


Protocol 031-201-00181
Statistical Analysis Plan
6 of 36
Version 2.0
List of Appendices
Appendix 1
Criteria for Identifying Vital Sign Values of Potential 
Clinical Relevance ........................................................................ 27
Appendix 2
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 28
Appendix 3
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 28
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
6


Protocol 031-201-00181
Statistical Analysis Plan
7 of 36
Version 2.0
1
Introduction
This statistical analysis plan (SAP) describes the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
data collected under the clinical protocol 031-201-00181. The SAP is consistent with 
latest version of protocol amendment 2 dated on 31 July 2019.
2
Trial Objectives
2.1
Primary Objectives
The primary objectives of this trial are

to determine the safety and tolerability of multiple-dose administrations of 
aripiprazole in adult subjects with schizophrenia or bipolar I disorder;

to establish the similarity of aripiprazole concentrations on the last day of the dosing 
interval following the final administration of aripiprazole into the gluteal muscle site 
in adult subjects with schizophrenia or bipolar I disorder;

to establish the similarity of aripiprazole exposure over the dosing interval following 
the administration of aripiprazole into the gluteal muscle site in adult subjects with 
schizophrenia or bipolar I disorder.
2.2
Secondary Objectives
The secondary objectives of this trial are

to determine the PK of aripiprazole;

to determine aripiprazole concentrations 7 days (C7) and 14 days (C14) after the first 
dose of aripiprazole for subjects enrolled to the robust sampling schedule;

to obtain information on the efficacy of aripiprazole over the course of 32 weeks.
3
Trial Design 
This is a phase 1b, open-label, multiple-dose, randomized, parallel-arm, multicenter 
(approximately 20 trial sites) trial in adult subjects with schizophrenia or bipolar I 
disorder. The trial design schematic is shown in Figure 3-1.
Subjects between the ages of 18 to 64 years old, inclusively, are randomized (1:1 
randomization) to receive multiple doses of 2 month (2M) long-acting injectable (LAI)
960 mg (4 injections) or aripiprazole IM depot 400 mg (8 injections) over the course of 
32 weeks. Aripiprazole 2M LAI 960 mg are administered at 56-day intervals and 
aripiprazole IM depot 400 mg are administered at 28-day intervals (+/- 2 days). A final 
visit occurs 56 (+/- 2) days after the last dose of aripiprazole 2M LAI 960 mg or 28 (+/-
2) days after the last dose of aripiprazole IM depot 400 mg. The randomization is
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
7


Protocol 031-201-00181
Statistical Analysis Plan
8 of 36
Version 2.0
stratified by PK sampling schedules (robust sampling schedule or sparse sampling 
schedule) and disease type (schizophrenia or bipolar I disorder). If enrollment of the 
number of subjects required for the robust sampling schedule is completed, the robust 
sampling trial sites may enroll new subjects to the sparse sampling schedule.
The trial consists of a screening period of up to 30 days, a treatment period of 169 (± 2) 
days, and a follow-up period of 56 (± 2) days after administration of the final dose for the 
aripiprazole 2M LAI 960 mg treatment group, or a treatment period of 197 (± 2) days, a 
follow-up period with 28 (± 2) days after administration of the final dose for the 
aripiprazole IM depot 400 mg treatment group. Individual participation is approximately 
255 (± 2) days.
Approximately 258 subjects (129 per treatment group) are to be enrolled into the trial 
with the expectation that approximately 170 subjects (85 per treatment group) complete 
the trial. An interim analysis may be conducted to ensure adequate power of the trial. 
Based on the possible sample size re-estimation in the proposed interim analysis, fewer 
subjects may be enrolled. Up to 76 subjects (38 per treatment group) are to be enrolled to 
the robust sampling schedule which is expected to result in at least 50 completers (25 per 
treatment group). And about 182 subjects (91 per treatment arm) are to be enrolled to the 
sparse sampling schedule which is expected to result in at least 120 completers (60 per 
treatment arm). Based on the possible sample size re-estimation in the proposed interim 
analysis, fewer subjects may be enrolled.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
8


Protocol 031-201-00181
Statistical Analysis Plan
9 of 36
Version 2.0
Figure 3-1
Trial Design Schematic
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
9


Protocol 031-201-00181
Statistical Analysis Plan
10 of 36
Version 2.0
4
Sample Size and Power Justification
To establish the similarity in primary PK variables, the lower bound of the 90% CI of the 
geometric means ratio (GMR) of C56 and AUC0-56 after the fourth dose of aripiprazole 
2M LAI 960 mg to C28 after the eighth dose and the sum of AUC0-28 values after the 
seventh and eighth doses of aripiprazole IM depot 400 mg should be greater than 80%, 
respectively.
It is estimated that a total of at least 100 subjects (i.e., 50 per group) completing the trial 
will have at least 80% power to ensure that the lower limit of the 90% CI of the GMR of 
C56 after the fourth dose of aripiprazole 2M LAI 960 mg (test) to C28 after the eighth 
dose of aripiprazole IM depot 400 mg (reference) is greater than 0.80, assuming that the 
actual GMR of concentrations is 1.0 and the CV is 46%. 
Among these 100 subjects, at least 30 completers enrolled to the robust sampling 
schedule will provide at least 80% power to ensure that the lower limit of the 90% CI of 
the GMR of AUC0-56 of aripiprazole 2M LAI 960 mg (test) to the sum of AUC0-28 values 
of aripiprazole IM depot 400 mg (reference) after the seventh and eighth doses is greater 
than 0.80, assuming the actual GMR of concentrations is 1.15 and the CV is 40%.
The assumption of CV used in the sample calculation is based on the PK data in the 
previous multiple-dose aripiprazole IM depot PK Trial 31-12-298.
Assuming a dropout rate of 34%, approximately 152 to 258 subjects are estimated to be 
enrolled to have 100 to 170 completers based on the proposed interim analysis.
5
Statistical Analysis Datasets
The datasets for analyses are defined as the following:

Randomized sample consists of all subjects who are randomized.

