Conditions: Congestive Heart Failure
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 45
Healthy volunteers: no

Brief summary:
To confirm the tolerability of intravenous administration of OPC-61815 at 8 or 16 mg once daily for a maximum of 5 days to CHF patients with volume overload despite having received diuretics (injection) other than vasopressin antagonists and who have difficulty with or are incapable of oral intake.

Detailed description:

Arms:
arm 1: Intravenous administration of OPC-61815 at 8 mg or 16 mg once daily for a maximum of 5 days. Starting with 8mg, increase the dose to 16mg on Day 2 or Day 3, according to the dose escalation criteria.

Interventions: intervention 1: OPC-61815 injection
Intervention descriptions: intervention 1: Intravenous administration of OPC-61815 at 8 mg or 16 mg once daily for a maximum of 5 days. Starting with 8mg, increase the dose to 16mg on Day 2 or Day 3, according to the dose escalation criteria.

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Open-label, Uncontrolled Clinical Trial to Confirm the Tolerability of 
OPC-61815 in Patients With Congestive Heart Failure Who Have Difficulty With or Are 
Incapable of Oral Intake 
 
 
 
 
NCT Number: NCT03962101 
PRT NO.: 263-102-00004 
Version Date: 17 April 2020 (Version 4.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
OPC-61815
CLINICAL PROTOCOL
A Multicenter, Open-label, Uncontrolled Clinical Trial to Confirm the Tolerability of 
OPC-61815 in Patients With Congestive Heart Failure Who Have Difficulty With or Are 
Incapable of Oral Intake
Protocol No. 263-102-00004
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase: 
3
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event 
Office of PV Operations
Department of Pharmacovigilance
Otsuka Pharmaceutical Co., Ltd
Email: IRE_263-102-00004@otsuka.jp
Amendment 3 (Ver. 4.0) Approval:
17 Apr 2020
Amendment 2 (Ver. 3.0) Approval:
26 Jun 2019
Amendment 1 (Ver. 2.0) Approval:
18 Mar 2019
Approval(Ver. 1.0):
5 Feb 2019
Date of Translation:
9 Jun 2020


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Protocol Synopsis 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product: 
OPC-61815
Protocol No.: 263-102-00004
Protocol Title:
A Multicenter, Open-label, Uncontrolled Clinical Trial to 
Confirm the Tolerability of OPC-61815 in Patients With 
Congestive Heart Failure Who Have Difficulty With or Are 
Incapable of Oral Intake
Clinical Phase/Trial 
Type:
Phase 3/Therapeutic confirmatory (safety)
Treatment Indication: For the treatment of congestive heart failure (CHF) with 
volume overload despite having received diuretics other than 
vasopressin antagonists
Objective(s): 
To confirm the tolerability of intravenous administration of 
OPC-61815 at 8 or 16 mg once daily for a maximum of 5 days 
to CHF patients with volume overload despite having received 
diuretics (injection) other than vasopressin antagonists and 
who have difficulty with or are incapable of oral intake.
Trial Design:
Multicenter, open-label, uncontrolled
Subject Population:
A total of 40 Japanese male and female CHF patients age 20 to 
85, inclusive, with volume overload (with lower limb edema, 
pulmonary congestion, or jugular venous distension) despite
having received injection diuretics other than vasopressin 
antagonists and who have difficulty with or are incapable of 
oral intake
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria:
1) Patients receiving loop diuretic injection at a dose 
equivalent to furosemide 20 mg/day or higher
2) CHF patients in whom lower limb edema, pulmonary 
congestion, and/or jugular venous distension due to 
volume overload is present
3) Male or female patients age 20 to 85, inclusive, at time 
of informed consent
4) Patients who are judged by the investigator or 
subinvestigator to have difficulty or be incapable of 
oral intake, including patients who are judged by the 
investigator or subinvestigator to require nothing by 
mouth (NPO) management


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5) Patients who are currently hospitalized or who are 
capable of being hospitalized from the time of 
informed consent until the end of the treatment period
6) Patients who are capable of giving informed consent
Exclusion Criteria:
1) Patients who are on a ventricular assist device
2) Patients who have any of the following diseases, 
complications, or conditions:

Suspected hypovolemia

Hypertrophic cardiomyopathy (excluding dilated 
phase)

Valvular disease with significant valvular stenosis

Hepatic encephalopathy with difficulty in adequate 
fluid intake
3) Patients who have experienced acute myocardial 
infarction within 30 days prior to the screening 
examination
4) Patients with a definite diagnosis of active myocarditis 
or amyloid cardiomyopathy
5) Patients who have any of the following medical 
histories:

History of sustained ventricular tachycardia or 
ventricular fibrillation within 30 days prior to the 
screening examination (for patients without an 
implantable cardioverter defibrillator)

History of cerebrovascular disease (excluding 
asymptomatic cerebral infarction) within 6 months 
prior to the screening examination

History of hypersensitivity or idiosyncratic reaction 
to benzazepines or benzazepine derivatives such as 
the ingredients of OPC-61815, tolvaptan, 
mozavaptan hydrochloride, and benazepril 
hydrochloride
6) Patients who have any of the following diseases, 
complications, or conditions:

Poorly controlled diabetes mellitus

Anuria

Dysuria associated with urinary tract obstruction, 
calculus, or tumor


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7) Patients with supine systolic blood pressure of 
<90 mmHg
8) Patients with any of the following abnormalities in 
laboratory test results:

Total bilirubin: >3.0 mg/dL

Serum or plasma creatinine: >3.0 mg/dL

Serum or plasma sodium concentration: 
<125 mEq/L

Serum or plasma sodium concentration: 
<147 mEq/L

Serum or plasma potassium concentration: 
>5.5 mEq/L
9) Patients with current symptoms or a history of hepatic 
impairment (including patients with aspartate 
aminotransferase [AST] or alanine aminotransferase 
[ALT] exceeding 3 times the upper limit of the 
reference range at the screening examination)
10) Patients who have undergone open-heart surgery (eg, 
open-heart surgery for valvular disease, coronary 
bypass surgery, or surgery in thoracic aorta) within 30 
days prior to the screening examination
11) Patients who have difficulty with spontaneous 
respiration or who have been on tracheal intubation 
under sedative therapy
12) Patients with severe disturbed consciousness (ie, coma 
or stupor)
13) Women who are breast-feeding or who have a positive 
pregnancy test result prior to receiving investigational 
product (IMP)
14) Sexually active men or women of childbearing 
potential (WOCBP) who do not agree to practice birth 
control or remain abstinent during the trial and for 30 
days after the final IMP administration
15) Patients who are otherwise judged to be ineligible by 
the investigator or subinvestigator
Trial Site(s):
Approximately 25 sites in Japan


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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
The IMPs administered in this trial will be a lyophilized 
formulation containing 8 or 16 mg of OPC-61815.
Subjects will receive once-daily 1-hour intravenous 
administration of OPC-61815 injection, beginning at a starting 
dose of 8 mg. Dose escalation will be assessed on Day 2 of the 
treatment period (and again on Day 3 of the treatment period, 
if applicable). If the dose escalation criteria are met, the dose 
will be increased to 16 mg; if the criteria are not met, 
administration will continue at 8 mg. If dose reduction 
becomes necessary after dose escalation to 16 mg due to 
occurrence of an adverse event, the dose will be reduced to 
8 mg. A second dose escalation to 16 mg following dose 
reduction will not be allowed.
The maximum duration of treatment will be 5 days; however, 
IMP treatment may be ended at a treatment period of shorter 
than 5 days at the discretion of the investigator or 
subinvestigator, if either of the following criteria is met:

All congestive symptoms are resolved and no further 
improvement in volume overload is necessary.

The subject becomes capable of fluid management by oral 
intake alone.
Trial Assessments:
Safety:
Adverse events (AEs), clinical laboratory tests, physical 
examination, vital signs (blood pressure, pulse rate, and body 
temperature), and 12-lead electrocardiogram (ECG)
Pharmacodynamics:
Urine volume, fluid intake, serum concentrations of sodium 
and potassium, serum osmolality, urine concentrations of 
sodium and potassium, urine osmolality, biomarker 
measurements (plasma concentrations of arginine vasopressin 
[AVP] and brain natriuretic peptide [BNP], plasma renin 
activity, and serum concentrations of N-terminal pro-brain 
natriuretic peptide [NT proBNP] and troponin I)
Efficacy:
Body weight, congestive symptom findings (lower limb 
edema, pulmonary congestion, jugular venous distension, 
hepatomegaly, cardiothoracic ratio, pulmonary rales, and 
cardiac third sound), dyspnea (respiratory rate, paroxysmal 
nocturnal dyspnea, orthopnea, and subject-assessed dyspnea), 
and New York Heart Association (NYHA) classification


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Screening/other:
Medical and medication history, physical examination, 
laboratory tests, vital signs, body weight, urine pregnancy test, 
and DNA storage
Criteria for 
Evaluation:
Safety:
AEs, clinical laboratory tests, physical examination, vital 
signs, and 12-lead ECG 
Pharmacodynamics:
Urine volume, fluid intake, fluid balance, serum concentrations 
of sodium and potassium, serum osmolality, urine excretions 
of sodium and potassium, urine osmolality, biomarker 
measurements (plasma concentrations of AVP and BNP, 
plasma renin activity, and serum concentrations of NT-
proBNP and troponin I)
Efficacy:
Body weight, congestive symptom findings, dyspnea, and 
NYHA classification
Statistical Methods:
Rationale for Sample Size:
Sample size: 40 subjects (number of subjects started on OPC-
61815)
For a sample size of 40 subjects, the probability of AE 
occurring at an incidence of 5% and 4% is respectively 87% 
and 80%.
Trial Duration:
Planned duration of the clinical trial: Apr 2019 to Sep 2020
Planned duration of trial participation for each subject: 
Maximum of 16 days (screening [1 day before start of IMP 
administration], 6 days for treatment period, and post-
treatment follow-up at 7 to 10 days after final IMP 
administration)


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Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................7
List of In-text Tables ...................................................................................13
List of In-text Figures..................................................................................14
List of Appendices........................................................................................15
List of Abbreviations and Definitions of Terms .......................................16
1
Introduction ........................................................................................19
1.1
Nonclinical Data................................................................................................21
1.2
Clinical Data......................................................................................................22
1.2.1
Phase 1 Trials of OPC-61815 in Healthy Male Subjects (Trials 263-08-
001, 263-09-001, and 263-10-005; Japan)......................................................22
1.2.2
Phase 2 Clinical Pharmacology Trial of OPC-61815 Injection in 
Congestive Heart Failure Patients With Volume Overload (Trial 263-
102-00001; Japan) ..........................................................................................23
1.2.3
Phase 3, Double-blind, Placebo-controlled Trial of Tolvaptan Tablet in 
Congestive Heart Failure Patients With Volume Overload (Trial 156-
06-002, Japan).................................................................................................25
1.3
Known and Potential Risks and Benefits ..........................................................26
2
Trial Rationale and Objectives..........................................................27
2.1
Trial Rationale...................................................................................................27
2.1.1
Rationale for the Uncontrolled and Open-label Design .................................28
2.2
Rationale for the Dosage Regimen....................................................................28
2.2.1
Selection of Dosage Regimen for the Phase 3 Confirmatory Trial (Trial 
263-102-00003) ..............................................................................................29
2.2.2
Rationale for the Dosage Regimen in This Trial............................................30
2.3
Trial Objective...................................................................................................32
3
Trial Design.........................................................................................32
3.1
Type/Design of Trial .........................................................................................32
3.2
Trial Treatments ................................................................................................33
3.2.1
Dosage Regimen.............................................................................................33
3.2.2
Dose Escalation Decision ...............................................................................35


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3.2.3
Treatment Duration.........................................................................................37
3.3
Trial Population.................................................................................................37
3.3.1
Number of Subjects and Description of Population .......................................37
3.3.2
Subject Selection and Numbering ..................................................................38
3.4
Eligibility Criteria..............................................................................................38
3.4.1
Informed Consent ...........................................................................................38
3.4.2
Inclusion Criteria ............................................................................................39
3.4.3
Exclusion Criteria...........................................................................................40
3.5
Endpoints...........................................................................................................42
3.5.1
Safety Endpoints.............................................................................................42
3.5.2
Pharmacodynamic Endpoints .........................................................................42
3.5.3
Efficacy Endpoints..........................................................................................43
3.6
Measures to Minimize/Avoid Bias....................................................................43
3.7
Trial Procedures ................................................................................................43
3.7.1
Schedule of Assessments................................................................................47
3.7.1.1
Screening Period (Day −1 to Predose on Day 1) ........................................47
3.7.1.1.1
Screening Examination............................................................................47
3.7.1.1.2
Urine Collection, and Measurement of Urine Volume and Fluid 
Intake .......................................................................................................48
3.7.1.2
Treatment Period (Day 1)............................................................................48
3.7.1.3
Treatment Period (Day 2)............................................................................51
3.7.1.4
Treatment Period (Day 3)............................................................................52
3.7.1.5
Dose Escalation Day (Day 2 or Day 3).......................................................53
3.7.1.6
Treatment Period (Days 4 and 5) ................................................................54
3.7.1.7
Treatment Period (Completion Assessment on Day 6 or Withdrawal 
Assessment) ................................................................................................55
3.7.1.8
Follow-up After End of the Treatment Period (7 to 10 Days After the 
Final IMP Administration)..........................................................................56
3.7.2
Safety Assessments.........................................................................................56
3.7.2.1
Adverse Events............................................................................................56
3.7.2.2
Clinical Laboratory Assessments................................................................57
3.7.2.3
Physical Examination and Vital Signs........................................................58


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3.7.2.4
Electrocardiogram Assessments..................................................................59
3.7.3
Efficacy Assessments .....................................................................................60
3.7.3.1
Body Weight ...............................................................................................60
3.7.3.2
Congestive Symptoms (Lower Limb Edema, Jugular Venous 
Distension, Hepatomegaly, Pulmonary Rales, and Cardiac Third 
Sound) .........................................................................................................60
3.7.3.3
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion)................61
3.7.3.4
Dyspnea.......................................................................................................61
3.7.3.5
NYHA Classification ..................................................................................62
3.7.4
Prior and Concomitant Medications...............................................................63
3.7.5
Pharmacodynamic and Pharmacogenomic Assessments................................63
3.7.5.1
Pharmacodynamic Assessment...................................................................63
3.7.5.1.1
Urine Volume ..........................................................................................63
3.7.5.1.2
Fluid Intake..............................................................................................65
3.7.5.1.3
Fluid Balance...........................................................................................66
3.7.5.1.4
Serum Sodium Concentration, Serum Potassium Concentration, 
Serum Osmolality, and Biomarkers (Plasma AVP Concentration, 
Plasma Renin Activity, Plasma BNP Concentration, Serum NT-
proBNP Concentration, and Serum Troponin I Concentration)..............66
3.7.5.1.5
Urine Sodium Excretion, Urine Potassium Excretion, and Urine 
Osmolality ...............................................................................................67
3.7.5.2
Pharmacogenomic Assessment...................................................................68
3.7.5.2.1
DNA Storage ...........................................................................................68
3.7.5.2.2
Potential Genomic/Genetic Analysis.......................................................69
3.7.6
End of Trial.....................................................................................................70
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................70
3.8.1
Entire Trial......................................................................................................70
3.8.2
Individual Site.................................................................................................71
3.8.3
Individual Subject Discontinuation ................................................................71
3.8.3.1
Treatment Discontinuation..........................................................................71
3.8.3.2
Documenting Reasons for Treatment Discontinuation...............................71
3.8.3.3
Withdrawal of Consent ...............................................................................72
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................73


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3.9
Screen Failures ..................................................................................................73
3.10
Definition of Completed Subjects.....................................................................74
3.11
Definition of Subjects Lost to Follow-up..........................................................74
3.12
Subject Compliance...........................................................................................75
3.13
Protocol Deviations...........................................................................................75
4
Restrictions..........................................................................................76
4.1
Prohibited Medications......................................................................................76
5
Reporting of Adverse Events.............................................................77
5.1
Definitions.........................................................................................................77
5.2
Eliciting and Reporting Adverse Events ...........................................................79
5.3
Immediately Reportable Events ........................................................................80
5.4
Potential Serious Hepatotoxicity.......................................................................81
5.5
Pregnancy..........................................................................................................81
5.6
Procedure for Breaking the Blind......................................................................82
5.7
Follow-up of Adverse Events............................................................................83
5.7.1
Follow-up of Nonserious Adverse Events......................................................83
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................83
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After the Date of Trial End (Last 
Scheduled Contact).........................................................................................83
6
Pharmacodynamic and Pharmacogenomic Analyses .....................84
7
Statistical Analyses .............................................................................84
7.1
Target Sample Size............................................................................................84
7.2
Datasets for Analysis.........................................................................................84
7.3
Handling of Missing Data .................................................................................84
7.4
Safety, Pharmacodynamic, and Efficacy Endpoint Analyses ...........................84
7.4.1
Safety Analysis ...............................................................................................84
7.4.1.1
Adverse Events............................................................................................85
7.4.1.2
Clinical Laboratory Data.............................................................................85
7.4.1.3
Vital Signs Data ..........................................................................................85
7.4.1.4
Electrocardiogram Data ..............................................................................86


