Clinical trial NCT03510663
Conditions: Congestive Heart Failure
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2018-05-08; Completion date: 2018-07-05
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To investigate the effects of intravenous administration of OPC-61815 at 16 and 32 mg on QT/QTc interval in healthy male subjects

Detailed description:

Arms: arm 1: OPC-61815 16mg will be intravenously administered once a week. arm 2: OPC-61815 32mg will be intravenously administered once a week. arm 3: 400mg tablet will be administrated once a week. arm 4: Placebo will be intravenously administered once a week.
Interventions: intervention 1: OPC-61815 16mg intervention 2: OPC-61815 32mg intervention 3: Moxifloxacin intervention 4: Placebos
Intervention descriptions: intervention 1: OPC-61815 16mg will be intravenously administered once a week. intervention 2: OPC-61815 32mg will be intravenously administered once a week. intervention 3: 400mg tablet will be administrated once a week. intervention 4: Placebo will be intravenously administered once a week.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Single-center, Randomized, Double-blind (for OPC-61815 and Placebo), Placebo- 
and Moxifloxacin Positive-controlled, 4-Period Crossover Trial to Evaluate the Effect 
of Single Intravenous Administration of OPC-61815 at 16 and 32 mg on QT/QTc 
Interval in Healthy Male Subjects 
 
 
 
NCT Number: NCT03510663 
PRT NO.: 263-102-00005 
Version Date: 27 February 2018 (Version 1.0) 


 
 
Protocol 263-102-00005 
 
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Protocol Version 1.0, 27 Feb 2018 
Title Page 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
OPC-61815 
 
CLINICAL PROTOCOL 
 
A Single-center, Randomized, Double-blind (for OPC-61815 and Placebo), Placebo- and 
Moxifloxacin Positive-controlled, 4-Period Crossover Trial to Evaluate the Effect of 
Single Intravenous Administration of OPC-61815 at 16 and 32 mg on QT/QTc Interval in 
Healthy Male Subjects  
 
Protocol No. 263-102-00005 
 
 
CONFIDENTIAL - PROPRIETARY INFORMATION 
 
Clinical Development Phase: 1 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd.  
 
Immediately Reportable Event: 
Department of Pharmacovigilance 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Email: IRE_263-102-00005@otsuka.jp 
 
 
Issue Date: 
 
 
 
 
27 Feb 2018 
 
Protocol Version Number: 
 
 
1.0 
 
Date of Translation:  
 
 
10 Sep 2018 
 
 
 
 
 


 
 
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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
OPC-61815 
Protocol No.: 263-102-00005 
 
Protocol Title: 
A Single-center, Randomized, Double-blind (for OPC-61815 
and Placebo), Placebo- and Moxifloxacin Positive-controlled, 
4-Period Crossover Trial to Evaluate the Effect of Single 
Intravenous Administration of OPC-61815 at 16 and 32 mg 
on QT/QTc Interval in Healthy Male Subjects 
Clinical Phase: 
Phase 1 
Treatment Indication: 
Congestive heart failure (CHF) patients with volume overload 
despite having received diuretics other than vasopressin 
antagonists 
Objective(s): 
To investigate the effects of 1-hour intravenous administration 
of OPC-61815 at 16 and 32 mg on QT/QTc interval in healthy 
male subjects 
Trial Design: 
Single-center, randomized, double-blind, placebo- and 
moxifloxacin positive-controlled, 4-period crossover trial  
Period 1 
Period 2 
Period 3 
Period 4 
Single administration of OPC-61815 at 16 or 32 mg, placebo, or 
moxifloxacin at 400 mg  
In each treatment period, subjects will be admitted on the day before 
administration of investigational medicinal product (IMP) and 
discharged on Day 2. 
A washout period of ≥6 days will be set from the day after IMP 
administration in each period until the start of administration in the 
next treatment period. 
Subject Population: 
Total of 48 healthy male subjects age 20 to 45 years, inclusive 
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria: 
1) Japanese male subjects age 20 to 45 years, inclusive, 
at time of informed consent 
2) Body mass index (BMI) (body weight in kg / [height 
in m]2) of at least 18.5 kg/m2 and less than 25.0 kg/m2 
as a result of at the screening examination 
3) Judged by the investigator or subinvestigator to be 
capable of providing written informed consent prior to 
start of any trial-related procedures and capable of 
complying with the procedures for this trial 
Exclusion Criteria: 
1) Subjects with a medical history of convulsive disorder, 


 
 
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long QT syndrome (including family history), syncope 
during swimming, or any other type of syncope or 
cryptogenic loss of consciousness 
2) Subjects with a serum electrolyte abnormality 
(hypokalemia, hypomagnesemia, hypocalcemia, etc) 
3) Subjects with a family history of sudden death 
4) Subjects with a history of heart disease such as 
hypertension, atherosclerosis, heart failure, 
bradycardia, or stroke, or who are using a pacemaker 
5) Subjects with 2 or more of the following abnormalities 
in 3 tests of 12-lead electrocardiography (ECG) and 2 
or more additional abnormalities in re-testing 
performed 1 hour after the first series of tests at the 
screening examination or on the day before Period 1 
IMP administration (Day −1) 
 
PR interval of >220 msec 
 
QRS interval of >120 msec 
 
QTcF of <320 msec or >450 msec 
 
Atrial fibrillation or atrial flutter 
 
Other worrisome cardiac findings  
6) Subjects who have received any other IMP in another 
clinical trial within 120 days prior to Period 1 IMP 
administration 
7) Subjects who have undergone blood collection (eg, 
blood donation) of >200 mL within 30 days, >400 mL 
within 90 days, or >1200 mL within 1 year prior to 
Period 1 IMP administration 
8) Subjects who have consumed any of the following 
products within the corresponding specified time prior 
to Period 1 IMP administration 
 
Products containing St John’s wort (Hypericum perforatum): 
Within 14 days prior to Period 1 IMP administration 
 
Grapefruit, Seville orange, or star fruit, or products processed 
from any of them: Within 7 days prior to Period 1 IMP 
administration 
 
Food or beverages containing alcohol or caffeine: Within 1 day 
prior to Period 1 IMP administration 
9) Subjects who have taken any prescription drugs, OTC 
drugs, Chinese herbal remedies, or vitamin 
supplements within 14 days or antibiotics within 30 
days prior to Period 1 IMP administration 
10) Subjects who have been exposed to any substance 
known to stimulate production of liver microsomal 


 
 
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enzymes (eg, occupational exposure to pesticides or 
organic solvents) within 30 days prior to Period 1 IMP 
administration 
11) Subjects who have used any tobacco products, 
nicotine replacement therapy, or electronic cigarettes 
or who have been exposed to second-hand smoke on a 
daily basis, within 60 days prior to Period 1 IMP 
administration, or who test positive in urine nicotine 
test at the screening examination 
12) Subjects who are sexually active but unable or 
unwilling to either use 2 types of approved 
contraception methods or remain abstinent during the 
trial and for 30 days after final IMP administration, or 
who plan to donate sperm during the period from the 
screening visit until 30 days after final IMP 
administration 
13) Subjects with a history of a clinically significant 
abnormality, or for whom a clinically significant 
abnormality is observed in the results of the screening 
examination, and the investigator, subinvestigator, or 
sponsor judges that the abnormality could place the 
subject at risk or affect evaluation of drug absorption, 
distribution, metabolism, or excretion  
Such abnormalities include, but are not limited to, a 
history or current symptoms of cardiac, hepatic, renal, 
nervous system, endocrine, gastrointestinal, 
respiratory, hematologic, and immune 
diseases/disorders. 
14) Subjects with a history of clinically significant drug or 
alcohol abuse 
15) Subjects with a history or current condition of 
hepatitis or acquired immunodeficiency syndrome 
(AIDS), or a positive test result for any of the 
following: Hepatitis B surface antigen (HBsAg), anti-
hepatitis C virus (HCV) antibody, AIDS 
antigen/antibody, or syphilis 
16) Subjects with a history of severe drug allergy or 
hypersensitivity to any of the following drugs:  
 
Any ingredients of OPC-61815 or tolvaptan 
 
Compounds containing benzazepine (mozavaptan hydrochloride, 
benazepril hydrochloride) 
 
Quinolone antibiotics, including moxifloxacin 
17) Subjects who have a positive test result in breath 


 
 
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alcohol test or urine drug test for detection of 
substance abuse at the screening examination or on the 
day before Period 1 IMP administration (Day −1) 
18) Subjects with a history of serious hemorrhage or 
bleeding tendency 
19) Subjects with blood collection difficulty 
20) Subjects with supine resting systolic blood pressure of 
>140 mmHg or <90 mmHg or supine resting diastolic 
blood pressure of >80 mmHg or <40 mmHg at the 
screening examination or on the day before Period 1 
IMP administration (Day 1) 
21) Subjects with supine resting pulse rate of >90 bpm or 
<45 bpm at the screening examination or on  the day 
before Period 1 IMP administration (Day 1) 
22) Subjects who are currently taking an antiarrhythmic 
agent of Class IA (quinidine, procainamide, etc) or 
Class III (amiodarone, sotalol, etc) 
23) Subjects with a history of serious psychological 
disorder whose participation in the clinical trial is 
judged to be inappropriate by the investigator or 
subinvestigator 
24)  Subjects who are otherwise judged by the investigator 
or subinvestigator to be inappropriate for participation 
in the clinical trial 
Trial Site(s): 
Soseikai Fukuoka Mirai Hospital Clinical Research Center 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration: 
OPC-61815 at 16 or 32 mg will be intravenously administered 
once by 1-hour infusion on the first day of each treatment 
period. 
Reference Product(s), 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration: 
Placebo injection corresponding to the dose of OPC-61815 
will be intravenously administered once by 1-hour infusion on 
the first day of each treatment period. One moxifloxacin 
400 mg tablet will be orally administered once on the first day 
of each treatment period. 
Trial Assessments: 
Pharmacokinetics: Blood collection for measurement of 
plasma drug concentrations 
Pharmacodynamics: 12-Lead Holter ECG 


 
 
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Safety: Adverse event reporting, clinical laboratory 
assessments, physical examination, vital signs, body weight, 
and 12-lead ECG 
Screening/other: Medical and medication history, breath 
alcohol test, urine drug screening, and blood screening for 
infectious diseases 
Criteria for 
Evaluation: 
Primary Endpoint: 
Time-matched difference between the OPC-61815 and 
placebo data in change from baseline for QTcF in 12-lead 
Holter ECG 
Secondary Endpoints: 
12-Lead Holter ECG parameters (heart rate, RR interval, PR 
interval, QRS interval, QT interval, and QTcF interval) and 
ECG waveform patterns 
Pharmacokinetic Endpoints:  
Plasma concentrations and pharmacokinetic parameters of 
OPC-61815 free form and tolvaptan  
Safety Endpoints: 
Adverse event reporting, clinical laboratory assessments, 
physical examination, vital signs (blood pressure, pulse rate, 
and body temperature), body weight, and 12-lead ECG 
Statistical Methods: 
Statistical Methods for Primary Endpoint: 
Central tendency analysis for OPC-61815 will be performed 
for subjects in the pharmacodynamic analysis set who 
completed all IMP treatments and for whom predose and 
postdose QT data are available for all 4 treatment periods. 
For each OPC-61815 dose, the upper limit of the 2-sided 90% 
confidence interval (CI) for the time-matched difference in 
the least squares mean for the change in QTcF from baseline 
compared to the placebo data will be evaluated to determine if 
it is lower than 10 msec at all postdose time points. Using a 
linear mixed effect model with baseline QTcF in each 
treatment period as a covariate, treatment, sequence, treatment 
period, time point, and interaction between treatment and time 
point as fixed effects, and subject as a random effect, point 
estimates and 2-sided 90% CIs for the time-matched 


 
 
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difference in the least squares mean for the change in QTcF 
from baseline compared to the placebo data will be calculated. 
Rationale for Determination of Sample Size 
The number of subjects required for central tendency analysis 
of QTcF, the primary endpoint, was calculated. 
The number of subjects was calculated to achieve a ≥90% 
probability of the upper limit of the 2-sided 90% CI (1-sided 
95% CI) for the time-matched difference in the mean values 
for the change in QTcF from baseline between the OPC-
61815 and placebo values being lower than 10 msec at all 
time points after administration of each OPC-61815 dose (16 
and 32 mg), and a ≥90% probability of the lower limit of the 
2-sided 98% CI (1-sided 99% CI) for the time-matched 
difference in the mean values for the change in QTcF from 
baseline between the moxifloxacin and placebo values being 
higher than 0 msec in at least one of the 5 assay sensitivity 
assessment time points (1, 1.5, 2, 3, and 4 hours) after 
administration of the positive control moxifloxacin. For the 
assay sensitivity CI, the increase of type 1 error due to the 
multiplicity of multiple time points was corrected using the 
Bonferroni method. 
Assuming the within-subject standard deviation to be 7.86, 
the effect size of moxifloxacin to be 9.6 msec based on the 
results of a previous trial (Protocol 331-10-242, a clinical trial 
of brexpiprazole for evaluation of QT/QTc interval in patients 
with schizophrenia and schizoaffective disorder), the effect 
size of OPC-61815 to be 3.0 msec (although no data are 
available) and the individual time points to be independent, 
the required number of subjects is 45 for each OPC-61815 
dose and 21 for moxifloxacin. Estimating a 5% 
discontinuation rate, a sample size of 48 subjects was 
considered necessary. 
Trial Duration: 
Total duration of the trial: Apr  to Jul 2018 
(The total duration of the trial for each subject will be a 


 
 
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maximum of 58 days, assuming a 6-day washout period 
between each treatment period, comprising the following trial 
periods: ) 
 Screening: Day −28 to Day −2 
 Periods 1 through 3: ≥7 days for each treatment period 
(1 day for administration and ≥6 days for washout) 
 Period 4: 2 days 
 Post treatment follow-up period: 6 to 8 days after the 
last IMP administration in Period 4   


 
 
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Table of Contents 
Title Page ........................................................................................................ 1 
Protocol 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 and Definitions of Terms ....................................... 18 
1 
Introduction ........................................................................................ 20 
1.1 
Nonclinical Data ................................................................................................21 
1.1.1 
Efficacy Pharmacology ...................................................................................21 
1.1.2 
Safety Pharmacology/General Pharmacology ................................................22 
1.2 
Clinical Data ......................................................................................................23 
1.2.1 
Single Intravenous Dose Trial in Healthy Adult Males (Phase 1) 
(Protocol No. 263-08-001) ..............................................................................23 
1.2.2 
Repeated Intravenous Dose Trial in Healthy Adult Males (Phase 1) 
(Protocol No. 263-09-001) ..............................................................................24 
1.2.3 
Intravenous Dose Trial on Rate of Injection in Healthy Adult Males 
(Phase 1) (Protocol No. 263-10-005) ..............................................................24 
1.2.4 
Clinical Pharmacological Dose Investigation Trial in Patients with 
Congestive Heart Failure (Protocol No. 263-102-00001) ..............................25 
1.3 
Pharmacokinetics/Pharmacodynamics ..............................................................26 
1.3.1 
Trial to Evaluate the Effect of Oral Tolvaptan on QTc in Healthy 
Adults (Protocol No. 156-03-245) ..................................................................26 
1.4 
Risks and Benefits .............................................................................................26 
2 
Trial Rationale and Objectives.......................................................... 27 
2.1 
Trial Rationale ...................................................................................................27 
2.2 
Dosing Rationale ...............................................................................................28 
2.2.1 
Regimen ..........................................................................................................28 
2.2.2 
Dose ................................................................................................................29 
2.3 
Trial Objectives .................................................................................................30 


 
 
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Trial Design ......................................................................................... 30 
3.1 
Type/Design of Trial .........................................................................................30 
3.2 
Trial Treatments ................................................................................................33 
3.3 
Trial Population .................................................................................................34 
3.3.1 
Number of Subjects and Description of Population .......................................34 
3.3.2 
Subject Selection and Numbering ..................................................................34 
3.4 
Eligibility Criteria..............................................................................................34 
3.4.1 
Informed Consent ...........................................................................................34 
3.4.2 
Inclusion Criteria ............................................................................................35 
3.4.3 
Exclusion Criteria ...........................................................................................36 
3.5 
Endpoints ...........................................................................................................38 
3.5.1 
Primary Endpoint(s) ........................................................................................38 
3.5.2 
Secondary Endpoint(s) ....................................................................................38 
3.5.3 
Pharmacokinetic Endpoints ............................................................................38 
3.5.4 
Safety Endpoints .............................................................................................38 
3.6 
Measures to Minimize/Avoid Bias ....................................................................38 
3.6.1 
Randomization ................................................................................................38 
3.6.2 
Blinding ..........................................................................................................39 
3.6.3 
Reading of 12-Lead Holter Electrocardiograms .............................................39 
3.7 
Trial Procedures ................................................................................................39 
3.7.1 
General Inpatient Procedures ..........................................................................42 
3.7.2 
Dietary Requirements .....................................................................................42 
3.7.3 
Schedule of Assessments ................................................................................43 
3.7.3.1 
Informed Consent ........................................................................................43 
3.7.3.2 
Screening .....................................................................................................43 
3.7.3.3 
Day Before IMP Administration (Day −1) in Period 1 ...............................44 
3.7.3.4 
Day 1 of Period 1 ........................................................................................44 
3.7.3.5 
Day 2 of Period 1 ........................................................................................45 
3.7.3.6 
Day Before IMP administration (Day −1) in Periods 2, 3, and 4 ...............46 
3.7.3.7 
Day 1 of Periods 2, 3, and 4 ........................................................................46 
3.7.3.8 
Day 2 of Periods 2, 3, and 4 ........................................................................47 


 
 
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3.7.3.9 
Withdrawal Examination ............................................................................47 
3.7.3.10 
Post-treatment Follow-up ............................................................................48 
3.7.3.11 
Post-trial Follow-up ....................................................................................48 
3.7.4 
Prior and Concomitant Medications ...............................................................48 
3.7.5 
Safety Assessments .........................................................................................48 
3.7.5.1 
Adverse Events............................................................................................48 
3.7.5.2 
Clinical Laboratory Assessments ................................................................49 
3.7.5.2.1 
Clinical Laboratory Tests ........................................................................49 
3.7.5.2.2 
Infectious Disease Screening ...................................................................49 
3.7.5.2.3 
Urine Drug Test, Urine Cotinine Test, and Breath Alcohol Test ............50 
3.7.5.3 
Physical Examination ..................................................................................50 
3.7.5.4 
Vital Signs (Blood Pressure, Pulse Rate, and Body Temperature) .............50 
3.7.5.5 
Body Weight ...............................................................................................51 
3.7.5.6 
12-Lead Electrocardiogram Assessments ...................................................51 
3.7.5.6.1 
Screening Examination and Day Before IMP Administration in 
Each Period (Day −1) ..............................................................................51 
3.7.5.6.2 
Days 1 and 2 in Each Period and Post-treatment Follow-up ...................52 
3.7.6 
Pharmacokinetic/Pharmacodynamic Assessments .........................................52 
3.7.6.1 
Pharmacokinetic Assessments ....................................................................52 
3.7.6.1.1 
Pharmacokinetic Blood Samples .............................................................52 
3.7.6.1.2 
Pharmacokinetic Urine Samples ..............................................................53 
3.7.6.2 
Pharmacodynamic Assessments .................................................................53 
3.7.6.2.1 
12-Lead Holter Electrocardiogram Assessments ....................................53 
3.7.7 
Genetic Assessments ......................................................................................54 
3.7.8 
Future Biospecimen Research Samples ..........................................................54 
3.7.9 
End of Trial .....................................................................................................54 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................54 
3.8.1 
Entire Trial ......................................................................................................54 
3.8.2 
Individual Site .................................................................................................54 
3.8.3 
Individual Subject Discontinuation ................................................................55 
3.8.3.1 
Treatment Discontinuation/Interruption During a Treatment Period..........55 
3.8.3.2 
Treatment Discontinuation (Withdrawal) ...................................................55 


 
 
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3.8.3.3 
Documenting Reasons for Discontinuation ................................................56 
3.8.3.4 
Withdrawal of Consent ...............................................................................57 
3.9 
Screen Failures ..................................................................................................57 
3.10 
Definition of Completed Subjects .....................................................................57 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................58 
3.12 
Subject Compliance ...........................................................................................58 
3.13 
Protocol Deviations ...........................................................................................58 
4 
Restrictions .......................................................................................... 59 
4.1 
Prohibited Medications......................................................................................59 
4.2 
Other Restrictions ..............................................................................................59 
4.2.1 
Food and Beverages ........................................................................................59 
4.2.2 
Smoking, Blood Donation, and Other Activities ............................................59 
5 
Reporting of Adverse Events ............................................................. 60 
5.1 
Definitions .........................................................................................................60 
5.2 
Eliciting and Reporting Adverse Events ...........................................................63 
5.3 
Immediately Reportable Events ........................................................................63 
5.4 
Potential Serious Hepatotoxicity .......................................................................64 
5.5 
Pregnancy ..........................................................................................................64 
5.6 
Procedure for Breaking the Blind ......................................................................65 
5.7 
Follow-up of Adverse Events ............................................................................66 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................66 
5.7.2 
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................67 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Last Scheduled Contact .........................67 
6 
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis ................................................................................................ 67 
6.1 
Pharmacokinetic Analysis Methods ..................................................................67 
6.1.1 
Pharmacokinetic Analysis Set ........................................................................67 
6.1.2 
Pharmacokinetic Analysis ..............................................................................68 
6.2 
Pharmacodynamic Methods ..............................................................................68 
6.3 
Pharmacokinetic/Pharmacodynamic Methods ..................................................69 