Safety sample includes all randomized subjects who receive at least 1 dose of 
aripiprazole injection, regardless of any protocol violation.

Pharmacokinetics sample consists of all dosed subjects who have 1 or more evaluable 
aripiprazole PK parameters. For analysis of the primary PK endpoint, only the 
completers with available values of the primary endpoints after the last scheduled 
injection are included.

Efficacy sample includes all randomized subjects who receive at least 1 dose of 
aripiprazole injection and have at least 1 efficacy assessment.
5.1
Definition of Baseline and Last Visit
Baseline is defined as the last evaluable assessment prior to aripiprazole IMP injection 
while last visit is defined as the last evaluable assessment upon completion or early 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10


Protocol 031-201-00181
Statistical Analysis Plan
11 of 36
Version 2.0
termination of treatment phase. Only subjects who receive at least 1 dose of 
investigational medical products and have assessment at both baseline and at least 1 post-
baseline visit are included in the analyses of change from baseline.
5.2
Trial Week Windows
The actual assessment date is mapped into the trial week. The definition of trial weeks for 
primary PK variables are described in Table 5.2-1 and the definitions of trial weeks for 
efficacy scales and safety scales such as Extrapyramidal Symptoms (EPS) rating scales
are included in Table 5.2-2 and Table 5.2-3. Trial days are derived from the formula: 
Trial Day = Date of assessment - Date of 1st IMP injection + 1. Based on the number of 
trial days, subjects are mapped to the corresponding trial week. For safety and efficacy 
variables, only the last observation within the same mapped trial week is used for 
imputing data on the following trial weeks in the derived last observation carried forward 
(LOCF) dataset. In addition, only last observations within the same mapped weeks are
reported in the summary tables by trial week.
Table 5.2-1
Time Window for Trial Weeks for Primary PK 
Variables C28 and C56
Scheduled 
Visit
(Day)
Mapped Week
(Trial Week)
Week Window
(Trial Day Range ± 2 
days)
197
28 (28 days after the 7th injection of 400 mg 
Abilify Maintena  
195-199
225
32 (28 days after the 8th injection of 400 mg 
Abilify Maintena or 56 days after the 4th
injection of 960 mg aripiprazole 2M LAI)
223-227
Table 5.2-2
Time Window for Mapping Trial Week for Efficacy 
Variables
Scheduled Visit
(Day)
Mapped Week
(Trial Week)
Week Window
(Trial Day Range)
1
Baseline
≤1 (before first IMP)
29
4
2-43
57
8
44-85
113
16
86-141
169
24
142-183
197
28
184-211
225
32
212-239
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
11


Protocol 031-201-00181
Statistical Analysis Plan
12 of 36
Version 2.0
Table 5.2-3
Time Window for Mapping Trial Week for Safety 
Variables
Scheduled Visit
(Day)
Mapped Week
(Trial Week)
Week Window
(Trial Day 
Range)
1
Baseline
≤1 (before first 
IMP)
8
1
2-11
15
2
12-18
22
3
19-25
29
4
26-43
57
8
44-71
85
12
72-99
113
16
100-127
141
20
128-155
169
24
156-183
197
28
184-211
225
32
212-239
5.3
Handling of Missing Data
No data imputation is done for missing data in the PK analysis. The last observation 
carried forward (LOCF) method is used to impute missing data of the safety EPS 
assessment scales and efficacy assessment scales at postbaseline visits. The observed case 
(OC) dataset corresponding to a visit consists of data from all subjects who are evaluated 
at that visit. In the LOCF dataset, missing data at a postbaseline visit are imputed with the 
value obtained at the nearest preceding visit, except that baseline values are not carried 
forward to impute missing values at a postbaseline visit. In addition, the Mixed effect 
Model Repeated Measure (MMRM) for selected efficacy endpoints are explored to 
address the potentially informational missing (refer to Section 9).
6
Primary and Secondary Outcome Variables 
6.1
Primary Safety Variables
Safety and tolerability are based on reported adverse events (AEs), vital signs, ECG
parameters, clinical laboratory test results (including blood/serum chemistry, hematology, 
urinalysis), physical examinations, EPS rating scales (including Simpson-Angus 
Neurologic Rating Scale [SAS], Abnormal Involuntary Movement Scale [AIMS], and 
Barnes Akathisia Rating Scale [BARS]), Visual Analog Scale (VAS) scores for pain 
perception, investigator’s assessment of most recent injection site, and suicidality via C-
SSRS.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
12


Protocol 031-201-00181
Statistical Analysis Plan
13 of 36
Version 2.0
6.2
Primary Pharmacokinetics Variables
The primary PK parameters to be estimated for aripiprazole are as follows: 

Plasma concentration of aripiprazole 56 days postdose (C56) of aripiprazole 2M LAI 
960 mg after the fourth dose and plasma concentration of aripiprazole 28 days 
postdose (C28) of aripiprazole IM depot 400 mg after the eighth dose over the course 
of 32 weeks;