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7.4.2
Pharmacodynamic Analyses...........................................................................86
7.4.3
Efficacy Analyses ...........................................................................................87
7.4.3.1
Body Weight ...............................................................................................87
7.4.3.2
Congestive Symptoms.................................................................................87
7.4.3.2.1
Lower Limb Edema and Pulmonary Congestion ....................................87
7.4.3.2.2
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic 
Ratio ........................................................................................................88
7.4.3.2.3
Pulmonary Rales and Cardiac Third Sound ............................................88
7.4.3.3
Dyspnea.......................................................................................................88
7.4.3.3.1
Respiratory Rate ......................................................................................88
7.4.3.3.2
Orthopnea and Paroxysmal Nocturnal Dyspnea......................................88
7.4.3.3.3
Subject-Assessed Dyspnea ......................................................................88
7.4.3.4
NYHA Classification ..................................................................................88
7.5
Analysis of Demographic and Baseline Characteristics....................................89
8
Management of Investigational Medicinal Product........................89
8.1
Packaging and Labeling ....................................................................................89
8.2
Storage...............................................................................................................89
8.3
Accountability ...................................................................................................89
8.4
Returns and Destruction....................................................................................89
8.5
Reporting of Product Quality Complaints.........................................................90
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................90
8.5.2
Information Required for Reporting Purposes ...............................................90
8.5.3
Return Process ................................................................................................91
8.5.4
Assessment/Evaluation...................................................................................91
9
Records Management.........................................................................91
9.1
Source Documents.............................................................................................91
9.2
Data Collection..................................................................................................91
9.3
File Management at the Trial Site.....................................................................92
9.4
Records Retention at the Trial Site....................................................................92
10
Quality Control and Quality Assurance...........................................93
10.1
Monitoring.........................................................................................................93


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10.2
Auditing.............................................................................................................93
11
Ethics and Responsibility...................................................................93
12
Confidentiality ....................................................................................94
13
Amendment Policy..............................................................................94
14
Publication Authorship Requirements.............................................95
15
References............................................................................................96


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List of In-text Tables
Table 2.2.1-1
Tolvaptan Exposures (Cmax and AUC24h) on Day 1 After 
Intravenous Administration of OPC-61815 and After Oral
Administration of Tolvaptan 15 mg (Mean ± SD).........................30
Table 2.2.1-2
Mean Differences and 95% Confidence Intervals in Log-
transformed Tolvaptan Exposure (Cmax and AUC24h) on 
Day 1 Between Intravenous Administration of OPC-61815 
and Oral Administration of Tolvaptan 15 mg................................30
Table 3.2.2-1
Day 2 Dose Escalation Criteria......................................................35
Table 3.2.2-2
Day 3 Dose Escalation Criteria......................................................36
Table 3.4.2-1
Inclusion Criteria ...........................................................................39
Table 3.4.3-1
Exclusion Criteria ..........................................................................40
Table 3.7-1
Schedule of Assessments...............................................................44
Table 3.7.1.2-1
Urine Collection Intervals After Start of IMP administration 
on Day 1
49
Table 3.7.1.2-2
Examinations/Tests and Timing After Start of IMP 
Administration on Day 1................................................................50
Table 3.7.1.5-1
Urine Collection Intervals on the Dose Escalation Day ................53
Table 3.7.1.5-2
Examinations/Tests and Timing on the Dose Escalation Day.......54
Table 3.7.2.2-1
Clinical Laboratory Assessments...................................................58
Table 3.7.3.2-1
Criteria for Assessment of Lower Limb Edema ............................60
Table 3.7.3.3-1
Criteria for Assessment of Pulmonary Congestion........................61
Table 3.7.3.5-1
NYHA Classification.....................................................................63
Table 3.7.5.1.1-1
Urine Collection Intervals..............................................................64
Table 3.7.5.1.1-2
Urine Volume Measurement Intervals...........................................65
Table 4.1-1
List of Prohibited Concomitant Medications and Foods ...............76
Table 4.1-2
Medications and Foods Which May Inhibit or Induce 
CYP3A4 Activity...........................................................................77
Table 7.4.3.2-1
Improvement Category of Lower Limb Edema and 
Pulmonary Congestion...................................................................87


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................33
Figure 3.2.1-1
Flowchart of the Dose Escalation Decision...................................34


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List of Appendices
Appendix 1
Handling and Shipment of Bioanalytical Samples ........................97
Appendix 2
Protocol Amendments/Administrative Changes............................99


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List of Abbreviations and Definitions of Terms
List of Abbreviations
Abbreviation
Definition
ADPKD
Autosomal dominant polycystic kidney disease
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AVP
Arginine vasopressin
BNP
Brain natriuretic peptide
cAMP
Cyclic adenosine 3',5'-monophosphate
CHF
Congestive heart failure
CI
Confidence interval
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EU
European Union
GCP
Good Clinical Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IMP
Investigational medicinal product
IRB
Institutional review board
IRE
Immediately reportable event
Ki
Inhibition constant
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PD
Pharmacodynamic
PK
Pharmacokinetic
PPK
Population pharmacokinetics
PQC
Product quality complaint
QTc
QT corrected for heart rate
SAE
Serious adverse event
SD
Standard deviation
SIADH
Syndrome of inappropriate secretion of antidiuretic hormone
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States


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WOCBP
Women of childbearing potential


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List of Pharmacokinetic Parameters
Abbreviation 
or term
Unit
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
CL
L/h
Total body clearance of drug from the plasma
Cmax
ng/mL
Peak (maximum) plasma concentration of the drug
t1/2,z
h
Terminal-phase elimination half-life
tmax
h
Time to maximum plasma concentration
Vz
L
Apparent volume of distribution during the terminal 
phase (λz)


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1
Introduction
Tolvaptan is an arginine vasopressin (AVP) V2 receptor antagonist synthesized by 
Otsuka Pharmaceutical Co., Ltd. (Otsuka Pharmaceutical). It promotes water excretion 
(aquaresis) without affecting electrolyte excretion, by specifically inhibiting the binding 
of AVP to V2-receptors at distal parts of the nephron. Congestive heart failure (CHF) is 
manifested by dyspnea, orthopnea, jugular venous distension, and other symptoms1, and 
treated primarily with diuretics.2 Conventional diuretics (mainly loop diuretics) exert 
their diuretic effect by increasing electrolyte excretion in the urine. This action makes 
them difficult to be a therapeutic option for patients with decreased serum electrolyte 
levels. Moreover, a dose increase is not always an option even in patients with 
insufficient response, as these drugs may impair renal function when administered at high 
doses. In contrast, an add-on diuretic effect can be expected with tolvaptan because of its 
different mechanism of action that differs from those of other conventional diuretics. 
Moreover, tolvaptan does not lower serum electrolyte levels and has little effect on renal 
function, making it an option for patients in whom dose increases or prolonged treatment 
with conventional diuretics is unsuitable.
In Japan, tolvaptan was approved under the trade name of Samsca® Tablets for “the 
treatment of volume overload in heart failure when adequate response is not obtained 
with other diuretics (eg, loop diuretics)” in 2010, for “the treatment of fluid retention in 
hepatic cirrhosis when adequate response is not obtained with other diuretics (eg, loop 
diuretics)” in 2013, and for “suppression of progression of autosomal dominant 
polycystic kidney disease (ADPKD) in patients with increased kidney volume and a rapid 
rate of increase” in 2014. Outside Japan, tolvaptan has received approvals for the 
following indications: “the treatment of clinically significant hypervolemic and 
euvolemic hyponatremia, including patients with heart failure and Syndrome of 
Inappropriate Antidiuretic Hormone (SIADH)” in the United States (US) in 2009, “the 
treatment of hyponatremia secondary to SIADH in adults” in the European Union (EU) in 
2009, “slowing the progression of cyst development and renal insufficiency of autosomal 
dominant polycystic kidney disease (ADPKD) in adults with chronic kidney diseases
stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease” in the 
EU in 2015, and “slowing kidney function decline in adults at risk of rapidly progressing 
ADPKD” in the US in 2018 (in overseas marketed under the name of Jinarc in the EU 
and Jynarque in the US). Tolvaptan is currently approved in more than 40 countries and 
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Tolvaptan has been has been administered to patients in clinical settings as an oral 
aquaretic and provides a useful treatment option for heart failure patients with volume 
overload despite having received other conventional diuretics. However, in clinical 
practice, there are unmet medical needs for intravenously injectable aquaretics with the 
similar effects to oral tolvaptan for the treatment of heart failure patients who transiently 
experience mildly decreased levels of consciousness associated with pulmonary edema 
leading to difficulty in oral drug intake, those in whom the absorption of an oral drug is 
decreased due to gastrointestinal edema (intestinal edema) associated with an increase in 
central venous pressure secondary to heart failure, those in whom administration of an 
oral drug is difficult while receiving oxygen therapy, and elderly patients with decreased 
swallowing function. Tolvaptan is not readily soluble in water and not suitable for 
development as an injection. Otsuka Pharmaceutical therefore synthesized the new 
intravenous aquaretic OPC-61815. OPC-61815 is a compound with improved water 
solubility of tolvaptan by the phosphorylation of the hydroxy group in the benzazepine 
ring, and it is readily metabolized to tolvaptan in the body through the hydrolysis of the 
phosphate ester site by an alkaline or acid phosphatase. OPC-61815 is being developed 
for “the treatment of volume overload in heart failure when adequate response is not 
obtained with other diuretics (eg, loop diuretics).”
To date, the following trials of OPC-61815 has been completed: three phase 1 trials in 
healthy males: a single intravenous dose trial (Trial 263-08-001), a repeated intravenous 
dose trial (Trial 263-09-001), and a trial investigating the rate of intravenous 
administration (Trial 263-10-005), as well as one phase 2 clinical pharmacology trial in 
CHF patients (Trial 263-102-00001). In addition, a phase 3 trial to confirm the non-
inferiority of OPC-61815 to tolvaptan tablet is ongoing in patients with CHF (Trial 263-
102-00003).
When treated with OPC-61815 just as with tolvaptan, patients with heart failure are 
required to appropriately maintain control of fluid balance by oral fluid intake to prevent 
adverse drug reactions associated with the aquaretic effect of the drug, such as 
hypernatremia, thirst, and dehydration. For adequate fluid management, although it is 
important for patients to keep an adequate fluid balance by oral fluid intake on their own, 
some patients have difficulty in keeping an adequate fluid balance by oral fluid intake 
particularly in patients with decreased swallowing function and those who transiently 
experience mild decreased levels of consciousness associated with pulmonary edema.
The timing of oral fluid intake is affected by the patient's subjective symptoms, such as 
thirst. In elderly patients and patients with decreased conscious levels who have difficulty 


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with or are incapable of sensing thirst (or incapable of complaining of thirst), fluid 
maintenance is expected to be more difficult, raising concerns of a possible higher risk of
hypernatremia and other related symptoms compared with those who are capable of oral 
fluid intake.
The above-mentioned phase 3 confirmatory trial (Trial 263-102-00003) uses tolvaptan 
tablet as a comparator and excludes patients with difficulty in oral intake. Therefore, a 
clinical trial to evaluate the tolerability of OPC-61815 in patients with heart failure who 
have difficulty with or are incapable of oral intake should be conducted separately from 
the phase 3 confirmatory trial.
This trial will be conducted to confirm the tolerability of intravenous administration of 
OPC-61815 once daily for a maximum of 5 days to CHF patients who have difficulty 
with or are incapable of oral intake.
1.1
Nonclinical Data
In a receptor binding study using 3H-AVP as a labeled ligand, OPC-61815 showed 
affinity for human AVP V2 receptor with an inhibition constant [Ki] value of 6.13 ± 1.34 
nM that was approximately 1/14 that of the main active metabolite tolvaptan (Ki, 0.43 ± 
0.06 nM). OPC-61815 showed low affinity for human AVP V1a receptor with a Ki value 
of 54.2 ± 16.8 nM that was approximately 1/4 that of tolvaptan (Ki, 12.3 ± 0.80 nM). 
Neither OPC-61815 nor tolvaptan had affinity for human AVP V1b receptor. OPC-61815 
and tolvaptan inhibited AVP-induced cyclic adenosine 3',5'-monophosphate (cAMP) 
production in a human endocervical carcinoma cell line expressing human AVP V2
receptors, indicating that both drugs have an AVP V2 receptor antagonistic activity. 
However, neither OPC-61815 nor tolvaptan alone increased cAMP production, 
suggesting that they possess no V2 receptor agonistic activity.
In conscious rats given a single intravenous administration of OPC-61815 at 0.1275 to 
12.75 mg/kg, dose dependent increase in urine volume and decreased urine osmolality 
were observed and neither of these effects were attenuated with a 7-day repeated 
intravenous administration of OPC-61815. In beagle dogs given a single intravenous 
administration of OPC-61815 at 0.1275 to 3.825 mg/kg, dose-dependent increase in urine
volume and decrease in urine osmolality were observed accompanied by a dose-
dependent increase in free water clearance, indicating that OPC-61815 is an aquaretic 
agent which increases free water excretion. In dogs, plasma AVP concentration increased 
after a single intravenous administration of OPC-61815, which was accompanied by no 


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increase in plasma renin activity, or activation of the renin-angiotensin system following 
furosemide administration.
In a rat model of histamine-induced increased vascular permeability, a single intravenous 
administration of OPC-61815 (0.3825 to 3.825 mg/kg administered 2 hours before 
histamine injection) dose-dependently increased urine volume and decreased urine 
osmolality, as well as a dose-dependently reduced the area of dye leakage at the 
histamine injection site. In a rat model of carrageenin-induced paw edema, a single 
intravenous administration of OPC-61815 (1.275 to 12.75 mg/kg administered 1 hour 
before carrageenin injection) inhibited the development of paw edema in a dose-
dependent manner.
In a rat model of hyponatremia, 5-day repeated ascending intravenous administration of 
OPC-61815 at 0.255 to 5.1 mg/kg dose-dependently increased the lowered plasma 
sodium concentration and also improved the hyponatremia-associated increases in water 
content observed in the brain and heart.
Based on the above results, OPC-61815 by intravenous administration shows potent 
aquaretic effects similar to those of tolvaptan and is expected to demonstrate clinical 
efficacy in the improvement of various disorders associated with body fluid retention due 
to abnormal water metabolism (eg, hyponatremia and edematous diseases).
For detailed nonclinical data, see the Investigator’s Brochure (IB).
1.2
Clinical Data
1.2.1
Phase 1 Trials of OPC-61815 in Healthy Male Subjects (Trials 263-
08-001, 263-09-001, and 263-10-005; Japan)
In a single intravenous dose trial (Trial 263-08-0013), OPC-61815 at 0.3, 1, 3, 7.5, 15, or 
30 mg, or placebo was intravenously administered over 5 minutes in 54 healthy male 
subjects. All of the adverse events (AEs) reported in the OPC-61815 groups were mild in 
severity and resolved without treatments or with symptomatic treatments.
In a repeated intravenous dose trial (Trial 263-09-0014), OPC-61815 at 1.25, 5, or 20 mg, 
or placebo was intravenously administered over 1 minute as a single dose followed by 
once daily dosing for 7 consecutive days after 1-day dose intermission from the initial 
dose in 36 healthy male subjects. Adverse events, including feeling abnormal, pruritus, 
and erythema occurred at higher frequency during or immediately after the end of 
administration of OPC-61815. Most of these events were considered to be related to the 


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IMP and had not been reported with the oral administration of tolvaptan. All of the AEs 
were mild or moderate in severity and resolved without treatments.
In order to investigate an injection duration that is capable of reducing the occurrence of 
the ADRs that had not been reported with oral administration of tolvaptan but reported in 
the repeated intravenous administration trial (263-09-001), and also to explore the causes 
of the ADRs, a trial investigating the rate of intravenous administration (Trial 263-10-
0055) was conducted. A single dose of OPC-61815 at 7.5 or 15 mg, or placebo was 
intravenously administered over 2 hours, 5 minutes, or 1 minute in 18 healthy male 
subjects, and AEs categorized as “feeling abnormal, pruritus, and erythema” which
occurred at higher frequency in the repeated intravenous dose trial (Trial 263-09-001) 
were extracted as adverse events of special interest (AESI). The incidences of the AESI
with a 2-hour intravenous administration were 1 of 12 subjects in the OPC-61815 group 
and 3 of 6 subjects in the placebo group; a causal relationship to the investigational 
medicinal product (IMP) was ruled out for the rash in the OPC-61815 group. The 
incidences of the AESI with a 5-minute infusion were 9 of 12 subjects in the OPC-61815 
group and 2 of 6 subjects in the placebo group, and those with a 1-minute infusion were 
10 of 11 subjects in the OPC-61815 group and 4 of 6 subjects in the placebo group. With 
the exception of 1 occurrence of erythema at the 1-minute intravenous administration, all 
occurrences in the OPC-61815 group were judged to be related to the IMP. All of the 
related AEs occurred during or immediately after the end of administration, and most of 
the events were transient and resolved without treatments. There were no clinically 
significant changes from baseline in the plasma histamine concentration.
For the detailed results of these trials, see the IB.
1.2.2
Phase 2 Clinical Pharmacology Trial of OPC-61815 Injection in 
Congestive Heart Failure Patients With Volume Overload (Trial
263-102-00001; Japan)
OPC-61815 at 2, 4, 8, or 16 mg was intravenously administered over 1 hour once daily 
for 5 consecutive days or tolvaptan 15-mg tablet was orally administered once daily for 5 
days in 60 patients with CHF who have volume overload despite having received 
diuretics other than vasopressin antagonists. A phase 2 trial was conducted with the 
primary objective to investigate the dose of OPC-61815 injection formulation achieving 
exposure equivalent to that for tolvaptan 15-mg tablet. The detailed results for the 
primary endpoint are described in Section 2.2.1.


