Conditions: Healthy Male Adults
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 74
Healthy volunteers: yes

Brief summary:
To investigate the bioequivalence of aripiprazole between administration of one ASC-01 tablet (aripiprazole 3 mg/sertraline 100 mg combination drug) and concomitant administration of one aripiprazole 3-mg tablet and two sertraline 50-mg tablets (Cohort 1).

To investigate food effect on plasma pharmacokinetics of aripiprazole and sertraline by single oral administration of ASC-01 under a fasting or fed condition (Cohort 2).

Detailed description:

Arms:
arm 1: At Day 1 in Period I, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered after 10 or more hours of fasting.

At Day 1 in Period II, Aripiprazole 3 mg and sertraline 100 mg will be administered after 10 or more hours of fasting. arm 2: At Day 1 in Period I, Aripiprazole 3 mg and sertraline 100 mg will be administered after 10 or more hours of fasting.

At Day 1 in Period II, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered after 10 or more hours of fasting. arm 3: At Day 1 in Period I, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered after 10 or more hours of fasting.

At Day 1 in Period II, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered 30 minutes after the start of breakfast. arm 4: At Day 1 in Period I, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered 30 minutes after the start of breakfast.

At Day 1 in Period II, ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) will be administered after 10 or more hours of fasting.

Interventions: intervention 1: ASC-01 intervention 2: Aripiprazole and sertraline
Intervention descriptions: intervention 1: Aripiprazole 3 mg/sertraline 100 mg combination drug intervention 2: Aripiprazole 3 mg and sertraline 100 mg

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Single-center, Open-label, Randomized, Two-treatment, Two-period Crossover Trial 
to Investigate Bioequivalence Between Single Administration of ASC-01 
(Aripiprazole/Sertraline Combination Drug) and Concomitant Single Administration 
of Aripiprazole and Sertraline and Food Effect on Pharmacokinetics of ASC-01 in 
Healthy Male Adults 
 
 
 
 
NCT Number: NCT03342963 
PRT NO.: 031-102-00214 
Version Date: 23 October 2017 (Version 1.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
ASC-01
CLINICAL PROTOCOL
A Single-center, Open-label, Randomized, Two-treatment, Two-period Crossover Trial to
Investigate Bioequivalence Between Single Administration of ASC-01
(Aripiprazole/Sertraline Combination Drug) and Concomitant Single Administration of
Aripiprazole and Sertraline and Food Effect on Pharmacokinetics of ASC-01 in Healthy
Male Adults
Protocol No.: 031-102-00214
CONFIDENTIAL PROPRIETARY INFORMATION
Clinical Development Phase:
I
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event Contact
PV Operation Office, Pharmacovigilance
Department, Otsuka Pharmaceutical Co.,
Ltd.
Phone: 3-2-27, Otedori, Chuo-ku, Osaka
541-0021
Email: IRE_031-102-00214@otsuka.jp
Release Date:
23 Oct 2017
Version No.:
1.0


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Synopsis
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product: ASC-01
(Aripiprazole/Sertraline Combination Drug)
Protocol No.: 031-102-00214
Protocol Title:
A Single-center, Open-label, Randomized, Two-treatment, Two-period
Crossover Trial to Investigate Bioequivalence Between Single Administration
of ASC-01 (Aripiprazole/Sertraline Combination Drug) and Concomitant
Single Administration of Aripiprazole and Sertraline and Food Effect on
Pharmacokinetics of ASC-01 in Healthy Male Adults
Clinical Phase:
Phase 1
Indication:
Depression/depressed state (Administration should be limited to patients who
showed an inadequate response to existing antidepressant therapy)
Objectives:
[Cohort 1: Bioequivalence] To investigate bioequivalence for aripiprazole
between administration of one ASC-01 tablet and concomitant administration
of one aripiprazole 3-mg tablet and two sertraline 50-mg tablets
[Cohort 2: Food effect] To investigate the effect of food on the plasma
pharmacokinetics of aripiprazole and sertraline following single oral
administration of ASC-01 under a fasting or fed condition
Trial Design:
A single-center, open-label, randomized, two-treatment, two-period crossover
trial will be conducted in two cohorts.
[Cohort 1: Bioequivalence]
Group
receiving the
following
administration
first
Period I
Period II
ASC-01
(A-1)
Single administration of
ASC-01
Concomitant single
administration of aripiprazole
and sertraline
Concomitant
administration
(B-1)
Concomitant single
administration of
aripiprazole and sertraline
Single administration of ASC-
01
[Cohort 2: Food effect]
Group
receiving the
following
administration
first
Period I
Period II
Fasting
(A-2)
Administration of ASC-01
under a fasting condition
Administration of ASC-01
under a fed condition
Fed
(B-2)
Administration of ASC-01
under a fed condition
Administration of ASC-01
under a fasting condition
Note) There will be a wash-out period of at least 35 days between each period.


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Trial Population:
Fifty-four and 20 healthy male adult subjects aged 20 to 40 years, inclusive,
will be enrolled in Cohort 1 (bioequivalence) and Cohort 2 (food effect),
respectively.
Key
Inclusion/Exclusion
Criteria:
[Common to both cohorts]
Inclusion Criteria
1)
Healthy male subjects aged 20 to 40 years, inclusive, at time of informed
consent
2)
Subjects with a body mass index (BMI = body weight [kg]/height [m]2)
of ≥18.5 and <25.0 kg/m2 at screening
3)
Subjects capable of providing written, informed consent prior to
initiation of any trial-related procedures, and, in the opinion of the
investigator or subinvestigator, of complying with all requirements of
the trial
Key Exclusion Criteria
1)
Subjects who have clinically significant abnormal medical history or
abnormalities in physical findings at screening that in the investigator’s
or subinvestigator’s opinion or in the sponsor’s opinion may place the
subject at risk or interfere with outcome variables, including drug
absorption, distribution, metabolism, and excretion
2)
Subjects who have a supine blood pressure of >140/90 mmHg or
<100/50 mmHg after ≥3 minutes of rest and an orthostatic blood 
pressure decline (difference between sitting and standing systolic blood
pressure) of ≥20 mmHg at screening (the sponsor may accept such 
subjects exceptionally only if the findings are considered clinically
insignificant)
3)
Subjects who have a supine pulse rate outside the range of 40 to 90 bpm
after ≥3 minutes of rest at screening (the sponsor may accept such 
subjects exceptionally only if the findings are considered clinically
insignificant)
4)
Subjects who have a history or complication of hepatitis or acquired
immunodeficiency syndrome or who have tested positive for hepatitis B
surface antigen, hepatitis C virus antibody, or HIV antigen or antibody
5)
Subjects who are judged by the investigator or subinvestigator to be
ineligible to participate in the trial due to a history of serious psychiatric


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disease
6)
Subjects who have a history of clinically significant drug or alcohol
abuse prior to screening examination
7)
Subjects who test positive in a breath alcohol test or a urine drug test for
substance abuse performed at the visit for screening examination or
hospitalization at the trial site
8)
Subjects who are sexually active and who are unable or unwilling to
practice two kinds of contraception or remain abstinent during the trial
and for 30 days after final investigational medicinal product (IMP)
administration or who plan to provide sperm during the period from the
visit for screening examination until 30 days after final IMP
administration
9)
Subjects who have a history of significant drug allergy
10) Subjects who have a history of significant bleeding or hemorrhagic
diathesis
11) Subjects who have provided >200 mL of blood or >600 mL of plasma
within 30 days prior to the first IMP administration
12) Subjects who have undergone blood collection (blood donation, etc.) of
>1200 mL in total within 1 year prior to the first IMP administration
13) Subjects who have difficulty with blood collection
14) Subjects who have received any IMP within 120 days prior to the first
IMP administration
15) Subjects who have smoked or been routinely exposed to secondhand
smoke within 2 months prior to screening or who tested positive in urine
cotinine test performed at the visit for screening or hospitalization at the
trial site
16) Subjects who have consumed food or drink containing St. John’s Wort
within 14 days prior to IMP administration in each treatment period or
who have consumed grapefruit, Seville orange, star fruit, or any food or
drink containing these items within 7 days prior to IMP administration in
each treatment period. Subjects who have consumed alcohol within 3
days prior to IMP administration in each treatment period
17) Subjects who have taken any prescription or nonprescription medicines,
Chinese medicines, or vitamins within 14 days or any antibiotics within
30 days prior to the first IMP administration


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18) Subjects who have undergone major gastrointestinal surgery (other than
an appendectomy)
19) Subjects who have been occupationally exposed to an insecticide or
organic solvent within 30 days prior to screening
20) Subjects who have a family history of long QT syndrome
21) Subjects who are visiting another hospital or department or who plan to
visit another hospital or department during the trial period
22) Subjects with no fixed address
23) Subjects determined by the investigator or subinvestigator to be
inappropriate for participation in this trial
Trial Site:
Fukuoka Mirai Hospital
Investigational
Medicinal Products,
Dose, Dosage
Regimen, Treatment
Duration, Formulation,
Mode of
Administration:
[IMP: ASC-01 Combination Tablets]
Cohort
Active Ingredient
(Content Per Tablet)
Single
Dose
Dose Regimen
1
Aripiprazole 3
mg/sertraline 100 mg
1 tablet
To be administered with approximately
150 mL of water after subjects have
fasted for at least 10 hours. (Single oral
administration under a fasting
condition)
2
To be administered with approximately
150 mL of water either after subjects
have fasted for at least 10 hours or at
30 minutes after the start of breakfast
(Single oral administration under a
fasting or fed condition)
[Reference formulation, etc: Aripiprazole tablets, sertraline tablets]
Cohort
Active Ingredient
(Content Per Tablet)
Single
Dose
Dose Regimen
1
Aripiprazole 3-mg tablet 1 tablet To be administered with
approximately 150 mL of water after
subjects have fasted for at least 10
hours (single oral administration under
a fasting condition)
Sertraline 50-mg tablet
Two
tablets


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Test Items:
[Common to both cohorts]
Pharmacokinetics: Blood collection for plasma drug concentration
measurement
Safety: Adverse events, clinical laboratory tests, physical examination, vital
signs (blood pressure, pulse rate, and temperature), 12-lead
electrocardiography, body weight, Columbia-Suicide Severity Rating Scale (C-
SSRS), and concomitant medications and therapies
Screening and others: Medical history, drug history, breath alcohol test, urine
drug test, immunological test, etc.
Endpoints:
Primary:
[Cohort 1: Bioequivalence]
Cmax and AUC168h of aripiprazole
[Cohort 2: Food effect]
Cmax, AUCt, AUC∞, and AUC168h of aripiprazole and sertraline
Secondary:
[Cohort 1: Bioequivalence]
1)
Plasma concentration of aripiprazole
2)
Pharmacokinetic parameters of aripiprazole
3)
Ratios of the Cmax, AUCt, AUC∞, AUC168h, MRT∞, and λz of
aripiprazole following administration of ASC-01 to those following
concomitant administration of aripiprazole and sertraline, and difference
in the tmax of aripiprazole between administration of ASC-01 and
concomitant administration of aripiprazole and sertraline (tmax for ASC-
01 administration minus tmax for concomitant administration)
[Cohort 2: Food effect]
1)
Plasma concentrations of aripiprazole and sertraline
2)
Pharmacokinetic parameters of aripiprazole and sertraline
3)
Ratios of the Cmax, AUCt, AUC∞, AUC168h, tmax, t1/2,z, and CL/F of
aripiprazole and sertraline for administration under a fed condition to
those for administration under a fasting condition, and difference in the
tmax of aripiprazole and sertraline between administration under a fed
condition and administration under a fasting condition (tmax for a fasting
condition minus tmax for a fed condition)
Safety (common to both cohorts)
Adverse events, clinical laboratory tests, physical examination, vital signs


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(blood pressure, pulse rate, and temperature), 12-lead electrocardiography,
body weight, and C-SSRS
Statistical Methods:
Statistical Methods for Primary Endpoints
In Cohort 1 (bioequivalence), analysis of variance will be performed on log-
converted (natural logarithm) values for the Cmax and AUC168h of aripiprazole-
using group (group receiving administration of ASC-01 first or group receiving
concomitant administration of aripiprazole and sertraline first), treatment (ASC-
01 or concomitant administration of aripiprazole and sertraline), subjects within
group, and treatment period as factors. The 90% confidence intervals for the
differences in the mean Cmax and AUC168h of aripiprazole between ASC-01
administration and concomitant administration of aripiprazole and sertraline will
be calculated. If the 90% confidence intervals are within the range of ln(0.8) to
ln(1.25), single administration of ASC-01 and single concomitant administration
of aripiprazole and sertraline will be judged to be bioequivalent for aripiprazole.
If an add-on subject study is conducted, bioequivalence will be assessed based
on the combined results of the trial and the add-on subject study using the same
criteria.
In Cohort 2 (food effect), analysis of variance will be performed on log-
converted (natural logarithm) values for the Cmax, AUCt, AUC∞, and AUC168h
of aripiprazole and sertraline using group (group receiving ASC-01 under a
fasting condition first or group receiving ASC-01 under a fed condition first),
treatment (administration under a fasting condition or under a fed condition),
subjects within group, and treatment period as factors. The 90% confidence
intervals for the differences in the mean Cmax, AUCt, AUC∞, and AUC168h of
aripiprazole and sertraline between administration under a fasting condition and
administration under a fed condition will be obtained.
If there are any subjects in each cohort from whom evaluable parameters cannot
be obtained in both Periods I and II, sensitivity analysis including those
subjects will also be performed.
Rationale for the Target Sample Size
For Cohort 1 (bioequivalence), the sample size was determined by the method
of Diletti as the number of subjects required for the 90% confidence intervals
for the differences in the log-converted mean Cmax and AUC168h of aripiprazole
between single administration of ASC-01 and concomitant single
administration of aripiprazole and sertraline to be within the acceptable range


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for bioequivalence of ln(0.8) to ln(1.25) based on the Guideline for
Bioequivalence Studies of Generic Products.
In the results of a pharmacokinetic trial conducted to examine the
bioavailability of ASC-01 (031-11-004), the ratios of the geometric mean Cmax
and AUC168h of aripiprazole were respectively 1.12 and 1.05 and the within-
subject variances were 0.029 and 0.006. The proportion of subjects excluded
from the pharmacokinetic analysis due to vomiting or withdrawal was
approximately 40%. Assuming the ratio of the geometric mean Cmax of
aripiprazole between administration of ASC-01 and concomitant administration
of aripiprazole and sertraline and the within-subject variance to be,
respectively, 1.1 and 0.029, the number of subjects required to ensure a
statistical power of 90% or higher is 16 per group (32 subjects in total).
Assuming a 40% rate of exclusion from analysis due to withdrawal or
vomiting, the sample size for Cohort 1 is set at 27 subjects per group (54
subjects in total).
For Cohort 2 (food effect), referring to FDA guidance, the sample size required
for the analysis of food effect on the pharmacokinetics of ASC-01 is 6 subjects
per group (12 subjects in total). In consideration of the possibility of exclusion
from analysis due to withdrawal or vomiting, the sample size for Cohort 2 is set
at 10 subjects per group (20 subjects in total).
Trial Duration:
Trial Duration: November 2017 to July 2018
Duration of trial participation for each subject: Up to 64 days with a wash-out
period of 35 days
([Common to both cohorts] Screening [21 to 2 days before the start of
administration], 8 days in Period I [5 days of hospitalization followed by 2
outpatient visits], 35 days or longer wash-out period, 8 days in Period II [5 days
of hospitalization followed by 2 outpatient visits])


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Table of Contents
Synopsis.......................................................................................................2
Table of Contents........................................................................................9
List of In-text Tables.................................................................................15
List of In-text Figures...............................................................................16
List of Appendices.....................................................................................17
List of Abbreviations ................................................................................18
1
Introduction.................................................................................19
1.1
Nonclinical Studies.........................................................................................20
1.2
Clinical Studies...............................................................................................20
1.3
Risks and Benefits ..........................................................................................20
2
Appropriateness and Objectives of the Trial.............................21
2.1
Trial Rationale ................................................................................................21
2.1.1
Bioequivalence (Cohort 1)..........................................................................21
2.1.2
Food Effect (Cohort 2)................................................................................22
2.2
Dosing Rationale and Regimen ......................................................................22
2.2.1
Dose Regimen.............................................................................................22
2.2.2
Dosage.........................................................................................................23
2.3
Trial Objectives ..............................................................................................24
2.3.1
Cohort 1.......................................................................................................24
2.3.2
Cohort 2.......................................................................................................24
3
Trial Design.................................................................................24
3.1
Type/Design of Trial.......................................................................................24
3.1.1
Cohort 1.......................................................................................................25
3.1.2
Cohort 2.......................................................................................................26
3.2
Method of Administration ..............................................................................27
3.2.1
Cohort 1.......................................................................................................27
3.2.1.1
ASC-01 Tablets .......................................................................................27
3.2.1.2
Aripiprazole Tablets and Sertraline Tablets............................................27
3.2.2
Cohort 2.......................................................................................................27
3.2.2.1
Administration under a fasting condition................................................27


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3.2.2.2
Administration under a fed condition......................................................27
3.3
Trial Population ..............................................................................................27
3.3.1
Number of Subjects and Population............................................................27
3.3.2
Issuance of Subject Identification Number.................................................28
3.4
Eligibility Criteria...........................................................................................28
3.4.1
Informed Consent........................................................................................28
3.4.2
Inclusion Criteria.........................................................................................29
3.4.3
Exclusion Criteria........................................................................................29
3.5
Endpoints........................................................................................................33
3.5.1
Cohort 1.......................................................................................................33
3.5.1.1
Primary Endpoint.....................................................................................33
3.5.1.2
Secondary Endpoints...............................................................................33
3.5.2
Cohort 2.......................................................................................................33
3.5.2.1
Primary Endpoint.....................................................................................33
3.5.2.2
Secondary Endpoints...............................................................................33
3.5.3
Safety (Common to Both Cohorts) .............................................................33
3.6
Measures to Minimize/Avoid Bias.................................................................34
3.7
Study Methods................................................................................................34
3.7.1
General Procedures During Hospitalization (Common to Both
Cohorts).......................................................................................................36
3.7.2
Meal Requirements .....................................................................................37
3.7.2.1
Cohort 1...................................................................................................37
3.7.2.2
Cohort 2...................................................................................................37
3.7.3
Schedule of Assessments ............................................................................38
3.7.3.1
Screening Examination (Common to Both Cohorts)...............................38
3.7.3.2
Hospitalization (day before investigational medicinal product
administration in each period, common to both cohorts)........................38
3.7.3.3
Day of Investigational Medicinal Product Administration (Day 1 of
Each Period) ............................................................................................39
3.7.3.3.1
Enrollment of Subjects and Assignment of Investigational
Medicinal Product to Subjects (Period I Only, Common to Both
Cohorts)................................................................................................39
3.7.3.3.2
Within 3 Hours Before Investigational Medicinal Product
Administration (Common to Both Cohorts)........................................39


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3.7.3.3.3
Investigational Medicinal Product Administration..............................40
3.7.3.3.3.1
Cohort 1 ...............................................................................................40
3.7.3.3.3.2
Cohort 2 ...............................................................................................40
3.7.3.3.4
After Investigational Medicinal Product Administration
(Common to Both Cohorts) .................................................................40
3.7.3.4
Day 2 of Each Period (Common to Both Cohorts)..................................41
3.7.3.5
Day 3 of Each Period (Common to Both Cohorts)..................................41
3.7.3.6
Day 4 of Each Period (Common to Both Cohorts)..................................42
3.7.3.7
Discharge (Day 5 of Each Period)/Discontinuation (Common to
Both Cohorts) ..........................................................................................42
3.7.3.8
Outpatient Visits (Days 7 and 8 of Each Period, Common to Both
Cohorts) ...................................................................................................42
3.7.3.8.1
Day 7 of Each Period ...........................................................................42
3.7.3.8.2
Day 8 of Each Period ...........................................................................43
3.7.4
Prior and Concomitant Medications (Common to Both Cohorts) ..............43
3.7.5
Safety Assessments (Common to Both Cohorts)........................................44
3.7.5.1
Adverse Events........................................................................................44
3.7.5.2
Clinical Laboratory Assessments ............................................................44
3.7.5.2.1
Clinical Laboratory Assessments.........................................................44
3.7.5.2.2
Immunological test...............................................................................44
3.7.5.2.3
Breath Alcohol Test, Urine Drug Test, and Urine Cotinine Test ........45
3.7.5.3
Physical Examination and Vital Signs ....................................................45
3.7.5.3.1
Physical Examination...........................................................................45
3.7.5.3.2
Vital Signs (Blood Pressure, Pulse Rate, and Temperature) ...............45
3.7.5.4
Electrocardiogram ...................................................................................46
3.7.5.5
Body Weight............................................................................................46
3.7.5.6
Columbia-Suicide Severity Rating Scale (C-SSRS) ...............................46
3.7.6
Pharmacokinetic Assessments ....................................................................47
3.7.6.1
Pharmacokinetic Assessments.................................................................47
3.7.6.2
Timing of Blood Collection.....................................................................47
3.7.6.3
Pharmacokinetic Plasma Samples ...........................................................47
3.7.6.4
Pharmacokinetic Urine Samples..............................................................47
3.7.7
Genetic Testing ...........................................................................................47