AUC0-56 for aripiprazole 2M LAI 960 mg after the fourth dose, and sum of AUC0-28 
for aripiprazole IM depot 400 mg after the seventh dose and eighth doses over the
course of 32 weeks, based on the PK data from subjects enrolled to the robust 
sampling schedule.
6.3
Secondary Pharmacokinetics Variables
The following secondary PK parameters are estimated for aripiprazole after the 
administration of aripiprazole 2M LAI 960 mg and aripiprazole IM depot 400 mg:

Cmax and tmax after the first and fourth doses of aripiprazole 2M LAI 960 mg;

AUC0-56 and C56 after the first dose of aripiprazole 2M LAI 960 mg;

AUC0-28 and AUC29-56 after the fourth dose of aripiprazole 2M LAI 960 mg;

Peak-to-trough percent fluctuation (PTF%) after the fourth dose of aripiprazole 2M
LAI 960 mg;

Cmax and tmax after the first, seventh and eighth doses of aripiprazole IM depot 400 
mg;

AUC0-28 and C28 after the first dose of aripiprazole IM depot 400 mg;

PTF% after the eighth dose of aripiprazole IM depot 400 mg.
Cmax, tmax, AUC, and PTF% are determined only from subjects enrolled to the robust 
sampling schedule; C56 and C28 are determined from subjects enrolled to the sparse and 
robust sampling schedule.
The following PK parameters are estimated for aripiprazole after administration of 
aripiprazole 2M LAI 960 mg + oral aripiprazole 10 to 20 mg for 7 days and aripiprazole 
IM depot 400 mg + oral aripiprazole 10 to 20 mg for 14 days (this endpoint is only for 
subjects enrolled to the robust sampling schedule): 

Plasma concentration of aripiprazole 7 days postdose (C7)

Plasma concentration of aripiprazole 14 days postdose (C14).
6.4
Secondary Efficacy Variables
The efficacy of aripiprazole IM depot administration in the gluteal muscle is assessed by 
the Positive and Negative Syndrome Scale (PANSS; schizophrenia subjects only),
Clinical Global Impression Severity (CGI-S; schizophrenia subjects only), Clinical 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
13


Protocol 031-201-00181
Statistical Analysis Plan
14 of 36
Version 2.0
Global Impression - Improvement (CGI-I), Subjective Well-being under Neuroleptic 
Treatment-Short Form (SWN-S), Montgomery-Asberg Depression Rating Scale 
(MADRS; bipolar subjects only), Young Mania Rating Scale (YMRS; bipolar subjects 
only), and Clinical Global Impression - Bipolar Version (CGI-BP; bipolar subjects only).
7
Summary of Trial Data
7.1
Subject Disposition 
Disposition of subjects including screened subjects and/or randomized subjects will be 
reported by treatment formulation, PK sampling schedule (i.e., robust or sparse) and 
disease type (i.e., schizophrenia or bipolar I disorder) in addition to summary by center. 
Durations of subjects staying in the treatment phase will be summarized by week,
treatment formulation, PK sampling schedule and disease type. Reasons for 
discontinuations will be tabulated by treatment formulation, PK sampling schedule and 
disease type. Subjects who are evaluated at the last scheduled visit (i.e., Day 225 visit for 
aripiprazole 2M LAI 960 mg and aripiprazole IM depot 400 mg) during the treatment 
phase will be defined as trial completers.
7.2
Demographic and Baseline Characteristics
Demographic characteristics (including age, weight, height, BMI, sex, race, and 
ethnicity) will be summarized for randomized sample using descriptive statistics 
(frequency, mean, median, standard deviation, maximum, minimum, and percentage 
when applicable) and reported by treatment formulation, PK sampling schedule and 
disease type.
Disease characteristics at baseline and psychiatric history (including efficacy assessments 
age of initial diagnosis for schizophrenia or bipolar I disorder) will be presented for the 
randomized sample by treatment formulation, PK sampling schedule and disease type. In 
calculating age of first diagnosis for schizophrenia or bipolar disorder, if both month and 
day are missing, June 1 is used. If only day is missing, date of 1 is used. If only month is 
missing, month June is used.
7.3
Treatment Compliance
Compliance of trial medication for aripiprazole 2M LAI 960 mg and IM depot 400 mg
will be summarized for the randomized sample. Compliance is defined as receiving the 
aripiprazole IM depot 400 mg injection in the minimum interval of 26 days or 960 mg 
aripiprazole 2M LAI injection at least 54 days after the prior injection.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
14


Protocol 031-201-00181
Statistical Analysis Plan
15 of 36
Version 2.0
Compliance of trial medication of oral aripiprazole in first 2 weeks is derived from total 
days taking oral tablets divided by 14 days for aripiprazole IM depot 400 mg injection 
group or 7 days for 960 mg aripiprazole 2M LAI injection group or total days in the trial if 
patients withdraw from the study before day 15.  Proportion of subjects reaching at least 
50%, 60%, 70%, 80% and 90% compliance to oral tablets are tabulated by treatment group,
disease type for subjects with PK robust sampling schedule.  
7.4
Prior and Concomitant Medications
Number and proportion of subjects taking concomitant medications will be tabulated for 
the randomized sample by treatment formulation and drug classification using the WHO 
drug dictionary (WHODRUG Global B3, March 2020 or later) and categorized by time 
periods: prior to start of trial therapy, during the trial therapy, and after the trial therapy.
Proportions of subjects taking a concomitant medication of benzodiazepine will be 
provided by treatment formulation and/or concomitant medication.  Concomitant 
medications for benzodiazepine are converted into lorazepam equivalent using the 
appropriate conversion factors.  Daily dose of benzodiazepine (lorazepam or equivalent) 
will be summarized by treatment formulation and/or concomitant medications. The daily 
dose for each subject is calculated in total dosage of lorazepam or equivalent divided by 
the duration of IMP treatment.  If subjects do not take benzodiazepine, daily dose for 
benzodiazepine will be considered as 0. Additionally, descriptive statistics for the 
duration (days) of benzodiazepine will be provided by treatment formulation and/or 
concomitant medications for subjects taking benzodiazepine only.
7.5
Protocol Deviations
Protocol deviations will be summarized by type of deviations and disease type.  Types of 
deviation include deviations in entry criteria, dosing, randomization, concomitant 
medication, procedural, etc. In addition, a subject listing will be provided describing the 
deviations for each subject including protocol deviation due to outbreak of COVID-19. 
During the restriction of COVID-19, the robust sampling subjects may remain in clinic 
until Day 225 and the sparse sampling subjects  are asked to come into the clinic on days 
where they need to receive the once-monthly or once-bimonthly injection of IMP and the 
final trial visit on Day 225. On those days, all assessments for the sparse sampling 
subjects will occur as specified in the protocol. On visit days between dosing visits / final 
study visit, only safety assessments (e.g. AEs, CSSRS, BARS and AIMS) for the sparse 
sampling subjects will be conducted remotely (virtually) to prioritize the health and 
safety of these subjects. Therefore, no impact is applicable to primary PK parameters and 
minimal impact is on secondary PK parameters.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
15