 
 
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6.4 
Pharmacogenomic Methods ..............................................................................69 
7 
Statistical Analysis .............................................................................. 69 
7.1 
Determination of Sample Size ...........................................................................69 
7.2 
Analysis Set .......................................................................................................70 
7.3 
Handling of Missing Data .................................................................................70 
7.4 
Primary and Secondary Endpoint Analyses ......................................................70 
7.4.1 
Primary Endpoint Analyses ............................................................................70 
7.4.2 
Secondary Endpoint Analyses ........................................................................71 
7.4.2.1 
Categorical Analysis ...................................................................................71 
7.4.2.2 
Electrocardiogram (12-lead Holter ECG) ...................................................72 
7.4.3 
Assay Sensitivity Assessment.........................................................................72 
7.5 
Analysis of Demographic and Baseline Characteristics....................................73 
7.6 
Safety Analysis ..................................................................................................73 
7.6.1 
Adverse Events ...............................................................................................73 
7.6.2 
Clinical Laboratory Data ................................................................................73 
7.6.3 
Vital Signs and Body Weight .........................................................................74 
7.6.4 
12-lead Electrocardiogram Data .....................................................................74 
7.7 
Pharmacodynamic Analysis ..............................................................................74 
8 
Management of Investigational Medicinal Product ........................ 74 
8.1 
Packaging and Labeling ....................................................................................74 
8.2 
Storage ...............................................................................................................74 
8.3 
Accountability ...................................................................................................75 
8.4 
Returns and Destruction ....................................................................................75 
8.5 
Reporting of Product Quality Complaints .........................................................75 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................75 
8.5.2 
Information Required for Reporting Product Quality Complaints .................76 
8.5.3 
Return Process for Product Quality Complaints .............................................76 
8.5.4 
Assessment/Evaluation ...................................................................................76 
9 
Records Management ......................................................................... 77 
9.1 
Source Documents .............................................................................................77 
9.2 
Data Collection ..................................................................................................77 


 
 
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9.3 
File Management at the Trial Site .....................................................................78 
9.4 
Record Retention at the Trial Site .....................................................................78 
10 
Quality Control and Quality Assurance ........................................... 79 
10.1 
Monitoring .........................................................................................................79 
10.2 
Auditing .............................................................................................................79 
10.3 
Protocol Deviations ...........................................................................................79 
11 
Ethics and Responsibility ................................................................... 80 
12 
Confidentiality .................................................................................... 80 
13 
Amendment Policy .............................................................................. 81 
14 
Publication Authorship Requirements ............................................. 81 
15 
References ............................................................................................ 83 
 
 


 
 
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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 35 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 36 
Table 3.7-1 
Schedule of Assessments .............................................................. 40 
Table 3.7-2 
Acceptable Windows for Postdose 
Examinations/Assessments (for All Treatment Periods) .............. 42 
Table 3.7.5.2-1 
Clinical Laboratory Assessments .................................................. 49 
Table 6.2-1 
Time Windows for 12-lead Holter ECG Data Capture ................. 69 
 


 
 
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List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic ................................................................. 32 
 


 
 
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List of Appendices 
Appendix 1 
Handling and Shipment of Bioanalytical Samples ....................... 84 
 


 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AVP 
Arginine vasopressin 
BMI 
Body mass index  
cAMP 
Cyclic adenosine 3', 5'-monophosphate 
CK (CPK) 
Creatine kinase 
CYP 
Cytochrome P450 
ECG 
Electrocardiography 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamyltransferase 
HBsAg 
hepatitis B surface antigen 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go related gene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
LDH 
Lactic dehydrogenase 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean Corpuscular Volume 
PQC 
Product quality complaint 
PK 
Pharmacokinetics  
QT 
QT interval  
QTc 
QT corrected for heart rate 
SIADH 
Syndrome of inappropriate secretion of antidiuretic hormone  
TEAE 
Treatment-emergent adverse event 
 


 
 
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List of Pharmacokinetic Parameters 
Abbreviation/ 
Term 
Unit 
Spelled-out Form or Definition 
AUC∞ 
ng·h/mL 
Area under the concentration-time curve from time zero to infinity 
AUC24h 
ng·h/mL 
Area under the concentration-time curve from time zero to 24 hours 
AUCt 
ng·h/mL 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap 
% 
Percentage of AUC due to extrapolation from tlast to infinity [(AUC∞ − 
AUCt)/AUC∞ × 100] 
CL 
L/h 
Total body clearance of drug from the plasma 
CL/BW 
L/h/kg 
CL normalized in body weight 
Cmax 
ng/mL 
Maximum (peak) plasma concentration of the drug 
λz 
h-1 
Apparent terminal-phase disposition rate constant (first-order) 
λz(point) 
 
Number of points used in computing λz. If λz cannot be estimated, zero 
λz(lower) 
h 
Lower limit on Time for values to be included in the calculation of λz  
λz(upper) 
h 
Upper limit on Time for values to be included in the calculation of λz  
z(Rsq) 
 
Goodness of fit statistic for the terminal elimination phase, adjusted for 
the number of points used in the estimation of λz  
t1/2,z 
h 
Terminal-phase elimination half-life  
tlast 
h 
Time of last measurable (positive) concentration  
tmax 
h 
Time to maximum (peak) plasma concentration  
Vz 
L 
Apparent volume of distribution during the terminal (λz) phase  
 


 
 
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1 
Introduction 
Tolvaptan is an orally effective nonpeptide arginine vasopressin (AVP) V2 receptor 
antagonist synthesized by Otsuka Pharmaceutical Co., Ltd. (hereinafter referred to as 
Otsuka) that inhibits water reabsorption in renal collecting ducts, thereby inducing an 
increase in water diuresis (aquaresis) without affecting electrolyte excretion. 
In Japan, tolvaptan was approved in 2010 under the trade name of Samsca tablets® 15 mg 
for the indication of “volume overload in heart failure when an adequate response is not 
obtained with other diuretics (eg, loop diuretics).” In 2013, a new indication of “body 
fluid retention in hepatic cirrhosis when an adequate response is not obtained with other 
diuretics (eg, loop diuretics)” was approved. In 2014, an additional marketing approval 
for the suppression of progression of autosomal dominant kidney disease (ADPKD) in 
patients with increased kidney volume and a rapid rate of increase was granted. The 
additional marketing approvals were granted for Samsca 7.5 mg tablet in 2013 and 30 mg 
tablet in 2014. Outside Japan, tolvaptan was approved for the treatment of clinically 
significant hypervolemic and euvolemic hyponatremia including patients with heart 
failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) in the US and for 
the treatment of hyponatremia secondary to SIADH in adult patients in Europe in 2009. 
In 2015, an additional marketing approval for indication to slow the progression of cyst 
development and renal insufficiency of ADPKD in adults with chronic kidney disease 
(CKD) Stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease 
was granted in Europe. Tolvaptan has been approved in over 40 countries/regions. 
Tolvaptan has been developed only as oral tablets because clinical development of 
tolvaptan in injection formulation has been difficult due to the low water solubility. Used 
as an oral aquaretic, tolvaptan provides a useful treatment option in clinical practice for 
the above-approved indications. However, there are unmet medical needs for intravenous 
aquaretics with a similar effect to oral tolvaptan for patients with impaired consciousness 
who are unable to take oral drugs, patients who cannot adequately absorb oral drugs due 
to gastrointestinal edema, patients on continuous oxygen therapy who therefore have 
difficulty taking oral drugs, and elderly patients with decreased swallowing function. 
Under such circumstances, Otsuka synthesized a new intravenous aquaretic, OPC-61815. 
OPC-61815 is a compound with improved water solubility achieved by phosphorylation 
of the hydroxyl group in the benzazepine ring of tolvaptan. When administered, the 
phosphate ester of OPC-61815 is hydrolyzed by alkali and acid phosphatase in the body 
to form tolvaptan as an active substance of OPC-61815, which is considered to work as 


 
 
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an aquaretic. OPC-61815 is under development with the expectation that it will have a 
beneficial therapeutic effect. 
So far, the following three phase 1 trials of OPC-61815 have been completed in healthy 
adult male subjects: single intravenous dose trial (263-08-001), repeated intravenous dose 
trial (263-09-001), and trial investigating the rate of intravenous administration (263-10-
005). Based on the results of these trials, another trial is currently ongoing to investigate 
the dose of OPC-61815 intravenous injection that achieves an exposure equivalent to that 
obtained with tolvaptan 15-mg oral tablet in patients with congestive heart failure. 
Tolvaptan, the active substance of OPC-61815, and its metabolites demonstrated no QTc 
interval prolongation in a completed trial (156-03-245) evaluating the effects of oral 
tolvaptan on the QTc interval in healthy subjects. However, the effect of OPC-61815 on 
the QTc interval before being metabolized into tolvaptan has yet to be studied. Otsuka 
has therefore decided to conduct this trial in healthy adult volunteers to evaluate the 
effect of OPC-61815 on the QT/QTc interval. 
Please refer to the Investigator's Brochure (IB) for further information on the results of 
nonclinical studies and clinical trials of OPC-61815. 1 Nonclinical and clinical data are 
summarized below. 
1.1 
Nonclinical Data 
1.1.1 
Efficacy Pharmacology 
In a receptor-binding study using [3H]-AVP as a labeled ligand, OPC-61815 exhibited 
affinity for the human AVP V2 receptor (Ki value: 6.13 ± 1.34 nM), but that affinity was 
about 1/14 that of the primary active metabolite tolvaptan (Ki value: 0.43 ± 0.06 nM). 
OPC-61815 also showed weak affinity for the human AVP V1a receptor (Ki value: 54.2 ± 
16.8 nM), only 1/4 that of tolvaptan (Ki value: 12.3 ± 0.80 nM). Like tolvaptan, OPC-
61815 did not show affinity for the human AVP V1b receptor. OPC-61815 and tolvaptan 
showed an antagonistic action against the V2 receptor in HeLa cells expressing the 
human AVP V2 receptor by inhibiting the production of cyclic adenosine 3’,5’-
monophosphate (cAMP) by AVP. However, neither OPC-61815 nor tolvaptan induced 
any increase in cAMP production by itself, indicating that they possess no intrinsic V2 
receptor agonistic activity. 
Conscious rats given a single intravenous administration of OPC-61815 (0.1275 to 
12.75 mg/kg) showed a dose-dependent increase in urine volume and decrease in urine 


 
 
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osmolality. These changes were not attenuated with 7-day repeated intravenous dosing. 
Beagle dogs given single intravenous administration of OPC-61815 (0.1275 to 
3.825 mg/kg) showed a dose-dependent increase in urine volume and decrease in urine 
osmolality. Free water clearance was dose-dependently increased in these dogs, 
indicating that OPC-61815 is an aquaretic agent which increases free water excretion. 
Dogs given a single intravenous administration of OPC-61815 showed an increase in 
plasma AVP concentrations without increase in plasma renin activity. This showed that, 
unlike furosemide, OPC-61815 does not activate the renin-angiotensin system. 
In a rat model of hyponatremia receiving 5 days of dose-escalating intravenous 
administration of OPC-61815 (0.255 to 5.1 mg/kg) showed an increase in the lowered 
plasma sodium concentration as the dose was increased. Water content in the brain and 
heart was increased due to hyponatremia, but it was improved after OPC-61815 
administration. 
Histamine-induced vascular hyperpermeability model rats showed a dose-dependent 
increase in urine volume and decrease in urine osmolality after a single intravenous 
administration of OPC-61815 (0.3825 to 3.825 mg/kg, 2 hours before histamine dosing), 
with a dose-dependent reduction in the area of pigment leakage at the histamine 
administration site. In a carrageenan-induced paw edema model, development of paw 
edema was dose-dependently inhibited after a single intravenous administration of OPC-
61815 (1.275 to 12.75 mg/kg, 1 hour before carrageenan dosing). 
These study results demonstrated the potent water diuretic action of intravenous OPC-
61815 as also observed with tolvaptan, thus showing its promising clinical efficacy in the 
treatment of various conditions associated with volume overload due to abnormal water 
metabolism such as hyponatremia and edematous disorders. 
1.1.2 
Safety Pharmacology/General Pharmacology 
The effects of OPC-61815 on the central nervous system (CNS) (general conditions and 
behavior), respiratory and cardiovascular systems, and human ether-a-go-go related gene 
(hERG) current were evaluated. 
A single dose of OPC-61815 was intravenously administered to male Sprague-Dawley 
rats at 0 (vehicle control), 12.75, 63.75, and 255 mg/kg to evaluate its effect on the CNS 
(general conditions and behavior). Doses of 12.75 mg/kg and higher increased urine 
output, and a dose of 255 mg/kg decreased spontaneous motor activity, contact reaction, 
body tension, and respiratory rate and was associated with abnormal posture. 


 
 
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A single dose of OPC-61815 was intravenously administered to unanesthetized male 
beagle dogs at 0 (vehicle control), 12.75, 38.25, and 127.5 mg/kg to evaluate its effect on 
the respiratory and cardiovascular systems. Doses of 12.75 mg/kg and higher increased 
urine output and concentration of plasma sodium and chloride and decreased the T wave 
amplitude. Doses of 38.25 mg/kg and higher increased heart rate. A dose of 127.5 mg/kg 
caused vomiting, increased respiratory rate, and decreased blood pressure and PR interval. 
Histamine release-related vasodilatation was considered to be involved in a fall in blood 
pressure, and experiments were conducted in anesthetized male beagle dogs. OPC-61815 
decreased blood pressure, increased heart rate, and slightly elevated plasma histamine 
concentrations immediately after a single intravenous administration at 100 mg/kg. 
However, pretreatment with an antihistamine did not prevent a drop in blood pressure. 
Based on these findings, it was concluded that the observed reduction in blood pressure 
was unrelated to the elevation in endogenous histamine levels. 
The effect of OPC-61815 on hERG current was evaluated in Chinese hamster ovary cell-
derived cell line (CHO-K1 cells) at concentrations of 0 (vehicle control), 10−6, 10−5, and 
10−4 mol/L. OPC-61815 had no effect on hERG current. 
1.2 
Clinical Data 
1.2.1 
Single Intravenous Dose Trial in Healthy Adult Males (Phase 1) 
(Protocol No. 263-08-001) 
In the phase 1 single intravenous dose trial (263-08-001), 54 healthy adult male subjects 
were given an intravenous administration (by 5-minute infusion) of OPC-61815 at 0.3, 1, 
3, 7.5, 15, or 30 mg or placebo. The plasma concentration of OPC-61815 free form 
reached a peak between the completion of injection and 0.020 hours after injection 
(median of time to maximum [peak] plasma concentration [tmax]) and quickly decreased 
to below the lower limit of quantitation (46.2 ng/mL) by 8 hours postdose in every dose 
group. The peak plasma concentration (Cmax), area under the concentration-time curve 
from time zero to infinity (AUC∞), and area under the concentration-time curve 
calculated to the last observable concentration at time t (AUCt) increased as the dose was 
increased. The mean terminal-phase elimination half-life (t1/2,z) was 0.63 to 1.7 hours. 
Tolvaptan rapidly appeared in the plasma following intravenous administration of OPC-
61815, with the plasma concentration peaking between 0.5 and 1.0 hours postdose and 
then decreasing to below the lower limit of quantitation (2.00 ng/mL) by 72 hours 
postdose in every dose group. The Cmax, AUC∞, and AUCt all increased dose-


 
 
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dependently, and the mean t1/2,z was between 2.2 and 5.7 hours. A dose-dependent 
increase in urine volume was observed following a single intravenous administration of 
OPC-61815 at 3 to 30 mg. There was little change in urine electrolyte excretion. Serum 
sodium concentration and serum osmolality increased, but there were no changes in 
serum potassium concentration. In terms of safety, all adverse events (AEs) reported in 
subjects treated with OPC-61815 were mild and resolved without treatment or with 
palliative treatment. 
1.2.2 
Repeated Intravenous Dose Trial in Healthy Adult Males 
(Phase 1) (Protocol No. 263-09-001) 
In the phase 1 repeated intravenous dose trial (263-09-001), 36 healthy adult male 
subjects were given a single intravenous administration of OPC-61815 at 1.25, 5, or 
20 mg or placebo, followed by a 1-day washout and repeated intravenous doses (by 1-
minute infusion) for 7 days. No accumulation of OPC-61815 free form or its main active 
metabolite (tolvaptan) was seen. The AUC and Cmax of plasma OPC-61815 free form and 
tolvaptan increased dose-dependently. During once-daily 7-day repeated intravenous 
administration of OPC-61815 at 5 and 20 mg, an increase in urine volume was observed. 
However, the increase did not expand in response to the 7-day repeated administration. In 
terms of safety, AEs that included feeling abnormal, pruritus, and erythema were reported 
frequently during and immediately after administration of OPC-61815. All the AEs were 
mild or moderate and subsequently resolved without treatment. However, because many 
of these events were judged to be potentially causally related to the investigational 
medicinal product (IMP) and were not reported in subjects treated with oral tolvaptan, it 
is suspected that OPC-61815 could be related to the occurrence of these events. 
1.2.3 
Intravenous Dose Trial on Rate of Injection in Healthy Adult 
Males (Phase 1) (Protocol No. 263-10-005) 
This trial was conducted to investigate the method of administration that can avert the 
potentially drug-related AEs reported in the phase 1 repeated intravenous dose trial of 
OPC-61815 (263-09-001) and not reported in subjects treated with oral tolvaptan. The 
trial was also aimed at exploring the cause of these potentially drug-related AEs. 
Eighteen healthy adult male subjects were given a single intravenous administration of 
OPC-61815 at 7.5 or 15 mg or placebo over different durations (2 hours, 5 minutes, and 
1 minute). The median tmax and mean t1/2,z of OPC-61815 free form after a 2-hour single 
intravenous administration were 1.8 to 2.0 hours and 1.0 to 1.3 hours, respectively. The 
mean Cmax of OPC-61815 free form after 2-hour administration was approximately 70% 


 
 
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lower than that after 5-minute and 1-minute administration. The median tmax and mean 
t1/2,z of tolvaptan after 2-hour administration were 2.3 hours and 3.9 to 4.6 hours, 
respectively. The mean Cmax of tolvaptan after 2-hour administration was comparable to 
that after 5- and 1-minute administration. The rate of increase in mean urine volume until 
4 hours after a 2-hour single intravenous administration of OPC-61815 was lower than 
that after both 5- and 1-minute administrations. Postdose hyposthenuria associated with 
decreased mean urine osmolality was observed with a slight elevation in the mean serum 
osmolality and serum sodium concentrations. AEs similar to feeling abnormal, pruritus, 
and erythema, etc. that were frequently reported in the repeated intravenous dose trial of 
OPC-61815 (263-09-001) were selected as notable AEs (hereafter, AEs of special 
interest). These AEs of special interest occurred in 1 of 12 subjects (8.3%) in the OPC-
61815 groups and in 3 of 6 subjects (50%) in the placebo group after 2-hour 
administration. An AE (rash) occurring in 1 OPC-61815-treated subject and AEs (feeling 
abnormal and urticaria) in 2 placebo-treated subjects were considered unrelated to IMP. 
AEs of special interest occurred in 9 of 12 subjects (75%) in the OPC-61815 groups and 
2 of 6 subjects (33.3%) in the placebo group after 5-minute administration. All the events 
were judged to be related to IMP. The AEs of special interest were reported in 10 of 11 
subjects (90.9%) in the OPC-61815 groups and in 4 of 6 subjects (66.6%) in the placebo 
group after 1-minute administration. All the events excluding an event of erythema in the 
OPC-61815 group were judged to be related to IMP. All the AEs causally related to IMP 
occurred during or immediately after intravenous administration. Most of those events 
resolved without treatment within 10 minutes after start of IMP administration. No severe 
cases were found among the AEs of special interest. Because there were no clinically 
significant changes from baseline in plasma histamine concentrations, the cause of the 
AEs of special interest is unclear. 
1.2.4 
Clinical Pharmacological Dose Investigation Trial in Patients with 
Congestive Heart Failure (Protocol No. 263-102-00001) 
Based on the results of 3 phase 1 trials in healthy adult males (263-08-001, 263-09-001, 
and 263-10-005), a phase 2 clinical pharmacological trial is ongoing to investigate the 
dose of OPC-61815 that achieves exposure equivalent to that obtained with tolvaptan 15-
mg tablet in patients with congestive heart failure with volume overload despite having 
received conventional diuretics other than vasopressin receptor antagonists. 