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1) Pharmacokinetics and Pharmacodynamics
After a single intravenous administration of OPC-61815 at 2, 4, 8, or 16 mg, the mean 
Cmax, AUC24h, AUCt, and AUC∞values of OPC-61815 free form and tolvaptan 
increased in a dose-dependent manner. The median tmax values of OPC-61815 free 
form and tolvaptan were from 1.03 to 1.04 and 1.48 to 1.76 hours, respectively, and 
the mean t1/2,z values were from 1.8 to 3.8 hours and 7.4 to 8.6 hours. The mean CL 
and Vz values of OPC-61815 free form were from 4.29 to 5.50 L/h and 10.5 to 24.7 
L, respectively. The mean ratios of AUC24h, AUCt, and AUC∞with tolvaptan to 
OPC-61815 free form were from 0.846 to 1.42, 0.847 to 1.45, and 0.989 to 1.77, 
respectively. Repeated intravenous administration of OPC-61815 at 2, 4, 8, or 16 mg 
once daily for 5 consecutive days resulted in no accumulation of OPC-61815 free 
form but an approximately 1.2- to 1.4-fold accumulation of tolvaptan. Tolvaptan 
exposure (Cmax and AUC24h) on Day 1, which was the primary variable, following 
single intravenous administration of OPC-61815 at 16 mg was the closest, and 
similar, to that following single administration of tolvaptan 15-mg tablet. Tolvaptan 
accumulated approximately 1.3-fold by repeated administration of tolvaptan 15 mg 
tablet once daily for 5 consecutive days, which was similar to the accumulation 
following repeated intravenous administration of OPC-61815 at 16 mg once daily for 
5 consecutive days. The pharmacokinetic parameters of metabolites DM-4103 and 
DM-4107 after a single intravenous administration and repeated intravenous 
administration of OPC-61815 at 16 mg were similar to those observed after a single 
and repeated oral administrations of tolvaptan 15-mg tablet, respectively.
When intravenously administered at 2, 4, 8, or 16 mg once daily for 5 days, OPC-
61815 increased the daily urine volume from baseline in all dose groups on the day 
after start of IMP administration and onward.
2) Efficacy and Safety
The changes (mean ± standard deviation [SD]) in body weight from baseline at the 
time of final IMP administration were −0.6 ± 0.6 kg in the OPC-61815 2-mg group, 
−1.1 ± 0.8 kg in the OPC-61815 4-mg group, −1.5 ± 1.1 kg in the OPC-61815 8-mg 
group, −2.1 ± 1.8 kg in the OPC-61815 16-mg group, and −1.7 ± 1.2 kg in the 
tolvaptan 15-mg tablet group; body weight decreased from baseline in all treatment 
groups.
The AEs reported by ≥2 subjects in the OPC-61815 group (all dose groups combined) 
were blood urea increased (4.2% [2 of 48 subjects] in the OPC-61815 group, 8.3% [1 


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of 12 subjects] in the tolvaptan 15-mg tablet group), and pyrexia, thirst, vessel 
puncture site reaction, blood creatinine increased, and headache (4.2% [2 of 48 
subjects] each in the OPC-61815 group and 0.0% [0 of 12 subjects] in the tolvaptan 
15-mg group). No deaths were reported. Two occurrences of serious adverse events
(SAEs) (atrial fibrillation, endocarditis) were reported by 1 subject in the OPC-61815 
4-mg group. Two subjects in the OPC-61815 4-mg group (atrial fibrillation, renal 
impairment) and 3 subjects in the tolvaptan 15-mg tablet group (liver disorder, 
hepatic congestion, renal impairment) discontinued IMP administration due to AEs. 
No subjects reported any AESI (eg, feeling abnormal, feeling hot, pruritus, rash, 
urticaria, erythema, hyperhidrosis, nausea, epigastric discomfort, or dyspnea) that 
occurred at higher frequency following bolus (1- or 5-minute) infusion of OPC-61815 
and were considered to be due to IMP in the phase 1 trials (Trials 263-09-001 and 
263-10-005).
For the detailed results of these trials, see the IB.
1.2.3
Phase 3, Double-blind, Placebo-controlled Trial of Tolvaptan 
Tablet in Congestive Heart Failure Patients With Volume 
Overload (Trial 156-06-002, Japan)
In a phase 3 trial of tolvaptan tablet (Trial 156-06-0026), tolvaptan at 15 mg/day or 
placebo was administered for 7 days to 110 adult CHF patients with volume overload 
despite having received conventional diuretics.
The changes (mean ± SD) in body weight from baseline at the time of final IMP 
administration were −1.54 ± 1.61 kg in the tolvaptan 15-mg group and −0.45 ± 0.93 kg in 
the placebo group. The decrease in body weight in the tolvaptan 15-mg group was
significantly greater than that in the placebo group (p <0.0001, t-test), with a difference 
(the tolvaptan 15-mg tablet group −the placebo group) of −1.09 kg (95% confidence 
interval [CI], −1.58 to −0.60 kg).
The AEs for which the incidence in the tolvaptan 15-mg group was ≥3%, and ≥3% higher 
than that in the placebo group were thirst (17.0% [9 of 53 subjects] in the tolvaptan 
15-mg group and 1.8% [1 of 57 subjects] in the placebo group), constipation (17.0% [9 of 
53 subjects] in the tolvaptan group and 5.3% [3 of 57 subjects] in the placebo group), 
pollakiuria (9.4% [5 of 53 subjects] in the tolvaptan group and 0.0% in the placebo 
group), nausea and malaise (5.7% [3 of 53 subjects] each in the tolvaptan group and 0.0% 
in the placebo group), and dizziness and headache (3.8% [2 of 53 subjects] each in the 
tolvaptan group and 0.0% in the placebo group). All of these AEs were mild to moderate 


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in severity. The thirst, constipation, and pollakiuria were considered to be related to the 
diuretic effect of tolvaptan.
Serious adverse events occurred in 2 subjects in the tolvaptan 15-mg group and 7 subjects 
in the placebo group; one of the 2 subjects in the tolvaptan 15-mg group experienced
renal failure chronic and (fatal) heart failure, and another subject experienced atrial 
fibrillation.
1.3
Known and Potential Risks and Benefits
The AEs reported frequently in the completed phase 1 trials of OPC-61815 in healthy 
male subjects (Trials 263-08-001, 263-09-001, and 263-10-005) are described below.
In a single intravenous dose trial (Trial 263-08-001), the AEs reported by ≥2 subjects in 
the OPC-61815 group were ventricular extrasystoles, abdominal pain, and blood 
cholesterol increased.
In a repeated intravenous dose trial (Trial 263-09-001), the AEs reported by ≥3 subjects 
in the OPC-61815 group were feeling abnormal, pruritus, blood uric acid increased, 
diarrhoea, pruritus generalised, erythema, and bradycardia.
In a trial investigating the rate of intravenous administration (Trial 263-10-005), the AEs
reported by ≥2 subjects receiving OPC-61815 as a 2-hour infusion were activated partial 
thromboplastin time prolonged at 7.5 mg; those reported by ≥2 subjects receiving 
OPC-61815 as a 5-minute infusion were erythema, hyperhidrosis, pruritus, and feeling 
hot at 7.5 mg, and erythema, hyperhidrosis, pruritus, and feeling abnormal at 15 mg; and 
those reported by ≥2 subjects receiving OPC-61815 as a 1-minute infusion were 
erythema, pruritus, feeling abnormal, and feeling hot at 7.5 mg, and erythema, 
hyperhidrosis, pruritus, and feeling abnormal at 15 mg.
In these phase 1 trials, no deaths occurred and no other SAEs were reported. When 
OPC-61815 was administered to healthy subjects as bolus (1- or 5-minute) infusion 
(Trials 263-09-001 and 263-10-005), feeling abnormal, feeling hot, pruritus, erythema, 
hyperhidrosis, nausea, epigastric discomfort, and dyspnoea were reported as AESI. In a 
trial investigating the rate of intravenous administration (Trial 263-10-005), on the other 
hand, a 2 hour infusion of OPC-61815 induced such AESI only in 1 of 12 subjects in the 
OPC-61815 group and 3 of 6 subjects in the placebo group. These results suggest that a 
longer infusion period may lessen the occurrence of the AESI. In a phase 2 clinical 
pharmacology trial in which OPC-61815 was administered to patients with CHF as a 
1-hour infusion (Trial 263-102-00001), no subjects reported the AESI that were 
considered to be caused by the IMP.


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OPC-61815 is metabolized to tolvaptan in the body through hydrolysis of the phosphate 
ester site by an alkaline or acid phosphatase, and the tolvaptan acts as an aquaretic. 
Therefore, OPC-61815 is expected to bring risks and benefits comparable to those of 
tolvaptan.
Tolvaptan, when administered to patients with cardiac edema, is known to be effective in 
body weight reduction and improvement of other symptoms (jugular venous distension, 
hepatomegaly, and lower limb edema) associated with the disease.7
In clinical trials involving patients with cardiac edema (Trials 156-03-001, 156-06-002, 
156-06-004, 156-06-006, 156-10-005, 156-12-809-01, and 156-TWA-1101), the AEs 
frequently reported (with an incidence ≥2%, and higher than that in the placebo group) in 
437 subjects treated with tolvaptan tablet were ventricular tachycardia, constipation, dry 
mouth, diarrhoea, vomiting, thirst, blood urea increased, blood uric acid increased, blood 
creatinine increased, blood potassium increased, blood sodium increased, blood glucose 
increased, blood urine present, platelet count decreased, dehydration, hyperkalaemia, 
dizziness, pollakiuria, renal impairment, and epistaxis. For the details regarding the AEs 
attributable to tolvaptan or OPC-61815 treatment that have been reported in clinical 
trials, see the IB.
The present trial will enroll patients with CHF who have difficulty with or are incapable 
of oral intake. In these patients, as compared with those who are able to drink water, the 
risks of AEs related to the aquaretic effect of OPC-61815 (eg, hypernatremia, 
dehydration, and thirst) may be increased due to their inability to control fluid balance by 
oral fluid intake.
2
Trial Rationale and Objectives
2.1
Trial Rationale
OPC-61815 is being developed for an intended approval in the same indication as that of 
tolvaptan, “the treatment of volume overload in heart failure when adequate response is 
not obtained with other diuretics (eg, loop diuretics)”
A phase 2 clinical pharmacology trial (Trial 263-102-00001) was conducted in patients 
with CHF to investigate a dose of OPC-61815 to achieve the exposure equivalent to an 
oral tolvaptan tablet at 15 mg using exposure of tolvaptan as a measure. The results 
indicated that OPC-61815 at 16 mg was equivalent to tolvaptan 15-mg tablet, and also 
indicated that OPC-61815 caused no significant safety concern in the dose range from 2 


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to 16 mg in patients with CHF. Based on the results of the phase 2 trial, a phase 3 trial 
(Trial 263-102-00003) was initiated to confirm the non-inferiority of OPC-61815 to 
tolvaptan 15-mg tablet using an OPC-61815 16-mg injection formulation that had been 
shown to be equivalent to tolvaptan 15-mg tablet and the trial is currently ongoing. In the 
phase 3 confirmatory trial (Trial 263-102-00003), tolvaptan is used as a comparator so 
patients who have difficulty with or are incapable of oral intake are excluded.
In patients with CHF who have difficulty with or are incapable of oral intake, and are 
thereby unable to control fluid balance by oral rehydration, there is a concern that the 
adverse drug reactions associated with the aquaretic effect of OPC-61815 including 
hypernatremia and dehydration may occur at a higher incidence compared with patients 
who are capable of oral fluid intake. Therefore, a clinical trial to evaluate the tolerability 
of OPC-61815 in patients with heart failure who have difficulty with or are incapable of 
oral intake should be conducted separately from the phase 3 confirmatory trial.
In view of the above, the present trial is considered to be appropriate to confirm the 
tolerability of repeated intravenous administration of OPC-61815 in patients with CHF 
who have difficulty with or are incapable of oral intake.
2.1.1
Rationale for the Uncontrolled and Open-label Design
Since this trial enrolls patients who have difficulty with or are incapable of oral intake, 
the use of tolvaptan tablet as a comparator is impossible. In addition, the trial population 
comprises patients who are judged to have an inadequate response to treatment with 
conventional diuretics other than vasopressin antagonists (standard treatment); therefore, 
setting a placebo or standard treatment group as a control group is considerably 
disadvantageous to the subjects and ethically inappropriate since the delay in care may 
lead to a poor diagnosis in subjects assigned to standard treatment group. The primary 
objective of this trial is to confirm the tolerability of OPC-61815 in patients with heart 
failure who have difficulty with or are incapable of oral intake, which is determined to be 
an objective that can be attained by an open-label design involving no comparator group.
2.2
Rationale for the Dosage Regimen
OPC-61815 is being developed for an intended approval for the same indication as that of 
tolvaptan, “the treatment of volume overload in heart failure when adequate response is 
not obtained with other diuretics (eg, loop diuretics),” and a phase 3 trial to confirm the 
non-inferiority to tolvaptan 15-mg tablet (Trial 263-102-00003) is ongoing. The only 
difference between the patient populations enrolled in the above phase 3 confirmatory 
trial (Trial 263-102-00003) and the present trial is whether or not patients who have 


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difficulty with or are incapable of oral intake are included. Therefore, the dosage regimen 
in this trial is set based on that used in the phase 3 confirmatory trial (Trial 263-102-
00003).
2.2.1
Selection of Dosage Regimen for the Phase 3 Confirmatory Trial 
(Trial 263-102-00003)
A phase 2 clinical pharmacology trial (Trial 263-102-00001) was conducted to determine 
the dose of OPC-61815 injection achieving the tolvaptan (aka, OPC-41061) exposure 
equivalent to that for tolvaptan 15-mg tablet after intravenous administration of OPC-
61815 in patients with CHF.
Table 2.2.1-1 shows the tolvaptan exposure (Cmax and AUC24h) on Day 1, the primary 
endpoint of the phase 2 trial (Trial 263-102-00001). Table 2.2.1-2 shows the mean 
differences, as well as their 95% CIs, in log-transformed tolvaptan exposure (Cmax and 
AUC24h) on Day 1 between intravenous administration of OPC-61815 and oral 
administration of Tolvaptan 15 mg.
Following 1-hour intravenous administration of OPC-61815 at 2, 4, 8, or 16 mg once 
daily, the exposure of tolvaptan at 16 mg of OPC-61815 was closest and similar to that 
observed after oral administration of tolvaptan tablet at 15 mg. The incidences of AEs
were 53.8% (7 of 13 subjects) in the OPC-61815 2-mg group, 58.3% (7 of 12 subjects) in 
the OPC-61815 4-mg group, 33.3% (4 of 12 subjects) in the OPC-61815 8-mg group, 
72.7% (8 of 11 subjects) in the OPC-61815 16-mg group, and 83.3% (10 of 12 subjects) 
in the tolvaptan 15-mg tablet group. All events were reported only in 1 or 2 subjects. No 
deaths occurred in the trial. Two occurrences of SAEs were reported in 1 subject in the 
OPC-61815 4-mg group. There were no reports of the AESI, which occurred at a higher 
frequency with bolus (1- or 5-minute) infusion of OPC-61815 and were considered to be 
related to IMP in the phase 1 trials in healthy adult subjects.
Based on these results, 16 mg once daily administered as a 1-hour infusion are selected as 
the dosage regimen of OPC-61815 for the ongoing phase 3 trial (Trial 263-102-00003) to 
confirm the non-inferiority of OPC-61815 to tolvaptan tablet.