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3.7.8
Future Biospecimen Research Samples ......................................................47
3.7.9
End of Trial .................................................................................................47
3.8
Discontinuation Criteria and Procedures........................................................48
3.8.1
Entire Trial ..................................................................................................48
3.8.2
Discontinuation at Individual Sites.............................................................48
3.8.3
Individual Subject Discontinuation.............................................................48
3.8.3.1
Treatment Discontinuation......................................................................48
3.8.3.2
Documenting Reasons for Treatment Interruption or
Discontinuation........................................................................................48
3.8.3.3
Withdrawal of Consent............................................................................49
3.9
Screen Failures................................................................................................49
3.10
Definition of Completed Subjects ..................................................................50
3.11
Definition of Subjects Lost to Follow-up .......................................................50
3.12
Subject Compliance........................................................................................50
3.13
Protocol Deviations ........................................................................................50
4
Restrictions (Common to Both Cohorts) ...................................51
4.1
Prohibited Medications or Therapies..............................................................51
4.2
Other Restrictions...........................................................................................51
4.2.1
Hospitalization of Subjects .........................................................................51
4.2.2
Restriction of Food Intake and Prohibition of Blood Donation..................51
4.2.3
Posture and Behavior ..................................................................................52
5
Adverse Event Reporting............................................................52
5.1
Definitions ......................................................................................................52
5.2
Eliciting and Reporting Adverse Events.........................................................54
5.3
Immediately Reportable Events (IRE)............................................................55
5.4
Potential Serious Hepatotoxicity ....................................................................55
5.5
Pregnancy .......................................................................................................55
5.6
Procedure for Breaking the Blind...................................................................57
5.7
Follow-up of Adverse Events.........................................................................57
5.7.1
Follow-up of Nonserious Adverse Events ..................................................57
5.7.2
Follow-up of Serious Adverse Events.........................................................57
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring After
the End of the Trial (Last Date of Observation) .........................................58


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6
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic
Analysis........................................................................................58
6.1
Pharmacokinetic Analysis Methods ...............................................................58
6.1.1
Cohort 1.......................................................................................................58
6.1.2
Cohort 2.......................................................................................................58
6.2
Pharmacodynamic Analysis Methods.............................................................59
6.3
Pharmacokinetic/Pharmacodynamic Analysis Methods.................................59
6.4
Pharmacogenomic Analysis Methods.............................................................59
7
Statistical Analyses......................................................................59
7.1
Sample Size ....................................................................................................59
7.2
Datasets for Analysis ......................................................................................60
7.2.1
Pharmacokinetic Analysis Set.....................................................................60
7.2.2
Bioequivalence Analysis Set.......................................................................60
7.2.3
Food Effect Analysis Set.............................................................................60
7.2.4
Safety Analysis Set .....................................................................................60
7.3
Handling of Missing Data...............................................................................60
7.4
Primary and Secondary Endpoint Analysis....................................................60
7.4.1
Primary Endpoint Analysis .........................................................................60
7.4.2
Secondary Endpoint Analysis .....................................................................61
7.5
Analysis of Demographic and Other Baseline Characteristics.......................61
7.6
Safety Analysis ...............................................................................................61
7.6.1
Adverse Events............................................................................................61
7.6.2
Clinical Laboratory Data.............................................................................62
7.6.3
Physical Examination and Vital Signs Data................................................62
7.6.4
Electrocardiogram Data ..............................................................................62
7.6.5
Other Safety Data........................................................................................62
7.6.5.1
Body Weight............................................................................................62
7.6.5.2
Columbia-Suicide Severity Rating Scale (C-SSRS) ...............................62
7.7
Pharmacodynamic Analysis............................................................................62
7.8
Decision to Conduct Add-on Subject Study...................................................62
8
Management of Investigational Medicinal Product..................63
8.1
Packaging and Labeling..................................................................................63


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8.2
Storage ............................................................................................................63
8.3
Accountability.................................................................................................64
8.4
Returns and Destruction .................................................................................64
8.5
Reporting of Product Quality Complaints ......................................................64
8.5.1
Eliciting and Reporting Product Quality Complaints .................................64
8.5.2
Information Required at the Time of Reporting Product Quality
Complaints ..................................................................................................65
8.5.3
Procedure for Returning Investigational Medicinal Product If There
Is a Product Quality Complaint...................................................................65
8.5.4
Assessment/Evaluation ...............................................................................65
9
Records Management .................................................................65
9.1
Source Documents..........................................................................................65
9.2
Data Collection...............................................................................................66
9.3
File Management at the Trial Site ..................................................................67
9.4
Records Retention at the Trial Site.................................................................67
10
Quality Control and Quality Assurance ....................................68
10.1
Monitoring......................................................................................................68
10.2
Auditing..........................................................................................................68
10.3
Protocol Deviations ........................................................................................68
11
Ethics and Responsibility............................................................69
12
Confidentiality.............................................................................70
13
Protocol Amendments.................................................................70
14
Publication Authorship Requirements ......................................71
15
References....................................................................................71


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List of In-text Tables
Table 3.4.2-1
Inclusion Criteria (Common to Both Cohorts) ........................ 29
Table 3.4.3-1
Exclusion Criteria (Common to Both Cohorts) ....................... 30
Table 3.7-1
Schedule of Assessments (Common to Both Cohorts)................. 35
Table 3.7-2
Acceptable Time Windows for Observations, Examinations,
and Evaluations After Investigational Medicinal Product
Administration (Common to Both Cohorts)................................. 36
Table 3.7.5.2-1
Clinical Laboratory Assessments.................................................. 44


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic................................................................. 25


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List of Appendices
Appendix 1
Bioanalytical Sample Handling and Shipment ................................ 73
Appendix 2
Baseline Columbia-Suicide Severity Rating Scale .......................... 74
Appendix 3
Since Last Visit Columbia-Suicide Severity Rating Scale .............. 77


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List of Abbreviations
Abbreviations
Definitions
5-HT1A
5-hydroxytryptamine 1A
5-HT2A
5-hydroxytryptamine 2A
AE
Adverse event
AUC168h
Area under the concentration-time curve from 0 to 168 hours
AUC∞
Area under the concentration-time curve from time zero to infinity
AUCt
Area under the concentration-time curve calculated to the last observable
concentration at time t
CL/F
Apparent clearance of drug from plasma after extravascular administration
Cmax
Maximum (peak) plasma concentration of the drug
CYP
Cytochrome P450
C-SSRS
Columbia-suicide severity rating scale
FDA
Food and Drug Administration
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional review board
IRE
Immediately reportable event
MRT∞
Mean residence time from time 0 to infinity
PQC
Product quality complaint
λz
Terminal elimination rate constant
SNRI
Serotonin-noradrenaline reuptake inhibitor
SSRI
Selective serotonin reuptake inhibitor
TEAE
Treatment-emergent adverse event
t1/2,z
Terminal-phase elimination half-life
tmax
Time to maximum (peak) plasma concentration


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1
Introduction
ASC-01 is a combination drug of aripiprazole and sertraline.
Aripiprazole, an antipsychotic drug developed by Otsuka Pharmaceutical Co., Ltd., is
primarily pharmacologically characterized by dopamine D2 receptor partial agonist
action; additionally, it induces serotonin 5-HT1A receptor partial agonist action and
serotonin 5-HT2A receptor antagonist action. Aripiprazole was approved for the treatment
of schizophrenia in the United States in 2002 and has been widely used in the European
Union and Asian countries including Japan, etc.1 As for depression/depressed state, the
first approval for the indication of "Adjunctive Treatment of Major Depressive Disorder"
was obtained in November 2007 in the United States,2 and the approval for the indication
of "depression, depressed state (Administration should be limited to patients who showed
an inadequate response to existing antidepressant therapy)" was obtained in June 2013 in
Japan.
Sertraline has been marketed in Japan for the treatment of "depression/depressive state"
and "panic disorder" since July 2006.3 It has been approved in 110 countries around the
world and used for more than 10 years.4 Moreover, relative to other selective serotonin
reuptake inhibitors (SSRIs), sertraline is characterized by a low risk of drug interactions
due to its limited effect on hepatic metabolic enzymes (CYPs).5
The first-line treatment for MDD is the use of antidepressants. The drugs mainly used are
SSRIs, such as paroxetine, fluvoxamine, sertraline, and escitalopram, and SNRIs, such as
milnacipran, duloxetine, and venlafaxine. However, remission rates with SSRIs and
SNRIs are only 30% to 40%.6 Unless remission is achieved, social dysfunction continues
and causes problems, such as unemployment, school dropout, or divorce.7
When response to a first-line drug is inadequate, various guidelines recommend the
combination of the first-line drug and an atypical antipsychotic as the next treatment
options.8,9,10 The Japanese Society of Mood Disorders Treatment Guideline lists
aripiprazole, quetiapine, olanzapine, and risperidone as atypical antipsychotics to be used
in combination with first-line antidepressant augmentation therapy; however, in Japan
only aripiprazole is approved as a therapeutic drug for "depression/depressive state."
For patients in whom the combination of a first-line drug and an atypical antipsychotic to
be used, a combination drug of aripiprazole and a first-line drug would require fewer
number of tablets to be taken than concomitant administration, providing increased
convenience for patients, and it was therefore decided to develop this combination drug.
Although this combination drug is not intended for patients with central disease, it has


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been reported that a decrease in the number of tablets to be taken can be expected to
improve medication adherence.11,12
1.1
Nonclinical Studies
Detailed information on relevant data from nonclinical studies with aripiprazole and
sertraline, including pharmacokinetic and toxicity studies in animals, is presented in the
Investigator’s Brochure.
1.2
Clinical Studies
In a clinical pharmacology trial in which pharmacokinetics after single administration of
ASC-01 tablet (aripiprazole 3 mg/sertraline 100 mg combination) and single concomitant
administration of one aripiprazole 3-mg tablet and two sertraline 50-mg tablets was
investigated in healthy male adults (031-11-004), the pharmacokinetics of aripiprazole
and sertraline after administration of ASC-01 and that after concomitant administration of
aripiprazole and sertraline were similar, with no major safety issues identified.
In a double-blind trial in patients with major depressive disorder (031-12-005), ASC-01
showed a statistically significant improvement in the mean change in MADRS total
score, the primary endpoint, compared with sertraline, indicating its efficacy in patients
with major depressive disorder who had an inadequate response to sertraline
monotherapy. The results of the secondary and other endpoints also supported the
efficacy of ASC-01.
Most adverse events in the ASC-01 group were mild or moderate in severity. The
incidence of serious adverse events and adverse events leading to discontinuation of the
study drug was not significantly different between the ASC-01 group and the sertraline
group. For other safety endpoints, there were no safety concerns in the ASC-01 group
compared with the sertraline group. There were no notable safety issues and ASC-01
treatment was well tolerated.
The results of this study suggested that ASC-01 is useful for patients with major
depressive disorder who have had an inadequate response to sertraline monotherapy.
1.3
Risks and Benefits
In a pharmacokinetic trial to investigate the bioavailability of ASC-01 in healthy male
adults (031-11-004), gastrointestinal disorders were observed in half of the subjects after
administration of ASC-01 and after concomitant administration of aripiprazole and
sertraline. These include nausea (48.0%, 12/25), vomiting (32.0%, 8/25), and diarrhoea
(4.0%, 1/25) after administration of ASC-01 and nausea (50.0%, 13/26) and vomiting
(30.8%, 8/26) after concomitant administration of aripiprazole and sertraline. In addition


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to the frequent gastrointestinal adverse events described above, other adverse events
occurring in two or more subjects in either administration group were decreased appetite
(12.0%, 3/25) and dizziness (8.0%, 2/25) after administration of ASC-01 and decreased
appetite (7.7%, 2/26) after concomitant administration of aripiprazole and sertraline, and
all of which were consistent with adverse drug reactions reported for commercially
available aripiprazole and sertraline.
Among the adverse events occurring at an incidence of ≥5% in the ASC-01 group in the 
double-blind trial in patients with major depressive disorder (031-12-005), akathisia was
the only one that occurred at an incidence of ≥2 times the incidence in the sertraline 
group. The incidence was 12.9% (27/209) in the ASC-01 group and 3.4% (7/203) in the
sertraline group.
Detailed information on ASC-01, including the risks and adverse reactions, is presented
in the Investigator's Brochure.
Since this trial was conducted in healthy subjects, there is no benefit to subjects from
participation in the trial.
2
Appropriateness and Objectives of the Trial
2.1
Trial Rationale
2.1.1
Bioequivalence (Cohort 1)
Clinical development of ASC-01 was begun in order to provide a treatment option for
patients with major depressive disorder who do not respond completely to sertraline
monotherapy and to contribute to improved convenience with an expected increase in
compliance by reducing the number of tablets that patients are required to take. A
pharmacokinetic trial (031-11-004) was conducted as a bioavailability trial to confirm the
appropriateness of this combination drug formulation by comparing pharmacokinetics
between single administration of ASC-01 and concomitant single administration of
aripiprazole and sertraline in healthy male adults.
Results showed the pharmacokinetic parameters of both aripiprazole and sertraline to be
similar between administration of ASC-01 and concomitant administration of the two
drugs. Furthermore, the results for sertraline met the bioequivalence criteria specified in
“Partial Revisions of the Guideline for Bioequivalence Studies of Generic Products”
(Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated
29 Feb 2012)13 (hereinafter referred to as the BE Guideline).
In view of circumstances that ASC-01 will be interchangeably used with concomitant
administration of aripiprazole tablet and sertraline tablet in the clinical setting, it was


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considered that the bioequivalence of aripiprazole should also be evaluated in accordance
with the BE Guideline.
This trial is designed in accordance with the BE Guideline to investigate bioequivalence
between single oral administration of one ASC-01 tablet and concomitant single oral
administration of one aripiprazole 3-mg tablet and two sertraline 50-mg tablets in a
crossover manner in healthy male adults.
Bioequivalence will be evaluated only for aripiprazole.
2.1.2
Food Effect (Cohort 2)
As “Clinical Pharmacokinetic Studies on Drugs” (Notification No. 796 of the Evaluation
and Licensing Division, PMSB, dated 01 Jun 2001) and “Methods of Studying Drug
Interactions” (Notification No. 813 of the Evaluation and Licensing Division, PMSB,
dated June 4, 2001) state that it is necessary to examine the effect of food on
gastrointestinal absorption using the final formulation for any oral formulation, it was
decided to further conduct a food effect trial for ASC-01.
Since no guidelines for the method of studying food effect have been issued in Japan, the
guidance for food effect studies issued by the FDA (“Guidance for Industry Food-Effect
Bioavailability and Fed Bioequivalence Studies”)14 and “Methods of Studying Drug
Interactions” were used as references, and to reduce the effect of variation among trial
subjects, a crossover method was selected from among the trial designs presented in those
documents.
2.2
Dosing Rationale and Regimen
2.2.1
Dose Regimen
[Cohort 1]
As the BE Guideline states that drugs are usually given to subjects with 100 to 200 mL
water (normally 150 mL) after fasting for more than 10 hours, the investigational
medicinal product (IMP) will be administered with approximately 150 mL of water after
subjects have fasted for at least 10 hours.
[Cohort 2]
For administration under a fasting condition, the IMP will be administered after subjects
have fasted for at least 10 hours as per the dose regimen in the BE Guideline as above.
For administration under a fed condition, the IMP will be administered with
approximately 150 mL of water at 30 minutes after the start of breakfast in reference to
the FDA Guidance.14


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2.2.2
Dosage
[Cohort 1]
The BE Guideline states that one dose unit or a clinical usual dose should generally be
employed.
One dose unit of aripiprazole in the currently approved dosage and administration for
depression/depressed condition is 3 mg, and the dose should not exceed 15 mg per day.
As the maximum dose for healthy adults was set at 6 mg due to clinical symptoms such
as sleepiness and dizziness being experienced by some subjects in a phase 1 single-dose
trial conducted prior to the first new drug application in Japan, and in view of the safety
information obtained in bioequivalence trials, for the present trial it was decided to use 3-
mg aripiprazole, at which aripiprazole does not induce major effects on subjects, taking
the following into consideration:
In clinical pharmacology trials of aripiprazole conducted in healthy adult subjects, 7
doses (0.25, 0.5, 1, 2, 3, 4, and 6 mg) were administered in a cumulative total of 319
subjects (the cumulative total was obtained by counting subjects separately once for each
dose or each period [Period I or II]; overall, 187 subjects participated in the trials).
Although no subjects experienced vomiting (as an adverse drug reaction) at doses of 0.25
to 2 mg, 1.73% (3/173) of subjects experienced vomiting at 3 mg. At 4 and 6 mg, the
incidence of vomiting was 5.26% (3/57) and 6.56% (4/61), respectively, indicating a
tendency for the incidence to increase as the dose increased.15 As it may not be possible
to evaluate normal absorption of the IMP in subjects experiencing vomiting, considering
the purpose of the present trial, it was concluded that a dose with a low incidence of
vomiting is preferable.
Regarding sertraline, one dose unit for the approved dosage regimen is 25 to 100 mg. No
specifically significant symptoms were observed in single-dose trials conducted in Japan
for sertraline administered at 50, 100, and 200 mg in healthy adult subjects.16
The Japanese Society of Mood Disorders Treatment Guideline states that an
augmentation therapy should be started if patients with moderate/severe depression show
an incomplete response to the first-line monotherapy at a sufficient dose and treatment
duration, which should be employed to prevent apparently refractory cases due to
insufficient dose and treatment duration. As the target patients for ASC-01 are expected
to be patients with depression/depressive state who show an incomplete response to
sertraline therapy at a sufficient dose and treatment duration, the dose of sertraline used
in the combination drug was set at 100 mg.


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Based on the above, subjects will receive either single administration of one tablet of
ASC-01 (aripiprazole 3 mg/sertraline 100 mg combination drug) or concomitant single
administration of one aripiprazole 3-mg tablet and two sertraline 50-mg tablets.
[Cohort 2]
For the same reasons as in Cohort 1, subjects will receive single administration of one
tablet of ASC-01 (aripiprazole, 3 mg/sertraline, 100 mg combination drug).
2.3
Trial Objectives
2.3.1
Cohort 1
To investigate bioequivalence for aripiprazole between administration of one ASC-01
tablet and concomitant administration of one aripiprazole 3-mg tablet and two sertraline
50-mg tablets
2.3.2
Cohort 2
To investigate the effect of food on the plasma pharmacokinetics of aripiprazole and
sertraline following single oral administration of ASC-01 under a fasting or fed condition
3
Trial Design
3.1
Type/Design of Trial
This is a single-center, open-label, randomized, two-treatment, two-period crossover trial
in healthy male adults conducted using 2 cohorts to investigate bioequivalence for
aripiprazole between administration of ASC-01 and concomitant administration of
aripiprazole and sertraline and the effect of food on the pharmacokinetics of ASC-01.
The trial design is outlined in Figure 3.1-1.