 
 
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1.3 
Pharmacokinetics/Pharmacodynamics 
As a reference, the results of a clinical thorough QT (tQT) trial of tolvaptan are 
summarized below. 
1.3.1 
Trial to Evaluate the Effect of Oral Tolvaptan on QTc in Healthy 
Adults (Protocol No. 156-03-245) 
A trial was conducted in the United Sates to evaluate the effect of oral tolvaptan on the 
QTc interval (QTcI) in healthy adult males and females.2 This was a parallel-group 
comparative trial to determine the mean change from baseline (mean) in QTcI at Day 1 
following a single oral administration or at Day 5 following once-daily repeated oral 
administration. A total of 160 healthy adult male and female subjects were randomized to 
receive 400 mg moxifloxacin tablets, placebo, 30 mg tolvaptan, or 300 mg tolvaptan so 
that each treatment group included 40 subjects (20 men and 20 women). 
The mean change in QTcI following single and repeated administrations in each 
tolvaptan group did not show a statistically significant prolongation of QTcI compared to 
the placebo group. On the other hand, the mean change in QTcI following single and 
repeated administrations in the 400 mg moxifloxacin group showed a statistically 
significant prolongation of QTcI compared to the placebo group. These findings indicated 
that neither tolvaptan nor its metabolites prolong QTcI. 
In terms of safety, AEs occurred in 19 of 43 subjects (44.2%) in the 30 mg tolvaptan 
group, 33 of 43 subjects (76.7%) in the 300 mg tolvaptan group, 10 of 43 subjects 
(23.3%) in the placebo group, and 21 of 42 subjects (50.0%) in the moxifloxacin group. 
Frequently reported AEs (incidence ≥5% in each dose group) in tolvaptan-treated 
subjects included thirst, pollakiuria, dry mouth, abdominal pain, nausea, headache, and 
throat irritation. Frequently reported AEs in moxifloxacin-treated subjects included 
dizziness, abdominal pain, nausea, dry mouth, pollakiuria, and dermatitis contact. 
Frequently reported AEs in placebo-treated subjects included headache, nausea, and 
pollakiuria. All AEs were mild or moderate in severity, demonstrating favorable 
tolerability after repeated oral administration of 30 mg and 300 mg tolvaptan. 
1.4 
Risks and Benefits 
No deaths or other serious adverse events (SAEs) were reported in the phase 1 trials of 
OPC-61815 in healthy adult male subjects (263-08-001, 263-09-001, and 263-10-005). 
Feeling abnormal, feeling hot, erythema, hyperhidrosis, pruritus, rash, urticaria, nausea, 
epigastric discomfort, and dyspnea were the significant AEs reported following 


 
 
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intravenous administration of OPC-61815 in Trials 263-09-001 and 263-10-005. Feeling 
abnormal, feeling hot, erythema, hyperhidrosis, pruritus, rash, urticaria, nausea, epigastric 
discomfort, and dyspnea, all of which frequently occurred in Trial 263-09-001, were 
selected as AEs of special interest. In Trial 263-10-005, 1- and 5-minute administrations 
were associated with frequent occurrences of AEs of special interest in OPC-61815-
treated subjects, whereas following a 2-hour administration, only 1 subject experienced 
an AE of special interest, and this was considered unrelated to IMP. These findings 
suggest that a longer duration of OPC-61815 administration would reduce the risk of 
developing these events. However, AEs of special interest reported in completed phase 1 
trials occurred during or immediately after IMP administration. Although most events 
spontaneously resolved within 10 minutes after start of IMP administration, subjects 
should be closely monitored for skin symptoms following start of IMP administration. 
This trial will use moxifloxacin 400-mg tablets as a positive control. Moxifloxacin has 
been approved in Japan as an oral quinolone antibiotic under the trade name of Avelox® 
tablets 400 mg. The incidence of potentially drug-related AEs (including abnormal 
laboratory changes) was 25.7% (130/505) in Japanese clinical trials of moxifloxacin 400-
mg tablets conducted before the time of approval. Common potentially drug-related AEs 
included diarrhoea (24/505, 4.8%), liver function test abnormal (22/505, 4.4%), nausea 
(18/505, 3.6%), dyspepsia (14/505, 2.8%), and abdominal pain (12/505, 2.4%). The 
incidence of potentially drug-related AEs in non-Japanese clinical trials was 25.1% 
(2314/9225). Common potentially drug-related AEs included nausea (653/9225, 7.1%), 
diarrhoea (461/9225, 5.0%), and dizziness (233/9225, 2.5%). Since moxifloxacin may 
cause shock or anaphylaxis, subjects should be carefully interviewed to ascertain if there 
is a history of allergy and drug hypersensitivity prior to IMP administration. 
This trial will enroll healthy adult males and subjects will receive no health benefit for 
their participation. 
Please refer to the package insert of Avelox® tablets 400 mg3 for further information on 
moxifloxacin. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Samsca tablets® (tolvaptan tablets) developed by Otsuka, used as an oral aquaretic agent 
in clinical practice, provide a useful treatment option in Japan for volume overload in 
heart failure when an adequate response is not obtained with other diuretics (eg, loop 


 
 
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diuretics). Under the circumstances where tolvaptan's poor water solubility has made it 
difficult to develop injectable formulations from tolvaptan, Otsuka synthesized the new 
intravenous aquaretic, OPC-61815. OPC-61815 is a compound with improved water 
solubility achieved by phosphorylation of the hydroxyl group in the benzazepine ring of 
tolvaptan. It is mandatory for OPC-61815, a novel compound, to be studied for its effect 
on the QT/QTc interval as specified in the International Council for Harmonization (ICH) 
Guideline E14.4 
In relation to tolvaptan, a pharmacologically active substance, the effect of oral tolvaptan 
on the QTc interval was evaluated in a clinical trial in healthy adults (156-03-245). 
Tolvaptan or its metabolites did not prolong the QTc interval. However, the effect of 
OPC-61815 on QTc interval before being metabolized into tolvaptan has yet to be studied. 
Otsuka has therefore decided to conduct this trial in healthy adult volunteers to evaluate 
the effect of OPC-61815 on the QT/QTc interval. This trial will use moxifloxacin as a 
positive control to ensure assay sensitivity. 
Three phase 1 clinical trials of OPC-61815 in healthy adult male subjects have been 
completed and the safety of the compound has been confirmed. Moxifloxacin is an 
approved medicinal product. 
In conclusion, the conduct of this trial is scientifically and ethically justified. 
2.2 
Dosing Rationale 
2.2.1 
Regimen 
In a repeated dose trial (263-09-001) in which OPC-61815 was intravenously 
administered by 1-minute infusion, subjects experienced feeling abnormal (8/27, 29.6%), 
pruritus (4/27, 14.8%), pruritus generalized (3/27, 11.1%), and erythema (3/27, 11.1%), 
none of which occurred in a single dose trial (263-08-001) in which OPC-61815 was 
intravenously administered by 5-minute infusion. Prompted by these findings, an 
intravenous dose trial on rate of injection (263-10-005) was conducted to investigate if 
any relationship existed between the occurrence of potentially drug-related AEs and the 
rate of administration (2 hours, 5 minutes, and 1 minute). In this trial, 7.5 and 15 mg 
OPC-61815 was administered at different administration rates. As a result, the above 
potentially drug-related AEs occurred following 1- or 5-minute intravenous 
administration, whereas they did not occur following 2-hour intravenous administration. 
These findings suggest that a longer duration of OPC-61815 administration would reduce 
the risk of developing the above potentially drug-related AEs. 


 
 
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PK models of plasma OPC-61815 and tolvaptan concentration were created using data 
from the prior phase 1 studies (263-08-001, 263-09-001, and 263-10-005) to perform 
simulations designed to investigate how the PK parameters of OPC-61815 and tolvaptan 
change in response to changes in rate of administration. The tmax of tolvaptan following 
simulated 2-hour intravenous administration of OPC-61815 was 2.25 hours, suggestive of 
longer tmax than that following actual oral administration of tolvaptan (2 hours). The tmax 
of tolvaptan following simulated 1-hour intravenous administration of OPC-61815 was 
1.5 hours, a shorter tmax than that following actual oral administration of tolvaptan 
(2 hours), indicating that an earlier onset of action can be expected following 1-hour 
intravenous administration. Based on these simulation results, OPC-61815 will be 
intravenously administered by 1-hour infusion in this trial. 
2.2.2 
Dose 
The ICH Guideline E14 states that the drug should be tested for QT/QTc prolongation at 
substantial multiples of the anticipated maximum therapeutic exposure, or that, if 
interactions involving metabolizing enzymes or transporters are expected, these effects 
could be studied under conditions of maximum inhibition. 
The recommended clinical dose of OPC-61815 is planned to be 8 mg for patients with 
congestive heart failure. In consideration of differences in body constitution and enzyme 
activity, 16 mg is assumed to achieve exposure equivalent to the maximum therapeutic 
exposure. 
Next, possible differences in the PK profile of OPC-61815 following OPC-61815 
administration between healthy adults and patients with congestive heart failure were 
considered. Intravenous administration of OPC-61815 does not involve an absorptive 
process in the gastrointestinal tract, and thus a gastrointestinal absorption-related effect 
on heart failure can be ruled out. Once administered, OPC-61815 is likely to be 
hydrolyzed by alkaline and acid phosphatases in the body. These enzymes occur in a 
variety of organs and blood5 and may be involved in hydrolysis. Although patients with 
heart failure have decreased blood flow in organs, heart failure is unlikely to affect 
hydrolysis (metabolism) of OPC-61815 when hydrolysis is occurring throughout the 
body. On the other hand, when heart failure manifests, a decrease both in blood flow in 
organs and in effective circulating blood volume results in a smaller volume of drug 
distribution for numerous drugs,6 and the distribution volume following intravenous 
administration in patients with congestive heart failure may be reduced to approximately 
half that in healthy adults.7 Therefore, the possibility that blood OPC-61815 


 
 
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concentrations in patients with congestive heart failure increase to double those in healthy 
adults should be anticipated. Based on these considerations, OPC-61815 administration at 
16 mg and 32 mg in healthy adults appears to cause an exposure equivalent to that 
following administration at 8 mg and 16 mg in patients with congestive heart failure, and 
these doses (16 mg and 32 mg) have been selected as the clinical dose and high dose, 
respectively, to be used in the trial. 
As described in Section 2.2.1, PK models of plasma OPC-61815 and tolvaptan 
concentration were created using data from the prior phase 1 studies (263-08-001, 263-
09-001, and 263-10-005) to perform simulations to estimate PK parameters following a 
single intravenous administration of OPC-61815. First, OPC-61815 exposure was 
investigated. The Cmax of OPC-61815 following simulated 1-hour intravenous 
administration of 32 mg OPC-61815 was as low as approximately 0.45-fold that 
following simulated 5-minute administration of 30 mg OPC-61815. The AUC24h of OPC-
61815 following simulated 1-hour intravenous administration of 32 mg OPC-61815 was 
approximately 1.1-fold that following simulated 5-minute administration of 30 mg OPC-
61815. Given that the safety of a single 5-minute intravenous administration of 30 mg 
OPC-61815 has been established in healthy adults (263-08-001), both doses, 16 and 
32 mg, can be administered safely provided patients are closely monitored. Next, 
tolvaptan exposure was investigated. The Cmax and AUC24h of tolvaptan following 
simulated 1-hour intravenous administration of 32 mg OPC-61815 were as low as 
approximately 0.45-fold and 0.18-fold, respectively, those following a single oral 
administration of 300 mg tolvaptan. Considering that the safety of a single oral 
administration of 300 mg tolvaptan has been established in healthy adults (156-03-245), 
1-hour intravenous administration of 16 mg and 32 mg OPC-61815 does not appear to 
raise significant safety concerns from the perspective of tolvaptan exposure. 
2.3 
Trial Objectives 
To investigate the effects of 1-hour intravenous administration of OPC-61815 at 16 and 
32 mg on QT/QTc interval in healthy adult male subjects. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a single-center, randomized, double-blind, placebo- and moxifloxacin active-
controlled, 4-period crossover trial in 48 healthy adult male subjects. OPC-61815 and 
placebo will be administered in a double-blind fashion and moxifloxacin tablets will be 


 
 
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administered in an open-label fashion, and the effects of 16 mg and 32 mg OPC-61815 on 
the QT/QTc interval will be evaluated. 
The trial design schematic is shown in Figure 3.1-1. 
Eligible subjects will be randomized to one of the predetermined treatment sequences 
prior to IMP administration on Day 1 of Period 1 (see Section 3.6.1 Randomization). 
Subjects will receive a single dose of OPC-61815, placebo, and moxifloxacin tablets in 
Periods 1 to 4 in the assigned sequence. Following the start of IMP administration, 
scheduled observations/examinations/assessments will be performed in a similar manner 
during each treatment period. A washout period of at least 6 days will be set between the 
days of IMP administration in a treatment period and the next treatment period. Post-
treatment follow-up will be performed 6 to 8 days after the administration in Period 4. In 
each treatment period, subjects will be admitted to hospital on the day before IMP 
administration (Day −1) and discharged on Day 2. 
 


 
 
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Figure 3.1-1 
Trial Design Schematic 
The end of trial date is counted from the start of the first IMP administration, with each washout period 
assumed to be 6 days. 
 
[Rationale for trial design] 
The ICH Guideline E14 states that a thorough QT/QTc study should have mechanisms to 
deal with potential bias, including use of randomization, appropriate blinding, and 
concurrent placebo control group. It also states that confidence in the ability of the study 
to detect QT/QTc prolongation can be greatly enhanced by the use of a concurrent 
positive control group. In accordance with these recommendations, this trial has a 
randomized, double-blind, placebo- and moxifloxacin active-controlled design. 
Moxifloxacin is selected as a positive control because it allows researchers to detect 
QT/QTc prolongation following a single administration. In addition, a crossover design 
allows all subjects to receive active drugs and placebo and thus has the advantage of 
requiring a smaller sample size than a parallel-group comparative design. 
Day 1 Day 2
Day 1 Day 2
Day 1 Day 2
Day 1 Day 2
(Day-1)
(Day-1)
(Day-1)
(Day-1)
Discharge
Discharge
Discharge
Discharge
Screening
(Days –28 to –2
before Period 1 IMP
administration)
Period 1
Period 2
Single administration of OPC-61815 (16 and 32 mg), placebo, or moxifloxacin
Period 3
Period 4
Randomization
End of trial (27-29 days after start of the first IMP administration)
Post-treatment follow-up 
(6-8 days after the administration in Period 4)
Informed consent (start of trial)
Screening examination
IMP administration
IMP administration
IMP administration
IMP administration
Admission
Washout
period
≥6 days
Admission
Admission
Admission
Washout
period
≥6 days
Washout
period
≥6 days


 
 
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Since OPC-61815 and moxifloxacin have a half-life of <3 hours and approximately 
14 hours, respectively, a washout period of ≥3 days may be sufficient for any IMP to be 
eliminated from the body. Considering that frequent blood samplings are planned in the 
trial, however, the duration of washout period was determined to be ≥6 days from the day 
after IMP administration. 
12-lead Holter electrocardiography (ECG) that allows continuous recording of the 
waveform and the time will be used to evaluate the primary and secondary endpoints. In 
consideration of the circadian ECG variations and changes in plasma OPC-61815 
concentrations, 12-lead Holter ECG will be performed until 24 hours have elapsed after 
start of IMP administration. In addition, considering plasma OPC-61815 concentrations, 
subjects will be monitored for safety until 24 hours have elapsed after start of IMP 
administration 
Subjects will be monitored until 24 hours have elapsed after start of IMP administration 
on an inpatient basis so that all subjects can have ECG monitoring under as close to the 
same conditions as possible. 
OPC-61815 is metabolized into tolvaptan in the body. A trial (156-03-245) in healthy 
adults evaluating the effect of orally administered tolvaptan on the QTc interval 
demonstrated that neither tolvaptan nor its metabolites prolong the QTc interval. This 
trial will therefore investigate only the effect of OPC-61815 on the QT/QTc interval. 
3.2 
Trial Treatments 
Each subject will receive a single dose of IMP in a fasted state (see 4.2.1 Food and 
Beverages) in the randomly assigned sequence. OPC-61815 (16 mg and 32 mg) and 
placebo will be intravenously administered by 1-hour infusion. Two OPC-61815 16-mg 
vials will be used for administration of 32 mg OPC-61815. A moxifloxacin 400 mg tablet 
will be orally administered with 240 mL of water. Each subject will start to receive IMP 
approximately the same time of the day in all treatment periods. The allowable duration 
of intravenous administration of 16 mg and 32 mg OPC-61815 and placebo will be 59 to 
65 minutes. The total number of IMP administration days is 4 days. Postdose monitoring 
will last up to Day 2 in each treatment period, and the duration of washout period starting 
on Day 2 is at least 6 days before IMP administration in the next treatment period. Post-
treatment follow-up will be performed 6 to 8 days after IMP administration in Period 4. 
[Rationale for treatment duration] 
The half-life of OPC-61815 is shorter than 3 hours and plasma OPC-61815 
concentrations following repeated-dose administration hardly accumulate in the steady 


 
 
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state. A single dose of positive control moxifloxacin sufficiently prolongs the QT/QTc 
interval. A single dose of each IMP should therefore allow appropriate evaluation of their 
effects on the QT/QTc interval. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
A total of 48 healthy male subjects age 20 to 45 years, inclusive, at time of informed 
consent will be enrolled in the trial. 
Subjects who were scheduled to receive IMP but withdrew consent before IMP allocation 
and subjects considered to be unavailable for IMP administration will be replaced by 
standby subjects. Subjects withdrawn from the trial after IMP allocation will not be 
replaced. 
3.3.2 
Subject Selection and Numbering 
Each subject will be assigned a subject identifier (site number [001] + subject number 
[S + 5-digit in-site serial number]) upon signing the informed consent form. The trial site 
will create and keep a list of all subjects who have given consent and their subject 
identifiers. 
3.4 
Eligibility Criteria 
Exceptions to the eligibility criteria will not be permitted during the trial, either by the 
investigator or subinvestigator or by the medical advisor. 
3.4.1 
Informed Consent 
Informed consent will be obtained from all subjects (or their guardians stipulated by the 
local law or legal representatives) on the basis of their free will. 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 ICH Good Clinical Practice (GCP) Guideline8 and local 
regulatory requirements. 
Investigators or subinvestigators may discuss the possibility that a potential subject may 
be allowed to enter the trial without first obtaining consent. However, a written informed 
consent must be obtained before initiation of any procedures that are performed for the 
purpose of determining eligibility for this trial, including withdrawal from current 
medication(s). 


 
 
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Potential subjects are free to refuse participation in the trial, or withdraw from the trial at 
any time, without justification, and their refusal or withdrawal will have no consequences 
for 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, an IRB-approved 
written ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or subinvestigator). If a trial collaborator has provided a supplemental 
explanation, the IRB-approved written ICF will be signed and dated by the trial 
collaborator as well. 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, so that they can make an informed and voluntary decision on their participation 
in the trial. 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Japanese male subjects age 20 to 45 years, inclusive, at time of informed consent 
2 
Body mass index (BMI) (body weight in kilogram / [height in meter]2) of at least 18.5 kg/m2 and 
less than 25.0 kg/m2 based on the results of the screening examination 
3 
Judged by the investigator or subinvestigator to be capable of providing written informed consent 
prior to start of any trial-related procedures and capable of complying with all the requirements for 
this trial 
 
[Rationale for inclusion criteria] 
1 Age: The lower limit of 20 years is the age at which an individual is legally regarded as an adult 
capable of taking responsibility for consent. The upper limit of 45 years is based on the consideration 
that individuals older than 45 years are likely to develop concurrent diseases. 
Race: Only Japanese subjects will be included because the trial will be conducted for the purpose of 
applying for a marketing approval in Japan. 
Sex: Only men will be included, because the possibility of pregnancy does not need to be considered in 
men. 
2 In order to reduce interindividual PK variations. 
3 In order to conduct the trial in an ethically appropriate manner. 
 