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Table 2.2.1-1
Tolvaptan Exposures (Cmax and AUC24h) on Day 1 After 
Intravenous Administration of OPC-61815 and After Oral 
Administration of Tolvaptan 15 mg (Mean ± SD)
Route of 
administration
Intravenous
Oral
Dose
OPC-61815
2 mg
OPC-61815
4 mg
OPC-61815
8 mg
OPC-61815
16 mg
Tolvaptan
15 mg
n
11
12
12
11
12
Cmax (ng/mL)
41.4 ± 11.4
98.6 ± 43.7
149 ± 61.7
282 ± 96.0
325 ± 194
AUC24h (ng∙h/mL)
356 ± 157
983 ± 563
1340 ± 522
2400 ± 1030
2850 ± 1580
Trial 263-102-00001
Table 2.2.1-2
Mean Differences and 95% Confidence Intervals in Log-
transformed Tolvaptan Exposure (Cmax and AUC24h) on 
Day 1 Between Intravenous Administration of OPC-61815 
and Oral Administration of Tolvaptan 15 mg
Dose
OPC-61815
2 mg
OPC-61815
4 mg
OPC-61815
8 mg
OPC-61815
16 mg
n
11
12
12
11
Cmax
(ng/mL)
−1.940
(−2.281, −1.598)
−1.114
(−1.447, −0.780)
−0.691
(−1.025, −0.357)
−0.050
(−0.392, 0.291)
AUC24h
(ng∙h/mL)
−2.003
(−2.408, −1.597)
−1.035
(−1.432, −0.639)
−0.664
(−1.060, −0.267)
−0.125
(−0.530, 0.281)
Trial 263-102-00001
Using transformed-values, the differences in tolvaptan exposure between each OPC-61815 injection 
group and the tolvaptan 15-mg tablet group were calculated by an analysis of variance with dose as a 
factor.
2.2.2
Rationale for the Dosage Regimen in This Trial
1) Dose Selection
The target population of this trial is patients with heart failure who have difficulty 
with or are incapable of oral intake, and are thereby unable to control fluid balance by 
oral fluid intake. Based on the risk of AEs associated with the aquaretic effect of 
OPC-61815 is expected to be increased in such subjects, OPC-61815 treatment is to 
be started with a low dose and the dose is to be increased to 16 mg (the dose used in 
the phase 3 confirmatory trial [Trial 263-102-00003]) after confirming the insufficient 
efficacy and allowable safety of the low dose according to prespecified dose 
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The starting dose is selected with reference to the Precautions for Dosage and 
Administration I-(4) of the package insert for Samsca Tablets: “When tolvaptan is 
administered to a patient in whom a rapid reduction in circulating plasma volume is 
not preferable, tolvaptan therapy may be started with 7.5 mg (half the usual dose).”
The pharmacodynamic effects of OPC-61815 are considered to vary depending on 
exposure to tolvaptan, which is the active ingredient of OPC-61815. Accordingly, in 
view of the pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) 
characteristics of tolvaptan observed in previous clinical trials of tolvaptan or 
OPC-61815, the appropriateness of the starting dose selected for this trial was 
examined as described below.
The dose-proportionality of tolvaptan exposure following intravenous administration 
of OPC-61815 observed in the phase 2 clinical pharmacology trial (Trial
263-102-00001) was analyzed and the results indicated the dose-proportionality of 
tolvaptan exposure at 2, 4, 8, and 16 mg.
A population pharmacokinetic (PPK) analysis (Trial 156-08-003) using data from 4
trials of tolvaptan in patients with CHF (Trials 156-03-001, 156-06-002, 156-06-004, 
and 156-06-006) indicated that a linear model fitted well for the tolvaptan 
pharmacokinetic profile data, indicating the dose-proportionality of tolvaptan 
exposure following the oral administration of tolvaptan.
As described above, tolvaptan exposure has been shown to be dose-proportional both 
after the oral administration of tolvaptan and the intravenous administration of 
OPC-61815. Therefore, the tolvaptan exposure after the intravenous administration of 
OPC-61815 at 8 mg (half the dose [16 mg]) was expected to be similar to that 
observed after the oral administration of tolvaptan at 7.5 mg (half the usual dose
[15 mg]).
In a PPK/PD analysis conducted on the plasma tolvaptan concentration and daily 
urine volume data from 3 trials of tolvaptan in patients with CHF (Trials 156-03-001, 
156-06-002, and 156-06-004), the relationship between tolvaptan AUC24h (estimated 
using posthoc parameter obtained from the PPK analysis) and daily urine volume was 
assessed. The assessment results showed that an Emax model fitted well for the 
relationship between tolvaptan AUC24h and daily urine volume, indicating that daily 
urine volume varied depending on tolvaptan AUC24h. The same model was used to 
estimate daily urine volume and its change from baseline based on the tolvaptan 
AUC24h observed after the intravenous administration of OPC-61815 at 16 mg and 


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8 mg in the phase 2 clinical pharmacology trial (Trial 263-102-00001). The estimated 
urine volume and its change from baseline decreased along with a decrease in 
tolvaptan AUC24h with a dose decrease from 16 mg to 8 mg.
Based on the above, an OPC-61815 starting dose of 8 mg, which is half the dose 
(16 mg) used in the phase 3 confirmatory trial (Trial 263-102-00003), is expected to 
produce a tolvaptan exposure similar to that observed after the oral administration of 
tolvaptan 7.5 mg. In addition, daily urine volume and its change from baseline at 
8 mg are expected to be lower than those at 16 mg. Thus, setting the starting dose of 
OPC-61815 at 8 mg is considered to be appropriate from the viewpoint of ensuring 
subject safety in this trial for patients with heart failure who have difficulty with or 
are incapable of oral intake, and are thereby unable to attain a fluid balance by oral 
fluid intake.
2) Dosage Regimen Selection
OPC-61815 is to be administered according to the same dosage regimen as that used 
in the phase 3 confirmatory trial (ie, dosing as a 1-hour infusion once daily). (See 
Section 2.2.1.)
2.3
Trial Objective
To confirm the tolerability of intravenous administration of OPC-61815 at 8 or 16 mg 
once daily for a maximum of 5 days to CHF patients with volume overload despite 
having received diuretics (injection) other than vasopressin antagonists and who have 
difficulty with or are incapable of oral intake.
3
Trial Design
3.1
Type/Design of Trial
This trial is a multi-center, uncontrolled, open-label trial to confirm the tolerability of 
intravenous administration of OPC-61815 at 8 or 16 mg once daily for a maximum of 5 
days to CHF patients with volume overload despite having received diuretics (injection) 
other than vasopressin antagonists and who have difficulty with or are incapable of oral 
intake. An overview of the trial design is presented in Figure 3.1-1.
Subjects who meet all of the inclusion criteria and fall under none of the exclusion 
criteria at the screening examination will be advanced to the treatment period during 
which OPC-61815 will be intravenously administered at 8 or 16 mg once daily. 
OPC-61815 treatment will start at 8 mg, and the investigator or subinvestigator will 


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increase the dose to 16 mg on Day 2 or 3 after confirming that the subject meets the dose 
escalation criteria. The procedures for dose escalation decision are shown in 
Section 3.2.2. The maximum treatment duration is 5 days; however, IMP treatment may 
be discontinued before Day 5 according to the rules specified in Section 3.2.3. 
Concomitant use of loop diuretics will continue until the end of the treatment period.
The completion assessment will be conducted on Day 6 (or the day after the final IMP 
administration) and the follow-up assessment will be conducted at some time between 7 
and 10 days after the final IMP administration. Subjects will be hospitalized from the 
time of informed consent to Day 6 (or the day after the final IMP administration).
Figure 3.1-1
Trial Design Schematic
a If IMP treatment is discontinued before Day 5, the same assessment as the completion assessment 
scheduled for Day 6 should be conducted on the day after the final IMP administration, followed by 
the follow-up assessment at any time between 7 and 10 days after the final IMP administration.
3.2
Trial Treatments
3.2.1
Dosage Regimen
The investigator or subinvestigator will administer OPC-61815 once daily as 1-hour 
infusion (55 to 70 minutes allowable) according to the IMP administration procedures
specified separately. OPC-61815 treatment will start with 8 mg, and eligibility for dose 
escalation will be assessed on Day 2 of the treatment period (and again on Day 3 of the 
treatment period, if applicable) according to Section 3.2.2. If the dose escalation criteria 
Screening 
period
Treatment period 
(up to 6 days)
Follow-up 
period
Informed consent 
(start of the trial)
Completion assessmenta
(the day after the final IMP 
administration)
Post-treatment follow-upa 
(end of the trial)
8 or 16 mg
OPC-61815 
administration
Continued treatment with injectable loop diuretics
Hospitalization (up to 7 days from the time of informed 
consent to the day after the final IMP administration)
(7 to 10 days after 
the final IMP 
administration)
Inpatient or 
outpatient setting
−1
Informed consent and 
screening examination
may be performed on 
Day 1.


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are met, the dose will be increased to 16 mg; if the criteria are not met, administration 
will continue at 8 mg.
When AEs associated with the aquaretic effect of OPC-61815 including hypernatremia, 
dehydration, and thirst occur or worsen after the dose is increased to 16 mg and dose 
reduction is judged to be necessary by the investigator or subinvestigator, the dose will be 
returned to 8 mg. The dose may not be re-escalated to 16 mg once it has been reduced to 
8 mg. The start time of administration on Day 2 and onward should coincide roughly 
(±1 hour, whenever possible) with the start time on Day 1.
A flowchart of the dose escalation decision is presented in Figure 3.2.1-1.
Figure 3.2.1-1
Flowchart of the Dose Escalation Decision
aWhen only No. 2 of the Day 2 dose escalation criteria is not met
bWhen any of No. 1, 3, or 4 of the Day 2 dose escalation criteria are not met
cWhen AEs associated with the aquaretic effect of OPC-61815 including hypernatremia, dehydration, 
and thirst occur or worsen, and dose reduction is judged to be necessary by the investigator or 
subinvestigator
The following information will be recorded in the source document and the electronic 
case report form (eCRF).

Times and dates at which OPC-61815 intravenous administration is started and ended 
(and suspension period, if the administration is suspended)

Dose
8 mg
Dose 
escalation 
decision
8 mg
8 mg
8 mg
8 mg
16 mg
16 mg
Dose 
escalation 
decision
16 mg
16 mg
Dose may 
be reduced
Dose may 
be reduced
Dose may 
be reduced


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
If eligibility for dose escalation is assessed, the result (date of assessment, and 
whether or not each criterion is met)

If the dose is reduced, the AE(s) leading to dose reduction
3.2.2
Dose Escalation Decision
1) Predose on Day 2
When all (No. 1 to No. 4) of the Day 2 dose escalation criteria (Table 3.2.2-1) are 
met, the dose will be increased to 16 mg.
When any of the following criteria are not met, the dose for Day 2 and onward will 
remain at 8 mg, and dose escalation assessment will not be repeated at predose on 
Day 3.

No. 1 of the Day 2 dose escalation criteria

No. 3 of the Day 2 dose escalation criteria

No. 4 of the Day 2 dose escalation criteria
Table 3.2.2-1
Day 2 Dose Escalation Criteria
1
An adequate response is absent (when either of the following is met).
1)
When the increase in daily urine volume from baseline (the daily urine volume through 
immediately predose on Day 1) is ≤500 mL:
Any congestive symptom (lower limb edema, hepatomegaly, jugular venous distension, 
cardiothoracic ratio, pulmonary rales, or cardiac third sound) is present.
2)
When the increase in daily urine volume from baseline (the daily urine volume through 
immediately predose on Day 1) is >500 mL or cannot definitely be concluded to be ≤500 mL:
Body weight did not decrease as compared with predose on Day 1 with no improvement in 
congestive symptoms.
2
The serum sodium concentration at predose on Day 2 is ≤147 mEq/L.a
3
An increase of >10 mEq/L in serum sodium concentration is not evident within 24 hours after start 
of IMP administration on Day 1.a
4
No safety concerns have arisen since the start of IMP administration on Day 1 at the discretion of 
the investigator or subinvestigator.
aIf serum sodium concentration measurement is difficult to perform at the trial site, plasma sodium 
concentrations will be used for the assessment.
2) Predose on Day 3
When only No. 2 of the Day 2 dose escalation criteria was not met, eligibility for dose 
escalation will be reassessed on Day 3 according to the Day 3 dose escalation criteria 
(Table 3.2.2-2).


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When all (No. 1 to No. 4) of the Day 3 dose escalation criteria are met, the dose will 
be increased to 16 mg. When any of the Day 3 dose escalation criteria are not met, the 
dose for Day 3 onward will remain at 8 mg.
Table 3.2.2-2
Day 3 Dose Escalation Criteria
1
An adequate response is absent.
1) Body weight did not decrease as compared with predose on Day 2 with no improvement in 
congestive symptoms.
2
The serum sodium concentration at predose on Day 3 is ≤147 mEq/L.a
3
An increase of >10 mEq/L in serum sodium concentration is not evident within 24 hours after the 
start of IMP administration on Day 2.a
4
No safety concerns have arisen since the start of IMP administration on Day 2 at the discretion of 
the investigator or subinvestigator.
aIf serum sodium concentration measurement is difficult to perform at the trial site, plasma sodium 
concentrations will be used for the assessment.
[Rationale for the Day 2 dose escalation criteria]
1.
The results from the OPC-61815 8-mg group, the OPC-61815 16-mg group, and 
the tolvaptan 15-mg group of the phase 2 clinical pharmacology trial (Trial 263-
102-00001) showed that the mean changes in body weight from baseline to the 
day after the final IMP administration of 5-day treatment were −2.0 kg and 
−1.1 kg, respectively, in subjects with a >500 mL change in daily urine volume 
from baseline to Day 2 (from the start of administration on Day 1 to predose on 
Day 2) and in those with a ≤500 mL change. This finding suggested that the 
decrease in body weight (the primary efficacy endpoint in the present trial) might 
be smaller in subjects in whom the change in daily urine volume from baseline to 
Day 2 was as small as ≤500 mL.
However, in some of the subjects with a >500 mL increase in daily urine volume 
from baseline to Day 2, body weight did not decrease from the previous day with 
no improvement in congestive symptoms, suggesting an insufficient improvement 
of volume overload; therefore, this criterion is set to enroll such subjects as well.
2.
This criterion is set because the upper limit of reference range of serum sodium 
concentration is 147 mEq/L.
3.
In the treatment of hyponatremia, there is a concern regarding the increased risk of 
osmotic demyelination syndrome due to a rapid increase in serum sodium 
concentration, and an alert has been indicating that the increase in serum sodium 
concentration should be ≤10 mEq/L per 24 hours; therefore, this criterion is set.


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4.
This criterion is based on safety considerations.
[Rationale for the Day 3 dose escalation criteria]
1.
No decrease in body weight combined with no improvement in congestive 
symptoms as compared with the previous day is considered to indicate an 
insufficient improvement in volume overload; therefore, this criterion is set.
2 to 4. Same as the Day 2 dose escalation criteria
3.2.3
Treatment Duration
The maximum duration of treatment will be 5 days; however, IMP treatment may be 
ended at a treatment period of shorter than 5 days at the discretion of the investigator or 
subinvestigator, if either of the following criteria is met:

All congestive symptoms are resolved and no further improvement in volume 
overload is necessary.

The subject becomes capable of fluid management by oral intake alone.
[Rationale for the treatment duration]
The maximum treatment duration in this trial is 5 days, which is the same as that in the 
phase 3 confirmatory trial (Trial 263-102-00003).
If all congestive symptoms disappear and further improvement in volume overload is 
judged unnecessary by the investigator or subinvestigator, IMP treatment will be ended
because no additional diuretic treatment is required. In addition, if fluid control by oral 
intake alone is attained during the treatment period, IMP treatment will be ended because 
the subject is judged to have recovered from difficulty in or incapability of oral intake.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The trial population will comprise a total of 40 Japanese male and female CHF patients 
aged 20 to 85, inclusive, with volume overload despite having received injection diuretics 
other than vasopressin antagonists and who have difficulty with or are incapable of oral 
intake and who are capable of being hospitalized from the time of informed consent until
the end of the treatment period.


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3.3.2
Subject Selection and Numbering
All subjects will be given a unique subject identifier (ID; site number [3 digits] + subject 
number [‘S’ + 5 digits]) upon providing consent. The site number will be designated by 
the sponsor. The subject number will be given in the order of informed consent from 
S00001 as the serial numbers in the trial sites. The trial site will prepare a list connecting 
all subjects consenting to participation in the trial and their subject identifiers, and retain 
the list.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects. The informed consent form 
(ICF) will be approved by the same institutional review board (IRB) that approves this 
protocol.
Each written information and ICF will comply with the ICH (International Conference on 
Harmonisation) Good Clinical Practice (GCP) Guideline8 and local regulatory 
requirements.
Investigators or subinvestigators may discuss trial availability and the possibility for 
entry with a potential subject without first obtaining consent. However, informed consent 
must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from 
current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once the appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator or subinvestigator, the IRB-approved 
written ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or subinvestigator), as well as by the trial coordinator, if he/she provides 
supplemental explanation. If the subject is able to consent but unable to sign the ICF for 
physical or therapeutic reasons, a witness should be present with the subject during the 
course of informed consent. To prove that the subject has been fully informed and has 
expressed his/her voluntary consent, the witness must sign and date the ICF, and write the 
name of the subject, the reason(s) that the subject is not able to personally sign the ICF, 
and the relationship between the subject and the witness in the margin of the ICF, while 
the signature section of the ICF should be left blank. The witness should be a person who 


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is independent of the trial and who cannot be unfairly influenced by persons involved 
with the trial. The subject will receive a copy of the written information and the signed
ICF; the original shall be kept on file by the investigator or subinvestigator.
Subjects, as well as their witnesses (if applicable), 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 a knowledgeable and 
voluntary decision on trial participation.
Deoxyribonucleic acid (DNA) storage is optional. Subjects who do not consent to DNA 
storage may participate in the trial.
Subjects must agree to restrictions to concomitant medications as described in 
Section 4.1.
Subjects who have consented to participation in the trial, but who does not receive IMP
are permitted to be re-screened once. In the event that the screening examination is 
repeated, a new ICF signed by the subject must be obtained and a new subject identifier 
will be assigned to the subject (see Section 3.9).
3.4.2
Inclusion Criteria
Subjects must meet all of the inclusion criteria in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1
Patients receiving loop diuretic injection at a dose equivalent to furosemide 20 mg/day or higher
2
CHF patients in whom lower limb edema, pulmonary congestion, and/or jugular venous distension 
due to volume overload is present
3
Male or female patients age 20 to 85, inclusive, at time of informed consent
4
Patients who are judged by the investigator or subinvestigator to have difficulty or be incapable of 
oral intake, including patients who are judged by the investigator or subinvestigator to require 
nothing by mouth (NPO) management
5
Patients who are currently hospitalized or who are capable of being hospitalized from the time of 
informed consent until the end of the treatment period
6
Patients who are capable of giving informed consent
[Rationale for the inclusion criteria]
1
This criterion is set to enroll patients who have volume overload despite having 
received diuretics other than vasopressin antagonists.
2
Volume overload may be manifested by lower limb edema, pulmonary congestion, 
jugular venous distension, hepatomegaly, and cardiac third sound. Among these 
manifestations, lower limb edema, pulmonary congestion, and jugular venous 
distension are selected for the inclusion criterion, because these symptoms are 