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Figure 3.1-1
Trial Design Schematic
There will be a wash-out period of at least 35 days between IMP administration in Periods I and II. The
number of days with a wash-out period of 35 days is shown.
Group A-1, group receiving administration of ASC-01 first; Group B-1, group receiving concomitant
administration of aripiprazole and sertraline first; Group A-2, group receiving administration of ASC-01
under a fasting condition first; and Group B-2, group receiving administration of ASC-01 under a fed
condition first
3.1.1
Cohort 1
A total of 54 healthy male adults will be randomized: 27 subjects into a group receiving
administration of ASC-01 first (Group A-1) and 27 subjects into a group receiving
concomitant administration of aripiprazole and sertraline first (Group B-1). On the
respective administration days in Periods I and II, the IMP will be orally administered
once after subjects have fasted for at least 10 hours. Subjects receiving ASC-01 in Period
I will receive concomitant administration of aripiprazole and sertraline in Period II, and
subjects receiving concomitant administration of aripiprazole and sertraline in Period I
will receive ASC-01 in Period II. The plasma concentration of aripiprazole will be
measured in each treatment period to examine pharmacokinetics.
The trial is designed in accordance with the BE Guideline. Furthermore, the results in the
trial will be handled in accordance with the BE Guideline.
Screening Period
Group
A-1
Group
B-1
Group
A-2
Group
B-2
Informed consent
(start of trial)
Screening examination
Randomization
Single administration
Single administration
Outpatient
visit
Outpatient
visit
Period I
Period II
Administration of
ASC-01 under a
fed condition
Administration of
ASC-01 under a
fasting condition
Hospitalization
Hospitalization
Concomitant single
administration of
aripiprazole and
sertraline
Single
administration of
ASC-01
Cohort 2
Food effect
Healthy
male
adults
Eligible
subjects
20 subjects
(10 subjects in
each group)
Administration of
ASC-01 under a
fasting condition
Wash-out
period
(at least 35
days)
Administration of
ASC-01 under a
fed condition
Cohort 1
Bioequivalence
Healthy
male
adults
Eligible
subjects
54 subjects
(27 subjects
in each
group)
Single
administration of
ASC-01
Wash-out
period
(at least 35
days)
Concomitant single
administration of
aripiprazole and sertraline


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Group
Period I
Wash-out
perioda
Period II
Group A-1
Group receiving
administration of
ASC-01 first
Single administration of ASC-
01
Concomitant single
administration of aripiprazole
and sertraline
Group B-1
Group receiving
concomitant
administration of
aripiprazole and
sertraline first
Concomitant single
administration of aripiprazole
and sertraline
Single administration of ASC-01
a: There will be a wash-out period of at least 35 days between IMP administration in Periods I and II.
3.1.2
Cohort 2
A total of 20 healthy male adults will be randomized: 10 subjects into a group receiving
administration of ASC-01 under a fasting condition first (Group A-2) and 10 subjects into
a group receiving administration of ASC-01 under a fed condition first (Group B-2). On
the respective administration days in Periods I and II, the IMP will be orally administered
once after subjects have fasted for at least 10 hours (for administration under a fasting
condition) or at 30 minutes after the start of breakfast (for administration under a fed
condition). Subjects receiving administration under a fasting condition in Period I will
receive administration under a fed condition in Period II, and subjects receiving
administration under a fed condition in Period I will receive administration under a
fasting condition in Period II. The plasma concentrations of aripiprazole and sertraline
will be measured in each treatment period to examine pharmacokinetics.
Group
Period I
Wash-out
perioda
Period II
Group A-2
Group receiving ASC-
01 under a fasting
condition first
Administration under a fasting
condition
Administration under a fed
condition
Group B-2
Group receiving ASC-
01 under a fed
condition first
Administration under a fed
condition
Administration under a fasting
condition
a: There will be a wash-out period of at least 35 days between IMP administration in Periods I and II.


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3.2
Method of Administration
3.2.1
Cohort 1
3.2.1.1
ASC-01 Tablets
One tablet of ASC-01 (3-mg aripiprazole/100-mg sertraline combination drug) will be
administered once with approximately 150 mL of water after subjects have fasted for at
least 10 hours.
3.2.1.2
Aripiprazole Tablets and Sertraline Tablets
One aripiprazole 3-mg tablet and two sertraline 50-mg tablets will be administered once
with approximately 150 mL of water after subjects have fasted for at least 10 hours.
3.2.2
Cohort 2
3.2.2.1
Administration under a fasting condition
One tablet of ASC-01 will be administered once with approximately 150 mL of water
after subjects have fasted for at least 10 hours.
3.2.2.2
Administration under a fed condition
One tablet of ASC-01 will be administered once with approximately 150 mL of water at
30 minutes after the start of breakfast.
[Rationale for the duration of treatment]
As the BE Guideline states that in principle, bioequivalence studies should be performed
by single-dose studies, a single dose will be administered in the present trial.
3.3
Trial Population
3.3.1
Number of Subjects and Population
Fifty-four healthy male adults aged 20 to 40 years, inclusive, will be enrolled in Cohort 1
and 20 in Cohort 2.
A few reserve subjects may be allowed to stand by until completion of IMP
administration in Period I. If a subject to be treated withdraws consent or the investigator
or subinvestigator determines that the subject should not be administered the IMP, the
subject will be replaced with a reserve subject. Subjects who are withdrawn from the trial
after randomization will not be replaced.


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3.3.2
Issuance of Subject Identification Number
Subject number (S + in-site serial number [5-digit]) will be assigned at the trial site in the
order of consent from 00001 at the time of written consent. At randomization, subjects
assigned to Cohort 1 (bioequivalence trial) will be assigned a site number of 101 and
subjects assigned to Cohort 2 will be assigned a site number of 201. The [site number (3
digits) + subject number] will be the subject identification number (ID). The trial site will
prepare and store a list of all subjects who have given informed consent and their subject
IDs.
3.4
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, neither by the
investigator nor subinvestigator, nor by the medical advisor.
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects. Consent will be documented
by signing the informed consent form. The informed consent form (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) Guidelines17, and local regulatory requirements.
Investigators or subinvestigators 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 before initiation of any procedures that are performed
solely for the purpose of determining eligibility for this trial, including withdrawal from
current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in
layman’s language to the subject by the investigator or subinvestigator, the IRB-approved
written ICF will be signed and dated by both the subject and the person obtaining consent
(investigator or subinvestigator). If a trial associate has provided a supplemental
explanation, the trial associate will also sign and date the consent form. The subject will
receive a copy of the signed ICF; the original shall be kept on file by the investigator or
subinvestigator.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes
to the protocol result in additional information that needs to be provided to the subjects,


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so that they can make a knowledgeable and voluntary decision on continued trial
participation after obtaining sufficient information.
3.4.2
Inclusion Criteria
Subjects must meet all of the inclusion criteria listed in Table 3.4.2-1.
Table 3.4.2-1 Inclusion Criteria (Common to Both Cohorts)
1
Healthy male subjects aged 20 to 40 years, inclusive, at time of informed consent
2
Subjects with a body mass index (BMI = body weight [kg]/height [m]2) of ≥18.5 and <25.0 kg/m2 at
screening
3
Subjects capable of providing written, informed consent prior to initiation of any trial-related
procedures, and in the opinion of the investigator or subinvestigator, of complying with all
requirements of the trial
[Rationale for inclusion criteria]
1. The lower age limit is set at the age at which subjects as legal adults are capable of
taking responsibility for providing informed consent, whereas the upper age limit is set
at 40 years, considering concerns for the possibility of subjects having a disease or
metabolic ability different from younger subjects, in reference to the Guideline for
Bioequivalence issued by the American Pharmacists Association. Male subjects are
specified in order to avoid the need to consider the possibility of pregnancy.
2. Specified to avoid a possible influence on pharmacokinetics.
3. Specified to ensure that subjects are capable of providing consent and to make it
possible for the investigator or subinvestigator to assess whether subjects are capable of
observing the protocol.
3.4.3
Exclusion Criteria
Subjects who meet any of the exclusion criteria listed in Table 3.4.3-1 will be excluded.


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Table 3.4.3-1 Exclusion Criteria (Common to Both Cohorts)
1
Subjects who have clinically significant abnormal medical history or abnormalities in physical
findings at screening that in the investigator’s or subinvestigator’s opinion or in the sponsor’s
opinion may place the subject at risk or interfere with outcome variables, including drug absorption,
distribution, metabolism, and excretion. These abnormalities may include, but are not limited to,
cardiac, hepatic, renal, neurological, endocrine, gastrointestinal, respiratory, hematological, and
immunological diseases/disorders (complications or medical history).
2 
Subjects who have a supine blood pressure of >140/90 mmHg or <100/50 mmHg after ≥3 minutes 
of rest and an orthostatic blood pressure decline (difference between sitting and standing systolic
blood pressure) of ≥20 mmHg at screening. 
The sponsor may accept such subjects exceptionally only if the findings are considered clinically
insignificant.
3 
Subjects who have a supine pulse rate outside the range of 40 to 90 bpm after ≥3 minutes of rest at 
screening.
The sponsor may accept such subjects exceptionally only if the findings are considered clinically
insignificant.
4
Subjects who have a history or complication of hepatitis or acquired immunodeficiency syndrome
or who have tested positive for hepatitis B surface antigen, hepatitis C virus antibody, or HIV
antigen or antibody
5
Subjects who are judged by the investigator or subinvestigator to be ineligible to participate in the
trial due to a history of serious psychiatric disease
6
Subjects who have a history of clinically significant drug or alcohol abuse prior to screening
examination
7
Subjects who test positive in a breath alcohol test or a urine drug test for substance abuse performed
at the visit for screening examination or hospitalization at the trial site
8
Subjects who are sexually active and who are unable or unwilling to practice two kinds of
contraception or remain abstinent during the trial and for 30 days after final IMP administration. If
contraception is used, two of the following methods must be used: vasectomy, tubal ligation,
intrauterine device, oral contraceptive pill, condom with spermicide, and occlusive cap with
spermicide (diaphragm or cervical cap).
Subjects who plan to provide sperm during the period from the visit for screening examination until
30 days after final IMP administration
9
Subjects who have a history of significant drug allergy
10
Subjects who have a history of significant bleeding or hemorrhagic diathesis


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11
Subjects who have provided >200 mL of blood or >600 mL of plasma within 30 days prior to the
first IMP administration
12
Subjects who have undergone blood collection (blood donation, etc.) of >1200 mL in total within 1
year prior to the first IMP administration
13
Subjects who have difficulty with blood collection
14
Subjects who have received any IMP within 120 days prior to the first IMP administration
15
Subjects who have smoked or been routinely exposed to secondhand smoke within 2 months prior
to screening or who tested positive in urine cotinine test performed at the visit for screening or
hospitalization at the trial site (urine cotinin concentration > 200 ng/mL)


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Table 3.4.3-1
Exclusion Criteria (Common to Both Cohorts) (continued)
16
Subjects who have consumed the following:

Subjects who have consumed food or drink containing St. John’s Wort within 14 days prior
to IMP administration in each treatment period

Subjects who have consumed grapefruit (including fruit juice), Seville orange (including
fruit juice), star fruit, or any food or drink containing these items within 7 days prior to IMP
administration in each treatment period

Subjects who have consumed alcohol within 3 days prior to IMP administration in each
treatment period
17
Subjects who have taken any prescription or nonprescription medicines, Chinese medicines, or
vitamins within 14 days or any antibiotics within 30 days prior to the first IMP administration. Such
subjects may be exceptionally eligible if, in the sponsor’s opinion, the medication is unlikely to
affect pharmacokinetic results.
18
Subjects who have undergone major gastrointestinal surgery (other than an appendectomy)
19
Subjects who have been occupationally exposed to an insecticide or organic solvent within 30 days
prior to screening
20
Subjects who have a family history of long QT syndrome
21
Subjects who are visiting another hospital or department or who plan to visit another hospital or
department during the trial period
22
Subjects with no fixed address
23
Subjects determined by the investigator or subinvestigator to be inappropriate for participation in
this trial
[Rationale for exclusion criteria]
1. Specified to confirm that subjects are healthy.
2 to 7. Specified because such subjects cannot be considered healthy.
8. Specified to ensure the safety of subjects and their partners.
9 to 14. Specified to ensure the safety of subjects.
15 to 17. Specified to avoid a possible influence on pharmacokinetics.
18 and 19. Specified to avoid a possible influence on pharmacokinetics due to exposure to substances
considered to stimulate liver microsomal enzymes.
20 to 23. Specified to ensure the safety of subjects.


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3.5
Endpoints
3.5.1
Cohort 1
3.5.1.1
Primary Endpoint

Cmax and AUC168h of aripiprazole
3.5.1.2
Secondary Endpoints
1) Plasma concentration of aripiprazole
2) Pharmacokinetic parameters of aripiprazole
3) Ratios of the Cmax, AUCt, AUC∞, AUC168h, MRT∞, and λz of aripiprazole
following administration of ASC-01 to those following concomitant
administration of aripiprazole and sertraline and the difference in the tmax of
aripiprazole between administration of ASC-01 and concomitant administration of
aripiprazole and sertraline (tmax for ASC-01 administration minus tmax for
concomitant administration)
3.5.2
Cohort 2
3.5.2.1
Primary Endpoint

Cmax, AUCt, AUC∞, and AUC168h of aripiprazole and sertraline
3.5.2.2
Secondary Endpoints
1) Plasma concentrations of aripiprazole and sertraline
2) Pharmacokinetic parameters of aripiprazole and sertraline
3) Ratios of the Cmax, AUCt, AUC∞, AUC168h, tmax, t1/2,z, and CL/F of aripiprazole
and sertraline for administration under a fed condition to those for administration
under a fasting condition and the difference in the tmax of aripiprazole and
sertraline between administration under a fed condition and administration under
a fasting condition (tmax for a fasting condition minus tmax for a fed condition)
3.5.3
Safety (Common to Both Cohorts)
Adverse events, clinical laboratory tests, physical examination, vital signs (blood
pressure, pulse rate, and temperature), 12-lead electrocardiography, body weight, and
Columbia-Suicide Severity Rating Scale (C-SSRS)


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3.6
Measures to Minimize/Avoid Bias
Since the primary endpoint of this trial is based on plasma drug concentrations, there will
be no bias without blinding. The trial will therefore be conducted by an open-label, two-
treatment, two-period crossover design. In Cohort 1, subjects will be randomly assigned
according to the assignment table to two groups, ie, a group receiving administration of
ASC-01 first (Group A-1) and a group receiving concomitant administration of one
aripiprazole 3-mg tablet and two sertraline 50-mg tablets first (Group B-1). In Cohort 2,
subjects will be randomly assigned according to the assignment table to two groups, ie, a
group receiving administration of ASC-01 under a fasting condition first (Group A-2) and
a group receiving administration of ASC-01 under a fed condition first (Group B-2).
3.7
Study Methods
The schedule of assessments is shown in Table 3.7-1.


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Table 3.7-1
Schedule of Assessments (Common to Both Cohorts)
Screening
testa
Period I
Period II
Outpatient
visit
Hospitalization
Outpatient
visit
Hospitalization
Outpatient
visit
Discontinuationc
(Day)
-21 to -2
-1
1
2
3
4
5
7
8
-1
1
2
3
4
5
7
8
(h)
predose
0
1
2
3
4
5
6
8
12
24
48
72
96 144 168
predose
0
1
2
3
4
5
6
8
12
24
48
72
96 144 168
Informed Consent
●
Wash-out periodb
Demographics
●
Height
●
Immunological Test
●
Alcohol Test,
Urine Drug and Cotinin Screen
●
●
●
Concomitant Medications/Therapies
Dosing
●
●
Blood Collection for Plasma Drug
Concentration Measurement
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
SAFETY
Adverse Events
Clinical Laboratory Tests
●
●
●
●
●
●
●
●
Physical Examination
●
●
●
●
●
●
●
●
Vital Signs (blood pressure, pulse
rate, and temperature)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
12-lead Electrocardiography
●
●
●
●
●
●
●
●
●
●
Body Weight
●
●
●
●
●
●
C-SSRS
●
●
●
●
●
●
●
●
●
●
a
After obtaining informed consent, each test will be performed between 21 and 2 days before the day of IMP administration in Period I.
b There will be a wash-out period of at least 35 days between IMP administration in Periods I and II.
c
If a subject refuses to receive examinations at the time of discontinuation, or if the investigator or subinvestigator determines that examinations cannot be
performed due to emergency, etc., only feasible observations/examinations among the specified examinations will be performed.
See Table 3.7-2 for the acceptable time windows for observations, examinations, and evaluations after IMP administration.


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Table 3.7-2
Acceptable Time Windows for Observations, Examinations, and
Evaluations After Investigational Medicinal Product
Administration (Common to Both Cohorts)
Item
Timing
Acceptable Time Window
Blood collection for plasma
drug concentration
measurement
1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96
hours after the start of administration of
IMP
3 minutes before and after each
blood collection time
144 and 168 hours after the start of
administration of IMP
1 hour before and after each
blood collection time
Confirmation of
concomitant
medications/therapies
Feasible time
Adverse Events
Feasible time
Clinical laboratory tests
96 and 168 hours after the start of
administration of IMP
2 hours before and after
examination time
Physical Examination
Feasible time on days 5 and 8
Vital signs
(blood pressure, pulse rate,
and temperature)
2, 4, 8, 24, 48, 72, and 96 hours after the
start of administration of IMP
Within 60 minutes before the
time of measurement and before
blood collection for
pharmacokinetics
144 and 168 hours after the start of
administration of IMP
2 hours before and after
examination time
12-lead electrocardiography
8 and 24 hours after the start of
administration of IMP
Within 60 minutes before the
time of measurement and before
blood collection for
pharmacokinetics
168 hours after the start of administration of
IMP
2 hours before and after
examination time
Body weight
168 hours after the start of administration of
IMP
2 hours before and after
examination time
C-SSRS
96 hours after the start of administration of
IMP
1 hour before and after
examination time
144 and 168 hours after the start of
administration of IMP
2 hours before and after
examination time
3.7.1
General Procedures During Hospitalization (Common to Both
Cohorts)
Subjects will remain seated or in a supine position for 8 hours after IMP administration.
However, another position may be used for a short period of time to perform the
procedures specified in the protocol. When subjects go to the toilet within 8 hours after
administration, it should be monitored and brief (<10 minutes). Subjects should be


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monitored to use the toilet within 8 hours after oral administration so that they do not
vomit and spit out their oral medication. Subjects may walk from 8 hours after
administration; however, they must refrain from strenuous exercise.
3.7.2
Meal Requirements
3.7.2.1
Cohort 1
During hospitalization, subjects should take meals (standard meals) prepared at the trial
site at around 9 AM (breakfast), 1 PM (lunch), and 7 PM (dinner), except breakfast on the
day of IMP administration. However, food intake will be prohibited from 10 PM on the
day before IMP administration to 4 hours after IMP administration because the IMP
should be administered after fasting for at least 10 hours. If a meal time overlaps with an
examination or blood collection, the meal will be given after the examination or blood
collection.
Only meals and beverages provided by the trial site will be allowed during
hospitalization. Drinking water will be prohibited for 2 hours before and after IMP
administration except for the time of IMP administration. Outside the above period,
subjects will basically be allowed to drink water ad libitum.
During hospitalization, meals other than breakfast prior to administration will be the
same in Periods I and II, and only meals prepared at the trial site will be taken at
predetermined times.
If breakfast is taken on the day of IMP administration, the time of starting breakfast will
be recorded in the case report form (CRF).
3.7.2.2
Cohort 2
During hospitalization, subjects should take meals (standard meal, Melander meal)
prepared at the trial site at around 9 AM (breakfast), 1 PM (lunch), and 7 PM (dinner)
except breakfast on the day of IMP administration.
In case of administration under a fasting condition, food intake will be prohibited from 10
PM on the day before IMP administration to 4 hours after IMP administration. In case of
administration under a fed condition, the standard meal provided by the trial site will be
used as the breakfast before administration, and the meal will be taken within 30 minutes.
If a meal time overlaps with an examination or blood collection, the meal will be given
after the examination or blood collection.
Only meals and beverages provided by the trial site will be allowed during
hospitalization. Drinking water will be prohibited for 2 hours before and after IMP


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administration except for the time of IMP administration. Outside the above period,
subjects will basically be allowed to drink water ad libitum.
During hospitalization, meals other than breakfast prior to administration will be the
same in Periods I and II, and only meals prepared at the trial site will be taken at
predetermined times.
If breakfast is taken on the day of IMP administration, the time of starting breakfast will
be recorded in the CRF.
3.7.3
Schedule of Assessments
3.7.3.1
Screening Examination (Common to Both Cohorts)
After obtaining the consent, the following observations, examinations, and evaluations
will be performed as screening within 21 days before hospitalization in Period I (Day –21
to Day –2) to determine eligibility for the study. The results of eligibility check will be
recorded in the source documents and CRF.
[Examination/investigation items]

Demographic data (date of birth, sex, race, ethnicity, drinking habit, and medical
history)

Height, body weight, and BMI (Height will be measured in 0.1 cm increments. When
measurement is performed to two or more decimal places, the value will be rounded
to one decimal place. BMI will be calculated based on height and body weight at
screening using the following formula: BMI = body weight [kg]/height [m]2.)