 
 
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3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. The 
day of IMP administration mentioned in these criteria denotes the scheduled 
administration day. If clinical laboratory tests are performed again at the discretion of the 
investigator or subinvestigator, they should be recorded according to the trial site's 
procedure. 
Subjects excluded as a result of positive urine drug, cotinine, or breath alcohol test, a 
failure to appropriately evaluate ECGs (exclusion criteria 1 to 5), or falling under 
exclusion criteria 21, 22, or 24 cannot be rescreened. However, subjects excluded as a 
result of falling under other exclusion criteria may be rescreened if any changes in the 
relevant condition are observed. For rescreening, the subject must sign a new ICF, be 
assigned a new subject identifier, and undergo all screening examinations/assessments 
again. 
Table 3.4.3-1 
Exclusion Criteria 
1 
Subjects with a medical history of convulsive disorder, long QT syndrome (including family history), 
syncope during swimming, or any other type of syncope or cryptogenic loss of consciousness 
2 
Subjects with a serum electrolyte abnormality (hypokalemia, hypomagnesemia, hypocalcemia, etc.) 
3 
Subjects with a family history of sudden death 
4 
Subjects with a history of heart disease such as hypertension, atherosclerosis, heart failure, 
bradycardia, or stroke, or who are using a pacemaker 
5 
Subjects with 2 or more of the following abnormalities in 3 tests of 12-lead ECG and 2 or more 
additional abnormalities in re-testing performed 1 hour after the first series of tests at the screening 
examination or on the day before Period 1 IMP administration (Day −1) 
 
PR interval of >220 msec 
 
QRS interval of >120 msec 
 
QTcF of <320 msec or >450 msec 
 
Atrial fibrillation or atrial flutter 
 
Other worrisome cardiac findings 
6 
Subjects who have received any other IMP in another clinical trial within 120 days prior to Period 1 
IMP administration 
7 
Subjects who have undergone blood collection (eg, blood donation) of >200 mL within 30 days, 
>400 mL within 90 days, or >1200 mL within 1 year prior to Period 1 IMP administration 
8 
Subjects who have consumed any of the following products within the corresponding specified time 
prior to Period 1 IMP administration 
 
Products containing St John’s wort (Hypericum perforatum): Within 14 days prior to Period 1 
IMP administration 
 
Products containing grapefruit, Seville orange, or star fruit: Within 7 days prior to Period 1 IMP 
administration 
 
Food or beverages containing alcohol or caffeine: Within 1 day prior to Period 1 IMP 
administration 
9 
Subjects who have taken any prescription drugs, OTC drugs, Chinese herbal remedies, or vitamin 
supplements within 14 days or antibiotics within 30 days prior to Period 1 IMP administration 


 
 
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Table 3.4.3-1 
Exclusion Criteria 
10 
Subjects who have been exposed to any substance known to stimulate production of liver microsomal 
enzymes (eg, occupational exposure to pesticides or organic solvents) within 30 days prior to Period 1 
IMP administration 
11 
Subjects who have used any tobacco products, nicotine replacement therapy, or electronic cigarettes, 
or who have been exposed to second-hand smoke on a daily basis, within 60 days prior to Period 1 
IMP administration, or who test positive in urine nicotine test at the screening examination 
12 
Sexually active men who: 
 
Are unable or unwilling to either use 2 types of approved contraception methods or remain 
abstinent during the trial and for 30 days after final IMP administration. 
If employing birth control, use 2 of the following approved methods of birth control: vasectomy, 
tubal ligation, intrauterine device, birth control pill, condom with spermicide, occlusive cap 
(vaginal diaphragm or cervical/vault cap) with spermicide. 
 
Plan to donate sperm within 30 days after final IMP administration. 
13 
Subjects with a history of a clinically significant abnormality, or for whom a clinically significant 
abnormality is observed in the results of the screening examination, and the investigator, 
subinvestigator, or sponsor judges that the abnormality could place the subject at risk or affect 
evaluation of drug absorption, distribution, metabolism, or excretion. 
Such abnormalities include, but are not limited to, a history or current symptoms of cardiac, hepatic, 
renal, nervous system, endocrine, gastrointestinal, respiratory, and hematic immune 
diseases/disorders. 
14 
Subjects with a history of clinically significant drug or alcohol abuse 
15 
Subjects with a history or current condition of hepatitis or acquired immunodeficiency syndrome 
(AIDS), or a positive test result for any of the following: Hepatitis B surface antigen (HBsAg), anti-
hepatitis C virus (HCV) antibody, AIDS antigen/antibody, or syphilis 
16 
Subjects with a history of severe drug allergy or hypersensitivity to any of the following drugs: 
 
Any ingredients of OPC-61815 or tolvaptan 
 
Compounds containing benzazepine (mozavaptan hydrochloride, benazepril hydrochloride) 
 
Quinolone antibiotics, including moxifloxacin 
17 
Subjects who have a positive test result in breath alcohol test or urine drug test for detection of 
substance abuse at the screening examination or on the day before Period 1 IMP administration 
(Day −1) 
18 
Subjects with a history of serious hemorrhage or bleeding tendency 
19 
Subjects with blood collection difficulty 
20 
Subjects with supine resting systolic blood pressure of >140 mmHg or <90 mmHg or supine resting 
diastolic blood pressure of >80 mmHg or <40 mmHg at the screening examination or on the day 
before Period 1 IMP administration (Day 1) (see Section 3.7.5.4 Vital Signs (Blood Pressure, Pulse 
Rate, and Body Temperature)) 
21 
Subjects with supine resting pulse rate of >90 bpm or <45 bpm at the screening examination or on the 
day before Period 1 IMP administration (Day 1) (see Section 3.7.5.4 Vital Signs (Blood Pressure, 
Pulse Rate, and Body Temperature)). 
22 
Subjects who are currently taking an antiarrhythmic agent of Class IA (quinidine, procainamide, etc.) 
or Class III (amiodarone, sotalol, etc.) 
23 
Subjects with a history of serious psychological disorder whose participation in the clinical trial is 
judged to be inappropriate by the investigator or subinvestigator 
24 
Subjects who are otherwise judged by the investigator or subinvestigator to be inappropriate for 
participation in the clinical trial 
 


 
 
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[Rationale for exclusion criteria] 
1 to 5  Based on exclusion criteria recommended in the ICH Guideline E14. 
6 In reference to the Standards for Intervals During Which Subjects Should Refrain from Participating in a 
Clinical Trial9 proposed by the Japan Association of Contract Institutes for Clinical Pharmacology. 
7 In reference to the blood sampling criteria10 proposed by the New Blood Programme Advisory 
Committee. 
8 It is reported that some food products containing St John's wort induce drug-metabolizing enzymes such 
as CYP3A4, and that grapefruit, Seville orange, and star fruit inhibit CYP3A4. Based on these reports, 
this criterion is used to avoid their possible effects on the PK of IMP. 
9 to 11  To avoid their possible effects on the PK of IMP. 
12 to 22  For safety reasons. 
23 and 24  For general safety and ethical reasons. 
 
3.5 
Endpoints 
3.5.1 
Primary Endpoint(s) 
Time-matched difference between the OPC-61815 and placebo data in change from 
baseline for QTcF in 12-lead Holter ECG 
3.5.2 
Secondary Endpoint(s) 
12-lead Holter ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTcF interval) and ECG waveform patterns 
3.5.3 
Pharmacokinetic Endpoints 
Plasma concentrations and pharmacokinetic parameters of OPC-61815 free form and 
tolvaptan 
3.5.4 
Safety Endpoints 
Adverse event reporting, clinical laboratory assessments, physical examination, vital 
signs (blood pressure, pulse rate, and body temperature), body weight, and 12-lead ECG 
3.6 
Measures to Minimize/Avoid Bias 
3.6.1 
Randomization 
Eligible subjects will be randomized at the equal ratio to one of different sequences of 4 
treatments (16 mg OPC-61815, 32 mg OPC-61815, placebo, and moxifloxacin). The 
sequences will be determined so that each treatment will be given equally in each 
treatment period. The details are provided in a separate document. 


 
 
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3.6.2 
Blinding 
In this trial, OPC-61815 and placebo will be administered in a double-blind fashion and 
moxifloxacin tables will be administered in an open-label fashion. 
The lyophilized OPC-61815 and placebo in vials are similar in their appearance but the 
two solutions will be distinguishable in appearance once prepared: Foam may be seen 
immediately after preparation but will disappear in a certain period of time. To maintain 
blindedness of all trial site staff participating in assessment during the trial, the trial site 
will appoint a third person (non-blinded staff) who is responsible for preparation of IMP.  
The person responsible for IMP preparation should be qualified with a pharmacist license 
for drug preparation and appointed at the trial site. The details on procedures of IMP 
preparation and maintenance of blindness at the trial site where the non-blinded staff 
responsible for IMP preparation is appointed will be specified separately in pharmacy 
manual. The non-blinded staff responsible for IMP preparation is required to maintain 
confidentiality of information related to the preparation of the IMP solution. Any queries 
related to IMP are to be addressed to the contact person specified in the manual rather 
than the trial monitor. 
To maintain access to IMP throughout the trial, the trial site may appoint a deputy person 
responsible for IMP preparation (non-blinded staff). 
3.6.3 
Reading of 12-Lead Holter Electrocardiograms 
The ICH Guideline E14 recommends blinded ECG assessment by a few skilled readers at 
the central ECG laboratory. It also states that the degree of inter- and intra-reader 
variability should be established by having the assessors reread a subset of the data under 
blinded conditions. In this trial, a few skilled readers will read ECGs at the central ECG 
laboratory and the assessors will reread a subset of the data to avoid 12-lead Holter ECG 
reading bias. 
3.7 
Trial Procedures 
Trial assessment time points are summarized in Table 3.7-1. Acceptable windows for 
postdose examinations/assessments (for all treatment periods) are shown in Table 3.7-2. 
 


 
 
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Table 3.7-1 
Schedule of Assessments 
 
Visits 
Hospitalization at Trial Site 
At 
Withdrawal 
Visits 
Screening 
Day Before 
Administration 
Period 1, 2, 3, and 4 (Washout Period: At least 6 days) 
Post-
treatment 
follow up 
Day 
Day -28 
to Day -2 
Day -1 
Day 1 
Day 2 
Time From Start of 
Administration 
(hours) 
 
 
Predose 
0 
0.5 
1 
1.5 
2 
3 
4 
6 
12 
24 
Start of 
Infusion 
 
End of 
Infusion 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug and 
cotinine, and breath 
alcohol tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Trial Assessments  
12-Lead Holter ECG 
 
 
Xd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood collection for 
plasma concentration 
measurement 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Clinical laboratory 
testb 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Vital signs (blood 
pressure, pulse rate, 
temperature)c 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Body weight 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication/therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: This table shows the schedule of assessments. For a summary of the assessment items and timepoints by trial period and day, refer to Section 3.7.3 
Schedule of Assessments. 


 
 
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aPerformed only on Day 1 of Period 1.  
bOf the blood biochemistry tests, only serum sodium and potassium will be measured at 6 and 12 hours postdose. 
cOnly blood pressure and pulse rate will be measured at 30 minutes, and 1, 2, 4, and 6 hours postdose. 
dPerformed at 1 hour, 30 minutes, and 15 minutes prior to IMP administration. 
ePerformed at the time of withdrawal during hospitalization. 
 


 
 
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Table 3.7-2 
Acceptable Windows for Postdose Examinations/Assessments 
(for All Treatment Periods) 
Examination/Assessment 
Time point (time from start of 
IMP administration) 
Acceptable window 
PK blood sampling 
(performed after completion 
of resting 12-lead Holter 
ECG) 
Day 1 
1 hour 
Within 2 minutes after end of IMP 
administrationa 
 
1.5 hours 
Specified time point + 2 minutes 
 
2 hours 
Specified time point + 3 minutes 
 
3 hours 
Specified time point + 5 minutes 
 
4 hours 
Specified time point + 10 minutes 
 
6 and 12 hours 
Specified time point + 15 minutes 
Day 2 
24 hours 
Specified time point + 30 minutes 
Clinical laboratory tests 
Day 1 
1, 6, and 12 hours 
Specified time point ± 30 minutes 
Day 2 
24 hours 
Specified time point ± 1 hour 
Physical examination 
Day 1 
1, 2, and 4 hours 
Specified time point ± 20 minutes 
Day 2 
24 hours 
Specified time point ± 1 hour 
Vital signs 
Day 1 
30 minutes 
20-45 minutes after start of IMP 
administration 
1, 2, 4, and 6 hours 
Specified time point ± 30 minutes 
Day 2 
24 hours 
Specified time point ± 1 hour 
Body weight 
Day 2 
24 hours 
Specified time point ± 1 hour 
12-lead ECG 
Day 1 
1, 2, 4, and 6 hours 
Specified time point ± 30 minutes 
Day 2 
24 hours 
Specified time point ±1 hour 
a For moxifloxacin, specified time point + 2 minutes 
 
3.7.1 
General Inpatient Procedures 
Subjects will be instructed to rest as much as possible and avoid strenuous exercise 
during hospitalization. 
IMP administration may cause dehydration. Subjects will be instructed to drink an 
appropriate amount of water to ensure their safety. 
Subjects will take a moxifloxacin 400-mg tablet with 240 mL of water and then undergo 
an oral check to see if the drug was appropriately consumed. Restroom visits must be 
supervised during the 4 hours postdose and should be brief (<10 minutes). In addition, 
during the 4-hour period after oral dosing, the subject's toilet use must be supervised to 
prevent self-induced emesis resulting in loss of the oral dose. 
3.7.2 
Dietary Requirements 
During hospitalization, subjects must not consume foods or beverage other than those 
provided by the trial site. If the mealtime coincides with a time point for 


 
 
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examination/assessment or blood sampling, subjects will undergo the 
examination/assessment or blood sampling before having a meal. 
3.7.3 
Schedule of Assessments 
3.7.3.1 
Informed Consent 
Prior to screening examination, the investigator or subinvestigator will obtain written 
informed consent from the subject. After obtaining consent from the subject, the 
investigator or subinvestigator will perform the screening examination. 
3.7.3.2 
Screening 
After obtaining informed consent, the investigator or subinvestigator will assign a subject 
identifier to each subject according to Section 3.3.2 Subject Selection and Numbering. 
Subjects will visit the trial site at any date and time that is convenient to them between 28 
and 2 days before Period 1 IMP administration and undergo the following 
examinations/assessments for eligibility assessment. The results of eligibility assessment 
will be recorded in the case report form (CRF). If a subject is judged to be eligible for the 
trial despite the presence of some abnormality, the reason for the judgment will be 
documented in the medical records and other relevant documents. 
For rescreened subjects, the previous subject identifier (S + 5-digit in-site serial number) 
will also be recorded in the CRF. 
 Subject demographics (birth date, complications, medical history [within 1 year 
before informed consent]) 
 Height, body weight, and body mass index (BMI) 
Height will be measured to the first decimal place in centimeters. If height is 
measured to the second decimal place, the measurement will be rounded off to the 
first 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. 
 Urine drug test, urine cotinine test, and breath alcohol test 
 Infectious disease screening 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 ECG (standard triplicate 12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 


 
 
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3.7.3.3 
Day Before IMP Administration (Day −1) in Period 1 
Subjects and standby subjects who are judged to be eligible based on the screening results 
will be admitted to the trial site on the day before Period 1 IMP administration (Day −1). 
They will undergo the following examinations/assessments and be rechecked against the 
inclusion and exclusion criteria. The date and results of recheck will be recorded in the 
screening list and the subject enrollment list. 
 Urine drug test, urine cotinine test, and breath alcohol test 
 Physical examination 
 Vital signs (blood pressure, pulse rate, body temperature) 
 ECG (standard triplicate 12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.4 
Day 1 of Period 1 
The investigator or subinvestigator will select subjects who are judged to be eligible 
based on the screening results and whose condition up to immediately before IMP 
administration indicates that they can safely receive IMP, assign them each a 
randomization number in the ascending order of the subject identifier, and randomize 
them to treatments. The date and number of randomization will be recorded in the CRF. 
Standby subjects will be discharged from the trial site once all the subjects to receive 
IMP administration are determined. 
Following randomization, subjects will receive IMP. 
The following examinations/assessments will be performed. 
1) Within 3 hours before IMP administration 
 Blood sampling for plasma drug concentration measurement 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis [urinalysis will 
take place after waking up and before IMP administration])  
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 
2) Within 2 hours before IMP administration 
 ECG (12-lead ECG) 
 


 
 
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3) Within 1 hour, 30 minutes, and 15 minutes before IMP administration 
 ECG (12-lead Holter ECG) 
 
4) Start of IMP administration (a 1-hour intravenous administration of an injection 
or a single administration of a tablet) 
 
5) Examinations/assessments after start of IMP administration 
 Blood sampling for plasma drug concentration measurement: 1, 1.5, 2, 3, 4, 6, and 
12 hours after start of IMP administration 
 ECG (12-lead Holter ECG): 1, 1.5, 2, 3, 4, 6, and 12 hours after start of IMP 
administration 
 Clinical laboratory tests 
Hematology, biochemistry, and urinalysis: 1 hour after start of IMP 
administration 
Serum electrolytes (sodium and potassium only): 6 and 12 hours after start of IMP 
administration (blood sampling will take place concurrently with that for plasma 
drug concentration measurement) 
 Physical examination: 1, 2, and 4 hours after start of IMP administration 
 Vital signs (blood pressure and pulse rate only): 30 minutes, 1, 2, 4, and 6 hours 
after start of IMP administration 
 ECG (12-lead ECG): 1, 2, 4, and 6 hours after start of IMP administration 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.5 
Day 2 of Period 1 
The following examinations/assessments will be performed at 24 hours after start of IMP 
administration. Subjects without safety problems will be discharged from the trial site. 
 Blood sampling for plasma drug concentration measurement 
 ECG (12-lead Holter ECG) 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 ECG (12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 


 
 
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3.7.3.6 
Day Before IMP administration (Day −1) in Periods 2, 3, and 4 
Subjects will visit the trial site for the following examinations/assessments. Subjects 
whose condition indicates that they can safely receive IMP will be admitted to the trial 
site. 
 Urine drug test, urine cotinine test, and breath alcohol test 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 ECG (12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.7 
Day 1 of Periods 2, 3, and 4  
The investigator or subinvestigator will perform the following examinations/assessments 
on subjects whose condition up to immediately before IMP administration indicates that 
they can safely receive IMP. 
1) Within 3 hours before IMP administration 
 Blood sampling for plasma drug concentration measurement 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis [urinalysis will 
take place after waking up and before IMP administration]) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 
2) Within 2 hours before IMP administration 
 ECG (12-lead ECG) 
 
3) Within 1 hour, 30 minutes, and 15 minutes before IMP administration 
 ECG (12-lead Holter ECG) 
 
4) Start of IMP administration (a 1-hour intravenous administration of an injection 
or a single administration of a tablet) 
 
5) Examinations/assessments after start of IMP administration 
 Blood sampling for plasma drug concentration measurement: 1, 1.5, 2, 3, 4, 6, and 
12 hours after start of IMP administration 


 
 
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 ECG (12-lead Holter ECG): 1, 1.5, 2, 3, 4, 6, and 12 hours after start of IMP 
administration 
 Clinical laboratory tests 
Hematology, biochemistry, and urinalysis: 1 hour after start of IMP 
administration 
Serum electrolytes (sodium and potassium only): 6 and 12 hours after start of IMP 
administration 
 Physical examination: 1, 2, and 4 hours after start of IMP administration 
 Vital signs (blood pressure and pulse rate only): 30 minutes, 1, 2, 4, and 6 hours 
after start of IMP administration 
 ECG (12-lead ECG): 1, 2, 4, and 6 hours after start of IMP administration 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.8 
Day 2 of Periods 2, 3, and 4  
The following examinations/assessments will be performed 24 hours after start of IMP 
administration. Subjects without safety problems will be discharged from the trial site. 
 Blood sampling for plasma drug concentration measurement 
 ECG (12-lead Holter ECG) 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 ECG (12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.9 
Withdrawal Examination 
Subjects who are withdrawn from the trial following any IMP administration will 
undergo the following observations/examinations. If a trial withdrawal takes place while 
the subject is not hospitalized, withdrawal examination is unnecessary and post-treatment 
follow-up will be performed instead. 
 Blood sampling for plasma drug concentration measurement 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Physical examination 


 
 
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 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 ECG (12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.10 
Post-treatment Follow-up 
Subjects will visit the trial site at any date and time that is convenient to them between 6 
and 8 days after the final IMP administration and undergo the following 
examinations/assessments. Subjects who are withdrawn from the IMP administration for 
any reason will also undergo the following examinations/assessments between 6 and 8 
days after withdrawal. 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Physical examination 
 Vital signs (blood pressure, pulse rate, and body temperature) 
 Body weight 
 ECG (12-lead ECG) 
 AEs 
 Concomitant medications/therapies 
 
3.7.3.11 
Post-trial Follow-up 
Subjects will be followed up as described in Section 5.7 Follow-up of Adverse Events. 
3.7.4 
Prior and Concomitant Medications 
The investigator or subinvestigator will record all medications (drug name, purpose of 
use, dose, frequency, route of administration, and start and end dates of treatment) and 
therapies (therapy name, purpose of use, and start and end dates of treatment) taken by 
the subject from 60 days prior to Day 1 of Period 1 through post-treatment follow-up 
(end of trial) in the CRF. 
3.7.5 
Safety Assessments 
3.7.5.1 
Adverse Events 
Refer to Section 5 Reporting of Adverse Events for the methods and timing for assessing, 
recording, and analyzing AEs. 