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hardly affected by other factors and were reported by many subjects in a phase 3
trial of tolvaptan (Trial 156-06-002) and a phase 2 trial (Trial 263-102-00001) of 
OPC-61815 in patients with CHF.
3
Subjects at lower limit of age 20 years are legal adults in Japan and therefore 
capable of being responsible for their consent. The upper age limit is set at 85 
years because many patients with CHF are elderly and also based on safety 
considerations.
4
This criterion is set to evaluate the safety of OPC-61815 in patients who have 
difficulty with or are incapable of oral intake.
5
This criterion is set to appropriately evaluate the safety of the IMP.
6
The criterion is set to ensure the ethically appropriate implementation of the trial.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1
Patients who are on a ventricular assist device
2
Patients who have any of the following diseases, complications, or conditions:
• Suspected hypovolemia
• Hypertrophic cardiomyopathy (excluding dilated phase)
• Valvular disease with significant valvular stenosis
• Hepatic encephalopathy with difficulty in adequate fluid intake
3
Patients who have experienced acute myocardial infarction within 30 days prior to the screening 
examination
4
Patients with a definite diagnosis of active myocarditis or amyloid cardiomyopathy
5
Patients who have any of the following medical histories:
• History of sustained ventricular tachycardia or ventricular fibrillation within 30 days prior to the 
screening examination (for patients without an implantable cardioverter defibrillator)
• History of cerebrovascular disease (excluding asymptomatic cerebral infarction) within 
6 months prior to the screening examination
• History of hypersensitivity or idiosyncratic reaction to benzazepines or benzazepine derivatives 
such as the ingredients of OPC-61815, tolvaptan, mozavaptan hydrochloride, and benazepril 
hydrochloride
6
Patients who have any of the following diseases, complications, or conditions:
• Poorly controlled diabetes mellitus
• Anuria
• Dysuria associated with urinary tract obstruction, calculus, or tumor
7
Patients with supine systolic blood pressure of <90 mmHg
8
Patients with any of the following abnormalities in laboratory test results:
• Total bilirubin: >3.0 mg/dL
• Serum or plasma creatinine: >3.0 mg/dL
• Serum or plasma sodium concentration: <125 mEq/L


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Table 3.4.3-1
Exclusion Criteria
• Serum or plasma sodium concentration: >147 mEq/L
• Serum or plasma potassium concentration: >5.5 mEq/L
9
Patients with current symptoms or a history of hepatic impairment (including patients with 
aspartate aminotransferase [AST] or alanine aminotransferase [ALT] exceeding 3 times the upper 
limit of the reference range at the screening examination)
10
Patients who have undergone open-heart surgery (eg, open-heart surgery for valvular disease, 
coronary bypass surgery, or surgery in thoracic aorta) within 30 days prior to the screening 
examination
11
Patients who have difficulty with spontaneous respiration or who have been on tracheal intubation 
under sedative therapy
12
Patients with severe disturbed consciousness (ie, coma or stupor)
13
Women who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP
14
Sexually active men or women of childbearing potential (WOCBP) who do not agree to practice 
birth control or remain abstinent during the trial and for 30 days after the final IMP administrationa
15
Patients who are otherwise judged to be ineligible by the investigator or subinvestigator
aNonchildbearing potential is defined as male and female subjects who are surgically sterile (ie, male 
subjects who have undergone bilateral orchidectomy and female subjects who have undergone 
bilateral oophorectomy and/or hysterectomy) and female subjects who have been postmenopausal for 
at least 12 consecutive months.
[Rationale for the exclusion criteria]
1
This criterion is set because the use of a ventricular assist device may affect 
the safety evaluation of the IMP and with a view toward subject safety.
2
Excessive diuretic treatment may adversely affect these symptoms.
3 to 9
These criteria are based on safety considerations.
10
This criterion is set because the safety, efficacy, and pharmacodynamics of 
the IMP could not be appropriately evaluated in such patients.
11, 12
These criteria are based on safety considerations.
13 to 15
These criteria are based on general safety and ethical considerations.


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3.5
Endpoints
3.5.1
Safety Endpoints
Adverse events, clinical laboratory tests, physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), and 12-lead electrocardiogram (ECG)
[Rationale for the safety endpoints]
Adverse events, clinical laboratory tests, physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), and 12-lead ECG are commonly used as 
endpoints of general safety.
3.5.2
Pharmacodynamic Endpoints
Urine volume, fluid intake, fluid balance, serum sodium concentration, serum potassium 
concentration, serum osmolality, urine sodium excretion, urine potassium excretion, urine 
osmolality, and biomarkers (plasma concentrations of AVP and brain natriuretic peptide
[BNP], plasma renin activity, and serum concentrations of N-terminal pro BNP [NT-
proBNP] and troponin I)
[Rationale for the pharmacodynamic endpoints]
Urine volume, urine osmolality, urine sodium excretion, urine potassium excretion, 
serum osmolality, serum sodium concentration, and serum potassium concentration are
selected as endpoints to evaluate the aquaretic effect of OPC-61815. Fluid intake and 
fluid balance are selected to evaluate the impact of aquaresis by OPC-61815 on fluid 
balance. Tolvaptan, which is the active ingredient of OPC-61815, is an AVP 
V2-receptor antagonist; therefore, plasma AVP concentration is selected to evaluate the 
effects on plasma AVP concentration. Plasma renin activity is selected to evaluate the 
impact of aquaresis by OPC-61815 on the renin-angiotensin system. The plasma 
concentrations of BNP, serum concentrations of NT-proBNP and troponin I are 
selected to evaluate the impact of the aquaretic effect of OPC-61815 on cardiac 
function.


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3.5.3
Efficacy Endpoints

Body weight

Congestive symptoms
Lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, cardiac 
third sound, cardiothoracic ratio, and pulmonary congestion

Dyspnea
Respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and subject-assessed dyspnea

New York Heart Association (NYHA) classification
[Rationale for the efficacy endpoints]
Body weight is selected as a measure that objectively reflects the general state of 
volume overload. Congestive symptoms and dyspnea are selected as symptoms or 
findings that reflect the volume overload state in patients with CHF. NYHA 
classification is selected as a measure that assesses subjective physical activity in 
patients with CHF.
3.6
Measures to Minimize/Avoid Bias
This trial is an uncontrolled trial.
3.7
Trial Procedures
Trial assessment time points are summarized in Table 3.7-1.
Serum sodium and potassium concentrations during the treatment period will be 
measured at both the central laboratory (central measurement) and the trial site (local 
measurement). If serum sodium and potassium concentration measurement is difficult to 
perform at the trial site, plasma sodium and potassium concentrations may be measured. 
Either serum or plasma should be used consistently for measurement of sodium and 
potassium concentrations in a given subject. However, serum sodium and potassium 
concentrations will be measured at the central laboratory. Clinical laboratory tests will be 
conducted at each trial site for the screening examination, and at the central laboratory
from Day 1 onward.


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Table 3.7-1
Schedule of Assessments
Day
Item
Screening
Treatment Period
Follow-up
Day −1 to 
Predose of 
Day 1 
1
2
3
4
5
Day 6/
At Withdrawal 
(Day After Final 
IMP 
Administration)
Day 12 to 15
/7 to 10 Days 
After Final 
IMP 
Administration
Informed consent
♦
Informed consent for DNA 
storage
○
Subject background
♦
Inclusion/exclusion criteria
♦
●
Confirmation of concomitant 
medication/therapy
Subject registration
♦
Hospitalization
IMP administration
X
X
X
X
X
Administration of diuretic agents
X
X
X
X
X
X
Dose escalationa
●
●
Confirmation of IMP compliance
♦
♦
♦
♦
♦
Cumulative urine volumeb
Urine volume, fluid intakeb
Urine sodium and potassium 
concentrations, urine osmolalityc
Serum sodiumd and potassium 
concentrationsd
♦
●e■
●■f
●■f
●
●
♦
♦
Serum osmolality
●■
●■f
●■f
●
●
♦
Body weight
♦
●e
●
●
●
●
♦
♦
Dyspneag
♦
♦
♦
♦
♦
♦
♦


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Table 3.7-1
Schedule of Assessments
Day
Item
Screening
Treatment Period
Follow-up
Day −1 to 
Predose of 
Day 1 
1
2
3
4
5
Day 6/
At Withdrawal 
(Day After Final 
IMP 
Administration)
Day 12 to 15
/7 to 10 Days 
After Final 
IMP 
Administration
Congestive symptomsh
♦
♦
♦
♦
♦
♦
♦
♦
Chest x-ray (cardiothoracic ratio, 
pulmonary congestion)i
♦
●
♦
Adverse events
Laboratory tests
♦j
●
♦
♦
Physical examination
♦
♦
♦
♦
♦
♦
♦
♦
Vital signs (blood pressure, pulse 
rate, body temperature)
♦
●e■
●■f
●■f
●
●
♦
♦
12-Lead ECGk
●■
♦
♦
NYHA classification
♦
♦
Biomarkersl
●
♦
Urine pregnancy test (WOCBP 
only)
♦
♦
Blood sampling for DNA 
storagem
○
Adjustment of infusion solutionn
X = Time of drug administration should not be markedly different on each day; ● = Before start of IMP administration; ■ = For measurements on Day 1 and 
the day of dose escalation assessment, see the corresponding time points after start of IMP administration as specified in Section 3.7.1.2 and 
Section 3.7.1.5; ♦ = At a feasible time (on Day 1, at a feasible time after start of IMP administration); ○ = Optional (subjects at sites with a DNA storage 
agreement who have given informed consent for DNA storage prior to start of the trial)
aDose escalation assessment: Required on Day 2, performed on Day 3 if applicable
bMeasurements of cumulative urine volume, urine volume, and fluid intake (with oral intake and intake via transfusions, nasogastric feeding tubes, and 
gastronomy tubes): Time intervals for measurement of cumulative urine volume (Table 3.7.5.1.1-1) and urine volume (Table 3.7.5.1.1-2) are set on Day 1 


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and the day of dose escalation. Cumulative urine volume and urine volume will be measured for each time interval as specified in Section 3.7.1.2 and 
Section 3.7.1.5. From Days 2 onwards, except the day of dose escalation, cumulative urine will be collected for 24 hours from the time of complete 
urination at predose and daily urine volume and fluid intake will be measured for that time interval.
cUrine sodium and potassium concentrations, and urine osmolality: Urine samples collected at each cumulative urine collection time interval as shown in 
Table 3.7.5.1.1-1 will be centrally measured by the contract research organization for clinical laboratory tests (central laboratory).
dSerum sodium and potassium concentrations: Measured both at the central laboratory and at the trial site for appropriate fluid management. If serum sodium 
and potassium concentration measurement is difficult to perform at the trial site, plasma sodium and potassium concentrations may be measured. Either 
serum or plasma samples should be used consistently for measurement of sodium and potassium concentrations in a given subject. However, serum sodium 
and potassium concentrations will be measured in the central laboratory. (At screening, serum or plasma sodium and potassium concentrations will be 
measured only at the trial site.)
eSerum sodium concentration (local measurement), serum potassium concentration (local measurement), body weight, chest x-ray, and vital signs (blood 
pressure, pulse rate, and body temperature): If measurements are performed on Day 1 as part of the screening examination, the measurements do not have 
to be repeated at predose on Day 1.
fPerformed on the day that the dose is increased to 16 mg.
gDyspnea: Respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and subject-assessed dyspnea (assessment of presence or absence of symptoms by 
subjects at screening)
hCongestive symptom findings: Lower limb edema, hepatomegaly, jugular venous distension, pulmonary rales, and cardiac third sound
iChest x-ray: Chest x-ray does not have to be repeated if it has been performed within 24 hours before informed consent. The results of chest x-ray performed 
prior to the acquisition of informed consent can be used to determine eligibility of the subject to participate in the trial.
jLaboratory tests: At screening, laboratory tests are performed at the trial site.
k If the serum potassium is confirmed to exceed 5.5 mEq/L at the trial site or the central laboratory at any time point in the period with no specified 12-lead 
ECG, a 12-lead ECG will be performed as an unscheduled examination.
lPlasma concentrations of AVP and BNP, plasma renin activity, and serum concentrations of NT-proBNP and troponin I
mDNA storage: In principle, blood sampling for DNA storage will be performed at predose on the day of initial IMP administration (Day 1). Informed consent 
for DNA storage must be obtained by the blood sampling for DNA storage. If blood sampling is not performed at that time or needs to be repeated, blood 
sampling will be performed at a feasible time during the trial period.
nThe infusion solution will be checked and adjusted according to the specifications for each day (see Section 3.7.1.2 to Section 3.7.1.6).


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3.7.1
Schedule of Assessments
3.7.1.1
Screening Period (Day −1 to Predose on Day 1)
3.7.1.1.1
Screening Examination
Between Day −1 and predose on Day 1, the investigator or subinvestigator will obtain 
consent from the subject, and then conduct the following examinations and tests to assess 
the eligibility of the subject for participation in the trial.
[Examinations and tests]

Subject background
(Birth date, sex, height, country, race, ethnicity, underlying disease, type of heart 
failure, presence and type of arrhythmias, presence of a pacemaker, presence of an 
implantable cardioverter defibrillator, complications, medical history, and reason(s) 
why oral intake is considered to be difficult or impossible)

Serum sodium concentration (local measurement)

Serum potassium concentration (local measurement)

Body weight

Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and subject-
assessed dyspnea [assessment of the presence of the symptoms by the subject])

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous distension, 
pulmonary rales, and cardiac third sound)

Chest x-ray (cardiothoracic ratio and pulmonary congestion)
Chest x-ray does not have to be repeated if it has been performed within 24 hours 
before informed consent. The results of chest x-ray performed prior to the acquisition 
of informed consent can be used to determine the eligibility of the subject to 
participate in the trial.

Clinical laboratory tests (local measurement)

Physical examination

Vital signs (blood pressure, pulse rate, and body temperature)

NYHA classification

Concomitant medications and therapies

Urine pregnancy test (WOCBP only)
Date of informed consent, subject identifier, the result of eligibility assessment, and 
subject characteristics will be recorded in the eCRF. Subjects must be hospitalized from 
the time of informed consent through the completion (withdrawal) assessment.


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3.7.1.1.2
Urine Collection, and Measurement of Urine Volume and Fluid 
Intake
1) Urine Collection
Subject are required to urinate completely at 24 hours before start of IMP 
administration on Day 1 and urine collection will be started to measure the daily urine 
volume through immediately predose on Day 1.
2) Urine Volume and Fluid Intake
At the same interval as the urine collection, urine volume and fluid intake (with oral 
intake and intake via transfusions, nasogastric feeding tubes, and gastronomy tubes) 
will be determined.
If the time interval between informed consent to the start of IMP administration is 
<24 hours, subject are required to urinate completely at a feasible time after informed 
consent, at which time urine collection will start and continue until immediately 
before start of IMP administration on Day 1. Urine volume and fluid intake will be 
determined as follows:
Urine volume and fluid intake for the 24 hours immediately before start of IMP 
administration on Day 1 during which the subject is receiving injectable loop 
diuretics will be determined. The measurement period (the dates and times that 
measurement started and ended), urine volume, and fluid intake will be identified 
based on the medical record or other records before informed consent (after loop 
diuretic therapy started).
3.7.1.2
Treatment Period (Day 1)
1) Predose

Urine sodium concentration (central measurement)

Urine osmolality (central measurement)

Urine potassium concentration (central measurement)

Serum sodium concentration (local measurement, central measurement)

Serum potassium concentration (local measurement, central measurement)

Serum osmolality (central measurement)

Biomarkers (central measurement)

Body weight

Chest x-ray (cardiothoracic ratio and pulmonary congestion)

Clinical laboratory tests (central measurement)

Vital signs (blood pressure, pulse rate, and body temperature)


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
12-Lead ECG

Blood sampling for DNA storage (central measurement)
If serum sodium concentration (local measurement), serum potassium concentration 
(local measurement), body weight, chest x-ray, and vital signs (blood pressure, pulse 
rate, and body temperature) are measured as the screening examination on Day 1, the 
measurements will not need to be repeated at predose on the same day.
2) Start of urine collection
Subject are required to urinate completely immediately before start of IMP 
administration to collect urinate at the time intervals shown in Table 3.7.1.2-1. At the 
end of each interval, subject are required to urinate completely to start urine 
collection for the next interval.
Table 3.7.1.2-1
Urine Collection Intervals After Start of IMP administration 
on Day 1
Urine collection interval
Allowable time window for the interval end 
0 to 4 hours after start of IMP administration
+1 hour
4 to 8 hours after start of IMP administration
+4 hours
8 hours after start of IMP administration to 
immediately before IMP administration on the 
next day
3) IMP administration
The investigator or subinvestigator will confirm that the subject meets all of the 
inclusion criteria and falls under none of the exclusion criteria, and administer the 
IMP to the subject.
4) Administration of diuretic agents
5) Examinations and tests after start of IMP administration
The examinations and tests shown in Table 3.7.1.2-2 will be conducted at each time
point.