Immunological tests (HBs antigen, HCV antibody, and HIV antigen/antibody tests)

Breath alcohol test, urine drug test, and urine cotinine test (the test will be performed
according to the procedure specified by the trial site)

Confirmation of concomitant medications and therapies

Adverse event assessment

Clinical laboratory tests

Physical examination

Vital signs (blood pressure, pulse rate, and temperature)

12-lead electrocardiography

C-SSRS (to be performed using Appendix 2 "Baseline Assessment Version.")
3.7.3.2
Hospitalization (day before investigational medicinal product
administration in each period, common to both cohorts)
Subjects to be treated and reserve subjects will visit the trial site on the day before IMP
administration (Day –1) in each period to confirm their intention to participate in the trial


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again. The following observations, examinations, and evaluations will be performed to
confirm the eligibility of subjects, and subjects will be hospitalized. Subjects will take
dinner and fast from around 10 PM. Subjects who completed Period I without
discontinuation will proceed to the next period.

Breath alcohol test, urine drug test, and urine cotinine test (the test will be performed
according to the procedure specified by the trial site)

Confirmation of concomitant medications and therapies

Adverse event assessment
3.7.3.3
Day of Investigational Medicinal Product Administration (Day 1
of Each Period)
3.7.3.3.1
Enrollment of Subjects and Assignment of Investigational
Medicinal Product to Subjects (Period I Only, Common to Both
Cohorts)
IMP will be assigned by cohort. Before administration on Day 1 in Period I, eligible
subjects will be randomly assigned to each treatment group according to the assignment
table. If a subject to be treated withdraws consent or is determined not to be able to
receive IMP prior to randomization, a new subject will replace the dropout subject to
receive IMP.
Subjects who are not randomized will be discharged from the trial site.
Subjects who are withdrawn from the trial after randomization will not be replaced.
3.7.3.3.2
Within 3 Hours Before Investigational Medicinal Product
Administration (Common to Both Cohorts)
The following observations, examinations, and evaluations will be performed.

Blood collection for plasma drug concentration measurement

Adverse event assessment

Clinical laboratory tests (samples for chemistry, hematology, and urinalysis will be
collected.)

Physical examination

Vital signs (blood pressure, pulse rate, and temperature)

12-lead electrocardiography

Body weight

C-SSRS (to be performed using Appendix 2 "Baseline Assessment Version.")

Confirmation of concomitant medications and therapies


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3.7.3.3.3
Investigational Medicinal Product Administration
3.7.3.3.3.1
Cohort 1
Subjects assigned to the group receiving administration of ASC-01 first (Group A-1) will
take one tablet of ASC-01 with approximately 150 mL of water after fasting for at least
10 hours in Period I and one aripiprazole 3-mg tablet and two sertraline 50-mg tablets
with approximately 150 mL of water after fasting for at least 10 hours in Period II.
Subjects assigned to the group receiving concomitant administration of aripiprazole and
sertraline first (Group B-1) will take one aripiprazole 3-mg tablet and two sertraline 50-
mg tablets with approximately 150 mL of water after fasting for at least 10 hours in
Period I and one tablet of ASC-01 with approximately 150 mL of water after fasting for
at least 10 hours in Period II. The date and time of administration and the drug
administered will be recorded in the CRF.
3.7.3.3.3.2
Cohort 2
Subjects assigned to the group receiving administration of ASC-01 under a fasting
condition first (Group A-2) will take one tablet of ASC-01 with approximately 150 mL of
water after fasting for at least 10 hours in Period I and one tablet of ASC-01 with
approximately 150 mL of water 30 minutes after the start of breakfast in Period II.
Subjects assigned to the group receiving administration of ASC-01 under a fed condition
first (Group B-2) will take one tablet of ASC-01 with approximately 150 mL of water 30
minutes after the start of breakfast in Period I and one tablet of ASC-01 with
approximately 150 mL of water after fasting for at least 10 hours in Period II. The date
and time of administration will be recorded in the CRF.
3.7.3.3.4
After Investigational Medicinal Product Administration
(Common to Both Cohorts)
The following observations, examinations, and evaluations will be performed. Lunch and
dinner will be provided.
Examination/Investigation
Item
Timing of Implementation (Time
After Administration on Day 1)
Acceptable Time Window
Blood collection for plasma
drug concentration
measurement
1, 2, 3, 4, 5, 6, 8, and 12
Within 3 minutes before and
after each blood collection
time
Confirmation of
concomitant medications
and therapies
Feasible time on Day 1
-


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Adverse event assessment
Feasible time on Day 1
-
Vital signs
(blood pressure, pulse rate,
and temperature)
2, 4, and 8
Within 60 minutes before the
time of measurement and
before blood collection for
plasma drug concentration
measurement
12-lead
electrocardiography
8
Within 60 minutes before the
time of measurement and
before blood collection for
plasma drug concentration
measurement
3.7.3.4
Day 2 of Each Period (Common to Both Cohorts)
The following observations, examinations, and evaluations will be performed. See "Table
3.7-2
Acceptable Time Windows for Observations, Examinations, and Evaluations
After Investigational Medicinal Product Administration (Common to Both Cohorts)" for
acceptable time windows.

Blood collection for plasma drug concentration measurement (24 hours after IMP
administration on Day 1)

Adverse event assessment

Vital signs (blood pressure, pulse rate, and temperature)

12-lead electrocardiography

Confirmation of concomitant medications and therapies
3.7.3.5
Day 3 of Each Period (Common to Both Cohorts)
The following observations, examinations, and evaluations will be performed. See "Table
3.7-2
Acceptable Time Windows for Observations, Examinations, and Evaluations
After Investigational Medicinal Product Administration (Common to Both Cohorts)" for
acceptable time windows.

Blood collection for plasma drug concentration measurement (48 hours after IMP
administration on Day 1)

Adverse event assessment

Vital signs (blood pressure, pulse rate, and temperature)

Confirmation of concomitant medications and therapies


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3.7.3.6
Day 4 of Each Period (Common to Both Cohorts)
The following observations, examinations, and evaluations will be performed. See "Table
3.7-2
Acceptable Time Windows for Observations, Examinations, and Evaluations
After Investigational Medicinal Product Administration (Common to Both Cohorts) for
acceptable time windows.

Blood collection for plasma drug concentration measurement (72 hours after IMP
administration on Day 1)

Adverse event assessment

Vital signs (blood pressure, pulse rate, and temperature)

Confirmation of concomitant medications and therapies
3.7.3.7
Discharge (Day 5 of Each Period)/Discontinuation (Common to
Both Cohorts)
The following observations, examinations, and evaluations will be performed on the day
of discharge or at the time of discontinuation. See "Table 3.7-2
Acceptable Time
Windows for Observations, Examinations, and Evaluations After Investigational
Medicinal Product Administration (Common to Both Cohorts)" for acceptable time
windows.

Blood collection for plasma drug concentration measurement (96 hours after IMP
administration on Day 1)

Adverse event assessment

Clinical laboratory tests (samples for chemistry, hematology, and urinalysis will be
collected.)

Physical examination

Vital signs (blood pressure, pulse rate, and temperature)

12-lead electrocardiography (at discontinuation)

Body weight (at discontinuation)

C-SSRS (to be performed using Appendix 3 "Since Last Visit Version.")

Confirmation of concomitant medications and therapies
3.7.3.8
Outpatient Visits (Days 7 and 8 of Each Period, Common to
Both Cohorts)
3.7.3.8.1
Day 7 of Each Period
The subjects will visit the trial site as outpatient and the following observations,
examinations, and evaluations will be performed. See "Table 3.7-2 Acceptable Time


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Windows for Observations, Examinations, and Evaluations After Investigational
Medicinal Product Administration (Common to Both Cohorts)" for acceptable time
windows.

Blood collection for plasma drug concentration measurement (144 hours after IMP
administration on Day 1)

Adverse event assessment

Vital signs (blood pressure, pulse rate, and temperature)

C-SSRS (to be performed using Appendix 3 "Since Last Visit Version.")

Confirmation of concomitant medications and therapies
3.7.3.8.2
Day 8 of Each Period
The subjects will visit the trial site as outpatient and the following observations,
examinations, and evaluations will be performed. See "Table 3.7-2 Acceptable Time
Windows for Observations, Examinations, and Evaluations After Investigational
Medicinal Product Administration (Common to Both Cohorts)" for acceptable time
windows.

Blood collection for plasma drug concentration measurement (168 hours after IMP
administration on Day 1)

Adverse event assessment

Clinical laboratory tests (samples for chemistry, hematology, and urinalysis will be
collected.)

Physical examination

Vital signs (blood pressure, pulse rate, and temperature)

12-lead electrocardiography

Body weight

C-SSRS (to be performed using Appendix 3 "Since Last Visit Version.")

Confirmation of concomitant medications and therapies
3.7.4
Prior and Concomitant Medications (Common to Both Cohorts)
The investigator or subinvestigator will record in the CRF all medications and therapies
used by the subject from 14 days prior to signing of informed consent until the end of the
evaluation period (defined as the period during which subjects are evaluated for trial
objectives). The investigator or subinvestigator will record in the CRF all medications
and therapies used by the subject for treatment of an adverse event or which caused an


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adverse event until the end of the trial (defined as the last date of contact or the date of
final contact attempt).
3.7.5
Safety Assessments (Common to Both Cohorts)
3.7.5.1
Adverse Events
See Section 5 for the methods and timing of assessment, recording, and analysis of
adverse events.
3.7.5.2
Clinical Laboratory Assessments
3.7.5.2.1
Clinical Laboratory Assessments
Laboratory data presented in Table 3.7.5.2-1 will be collected as specified in the
Schedule of Assessments (Table 3.7-1). Tests will be performed according to the
procedures specified by the trial site. The date and time of blood and urine collection will
be recorded in the CRF.
Table 3.7.5.2-1
Clinical Laboratory Assessments
Hematology
White blood cell (WBC) count and absolute and
differential
Red blood cell (RBC) count
Hematocrit
Hemoglobin
Platelets
Urinalysis
Bilirubin
Glucose
Ketones
Urinary occult blood
Protein
Urobilinogen
pH
Serum Chemistry
Alanine aminotransferase (ALT)
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Total Bilirubin
Blood urea nitrogen (BUN)
Calcium
Chloride
Total cholesterol
Creatinine
Creatinine phosphokinase
Gamma-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Inorganic phosphorus
Potassium
Total protein
Sodium
Uric acid
Triglycerides
3.7.5.2.2
Immunological Test
The following data will be collected on the days specified in the Schedule of Assessments
(Table 3.7-1). Tests will be performed according to the procedures specified by the trial
site. The date and time of blood collection will be recorded in the CRF.


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
Hepatitis B surface antigen (HBsAg)

Hepatitis C virus antibody (HCV antibody)

Human immunodeficiency virus (HIV antigen/antibody)
3.7.5.2.3
Breath Alcohol Test, Urine Drug Test, and Urine Cotinine Test
The following data will be collected on the days specified in the Schedule of Assessments
(Table 3.7-1). Tests will be performed according to the procedures specified by the trial
site. The date and time of the test, date and time of urine collection, and test results will
be recorded in the CRF.

Breath alcohol

Amphetamines

Barbiturates

Benzodiazepines

Cannabinoids

Cocaine

Opiates

Phencyclidine

Urine cotinine
3.7.5.3
Physical Examination and Vital Signs
3.7.5.3.1
Physical Examination
A complete medical history will be obtained at the screening visit. Physical examination
will be performed at screening, admission, discharge/discontinuation, and outpatient
visits. Physical examination will include head, ears, eyes, nose, throat, chest, abdomen,
genitourinary tract, extremities, nerves, and skin and mucosal sites. The investigator or
subinvestigator will be primarily responsible for the assessment of physical findings. The
same individual should perform all physical examinations for an individual subject
whenever possible. For the screening examination and the examination before IMP
administration in each period, the date of assessment and the results of assessment will be
recorded in the CRF. For Days 5 and 8 (or at discontinuation) in each period, only the
date of assessment will be recorded in the CRF. Any clinically significant physical
findings not present at baseline but observed after IMP administration will be recorded as
an adverse event and monitored until its outcome has been sufficiently evaluated.
3.7.5.3.2
Vital Signs (Blood Pressure, Pulse Rate, and Temperature)


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Vital signs will be measured and recorded according to the schedule presented in Section
3.7.3. Blood pressure and pulse rate will be measured after the subject has maintained the
supine position for at least 3 minutes. Standing and sitting blood pressure will be
measured at screening only. Body temperature will be measured in the supine position.
At screening, the standing and sitting position blood pressure will as well be obtained,
and the difference in systolic blood pressure between the standing and sitting position
will be calculated. Vital signs will be obtained at each scheduled time point and prior to
blood collection for pharmacokinetics (if applicable). The date, time, and results of the
assessment will be recorded in the CRF.
3.7.5.4
Electrocardiogram
Electrocardiograms will be performed and recorded according to the schedule presented
in Section 3.7.3. Electrocardiograms will be obtained prior to blood collection for
pharmacokinetics at each scheduled time point (if applicable). A resting (at least 10
minutes) 12-lead electrocardiogram will be recorded in the supine position. The date of
examination, time of measurement, heart rate, PR interval, QRS time, QT interval, and
QTc (Fridericia correction method [QTcF] and Bazzett correction method [QTcB]) will
be recorded in the CRF. The investigator or subinvestigator will assess each
electrocardiogram data, investigate whether the data are normal or abnormal, and record
the assessment results and findings in the CRF. The original 12-lead electrocardiogram
tracing will be retained in the medical record or investigator file.
3.7.5.5
Body Weight
Body weight will be measured to the nearest 0.1 kg at specified times and on the same
scale throughout the trial. The date, time, and results of measurements will be recorded in
the source documents and CRF.
3.7.5.6
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS assessment will be performed at screening and prior to administration in
each period using the Baseline Version according to the schedule presented in Section
3.7.3 of this protocol. On Days 5, 7, and 8 (or at discontinuation) in each period, the C-
SSRS assessment will be performed using the Since Last Visit Version with the start day
of administration in each period as the base point. The C-SSRS captures the occurrence,
severity, and frequency of suicide-related thoughts and behaviors during the assessment
period. The Baseline Version of C-SSRS (Baseline Columbia-Suicide Severity Rating
Scale) is attached in Appendix 2, and the Since Last Visit Version of C-SSRS (Since Last
Visit Columbia-Suicide Severity Rating Scale) is attached in Appendix 3. The date and
results of the assessment will be recorded in the CRF.


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3.7.6
Pharmacokinetic Assessments
3.7.6.1
Pharmacokinetic Assessments
Cohort 1
Plasma concentrations of aripiprazole will be measured.
Cohort 2
Plasma concentrations of aripiprazole and sertraline will be obtained.
3.7.6.2
Timing of Blood Collection
Samples will be collected before and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 144, and 168
hours after administration on Day 1 in each period. The date and time of blood collection
will be recorded in the CRF.
3.7.6.3
Pharmacokinetic Plasma Samples
Venous blood will be collected via an indwelling catheter or direct venipuncture into a
blood collection tube containing heparin sodium. When an indwelling catheter is used, it
will be filled with saline or heparin as needed for placement. The collected blood will be
mixed by inversion and plasma will be separated by centrifugation. All plasma samples
will be shipped to the drug concentration measurement facility as described in Appendix
1. Detailed instructions for sample handling and shipment are provided in Appendix 1.
The results of measurement will be reported directly from the drug concentration
measurement facility to the sponsor. Therefore, recording in the CRF is not required.
3.7.6.4
Pharmacokinetic Urine Samples
Urine samples for measurement will not be collected.
3.7.7
Genetic Testing
No genetic testing will be performed in this trial.
3.7.8
Future Biospecimen Research Samples
No future biospecimen research is planned for this trial.
3.7.9
End of Trial
The visit on Day 8 in Period II or the time of discontinuation will be considered as the
“end of trial date,” which will be the “last date of visit or contact” or the “date of final
contact attempt.”


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3.8
Discontinuation Criteria and Procedures
3.8.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be
given to the head of the trial site and regulatory authorities in accordance with regulatory
requirements.
3.8.2
Discontinuation at Individual Sites
The sponsor, investigator, or institutional review board reserves the right to terminate a
particular trial site’s participation as necessary for medical, safety, regulatory, ethical, or
other reasons in accordance with applicable laws, regulations, and GCP as well as for
reasons such as no enrollment of subjects and noncompliance with the protocol. The
sponsor will be notified promptly if the trial is terminated by the investigator or the IRB
at the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
After treatment assignment, a subject may stop treatment permanently for a variety of
reasons. Treatment discontinuations may be initiated by a subject or may become
medically necessary due to adverse events (AEs), required treatment with a disallowed
medication or therapy, or other issues, as determined by the investigator or
subinvestigator. Subjects who discontinue treatment will be withdrawn from the trial.
Subjects who discontinue will be encouraged to undergo all the examinations at
discontinuation and follow-up examinations, and the examinations at discontinuation
should be performed as soon as possible after treatment discontinuation.
3.8.3.2
Documenting Reasons for Treatment Interruption or
Discontinuation
All subjects may withdraw consent from the trial at any time, and the investigator or
subinvestigator may terminate a subject’s participation in the trial at any time if
medically necessary. Additionally, subjects must be withdrawn from the trial for any of
the following reasons:

Reason related to adverse event

Subject decides to discontinue because of annoyance or discomfort due to a
nonserious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator
or subinvestigator (eg, cases with IMP-related safety concern)

Serious adverse event (SAE)


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
Other potentially IMP-related safety concerns or AEs

Death

Reason unrelated to medical condition (provide details and confirm history of the
subject’s adverse event)

Withdrawal of consent (full written consent withdrawal)

Lost to follow-up

Discontinuation of the whole or part of the trial by the sponsor
If the subject (temporarily interrupts or) discontinues IMP due to an adverse event, the
investigator or subinvestigator or other trial personnel will make every effort to follow
the event until it resolves or stabilizes or the subject is lost to follow-up or has died. The
procedures in "3.8.3.1 Treatment Discontinuation" must be followed.
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 and can only withdraw consent 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.
Subjects who discontinue will be encouraged to undergo all the examinations at
discontinuation and follow-up examinations, and the examinations at discontinuation
should be performed as soon as possible after treatment discontinuation.
3.9
Screen Failures
A screen failure is a subject from whom informed consent is obtained and is documented
in writing, but who is not randomized or assigned trial treatment.
If a subject meets the definition of a screen failure in this trial, the following information
will be recorded in the CRF:

Date of informed consent

Date of investigation

Sex

Birth date

Race

Ethnicity


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
Country

Whether or not the subject met the inclusion criteria (If the subject did not meet the
inclusion criteria, the item numbers should also be recorded.)

Whether or not the subject met the exclusion criteria (If the subject met the exclusion
criteria, the item numbers should also be recorded.)