Protocol 031-201-00181
Statistical Analysis Plan
16 of 36
Version 2.0
8
Safety Analyses
Safety assessments including adverse events (AEs), vital signs, ECGs, clinical laboratory 
monitoring (serum chemistry, hematology, urinalysis), physical examinations, EPS, VAS 
scores for pain perception, investigator’s assessment of most recent injection site, and 
suicidality via the C-SSRS will be summarized for the safety sample by treatment 
formulation and disease type in addition to all treated subjects.
In summarizing the incidence of clinically relevant abnormalities in clinical laboratory 
results, vital sign measurements and ECG measurements, a subject must have had an 
evaluation that meets the specified criteria.  Incidence rate will be calculated as the 
number of subjects having at least 1 abnormality in the treatment phase divided by the 
number of subjects in the safety sample.
Safety data collected during in-clinic visits and virtual visits are summarized together.
8.1
Exposure to Trial Medication
Exposure to aripiprazole IMP injections for the safety sample will be summarized using
percentage of subjects receiving injections and trial day of each injection from date of 
randomization by treatment formulation, PK sampling schedule and disease type.   
Exposure to oral aripiprazole during the first 1 or 2 weeks after first injection will be 
summarized using percentage of subjects exposed to oral aripiprazole and daily dose by 
week in the randomization phase, treatment formulation, disease type and PK sampling 
schedule.
8.2
Adverse Events
All AEs are coded using Medical Dictionary for Regulatory Activities (MedDRA 
Version 23.0 or later).  A treatment-emergent adverse event (TEAE) is defined as an AE 
which starts after start of first IMP injection or an AE continues from baseline of the 
treatment phase and was serious, trial drug-related or results in death, discontinuation, 
interruption or reduction of trial medication.  The incidences of the following TEAEs will 
be reported by MedDRA preferred term, treatment formulation and disease type:

TEAEs by severity,

Potentially drug related TEAEs,

TEAEs with an outcome of death,

Serious TEAEs,

Discontinuations due to TEAEs,

Non-Serious TEAEs.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
16


Protocol 031-201-00181
Statistical Analysis Plan
17 of 36
Version 2.0
In addition, sub-group analysis for incidence of TEAEs will be summarized by sex (male 
and female), race (Caucasian, African American and Other), ethnicity (Hispanic/Latino
and Not Hispanic/Not Latino), age (< 45 years old and ≥ 45 years old at baseline), BMI 
(≤ 28 kg/m2 and > 28 kg/m2 at baseline), disease type, and PK Robust/Sparse Sampling 
schedule.
8.3
Vital Signs
Vital signs include body temperature in supine position, systolic/diastolic blood pressure 
in supine and standing position and heart rate.  Potential clinically relevant vital sign 
abnormalities will be listed, the criteria for which are provided in Appendix 1.  
Incidences of clinically relevant vital signs abnormalities based on observations during
scheduled visits and unscheduled post-baseline visits will be tabulated by treatment 
formulation and disease type. In addition, vital sign parameters and changes from 
baseline will be summarized by scheduled visit, treatment formulation and disease type.
If vital sign assessments are repeated for the same trial visit, the last repeat values will be 
used for production of summary tables.  This is accomplished by sorting patient data by 
visit date and visit time (if applicable) within the same trial visit.
8.4
Physical Examinations
Physical examination data will be listed by subjects.
8.5
Clinical Laboratory
Clinical laboratory tests include serum chemistry, hematology, urinalyses and other lab 
analyses.  Potentially clinically relevant laboratory test abnormalities will be listed by 
subject and by test.  Criteria for potentially clinically relevant laboratory test 
abnormalities are provided in Appendix 2. Subjects with aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) ≥ 3 x upper limit of normal value and total 
bilirubin ≥ 2 x upper limit of normal value will be listed.  The incidences of potentially 
clinically relevant laboratory tests abnormalities based on observations during scheduled 
and unscheduled post-baseline visits will be tabulated by treatment formulation and 
disease type. Summary statistics for clinical laboratory measurements and changes from 
baseline will be presented by trial visit, treatment formulation and disease type.
If laboratory tests assessments are repeated for the same mapped trial visit, the last 
repeated values will be used for summary tables.  This is accomplished by sorting patient 
data by visit date and visit time (if applicable) within the same trial visit.  If the lab data 
are recorded as ranges (i.e., including < or > limit of quantification), these data are not 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
17