 
 
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3.7.5.2 
Clinical Laboratory Assessments 
3.7.5.2.1 
Clinical Laboratory Tests 
Clinical laboratory tests listed in Table 3.7.5.2-1 will be performed at the scheduled time 
points (see Table 3.7-1 and Table 3.7-2) according to the procedure specified by the trial 
site. To ensure subject safety, serum sodium and potassium concentrations will be 
determined at 6 and 12 hours after start of IMP administration on Day 1 in each treatment 
period. Blood sampling for serum sodium and potassium will take place concurrently 
with that for plasma drug concentration measurement. The investigator or subinvestigator 
will promptly review the test results. The dates and times of blood and urine samplings 
will be recorded in the CRF. The test results and reference values will be reported 
directly to the sponsor in the electronic format, and recording in the CRF is unnecessary. 
Table 3.7.5.2-1 
Clinical Laboratory Assessments 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Red blood cell count 
White blood cell count with differential 
 
Urinalysis: 
Specific gravity 
pH 
Qualitative testing 
   Protein 
   Glucose 
   Occult blood 
   Ketones 
   Bilirubin 
   Urobilinogen 
Serum Chemistry: 
Protein, total 
Albumin 
Bilirubin, total 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
γ-Glutamyl transferase (γ-GTP) 
Lactic dehydrogenase (LDH) 
Creatine kinase (CK [CPK]) 
Glucose 
Cholesterol, total 
Triglycerides 
Urea nitrogen 
Creatinine 
Uric acid 
Serum electrolytes 
   sodium (Na), magnesium (Mg) 
   potassium (K), calcium (Ca) 
   chloride (Cl) 
 
3.7.5.2.2 
Infectious Disease Screening 
The following tests will be performed at screening according to the procedure specified 
by the trial site. The date and time of blood sampling and test results will be recorded in 
the CRF. 
 Hepatitis B surface antigen (HBsAg) 
 Anti-hepatitis C virus (HCV) antibody  
 Human immunodeficiency virus (HIV) antigen/antibody 
 Syphilis 


 
 
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3.7.5.2.3 
Urine Drug Test, Urine Cotinine Test, and Breath Alcohol Test 
The following tests will be performed at the time points specified in Table 3.7-1 
according to the procedure specified by the trial site. The date and time of urine sampling, 
date and time of test, and test results will be recorded in the CRF. 
 Urine drug test (amphetamine, barbiturates, benzodiazepines, cannabinoid, 
cocaine, opiates, and phencyclidine) 
 Urine cotinine test 
 Breath alcohol test 
 
3.7.5.3 
Physical Examination 
Physical examinations will be performed at the scheduled time points (see Table 3.7-1 
and Table 3.7-2). The head, ears, eyes, nose and pharynx, chest, abdomen, urogenital 
organs, limbs, nervous system, and skin and mucous membrane will be examined. 
The date and results of the screening physical examination will be recorded in the CRF 
and only the dates of post-screening physical examinations will be recorded in the CRF. 
Any clinically relevant physical findings that are noted after screening but not at 
screening will be identified as AEs and recorded in the CRF. 
It is preferable for the same physician to perform all physical examinations for any 
individual subject throughout the course of the trial. 
3.7.5.4 
Vital Signs (Blood Pressure, Pulse Rate, and Body 
Temperature) 
Vital signs will be measured at the scheduled time points (see Table 3.7-1 and Table 3.7-
2). Blood pressure (diastolic and systolic) and pulse rate will be measured in the supine 
position using a well-maintained instrument after the subject has rested for at least 
3 minutes. Blood pressure and pulse rate measurement at each time point after start of 
IMP administration will take place after completion of 12-lead Holter ECG and blood 
sampling. Blood pressure and pulse rate measurement at 30 minutes, 1 and 2 hours after 
start of IMP administration will take place by the time when the subject starts to rest for 
the next 12-lead Holter ECG. 
Whether or not the measurement was performed, together with the date and time of 
measurement and the blood pressure and pulse rate measurements will be recorded in the 
CRF. 


 
 
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Subjects whose blood pressure or pulse rate measurement at screening or at admission 
meets the relevant exclusion criteria but is not considered clinically meaningful will then 
have their blood pressure or pulse rate measured in triplicate at intervals of 10 minutes. 
Those with 2 of 3 measurements not meeting the relevant exclusion criteria will be 
enrolled in the trial. 
Axillary temperature will be measured to the first decimal place in Celsius using a well-
maintained thermometer. Whether or not the measurement was performed, together with 
the date and time of measurement and the temperature measurement will be recorded in 
the CRF. When the thermometer uses measures to the second or more decimal place, the 
reading is rounded to the first decimal place. 
3.7.5.5 
Body Weight 
Body weight will be measured at the scheduled time points (see Table 3.7-1 and Table 
3.7-2). Subjects must urinate at least once after waking up. After minimizing the effect of 
bowel movement and clothing-related variations, body weight will be measured using a 
well-maintained scale. The date and time of measurement and body weight measurement 
in kilograms (to the first decimal place) will be recorded in the CRF. When the scale uses 
measures to the second or more decimal place, the reading is rounded off to the first 
decimal place. 
3.7.5.6 
12-Lead Electrocardiogram Assessments 
The investigator or subinvestigator will globally assess whether ECG findings are normal 
or abnormal based on ECG charts and record the assessment result, and if abnormal, 
together with the abnormal finding, in the CRF. The date and time of measurement (if 
done in triplicate, only the first measurement), heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTcF interval are all to be recorded in the CRF. As a general 
rule, an abnormal finding will be identified as an AE; however, for an abnormal finding 
that the investigator or subinvestigator does not judge to be an AE, the reason for the 
judgment will be recorded in the source documents. 
Refer to Section 3.8.3 Individual Subject Discontinuation for the procedure for trial 
discontinuation due to abnormal 12-lead ECGs. 
3.7.5.6.1 
Screening Examination and Day Before IMP Administration in 
Each Period (Day −1) 
Resting 12-lead ECG will be performed at the scheduled time points (see Table 3.7-1 and 
Table 3.7-2) using a well-maintained standard 12-lead electrocardiograph provided by the 
trial site according to the procedure specified by the trial site. 


 
 
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12-lead ECG will be performed in triplicate with electrodes placed at the same places at 
all time points wherever possible. 
3.7.5.6.2 
Days 1 and 2 in Each Period and Post-treatment Follow-up 
Resting 12-lead ECGs will be performed at the scheduled time points (see Table 3.7-1 
and Table 3.7-2) using a well-maintained standard 12-lead electrocardiograph provided 
by the trial site or a 12-lead Holter electrocardiograph supplied by the central ECG 
laboratory according to the procedure specified by the trial site. 
12-lead ECG will be performed once, not in triplicate, with electrodes placed at the same 
places at all time points wherever possible. 
3.7.6 
Pharmacokinetic/Pharmacodynamic Assessments 
3.7.6.1 
Pharmacokinetic Assessments 
3.7.6.1.1 
Pharmacokinetic Blood Samples 
1) Blood sampling/measurement method 
Blood samples will be collected at the scheduled time points as shown in Table 3.7-1 
for all treatments with OPC-61815, placebo, and moxifloxacin to measure plasma 
concentrations of OPC-61815 free form and tolvaptan. Concentrations of 
moxifloxacin and additional metabolites that are not identified in the protocol may 
also be analyzed if new information becomes available. 
All plasma samples will be shipped to the bioanalytical laboratory. Detailed handling 
and shipping instructions are provided in Appendix 1. Whether or not blood was 
collected, and the date and time of blood sampling will be recorded. The bioanalytical 
laboratory will report the analysis results directly to the sponsor. Recording of 
analysis results in the CRF is unnecessary. 
After unblinding, the bioanalytical laboratory will submit the bioanalytical data, or 
table(s) of drug concentrations, in electronic format to the sponsor. 
2) Rationale for blood sampling schedule 
The following time points for blood sampling were determined for Day 1 according 
to the results of 1-hour OPC-61815 injection simulation based on the population PK 
models developed using the results of a single intravenous dose trial of OPC-61815 in 
healthy adults (263-08-001), a repeated intravenous dose trial of OPC-61815 in 
healthy adults (263-09-001), and an intravenous dose trial on rate of injection of 
OPC-61815 in healthy adults (263-10-005), as well as in consideration of feasibility, 
so that necessary PK parameters of OPC-61815 free form and tolvaptan can be 


 
 
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calculated: 1 predose time point; estimated tmax of OPC-61815 free form (1 hour after 
start of administration) by simulation and 3 time points (1, 1.5, and 2 hours after start 
of IMP administration) around estimated tmax of tolvaptan by simulation; 3 time 
points (3, 4, and 6 hours after start of IMP administration) that are estimated to be in 
the elimination phase of OPC-61815 free form; and 3 time points (6, 12, and 24 hours 
after start of IMP administration) that are estimated to be in the elimination phase of 
tolvaptan. Since, in accordance with the Questions and Answers 3-2 in the ICH 
Guideline E14, this trial should be conducted uniformly following the specified trial 
procedures, blood samples will also be collected when moxifloxacin is administered 
in an open-label fashion. 
3.7.6.1.2 
Pharmacokinetic Urine Samples 
PK urine samples will not be collected. 
3.7.6.2 
Pharmacodynamic Assessments 
3.7.6.2.1 
12-Lead Holter Electrocardiogram Assessments 
1) Procedure 
12-lead Holter ECG will be performed using a 12-lead Holter electrocardiograph 
supplied by the central ECG laboratory according to the procedure specified by the 
central ECG laboratory. 
Subjects will be connected to a 12-lead Holter electrocardiograph prior to ECG 
recording performed at 1 hour before IMP administration on Day 1 in each treatment 
period. To standardize the test conditions for all time points for assessment, subjects 
will remain at rest in the supine position (they are conscious but must remain silent) 
for approximately 10 minutes from 15 minutes before the specified time point and 
will then continue in the resting state in the supine position (they must remain 
motionless and nobody should speak to them) for approximately 5 minutes from 
5 minutes before the specified time point. Electrodes will be placed at the same places 
at all time points wherever possible. If the time point for 12-lead Holter ECG 
coincides with a time point for examination/assessment or blood sampling, subjects 
will undergo 12-lead Holter ECG before the examination/assessment or blood 
sampling. 
The dates and times of start and end of ECG recording and the dates and times of start 
and end of the resting state will be recorded in the CRF. The time displayed on an 
appropriate clock in the trial site will be recorded. 


 
 
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2) Data transfer 
The trial site will send all 12-lead Holter ECG data to the central ECG laboratory 
according to a separately specified procedure. 
3) Retrieval of ECG analysis results 
The sponsor will receive from the central ECG laboratory the analysis results, or 12-
lead Holter ECG analysis report (heart rate, RR interval, PR interval, QRS interval, 
QT interval, and QTcF interval), and ECG waveform patterns. Recording of ECG 
analysis results in the CRF is unnecessary. 
4) Assessments 
The investigator or subinvestigator will globally assess whether ECG findings are 
normal or abnormal based on the 12-lead Holter ECG analysis report, and record 
whether or not an ECG was performed, the date of ECG, and normal/abnormal 
assessment (with the finding if abnormal) in the source documents. As a general rule, 
an abnormal finding will be identified as an AE; however, for an abnormal finding 
that the investigator or subinvestigator does not judge to be an AE, the reason for the 
judgment will be recorded in the source documents. 
3.7.7 
Genetic Assessments 
No genetic assessments are planned in this trial. 
3.7.8 
Future Biospecimen Research Samples 
No future biospecimen research assessments are planned in this trial. 
3.7.9 
End of Trial 
The end of trial date is defined as the end date of post-treatment follow-up. If the subject 
is lost to follow up, it will be the date of the final contact attempt. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial 
In the event of sponsor termination or suspension of 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 
Individual Site 
The sponsor, investigator, or the IRB has the right to terminate the participation of a 
particular trial site, if necessary, due to lack of subject enrollment, noncompliance with 


 
 
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the protocol, or if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP. The head of the trial site 
shall promptly notify the sponsor, if the termination of the trial was determined by the 
investigator or the IRB at the trial site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation/Interruption During a Treatment 
Period 
After the first dose of IMP, a subject may permanently stop or interrupt treatment during 
any of the treatment periods for a variety of reasons. Treatment discontinuation or 
interruption in any treatment period may be initiated by a subject or may become 
medically necessary due to AEs, required treatment with a prohibited medication or 
therapy, or for other reasons, as determined by the investigator or subinvestigator. Even 
when a subject discontinues or interrupts treatment during a treatment period, the subject 
may continue participation in the trial, if the investigator or subinvestigator decides that 
the subject is eligible for resuming treatment or receiving IMP for the remaining periods 
and if the subject is willing to continue the trial. 
3.8.3.2 
Treatment Discontinuation (Withdrawal) 
After the first dose of IMP, a subject may permanently stop treatment for a variety of 
reasons. Treatment discontinuations may be initiated by a subject or may become 
medically necessary due to AEs, required treatment with a prohibited medication or 
therapy, or for other reasons, as determined by the investigator or subinvestigator. Any 
subject who is unwilling to continue the trial after discontinuing treatment during a 
treatment period (see Section 3.8.3.1) must be withdrawn from the trial. Subjects who 
withdrew after the start of the IMP administration should be encouraged to complete all 
early termination (ET) assessments as soon as possible after withdrawal. 
If any of the following AEs occur, the subject must be withdrawn from the trial for safety 
reasons after discontinuation of IMP: 
 
Occurrence of severe drug hypersensitivity 
 
Occurrence of severe AEs of special interest (feeling abnormal, feeling hot, erythema, 
hyperhidrosis, pruritus, rash, urticaria, nausea, epigastric discomfort, dyspnoea) 
 
AST or ALT ≥3 times the upper limit of normal (ULN) 
 
≥12 mEq/L increase in serum sodium concentration within 24 hours of IMP 
administration compared to baseline 
 
A serum sodium concentration of ≥155 mEq/L 


 
 
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 
Regarding 12-lead ECG findings the day before IMP administration (Day −1) in 
Periods 2, 3, and 4, QTcF interval of <320 msec or >450 msec observed in at least 2 
of 3 ECG recordings performed 1 hour after preceding observation of QTcF interval 
in either range in at least 2 of 3 ECG recordings 
 Regarding 12-lead ECG findings after start of IMP administration in each period, 
QTcF interval of >500 msec observed in an ECG recording 1 hour after preceding 
observation of QTcF interval in the same range (if a 12-lead ECG recording is 
originally scheduled 1 hour after the first recording, the scheduled test constitutes the 
re-examination.) 
 
3.8.3.3 
Documenting Reasons for Discontinuation 
All subjects have the right to withdraw from the trial and the investigator or 
subinvestigator can discontinue a subject’s participation in the trial at any time, if 
medically necessary. In addition, subjects meeting the following criteria must be 
withdrawn from the trial. Only one reason for discontinuation (the main reason) can be 
recorded in the CRF: 
 Investigator/subinvestigator or subject decision (AE) 
 AEs requiring discontinuation 
 AEs meeting the criteria specified in Section 3.8.3.2 Treatment Discontinuation 
(Withdrawal) 
 Investigator/subinvestigator decision (other than AE) 
 Major protocol deviation (other than non-compliance with IMP) 
 Failure to meet the inclusion criteria or coming under the exclusion criteria 
 Trial terminated by sponsor 
 Withdrawal of consent by subject (if confirmed not related to an AE) 
 Lost to follow-up 
 
If the subject discontinues IMP due to an AE, the investigator, subinvestigator, or other 
trial personnel will make every effort to follow the event until it has resolved or stabilized 
or the subject is lost to follow-up or dies. Follow-up procedures in Section 5.7 Follow-up 
of Adverse Events must be followed. If there are withdrawals prior to randomization, 
subjects may be replaced as described in Section 3.3.1 Number of Subjects and 
Description of Population. 


 
 
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3.8.3.4 
Withdrawal of Consent 
All subjects have the right to withdraw their consent for further participation in the trial at 
any time without sustaining a disadvantage. Subjects cannot withdraw consent to the use 
of data already collected as part of the trial, but only for future participation. 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of caution 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 ensure the integrity of the trial. 
Subjects who withdrew after the start of the IMP administration should be encouraged to 
complete all ET assessments as soon as possible after withdrawal. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented (ie, subject signs an ICF), but who is not randomized or assigned trial 
treatment. 
Screen failure subjects are permitted to be rescreened. In the event that the subject is 
rescreened for trial participation, a new ICF must be signed, a new subject identifier 
assigned, and all screening procedures repeated. 
For each screen failure subject, the following information shall be documented in the 
ICF: 
 Visit date 
 Date of consent 
 Screened date 
 Birth date 
 Result of eligibility assessment (indicate the article number of the criterion the subject 
failed to meet) 
 Date of screen failure assessment 
 Reason for screen failure assessment 
 
3.10 
Definition of Completed Subjects 
The evaluation period is defined as the time period during which the subject is evaluated 
for primary and secondary objectives of the trial regardless of whether all IMP doses 
were administered. Subjects who are evaluated at the last scheduled visit during the 


 
 
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evaluation period will be defined as trial completers. For the purposes of this trial, 
subjects who complete the examinations on Day 2 of Period 4 will be defined as trial 
completers. 
3.11 
Definition of Subjects Lost to Follow-up 
For subjects who cannot be contacted before or after discharge in Period 4, and whose 
reason for discontinuation is not known (eg, withdrew consent or AE, etc.), except those 
who have completed the trial as defined in Section 3.10 Definition of Completed Subjects, 
the reason for discontinuation will be classified as “lost to follow-up.” 
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone. If such attempts fail, the site will attempt to contact the 
subject via certified mail or an alternative method before assigning a “lost to follow-up” 
status. For each case of “lost to follow-up,” the attempts made to contact the subject, 
whether or not AEs occurred, date(s) of contact, and contact method will be documented 
in the CRF. 
3.12 
Subject Compliance 
The subject will be under management of the investigator or subinvestigator during the 
trial period. The investigator or subinvestigator will instruct the subject to comply with: 
 Protocol-specified schedule during trial participation 
 The restrictions described in Section 4 Restrictions 
 Keeping confidential all the information the subject has acquired through 
participation in the trial 
 
3.13 
Protocol Deviations 
In the event of a major deviation from the protocol due to an emergency, accident, or 
mistake (eg, IMP dispensing error, subject dosing error, concomitant medication error, or 
violations of other restrictions), the investigator, subinvestigator, or designee will contact 
the sponsor at the earliest possible time by telephone. The investigator, subinvestigator, 
medical advisor, and sponsor will come to a joint decision as quickly as possible 
regarding the subject’s continuation in the trial. If the decision reached is to allow the 
subject to continue in the trial, this must be documented by the investigator or 
subinvestigator and the sponsor and approved by the medical advisor. 


 
 
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4 
Restrictions 
4.1 
Prohibited Medications 
None of the medications specified below, excluding the planned IMP, may be taken for 
the following periods: 
 The use of prescription, over-the-counter or herbal medications, or vitamin 
supplements is prohibited from 14 days prior to dosing in Period 1 until completion of 
post-treatment follow-up 
 The use of antibiotics is prohibited from 30 days prior to dosing in Period 1 until 
completion of post-treatment follow-up 
 
4.2 
Other Restrictions 
4.2.1 
Food and Beverages 
1) The intake of following food and beverages is prohibited for the duration 
indicated: 
 Products containing St John’s wort (Hypericum perforatum): Within 14 days prior 
to Period 1 IMP administration until completion of post-treatment follow-up 
 Products containing grapefruit, Seville orange, or star fruit: Within 7 days prior to 
Period 1 IMP administration until completion of post-treatment follow-up 
 Food or beverages containing alcohol: Within 1 day prior to Period 1 IMP 
administration until completion of post-treatment follow-up 
 Food or beverages containing caffeine: Within 1 day prior to IMP administration 
until discharge in each period 
 All food products (ie, fasting): For at least 10 hours before and 4 hours after IMP 
administration 
 Beverages containing sugar:  Within 1 day prior to IMP administration until 
discharge in each period 
 
4.2.2 
Smoking, Blood Donation, and Other Activities 
The following activities are prohibited between screening examination and completion of 
post-treatment follow-up: 
1) Smoking 
2) Blood donation 
3) Strenuous exercise 
 


 
 
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5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a medicinal product which does not necessarily have a causal relationship 
with the treatment. Adverse events would not include conditions recorded as a concurrent 
disease at the scheduled screening if such conditions at baseline were fully recognized 
and did not worsen. 
An adverse drug 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 
IMP caused the AE. 
A 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 at the time of the event. It does not include 
an event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability. 
 Requires hospitalization or prolongation of hospitalization. 
 Hospitalization itself should not be reported as a serious treatment-emergent 
adverse event (TEAE); whenever possible the reason for 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. 
 


 
 
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Immediately Reportable Event (IRE) is: 
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential serious hepatotoxicity (see Section 5.4). 
 Pregnancies in female partners of male subjects. Although normal pregnancy is not an 
AE, it must be reported to the sponsor using an IRE form. Pregnancy will only be 
documented in the CRF as an AE if there is a complication in the mother or 
abnormality in the newborn. 
 