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Table 3.7.1.2-2
Examinations/Tests and Timing After Start of IMP 
Administration on Day 1
Item
Timing
Allowable time window
Urine volume and fluid intake
0 to 1 hour after start of IMP 
administration
+15 minutesa
1 to 2 hours after start of IMP 
administration
+30 minutesa
2 to 4 hours after start of IMP 
administration
+1 houra
4 to 6 hours after start of IMP 
administration
+1 houra
6 to 8 hours after start of IMP 
administration
+4 hoursa
8 hours after start of IMP administration 
to immediately before start of IMP 
administration on the next day
Urine sampling for the 
measurement of urine sodium 
concentration, urine potassium 
concentration, and urine 
osmolality
At the end of each urine collection 
interval shown in Table 3.7.1.2-1
12-Lead ECG
1 hour after start of IMP administration
+1 hour
Vital signs (blood pressure, 
pulse rate, and body 
temperature)
1 hour after start of IMP administration
+1 hour
4 hours after start of IMP administration
+1 hour
8 hours after start of IMP administration
+4 hours
Serum osmolality, serum 
sodium concentration, and 
serum potassium concentration 
(Serum sodium and potassium 
concentrations will be measured 
also at the trial site.)
4 hours after start of IMP administration
+1 hour
8 hours after start of IMP administration
+4 hours
aAllowable time window for the end of each interval
6) At a feasible time after start of IMP administration

Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and 
subject-assessed dyspnea)

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Physical examination

Adverse Events

Concomitant medications and therapies

Confirmation of IMP compliance
7) Adjustment of infusion solution
Infusion solution will be checked and adjusted at least 3 times to correct electrolyte 
abnormalities based on the blood pressure, pulse rate, body weight, serum sodium 


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concentration, serum potassium concentration, urine volume, fluid intake, and other 
parameters measured before, and at 4 and 8 hours after start of IMP administration.
3.7.1.3
Treatment Period (Day 2)
1) Predose

Urine sodium concentration (central measurement)

Urine osmolality (central measurement)

Urine potassium concentration (central measurement)

Serum sodium concentration (local measurement, central measurement)

Serum potassium concentration (local measurement, central measurement)

Serum osmolality (central measurement)

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)
2) Start of urine collection
Subject are required to urinate completely immediately before start of IMP 
administration and urine collection will start.
3) Dose escalation decision
Eligibility for dose escalation will be assessed as described in Section 3.2.2.
4) IMP administration
5) Administration of diuretic agents
6) 4 and 8 hours after the start of IMP administration (only when the dose is 
increased on Day 2)
In addition to the examinations and tests scheduled for Day 2, the procedures shown 
in Section 3.7.1.5 will be conducted.
7) At a feasible time on Day 2

Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and 
subject-assessed dyspnea)

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Physical examination

Adverse Events

Concomitant medications and therapies

Confirmation of IMP compliance
8) Adjustment of infusion solution
Infusion solution will be checked and adjusted at least once to correct electrolyte 
abnormalities based on the blood pressure, pulse rate, body weight, serum sodium 


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concentration, serum potassium concentration, urine volume, fluid intake, and other 
parameters measured before start of IMP administration.
3.7.1.4
Treatment Period (Day 3)
1) Predose

Urine sodium concentration (central measurement)

Urine osmolality (central measurement)

Urine potassium concentration (central measurement)

Serum sodium concentration (local measurement, central measurement)

Serum potassium concentration (local measurement, central measurement)

Serum osmolality (central measurement)

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)
2) Start of urine collection
Subject are required to urinate completely immediately before start of IMP 
administration and urine collection will start.
3) Dose escalation decision (see Figure 3.2.1-1 only when required)
If applicable, eligibility for dose escalation will be reassessed as described in 
Section 3.2.2.
4) IMP administration
5) Administration of diuretic agents
6) 4 and 8 hours after the start of IMP administration (only when the dose is 
increased on Day 3)
In addition to the examinations and tests scheduled for Day 3, the procedures shown 
in Section 3.7.1.5 will be conducted.
7) At a feasible time on Day 3

Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and 
subject-assessed dyspnea)

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Physical examination

12-Lead ECG

Adverse Events

Concomitant medications and therapies

Confirmation of IMP compliance


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8) Adjustment of infusion solution
Infusion solution will be checked and adjusted at least once to correct electrolyte 
abnormalities based on the blood pressure, pulse rate, body weight, serum sodium 
concentration, serum potassium concentration, urine volume, fluid intake, and other 
parameters measured before start of IMP administration.
3.7.1.5
Dose Escalation Day (Day 2 or Day 3)
On the day on which the dose is increased (the first day OPC-61815 is administered at 
16 mg), the following examinations and tests will be conducted.
1) Urine Collection
Urine will be collected at the intervals shown in Table 3.7.1.5-1. At the end of each 
interval, subject are required to urinate completely to start urine collection for the
next interval.
Table 3.7.1.5-1
Urine Collection Intervals on the Dose Escalation Day
Urine collection interval
Allowable time window for the interval end
0 to 4 hours after start of IMP administration
+1 hour
4 to 8 hours after start of IMP administration
+4 hours
8 hours after start of IMP administration to 
immediately before IMP administration on the next day
2) Examinations and tests after start of IMP administration
In addition to the procedures scheduled for each day, the examinations and tests 
shown in Table 3.7.1.5-2 will be conducted at each time point.


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Table 3.7.1.5-2
Examinations/Tests and Timing on the Dose Escalation Day
Item
Timing
Allowable time window
Urine volume and fluid intake
0 to 4 hours after start of IMP 
administration
+1 houra
4 to 8 hours after start of IMP 
administration
+4 hoursa
8 hours after start of IMP 
administration to immediately before 
start of IMP administration on the 
next day
Urine sampling for the 
measurement of urine sodium 
concentration, urine potassium 
concentration, and urine osmolality
At the end of each urine collection 
interval shown in Table 3.7.1.5-1
Vital signs (blood pressure, pulse 
rate, and body temperature)
4 hours after start of IMP 
administration
+1 hour
8 hours after start of IMP 
administration
+4 hours
Serum osmolality, serum sodium 
concentration, and serum potassium 
concentration (Serum sodium and 
potassium concentrations will also 
be measured at the trial site.)
4 hours after start of IMP 
administration
+1 hour
8 hours after start of IMP 
administration
+4 hours
aAllowable time window for the end of each interval
3) Adjustment of infusion solution
The following procedure will be added to the procedures scheduled for each day.
Infusion solution will be checked or adjusted at least twice after start of IMP 
administration to correct electrolyte abnormalities based on the blood pressure, pulse 
rate, body weight, serum sodium concentration, serum potassium concentration, urine 
volume, fluid intake, and other parameters measured at 4 and 8 hours after start of 
IMP administration.
3.7.1.6
Treatment Period (Days 4 and 5)
1) Predose

Urine sodium concentration (central measurement)

Urine osmolality (central measurement)

Urine potassium concentration (central measurement)

Serum sodium concentration (local measurement, central measurement)

Serum potassium concentration (local measurement, central measurement)

Serum osmolality (central measurement)

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)


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2) Start of urine collection
Subject are required to urinate completely immediately before start of IMP 
administration and urine collection will start.
3) IMP administration
4) Administration of diuretic agents
5) At a feasible time on each day

Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and 
subject-assessed dyspnea)

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Physical examination

Adverse Events

Concomitant medications and therapies

Confirmation of IMP compliance
6) Adjustment of infusion solution
Infusion solution will be checked and adjusted at least once to correct electrolyte 
abnormalities based on the blood pressure, pulse rate, body weight, serum sodium 
concentration, serum potassium concentration, urine volume, fluid intake, and other 
parameters measured before start of IMP administration.
3.7.1.7
Treatment Period (Completion Assessment on Day 6 or 
Withdrawal Assessment)
The investigator or subinvestigator will conduct the completion assessment at a feasible 
time on Day 6 as described below. If IMP administration is discontinued before Day 5, 
the same assessment as the completion assessment on Day 6 will be conducted as the 
withdrawal assessment on the day after the final IMP administration, whenever possible.
1) At the end of urine collection

Urine sodium concentration (central measurement)

Urine osmolality (central measurement)

Urine potassium concentration (central measurement)
2) At a feasible time

Serum sodium concentration (local measurement, central measurement)

Serum potassium concentration (local measurement, central measurement)

Serum osmolality (central measurement)

Biomarkers (central measurement)

Body weight


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
Dyspnea (respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and 
subject-assessed dyspnea)

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Chest x-ray (cardiothoracic ratio and pulmonary congestion)

Clinical laboratory tests (central measurement)

Physical examination

Vital signs (blood pressure, pulse rate, and body temperature)

12-Lead ECG

NYHA classification

Adverse Events

Concomitant medications and therapies
3.7.1.8
Follow-up After End of the Treatment Period (7 to 10 Days After 
the Final IMP Administration)
The investigator or subinvestigator will conduct the following examinations and tests 
within 7 to 10 days after the final IMP administration. If the subject has already been 
discharged from the trial site, the follow-up may be conducted on an outpatient basis.

Serum sodium concentration (central measurement)

Serum potassium concentration (central measurement)

Body weight

Congestive symptoms (lower limb edema, hepatomegaly, jugular venous 
distension, pulmonary rales, and cardiac third sound)

Clinical laboratory tests (central measurement)

Physical examination

Vital signs (blood pressure, pulse rate, and body temperature)

Adverse Events

Urine pregnancy test (WOCBP only)

Concomitant medications and therapies
3.7.2
Safety Assessments
3.7.2.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.


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3.7.2.2
Clinical Laboratory Assessments
Venous blood and urine samples for clinical laboratory tests (Table 3.7.2.2-1) will be 
collected at the prespecified time points, and the date and time of blood sampling and 
urine collection will be recorded in the source document.
At the screening examination, clinical laboratory tests will be conducted at the trial site 
according to the procedures specified by the site. The status (collected/not collected), the 
dates and times of blood sampling and urine collection, and the results of measurements 
will be recorded in the eCRF.
From Day 1 onward, the samples will be shipped to the central laboratory. The central 
laboratory will measure the prespecified laboratory parameters according to the 
procedures specified by the laboratory and provide the results of the measurements to the 
sponsor and the investigator or subinvestigator. The status (collected/not collected), the 
date and time of blood sampling and urine collection will be recorded in the eCRF. The 
electronic file submitted to the sponsor by the central laboratory will be regarded as the 
source document; therefore, entry of the results in the eCRF will be unnecessary.
Serum sodium and potassium concentrations will also be measured at the trial site for 
appropriate fluid management during the screening and treatment periods. The status 
(measured/not measured), the date and time of blood sampling, and the result of 
measurement of the serum sodium concentrations and potassium concentrations during 
the screening period will be recorded in the source document and the eCRF, and those of 
the serum potassium concentrations during the treatment period will be recorded in the 
source document. If serum sodium and potassium concentration measurement is difficult 
to perform at the trial site, plasma sodium and potassium concentration may be measured. 
Either serum or plasma should be used consistently for measurement of sodium and 
potassium concentrations in a given subject. However, serum sodium and potassium
concentrations will be measured at the central laboratory. If the serum potassium is 
confirmed to exceed 5.5 mEq/L at the trial site or the central laboratory at any time point 
in the period with no specified 12-lead ECG, a 12-lead ECG will be performed in 
reference to Section 3.7.2.4.


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Table 3.7.2.2-1
Clinical Laboratory Assessments
Hematology
Red Blood Cell count
Hemoglobin
Hematocrit
White Blood Cell count with differential
(neutrophils, eosinophils, basophils, monocytes, 
and lymphocytes)
Platelet count
Serum Chemistry
Total protein
Albumin
Total bilirubin
AST
ALT
Alkaline phosphatase 
γ-Glutamyl transpeptidase
Lactate dehydrogenase
Creatine kinase (creatine phosphokinase)
Glucose
Total cholesterol
Triglycerides
Blood urea nitrogen
Creatinine
Uric acid
Serum or plasma electrolytes (sodium [Na], 
potassium [K], chloride [Cl], calcium [Ca])
Urinalysis (qualitative)
pH
Protein
Glucose
Occult blood
Ketone bodies
Bilirubin
Urobilinogen
Additional tests
Pregnancy test for WOCBP (hCG test)a
hCG = human chorionic gonadotropin
aA urine pregnancy test will be conducted at screening and follow-up. If the urine pregnancy test is 
positive, a serum test will be conducted at the central laboratory as described in Section 5.5.
If the subject is a WOCBP, a pregnancy test should be performed at screening 
examination and the result must be obtained before initial IMP administration. A 
diagnostic test kit provided by the sponsor will be used for the urine human chorionic 
gonadotropin (hCG) test. If the test result is unclear, the urine hCG test will be repeated. 
The investigator or subinvestigator will confirm the test result and record the status, the 
date, and the result (positive or negative) of the test in the source document and the 
eCRF.
3.7.2.3
Physical Examination and Vital Signs
1) Physical examination
The investigator or subinvestigator will check the physical conditions of the subject 
by interview and other methods at the prespecified time points. The physical 
examination includes the observation of the head, ears, eyes, nose and pharynx, chest, 
abdomen, genitourinary tract, extremities, nerves, and skin/mucosae. At the screening 
examination, the date and the results of assessment will be recorded in the source 
document and the eCRF. At subsequent assessments, only the date of assessment will 
be recorded in the source document and the eCRF. A clinically important physical 
finding that is absent at the screening examination but observed at any postdose
assessment will be recorded as an AE.


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2) Vital signs (blood pressure, pulse rate, and body temperature)
At the prespecified time points, axillary temperature will be measured after the 
subject is kept rested according to the procedures specified by the trial site. The 
measurement result of body temperature to the first decimal place will be recorded. 
The result will be rounded to the first decimal place even if the measurement value is 
shown in the second decimal place or more. Blood pressure (systolic and diastolic) 
and pulse rate will be measured after the subject is kept supine for at least 3 minutes. 
The date and time, and the results of measurements will be recorded in the source 
document and the eCRF.
3.7.2.4
Electrocardiogram Assessments
At the prespecified time points, a rest 12-lead ECG will be recorded using the ECG 
monitor provided by the central ECG measurement facility and according to the 
procedure specified by the facility. However, if the serum potassium is confirmed to 
exceed 5.5 mEq/L at the trial site or the central laboratory at any time point in the period 
with no specified 12-lead ECG, a 12-lead ECG will be performed as an unscheduled
examination. The investigator or subinvestigator will interpret each ECG chart as normal 
or abnormal, and record the status (measured/ not measured), the date of recording, as 
well as the interpretation (normal or abnormal [details, if abnormal]) in the source 
document and the eCRF.
The ECG record will be sent to the central ECG measurement facility to measure the 
heart rate, RR interval, PR interval, QRS axis, QT interval, and QTc (QT corrected for 
heart rate) interval (QTcB, QTcF). The central ECG measurement facility will in turn 
send the 12-lead ECG analysis report to the investigator or subinvestigator.
The investigator or subinvestigator will reconfirm the interpretation of the 12-lead ECG 
referring to the analysis report, which will then be signed and retained.
The electronic file of the 12-lead ECG analysis report provided to the sponsor by the 
central ECG measurement facility will be used as the source document; therefore, entry 
of the heart rate, RR interval, PR interval, QRS axis, QT interval, and QTc interval 
(QTcB, QTcF) in the eCRF will be unnecessary.


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3.7.3
Efficacy Assessments
3.7.3.1
Body Weight
The investigator or subinvestigator will instruct the subject to urinate at least once after 
waking up, minimizing the influences of defecation and clothing, and then measure the 
body weight before breakfast using a scale appropriately maintained. The date and time 
of measurement, and the measured body weight (in kg, to the first decimal place) will be 
recorded in the source document and the eCRF. The result will be rounded to the first
decimal place even if the measurement value is shown in the second decimal place or 
more.
3.7.3.2
Congestive Symptoms (Lower Limb Edema, Jugular Venous 
Distension, Hepatomegaly, Pulmonary Rales, and Cardiac Third 
Sound)
The investigator or subinvestigator will examine congestive symptoms including lower 
limb edema, jugular venous distension, hepatomegaly, pulmonary rales, and cardiac third 
sound, and assess the presence and severity of each symptom as described below. The 
date and the result of assessment will be recorded in the source document and the eCRF.
1) Lower limb edema
The tibial border or dorsum pedis, in principle, will be examined for the presence of 
edema with the subject seated or placed supine, and the severity of edema will be 
assessed according to the criteria shown in Table 3.7.3.2-1. The body position used 
during the examination of lower limb edema must not be changed throughout the trial 
period.
Table 3.7.3.2-1
Criteria for Assessment of Lower Limb Edema
Severity
Assessment criteria
0
Absent
No pitting is detectable.
1
Mild
Slight pitting is detected.
2
Moderate
Pitting is present.
3
Severe
Easily visible edema is present.
2) Jugular venous distension
The presence of jugular venous distension will be checked, and if present, the height 
(in cm) from the sternal angle to the highest point of pulsation in the internal jugular 
vein will be measured with the subject in a semi-upright position. The measurement 
result to the first decimal place will be recorded.


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3) Hepatomegaly
The presence of a palpable liver will be checked and, if present, the width (distance 
from the right costal arch of the right chest, in cm) will be measured. The 
measurement result to the first decimal place will be recorded.
4) Pulmonary rales
The presence of pulmonary rales will be checked by auscultation.
5) Cardiac third sound
The presence of cardiac third sound will be checked by auscultation.
3.7.3.3
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion)
The investigator or subinvestigator will take a chest x-ray, and record the date of the 
examination in the source document and the eCRF. The cardiothoracic ratio and 
pulmonary congestion will be assessed as described below.
1) Cardiothoracic ratio
The investigator or subinvestigator will measure the cardiothoracic ratio and record 
the result in the source document and the eCRF. The result will be expressed to 1
decimal place rounded from 2 decimals, whenever possible.
2) Pulmonary congestion
The investigator or subinvestigator will assess the severity of pulmonary congestion 
according to the criteria shown in Table 3.7.3.3-1, and record the result of the 
assessment in the source document and the eCRF.
Table 3.7.3.3-1
Criteria for Assessment of Pulmonary Congestion
Severity
Assessment criteria
0
Absent
No congestion
1
Mild
Pulmonary venous congestion
2
Moderate
Interstitial pulmonary edema
3
Severe
Alveolar pulmonary edema
Adapted from Forrester JS, et al.9
3.7.3.4
Dyspnea
1) Respiratory rate
The respiratory rate per minute will be measured with the subject seated or placed 
supine, and the status (measured/not measured) the date, and the result of 
measurement will be recorded in the source document and the eCRF. The body 
position while respiratory rate is measured must not be changed throughout the trial 
period.