Protocol 031-201-00181
Statistical Analysis Plan
18 of 36
Version 2.0
included in the calculations for changes from baseline but included in the calculations for 
incidences.  
The incidence of prolactin level above the upper limit of normal range (potentially 
clinically relevant change) will be calculated by treatment formulation and disease type. 
Summary statistics (mean, standard deviation, median, minimum, and maximum) and 
changes from baseline in prolactin concentration will be presented by trial visit, treatment
formulation and disease type. Similar analyses will be performed for male and female, 
respectively. Additionally, incidences of treatment-emergent relevant changes in lipid 
parameters and glucose (as defined in Table 8.5-1) will be summarized by treatment 
formulation and disease type, though those blood samples are not required to be collected 
at the fasted state.
Table 8.5-1
Criteria for Treatment-emergent Relevant Changes in 
Lipids Parameters and Glucose
Parameters
Baseline
Any Post-baseline
Total Cholesterol (mg/dL)
Normal <200        
High >=240               
Borderline 200~<240    
High >=240               
Normal/Borderline <240
High >=240               
Normal <200            
Borderline/High >=200    
Any Value              
Increased >=40           
LDL Cholesterol (mg/dL)
Normal <100        
High >=160               
Borderline 100~<160    
High >=160               
Normal/Borderline <160
High >=160               
Normal <100            
Borderline/High >=100    
Any Value              
Increased >=30           
HDL Cholesterol (mg/dL)
Normal >=40        
Low<40               
Any Value              
Decreased >=20           
Triglycerides (mg/dL)
Normal <150        
High >=200               
Normal <150        
Very High >=500               
Borderline 150~<200    
High >=200               
Borderline 150~<200    
Very High >=500               
Normal/Borderline <200
High >=200               
Normal/Borderline <200
Very High >=500               
Normal <150            
Borderline/High/Very High
>=150    
Normal/Borderline /High
>=200
Very High >=500               
Any Value              
Increased >=50          
Glucose (mg/dL)
Normal <100        
High >=126               
Impaired Fasting Glucose 
100~<126
High >=126               
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
18


Protocol 031-201-00181
Statistical Analysis Plan
19 of 36
Version 2.0
Table 8.5-1
Criteria for Treatment-emergent Relevant Changes in 
Lipids Parameters and Glucose
Parameters
Baseline
Any Post-baseline
Normal/ Impaired Fasting 
Glucose <126
High >=126               
Any Value              
Increased >=10           
Note: The National Cholesterol Education Program (NCEP) Adult Treatment Program Classifications of lipids 
(refer to fasting lipid measurements) are used for lipid parameters and the American Diabetes Association 
Criteria are used for glucose.
8.6
Electrocardiogram
ECG measurements including PR, QRS, QT and RR are taken from three consecutive 
complexes (representing three consecutive heart beats). The mean value of the available 
ECG measurements will be calculated and used in the summary table. For the calculation 
of QT correction by heart rate, QTc is considered as missing only if all three consecutive 
beats are unreadable. For each ECG, QT and RR intervals from three consecutive 
complexes (representing three consecutive heart beats) will be measured manually. The 
QT correction is performed on beat-to-beat basis. The mean of ratios (beat-to-beat) is 
calculated by (QTc1 + QTc2 + QTc3)/3 using each QT-RR pair: (QT1, RR1), (QT2, 
RR2) and (QT3, RR3). The corrected QT intervals for QTcB, QTcF, and QTcN are 
defined as follows:

QTcB is the length of the QT interval corrected for heart rate by Bazett’s formula: 
QTcB = QT / (RR)1/2,

QTcF is the length of the QT interval corrected for heart rate by Fredericia’s 
formula: QTcF = QT / (RR)1/3,

QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT/ (RR) 0.37.
Potentially clinically relevant ECG abnormalities will be listed by subject. The criteria 
for potentially clinically relevant ECG abnormalities are provided in Appendix 3. 
Incidences of abnormal ECGs of potential clinical relevance, based on the observations 
during scheduled and unscheduled post-baseline visits will be tabulated by treatment 
formulation and disease type. Descriptive statistics of change from baseline in ECG 
intervals of PR, QRS, RR, QT and QTc, will be presented by trial visit, treatment 
formulation and disease type.  In addition, incidences of categorical change in ECG -
QTc will be provided for the following categories: change from baseline >30 millisecond
(MS) to <60 MS, change from baseline ≥60 MS, new onset >450 MS, new onset >480 
MS and new onset >500 MS.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
19