Clinical Laboratory Value Changes: It is the investigator’s or subinvestigator’s 
responsibility to review the results of all laboratory tests as they become available. This 
review will be documented by the investigator’s or subinvestigator’s dated signature on 
the laboratory report. For each abnormal laboratory test result, the investigator or 
subinvestigator needs to ascertain if this is an abnormal (ie, clinically relevant) change 
from baseline for that individual subject. This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed. The 
investigator 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 relevant by the investigator or subinvestigator (eg, subject is symptomatic, 
requiring corrective treatment or further evaluation), leads to treatment discontinuation, 
or meets one or more of the criteria for being serious, the condition is considered an AE. 
 
Severity: The intensity of an AE will be graded on the following 3-point scale and 
reported as indicated in the CRF: 
1 = Mild: 
Discomfort noticed, but no disruption to activities of daily living. 
2 = Moderate: Discomfort sufficient to reduce or affect activities of daily living. 
3 = Severe: 
Inability to work or perform activities of daily living. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of IMP: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between IMP and the AE. 
Not Related:  
There is no temporal or reasonable relationship between IMP and the AE. 


 
 
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Date of occurrence and resolution (when possible, both date and time of occurrence and 
resolution) 
Date of occurrence: It is the day an AE occurred (or when an AE was first noticed). 
When a reported AE worsened in severity or seriousness, the date of 
worsening is recorded as the date of occurrence. 
Date of resolution: It is the day an AE resolved (if it is unknown, the day on which it 
was confirmed that the AE resolved). The date of blood/urine 
collection is documented as the date of resolution of abnormal 
laboratory test results. For deaths, the date of death is recorded 
instead as the date of resolution. 
 
Action taken in relation to IMP administration 
Any action taken in relation to IMP administration will be documented as follows: 
 
Unchanged 
 
Discontinued 
 
Interrupted 
 
Not applicable 
 
Outcome 
The outcome of an AE will be recorded by selecting one of the 6 outcomes listed below. 
For deaths, the date of death is recorded. If the outcome is relieved (recovering), not 
resolved, or unknown, the date on which the outcome is determined is documented. 
 
Resolved 
 
Relieved (recovering)  
 
Not resolved  
 
Resolved with sequalae 
 
Died 
 
Unknown (eg, unavailable for follow-up for some reason) 
 


 
 
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5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will assess subjects for the occurrence of AEs from 
the time the ICF is signed until the end of the trial. For this trial, information on AEs will 
be followed until 6 to 8 days after the last dose of IMP in Period 4. To avoid bias in 
eliciting AEs, subjects should be asked the following nonleading question: “How are you 
feeling?” All AEs (serious and nonserious) found in the subject must be recorded in the 
source documents and the CRF provided by the sponsor. AE and serious AE collection is 
to begin after the subject has signed the ICF. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
AEs only if there are unusual or severe clinical features that were not present, not 
experienced earlier, or not expected based on the course of the condition. 
When a reported AE worsened in severity or seriousness, the AE should be reported as a 
new AE in the CRF. 
In addition, the sponsor must be notified immediately, normally by e-mail, of any IREs 
according to the procedure outlined in Section 5.3 Immediately Reportable Events. 
Special attention should be paid to recording hospitalization and concomitant medications. 
5.3 
Immediately Reportable Events 
The investigator or subinvestigator must report any SAE, potential serious hepatotoxicity, 
or confirmed pregnancy (in partners of subjects) to the sponsor, normally by e-mail, 
immediately after the investigator, subinvestigator, or designee becomes aware of the 
event. An IRE form should then be completed and sent by e-mail to the sponsor, using 
the contact information on the title page of this protocol. (Please note that the IRE form is 
a specific form provided by the sponsor and is NOT the AE column in the CRF.) 
Subjects experiencing SAEs/IREs should be followed clinically as described in 
Section 5.7.2 Follow-up of Serious Adverse Events and Immediately Reportable Events. 
It is expected that the investigator or subinvestigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor. 


 
 
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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), the 
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 record it as an AE in the CRF. 
5.5 
Pregnancy 
Women of childbearing potential (WOCBP) are women whose menstruation has started 
and who are not documented as sterile (ie, who have had a bilateral oophorectomy or 
hysterectomy, or who have been in the menopause for at least 12 months). 
For each male subject who is sexually active with WOCBP, there must be a documented 
agreement that the subject and his partner will take effective measures (ie, 2 different 
approved methods of birth control) to prevent pregnancy during the course of the trial and 
for at least 30 days after the last dose of IMP. Unless the subject or his partner is sterile 
(ie, women who have had a bilateral oophorectomy, have had a hysterectomy, or have 
been in the menopause for at least 12 consecutive months; or men who have had a 
bilateral orchidectomy) or agrees to remain abstinent during the trial and for 30 days after 
the last dose of IMP, 2 of the following approved methods of birth control must be used: 
vasectomy, tubal ligation, intrauterine device, birth control pills, condom with spermicide, 
or occlusive cap (vaginal diaphragm or cervical/vault cap) with spermicide. Any single 
method of birth control, including vasectomy and tubal ligation, may fail, leading to 
pregnancy. The contraceptive methods will be documented in the CRF. Male subjects 
must also agree not to donate sperm from trial screening until 30 days have elapsed after 
the last dose of IMP. 
Before enrolling subjects in this clinical trial, the investigator or subinvestigator must 
review the information below about trial participation as part of the consent obtaining 
process. The topics should generally include: 
 General information 
 Informed consent form 
 Pregnancy prevention information 
 Drug interactions with hormonal contraceptives 
 Contraceptives in current use 
 Follow-up of a reported pregnancy 
 


 
 
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Before trial enrollment, men and WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risks associated with an 
unintentional pregnancy. Subjects must sign the ICF confirming that the above-
mentioned risks and the consequences were discussed. 
Subjects will be instructed to contact the investigator or subinvestigator immediately if 
their partners suspect that they might be pregnant (eg, missed or late menstrual cycle) 
during the trial. 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy in a subject's partner associated with IMP exposure during the trial and until 
30 days after the last dose of IMP, and record the event in the IRE form and forward it to 
the sponsor. The sponsor will forward the Pregnancy Surveillance Form(s) to the 
investigator or subinvestigator to monitor the outcome of the pregnancy. 
Protocol-required procedures for follow-up must be performed. Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, using the Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 
6 months from the date of birth. 
5.6 
Procedure for Breaking the Blind 
In the event of an emergency unblinding (knowledge of a subject’s treatment is required 
for the subject’s clinical care and safety), the investigator or subinvestigator is to contact 
the sponsor by phone in order to explain why opening the treatment assignment code is 
necessary, with both coming to a joint decision if this action is warranted. However, to 
prevent delays to the investigator, subinvestigator, or medical personnel responding to a 
potential emergency situation, unblinding of IMP will not be dependent upon the 
approval from the sponsor (ie, the investigator or subinvestigator will be able to obtain 
the code breaking information independent of the sponsor). The investigator or 
subinvestigator must contact the sponsor by telephone or e-mail within 24 hours of 
opening the code to explain why opening the treatment assignment code was necessary. If 
the treatment assignment code is unblinded, the sponsor’s Clinical Safety and 
Pharmacovigilance Department must be notified immediately by the investigator or 
subinvestigator through the IRE reporting process. Documentation of breaking the blind 
will be recorded in the subject’s medical record with the date and time the blind was 
broken, along with the names of the personnel involved, as well as on the appropriate 


 
 
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pages of the CRF for any AEs leading to the breaking of the blind. Once the blind is 
broken for a subject, that subject is not allowed to reinitiate treatment with IMP. 
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 in the AE 
column in the CRF, with the current status (ongoing or resolved/recovered) noted. All 
nonserious events (excluding IREs) that are ongoing at the last scheduled contact will be 
recorded as ongoing in the CRF. For any AE that has been identified during the course of 
the trial, additional relevant medical history information may be requested by the sponsor 
during data analysis to further ascertain causality (including, but not limited to, 
information such as risk-related behavior, family history and occupation). Follow-up 
information after the last scheduled contact will be recorded in the subject’s medical 
record. 
Based on the results of preceding phase 1 studies, feeling abnormal, feeling hot, erythema, 
hyperhidrosis, pruritus, rash, urticaria, nausea, epigastric discomfort, and dyspnoea have 
been selected as AEs of special interest. Because it is suspected that these AEs of special 
interest will occur, a new formulation with excipients different from those in the previous 
formulation will be used in this trial. The results of a trial investigating the rate of 
intravenous administration (263-10-005) also suggest that the AEs of special interest can 
be decreased by prolonging the duration of administration. However, because the causes 
of the AEs of special interest are unknown, a prick test will be performed on subjects 
who experience an AE of special interest in this trial to identify the cause. The 
investigator, subinvestigator, or designee will perform the prick test after the last dose of 
IMP (after Period 4 in completed subjects and at an appropriate timing after 
discontinuation for discontinued subjects) on subjects who experience any AE of special 
interest during the course of the trial after administration of OPC-61815 at 16 mg, 32 mg, 
or placebo. The prick test will be performed according to a separately defined procedure. 
When the investigator or subinvestigator decides that the prick test is unnecessary for a 
subject experiencing an AE of special interest arising from a clear cause, the reason for 
the decision will be documented in the source document. The use of anti-histamine drugs 
is prohibited for 3 days prior to the prick test. Whether a prick test was performed, as 
well as the date and time, result, and interpretation of the test (if performed), will be 
documented in the CRF. 


 
 
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5.7.2 
Follow-up of Serious Adverse Events and Immediately 
Reportable Events 
In this trial, subjects will be monitored closely for serious AEs and IREs until the end of 
the trial (last scheduled contact). 
Serious AEs and IREs that are identified by or ongoing at the last scheduled contact must 
be recorded in the AE column in the CRF. If new information related to the SAE or IRE 
(eg, resolution of the event) was obtained after the last scheduled contact with the subject 
before the end of the entire trial, the information must be documented in the IRE form 
and reported to the sponsor and also documented in the AE column in the CRF. 
SAEs and IREs must be followed, with any significant follow-up information reported to 
the sponsor using the IRE form, until the 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. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After Last Scheduled 
Contact 
Any new SAEs and IREs that are reported to the investigator or subinvestigator after the 
last scheduled contact and determined by the investigator or subinvestigator to be related 
to the use of IMP should be reported to the sponsor. In other words, these events are 
SAEs and IREs that are identified at the time of follow-up telephone contact or at any 
other time point after the defined trial period. The investigator or subinvestigator should 
follow SAEs and IREs identified after the defined trial period and continue to report any 
significant follow-up information to the sponsor using the IRE form until the events have 
resolved or stabilized, or the subject is lost to follow-up or has died. 
6 
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic 
Analysis 
6.1 
Pharmacokinetic Analysis Methods 
6.1.1 
Pharmacokinetic Analysis Set 
Pharmacokinetic analysis set includes subjects who are included in the safety analysis set 
and whose plasma drug concentration was measured. 


 
 
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6.1.2 
Pharmacokinetic Analysis 
1) Endpoints 
a) Plasma OPC-61815 free form and tolvaptan (OPC-41061) concentrations 
b) PK parameters of plasma OPC-61815 free form and tolvaptan (OPC-41061) 
Cmax, AUC24h, AUCt, AUC∞, tmax, λz, AUC_%Extrap, tlast, t1/2,z, CLa, 
CL/BWa, Vza 
aCalculated for OPC-61815 only 
 
2) Statistical analysis method 
Descriptive statistics will be calculated in the following manner: 
a) Plasma drug concentration 
 At each blood collection time point, descriptive statistics will be 
calculated by analyte and treatment. 
 Descriptive statistics to be calculated: Number of subjects, arithmetic 
mean, standard deviation, coefficient of variation, minimum, median, and 
maximum. 
b) Plasma pharmacokinetic parameters excluding λz, λz(lower), λz(upper), 
λz(point), and z(Rsq) 
 Descriptive statistics will be calculated for each parameter by analyte and 
treatment. 
 Descriptive statistics to be calculated: Number of subjects, arithmetic 
mean, standard deviation, coefficient of variation, geometric mean, 
minimum, median, and maximum. 
 
6.2 
Pharmacodynamic Methods 
12-lead Holter ECG parameters will be analyzed at a central ECG laboratory. The central 
laboratory will obtain 3 snapshots for each scheduled ECG from the 12-lead Holter ECG 
data sent from the trial site, determine the ECG parameters (heart rate, RR interval, PR 
interval, QRS interval, QT interval, and QTcF interval), and assess waveform patterns. 
Time windows for data capture are presented in Table 6.2-1. Each data capture will be 
obtained at an interval of at least 1 minute. The mean from 3 captures will be recorded as 
the value for each ECG measurement. 


 
 
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Table 6.2-1 
Time Windows for 12-lead Holter ECG Data Capture 
Schedule for 12-lead Holter ECG Data Capturea 
Time Window 
Day 1 
1 hour before IMP administration 
Within −5 minutes 
 
30 minutes before IMP administration 
 
15 minutes before IMP administration 
 
1 hour after start of IMP administration 
Within 5 minutes before end of IMP 
administrationb 
 
1.5 hours after start of IMP administration 
Within −5 minutes 
 
2 hours after start of IMP administration 
 
3 hours after start of IMP administration 
 
4 hours after start of IMP administration 
 
6 hours after start of IMP administration 
 
12 hours after start of IMP administration 
Day 2 
24 hours after start of Day 1 IMP 
administration 
a: For moxifloxacin, “IMP administration” instead of “start of IMP administration” in the above table 
b: “Within −5 minutes” for moxifloxacin 
 
6.3 
Pharmacokinetic/Pharmacodynamic Methods 
For subjects who have QT data and plasma OPC-61815 concentration data after 
administration of OPC-61815, as well as QT data after placebo administration at the 
matching time points, differences between OPC-61815 and placebo in change in QTcF 
interval from baseline at the matching time points are analyzed. A linear mixed-effects 
model is used, taking plasma OPC-61815 concentration as a fixed effect and subject as a 
random effect, to investigate the relationships between plasma OPC-61815 concentration 
and pharmacodynamic parameters. 
6.4 
Pharmacogenomic Methods 
No pharmacogenomic analyses are planned. 
7 
Statistical Analysis 
7.1 
Determination of Sample Size 
The number of subjects required for central tendency analysis of QTcF, the primary 
endpoint, was calculated. The number of subjects was calculated to achieve a ≥90% 
probability of the upper limit of the 2-sided 90% CI (1-sided 95% CI) for the time-
matched difference in the mean values for the change in QTcF from baseline between the 
OPC-61815 and placebo values being lower than 10 msec at all time points after 
administration of each OPC-61815 dose (16 and 32 mg), and a ≥90% probability of the 
lower limit of the 2-sided 98% CI (1-sided 99% CI) for the time-matched difference in 


 
 
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the mean values for the change in QTcF from baseline between the moxifloxacin and 
placebo values being higher than 0 msec in at least one of the 5 assay sensitivity 
assessment time points (1, 1.5, 2, 3, and 4 hours) after administration of the positive 
control moxifloxacin. For the assay sensitivity CI, the increase of type 1 error due to the 
multiplicity of multiple time points was corrected using the Bonferroni method. 
Assuming the within-subject standard deviation to be 7.86, the effect size of 
moxifloxacin (difference between moxifloxacin and placebo in change from baseline) to 
be 9.6 msec based on the results of a previous trial (Protocol 331-10-242, a clinical trial 
of brexpiprazole for evaluation of QT/QTc interval in patients with schizophrenia and 
schizoaffective disorder), the effect size of OPC-61815 to be 3.0 msec (although no data 
are available) and the individual time points to be independent, the required number of 
subjects is 45 for each OPC-61815 dose and 21 for moxifloxacin. Estimating a 5% 
discontinuation rate, a sample size of 48 subjects was considered necessary. 
7.2 
Analysis Set 
The pharmacodynamic analysis set will consist of subjects treated with at least 1 dose of 
IMP who have QT data at baseline and at least 1 postdose time point. 
The safety analysis set will consist of subjects who received at least 1 dose of IMP and 
have postdose safety data. 
7.3 
Handling of Missing Data 
No data imputation will be performed for missing data. 
7.4 
Primary and Secondary Endpoint Analyses 
12-lead Holter ECG data will be used. For each parameter, the mean of measurements 
from 3 predose time points (1 hour, 30 minutes, and 15 minutes before IMP 
administration) in each period will be used as the baseline value. Changes from baseline 
in corresponding period will be calculated at each postdose time point. 
7.4.1 
Primary Endpoint Analyses 
The primary endpoint is the time-matched difference between the OPC-61815 and 
placebo data in change from baseline for QTcF in 12-lead Holter ECG. Central tendency 
analysis for OPC-61815 will be performed for subjects in the pharmacodynamic analysis 
set who appropriately completed all IMP treatments (OPC-61815 16 mg, OPC-61815 
32 mg, placebo, and moxifloxacin) (ie, in whom the administration of the injections was 
completed within the time windows presented in Section 3.2 Trial Treatments without 


 
 
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interruption after the first 30 minutes) and for whom predose and postdose QT data are 
available for all 4 treatment periods. 
For each OPC-61815 dose (16 mg and 32 mg), the upper limit of the CI for the time-
matched difference in the least squares mean for the change in QTcF from baseline 
compared to the placebo data will be evaluated to determine if it is lower than 10 msec at 
all postdose time points using the hypothesis presented below. Because the alternative 
hypothesis is an intersection hypothesis, the 2-sided 90% CI (1-sided 95%) will be 
calculated without type 1 error adjustment. 
 
𝜇𝐴(𝑖): Mean change from baseline in QTcF interval at time i after OPC-61815 
administration 
𝜇𝑃(𝑖): Mean change from baseline in QTcF interval at time i after placebo 
administration 
i = 1,2, ⋯,8 respectively correspond to 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after start 
of IMP administration 
Using a linear mixed effect model with baseline QTcF in each treatment period as a 
covariate, treatment, sequence, treatment period, time point, and interaction between 
treatment and time point as fixed effects, and subject as a random effect, point estimates 
and CIs for the time-matched difference in the least squares mean for the change in QTcF 
from baseline compared to the placebo data will be calculated. 
7.4.2 
Secondary Endpoint Analyses 
Analyses described in the subsequent sections will be performed per treatment in the 
pharmacodynamic analysis set. 
7.4.2.1 
Categorical Analysis 
The number and percentage of subjects who fulfilled the following criteria for QTcF 
interval at least once after IMP administration are calculated. The same calculation will 
also be performed at each time point. 
1) Prolongation of absolute QTc interval: 
 QTc interval >450 msec 
𝐻0:   𝜇𝐴(𝑖) −𝜇𝑃(𝑖) ≥10 , i = 1,2, ⋯,8 
𝐻1:   𝜇𝐴(𝑖) −𝜇𝑃(𝑖) < 10 , i = 1,2, ⋯,8 


 
 
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 QTc interval >480 msec 
 QTc interval >500 msec 
 
2) Change from baseline in QTc interval: 
 >30 msec increase in QTc interval from baseline 
 >60 msec increase in QTc interval from baseline 
 
7.4.2.2 
Electrocardiogram (12-lead Holter ECG) 
For each parameter, descriptive statistics will be calculated for measurements and 
changes from baseline at each time point. A shift table of normal/abnormal assessments 
at each postdose time point compared to baseline will also be created. A frequency 
distribution of each waveform pattern will be drawn. 
7.4.3 
Assay Sensitivity Assessment 
As an assay sensitivity assessment, moxifloxacin will be evaluated as a positive control 
using the same analysis set and statistical method as those stated in Section 7.4.1 Primary 
Endpoint Analyses. 
For moxifloxacin, the lower limit of the CI for the time-matched difference in the least 
squares mean for the change in QTcF from baseline compared to the placebo data will be 
evaluated if it is higher than 0 msec at any of the postdose time points using the 
hypothesis presented below. Because of the multiplicity arising from assay sensitivity 
assessments at 5 postdose time points (1, 1.5, 2, 3, and 4 hours), type 1 error adjustment 
will be performed using the Bonferroni method, and the 2-sided 98% (1-sided 99%) CI 
will be calculated. 
 
𝜇𝑀(𝑖): Mean change from baseline in QTcF interval at time i after moxifloxacin 
administration 
𝜇𝑃(𝑖): Mean change from baseline in QTcF interval at time i after placebo 
administration 
i =  1,2, ⋯,5 respectively correspond to 1, 1.5, 2, 3, and 4 hours after IMP 
administration 
𝐻0:   𝜇𝑀(𝑖) −𝜇𝑃(𝑖) ≤0 , i = 1,2, ⋯,5 
𝐻1:   𝜇𝑀(𝑖) −𝜇𝑃(𝑖) > 0 , i = 1,2, ⋯,5 


 
 
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7.5 
Analysis of Demographic and Baseline Characteristics 
Frequency distribution or descriptive statistics will be calculated for baseline 
characteristics per sequence and as a whole in the pharmacodynamic analysis set and 
safety analysis set. 
7.6 
Safety Analysis 
Tabulations discussed in the subsequent sections will be performed per treatment in the 
safety analysis set. 
7.6.1 
Adverse Events 
All AEs will be coded by system organ class and preferred term of the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of the following events 
will be summarized: 
 TEAEs 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of IMP 
When the same AE occurs more than once during one treatment period in the same 
subject, the most severe event is included in incidence calculation. The incidence of 
TEAEs potentially causally related to IMP will also be summarized. 
In Periods 1, 2, and 3, TEAEs are the events occurring after the start of IMP 
administration in each period until the start of IMP administration in the subsequent 
period. In Period 4, AEs that occur after the start of IMP are recorded as TEAEs. 
7.6.2 
Clinical Laboratory Data 
For clinical laboratory data other than qualitative urine tests, descriptive statistics will be 
calculated for measurements and changes from baseline at each postdose time point. For 
qualitative urine test data, a shift table comparing test results at each postdose time point 
to baseline will be created. Each clinical laboratory test result other than qualitative urine 
tests will be categorized into “within normal,” “below the lower limit of normal,” and 
“above the upper limit of normal” using the trial site’s reference range to create a shift 
table of test results at each postdose time point compared to baseline. 