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2) Paroxysmal nocturnal dyspnea
The presence of paroxysmal nocturnal dyspnea (a sensation of shortness of breath that 
occurs during sleep and awakens the subject) will be checked by interview.
3) Orthopnea
The presence of orthopnea will be checked by interview.
4) Subject-assessed dyspnea
During the screening period, the subject will personally check for the presence of 
dyspnea symptoms. From Day 1 onward, the subject will assess the current dyspnea 
symptoms as compared with his/her own assessment in the screening period using the 
7-level Likert scale shown below. If no dyspnea symptoms are present in the 
screening period, one of the following categories will be chosen on Day 1 onward: 
“markedly deteriorated,” “moderately deteriorated,” “mildly deteriorated,” or 
“unchanged.”

Markedly deteriorated

Moderately deteriorated

Mildly deteriorated

Unchanged

Mildly improved

Moderately improved

Markedly improved
The investigator or subinvestigator will ask the following question: “How severe is 
your current respiratory status as compared with the respiratory discomfort you 
sensed immediately before the start of the initial IMP administration?”
The status (assessed/not assessed), date of assessment, presence of dyspnea symptoms 
(paroxysmal nocturnal dyspnea and orthopnea), and result of subject-assessed 
dyspnea will be recorded in the source document and the eCRF.
3.7.3.5
NYHA Classification
The investigator or subinvestigator will assess the NYHA classification2 and record the 
date and result of the assessment in the source document and the eCRF.


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Table 3.7.3.5-1
NYHA Classification
Functional capacity
Class I
Patients with cardiac disease, but without resulting in a limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
Class II
Patients with cardiac disease resulting in a mild or moderate limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in a marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
Class IV
Patients with cardiac disease resulting in an inability to carry on any physical activity. 
Symptoms of heart failure or anginal syndrome may be present, even at rest. If any 
physical activity is undertaken, discomfort is increased.
3.7.4
Prior and Concomitant Medications
The investigator or subinvestigator will record all concomitant medications and therapies 
taken by the subject from the time of informed consent through the post-treatment 
follow-up assessment in the eCRF. The investigator or subinvestigator will also record all 
medications and therapies taken by the subject for treatment of an AE or which caused an 
AE, until the end of the trial (defined as the last schedule visit/contact or final contact 
attempt with the last subject) on the eCRF.
For concomitant medications, the following information will be recorded in the eCRF: 
medication, indication, dose, frequency, route, start date, and end date. For concomitant 
therapies, the following information will be recorded in the eCRF: therapy, indication, 
start date, and end date.
3.7.5
Pharmacodynamic and Pharmacogenomic Assessments
3.7.5.1
Pharmacodynamic Assessment
3.7.5.1.1
Urine Volume
In this trial, urine collection intervals and urine volume measurement intervals will be 
defined separately.
1) Urine collection interval
Urine collection intervals are shown in Table 3.7.5.1.1-1. At the end of each urine 
collection interval, subjects are required to urinate completely.


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Table 3.7.5.1.1-1
Urine Collection Intervals
Time point
Start of the interval
End of the interval
Allowable time 
window for the 
interval end
Day −1
23 to 25 hours before 
start of IMP 
administration on Day 1
Point in time at which 
urination immediately 
before start of IMP 
administration is 
completed
Day 1 and the dose 
escalation day
Point in time at which 
urination immediately 
before start of IMP 
administration is 
completed
4 hours after start of 
IMP administration
+1 hour
4 hours after start of 
IMP administration
8 hours after start of 
IMP administration
+4 hours
8 hours after start of 
IMP administration
Immediately before IMP 
administration on the 
next daya
Day 2 and onward
(except for the dose 
escalation day)
Point in time at which 
urination immediately 
before start of IMP 
administration is 
completed
Immediately before IMP 
administration on the 
next daya
aOr 24 hours (allowable time window, ±1 hour) after the complete urination immediately before start of 
the final IMP administration, if not applicable
2) Urine volume measurement intervals
Urine volume will be measured at the intervals shown in Table 3.7.5.1.1-2, and the 
status (measured/not measured), the dates and times the measurement started and 
ended, and the result of measurement will be recorded in the source document and the 
eCRF.


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Table 3.7.5.1.1-2
Urine Volume Measurement Intervals
Time point
Measurement interval
Allowable time 
window for the 
interval end
Day −1
Same as the urine collection interval (daily urine volume)
Day 1
Point in time at which urination immediately before IMP 
administration is completed to 1 hour after start of IMP 
administration
+15 minutes
1 to 2 hours after start of IMP administration
+30 minutes
2 to 4 hours after start of IMP administrationa
+1 hour
4 to 6 hours after start of IMP administration
+1 hour
6 to 8 hours after start of IMP administrationa
+4 hours
8 hours after start of IMP administration to immediately 
before IMP administration on the next daya
Dose escalation day
Point in time at which urination immediately before IMP 
administration is completed to 4 hour after start of IMP 
administrationa
+1 hour
4 to 8 hours after start of IMP administrationa
4 hours
8 hours after start of IMP administration to immediately 
before IMP administration on the next daya
Day 2 and onward
(except the dose 
escalation day)
Same as the urine collection interval (daily urine volume)
aUrine volume will be measured after urination at the end of the urine collection period is completed.
If the exact urine volume cannot be measured because part of the urine is discarded or for 
other reasons, the urine volume for that interval will be handled as missing data. If a 
diaper or an incontinence pad is used by necessity, urine volume may be estimated by 
comparing the weight of the diaper or incontinence pad before and after use (converting 1
gram to 1 milliliter).
The daily urine volume on Day 1 or the dose escalation day will be the sum of the urine 
volumes for all the measurement intervals on that day (the daily urine volume will be 
calculated by the sponsor; therefore, entry in the eCRF will be unnecessary).
3.7.5.1.2
Fluid Intake
At the same interval as urine volume measurement, fluid intake (with oral intake and 
intake via transfusions, nasogastric feeding tubes, and gastronomy tubes) will be 
measured, and the status (measured/not measured), the dates and times the measurement 
started and ended, and the result of measurement will be recorded in the source document 
and the eCRF.


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The daily fluid intake on Day 1 or the dose escalation day will be the sum of the fluid 
intakes for all the measurement intervals on that day (the daily fluid intake will be 
calculated by the sponsor; therefore, entry in the eCRF will be unnecessary).
3.7.5.1.3
Fluid Balance
A fluid balance will be calculated by subtracting the “urine volume” from the “fluid 
intake.” Fluid balances will be calculated by the sponsor; therefore, entry in the eCRF 
will be unnecessary.
3.7.5.1.4
Serum Sodium Concentration, Serum Potassium 
Concentration, Serum Osmolality, and Biomarkers (Plasma 
AVP Concentration, Plasma Renin Activity, Plasma BNP 
Concentration, Serum NT-proBNP Concentration, and Serum 
Troponin I Concentration)
At the specified time points, venous blood will be collected for the following 
examinations and tests, and the date and time of blood sampling will be recorded in the 
source document and the eCRF.

Serum sodium concentration

Serum potassium concentration

Serum osmolality

Biomarkers (plasma AVP concentration, plasma renin activity, plasma BNP 
concentration, serum NT-proBNP concentration, and serum troponin I concentration)
For the procedures for sample collection, processing, and storage, see Appendix 1.
All the samples will be shipped to the central laboratory. The central laboratory will 
centrally measure the laboratory parameters according to the procedures specified by the 
laboratory and report the results of the measurements to the sponsor and the investigator 
or subinvestigator. An electronic file containing the measurement results will be provided 
to the sponsor from the central laboratory; therefore, entry in the eCRF will be 
unnecessary.
In addition to the serum sodium and potassium measurement at central laboratory, serum 
sodium and potassium concentrations will also be measured at the trial site for 
appropriate fluid management during the screening and treatment periods and the results
of the local measurements will be recorded in the source document. The result of the 
serum sodium concentration measurement will also be recorded in the eCRF. If serum 
sodium and potassium concentration measurement is difficult to perform at the trial site, 
plasma sodium and potassium concentrations may be measured. Either serum or plasma 


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samples should be used consistently for measurement of sodium and potassium
concentrations in a given subject. However, serum sodium and potassium concentrations
will be measured in the central laboratory.
Serum sodium and potassium concentrations for pharmacodynamic assessment will be 
replaced by the data obtained as part of the clinical laboratory tests performed at the same 
blood sampling point as specified in Section 3.7.2.2.
3.7.5.1.5
Urine Sodium Excretion, Urine Potassium Excretion, and 
Urine Osmolality
1) Measurements at the central laboratory
From the urine collected for each interval shown in Table 3.7.5.1.1-1, a sample will 
be taken. For the procedures for sample collection, processing, and storage, see 
Appendix 1.
All the samples will be shipped to the central laboratory. The central laboratory will 
centrally measure the laboratory parameters according to the procedures specified by 
the laboratory and report the results of the measurements to the sponsor and the 
investigator or subinvestigator. The original document for the measurement results is 
an electronic file provided to the sponsor from the central laboratory; therefore, entry
of the measurement results in the eCRF will be unnecessary.
If urine collection for measuring daily urine volume cannot be made because part of 
the urine is discarded or for other reasons, no sample will be shipped to the central 
laboratory. The urine sodium concentration, urine potassium concentration, and urine 
osmolality on that day will be handled as missing data.
2) Urine sodium excretion and urine potassium excretion
Urine sodium excretion and urine potassium excretion will be calculated by 
multiplying the urine sodium concentration and the urine potassium concentration 
obtained at the central laboratory, respectively, by the urine volume.
Urine sodium and potassium excretions will be calculated by the sponsor; therefore, 
entry in the eCRF will be unnecessary.


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3.7.5.2
Pharmacogenomic Assessment
3.7.5.2.1
DNA Storage
1) Rationale for DNA Storage
In this trial, DNA samples will be stored on a voluntary basis. DNA storage will be 
conducted on subjects who provide written consent, only at trial sites that provide 
prior agreement regarding DNA storage.
In Q&A 1 in the “Clinical Trials using Pharmacogenomics” (PFSB/ELD Notification 
No. 0930007 of the Evaluation and Licensing Division, Pharmaceutical and Food 
Safety Bureau, Ministry of Health, Labour and Welfare [MHLW] dated 30 Sep 
2008)10, the MHLW states that DNA samples for possible genomic/genetic analysis 
to evaluate the IMP (PK, efficacy, safety, etc.) may be collected from subjects during 
the clinical trial in either of the following cases: 1) the target and timing of the 
potential genomic/genetic analysis has been specifically identified at the time of the 
trial, or 2) although the target or timing of the potential genomic/genetic analysis has 
not been specifically identified at the time of the trial, but it is planned to conduct 
analysis for the evaluation of the IMP in future. The MHLW also states in Q&A 2 in 
the same notification, that samples for possible genomic/genetic analysis with a 
purpose independent of the evaluation of the IMP may be collected from subjects 
during the trial. Furthermore, Section 1.4 General Principles of The International 
Council for Harmonization (ICH) E18 Guidelines, “Genomic Sampling and 
Management of Genomic Data” states that, “With advances in science and increased 
awareness of the impact of genomics, there is a need and an opportunity to maximize 
the value of collected samples and the data generated therefrom. Therefore, genomic 
sample acquisition is strongly recommended in all phases and studies of clinical 
development.”11
In this trial, the collection of DNA samples is planned to coincide with other trial 
examinations and tests to minimize the burden on the subjects. Thus, the voluntary 
collection and storage of DNA samples in this trial is appropriate.
2) Purposes
Samples for DNA analysis will be collected from the subjects to enable a future 
exploratory investigation regarding DNA variants relating to individual differences in 
responsiveness (eg, efficacy, safety, PK) to the IMP, and/or the disease-associated 
DNA variants.


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3) Target subject group
DNA storage will be conducted at trial sites at which the IRB provides prior approval 
for blood sampling for DNA storage. A blood sample for DNA storage will be 
collected only from subjects who provide voluntary consent to DNA storage.
4) Timing of blood sampling
A blood sample for DNA storage will be collected at predose on Day 1. If a blood 
sample cannot be collected at predose on Day 1 or re-collection is required for any 
reason, blood sampling may be repeated at a feasible time during the trial period. The 
date and time of blood sampling will be recorded in the source document and the 
eCRF.
5) Sample for DNA storage
For the detailed procedures for sample collection, handling, and shipment, see 
Appendix 1. The DNA samples will be stored until 1) possible genomic/genetic 
analysis is determined to be unnecessary, 2) 15 years has passed since informed 
consent has been obtained from the first subject, or 3) the subject withdraws consent 
to DNA storage, whichever comes first.
3.7.5.2.2
Potential Genomic/Genetic Analysis
Genomic/genetic analysis will be conducted if analysis is determined to be useful for the 
purposes described in Section 3.7.5.2.1 2).
When it is determined to conduct genomic/genetic analysis, a pharmacogenomics
protocol will be prepared and approved by the research review committee at the sponsor, 
and the analysis will be then conducted according to applicable regulations. The results of 
the genomic/genetic analysis will not be included in the final study report, but 
documented separately as a research report.
The target of potential genomic/genetic analysis has not yet been identified. Genome-
wide association analysis using DNA chips, DNA microarrays, or next-generation DNA 
sequencers may be conducted, however, the results of the analysis will not be used for 
purposes other than those described in Section 3.7.5.2.1 2).
DNA samples for possible genomic/genetic analysis will be double coded by the DNA 
repository and shipped to the genomic/genetic analysis laboratory (not yet designated), at 
which the genomic/genetic analysis will be conducted using the double-coded samples.
1) Informed consent for participation in DNA storage and its withdrawal
Written information regarding DNA storage and possible genomic/genetic analysis 
using DNA samples will be prepared separately from written information for the trial, 


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and informed consent for participation in DNA storage will be obtained from the 
subject. The date of the informed consent obtained from the subject will be recorded 
in the source document and the eCRF. Consent from subjects who are able to consent, 
but unable to sign the ICF for physical or therapeutic reasons will be obtained in a 
manner similar to that described in Section 3.4.1.
If a subject withdraws the consent for DNA storage during the storage period, the 
sponsor will request the biorepository to discard the sample of the subject, and the 
biorepository will discard the samples in such a way that the subject cannot be 
identified. If individual samples cannot be identified because information connecting 
samples and subjects identifiers (eg, code list) is destroyed or for other reasons, the 
sample of a subject who withdraws consent may not be consequently discarded.
Withdrawal from participation in the trial will not result in withdrawal from 
participation in DNA storage. If the results of a potential genomic/genetic analysis 
have been obtained at the time of consent withdrawal, the results will not be 
discarded.
2) Disclosure of the results of genomic/genetic analysis to subjects
Even if some information is obtained from the genomic/genetic analysis, the analysis 
results will be only exploratory and at an early stage of research, and their scientific 
reliability such as precision or certainty will not have been adequately demonstrated. 
Disclosure of information without established scientific reliability will not be 
beneficial to subjects. Therefore, the sponsor will not disclose the results of 
genomic/genetic analysis to subjects, in principle.
3.7.6
End of Trial
The end of trial date is defined as the last date of visit/contact or the date of final contact 
attempt from the post-treatment follow-up eCRF page for the last subject completing or 
withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial
If the sponsor terminates 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.


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3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB 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 will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator or 
subinvestigator. However, each investigator or subinvestigator must comprehensively 
review the circumstances and offer the subject options for continued treatment to the 
degree possible as described in Section 3.8.3.4.
A subject who initiates treatment and then discontinues the treatment will be encouraged 
to undergo all of the examinations and tests specified for the withdrawal assessment. The 
withdrawal assessment will be conducted according to Section 3.7.1.7.
3.8.3.2
Documenting Reasons for Treatment Discontinuation
A subject may discontinue participation in the trial at any time, and the investigator or 
subinvestigator may discontinue a subject’s participation in the trial if medically 
necessary. Subjects who fall under any of the following must be withdrawn from the trial. 
If a subject discontinues treatment, a single reason for the discontinuation (the main 
reason) will be recorded in the eCRF.
1) Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard

AST or ALT value is ≥3 times the upper limit of normal (ULN).

Serum or plasma sodium concentration measured at the trial site or the central 
laboratory increases by ≥12 mEq/L from immediately predose within 24 hours 
after start of the IMP administration.

The serum or plasma sodium concentration measured at the trial site or the 
central laboratory is ≥155 mEq/L during the treatment period.

The onset of drug-induced hypersensitivity is suspected.


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
Any severe AESI (feeling abnormal, feeling hot, erythema, hyperhidrosis, 
pruritus, rash, urticaria, nausea, epigastric discomfort, or dyspnea) occurs.

Continuing IMP places the subject at undue risk as determined by the 
investigator or subinvestigator (eg, a safety concern that is possibly, probably, 
or likely related to IMP).