Screen failure date

Reason for screen failure
3.10
Definition of Completed Subjects
The evaluation period is defined as the time period during which the subject is evaluated
for trial objectives, regardless of whether or not the IMP is administered. Subjects who
have undergone the last scheduled evaluation during the evaluation period are defined as
having completed the trial. In this trial, subjects who have undergone the evaluation on
Day 8 in Period II are defined as having completed the trial.
3.11
Definition of Subjects Lost to Follow-up
If a subject cannot be reached on or before Day 8 in Period II and the reason for
discontinuation (eg, withdrawal of consent or onset of adverse events) is unknown, the
reason for discontinuation will be regarded as lost to follow-up except for the subjects
who completed the trial as defined in Section 3.10.
The site will make 3 documented attempts to contact the subject by telephone and in the
event the site is unable to reach the subject by telephone, the site will attempt to contact
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 administration time and dose of each IMP will be recorded in the source documents
and CRF. Further, information regarding missed or inappropriate doses will be recorded
in the source documents and CRF. The oral cavity will be checked at the time of oral
administration to make sure the subject takes the IMP.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or
mistake (eg, IMP dispensing or subject dosing error, violation of concomitant medication
criteria), the investigator or subinvestigator, or designee will contact the sponsor at the
earliest possible time by telephone. The investigator or subinvestigator, medical advisor,
and sponsor will come as quickly as possible to a joint decision regarding the subject’s


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continuation in the trial. This decision will be documented by the investigator or
subinvestigator and the sponsor and reviewed by the medical advisor.
The investigator or subinvestigator will record all protocol deviations in the source
documents.
The investigator or subinvestigator will enter specified items among protocol deviations
in the CRF according to the procedure for preparing the CRF prepared by the sponsor.
4
Restrictions (Common to Both Cohorts)
4.1
Prohibited Medications or Therapies
No medications other than the planned IMP may be taken during the trial. The use of
prescription, over-the-counter, or herbal medications, vitamin supplements, or St. John's
wort within 14 days prior to the first dosing and during the trial, and antibiotics within
30 days prior to the first dosing and during the trial is prohibited. Compassionate use
must be discussed with the sponsor on a case-by-case basis and the reason must be
documented.
4.2
Other Restrictions
4.2.1
Hospitalization of Subjects
Subjects will be hospitalized from the day before IMP administration in each period until
completion of the examinations on Day 5 of IMP administration. The investigator or
subinvestigator will confirm that there is no problem in the safety of subjects and then
discharge the subjects.
4.2.2
Restriction of Food Intake and Prohibition of Blood Donation
Subjects will be prohibited from taking any food or drink containing St. John’s wort from
14 days before IMP administration to the completion of blood collection at 168 hours
after administration on Day 8 in each treatment period.
Grapefruits, grapefruit products, Seville oranges, Seville orange products, starfruits, and
star fruit products will be prohibited from 7 days before IMP administration to the
completion of blood collection at 168 hours after administration on Day 8 in each
treatment period.
Subjects will be prohibited from taking alcohol from 3 days before IMP administration to
the completion of blood collection at 168 hours after administration on Day 8 in each
treatment period.


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Ingestion of food and beverages containing methylxanthine (eg, caffeinated coffee, tea,
carbonated beverages, and chocolate) will be prohibited from the time of hospitalization
to the completion of blood collection at 168 hours after administration on Day 8 in each
treatment period.
Blood donation will be prohibited during the trial.
4.2.3
Posture and Behavior
For 8 hours after administration on the day of IMP administration, rapid change of body
position should be avoided, except when necessary for examination, etc., and subjects
should sit in a chair or lie in a supine position. Subjects may walk from 8 hours after
administration; however, they will be instructed to avoid strenuous exercise.
Irregular activities such as strenuous exercise, overeating and overdrinking, and staying
up late should be avoided during the trial because they may affect the safety evaluation.
5
Adverse Event Reporting
5.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject
administered an IMP and which does not necessarily have a causal relationship with the
IMP. Adverse events would not include information recorded as complications at
screening for pre-planned procedures for which the underlying condition was known and
no worsening occurred.
An adverse reaction is any untoward and unintended response to an IMP related to any
dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting,
“reasonable possibility” means there is evidence to suggest a causal relationship between
the IMP and the AE. “Suspected adverse reaction” implies a lesser degree of certainty
about causality.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator or
subinvestigator, 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 disability/incapacity

Requires inpatient hospitalization or prolongs hospitalization.


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̵
Hospitalization itself should not be reported as a serious treatment-emergent AE
(TEAE); 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
serious TEAEs.

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) includes any event that results in any of the
following outcomes:

Any SAE

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4 Potential Serious Hepatotoxicity).

Pregnancy in the partner of a male subject. 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 be recorded in the adverse event section of the CRF only if
there is a complication or an abnormality in the newborn.
Clinical Laboratory Test Value Changes: It is the investigator’s or subinvestigator’s
responsibility to review the results of laboratory tests for each individual subject as they
become available. This review will be documented by the investigator’s or
subinvestigator’s dated signature on the laboratory report. The investigator or
subinvestigator should ascertain whether each abnormal laboratory value is an abnormal
change (ie, a clinically significant change) from baseline for that subject. It does not
necessarily have to be determined when an abnormal value is observed for the first time.
In addition, the investigator or subinvestigator 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 significant by the investigator or subinvestigator (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.


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Severity: Adverse events will be graded on a 3-point scale below and reported as
indicated in the CRF.
1 =Mild:
Discomfort noticed, but no disruption to daily activity.
2 =Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 =Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is
defined as follows:
Related:
There is a reasonable possibility of a temporal and causal
relationship between the IMP and the AE.
Not Related:
There is no temporal or causal relationship between the IMP and
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator or subinvestigator must assess or examine the subject for the occurrence
of adverse events. Adverse event information will be followed until the end of the trial
specified in Section 3.7.9. To avoid bias in eliciting AEs, subjects should be asked the
nonleading question: “How have you been feeling?” All AEs (serious and nonserious)
reported by the subject must be recorded on the source documents and CRF provided by
the sponsor. Since this is a crossover trial, changes from baseline in Period II will be
evaluated for adverse events in Period II. The following items will be recorded in the
CRF in accordance with the procedure for preparing the CRF prepared by the sponsor.

Name of event

Date of onset (time should also be recorded during hospitalization whenever possible)
and date of resolution

Severity

Seriousness (if applicable, the details should be recorded)

Causal relationship with the IMP

Outcome (recovered/resolved, recovering/resolving, recovered/resolved with
sequelae, not recovered/not resolved, fatal, unknown)
Collection of adverse events and serious adverse events will commence after the subject
has signed the informed consent form and will continue until the last date of observation.


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Medical terminology should be used for AE reporting. Adverse events should be reported
as a single unifying diagnosis whenever possible or, in the absence of a unifying
diagnosis, as individual signs or symptoms. Exacerbation or disease progression should
be reported as an AE only if there are unusual or severe clinical features that were not
present, or experienced earlier, or not expected based on the course of the condition.
Any change in severity or seriousness of a reported adverse event must be reported as a
new adverse event on the CRF.
In addition, the sponsor must be notified immediately by telephone or e-mail of any IREs
according to the procedure outlined in “Section 5.3 Immediately Reportable Events
(IRE).” Special attention should be paid to recording hospitalization and concomitant
medications.
5.3
Immediately Reportable Events (IRE)
After the investigator or subinvestigator, or designee becomes aware of any serious
adverse event, potential serious hepatotoxicity, drug-induced liver injury, or confirmed
pregnancy, the investigator or subinvestigator must immediately report the event. The
investigator or subinvestigator should complete the immediately reportable event form
(IRE form) and e-mail or overnight courier to the sponsor (see protocol title page for
contact information). (Note that the IRE form is a dedicated form provided by the
sponsor and not the adverse event section of the CRF.)
Subjects with serious adverse events should be followed as described in Section 5.7.2.
The investigator or subinvestigator should give appropriate treatment to the subject and
promptly report the latest information on the subject’s condition 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 in the CRF.
5.5
Pregnancy
Females of childbearing potential (FOCBP) are females 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 males and FOCBP, or their partners, who are sexually active, there must be a
documented agreement that the subject and their partner will take effective measures


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(ie, 2 different approved methods of birth control) to prevent pregnancy during the course
of the trial and for 30 days after the last dose of IMP. Unless the subject or their partner is
sterile (ie, females who have had a bilateral oophorectomy, have had a hysterectomy, or
have been postmenopausal for at least 12 consecutive months; or males who have had a
bilateral orchiectomy) or agrees to remain abstinent during the trial, 2 of the following
approved methods of birth control must be used: (vasectomy, tubal ligation, intrauterine
device, birth control pill, condom with spermicide, or occlusive cap [vaginal diaphragm
or cervical 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 CRF. Male subjects must also agree not to donate sperm from
trial screening through 30 days after the last dose of IMP.
Before enrolling males in this clinical trial, investigators or subinvestigators 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

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, males 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.
All subjects must be instructed to contact the investigator or subinvestigator immediately,
during the trial, if their partner suspects that they might be pregnant (eg, missed or late
menstrual cycle).
The investigator or subinvestigator must immediately notify the sponsor of any
pregnancy associated with IMP exposure during the trial and for at least 30 days after the
last dose of IMP, and record the event on the IRE form and forward it to the sponsor. The
sponsor will forward the Pregnancy Surveillance Form(s) to the investigator or
subinvestigator for monitoring the outcome of the pregnancy.
The investigator or subinvestigator must report to the sponsor, on the Pregnancy
Surveillance Form(s), follow-up information regarding the course of the pregnancy,


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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.
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 CRF with the current status (ongoing or resolved/recovered) noted. For subjects who
have an adverse event or have not recovered from an adverse event at the end of the trial
(last date of observation), a post-treatment follow-up visit should be scheduled at least
every 4 weeks until the adverse event resolves or stabilizes or the subject is lost to
follow-up or has died. This follow-up information will be documented in the subject’s
medical record. Resolution means that the subject has returned to the baseline state of
health and stabilized means that the investigator or subinvestigator does not expect any
further improvement or worsening of the subject’s condition. All nonserious events that
are ongoing at the end of the trial (last date of observation) will be recorded as “ongoing”
in the CRF. For any AE having been identified throughout the trial, during analysis,
additional relevant medical history information may be requested by the sponsor to
further ascertain causality (including, but not limited to, information such as risk-related
behavior, family history, and occupation).
5.7.2
Follow-up of Serious Adverse Events
Any serious adverse event that is ongoing at the end of the trial (last date of observation)
must be recorded on the adverse event page of the CRF and reported to the sponsor as
described in Section 5.3. Reportable events include previously reported serious adverse
events that have not resolved or new serious adverse events. All serious adverse events
that are ongoing at the end of the trial (last date of observation) must be recorded as
“ongoing” in the CRF. The investigator or subinvestigator will continue to follow up to
the point these serious adverse events have resolved or stabilized, or the subject is lost to
follow-up, or has died. Resolution means that the subject has returned to the baseline
state of health and stabilized means that the investigator or subinvestigator does not
expect any further improvement or worsening of the subject’s condition. The investigator
or subinvestigator will continue to report any significant follow-up information to the
sponsor on the IRE form up to the point the serious adverse event has resolved or
stabilized, or the subject is lost to follow-up, or has died.


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5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring
After the End of the Trial (Last Date of Observation)
Any new serious adverse events reported by a subject to the investigator or
subinvestigator which occur after the end of the trial (last date of observation) and are
determined by the investigator or subinvestigator to be reasonably associated with the use
of the IMP, should be reported to the sponsor. This may include serious adverse events
that are captured on follow-up telephone contact or at any other time point after the
defined trial period. For serious adverse events identified after the end of the trial (last
date of observation), the investigator or subinvestigator will follow up the event until it
resolves or stabilizes or the subject is lost to follow-up or has died and report crucial
follow-up information to the sponsor using the immediately reportable event form (IRE
form).
6
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic
Analysis
6.1
Pharmacokinetic Analysis Methods
6.1.1
Cohort 1
In Cohort 1, blood samples for measurement of aripiprazole will be collected before and
1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 144, and 168 hours after administration in each
period. The pharmacokinetic parameters (Cmax, AUCt, AUC∞, AUC168h, tmax, t1/2,z, λz, tlast,
CL/F, AUC_%Extrap, and MRT∞) of aripiprazole will be calculated by non-
compartmental pharmacokinetic analysis. Descriptive statistics of plasma concentrations
and pharmacokinetic parameters of aripiprazole will be presented by treatment (ASC-01
or concomitant administration of aripiprazole and sertraline).
6.1.2
Cohort 2
In Cohort 2, blood samples for measurement of aripiprazole and sertraline will be
collected before and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 144, and 168 hours after
administration in each period. The pharmacokinetic parameters (Cmax, AUCt, AUC∞,
AUC168h, tmax, t1/2,z, λz, tlast, CL/F, AUC_%Extrap, and MRT∞) of aripiprazole and
sertraline will be calculated by non-compartmental pharmacokinetic analysis. Descriptive
statistics of plasma concentrations and pharmacokinetic parameters of aripiprazole and
sertraline will be presented by treatment (administration under a fasting condition or
under a fed condition).


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6.2
Pharmacodynamic Analysis Methods
Pharmacodynamic endpoints will not be examined.
6.3
Pharmacokinetic/Pharmacodynamic Analysis Methods
No pharmacokinetic/pharmacodynamic analyses are planned.
6.4
Pharmacogenomic Analysis Methods
No pharmacogenomic analyses are planned.
7
Statistical Analyses
7.1
Sample Size
For Cohort 1, the sample size was determined by the method of Diletti18 as the number of
subjects required for the 90% confidence intervals for the differences in the log-converted
mean Cmax and AUC168h of aripiprazole between single administration of ASC-01 and
concomitant single administration of aripiprazole and sertraline to be within the
acceptable range for bioequivalence of ln(0.8) to ln(1.25) based on the BE Guideline.13
In the results of a pharmacokinetic trial conducted to examine the bioavailability of ASC-
01 (031-11-004), the ratios of the geometric mean Cmax and AUC168h of aripiprazole were
respectively 1.12 and 1.05 and the within-subject variances were 0.029 and 0.006. The
proportion of subjects excluded from the pharmacokinetic analysis due to vomiting or
withdrawal was approximately 40%.
Assuming the ratio of the geometric mean Cmax of aripiprazole between administration of
ASC-01 and concomitant administration of aripiprazole and sertraline and the within-
subject variance to be, respectively, 1.1 and 0.029, the number of subjects required to
ensure a statistical power of 90% or higher is 16 per group (32 subjects in total).
Assuming a 40% rate of exclusion from analysis due to withdrawal or vomiting, the
sample size for Cohort 1 is set at 27 subjects per group (54 subjects in total).
For Cohort 2, referring to the FDA guidance,14 the sample size required for the analysis
of food effect on the pharmacokinetics of ASC-01 is 6 subjects per group (12 subjects in
total). In consideration of the possibility of exclusion from analysis due to withdrawal or
vomiting, the sample size for Cohort 2 is set at 10 subjects per group (20 subjects in
total).


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7.2
Datasets for Analysis
7.2.1
Pharmacokinetic Analysis Set
Subjects who received the IMP and whose plasma concentration was measured
7.2.2
Bioequivalence Analysis Set
Subjects from whom Cmax and AUC168h were obtained in both Periods I and II in Cohort 1
7.2.3
Food Effect Analysis Set
Subjects from whom Cmax, AUCt, AUC∞, and AUC168h were obtained in both Periods I
and II in Cohort 2
7.2.4
Safety Analysis Set
Subjects who received at least one dose of IMP
7.3
Handling of Missing Data
Missing data will not be imputed.
7.4
Primary and Secondary Endpoint Analysis
The following analyses will be performed on the bioequivalence analysis set for Cohort 1
and the food effect analysis set for Cohort 2.
7.4.1
Primary Endpoint Analysis
In Cohort 1, analysis of variance will be performed on log-converted (natural logarithm)
values for the Cmax and AUC168h of aripiprazole using group (group receiving
administration of ASC-01 first or group receiving concomitant administration of
aripiprazole and sertraline first), treatment (ASC-01 or concomitant administration of
aripiprazole and sertraline), subjects within group, and treatment period as factors. The
90% confidence intervals for the differences in the mean Cmax and AUC168h of
aripiprazole between ASC-01 administration and concomitant administration of
aripiprazole and sertraline will be calculated. If the 90% confidence intervals are within
the range of ln(0.8) to ln(1.25), single administration of ASC-01 and single concomitant
administration of aripiprazole and sertraline will be judged to be bioequivalent for
aripiprazole.
If an add-on subject study is conducted, bioequivalence will be assessed based on the
combined results of this trial and the add-on subject study using the same criteria.


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In Cohort 2, analysis of variance will be performed on log-converted (natural logarithm)
values for the Cmax, AUCt, AUC∞, and AUC168h of aripiprazole and sertraline using group
(group receiving ASC-01 under a fasting condition first or group receiving ASC-01 under
a fed condition first), treatment (administration under a fasting condition or under a fed
condition), subjects within group, and treatment period as factors. The 90% confidence
intervals for the differences in the mean Cmax, AUCt, AUC∞, and AUC168h of aripiprazole
and sertraline between administration under a fasting condition and administration under
a fed condition will be calculated.
If there are any subjects in each cohort from whom evaluable parameters cannot be
obtained in both Periods I and II, sensitivity analysis including those subjects will also be
performed.
7.4.2
Secondary Endpoint Analysis
Described in "6.1 Pharmacokinetic Analysis Methods."
7.5
Analysis of Demographic and Other Baseline Characteristics
Frequency distributions or descriptive statistics for age, height, body weight (screening
period), BMI, past history or present illness will be generated for each randomized group
and for the entire population in the bioequivalence analysis set in Cohort 1 and in the
food effect analysis set in Cohort 2. Similar summarizations will be performed for other
analysis sets by cohort as necessary.
7.6
Safety Analysis
Safety analysis will be performed by cohort and treatment in the safety analysis set.
Baseline will be the value immediately before IMP administration in each period.
7.6.1
Adverse Events
All AEs will be coded by system organ class and preferred term according to the Medical
Dictionary for Regulatory Activities (MedDRA). The incidence of the following events
will be summarized:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs
Additionally, TEAEs related to the IMP will be summarized in the same manner.


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7.6.2
Clinical Laboratory Data
For each clinical laboratory parameter other than urine qualitative test parameters,
descriptive statistics of the measured values at each time point and change from baseline
will be determined. For qualitative urinalysis parameters in clinical laboratory tests, shift
tables from baseline to each time point will be generated. Clinical laboratory parameters
other than qualitative urinalysis parameters will be classified as "within reference range,"
"below reference range," or "above reference range" using institutional reference values,
and shift tables from baseline to each time point will be generated.
7.6.3
Physical Examination and Vital Signs Data
For physical examination, physical findings of individual subjects will be listed.
For vital signs, descriptive statistics of measured values and changes from baseline will
be presented by time.
7.6.4
Electrocardiogram Data
For each parameter of 12-lead electrocardiography, descriptive statistics of the measured
values at each time point and change from baseline will be determined. For
normal/abnormal assessment of 12-lead electrocardiography, a shift table from baseline
to each time point will be prepared. Categorical analysis will be performed for the
measured values of corrected QT interval (Fridericia correction method [QTcF] and
Bazzett correction method [QTcB]) and their changes from baseline at each time point,
and the number and percentage will be calculated.
7.6.5
Other Safety Data
7.6.5.1
Body Weight
For body weight, descriptive statistics will be provided for measured values and changes
from baseline.
7.6.5.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS of individual subjects will be presented in a listing.
7.7
Pharmacodynamic Analysis
No pharmacodynamic analyses are planned.
7.8
Decision to Conduct Add-on Subject Study
For Cohort 1, if bioequivalence cannot be demonstrated in this trial due to an insufficient
number of subjects, an add-on subject study may be performed once in the same manner


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as the trial. However, the add-on subject study should be conducted using at least half the
number of subjects included in the trial. The add-on subject study will not be conducted
in the following cases:

The difference in the mean log-converted Cmax and AUC168h between administration
of ASC-01 and concomitant administration of aripiprazole and sertraline does not fall
within the range of ln(0.8) to ln(1.25) as a result of this trial.

The number of subjects required for the add-on subject study calculated from the
results of the trial is considered unfeasible from an ethical or scientific point of view.
When data from the add-on subject study are pooled and analyzed with the data from the
trial, study will also be included as a variable factor in the analysis.
8
Management of Investigational Medicinal Product
ASC-01 is a test formulation and will be provided as an IMP. Aripiprazole 3-mg tablets
will be provided as a reference formulation, and sertraline 50-mg tablets will be provided
as a reference formulation, etc., for consistency of conditions.
Refer to the Investigator's Brochure and the Clinical Operations Manual for details of
management of IMP and reference formulation, etc.
8.1
Packaging and Labeling
The IMP will be provided to the IMP manager by the sponsor or a designated contractor.
Each package box to be used during the treatment period will be labelled to state “For
clinical trial use only” as well as the protocol number, IMP code or generic name,
quantity, lot number, expiration date, storage conditions, sponsor’s name and address,
and precautions for use.
8.2
Storage
The IMP and reference formulation, etc., will be stored in a securely locked cabinet or
enclosure. Access will be limited to the IMP manager. The IMP administrator must not
provide the IMP and reference formulation, etc., to subjects not participating in this trial.
The IMP and reference formulation, etc., will be stored at room temperature.
The trial site staff will measure and record the temperature in the drug storage area at
least once a working day.