Protocol 031-201-00181
Statistical Analysis Plan
20 of 36
Version 2.0
If ECG assessments are repeated for the same trial visit, the last repeated values will be 
used for generation of mean change from baseline. This is accomplished by sorting 
patient data by visit date and visit time (if applicable) within the same trial visit.
8.7
Suicidality
Suicidality data collected from the C-SSRS assessments will be summarized by treatment 
formulation and disease type in incidence of suicidality; suicidal behavior only, 
emergence of suicidal behavior; suicidal ideation only, emergence of suicidal ideation, 
emergence of serious suicidal ideation, and worsening of suicidal ideation at trial visits
and last visit in addition to overall during the treatment phase.
Suicidality is defined as reporting any suicidal ideation or behavior. Suicidal behavior 
only is defined as reporting any type of suicidal behaviors (actual attempt, interrupted 
attempt, aborted attempt and preparatory acts or behavior) throughout assessment period.  
Emergence of suicidal behavior is defined as having no suicidal behavior at baseline and 
reporting any type of behavior at post-baseline.  Suicidal ideation only is defined as 
reporting any type of suicidal ideation. Emergence of suicidal ideation is defined as 
having no suicidal ideation at baseline and reporting any type of ideation during 
treatment. Emergence of serious suicidal ideation is defined as having no suicidal 
ideation at baseline and reporting serious suicidal ideation with score of 4 or 5 on suicidal 
ideation severity rating during the treatment. In assessment of suicidal ideation and level 
of severity, each person is given a score of 0 (no ideation present) to 5 (active ideation 
with plan and intent).  Worsening of suicidal ideation is defined as having greater
severity of ideation for the most severe suicidal ideation at post baseline than at baseline. 
Numbers of patients reporting suicidal behavior are also reported by type of suicidal 
behavior.  
Descriptive statistics of the incidence of suicidality and incidence of suicidality by type 
(suicidal behavior and suicidal ideation), as well as the mean changes of Suicidal Ideation 
Intensity (SSI) total scores for most severe ideation from baseline will be reported by trial 
visit, treatment formulation and disease type. The suicidal ideation intensity total score is
the sum of suicidal ideation severity rating scores for frequency, duration, controllability, 
deterrents and reasons for ideation.  For each item, each subject gets intensity score from 
0 (none) to 5 (worst).  Therefore, SSI total score is a range from 0 to 25.  If the subject 
did not endorse any suicidal ideation, a score of 0 is given for the intensity scale.
There are 9 categories for Columbia Classification Algorithm of Suicide Assessment (C-
CASA) method, which are coded as below,
1. completed suicide; 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
20


Protocol 031-201-00181
Statistical Analysis Plan
21 of 36
Version 2.0
2. suicide attempt; 
3. preparatory actions toward imminent suicidal behavior;
4. suicidal ideation;
5. self-injurious behavior, intent unknown;
6. not enough information: death; 
7. non-suicidal self-injurious behavior; 
8. other (Accident; Psychiatric, Medical); 
9. not enough information: non-death.
Data collected from C-SSRS will be mapped into C-CASA category as specified in Table 
8.7-1. Incidence of potential suicidality events using C-CASA category will be provided 
for safety sample.
Table 8.7-1
Mapping C-SSRS to C-CASA
C-SSRS
C-CASA Category
Completed Suicide
1. Completed Suicide
Actual Attempt
2. Suicide Attempt
-Interrupted Attempt
-Aborted Attempt
-Preparatory Acts or Behavior
3. Preparatory Actions 
Toward Imminent Suicidal
Behavior
1. Wish to Die
2. Non-Specific Active Suicidal Thoughts
3. Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
4. Active Suicidal Ideation with Some intent To Act, without 
Specific Plan
5. Active Suicidal Ideation with specific Plan and Intent
4. Suicidal Ideation
Non-suicidal Self-injurious Behavior
7. Non-suicidal Self-
injurious Behavior
8.8
Extrapyramidal Symptoms Scales
Extrapyramidal Symptoms (EPS) rating scales include the Simpson-Angus Scale (SAS), 
Barnes Akathisia Rating Scale (BARS) and Abnormal Involuntary Movement Scale 
(AIMS).  The variables to be analyzed are,

Change from Baseline in SAS Total Score, 

Change from Baseline in BARS Global Score, 

Change from Baseline in AIMS Movement Rating Score.
The SAS total score (range 10 - 50) is the sum of the rating scores for 10 items from the 
SAS panel in the Case Report Form (CRF).  The BARS global score (range 0 - 5) is 
derived from the global clinical assessment of akathisia from the BARS panel in the 
CRF.  The AIMS movement rating score (range 0 - 28) is the sum of the rating scores for 
facial and oral moments (i.e., item 1 - 4), extremity movements (i.e. item 5 - 6), and trunk 
movements (i.e. item 7).  A missing value of any item for the SAS or the AIMS 
movements scale could result in a missing SAS total score or AIMS movement rating 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21


Protocol 031-201-00181
Statistical Analysis Plan
22 of 36
Version 2.0
score. LOCF missing data imputation will be performed those scores. Descriptive 
statistics of the EPS rating scales for both LOCF and OC data and the mean changes of
the scales from baseline will be reported by trial week, treatment formulation and disease 
type.
8.9
Injection Site Pain
Descriptive statistics for VAS scores for pain perception will be tabulated by treatment 
formulation and disease type at each injection (predose and after dose). Investigator’s 
assessment of most recent injection site including pain, swelling, redness, and induration 
will be reported in 4-point categorical scale (absent, mild, moderate and severe) and will 
be summarized by treatment formulation and disease type at each injection (predose and 
after dose).
8.10
Special Interest Adverse Events
Incidence of treatment emergent special interest adverse events will be tabulated by 
treatment formulation and MedDRA preferred terms for EPS-related AEs, weight-related 
AEs, glucose-related AEs, lipid-related AEs, white blood cell abnormalities, orthostasis-
related AEs, prolactin-related AEs, QT-interval AEs, suicidality -related AEs and 
injection-site-related AEs. In addition, proportion of subjects received anticholinergic 
medication for treatment-emergent EPS-related events will be presented.
9
Efficacy Analyses
Efficacy assessments for all subjects includes Clinical Global Impression - Improvement 
(CGI-I) and Subjective Well-being under Neuroleptic Treatment - Short Form (SWN-S).
The Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression -
Severity (CGI-S) are assessed for schizophrenia subjects only. Montgomery-Asberg 
Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Clinical 
Global Impression - Bipolar Version (CGI-BP) are assessed for bipolar I disorder 
subjects only. All efficacy assessments will be summarized for the efficacy sample at 
each mapped trial week by treatment formulation and disease type (if applicable).
PANSS total score (range 30-210) is the sum of the rating scores for 7 positive scale 
items, 7 negative scale items, and 16 general psychopathology scale items from the 
PANSS scale.  A missing value for any item would result in a missing PANSS total 
score. PANSS positive subscale score (range 7-49) is the sum of the rating scores for the 
7 positive scale items from the PANSS scale.  PANSS negative subscale score (range 7-
49) is the sum of the rating scores for the 7 negative scale items from the PANSS scale.
CGI-S score (range 0-7), CGI-I score (range 0-7), CGI-BP severity score (range 0-7) and 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
22