 
 
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7.6.3 
Vital Signs and Body Weight 
Descriptive statistics will be calculated for measurements and changes from baseline at 
each postdose time point. 
7.6.4 
12-lead Electrocardiogram Data 
For each parameter, descriptive statistics will be calculated for measurements and 
changes from baseline at each postdose time point. On normal/abnormal assessment, a 
shift table comparing data at each postdose time point to baseline will be created. 
7.7 
Pharmacodynamic Analysis 
Discussed in Section 7.4 Primary and Secondary Endpoint Analyses. 
8 
Management of Investigational Medicinal Product 
OPC-61815 16 mg and placebo are test formulations. They are provided for the trial as 
IMP. Moxifloxacin (Avelox Tablets 400 mg, marketed by Bayer Yakuhin, Ltd.) is 
provided as the reference formulation. See the Investigator’s Brochure of OPC-61815 
and/or clinical operations manual for management of IMP and the reference formulation. 
8.1 
Packaging and Labeling 
Both IMP and the reference formulation will be provided to the IMP manager by the 
sponsor or designated agent. The IMP (OPC-61815 16 mg or placebo) will be provided in 
vials. Eight vials stored in a box constitute the subject kit. A label stating that the content 
is for clinical trial use, as well as the protocol number, IMP name, lot number, expiration 
date, storage conditions, and sponsor’s name and address, will be affixed to each vial and 
box. Moxifloxacin will be provided in the usual commercial box. 
8.2 
Storage 
IMP and the reference formulation will be stored in a securely locked cabinet or 
enclosure. Access will be limited to the IMP manager who is responsible for IMP 
preparation at the trial site (non-blinded staff) to prevent any other person from preparing 
the drugs. The IMP manager must not provide IMP or reference formulation to any 
subject not participating in the trial. 
IMP and the reference formulation will be stored at room temperature. 
The clinical site staff will maintain a temperature log in the drug storage area and record 
the temperature at least once each working day. 


 
 
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8.3 
Accountability 
The IMP manager must maintain an inventory record of both IMP and the reference 
formulation received, dispensed, administered, destroyed, and returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused/partially used IMP and the 
reference formulation must be returned to the sponsor or a designated agent. 
All IMPs and reference formulations returned to the sponsor must be accompanied by 
appropriate documentation and be clearly identified by the protocol number and trial site 
number indicated on the outside of the shipping container. Returned supplies should be in 
the original containers. The assigned trial monitor will facilitate the return of used and 
partially used IMP and the reference formulation. 
8.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate, or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of IMP 
and the reference formulation or medical device after it is released for distribution. 
Examples include, but are not limited to, the following: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle (eg, under/over-fill, no safety seal) 
 Vial defects 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means during the entire period including the receipt from the sponsor or sponsor’s 
designee, treatment, destruction, and final check of IMP and the reference formulation. 


 
 
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The investigator, subinvestigator, or designee must notify the sponsor or sponsor’s 
designee of the information specified in Section 8.5.2 Information Required for 
Reporting Product Quality Complaints by e-mail immediately after becoming aware of 
the PQC (e-mail address: PQC_263-102-00005@otsuka.jp). 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator who should then follow one of the reporting mechanisms below. 
Precautions should be taken to maintain blinding at the trial site when reporting a PQC on 
the quality of the IMP. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
The following information is required for reporting purposes: 
 Description of complaint 
 Reporter identification (eg, subject, investigator or subinvestigator with site 
information, non-blinded [responsible for IMP preparation] or blinded staff) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, drug number if assigned) 
 Clinical trial protocol information (number and trial name) 
 Dosage form/strength (if known) 
 Pictures (if available) 
 Availability for return 
 
8.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if a complaint sample is available for return. If a 
complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs concerning the IMP will be handled by the sponsor. 
PQCs concerning the reference formulation will be assessed/evaluated by the sponsor or, 
when necessary, discussed with the marketing authorization holder, etc. 


 
 
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9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the original records of results of observations and 
activities of a clinical investigation. Source documents will include, but are not limited to, 
progress notes, electronic data (including drug concentration data, clinical laboratory data, 
12-lead ECG analysis reports), screening logs, and recorded data from automated 
instruments. All source documents pertaining to this trial (excluding 12-lead ECG 
analysis reports and drug concentration data) will be retained by the trial site 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 direct access to source data/documents conducted by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the clinic, the investigator or subinvestigator will record 
progress notes to document all significant observations and findings. 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 all AEs, and the 
investigator’s or subinvestigator’s assessment of relationship to the IMP must also be 
recorded; 
 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed; 
 The dated signature (or initials) of all clinicians (or designee) who made an entry in 
the progress notes. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in paper progress notes and other paper 
source documents will be initialed and dated on the day the change is made by a trial site 


 
 
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staff member authorized to make the change. Changes will be made by striking through 
the erroneous data with a single line (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 document by the 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information in the trial progress notes and other source documents will be entered by trial 
site personnel directly into the sponsor’s electronic data capture (EDC) system. Changes 
to the data will be captured automatically in the audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site files are kept in accordance with 
Section 8 of the ICH Guideline E6 GCP and as required by applicable local regulations. 
The trial site files will include all source documents, as well as completed CRFs for all 
subjects screened or enrolled at the trial site. The trial site will take measures to ensure 
confidentiality and prevent accidental or premature destruction of these documents during 
the retention period. 
9.4 
Record Retention at the Trial Site 
The trial site will retain all trial-related documents and records for either of the time 
periods indicated below, whichever is longer. However, if the sponsor requires a longer 
archiving period, the head of the trial site will consult with the sponsor on the period and 
procedures for record retention. 
 The date 2 years after the manufacturing and marketing approval date. However, if 
the head of the trial site receives notification from the sponsor that development has 
been terminated or that the results of the trial will not be submitted with the approval 
application, the date 3 years after the receipt of such notification; or 
 The date 3 years after the termination or completion of the trial. 
The trial site must not dispose of any records relevant to this trial without either 
(1) obtaining written permission from the sponsor or (2) providing the sponsor with an 
opportunity to collect such records. The trial site will be responsible for retaining 
adequate and accurate electronic or hard copy source documents of all observations and 
data generated during this trial. Such documents are open to inspection by the sponsor 
and relevant regulatory authorities. 


 
 
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10 
Quality Control and Quality Assurance 
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to conduct this trial in 
accordance with established research principles, ICH Guideline E6 GCP: Consolidated 
Guidance, and applicable regulatory requirements and local laws. As part of a concerted 
effort to fulfill these obligations (ie, to keep the staff updated on the progress of the trial), 
the sponsor’s (or sponsor designee’s) monitors will visit the site during the trial, as well 
as communicate regularly via telephone, e-mail, and written communications. In addition, 
all investigators, subinvestigators, and trial site clinical personnel will undergo initial and 
ongoing training for this particular trial, and this training will be clearly documented. 
10.2 
Auditing 
The sponsor’s (or designee’s) Quality Assurance Unit (or its representative) may conduct 
trial site audits. Audit items will include, but are not limited to, IMP supply, presence of 
required documents, the informed consent process, and comparison of CRFs with source 
documents. The investigator is supposed to cooperate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
10.3 
Protocol Deviations 
Due to the complexity of clinical trial protocols and despite training and preventive 
measures, deviations from the written protocol may occur and potentially result in harm 
to subjects, biased or inaccurate results, and rejection of all or part of the trial data. Per 
Section 10.2 of the ICH Guideline E3 Structure and Content of Clinical Study Reports, 
protocol deviations should be appropriately summarized by site and grouped into 
different categories such as: 
 Those who entered the study even though they did not satisfy the entry criteria. 
 Those who developed withdrawal criteria during the study but were not withdrawn. 
 Those who received the wrong treatment or incorrect dose. 
 Those who received an excluded concomitant treatment. 
Otsuka categorizes clinical protocol deviations into major and minor. A major deviation 
is an intentional or accidental action or omission in a trial conduct that could potentially 
have a negative impact on the integrity of the trial’s primary scientific objectives or has 


 
 
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significant potential to have a negative impact on the safety or efficacy assessments of 
any trial subject. Major deviations are those that might significantly affect the 
completeness, accuracy, or reliability of the trial data or that might significantly affect a 
subject’s rights, safety, or well-being. 
A minor deviation is an intentional or accidental action or omission during trial conduct 
in which the protocol is not strictly followed, but which has an inconsequential impact on 
the integrity of the trial as a whole or the safety or efficacy analyses of an individual 
subject. 
All protocol deviations are to be categorized as major or minor according to the above 
definitions and only major deviations will be summarized in the clinical study report. 
If the same protocol deviation occurs for multiple subjects, it must be recorded separately 
for each subject. 
Investigators or subinvestigators are expected to document potential protocol deviations, 
as well as their medical assessment regarding the continued participation of the subject(s) 
due to the protocol deviation, and to record only major deviations in the CRF. 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
the Declaration of Helsinki, international ethical principles derived from Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations. The trial site will seek approval/favorable opinion by an IRB 
according to regional requirements and provide that approval/favorable opinion to the 
sponsor in writing. The IRB will evaluate the ethical, scientific, and medical 
appropriateness of the trial. Further, in preparing and handling CRFs, the investigator, 
subinvestigator, and their staff will take adequate measures to protect subject privacy. To 
this end, a subject number or subject identifier will be used to identify each subject. 
Financial aspects, subject insurance, and publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly involved in the trial without the sponsor’s prior written 
permission. Subject confidentiality requirements of the country where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor’s authorized 


 
 
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staff members (or representatives) may be allowed full access to inspect and copy the 
records in accordance with local requirements. All IMPs, subjects’ body fluids, and other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor. 
Subjects will be identified only by unique subject identifiers in CRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials, if necessary, in accordance with local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment is to 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’s approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as those 
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, 
followed by IRB notification within the time window specified by local regulations. The 
sponsor will submit the amended protocol to the applicable regulatory agency within the 
time window specified by local regulations. 
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 is shown by the IRB, written informed 
consent will be obtained anew from subjects enrolled in the trial before they proceed to 
continued participation and before the amendment-specified changes in the trial are 
implemented. 
14 
Publication Authorship Requirements 
Authorship for any publications resulting from the conduct of Otsuka-sponsored trials 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 


 
 
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criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 


 
 
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15 
References 
1 
Otsuka Pharmaceutical Co., Ltd. Investigator’s brochure. OPC-41061, 2017. 
2 
Otsuka Maryland Research Institute, Inc. Maryland clinical research. A parallel-arm, 
double-blind, placebo-controlled, multiple dose administration study of tolvaptan oral 
tablets and moxifloxacin oral tablets on ecg qtc interval in healthy men and women. 
In-house clinical study report 156-03-245, issued 2005. 
3 
Oral new quinolone antibacterial agent Avelox Tablets 400 mg (moxifloxacin 
hydrochloride tablets) [package insert]. Bayer Yakuhin Ltd; Revised Oct 2017. 
4 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry 
of Health, Labour and Welfare of Japan. The Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs. PFSB/ELD 
Notification (1023-1); 2009. 
5 
Igawa M, Kishi H, Ishibe T. Pathological diagnosis with isoenzyme assay: acid 
phosphatase (ACP). Jap J Clin Med. 1995;53(5):1203-8. 
6 
Kato R. Clinical pharmacokinetics. 3rd ed. Tokyo, Japan: Nankodo Co Ltd; 
2003:276-80. 
7 
Takada K. Pharmacokinetics—fundamentals and application—. 2nd ed. Tokyo, 
Japan: Jiho Inc; 2002:363. 
8 
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/E
6/E6_R1_Guideline.pdf. 
9 
Japan Association of Contract Institutes for Clinical Pharmacology. Standards for 
intervals during which subjects should refrain from participating in a clinical trial. 
2015. 
10 New Blood Programme Advisory Committee. Blood withdrawal criteria. 2011. 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Single-center, Randomized, Double-blind (for OPC-61815 and Placebo), Placebo- 
and Moxifloxacin Positive-controlled, 4-Period Crossover Trial to Evaluate the Effect 
of Single Intravenous Administration of OPC-61815 at 16 and 32 mg on QT/QTc 
Interval in Healthy Male Subjects 
 
 
 
 
 
NCT Number: NCT03510663 
PRT NO.: 263-102-00005 
Version Date: 25 September 2018 (Version 1.0) 


  
  
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational Medicinal Product 
OPC-61815 
 
 
 
Protocol No. 263-102-00005 
 
 
 
A Single-center, Randomized, Double-blind (for OPC-61815 and Placebo), Placebo- and 
Moxifloxacin Positive-controlled, 4-Period Crossover Trial to Evaluate the Effect of 
Single Intravenous Administration of OPC-61815 at 16 and 32 mg on QT/QTc Interval in 
Healthy Male Subjects 
 
Statistical Analysis Plan 
 
Version: Final 1.0 
Date: 25 Sep 2018 
Protocol Version 1 Date: 27 Feb 2018 
Date of Translation: 15 Nov 2018 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 
 


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Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 7 
2 
Trial Objectives ..................................................................................... 7 
3 
Trial Design ........................................................................................... 7 
3.1 
Type/Design of Trial ...........................................................................................7 
3.2 
Trial Treatments ..................................................................................................7 
3.3 
Trial Population ...................................................................................................8 
3.4 
Handling of Time Points .....................................................................................8 
4 
Sample Size ............................................................................................ 8 
5 
Statistical Analysis Sets ........................................................................ 9 
5.1 
Pharmacodynamic Analysis Set ..........................................................................9 
5.2 
Safety Analysis Set ..............................................................................................9 
5.3 
Pharmacokinetic Analysis Set .............................................................................9 
5.4 
Handling of Missing Data ...................................................................................9 
6 
Primary and Secondary Outcome Variables ..................................... 9 
6.1 
Primary Outcome Variables ................................................................................9 
6.2 
Secondary Outcome Variables ............................................................................9 
6.3 
Pharmacokinetic Outcome Variables ..................................................................9 
6.4 
Safety Outcome Variables ...................................................................................9 
7 
Disposition and Demographic Analysis ............................................ 10 
7.1 
Subject Disposition............................................................................................10 
7.2 
Demographic and Baseline Characteristics .......................................................10 
7.3 
Medical History .................................................................................................10 
7.4 
Treatment Compliance ......................................................................................10 
7.5 
Prior and Concomitant Medication ...................................................................11 
7.6 
Protocol Deviations ...........................................................................................11 
8 
Efficacy Analyses ................................................................................ 11 
9 
Safety Analyses ................................................................................... 11 


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9.1 
Extent of Exposure ............................................................................................11 
9.2 
Adverse Events ..................................................................................................11 
9.3 
Clinical Laboratory Data ...................................................................................12 
9.4 
Vital Sign Data and Body Weight .....................................................................12 
9.5 
Physical Examination Data ...............................................................................12 
9.6 
Electrocardiogram Data .....................................................................................12 
10 
Pharmacokinetic Analyses ................................................................. 12 
10.1 
Statistical Analyses of Primary Pharmacokinetic Endpoints ............................14 
10.2 
Statistical Analyses of Secondary Pharmacokinetic Endpoints ........................14 
10.3 
Technical Details of Pharmacokinetic Statistical Analyses ..............................14 
10.4 
Pharmacokinetic and Pharmacodynamic Analyses ...........................................15 
11 
Pharmacodynamic Analyses .............................................................. 15 
11.1 
Primary and Secondary Endpoint Analyses ......................................................15 
11.1.1 
Primary Endpoint Analyses ............................................................................15 
11.1.2 
Secondary Endpoint Analysis .........................................................................17 
11.1.2.1 
Categorical Analysis ...................................................................................17 
11.1.2.2 
Electrocardiogram (12-lead Holter Electrocardiogram) .............................17 
11.1.3 
Assay Sensitivity Assessment.........................................................................18 
12 
Pharmacogenomic Analyses .............................................................. 18 
13 
Interim Analysis .................................................................................. 18 
14 
Changes in Planned Analysis ............................................................. 18 
15 
References ............................................................................................ 19 
 


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List of Appendices 
Appendix 1 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 20 
Appendix 2 
List of Summary Tables ................................................................ 21 
Appendix 3 
List of Subject Data Listings......................................................... 24 
Appendix 4 
Drugs and Food That May Induce or Inhibit CYP3A4................. 26 
Appendix 5 
Molecular Weight and Lower Limit of Quantitation of 
Plasma Drug Concentration .......................................................... 27 
 


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List of Abbreviations and Definition of Terms 
Abbreviation Definition 
AE 
Adverse event 
BMI 
Body mass index 
CRF 
Case report form 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term 
QT 
QT interval 
QTc 
QT corrected for heart rate 
SAE 
Serious adverse event 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
 


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Pharmacokinetics Parameter Table 
Abbreviation 
and Term 
Unit 
Unabbreviated Expression or Definition 
AUC∞ 
ng·h/mL 
Area under the concentration-time curve from time zero to infinity 
AUC24h 
ng·h/mL 
Area under the concentration-time curve from time zero to 24 hours 
AUCt 
ng·h/mL 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap 
% 
Percentage of AUC due to extrapolation from tlast to infinity [(AUC∞ 
− AUCt)/AUC∞ × 100] 
CL 
L/h 
Total body clearance of drug from the plasma 
CL/BW 
L/h/kg 
CL normalized in body weight 
Cmax 
ng/mL 
Maximum (peak) plasma concentration of the drug 
λz 
h-1 
Apparent terminal-phase disposition rate constant (first-order) 
λz(point) 
 
Number of points used in computing λz. If λz cannot be estimated, 
zero. 
λz(lower) 
h 
Lower limit on Time for values to be included in the calculation of λz 
λz(upper) 
h 
Upper limit on Time for values to be included in the calculation of λz  
z(Rsq) 
 
Goodness of fit statistic for the terminal elimination phase, adjusted 
for the number of points used in the estimation of λz  
t1/2,z 
h 
Terminal-phase elimination half-life 
tlast 
h 
Time of last measurable (positive) concentration 
tmax 
h 
Time to maximum (peak) plasma concentration 
Vz 
L 
Apparent volume of distribution during the terminal (λz) phase 
Vz/BW 
L/kg 
Vz normalized in body weight 
 


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1 
Introduction 
This statistical analysis plan documents the details of the statistical analysis methodology 
to be applied in the protocol of Study 263-102-00005. 
2 
Trial Objectives 
To investigate the effects of 1-hour intravenous administration of OPC-61815 at 16 and 
32 mg on QT/QTc interval in healthy adult male subjects. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a single-center, randomized, double-blind, placebo- and moxifloxacin active-
controlled, 4-period crossover trial in 48 healthy adult male subjects. OPC-61815 and 
placebo will be administered in a double-blind fashion and moxifloxacin tablets will be 
administered in an open-label fashion, and the effects of 16 mg and 32 mg OPC-61815 on 
the QT/QTc interval will be evaluated. 
Eligible subjects will be randomized to one of the predetermined treatment sequences 
prior to investigational medicinal product (IMP) administration on Day 1 of Period 1 (see 
Protocol 3.6.1 Randomization). Subjects will receive a single dose of OPC-61815, 
placebo, and moxifloxacin tablets in Periods 1 to 4 in the assigned sequence. Following 
the start of IMP administration, scheduled observations/examinations/assessments will be 
performed in a similar manner during each treatment period. A washout period of at least 
6 days will be set between the days of IMP administration in a treatment period and the 
next treatment period. Post-treatment follow-up will be performed 6 to 8 days after the 
administration in Period 4. In each treatment period, subjects will be admitted to hospital 
on the day before IMP administration (Day −1) and discharged on Day 2. 
3.2 
Trial Treatments 
Each subject will receive a single dose of IMP in a fasted state (see Protocol 4.2.1 Food 
and Beverages) in the randomly assigned sequence. OPC-61815 (16 mg and 32 mg) and 
placebo will be intravenously administered by 1-hour infusion. Two OPC-61815 16-mg 
vials will be used for administration of 32 mg OPC-61815. A moxifloxacin 400 mg tablet 
will be orally administered with 240 mL of water. Each subject will start to receive IMP 
approximately the same time of the day in all treatment periods. The allowable duration 
of intravenous administration of 16 mg and 32 mg OPC-61815 and placebo will be 59 to 
65 minutes. The total number of IMP administration days is 4 days. Postdose monitoring 
will last up to Day 2 in each treatment period, and the duration of washout period starting 


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on Day 2 is at least 6 days before IMP administration in the next treatment period. Post-
treatment follow-up will be performed 6 to 8 days after IMP administration in Period 4. 
3.3 
Trial Population 
A total of 48 healthy male subjects age 20 to 45 years, inclusive, at time of informed 
consent will be enrolled in the trial. 
Subjects who were scheduled to receive IMP but withdrew consent before IMP allocation 
and subjects considered to be unavailable for IMP administration will be replaced by 
standby subjects. Subjects withdrawn from the trial after IMP allocation will not be 
replaced. 
3.4 
Handling of Time Points 
CRF Visit values and Time point values at each time point (after the day before 
administration) will be used in summaries (but values at the time of discontinuation will 
not be used in summaries). Unscheduled Visit values will not be used. 
4 
Sample Size  
The number of subjects required for central tendency analysis of QTcF, the primary 
endpoint, was calculated. The number of subjects was calculated to achieve a ≥90% 
probability of the upper limit of the 2-sided 90% CI (1-sided 95% CI) for the time-
matched difference in the mean values for the change in QTcF from baseline between the 
OPC-61815 and placebo values being lower than 10 msec at all time points after 
administration of each OPC-61815 dose (16 and 32 mg), and a ≥90% probability of the 
lower limit of the 2-sided 98% CI (1-sided 99% CI) for the time-matched difference in 
the mean values for the change in QTcF from baseline between the moxifloxacin and 
placebo values being higher than 0 msec in at least one of the 5 assay sensitivity 
assessment time points (1, 1.5, 2, 3, and 4 hours) after administration of the positive 
control moxifloxacin. For the assay sensitivity CI, the increase of type 1 error due to the 
multiplicity of multiple time points was corrected using the Bonferroni method. 
Assuming the within-subject standard deviation to be 7.86, the effect size of 
moxifloxacin (difference between moxifloxacin and placebo in change from baseline) to 
be 9.6 msec based on the results of a previous trial (Protocol 331-10-242, a clinical trial 
of brexpiprazole for evaluation of QT/QTc interval in patients with schizophrenia and 
schizoaffective disorder), the effect size of OPC-61815 to be 3.0 msec (although no data 
are available) and the individual time points to be independent, the required number of 
subjects is 45 for each OPC-61815 dose and 21 for moxifloxacin. Estimating a 5% 
discontinuation rate, a sample size of 48 subjects was considered necessary. 