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8.3
Accountability
. The IMP manager maintain an inventory record of IMP and reference formulation
received, dispensed, administered, and returned (or destroyed).
8.4
Returns and Destruction
At the completion or termination of the trial, all unused or partially used IMP and
reference formulation, etc., must be returned to the sponsor.
All IMPs and reference formulations, etc., to be returned to the sponsor must be
accompanied by documentation of storage and the protocol number and site number must
be clearly identified on the outermost portion of the shipping container. Returned IMP
and reference formulation, etc. should be in the original containers. The monitor in
charge will support the return of unused or partially used IMP and reference formulation,
etc.
8.5
Reporting of Product Quality Complaints
A product quality complaint (PQC) is any deficiency or complaint related to the identity,
quality, labeling, packaging, reliability, safety, durability, tampering, counterfeiting,
theft, efficacy, or function of an IMP or medical device that is reported in writing,
electronically, or orally by a healthcare professional, consumer, subject, medical
representative, competent authority, regulatory authority, partner company, affiliate, or
another third party after it is provided for distribution. Examples include, but are not
limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under-fill, 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 subinvestigator or designee must record each PQC identified through
any means from the receipt of the IMP from the sponsor or sponsor’s designee, including
subject dosing, through and including last confirmation and up to destruction. The


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investigator or subinvestigator or designee must immediately notify the sponsor (or
designee) of the PQC by e-mail or telephone as indicated below.

PQC_031-102-00214@otsuka.jp
Send the information shown in "8.5.2 Information Required at the Time of Reporting
Product Quality Complaints" to the above e-mail address.
Identification of a PQC by the subject should be reported to the investigator or
subinvestigator, who should then follow the reporting mechanism above.
8.5.2
Information Required at the Time of Reporting Product Quality
Complaints
The following information is required for reporting:

Description of complaint

Reporter identification (eg, subject, investigator or subinvestigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

Product name (product or compound name, kit number, or bottle number)

Clinical protocol reference (number and trial name)

Dosage form/strength (if known)

Pictures of complaint sample (if available)

Availability of complaint sample for return
8.5.3
Procedure for Returning Investigational Medicinal Product If
There Is a Product Quality Complaint
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 return instructions,
when applicable.
It must be documented in the site accountability record that the complaint sample for a
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a
clinical investigation. Source documents will include but are not limited to medical


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records, electronic data, screening logs, and recorded data from automated instruments or
applications. 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 site, an investigator or a subinvestigator will record
information 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 or subinvestigator’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 or subinvestigator’s assessment of relationship to IMP must also be
recorded;

Description of medical practice performed

The signature (or initials) and date of the investigator or subinvestigator (or designee)
who made an entry in the medical record.
In addition, any contact with the subject via telephone or other means that provides
significant clinical information will also be documented in the medical record as
described above. Any changes to information in medical records and other 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
investigator or subinvestigator. If electronic data systems are used, a full audit trail of the
change must be maintained.
Information from medical records and other source documents will be directly entered by
investigative site personnel in the sponsor’s electronic data capture (EDC). Changes to


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the data will be captured by an automatic audit trail. Information recorded in medical
records and other source documents will be immediately and clearly transcribed to the
CRF and submitted to the sponsor. Any changes to information in paper source
documents or CRF 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
investigator or subinvestigator.
9.3
File Management at the Trial Site
The head of the trial site will ensure that the files are stored at the trial site in accordance
with ICH GCP Guideline E6, Section 8 and applicable local regulations. The files to be
stored at the trial site will contain all source documents and data from the completed CRF
for all subjects screened or enrolled at the site. The investigator or trial site must take
measures to maintain the confidentiality of these records and to prevent their loss or
destruction during the required retention period.
9.4
Records Retention at the Trial Site
The trial site will retain all documents and records related to this trial for either of the
following 2 periods, whichever comes later. However, if the sponsor requires a longer
retention period, the retention period and retention method will be discussed with the
sponsor.

A period of at least 2 years after the date on which approval to market the drug is
obtained; However, if a notification is received that development is discontinued or
results of the trial will not be attached to the approval application form, the date 3
years after the date of receipt of the notification that development is discontinued or
results of the trial will not be attached to the application form.

Three years after discontinuation or completion of the trial
The investigator must not dispose of any records relevant to this trial without either
(1) written permission from the sponsor or (2) provision of an opportunity for 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 discontinues participation in the trial or in case of discontinuation
during the record retention period (eg, due to relocation, retirement, site closure), all trial-


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related records must be transferred to a mutually agreed-upon designee for the closure of
the trial site within a sponsor-specified time frame. Notice of such transfer will be given
to the sponsor in writing.
10
Quality Control and Quality Assurance
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to carefully follow this trial in
accordance with established research principles, ICH E6 GCP: Consolidated Guidance,
and applicable regulatory requirements and local laws. As part of an effort to fulfill these
obligations (ie, ensure personnel are kept up to date regarding the progress of the trial),
the monitor of the sponsor (or representative of the sponsor) will visit the trial site during
the course of the trial in addition to regular contacts by phone, e-mail, and written
document. In addition, all investigators or subinvestigators and trial site personnel will
undergo initial and ongoing training for this particular trial, and this training will be
clearly documented.
10.2
Auditing
The Quality Assurance Unit (or its representative) of the sponsor (or designee) may
conduct trial site audits. Audits will include, but are not limited to, IMP supply, presence
of required documents, the informed consent process, and a review of the CRF with
source documents, as applicable. The investigator will agree to cooperate and participate
with audits.
Regional regulatory authorities may inspect the investigator site during or after the trial.
The investigator will fully cooperate with such inspections and will contact the sponsor
immediately if such an inspection occurs.
10.3
Protocol Deviations
Due to the complexity of the protocol, protocol deviations may occur despite training and
preventative measures, and such deviations may result in harm to subjects, biased or
inaccurate results, or rejection of all or part of the trial data. According to Section 10.2 of
the ICH E3 “Guideline for Structure and Content of Clinical Study Reports,” protocol
deviations should be appropriately summarized by trial site and categorized as follows:

Subject enrolled in violation of eligibility criteria

Subject met the withdrawal criteria during the study but were not withdrawn

Subject received the wrong treatment or incorrect dose

Subject received an excluded concomitant treatment


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Otsuka Pharmaceutical classifies protocol deviations as significant or minor. A
significant deviation is any intentional or unintentional act/omission during the conduct
of a clinical trial that may have an adverse effect on the integrity of the primary scientific
objective of the trial or that may have a significant potential effect on the safety
evaluation of subjects. A significant deviation is one that may significantly affect the
integrity, accuracy, or reliability of the trial data or that may significantly affect the
rights, safety, or welfare of subjects.
A minor deviation is any intentional or unintentional act/omission during the conduct of a
clinical trial that is not in strict compliance with the protocol but has minimal impact on
the overall integrity of the trial or on the evaluation of safety or efficacy analysis in an
individual subject.
All protocol deviations will be classified as significant or minor based on the definitions
described above, and only significant deviations will be summarized in the clinical study
report.
If the same type of protocol deviation occurs in more than one subject, the deviation must
be recorded separately for each subject.
The investigator or subinvestigator will document any suspected protocol deviations and
also document medical judgment as to whether or not to continue the subject's
participation in the trial due to protocol deviations.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP guidelines (E6),
international ethical principles derived from the Declaration of Helsinki and Council for
International Organizations of Medical Science (CIOMS) guidelines, and applicable local
laws and regulations. Each trial site will seek approval/favorable opinion by an IRB
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 the CRF, the investigator or
subinvestigator, and their staff will take measures to ensure adequate care in protecting
subject privacy. To this end, a subject number or subject ID will be used to identify each
subject.
Financial aspects, subject insurance, and the publication policy for the trial will be
documented in the agreement between the sponsor and the investigator.


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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 ID in the CRF. If further subject
identification is required, subjects’ full names may be made known to a regulatory
agency or other authorized officials if necessary, subject to local regulations.
13
Protocol Amendments
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 change to
the protocol, whether an overall change or a change for specific trial site(s), must be
handled as a protocol amendment. Any amendment will be written by the sponsor. Each
amendment will be submitted to the IRB, as required by local regulations. Except for
“administrative” or “nonsubstantial” amendments, investigators or subinvestigators 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 agencies 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.


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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 subjects 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 subjects consent to such acknowledgement in any
publications resulting from its conduct.
15
References
1
Drug interview form of aripiprazole preparation (ABILIFY® tablets, 1 mg, 3 mg, 6 mg, and 12
mg; OD tablets, 3 mg, 6 mg, 12 mg, and 24 mg; ABILIFY® powder 1%; and ABILIFY® oral
solution 0.1%), Mar 2017 (revised version 19)
2
Bristol-Myers Squibb Company, Otsuka America Pharmaceutical, Inc. ABILIFY® (aripiprazole)
tablets, ABILIFY DISCMELT® (aripiprazole) orally disintegrating tablets, ABILIFY®
(aripiprazole) oral solution, and ABILIFY® (aripiprazole) injection for intramuscular use only.
US package insert updated in Dec 2017
3
Package insert of sertraline hydrochloride (Jzoloft tablets, 25 mg, 50 mg, and 100 mg, and OD
tablets, 25 mg, 50 mg, and 100 mg), Mar 2015 (revised version 13)
4
Drug interview form of sertraline hydrochloride (Jzoloft tablets, 25 mg, 50 mg, and 100 mg, and
OD tablets, 25 mg, 50 mg, and 100 mg), Mar 2016 (revised version 15)
5
Harada Y, Kohara N, Imaeda T. Pharmacological, pharmacokinetic, and clinical characteristics
of sertraline hydrochloride (Jzoloft TM tablets, 25 mg and 50 mg) for the treatment of depression
and panic disorder. Folia Pharmacologica Japonica 2006;128:417-26.
6
Inoue T, Suzuki K, Nakagawa S, et al. Study of treatment for SSRI/SNRI-resistant depression.
Psychiatria et Neurologia Japonica 2003;105:1318.
7
Lecrubier Y. How do you define remission ?. Acta Psychiatr Scand 2002; 106: 7-11.


Protocol 031-102-00214
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8
Japanese Society of Mood Disorders Treatment Guidelines Committee. Japanese Society of
Mood Disorders Treatment Guideline II. Depression (DSM-5)/Major Depressive Disorder 2016.
[Internet]: 31 Jul 2016 [Connected on 24 Oct 2016]. Connection destination:
http://www.secretariat.ne.jp/jsmd/mood_disorder/img/160731.pdf
9
Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, et al.
Practice guideline for the treatment of patients with major depressive disorder, Third edition.
2010.
10
Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, et al. World federation of
societies of biological psychiatry (WFSBP) guidelines for biological treatment of unipolar
depressive disorders in primary care. World J Biol Psychiatry. 2007;8(2):67-104.
11
Xie L, Frech-Tamas F, Marrett E, Baser O. A medication adherence and persistence comparison
of hypertensive patients treated with single-, double- and triple-pill combination therapy. Curr
Med Res Opin. 2014;30(12):2415-22.
12
Patel BV, Leslie RS, Thiebaud P, Nichol MB, Tang SS, Solomon H, et al. Adherence with
single-pill amlodipine/atorvastatine vs a two-pill regimen. Vasc Health Risk Maneg.
2008;4(3):673-81.
13
Guideline for Bioequivalence Studies of Generic Products (Division-Notification 0229 No. 10 of
the Pharmaceutical and Food Safety Bureau, dated 29 Feb 2012)
14
Guidance for industory: Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S.
department of Health and Human Services Food and Drug Administration Center for Drug
Evaluation and Research (CDER); 2002
15
Shimada E, Murasaki M, Kawaguchi T, Fukuyama Y. Phase I clinical studies of aripiprazole—
safety and pharmacokinetics in healthy adult male volunteers after single and repeated
administration. Japanese Journal of Clinical Psychopharmacology 2005;8:695-731.
16
Ueshima K, Otsubo T, Ota A, Nozaki S, Inamoto A, Hashimoto T et al. Phase I study of
sertraline hydrochloride (CP-51, 974-1)—single-dose study. Japanese Journal of
Neuropsychopharmacology 1997;19:395-423.
17
International Council for Harmonisation (ICH) [homepage on the Internet]. E6: Good Clinical
Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 Jun 1996; cited 2014 Dec
5]. Available from:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf.
18
Diletti.E, Hauschke.D, Steinijans.W.V. Sample size determination for bioequivalence assessment
by means of confidence intervals. International J.of Clinical Pharmacology, Therapy, and
Toxicology. 1991;29(1):1-8.


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Appendix 1
Bioanalytical Sample Handling and Shipment
Handling of Samples
Each storage tube should be labeled securely. The label should include the protocol
number, subject number or subject ID, time of administration (eg, Periods I and II), and
time of sampling (eg, 8 hours after administration). The actual time of collection, not the
scheduled time of collection, should be accurately entered in the CRF.
Plasma Samples
Venous blood should be collected via an indwelling catheter or direct venipuncture into a
2-mL evacuated blood collection tube containing heparin sodium. When an indwelling
catheter is used, it should be filled with saline or heparin as needed for placement. After
blood sample collection, the tube should be gently inverted several times to mix the
contents well. Within 45 minutes after collection, the sample should be centrifuged in a
refrigerated centrifuge at about 4C (1500 to 1800 × G [about 3000 rpm] for about 10
minutes). Approximately equal volumes of plasma should be transferred into two
appropriately labeled storage tubes using a standard laboratory technique. Within 90
minutes of collection, the two plasma samples should be stored in a freezer set to – 15C
or colder. Aliquot plasma sample 1 should be sent to Sumika Chemical Analysis Service,
Ltd. (SCAS). Aliquot plasma sample 2 should be sent to SCAS separately from aliquot
plasma sample 1. Samples should be placed in an airtight container filled with dry ice
sufficient for shipment.
Any remaining plasma samples will be stored at SCAS and destroyed after the clinical
study report has been prepared.


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Appendix 2
Baseline Columbia-Suicide Severity Rating Scale
Columbia-Suicide Severity Rating Scale
(C-SSRS)
Baseline Assessment
14 Jan 2009 Version
Posner, K.; Brent, D.;Lucas, C; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny,
J.; Burke, A.; Oquendo, M.;Mann, J.
Disclaimer:
This scale is intended for use by trained physicians. The questions on the Columbia-Suicide Severity Rating Scale
(C-SSRS) are suggested examples of assessment methods.
The final determination of suicidality is left to the physician.
The definition of suicidal behavior in this scale is based on that used in The Columbia Suicide History
Form.*
*Development: John Mann, MD, and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M.A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In
M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103-130, 2003.)
If you wish to copy or reproduce the C-SSRS, please contact the following:
Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New York, New York.10032
For training or other questions, please contact: posnerk@childpsych.columbia.edu.
C-SSRS Baseline-Japan/Japanese-Version of 12 Mar 10-Mapi Research Institute.
ID5353/C-SSRS-Baseline_AU3.0_jpn-JP.doc


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Suicidal Ideation
Ask 1 and 2. If both are no, proceed to the Suicidal Behavior section.
If the answer to 2 is yes, ask 3, 4, and 5. If the answer to 1 or 2 is yes, complete the Degree of Suicidal Ideation section
below.
The time in life
when suicidal
ideation was
most severe
1. Desire to die
When the subject acknowledges that he wants to die, not live anymore, or not wake up while asleep.
Have you ever wanted to die or not wake up while asleep?
If yes, details
Yes
□
No
□
2. Active suicidal ideation - not specific
When the subject acknowledges that there was vague and non-specific suicidal ideation (eg, “I have thought about suicide”) but the method
of suicide, related measures, intent, or plan was not considered.
Have you actually felt like killing yourself?
If yes, details
Yes
□
No
□
3. Active suicidal ideation with any methods (not plan) without intent to act
When the subject acknowledges that he had suicidal ideation and considered at least one suicide method during the evaluation period. This
is different from the specific plan (date and time, location, and method) (eg, suicide method was considered but no specific plan was
developed). It also includes the answer, “I thought I would die with a drug, but I don't have a concrete plan for when, where, and how to
implement it, and I think I never do it.”
Have you thought about how to commit suicide?
If yes, details
Yes
□
No
□
4. Active suicidal ideation with some intent to act, without specific plan
When the subject acknowledges that he has suicidal ideation with some intent to act on such thoughts. It is different from the statement, “I
have thoughts (of suicide), but I have no intention to do anything.”
Have you ever thought you would like to commit suicide and want to execute it?
If yes, details
Yes
□
No
□
5. Active suicidal ideation with specific plan and intent
When the subject has suicidal ideation with a specific plan (complete or partial) and some intent to act.
Do you have a specific plan for how to commit suicide? Do you intend to implement the plan?
If yes, details
Yes
□
No
□
Degree of Suicidal Ideation
The following questions rate the most severe suicidal ideation (eg, in 1 to 5 above, 1 represents the least severe ideation and
5 represents the most severe ideation). Ask when suicidal ideation was most severe.
Most severe suicidal ideation:
Most severe
Type no. (1 to 5)
Description of suicidal ideation
Frequency
How often did you think so?
____
(1) Less than once a week
(2) Once a week
(3) Two to five times a week
(4) Every day/almost every day
(5) Many times a day
Duration
How long did these thoughts last?
____
(1) Several seconds to several minutes/instantaneous
(2) Less than 1 hour/for a while
(3) 1 to 4 hours/quite a while
(4) 4 to 8 hours/most of the day
(5) 8 hours or more/continuous
Control
Can/could you suppress thoughts of suicide or thoughts of wanting to die if you want/wanted to?
____
(1) Easily able to suppress thoughts
(2) Can suppress thoughts although it is a little difficult
(3) Some difficulty but can suppress thoughts
(4) Very difficult but can suppress thoughts
(5) Cannot suppress thoughts
(0) Not willing to suppress thoughts
Deterrents
Is there any person or thing (eg, family, religion, pain of dying) that suppressed your thoughts of wanting to die
or stopped you from committing suicide?
____
(1) Deterrents stopped me from committing suicide
(2) Deterrents probably stopped me from committing suicide
(3 ) Not sure if the deterrents stopped me from committing suicide
(4) Deterrents probably do not stop me from committing suicide
(5) Deterrents do not stop me from committing suicide
(0) Not applicable
Reasons for Suicidal Ideation
Why did you want to die or commit suicide? Was it to end the pain or evade the emotions you had at that time
(eg, you could not live with such pain or emotions)? Was it to get someone’s attention, revenge, or a reaction?
Was it both?
____
(1) Solely to get someone’s attention, revenge, or a reaction
(2) Mostly to get someone’s attention, revenge, or a reaction
(3) Both (50/50) to get someone’s attention, revenge, or a reaction
and to end the pain
(4) Mostly to end the pain (unable to live with the pain or emotions)
(5) Solely to end the pain (unable to live with the pain or emotions)
(0) Not applicable