Protocol 031-201-00181
Statistical Analysis Plan
23 of 36
Version 2.0
CGI-BP change from preceding phase score (range 0-7) are directly retrieved from CRF 
data.
SWN-S total score (range 20-120) is the sum of the rating scores for 10 positive scale 
items (items 2+, 3+, 5+, 7+, 8+, 13+, 15+, 18+, 19+, 20+) and 10 negative scale items 
(items 1-, 4-, 6-, 9-, 10-, 11-, 12-, 14-, 16-, 17-). SWN-S subscale total score (range 4-24) 
is the sum of the rating scores for the 4 items in each of the 5 subscales: mental 
functioning (3+, 7+, 11-, 17-), social integration (8+, 13+, 6-, 14-), emotional regulation 
(18+, 20+, 4-, 10-), physical functioning (2+, 5+, 9-, 16-), and self-control (15+, 19+, 1-, 
12-). For items marked with a ‘+’, the scoring is ‘not at all = 1’, ‘hardly at all = 2’, ‘a 
little = 3’, ‘somewhat = 4’, ‘much = 5’, and ‘very much = 6’. For items marked with a ‘-
‘, the scoring is reversed. response choices and scoring are as follows: not at all = 6, 
hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. A missing value of 
any items in the SWN-S would result in a missing total or a subscale total score.
The MADRS is utilized as the primary assessment of a subject’s level of depressive 
symptoms and must be administered using a structured interview guide. This scale 
consists of 10 items each with 7 defined grades of severity on 0 to 6 scale (reported 
sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration 
difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts).  
MADRS total score is sum of 10 item score with range from 0~60. The missing score for 
any 1 item will result in a missing MADRS total score.  MADRS total score will be 
summarized by trial week for each treatment formulation.
The YMRS consists of 11 items assessing the core symptoms of mania and is based on 
the subject’s subjective report of his or her clinical condition. Additional information is 
based upon clinical observations made during the clinical interview. Each item has 5 
defined categories of severity with 4 items graded on a 0 to 8 scale (irritability, speech, 
content, and disruptive-aggressive behavior) and 7 items graded on a 0 to 4 scale 
(elevated mood, increased motor activity/energy, sexual interest, sleep, language-thought 
disorder, appearance, and insight).  YMRS total score is sum of 11 item score with range 
from 0~60. The missing score for any 1 item will result in a missing YMRS total score. 
YMRS total score will be summarized by trial week for each treatment formulation.
The CGI-BP scale refers to the global impression of the subject with respect to bipolar 
disorder. The scale rates the subject’s severity of illness (CGI-BP-Severity: mania, 
depression, and overall bipolar illness) and change from baseline visit (CGI-BP Change 
from Preceding Phase: mania, depression, and overall bipolar illness) based on a 7-point 
scale (rang 1-7).
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
23


Protocol 031-201-00181
Statistical Analysis Plan
24 of 36
Version 2.0
LOCF missing data imputation will be performed for all efficacy assessments. Changes 
from baseline in SWN-S total score and SWN-S subscale total score for all efficacy 
sample in addition to PANSS total score, PANSS positive subscale total score, PANSS 
negative subscale total score, CGI-Severity score, MADRS total score, YMRS total 
score, CGI-BP-Severity score will be summarized using descriptive statistics, if 
applicable.  CGI-Improvement score and CGI-BP change from preceding phase score are
also summarized using descriptive statistics, if applicable. 
In addition, the linear mixed-effects mode will be used to explore the effect of the 
treatment and change from baseline over the time for efficacy endpoints, i.e. SWN-S total 
score, PANSS total score and YMRS total score.  Change from baseline in those efficacy 
endpoints will be analyzed using MMRM analysis with a restricted maximum likelihood 
(REML) approach. Analyses will include the categorically fixed effects of treatment, 
disease type (if applicable), PK sample scheduling (if applicable), trial week, and 
treatment-by trial week interaction, as well as the covariates of baseline-score-by-week 
interaction in addition to subject as random effect. An unstructured covariance structure 
will be used to model the within-subject errors and Kenward-Rodger degree of freedom 
will be used to test the fixed effects. If this analysis approach fails to converge, the 
covariance structures of heterogeneous compound symmetry will be utilized in the 
analysis and the “sandwich” estimator of the variance covariance matrix of the fixed 
effects parameters will be used in order to deal with possible model misspecification of 
the covariance matrix. 95% confidence intervals (CIs) for difference of changes from 
baseline in efficacy endpoints or values of efficacy endpoints between aripiprazole 2M 
LAI 960mg and IM depot 400 mg will be provided at trail weeks as well.
10
Pharmacokinetics Analysis
The pharmacokinetic parameters will be calculated using Noncompartmental Analysis 
(NCA) SAS macro (version 1.0). In general, the individual and summary tables, using 
descriptive statistics (N, median, mean, standard deviation, coefficient of variation, 
minimum, maximum), of pharmacokinetic parameters will be summarized descriptively
by treatment formulation. Descriptive statistics for aripiprazole and dehydro-aripiprazole
concentration data will be presented.
10.1
Primary Pharmacokinetics Endpoint Analyses
The following PK parameters will be estimated and summarized descriptively for 
aripiprazole: C56 and AUC0-56 of aripiprazole 2M LAI 960 mg after the fourth dose, C28
of aripiprazole IM depot 400 mg after the eighth dose, and the sum of AUC0-28 of 
aripiprazole IM depot 400 mg after the seventh and eighth dose over the course of 32
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
24