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5 
Statistical Analysis Sets 
5.1 
Pharmacodynamic Analysis Set 
The pharmacodynamic analysis set will consist of subjects treated with at least 1 dose of 
IMP who have QT data at baseline and at least 1 postdose time point. 
5.2 
Safety Analysis Set 
The safety analysis set will consist of subjects who received at least 1 dose of IMP and 
have postdose safety data. 
5.3 
Pharmacokinetic Analysis Set 
Pharmacokinetic analysis set includes subjects who are included in the safety analysis set 
and whose plasma drug concentration was measured. However, plasma drug 
concentrations will not be measured for placebo and moxifloxacin administration. 
5.4 
Handling of Missing Data 
No data imputation will be performed for missing data. 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variables 
Time-matched difference between the OPC-61815 and placebo data in change from 
baseline for QTcF in 12-lead Holter ECG 
6.2 
Secondary Outcome Variables 
12-lead Holter ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTcF interval) and ECG waveform patterns 
6.3 
Pharmacokinetic Outcome Variables 
Plasma concentrations and pharmacokinetic parameters of OPC-61815 free form and 
tolvaptan 
6.4 
Safety Outcome Variables 
Adverse event reporting, clinical laboratory assessments, physical examination, vital 
signs (blood pressure, pulse rate, and body temperature), body weight, and 12-lead ECG 


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7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
For subjects from whom informed consent was obtained (screened subjects), the number 
of subjects whom informed consent was obtained, the numbers and percentages of 
randomized subjects, subjects administered IMP, completed subjects after IMP 
administration, and discontinued subjects after IMP administration (the denominator 
indicates the number of randomized subjects) will be summarized as a whole and per 
sequence. For discontinued subjects after IMP administration, the number and percentage 
of subjects by reason for discontinuation will be summarized. 
For randomized subjects, the number and percentage of subjects included in each 
statistical analysis set and central tendency analysis (11.1.1 Primary Endpoints Analysis) 
will be summarized as a whole and per sequence. 
7.2 
Demographic and Baseline Characteristics 
For the pharmacodynamic analysis set and the safety analysis set, descriptive statistics 
(number of subjects, mean, standard deviation, minimum, median, and maximum) for age, 
height (cm), body weight (kg) at screening, and BMI (kg/m2) will be calculated as a 
whole and per sequence. 
7.3 
Medical History 
For the pharmacodynamic analysis set and the safety analysis set, frequency distribution 
(number of subjects, %) of the presence or absence of medical history and complications 
will be calculated as a whole and per sequence. 
7.4 
Treatment Compliance 
For the pharmacodynamic analysis set and the safety analysis set, frequency distribution 
of subjects who satisfy all the following conditions for each treatment (OPC-61815 16 
mg, OPC-61815 32 mg, placebo, or moxifloxacin) will be calculated by treatment as a 
whole and per sequence. 
 Injection (OPC-61815 16 or 32 mg, or placebo) 
 Single intravenous administration over a period of 1 hour (allowable time range: 
59 to 65 minutes) once daily in a fasting state. 
 Administration of full dose of IMP completed within allowable time range. 
 No interruption of administration from 30 minutes after the start. 
 Tablet (moxifloxacin) 
 Administration of full dose of IMP completed. 


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7.5 
Prior and Concomitant Medication 
Prior and concomitant medications will not be tabulated in this trial. 
7.6 
Protocol Deviations 
Protocol deviations will not be tabulated in this trial. 
8 
Efficacy Analyses 
Not applicable. 
9 
Safety Analyses 
The following analyses will be performed per treatment in the safety analysis set. The 
baseline will be the value before the start of IMP administration on Day 1 in each 
treatment period. 
9.1 
Extent of Exposure 
The percentage of administered subjects to randomized subjects will be calculated. 
9.2 
Adverse Events 
All adverse events (AEs) will be coded by system organ class (SOC) and preferred term 
(PT) (Medical Dictionary for Regulatory Activities [MedDRA]). The incidence of the 
following events will be summarized by all events, by SOC, and by PT: 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuations of the IMP (calculated only when treatment is 
injection) 
When the same AE occurs more than once during one treatment period in the same 
subject, the most severe event is included in incidence calculation. The incidence of 
TEAEs potentially causally related to IMP will also be summarized. 
In Periods 1, 2, and 3, TEAEs are the events occurring after the start of IMP 
administration in each period until the start of IMP administration in the subsequent 
period. In Period 4, AEs that occur after the start of IMP are recorded as TEAEs. 


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9.3 
Clinical Laboratory Data 
For clinical laboratory data other than qualitative urine tests, descriptive statistics will be 
calculated for measurements and changes from baseline at each postdose time point. For 
qualitative urine test data, a shift table comparing test results at each postdose time point 
to baseline will be created. Each clinical laboratory test result other than qualitative urine 
tests will be categorized into “within normal,” “below the lower limit of normal,” and 
“above the upper limit of normal” using the trial site’s reference range to create a shift 
table of test results at each postdose time point compared to baseline. 
9.4 
Vital Sign Data and Body Weight 
For each item (blood pressure, pulse rate, body temperature, and body weight), 
descriptive statistics will be calculated for measurements and changes from baseline at 
each postdose time point. 
9.5 
Physical Examination Data 
Physical findings will not be tabulated in this trial. 
9.6 
Electrocardiogram Data 
For each parameter (heart rate, RR interval, PR interval, QRS interval, QT interval and 
QTcF interval) of 12-lead electrocardiogram (ECG), descriptive statistics will be 
calculated for measurements and changes from baseline at each postdose time point. On 
normal/abnormal assessment, a shift table comparing data at each postdose time point to 
baseline will be created. 
10 
Pharmacokinetic Analyses 
1) Endpoints 
a) Plasma OPC-61815 free form and tolvaptan (OPC-41061) concentrations 
b) PK parameters of plasma OPC-61815 free form and tolvaptan (OPC-41061) 
Cmax, AUC24h, AUCt, AUC∞, tmax, λz, AUC_%Extrap, tlast, t1/2,z, CLa, 
CL/BWa, Vza, Vz/BWa 
aCalculated for OPC-61815 only 
 
2) Handling of Data 
a) Nonacceptance of data will be determined in accordance with the following 
conditions in this trial. 
 For each analyte, if blood sampling is conducted outside the time window 
for the analyses (see Table 10-1Table 10-1 and Table 10-2Table 10-2), the 
data will be excluded from the calculation of descriptive statistics for 
plasma concentrations at that time point. However, it will be used for the 


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calculation of pharmacokinetic parameters, and if the calculation of 
pharmacokinetic parameters is determined to be unsuitable, the parameter 
will not be adopted. 
 
Table 10-1 
Acceptable Window for Analysis of OPC-61815 (Same in 
each period) 
Time Point 
Acceptable Window 
Day 1 
Predose 
Within 3 hours before IMP administration 
 
1 hour 
Within 2 minutes after end of administration 
 
1.5 hours 
Specified time point + 2 minutes 
 
2 hours 
Specified time point + 3 minutes 
 
3 hours 
Specified time point + 5 minutes 
 
4 hours 
Specified time point + 10 minutes 
 
6 and 12 hours 
Specified time point + 15 minutes 
Day 2 
24 hours 
Specified time point + 30 minutes 
 
Table 10-2 
Acceptable Window for Analysis of OPC-41061 (Same in 
each period) 
Time Point 
Acceptable Window 
Day 1 
Predose 
Within 3 hours before IMP administration 
 
1 hour 
Within 2 minutes after end of administration 
 
1.5 hours 
Specified time point + 10 minutes 
 
2 hours 
Specified time point + 10 minutes 
 
3 hours 
Specified time point + 10 minutes 
 
4 hours 
Specified time point + 10 minutes 
 
6 and 12 hours 
Specified time point + 15 minutes 
Day 2 
24 hours 
Specified time point + 30 minutes 
 None of the plasma concentrations after use of drugs or food (see 
Appendix 4Appendix 4) which may inhibit or induce CYP3A4 activity 
will be used for calculating descriptive statistics at that time. Of the 
parameters calculated with data including plasma concentrations excluded 
from descriptive statistics, the parameters determined to be unsuitable for 
the calculations will not be adopted. 
 For OPC-61815 injection 16 mg and 32 mg groups, in the case that IMP 
administration was not performed by the following administration method 
or in the event of missing a dose, the plasma concentrations on the period 
(treatment) will not be used for the calculation of descriptive statistics. 
The parameters calculated with data including plasma concentrations 
excluded from descriptive statistics will not be adopted. 
 Single intravenous administration over a period of 1 hour (allowable 
time range: 59 to 65 minutes) once daily in a fasting state 
 Administration of full dose of IMP completed within allowable time 
range. 
 No interruption of administration from 30 minutes after the start. 
書式変更:


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b) Plasma concentrations below lower limit of quantitation that occur prior to 
and after the first measurable concentration will be imputed to 0 (ng/mL) and 
as missing, respectively. Lower limit of quantitation of each analyte is listed 
in Appendix 5Appendix 5. 
c) Concentrations reported as Not Analyzed (NA) or Not Determined (ND) are 
regarded as missing values. 
d) Unused concentrations and the unadopted parameters should be outputted in 
the list. 
e) Missing or unused concentrations and parameter values that cannot be 
calculated or adopted will not be used for tabulation. 
 
3) Statistical analysis method 
Descriptive statistics will be calculated in the following manner: 
a) Plasma drug concentration 
 At each blood collection time point, descriptive statistics will be 
calculated by analyte and treatment. 
 Descriptive statistics to be calculated for plasma drug concentration will 
be number of analyzed subjects, number of subjects included in the 
tabulation, arithmetic mean, standard deviation, coefficient of variation, 
minimum, median, and maximum. However, descriptive statistics will be 
calculated only at the time point when the number of subjects included in 
the tabulation exceeds half of the number of analyzed subjects. 
b) Plasma pharmacokinetic parameters excluding λz, λz(lower), λz(upper), 
λz(point), and λz(Rsq) 
 Descriptive statistics will be calculated for each parameter by analyte and 
treatment. 
 Descriptive statistics to be calculated for plasma drug concentration will 
be number of analyzed subjects, number of subjects included in the 
tabulation, arithmetic mean, standard deviation, coefficient of variation, 
geometric mean, minimum, median, and maximum. However, descriptive 
statistics will be calculated only when the number of subjects included in 
the tabulation exceeds half of the number of analyzed subjects. 
 
10.1 
Statistical Analyses of Primary Pharmacokinetic Endpoints 
Not applicable. 
10.2 
Statistical Analyses of Secondary Pharmacokinetic Endpoints 
Not applicable. 
10.3 
Technical Details of Pharmacokinetic Statistical Analyses 
Not applicable. 


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10.4 
Pharmacokinetic and Pharmacodynamic Analyses 
For subjects who have QT data and plasma OPC-61815 concentration data after 
administration of OPC-61815 (adopted concentration at 10 Pharmacokinetic Analyses 2) 
Handling of Data), as well as QT data after placebo administration at the matching time 
points, differences between OPC-61815 and placebo in change in QTcF interval from 
baseline at the matching time points are analyzed. A linear mixed-effects model is used, 
taking plasma OPC-61815 concentration as a fixed effect and subject as a random effect 
(slope and intercept), to estimate the intercept and the coefficient of plasma OPC-61815 
concentration. A scatter plot of plasma OPC-61815 concentrations (horizontal axis) and 
the time-matched differences (vertical axis) between the OPC-61815 and placebo data in 
change from baseline for QTcF will be created and a regression line will be plotted. 
SAS code is shown below. 
proc mixed method=reml; 
  class subject; 
  model corrected_QTcF = conc / s alpha=0.05; 
  random int conc / subject=subject type=vc; 
run; 
11 
Pharmacodynamic Analyses 
12-lead Holter ECG data will be used. For each parameter, the mean (rounded integer 
value in each unit [beats/min, msec]) of measurements from 3 predose time points (1 
hour, 30 minutes, and 15 minutes before IMP administration) in each period will be used 
as the baseline value. If missing is occurred at any of 3 predose time points in each period, 
a mean value will be calculated using the points at which the values were obtained and 
will be used as the baseline value. Changes from baseline in corresponding period will be 
calculated at each postdose time point. 
11.1 
Primary and Secondary Endpoint Analyses 
11.1.1 
Primary Endpoint Analyses 
The primary endpoint is the time-matched difference between the OPC-61815 and 
placebo data in change from baseline for QTcF in 12-lead Holter ECG. Central tendency 
analysis for OPC-61815 will be performed for subjects in the pharmacodynamic analysis 
set who appropriately completed all IMP treatments (OPC-61815 16 mg, OPC-61815 32 
mg, placebo, and moxifloxacin) (ie, in whom the administration of the injections was 
completed within the time windows presented in Protocol 3.2 Trial Treatments [the 
duration of intravenous administration of OPC-61815 16 mg or 32 mg or placebo: 59 to 


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65 minutes] without interruption of administration from 30 minutes after the start, as well 
as the condition described in 7.4 Treatment Compliance) and for whom predose and 
postdose QT data are available for all 4 treatment periods. 
For each OPC-61815 dose (16 mg and 32 mg), the upper limit of the CI for the time-
matched difference in the least squares mean for the change in QTcF from baseline 
compared to the placebo data will be evaluated to determine if it is lower than 10 msec at 
all postdose time points using the hypothesis presented below. Because the alternative 
hypothesis is an intersection hypothesis, the 2-sided 90% CI (1-sided 95%) will be 
calculated without type 1 error adjustment. 
 
 
 
𝜇𝐴(𝑖): Mean change from baseline in QTcF interval at time i after OPC-61815 
administration 
𝜇𝑃(𝑖): Mean change from baseline in QTcF interval at time i after placebo administration 
i = 1,2, ⋯,8 respectively correspond to 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after start of 
IMP administration 
 
Using a linear mixed effect model with baseline QTcF in each treatment period as a 
covariate, treatment, sequence, treatment period, time point, and interaction between 
treatment and time point as fixed effects, and subject as a random effect, point estimates 
and CIs for the time-matched difference in the least squares mean for the change in QTcF 
from baseline compared to the placebo data will be calculated. 
SAS code is shown below. The data set will include all 4 treatments data. 
proc mixed method=reml; 
  class treatment subject time arm period; 
  model change = arm period treatment time treatment*time baseline/ s ddfm=satterth; 
  random subject(arm); 
  lsmeans treatment*time/diff pdiff cl alpha=0.1; 
run; 
𝐻0:   𝜇𝐴(𝑖) −𝜇𝑃(𝑖) ≥10 , i = 1,2, ⋯,8 
𝐻1:   𝜇𝐴(𝑖) −𝜇𝑃(𝑖) < 10 , i = 1,2, ⋯,8 


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11.1.2 
Secondary Endpoint Analysis 
Analyses described in the subsequent sections will be performed per treatment in the 
pharmacodynamic analysis set. 
11.1.2.1 
Categorical Analysis 
The number and percentage of subjects who fulfilled the following criteria for QTcF 
interval at least once after IMP administration are calculated. The same calculation will 
also be performed at 3 predose time points and each postdose time point for 1), and at 
each postdose time point for 2). 
1) Prolongation of absolute QTc interval: 
QTc interval > 450 msec 
QTc interval> 480 msec 
QTc interval> 500 msec 
2) Change from baseline in QTc interval: 
> 30 msec increase in QTc interval from baseline 
> 60 msec increase in QTc interval from baseline 
 
11.1.2.2 
Electrocardiogram (12-lead Holter Electrocardiogram) 
For each parameter (heart rate, RR interval, PR interval, QRS interval, QT interval, and 
QTcF interval), descriptive statistics will be calculated for measurements and changes 
from baseline at each time point. 
A shift table of normal/abnormal assessments at each postdose time point compared to 
baseline will also be created. In a triplicate 12-lead ECG at each time point, an ECG 
parameter will be assessed as “normal” only when all 3 measurements are normal; 
otherwise it will be assessed as “abnormal” (ie, if any measurement is abnormal). In 
baseline assessment of 12-lead Holter ECGs at 3 predose time points (1 hour, 30 minutes, 
and 15 minutes before IMP administration) in each period, an ECG parameter will be 
assessed as “normal” only when all measurements at 3 predose time points are normal; 
otherwise it will be assessed as “abnormal” (ie, if any measurement is abnormal). 
For the electrocardiographic waveform pattern, the number and percentage of subjects 
satisfying each Change Relative to Baseline at least once after IMP administration based 
on Criteria for Identifying ECG Measurements of Potential Clinical Relevance (Appendix 
1Appendix 1) will be calculated. The same calculation will also be performed at each 
time point. 


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11.1.3 
Assay Sensitivity Assessment 
As an assay sensitivity assessment, moxifloxacin will be evaluated as a positive control 
using the same analysis set, data set, and statistical method as those stated in 11.1.1 
Primary Endpoint Analyses. 
For moxifloxacin, the lower limit of the CI for the time-matched difference in the least 
squares mean for the change in QTcF from baseline compared to the placebo data will be 
evaluated if it is higher than 0 msec at any of the postdose time points using the 
hypothesis presented below. Because of the multiplicity arising from assay sensitivity 
assessments at 5 postdose time points (1, 1.5, 2, 3, and 4 hours), type 1 error adjustment 
will be performed using the Bonferroni method, and the 2-sided 98% (1-sided 99%) CI 
will be calculated (alpha = 0.02 in SAS code in 11.1.1 Primary Endpoint Analyses). 
 
 
 
𝜇𝑀(𝑖): Mean change from baseline in QTcF interval at time i after moxifloxacin 
administration 
𝜇𝑃(𝑖): Mean change from baseline in QTcF interval at time i after placebo administration 
i =  1,2, ⋯,5  respectively correspond to 1, 1.5, 2, 3, and 4 hours after IMP 
administration 
12 
Pharmacogenomic Analyses 
No pharmacogenomic analysis will be performed. 
13 
Interim Analysis 
No interim analysis will be performed. 
14 
Changes in Planned Analysis 
 For omission in entry, "Vz/BW” was added in Protocol 6.1.2 (1) Endpoints. 
 For erroneous entry, "Apparent" in the definition of "Vz” in the Pharmacokinetics 
Parameter Table was deleted. 
 
𝐻0:   𝜇𝑀(𝑖) −𝜇𝑃(𝑖) ≤0 , i = 1,2, ⋯,5 
𝐻1:   𝜇𝑀(𝑖) −𝜇𝑃(𝑖) > 0 , i = 1,2, ⋯,5 


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15 
References 
None.