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Suicidal Behavior
(Tick all that apply. Asked about all types of suicidal behavior listed below.)
In past life
Suicide attempt:
When behavior that may cause self-harm was associated with any desire to die as a result of the behavior. When the behavior was considered to some
extent as a means of suicide. This includes cases where the intent to commit suicide is not complete. If the subject has an intent or desire to die as a
result of the behavior even a little, it is considered a "suicide attempt." This includes cases where there is a risk of physical damage even without
actual physical damage. When a gun is in the mouth and the trigger is pulled, it is considered a "suicide attempt" even if the gun is broken and
no physical damage is caused.
When suicidal intent is presumed: When suicidal intent can be presumed from the behavior and circumstances even if the subject denies intent or desire
to die. For example, when behavior is extremely lethal and obviously not an accident, and its only possible intent is suicide (eg, gunshot to head, jumping
from an upper floor). Even if the subject denies intent to commit suicide, the intent to commit suicide can be presumed if the subject believes at the time
that his behavior may result in death.
Have you ever attempted suicide?
Have you done anything to harm yourself?
Have you done any dangerous behavior that could result in death?
What did you do?
Was ______ as a means of suicide?
Did you want to die (even a little) when you ______?
Were you trying to die when you ______?
Or, were you aware of the possibility of death when you ______?
Or did you not intend to die when you did it, and did you have another reason (eg, stress relief, feel better, get
sympathy, change circumstances)? (Self-injurious behavior without suicidal intent)
If yes, details
Have you had any self-injurious behavior without suicidal intent?
Yes No
□□
Total number
of times
_____
Yes No
□□
Interrupted suicide attempt:
When behavior that might result in self-harm was interrupted (due to external factors) (if it had not been interrupted, it would have resulted in
“suicide attempt”).
Drug overdose: The subject took the drug in hand but stopped taking it. Even a small dose is considered a "suicide attempt" rather than an "interrupted
suicide attempt." Gun suicide: The subject directed a gun to himself, but someone took the gun away or prevented him from pulling the trigger in some
way. When the subject pulls the trigger, even if the gun fails to fire, it is considered a "suicide attempt." Jumping: The subject was in a position to jump
down but was pulled down. Hanging: A rope was around the neck but hanging was blocked.
Have you been stopped by someone else or something after you started to commit suicide and before you
actually proceed to behavior that would end your life?
If yes, details
Yes No
□□
Total number
of times
_____
Self-interrupted suicide attempt:
When the subject nearly attempted suicide but held back before actually proceeding to self-destructive behavior. This is similar to an example
of "interrupted suicide attempt," but it refers to the case where suicide attempt was interrupted by the subject himself and not by something
else.
Have you held back after starting to commit suicide and before actually proceeding to behavior that would end
your life?
If yes, details
Yes No
□□
Total number
of times
_____
Preparatory behavior:
Any preparation or behavior in preparation for suicide that exceeds the level of verbalizing or thinking about suicide. For example, preparing
for suicide means (eg, obtain drugs, purchase weapons) and preparing for death from suicide (eg, release personal belongings, write a suicide
note).
Have you taken any action in preparation for suicide attempt or suicide? (eg, obtain a drug, obtain a weapon,
release an important thing, write a suicide note)
If yes, details
Yes No
□□
Suicidal behavior:
Suicidal behavior was observed during the evaluation period.
Yes No
□□
Answer only when "suicide attempt" occurred
Date of
most
recent
suicide
attempt:
Date of
most lethal
suicide
attempt:
Date of first
suicide
attempt:
Actual lethality/physical damage:
0. No physical damage or extremely mild physical damage (eg, scratch)
1. Mild physical damage (eg, slurred speech, first-degree burns, mild bleeding, sprain)
2. Moderate physical damage requiring treatment (eg, conscious but lightheaded, somewhat responsive,
second-degree burns, bleeding from vessel)
3. Slightly severe physical damage that requires hospitalization and likely to require intensive care (eg,
comatose but normal reflexes, third-degree burns of <20%, major bleeding but can recover, major fractures)
4. Severe physical damage requiring hospitalization with intensive care (eg, comatose with reflexes missing,
third-degree burns of ≥20%, major bleeding with unstable vital signs, major damage to life-threatening area)
5. Death
Enter code
______
Enter code
______
Enter code
______
Likelihood of Lethality: Answer only if actual lethality/physical damage = 0
The lethality of "suicide attempt" without physical damage. (In the following cases, there is no actual physical
damage but extremely high likelihood of lethality: The subject put a gun in the mouth and pulled the trigger, but
no physical damage occurred because the gun did not fire. The subject lay on train railway but exited before
being run over.)
0 = Suicidal behavior with low potential for physical damage
1 = Suicidal behavior that is likely to cause physical damage but unlikely to result in death
2 = Suicidal behavior that is likely to result in death despite treatment
Enter code
______
Enter code
______
Enter code
______


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Appendix 3
Since Last Visit Columbia-Suicide Severity Rating Scale
Columbia-Suicide Severity Rating Scale
(C-SSRS)
Since Last Visit
14 Jan 2009 Version
Posner, K.; Brent, D.;Lucas, C; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny,
J.; Burke, A.; Oquendo, M.;Mann, J.
Disclaimer:
This scale is intended for use by personnel trained in its administration. The questions on the Columbia-Suicide
Severity Rating Scale (C-SSRS) are suggested examples of assessment methods.
The final determination on the presence or absence of suicidal ideation or behavior is left to the individual who
administered the scale.
The definition of suicidal behavior in this scale is based on that used in The Columbia Suicide History
Form.*
*Development: John Mann, MD, and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M.A.,
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In
M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103-130, 2003.)
If you wish to copy or reproduce the C-SSRS, please contact the following: Kelly Posner, Ph.D., New York
State Psychiatric Institute, 1051 Riverside Drive, New York, New York, 10032
For training or other questions, please contact: posnerk@childpsych.columbia.edu.
© 2008 The Research Foundation for Mental Hygiene, Inc.
C-SSRS Since Last Visit-Japan/Japanese-Version of 10 Jul 15-Mapi.
ID0415933/C-SSRS-SinceLastVisit_AU5.1_jpn-JP.doc


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Suicidal Ideation
Ask 1 and 2. If both are no, proceed to the Suicidal Behavior section. If the answer to 2 is yes, ask 3, 4, and 5. If the answer to
1 or 2 is yes, complete the Degree of Suicidal Ideation section below.
Since Last
Visit
1. Desire to die
When the subject acknowledges that he wants to die, not live anymore, or not wake up while asleep.
Have you ever wanted to die or not wake up while asleep?
If yes, details
Yes
No
□
□
2. Active suicidal ideation - not specific
When the subject acknowledges that there was vague and non-specific suicidal ideation (eg, “I have thought about suicide") during the
evaluation period but the method of suicide, related measures, intent, or plan was not considered.
Have you actually felt like killing yourself?
If yes, details
Yes
No
□
□
3. Active suicidal ideation with any methods (not plan) without intent to act
When the subject acknowledges that he had suicidal ideation and considered at least one suicide method during the evaluation period.
This is different from the specific plan (date and time, location, and method) (eg, suicide method was considered but no specific plan was
developed). It also includes the answer, "I thought I would die with a drug, but I don't have a concrete plan for when, where, and how to
implement it, and I think I never do it."
Have you thought about how to commit suicide?
If yes, details
Yes
No
□
□
4. Active suicidal ideation with some intent to act, without specific plan
When the subject acknowledges that he has suicidal ideation with some intent to act on such thoughts. It is different from the statement, “I
have thoughts (of suicide), but I have no intention to do anything.”
Have you ever thought you would like to commit suicide and want to execute it?
If yes, details
Yes
No
□
□
5. Active suicidal ideation with specific plan and intent
When the subject has suicidal ideation with a specific plan (complete or partial) and some intent to act.
Do you have a specific plan for how to commit suicide? Do you intend to implement the plan?
If yes, details
Yes
No
□
□
Degree of Suicidal Ideation
The following questions rate the most severe suicidal ideation (eg, in 1 to 5 above, 1 represents the least severe ideation
and 5 represents the most severe ideation).
Most severe suicidal ideation:
__________
______________________________________
Type no. (1 to 5)
Description of suicidal ideation
Most severe
Frequency
How often did you think so?
__
(1) Less than once a week
(2) Once a week
(3) Two to five times a week
(4) Every day/almost every day
(5) Many times a day
Duration
How long did these thoughts last?
__
(1) Several seconds to several minutes/instantaneous
(2) Less than 1 hour/for a while
(3) 1 to 4 hours/quite a while
(4) 4 to 8 hours/most of the day
(5) 8 hours or more/continuous
Control
Can/could you suppress thoughts of suicide or thoughts of wanting to die if you want/wanted to?
__
(1) Easily able to suppress thoughts
(2) Can suppress thoughts although it is a little difficult
(3) Some difficulty but can suppress thoughts
(4) Very difficult but can suppress thoughts
(5) Cannot suppress thoughts
(0) Not willing to suppress thoughts
Deterrents
Is there any person or thing (eg, family, religion, pain of dying) that suppressed your thoughts of wanting to die or stopped
you from committing suicide?
__
(1) Deterrents stopped me from committing suicide
(2) Deterrents probably stopped me from committing suicide
(3 ) Not sure if the deterrents stopped me from committing suicide
(4) Deterrents probably do not stop me from committing suicide
(5) Deterrents do not stop me from committing suicide
(0) Not applicable
Reasons for Suicidal Ideation
Why did you want to die or commit suicide? Was it to end the pain or evade the emotions you had at that time (eg, you
could not live with such pain or emotions)? Was it to get someone’s attention, revenge, or a reaction? Was it both?
__
(1) Solely to get someone’s attention, revenge, or a reaction
(2) Mostly to get someone’s attention, revenge, or a reaction
(3) Both (50/50) to get someone’s attention, revenge, or a reaction and to
end the pain
(4) Mostly to end the pain (unable to live with the pain or emotions)
(5) Solely to end the pain (unable to live with the pain or emotions)
(0) Not applicable
© 2008 The Research Foundation for Mental Hygiene, Inc.
C-SSRS–Since Last Visit (14 Jan 2009 Version)
Page 1/2


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Suicidal Behavior
(Tick all that apply. Asked about all types of suicidal behavior listed below.)
Since Last
Visit
Suicide attempt:
When behavior that may cause self-harm was associated with any desire to die as a result of the behavior. This includes cases where the intent to
commit suicide is not complete. If the subject has an intent or desire to die as a result of the behavior even a little, it is considered a "suicide attempt."
This includes cases where there is a risk of physical damage even without actual physical damage. When a gun is in the mouth and the
trigger is pulled, it is considered a "suicide attempt" even if the gun is broken and no physical damage is caused.
Yes
No
□
□
When suicidal intent is presumed: When suicidal intent can be presumed from the behavior and circumstances even if the subject denies intent or desire
to die. For example, when behavior is extremely lethal and obviously not an accident and its only possible intent is suicide (eg, gunshot to head, jumping
from an upper floor). Even if the subject denies intent to commit suicide, the intent to commit suicide can be presumed if the subject believes at the time
that his behavior may result in death.
Have you ever attempted suicide?
Have you done anything to harm yourself?
Have you done any dangerous behavior that could result in death?
What did you do?
Was ______ as a means of suicide?
Did you want to die (even a little) when you ______?
Were you trying to die when you ______?
Or, were you aware of the possibility of death when you ______?
Did you not intend to die when you did it, and did you have another reason (eg, stress relief, feel better, get
sympathy, change circumstances)? (Self-injurious behavior without suicidal intent)
If yes, details
Total number
of times
______
Have you had any self-injurious behavior without suicidal intent?
Yes
No
□
□
Interrupted suicide attempt:
When behavior that might result in self-harm was interrupted (due to external factors) (if it had not been interrupted, it would have resulted
in “suicide attempt”).
Drug overdose: The subject took the drug in hand but stopped taking it. Even a small dose is considered a “suicide attempt” rather than an “interrupted
suicide attempt.” Gun suicide: The subject directed a gun to himself but someone took the gun away or prevented him from pulling the trigger in some
way. When the subject pulls the trigger, even if the gun fails to fire, it is considered a “suicide attempt.” Jumping: The subject was in a position to jump
down but was pulled down. Hanging: A rope was around the neck but hanging was blocked.
Yes
No
□
□
Have you been stopped by someone else or something after you started to commit suicide and before you actually
proceed to behavior that would end your life?
If yes, details
Total number
of times
___
Self-interrupted suicide attempt:
When the subject nearly attempted suicide but held back before actually proceeding to self-destructive behavior. This is similar to an example of
"interrupted suicide attempt," but it refers to the case where suicide attempt was interrupted by the subject himself and not by something else.
Yes
No
□
□
Have you held back after starting to commit suicide and before actually proceeding to behavior that would end your life?
If yes, details
Total number
of times
___
Preparatory behavior:
Any preparation or behavior in preparation for suicide that exceeds the level of verbalizing or thinking about suicide. For example, preparing
for suicide means (eg, obtain drugs, purchase weapons) and preparing for death from suicide (eg, release personal belongings, write a
suicide note).
Yes
No
□
□
Have you taken any action in preparation for suicide attempt or suicide (eg, obtain a drug, obtain a weapon, release an
important thing, write a suicide note)?
If yes, details
Suicidal behavior:
Suicidal behavior was observed during the evaluation period.
Yes
No
□
□
Completed suicide:
Yes
No
□
□
Answer only when "suicide attempt" occurred
Date
of
most
lethal
suicide
attempt:
Actual lethality/physical damage:
0. No physical damage or extremely mild physical damage (eg, scratch)
1. Mild physical damage (eg, slurred speech, first-degree burns, mild bleeding, sprain)
2. Moderate physical damage requiring treatment (eg, conscious but lightheaded, somewhat responsive, second-degree burns, bleeding from vessel)
3. Slightly severe physical damage that requires hospitalization and likely to require intensive care (eg, comatose but normal reflexes, third-degree burns
of <20%, major bleeding but can recover, major fractures)
4. Severe physical damage requiring hospitalization with intensive care (eg, comatose with reflexes missing, third-degree burns of ≥20%, major bleeding 
with unstable vital signs, major damage to life-threatening area)
5. Death
Enter code
___
Likelihood of Lethality: Answer only if actual lethality/physical damage = 0
The lethality of “suicide attempt” without physical damage (In the following cases, there is no actual physical damage but extremely high likelihood of
lethality: The subject put a gun in the mouth and pulled the trigger, but no physical damage occurred because the gun did not fire. The subject lay on
train railway but exited before being run over.)
0 = Suicidal behavior with low potential for physical damage
1 = Suicidal behavior that is likely to cause physical damage but unlikely to result in death
2 = Suicidal behavior that is likely to result in death despite treatment
Enter code
___
© 2008 The Research Foundation for Mental Hygiene, Inc.
C-SSRS–Since Last Visit (14 Jan 2009 Version)
Page 2/2

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Single-center, Open-label, Randomized, Two-treatment, Two-period Crossover Trial 
to Investigate Bioequivalence Between Single Administration of ASC-01 
(Aripiprazole/Sertraline Combination Drug) and Concomitant Single Administration 
of Aripiprazole and Sertraline and Food Effect on Pharmacokinetics of ASC-01 in 
Healthy Male Adults 
 
 
 
 
NCT Number: NCT03342963 
PRT NO.: 031-102-00214 
Version Date: 19 February 2018 (Version 1.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational New Drug
ASC-01
Protocol No.: 031-102-00214
A Single-center, Open-label, Randomized, Two-treatment, Two-period Crossover Trial to
Investigate Bioequivalence Between Single Administration of ASC-01
(Aripiprazole/Sertraline Combination Drug) and Concomitant Single Administration of
Aripiprazole and Sertraline and Food Effect on Pharmacokinetics of ASC-01 in Healthy
Male Adults
Statistical Analysis Plan
Version: 1.0
Date: Feb 19, 2018
Protocol Date: Oct 23, 2017
Confidential


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Table of Contents
Table of Contents........................................................................................2
List of Appendices.......................................................................................5
List of Abbreviations and Definition of Terms .........................................6
1
Introduction........................................................................................8
2
Trial Objectives..................................................................................8
2.1
Cohort 1...............................................................................................................8
2.2
Cohort 2...............................................................................................................8
3
Trial Design........................................................................................8
3.1
Type/Design of Trial ...........................................................................................8
3.1.1
Cohort 1 ............................................................................................................9
3.1.2
Cohort 2 ..........................................................................................................10
3.2
Method of Administration.................................................................................11
3.2.1
Cohort 1 ..........................................................................................................11
3.2.1.1
ASC-01 Tablets...........................................................................................11
3.2.1.2
Aripiprazole Tablets and Sertraline Tablets................................................11
3.2.2
Cohort 2 ..........................................................................................................11
3.2.2.1
Administration under a fasting condition....................................................11
3.2.2.2
Administration under a fed condition .........................................................11
3.3
Trial Population.................................................................................................11
3.4
Handling of Time Points ...................................................................................11
4
Sample Size.......................................................................................12
4.1
Decision to Conduct Add-on Subject Study......................................................12
5
Statistical Analysis Datasets ............................................................13
5.1
Pharmacokinetic Analysis Set...........................................................................13
5.2
Bioequivalence Analysis Set.............................................................................13
5.3
Food Effect Analysis Set...................................................................................13
5.4
Safety Analysis Set (SAS).................................................................................13
5.5
Handling of Missing Data .................................................................................13
6
Primary and Secondary Outcome Variables..................................13
6.1
Cohort 1.............................................................................................................13


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6.1.1
Primary Outcome Variables ...........................................................................13
6.1.2
Secondary Outcome Variables .......................................................................13
6.2
Cohort 2.............................................................................................................14
6.2.1
Primary Outcome Variables ...........................................................................14
6.2.2
Secondary Outcome Variables .......................................................................14
7
Disposition and Demographic Analysis ..........................................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
Efficacy Analysis..............................................................................15
9
Safety Analyses.................................................................................15
9.1
Extent of Exposure............................................................................................15
9.2
Adverse Events..................................................................................................15
9.3
Clinical Laboratory Data...................................................................................16
9.4
Vital Sign Data..................................................................................................16
9.5
Physical Examination Data ...............................................................................16
9.6
Electrocardiogram Data.....................................................................................16
9.7
Body Weight......................................................................................................16
9.8
Columbia Suicide Severity Rating Scale (C-SSRS)..........................................16
10
Pharmacokinetic Analyses...............................................................17
10.1
Statistical Analysis of Primary Endpoint ..........................................................17
10.2
Pharmacokinetic Analysis Methods ..................................................................18
10.3
Details of Pharmacokinetic Statistical Analysis Methods.................................18
10.3.1
Exclusion from Pharmacokinetic Analysis.....................................................18
10.3.1.1
When Blood Collection Time Is Outside Acceptable Time Window.........18
10.3.1.2
When a Subject Vomits...............................................................................18
10.3.1.3
When Prohibited Concomitant Medication Is Used ...................................19
10.3.2
Reporting of Concentrations and Parameters .................................................19
11
Pharmacodynamic Analyses............................................................20
12
Pharmacogenomic Analyses ............................................................20


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13
Interim Analysis...............................................................................20
14
Changes in the Planned Analyses....................................................20
15
References........................................................................................ 20


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List of Appendices
Appendix 1
List of Summary Tables................................................................ 18
Appendix 2
List of Subject Data Listings......................................................... 21


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List of Abbreviations and Definition of Terms
Abbreviation
Definition
AUC168h
Area under the concentration-time curve from 0 to 168 hours
AUCt
Area under the concentration-time curve calculated to the last
observable concentration at time t
AUC∞
Area under the concentration-time curve from time zero to infinity
BE
Bioequivalence
BMI
Body mass index
C-SSRS
Columbia-suicide severity rating scale
CL/F
Apparent clearance of drug from plasma after extravascular
administration
Cmax
Maximum (peak) plasma concentration of the drug
CV
Coefficient of Variation
FDA
Food and Drug Administration
GMR
Geometric Mean Ratio
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
MRT∞
Mean residence time from time 0 to infinity
NCA
Non Compartment Analysis
PT
Preferred Term
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
SOC
System Organ Class
t1/2,z
Terminal-phase elimination half-life
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
λz
Terminal elimination rate constant
AUC_%Extrap
Ratio of area under the concentration-time curve from tlast to infinity to
AUC∞
CL/F/BW
Apparent clearance of drug from plasma after extravascular
administration per unit body weight
Vz/F
Volume of distribution in the terminal phase after extravascular
administration
Vz/F/BW
Volume of distribution in the terminal phase after extravascular
administration per unit body weight
Tlast
Last measurable time
λz(Rsq)
Coefficient of determination adjusted for degrees of freedom for λz


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estimation
λz(point)
Measurement points for λz estimation
λz(upper)
End time of the range of measurement points at the time of λz
estimation
λz(lower)
Start time of the range of measurement points at the time of λz
estimation


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1
Introduction
This statistical analysis plan describes the detailed statistical analysis methods planned
for Trial 031-102 00214.
2
Trial Objectives
2.1
Cohort 1
To investigate bioequivalence for aripiprazole between administration of one ASC-01
tablet and concomitant administration of one aripiprazole 3-mg tablet and two sertraline
50-mg tablets
2.2
Cohort 2
To investigate the effect of food on the plasma pharmacokinetics of aripiprazole and
sertraline following single oral administration of ASC-01 under a fasting or fed condition
3
Trial Design
3.1
Type/Design of Trial
This is a single-center, open-label, randomized, two-treatment, two-period crossover trial
in healthy male adults conducted using 2 cohorts to investigate bioequivalence for
aripiprazole between administration of ASC-01 and concomitant administration of
aripiprazole and sertraline and the effect of food on the pharmacokinetics of ASC-01.
The trial design is outlined in Figure 3.1-1.