Protocol 031-201-00181
Statistical Analysis Plan
25 of 36
Version 2.0
weeks. Values for AUC0-28, and AUC0-56 will be summarized based on samples from 
subjects enrolled to the robust sampling schedule; whereas C28 and C56 will be 
summarized based on samples from subjects enrolled to the robust and sparse sampling 
schedules.
The 90% confidence interval (CI) of GMR of C56 of aripiprazole after the fourth injection 
of aripiprazole 2M LAI 960 mg (test) to C28 after the eighth injection of aripiprazole IM 
depot 400 mg (reference) will be provided. An analysis of variance will be performed on 
the natural-log transformed PK parameters using the MIXED procedure in the Statistical 
Analysis System (SAS). The mixed-effects linear model will include treatment 
formulation, disease type (if applicable), and PK sampling schedule (if applicable) as
fixed effects and subject as a random effect. The least squares mean for the 2 treatment 
formulations, their difference, and the 90% CI for their difference will be derived. The 
antilog of the confidence limits will provide the 90% CI for the GMR of the 2 treatments. 
For subjects enrolled to the robust sampling schedule, the values of AUC0-28 after the 
seventh and eighth doses of aripiprazole IM depot 400 mg (reference) will be summed up 
before analyzing by the same method together with AUC0-56 after the fourth injection of 
aripiprazole 2M LAI 960 mg (test). Only subjects who receive the fourth dose of 
aripiprazole 2M LAI 960 mg or the seventh and eighth dose of aripiprazole IM depot 400 
mg and have C56, C28, AUC0-28, and AUC0-56 values determined for the respective 
treatments will be included in the analysis.
10.2
Secondary Pharmacokinetics Endpoint Analyses
Individual and summary tables, using descriptive statistics (N, median, mean, standard 
deviation, coefficient of variation, minimum, maximum) will be provided for the 
following aripiprazole PK endpoints,

Cmax and tmax after the first and fourth doses of aripiprazole 2M LAI 960 mg,

AUC0-56 and C56 after the first dose of aripiprazole 2M LAI 960 mg,

AUC0-28 and AUC29-56 after the fourth dose of aripiprazole 2M LAI 960 mg,

PTF% after the fourth dose of aripiprazole 2M LAI 960 mg (for aripiprazole 
only),

Cmax and tmax after the first, seventh and eighth doses of aripiprazole IM depot 400 
mg,

AUC0-28 and C28 after the first dose of aripiprazole IM depot 400 mg,

PTF% after the eighth dose of aripiprazole IM depot 400 mg (for aripiprazole 
only),
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
25


Protocol 031-201-00181
Statistical Analysis Plan
26 of 36
Version 2.0

C7 and C14 after the first injection of aripiprazole 2M LAI 960 mg and 
aripiprazole IM depot 400 mg from subjects enrolled to the robust sampling 
schedule.
Values for Cmax, AUC, tmax, and PTF% will be summarized based on samples from 
subjects enrolled to the robust sampling schedule; whereas C28 and C56 will be 
summarized based on samples from subjects enrolled to the robust and sparse sampling 
schedules.
 
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26


Protocol 031-201-00181
Statistical Analysis Plan
27 of 36
Version 2.0
Appendix 1
Criteria for Identifying Vital Sign Values 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
Orthostatic Hypotension
≥ 20 mmHg decrease in systolic blood 
pressure and a ≥ 25 bpm increase in 
heart rate from supine to 
sitting/standing
Not Applicable
Weight
-
7% increase
7% decrease
Temperature
37.8°C
1.1°C increase
a In 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.
b As 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).
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
27


Protocol 031-201-00181
Statistical Analysis Plan
28 of 36
Version 2.0
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
3 x upper limit of normal (ULN)
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
LDH
3 x ULN
BUN
30 mg/dL
Creatinine
2.0 mg/dL
Uric acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
CPK
3 x ULN
Prolactin
> ULN
Hematology
Hematocrit
Men
37 % and decrease of 3 percentage points from baseline
Women
32 % and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
White blood count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
1,500/mm3
Platelet count
75,000/mm3 or 700,000/mm3
Urinalysis a
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
Potassium
3.0 mEq/L or 5.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
115 mg/dL 
Non-fasting
200 mg/dL
Total cholesterol, fasting
240 mg/dL 
LDL cholesterol, fasting
160 mg/dL 
HDL cholesterol, fasting
30 mg/dL 
Triglycerides, fasting
Men
160 mg/dL
Women
120 mg/dL
a As 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).
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
28


Protocol 031-201-00181
Statistical Analysis Plan
29 of 36
Version 2.0
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/T Morphological
Myocardial ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTc > =450 msec 
> =10% increase
a In 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.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, or 
other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
29
















This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: P03120100181_Statistical Analysis Plan
Document Number: 
Document Version: 3.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
17-Jul-2020
13:48:50
Biostatistics Approval
17-Jul-2020
03:09:42
Clinical Pharmacology
Approval
20-Jul-2020
15:06:29
Clinical Study Report 031-201-00181
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
37