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Figure 3.1-1
Trial Design Schematic
There will be a wash-out period of at least 35 days between investigational medicinal product
administration in Periods I and II. The number of days with a wash-out period of 35 days is shown.
Group A-1, group receiving administration of ASC-01 first; Group B-1, group receiving concomitant
administration of aripiprazole and sertraline first; Group A-2, group receiving administration of ASC-01
under a fasting condition first; and Group B-2, group receiving administration of ASC-01 under a fed
condition first
3.1.1
Cohort 1
A total of 54 healthy male adults will be randomized: 27 subjects into a group receiving
administration of ASC-01 first (Group A-1) and 27 subjects into a group receiving
concomitant administration of aripiprazole and sertraline first (Group B-1). On the
respective administration days in Periods I and II, the investigational medicinal product
(IMP) will be orally administered once after subjects have fasted for at least 10 hours.
Subjects receiving ASC-01 in Period I will receive concomitant administration of
aripiprazole and sertraline in Period II, and subjects receiving concomitant administration
of aripiprazole and sertraline in Period I will receive ASC-01 in Period II. The plasma
concentration of aripiprazole will be measured in each treatment period to examine
pharmacokinetics.
The trial is designed in accordance with the BE Guideline.1 Furthermore, the results in
the trial will be handled in accordance with the BE Guideline.
Group
Period I
Wash-out
Period II
Screening Period
Group
A-1
Group
B-1
Group
A-2
Group
B-2
Informed consent
(start of trial)
Screening examination
Randomization
Single administration
Single administration
Outpatient
Visit
Outpatient
Visit
Period I
Period II
Administration of
ASC-01 under a fed
condition
Administration of ASC-01
under a fasting condition
Hospitalization
Hospitalization
Concomitant single
administration of
aripiprazole and sertraline
Single administration of
ASC-01
Cohort 2
Food effect
Healthy
male
adults
Eligible
subjects
20 subjects
(10 subjects
in each
group)
Administration of
ASC-01 under a
fasting condition
Wash-out
period
(at least 35
days)
Administration of ASC-01
under a fed condition
Cohort 1
Bioequivalence
Healthy
male
adults
Eligible
subjects
54 subjects
(27 subjects
in each
group)
Single administration of
ASC-01
Wash-out
period
(at least 35
days)
Concomitant single
administration of
aripiprazole and sertraline


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Group A-1
Group receiving
administration of ASC-
01 first
Single administration of ASC-01
perioda
Concomitant single administration
of aripiprazole and sertraline
Group B-1
Group receiving
concomitant
administration of
aripiprazole and
sertraline first
Concomitant single
administration of aripiprazole and
sertraline
Single administration of ASC-01
a: There will be a wash-out period of at least 35 days between investigational medicinal product
administration in Periods I and II.
3.1.2
Cohort 2
A total of 20 healthy male adults will be randomized: 10 subjects into a group receiving
administration of ASC-01 under a fasting condition first (Group A-2) and 10 subjects into
a group receiving administration of ASC-01 under a fed condition first (Group B-2). On
the respective administration days in Periods I and II, the IMP will be orally administered
once after subjects have fasted for at least 10 hours (for administration under a fasting
condition) or at 30 minutes after the start of breakfast (for administration under a fed
condition). Subjects receiving administration under a fasting condition in Period I will
receive administration under a fed condition in Period II, and subjects receiving
administration under a fed condition in Period I will receive administration under a
fasting condition in Period II. The plasma concentrations of aripiprazole and sertraline
will be measured in each treatment period to examine pharmacokinetics.
Group
Period I
Wash-out
perioda
Period II
Group A-2
Group receiving ASC-
01 under a fasting
condition first
Administration under a fasting
condition
Administration under a fed
condition
Group B-2
Group receiving ASC-
01 under a fed
condition first
Administration under a fed
condition
Administration under a fasting
condition
a: There will be a wash-out period of at least 35 days between investigational medicinal product
administration in Period I and Period II.


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3.2
Method of Administration
3.2.1
Cohort 1
3.2.1.1
ASC-01 Tablets
One tablet of ASC-01 (3-mg aripiprazole/100-mg sertraline combination drug) will be
administered once with approximately 150 mL of water after subjects have fasted for at
least 10 hours.
3.2.1.2
Aripiprazole Tablets and Sertraline Tablets
One aripiprazole 3-mg tablet and two sertraline 50-mg tablets will be administered once
with approximately 150 mL of water after subjects have fasted for at least 10 hours.
3.2.2
Cohort 2
3.2.2.1
Administration under a fasting condition
One tablet of ASC-01 will be administered once with approximately 150 mL of water
after subjects have fasted for at least 10 hours.
3.2.2.2
Administration under a fed condition
One tablet of ASC-01 will be administered once with approximately 150 mL of water at
30 minutes after the start of breakfast.
3.3
Trial Population
Fifty-four healthy male adults aged 20 to 40 years, inclusive, will be enrolled in Cohort 1
and 20 in Cohort 2.
A few reserve subjects may be allowed to stand by until completion of IMP
administration in Period I. If a subject to be treated withdraws consent or the investigator
or subinvestigator determines that the subject should not be administered the IMP, the
subject will be replaced with a reserve subject. Subjects who are withdrawn from the trial
after randomization will not be replaced.
3.4
Handling of Time Points
Data measured at the time points specified in the protocol will be used. Data from
examinations at discontinuation and unscheduled examinations will be presented in
listings but not used for tabulation.


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4
Sample Size
For Cohort 1, the sample size was determined by the method of Diletti2 as the number of
subjects required for the 90% confidence intervals for the differences in the log-converted
mean Cmax and AUC168h of aripiprazole between single administration of ASC-01 and
concomitant single administration of aripiprazole and sertraline to be within the
acceptable range for bioequivalence of ln(0.8) to ln(1.25) based on the BE Guideline.1
In the results of a pharmacokinetic trial conducted to examine the bioavailability of ASC-
01 (031-11-004), the ratios of the geometric mean Cmax and AUC168h of aripiprazole were
respectively 1.12 and 1.05 and the within-subject variances were 0.029 and 0.006. The
proportion of subjects excluded from the pharmacokinetic analysis due to vomiting or
withdrawal was approximately 40%.
Assuming the ratio of the geometric mean Cmax of aripiprazole between administration of
ASC-01 and concomitant administration of aripiprazole and sertraline and the within-
subject variance to be, respectively, 1.1 and 0.029, the number of subjects required to
ensure a statistical power of 90% or higher is 16 per group (32 subjects in total).
Assuming a 40% rate of exclusion from analysis due to withdrawal or vomiting, the
sample size for Cohort 1 is set at 27 subjects per group (54 subjects in total).
For Cohort 2, referring to the FDA guidance,3 the sample size required for the analysis of
food effect on the pharmacokinetics of ASC-01 is 6 subjects per group (12 subjects in
total). In consideration of the possibility of exclusion from analysis due to withdrawal or
vomiting, the sample size for Cohort 2 is set at 10 subjects per group (20 subjects in total).
4.1
Decision to Conduct Add-on Subject Study
For Cohort 1, if bioequivalence cannot be demonstrated in this trial due to an insufficient
number of subjects, an add-on subject study may be performed once in the same manner
as the trial. However, the add-on subject study should be conducted using at least half the
number of subjects included in the trial. The add-on subject study will not be conducted
in the following cases:

The difference in the mean log-converted Cmax and AUC168h between
administration of ASC-01 and concomitant administration of aripiprazole and
sertraline does not fall within the range of ln(0.8) to ln(1.25) as a result of this
trial.

The number of subjects required for the add-on subject study calculated from the
results of the trial is considered unfeasible from an ethical or scientific point of
view.


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When data from the add-on subject study are pooled and analyzed with the data from this
trial, study as a variable factor will also be incorporated into the analysis.
5
Statistical Analysis Datasets
5.1
Pharmacokinetic Analysis Set
Subjects who received the IMP and whose plasma concentration was measured
5.2
Bioequivalence Analysis Set
Subjects from whom Cmax and AUC168h were obtained in both Periods I and II in Cohort 1
5.3
Food Effect Analysis Set
Subjects from whom Cmax, AUCt, AUC∞, and AUC168h were obtained in both Periods I
and II in Cohort 2
5.4
Safety Analysis Set (SAS)
Subjects who received at least one dose of IMP
5.5
Handling of Missing Data
Missing data will not be imputed.
6
Primary and Secondary Outcome Variables
6.1
Cohort 1
6.1.1
Primary Outcome Variables

Cmax and AUC168h of aripiprazole
6.1.2
Secondary Outcome Variables
1) Plasma concentration of aripiprazole
2) Pharmacokinetic parameters of aripiprazole
3) Ratios of the Cmax, AUCt, AUC∞, AUC168h, MRT∞, and λz of aripiprazole
following administration of ASC-01 to those following concomitant
administration of aripiprazole and sertraline and the difference in the tmax of
aripiprazole between administration of ASC-01 and concomitant administration of
aripiprazole and sertraline (tmax for ASC-01 administration minus tmax for
concomitant administration)


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6.2
Cohort 2
6.2.1
Primary Outcome Variables

Cmax, AUCt, AUC∞, and AUC168h of aripiprazole and sertraline
6.2.2
Secondary Outcome Variables
1) Plasma concentrations of aripiprazole and sertraline
2) Pharmacokinetic parameters of aripiprazole and sertraline
3) Ratios of the Cmax, AUCt, AUC∞, AUC168h, t1/2,z, and CL/F of aripiprazole and
sertraline for administration under a fed condition to those for administration
under a fasting condition and the difference in the tmax of aripiprazole and
sertraline between administration under a fed condition and administration under
a fasting condition (tmax for a fed condition minus tmax for a fasting condition)
7
Disposition and Demographic Analysis
7.1
Subject Disposition
The number of subjects screened will be ascertained, and the number randomized, the
number who complete the trial, the number who discontinue the trial, and the number for
each reason for discontinuation will be calculated overall and by group for each cohort.
In addition, of the randomized subjects, the number who complete the trial, the number
who discontinue the trial, and the percentage by reason for discontinuation will be
calculated.
The number and proportion of subjects included in each analysis set will be calculated in
randomized subjects overall and by group for each cohort.
7.2
Demographic and Baseline Characteristics
Descriptive statistics (number of subjects, mean, standard deviation, minimum, median,
and maximum) will be calculated for age, height, body weight (screening period), and
BMI for each randomized group and for the entire population in the bioequivalence
analysis set in Cohort 1 and in the food effect analysis set in Cohort 2. In addition,
frequency distributions of the presence/absence of previous illness and present illness
(number of subjects and percentage) will be generated for each randomized group and for
the entire population. Similar summarizations will be performed for the pharmacokinetic
analysis set and the safety analysis set by cohort as necessary.
7.3
Treatment Compliance
No tabulation will be performed in this study.


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7.4
Prior and Concomitant Medications
No tabulation will be performed in this study.
7.5
Protocol Deviations
No tabulation will be performed in this study.
8
Efficacy Analysis
Not applicable.
9
Safety Analyses
For the safety analysis set, data will be tabulated by cohort and treatment. Baseline will
be the value immediately before IMP administration (before administration on the day of
IMP administration) in each period.
9.1
Extent of Exposure
The number and percentage of subjects treated in each period will be summarized overall
and by group.
9.2
Adverse Events
All adverse events (AEs) will be coded by system organ class (SOC) and preferred term
(PT) according to the Medical Dictionary for Regulatory Activities (MedDRA Version
20.1). The number and percentage of subjects (using the number of subjects who received
each treatment as the denominator) with the following events will be calculated overall
and by SOC and PT:

Treatment-emergent AEs (TEAEs),

TEAEs by severity.
TEAEs in each period are defined as AEs occurring after the start of administration of the
IMP until 8 days after administration of the IMP. If a subject experiences the same event
multiple more than once during the same period, the highest severity will be used.
TEAEs related to the IMP will also be summarized in the same manner.
In addition, the number and percentage of subjects (using the number of subjects who
received each treatment as the denominator) with the following events will be calculated:

TEAEs with an outcome of death,

Serious TEAEs.


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9.3
Clinical Laboratory Data
For each clinical laboratory parameter other than urine qualitative test parameters,
descriptive statistics of the measured values at each time point and change from baseline
will be determined. For qualitative urinalysis parameters in clinical laboratory tests, shift
tables from baseline to each time point will be generated. Clinical laboratory parameters
other than qualitative urinalysis parameters will be classified as “within reference range,”
“below reference range,” or “above reference range” using institutional reference values,
and shift tables from baseline to each time point will be generated.
9.4
Vital Sign Data
For each vital sign parameter, descriptive statistics of the measured values at each time
point and change from baseline will be determined.
9.5
Physical Examination Data
For physical examination, physical findings of individual subjects will be listed.
9.6
Electrocardiogram Data
For each parameter of 12-lead electrocardiography, descriptive statistics of the measured
values at each time point and change from baseline will be determined. For
normal/abnormal assessment of 12-lead electrocardiography, a shift table from baseline
to each time point will be prepared. The number and percentage of subjects who meet the
following criteria for the measured values of corrected QT interval (Fridericia correction
method [QTcF] and Bazzett correction method [QTcB]) and their changes from baseline
after IMP administration will be calculated.

Measured value is “>450 msec,” “>480 msec,” or “>500 msec.”

Change from baseline is “>30 msec” or “>60 msec.”
9.7
Body Weight
For body weight, descriptive statistics of the measured values at each time point and
change from baseline will be determined.
9.8
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS of individual subjects will be presented in a listing.


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10
Pharmacokinetic Analyses
10.1
Statistical Analysis of Primary Endpoint
The following analyses will be performed on the bioequivalence analysis set for Cohort 1
and the food effect analysis set for Cohort 2.
In Cohort 1, analysis of variance will be performed on log-converted (natural logarithm)
values for the Cmax and AUC168h of aripiprazole-using group (group receiving
administration of ASC-01 first or group receiving concomitant administration of
aripiprazole and sertraline first), treatment (ASC-01 or concomitant administration of
aripiprazole and sertraline), subjects within group, and treatment period as factors. The
90% confidence intervals for the differences in the mean Cmax and AUC168h of
aripiprazole between ASC-01 administration and concomitant administration of
aripiprazole and sertraline will be calculated. If the 90% confidence intervals are within
the range of ln(0.8) to ln(1.25), single administration of ASC-01 and single concomitant
administration of aripiprazole and sertraline will be judged to be bioequivalent for
aripiprazole.
If an add-on subject study is conducted, bioequivalence will be assessed based on the
combined results of the trial and the add-on subject study using the same criteria. When
data from the add-on subject study are pooled and analyzed with the data from the trial,
study will also be included as a variable factor (fixed effect) in the mixed effects model
for analysis of variance and sensitivity analysis of the primary analysis.
In Cohort 2, analysis of variance will be performed on log-converted (natural logarithm)
values for the Cmax, AUCt, AUC∞, and AUC168h of aripiprazole- and sertraline-using
group (group receiving ASC-01 under a fasting condition first or group receiving ASC-01
under a fed condition first), treatment (administration under a fasting condition or under a
fed condition), subjects within group, and treatment period as factors. The 90%
confidence intervals for the differences in the mean Cmax, AUCt, AUC∞, and AUC168h of
aripiprazole and sertraline between administration under a fasting condition and
administration under a fed condition will be calculated.
If there are any subjects in each cohort from whom evaluable parameters cannot be
obtained in both Periods I and II, sensitivity analysis including those subjects will be
performed. For the pharmacokinetic parameters of the primary endpoint, the 90%
confidence interval of the mean difference between the treatments will be determine for
each cohort using the mixed effects model by use of log-converted (natural logarithm)
values with group, treatment, and treatment period as fixed effects and subjects within


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group as a random effect. The Kenward-Roger method will be used to calculate the
degrees of freedom.
10.2
Pharmacokinetic Analysis Methods
For each cohort, blood collection will be performed before and at 1, 2, 3, 4, 5, 6, 8, 12, 24,
48, 72, 96, 144, and 168 hours after administration on Day 1 in each period. PK
parameters and their descriptive statistics will be calculated in the pharmacokinetic
analysis set as follows.
In Cohort 1, pharmacokinetic parameters (Cmax, AUCt, AUC∞, AUC168h, tmax, t1/2,z, λz, tlast,
CL/F, CL/F/BW, Vz/F, Vz/F/BW, AUC_%Extrap, and MRT∞) of aripiprazole will be
calculated by non-compartmental analysis (NCA). Descriptive statistics of plasma
concentrations and pharmacokinetic parameters of aripiprazole will be presented by
treatment (ASC-01 or concomitant administration of aripiprazole and sertraline).
In Cohort 2, pharmacokinetic parameters (Cmax, AUCt, AUC∞, AUC168h, tmax, t1/2,z, λz, tlast,
CL/F, CL/F/BW, Vz/F, Vz/F/BW, AUC_%Extrap, and MRT∞) of aripiprazole and
sertraline will be calculated by NCA. Descriptive statistics of plasma concentrations and
pharmacokinetic parameters of aripiprazole and sertraline will be presented by treatment
(administration under a fasting condition or under a fed condition).
10.3
Details of Pharmacokinetic Statistical Analysis Methods
10.3.1
Exclusion from Pharmacokinetic Analysis
10.3.1.1
When Blood Collection Time Is Outside Acceptable Time
Window
If the blood collection time is outside the acceptable time window and the data are
determined to be inappropriate for calculation of descriptive statistics of plasma
concentrations, the data will be included in NCA but excluded from calculation of
descriptive statistics.
10.3.1.2
When a Subject Vomits
If vomiting occurs within less than twice the median tmax, the subject will be excluded
from pharmacokinetic analysis. The median tmax value for the group to which the subject
belongs calculated by excluding the subject who vomited will be used as the criterion for
assessment.


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10.3.1.3
When Prohibited Concomitant Medication Is Used
If a subject uses a prohibited medication that could affect the pharmacokinetics of the
IMP, the subject will be excluded from pharmacokinetic analysis.
10.3.2
Reporting of Concentrations and Parameters
1) Drug concentration values below the lower limit of quantitation will be
considered as 0.
2) CL/F/BW and Vz/F/BW will be calculated by dividing CL/F and Vz/F
respectively by body weight (kg) measured prior to IMP administration.
3) Descriptive statistics to be calculated will be the number of subjects, arithmetic
mean, standard deviation, coefficient of variation, minimum, median, and
maximum for plasma drug concentrations, and the number of subjects, arithmetic
mean, standard deviation, coefficient of variation, geometric mean, minimum,
median, and maximum for parameters other than tmax and tlast. For tmax and tlast,
the number of subjects, minimum, median, and maximum will be calculated.
Descriptive statistics will not be calculated for λz (Rsq), λz (point), λz (upper), and
λz (lower). If the number of subjects included is 0, descriptive statistics will not
be calculated. If the number of subjects included is 1 or 2, only the number of
subjects, arithmetic mean, geometric mean (parameters other than tmax and tlast),
maximum, and minimum will be calculated.
4) Arithmetic mean and standard deviation will be used to plot the plasma
concentration versus time profile.
5) Individual values and descriptive statistics of pharmacokinetic parameters will be
displayed in the number of digits in Table 10.3.2-1. The coefficient of variation
(CV%) of the descriptive statistics will be rounded to the first decimal place.
Table 10.3.2-1
List of Handling of Numerical Values
AUCt, AUC∞, AUC168h
Three significant digits
AUC%Extrap
First decimal place
Cmax
Three significant digits
CL/F, CL/F/BW
Three significant digits
MRT∞ 
First decimal place
tmax
First decimal place
tlast
First decimal place
t1/2,z
First decimal place
λz
Three significant digits
λz (point)
Integer
λz (lower), λz (upper)
Second decimal place
λz (Rsq)
Fourth decimal place
Vz/F, Vz/F/BW
Three significant digits
Geometric mean ratio (GMR)
Fourth decimal place
Confidence interval of GMR
Fourth decimal place


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11
Pharmacodynamic Analyses
There will be no pharmacodynamic analyses in this trial.
12
Pharmacogenomic Analyses
There will be no pharmacogenomic analyses in this trial.
13
Interim Analysis
None
14
Changes in the Planned Analyses
For categorical analysis of corrected QT interval, the number and percentage of subjects
who met the criteria after IMP administration, not at each time point, will be calculated.