Serious adverse event

Other potentially IMP-related safety concerns or AEs
2) Withdrawal of informed consent by the subject (when it is confirmed to be 
unrelated to AEs)
3) Protocol deviations (other than poor compliance with the IMP administration
rules)

Deviations related to the inclusion or exclusion criteria

Deviations related to prohibited concomitant medications
4) Judgment by the investigator or subinvestigator (for the reasons other than an AE)
5) Death
6) Lost to follow-up
7) Pregnancy (see Section 5.5)
8) Technical problems (eg, malfunctions of medical devices)
9) Premature termination of the entire or part of the trial by the sponsor
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 until the subject is lost to follow-up or has died.
3.8.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 
medically necessary. Unless the subject provides their written withdrawal of consent or 
there is other written documentation by the investigator or subinvestigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether at trial 
site, by telephone, or by an in-home visit).


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
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, or social media sources).
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.1). A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule. Therefore, the investigator or 
subinvestigator should follow the procedures outlined in Section 3.8.3.4 to determine if 
the subject can continue participation in the trial if modifications to his/her treatment 
and/or schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above degrees of follow-up are considered to have completely 
withdrawn their consent to participate in the trial.
3.8.3.4
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be given instructions to meet and discuss with the subject their 
options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons for the 
subject’s desire to withdraw consent.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained, but who does 
not receive the IMP.


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Subjects who have consented to participation in the trial but did not receive the IMP are 
permitted to be re-screened once. In the event that the screening examination is repeated, 
a new ICF signed by the subjects must be obtained and a new subject identifier will be 
assigned to the subject.
If the subject meets the definition of a screen failure, the following information will be 
recorded in the eCRF:

Subject identifier

Date of informed consent

Visit date (on which the screening examination is conducted)

Date of demographic data collection

Sex

Birth date

Race

Ethnicity

Country

Whether the subject meets all of the inclusion criteria (the criterion number(s) the 
subject does not meet, if any)

Whether the subject falls under any of the exclusion criteria (the criterion number(s) 
the subject falls under, if any)

Screen failure date

Reason(s) for screen failure
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
the primary and/or secondary objectives of the trial irrespective of whether or not the 
subject was administered all doses of the IMP. For purposes of this trial, subjects who 
undergo the completion assessment on Day 6 (or the day after the final IMP 
administration) will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the completion assessment on Day 6 of 
the treatment period (or the day after the final IMP administration), who do not have a 
known reason for discontinuation (eg, withdrew consent or AE), and for whom a survival 
status at the end of the trial cannot be determined will be classified as “lost to follow-up.” 
Survival status can be determined from a variety of sources, either by obtaining 


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acceptable documentation for death (ie, death certificate, medical records, public records, 
statement by a family member or primary care physician) or acceptable documentation 
for life (ie, direct contact with the subject, medical records, successful telephone contact 
with the subject, statement by a family member or primary care physician, or public 
records).
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event they are unable to reach the subject by 
telephone, they will attempt to contact the subject via certified mail or an alternative 
similar method, where appropriate, before assigning a “lost to follow-up” status. If the 
subject is classified as “lost to follow-up,” the status (contacted/not contacted), date of 
contact, and attempted contact method will be recorded in the eCRF.
3.12
Subject Compliance
Subjects will remain under the control of the investigator or subinvestigator throughout 
the trial period. The investigator or subinvestigator will direct subjects to comply with the 
matters described below.

Subjects must follow the prespecified trial schedule.

Subjects must not use the prohibited concomitant medications (see Section 4.1).
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, subject enrolled in violation of eligibility criteria or concomitant medication 
criteria), the investigator, subinvestigator, or designee will contact the sponsor at the 
earliest possible time by telephone. The investigator or subinvestigator and sponsor will 
come as quickly as possible to a joint decision regarding the subject’s continuation in the 
trial. This decision will be documented by the investigator or subinvestigator and the 
sponsor, and reviewed by the site monitor.
If a major deviation occurs, the onset date and the details of the deviation will be 
recorded in the source document and the eCRF.


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4
Restrictions
4.1
Prohibited Medications
From the time of informed consent to the completion assessment on Day 6 (the day after 
the final IMP administration) or the withdrawal assessment, use of the following items
listed in Table 4.1-1 and Table 4.1-2 will be prohibited.
Table 4.1-1
List of Prohibited Concomitant Medications and Foods
No.
Prohibited medications and foods
1
Vasopressin antagonists
2
Medications and foods which may inhibit or induce the activity of CYP 3A4 (see Table 4.1-2)
3
Medications including investigational drugs other than OPC-61815 that are unapproved in 
Japan
CYP = cytochrome P450
[Rationale for the prohibited concomitant medications and foods]
1,2
These medications and foods may confound the safety evaluation of the IMP.
3
The safety of these medications has not been established in Japanese patients.


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Table 4.1-2
Medications and Foods Which May Inhibit or Induce 
CYP3A4 Activity
Therapeutic category
Drugs
(1) CYP3A4 inhibitors (except external use agents)
Antimicrobial drugs
Clarithromycin, erythromycin, fluconazole, itraconazole, miconazole, 
norfloxacin, chloramphenicol, voriconazole, and ciprofloxacin
Anti-HIV drugs
Atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, lopinavir, telaprevir, 
fosamprenavir, cobicistat, darunavir, and elvitegravir 
Drugs for viral liver 
diseases
Ombitasvir, paritaprevir, and ritonavir
Calcium channel 
blockers
Diltiazem and verapamil
Antidepressants
Fluvoxamine
Antiulcer drugs
Cimetidine
Anticancer drugs
Imatinib and crizotinib
Immunosuppressants
Cyclosporine
Antiemetics
Aprepitants
Other medications
Tofisopam, istradefylline, and clotrimazole
Foods
Grapefruit, star fruit, Seville orange, and their processed products
(2) CYP3A4 inducers (except external use agents)
Barbiturates
Phenobarbital, amobarbital, pentobarbital, barbital, secobarbital, and 
primidone
Adrenal corticosteroids
Cortisone, hydrocortisone, prednisolone, methylprednisolone, triamcinolone, 
dexamethasone, betamethasone, paramethasone, and fludrocortisone
Antihypertensive drugs
Bosentan
Anti-HIV drugs
Efavirenz, etravirine, and nevirapine
Antiepileptics
Carbamazepine, phenytoin, and oxcarbazepine
Antitubercular drugs
Rifampicin and rifabutin
Anticancer drugs
Enzalutamide and mitotane
Other medications
Modafinil
Foods
Products containing St. John’s Wort
HIV = human immunodeficiency virus
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as medical history at screening for pre planned procedures for which the underlying 
condition was known and no worsening occurred. An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.


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An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does 
not include an event that, had it occurred in a more severe form, might have 
caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a “serious” AE.
Immediately Reportable Event (IRE):

Any SAE.

All SAEs occurring during the trial period

An SAE that occurs during the follow-up period and is considered to be 
reasonably related to the IMP; or, an AE that exists before the start of the 
follow-up period, and falls under the definition of an SAE during the follow-
up period and is considered to be reasonably related to the IMP.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented on the AE eCRF if there is an 
abnormality or complication. The above applies to pregnancies of both subjects 
and their partners.


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Clinical Laboratory Test Value Changes: It is the investigator or subinvestigator’s 
responsibility to review the results of all laboratory tests as they become available. This 
review will be documented by the investigator or subinvestigator’s dated signature on the 
laboratory report. For each abnormal laboratory test result, the investigator needs to 
ascertain if this is an abnormal (ie, clinically significant) change from baseline for that 
individual subject. This determination, however, does not necessarily need to be made the 
first time an abnormal value is observed. The investigator 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 medically relevant by the investigator or 
subinvestigator (subject is symptomatic, requiring corrective treatment or further 
evaluation), or if the laboratory value leads to discontinuation, and/or fulfills a 
seriousness criterion, this is considered an AE.
Severity: Adverse events will be graded on a 3-point scale. The intensity of an adverse 
experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the non-leading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRFs provided by the 
sponsor. The AE, onset date, resolution date, seriousness, severity, causal relationship to 
the IMP (IMP Causality), action taken with IMP treatment, and outcome will be recorded 
in the source document and the eCRF. If any AESI (feeling abnormal, feeling hot, 
erythema, hyperhidrosis, pruritus, rash, urticaria, nausea, epigastric discomfort, or 


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dyspnea) occurs, also the time of onset and the time of resolution will be recorded. 
Adverse event and SAE collection will begin after the subject consents to participation in 
the trial.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. If an AE that 
has been previously reported worsens and its severity or seriousness changes, it will be 
recorded as a new AE in the eCRF.
The sponsor must be notified immediately by e-mail of any IRE according to the 
procedure outlined in Section 5.3. Special attention should be paid to recording 
hospitalization and concomitant medications.
The following information will be recorded in the eCRF according to the eCRF entry 
instructions provided by the sponsor.

Adverse event

Onset date (also the time, for AEs occurring during stay at the trial site, whenever 
possible) and resolution date

Severity

Seriousness (If serious, specify the category of seriousness.)

IMP causality

Measures taken with IMP administration

Outcome
5.3
Immediately Reportable Events
The investigator must report within 24 hours after either the investigator, subinvestigator,
or site personnel become aware of any SAE, potential serious hepatotoxicity, or 
confirmed pregnancy, by e-mail to the sponsor using the contact information on the cover 
page of this protocol. An IRE form must be completed and sent by e-mail to the sponsor. 
(Please note that the IRE form is NOT the AE eCRF.)
Subjects experiencing SAEs or IREs should be followed until the event has resolved or 
stabilized, or until 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 


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the subject’s condition. 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.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is ≥3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is ≥2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eCRF.
5.5
Pregnancy
Women of child-bearing potential are defined as female subjects for whom menstruation 
has started and who are not documented as sterile (ie, have had a bilateral oophorectomy 
and/or hysterectomy or who have been postmenopausal for at least 12 months).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures (ie, double 
barrier method) to prevent pregnancy during the course of the trial and for 30 days after 
the last dose of IMP. Unless the subject is sterile (ie, women who have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 12 
consecutive months; or men who have had a bilateral orchidectomy) or remains abstinent, 
2 of the following precautions must be used: vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, or condom with spermicide.
Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all WOCBP. The topics should generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an ICF stating that the above mentioned risk factors 
and the consequences were discussed with her.


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A urine and/or serum pregnancy test for hCG will be performed at screening on all 
WOCBP. If a urine test is performed and is positive, the investigator will follow up with 
a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. (In an exceptional case 
where the subject is in a potentially life threatening situation, continuation of 
participation in the trial may be considered, but it should be determined after 
consultations with the Department of Pharmacovigilance, Otsuka Pharmaceutical [for the 
contact information, see the cover page of this protocol]).
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form and forward it to the sponsor. The 
sponsor will forward Pregnancy Surveillance Form(s) for monitoring the outcome of the 
pregnancy.
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 
6 months from the date of birth.
5.6
Procedure for Breaking the Blind
Not applicable, as this trial is an open-label trial.


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5.7
Follow-up of Adverse Events
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk 
related behavior, family history, and occupation). Follow-up information after the end of 
the trial date (the date of the last scheduled contact) will be recorded in the subject’s 
medical record.
5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs for 7 to 10 days 
after the final IMP administration (up to the date of the trial end [the last scheduled 
contact]).
Serious AEs and IREs that are identified or ongoing on the date of the trial end must be 
recorded as such on the AE eCRF page. If updated information (eg, resolved status) on 
SAE or IRE status becomes available after a subject’s last scheduled contact up to the last 
visit of the last subject for the entire trial, this must be reported to the sponsor and 
recorded on the AE eCRF page, according to the appropriate reporting procedures. The 
investigator or subinvestigator will follow SAEs and IREs until the event has resolved or
stabilized, or the subject is lost to follow-up or has died, and continue to report any 
significant follow-up information on an IRE form to the sponsor.
5.7.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After the Date of Trial 
End (Last Scheduled Contact)
Any new SAEs or IREs reported to the investigator or subinvestigator, which occur after 
the end of trial (last scheduled contact) and are determined by the investigator or 
subinvestigator to be reasonably associated with the use of the IMP, should be reported to 
the sponsor. This may include SAEs or IREs that are captured on follow-up telephone 
contact or at any other timepoint after the defined trial period. The investigator or 
subinvestigator should follow SAEs or IREs identified after the defined trial period, and 


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continue to report any significant follow-up information on an IRE form to the sponsor 
until the events are resolved or stabilized, or the subject is lost to follow-up or has died.
6
Pharmacodynamic and Pharmacogenomic Analyses
For pharmacodynamic analyses, see Section 7.4.2, and for pharmacogenomic analyses, 
see Section 3.7.5.2.
7
Statistical Analyses
7.1
Target Sample Size
Sample size: 40 subjects (number of subjects started on OPC-61815). For a sample size 
of 40 subjects, the probability of AE occurring at an incidence of 5% and 4% is 
respectively 87% and 80%.
7.2
Datasets for Analysis
The safety dataset includes all subjects who received at least one dose of IMP.
The pharmacodynamic dataset includes all subjects who received at least one dose of 
IMP and have postdose pharmacodynamic data.
The efficacy dataset includes all subjects who received at least one dose of IMP and have 
postdose efficacy data.
7.3
Handling of Missing Data
Missing data at the time of final IMP administration will be imputed using the last 
available data obtained by the day after the final IMP administration.
7.4
Safety, Pharmacodynamic, and Efficacy Endpoint Analyses
7.4.1
Safety Analysis
The following analyses will be conducted on the safety dataset. The same analyses will 
be conducted by the timing of dose escalation (ie, subjects achieving a dose escalation to 
16 mg on Day 2, those achieving a dose escalation to 16 mg on Day 3, and those 
achieving no dose escalation to 16 mg).


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7.4.1.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. The incidence of the following events will be summarized:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
IMP-related TEAEs will be summarized in the same manner as shown above.
7.4.1.2
Clinical Laboratory Data
Clinical laboratory data obtained from central measurements will be used for analyses. 
For clinical laboratory test parameters other than qualitative urinalysis, measured values 
and changes from baseline at each time point and at the time of final IMP administration
will be summarized using descriptive statistics (the number of subjects, mean, SD, 
minimum, median, and maximum). For qualitative urinalysis parameters, shift tables will 
be prepared at each time point and at the time of final IMP administration compared with 
baseline. In addition, measured values of clinical laboratory test parameters other than 
qualitative urinalysis will be categorized as below, within, or above the normal range, and 
shift tables will be prepared at each postdose time point and at the time of final IMP 
administration compared with baseline.
The numbers and percentages of subjects who have a visit with serum total bilirubin 
value of ≥2 times the ULN, and an AST or ALT value of ≥3 times the ULN at any 
postdose time point will be calculated.
The numbers and percentages of subjects experiencing the following events after IMP 
administration will be calculated.

A serum sodium concentration >147 mEq/L

A >10 mEq/L increase in serum sodium concentration within 24 hours after the start 
of IMP administration
7.4.1.3
Vital Signs Data
For vital signs (blood pressure, pulse rate, and body temperature), measured values and 
changes from baseline at each time point and at the time of final IMP administration will 
be summarized using descriptive statistics.


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7.4.1.4
Electrocardiogram Data
For 12-lead ECG parameters, measured values and changes from baseline will be 
summarized at each time point and at the time of final IMP administration using 
descriptive statistics.
The numbers and percentages of subjects who have a QTc interval of >450, >480, or 
>500 msec at any postdose time point until the time of final IMP administration will be 
calculated. The numbers and percentages of subjects who have a change in QTc interval
from baseline of >30 and >60 msec at any postdose time point or at the time of final IMP 
administration will be calculated. Also at baseline and at each postdose time point, the 
numbers and percentages of subjects will be calculated in the same manner as described 
above. 
A shift table showing QTc interval interpretation (normal or abnormal) will be prepared 
at each postdose time point and at the time of final IMP administration compared to 
baseline.
7.4.2
Pharmacodynamic Analyses
A pharmacodynamic analysis will be conducted on the pharmacodynamic dataset. In the 
analysis of serum sodium and potassium concentrations, the results of central
measurement will be used. The same analyses will also be conducted by the timing of 
dose escalation (ie, subjects achieving a dose escalation to 16 mg on Day 2, those 
achieving a dose escalation to 16 mg on Day 3, and those not achieving a dose escalation 
to 16 mg).
For the following parameters, measured values and changes from baseline will be 
summarized at each time point.

Urine volume

Fluid Intake

Fluid Balance

Serum sodium concentration

Serum potassium concentration

Serum osmolality

Biomarkers (plasma AVP concentration, plasma renin activity, plasma BNP 
concentration, serum NT-proBNP concentration, and serum troponin I concentration)

Urine sodium excretion

Urine potassium excretion


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
Urine osmolality
In subgroups composed of subjects achieving a dose escalation to 16 mg on Day 2 and 
Day 3 changes in serum sodium concentration, serum potassium concentration, and 
serum osmolality at each time point during the period from predose on the dose 
escalation day to predose on the following day will be summarized using descriptive 
statistics.
7.4.3
Efficacy Analyses
The following analyses will be conducted on the efficacy dataset. The same analyses will 
be conducted by the timing of dose escalation (ie, subjects achieving a dose escalation to 
16 mg on Day 2, those achieving a dose escalation to 16 mg on Day 3, and those not 
achieving a dose escalation to 16 mg).
7.4.3.1
Body Weight
Measured values, and changes and percent changes from baseline at each time point and 
at the time of final IMP administration will be summarized using descriptive statistics.
7.4.3.2
Congestive Symptoms
7.4.3.2.1
Lower Limb Edema and Pulmonary Congestion
The improvement rate and the resolution rate at the time of final IMP administration will 
be determined. The improvement rate is defined as the proportion of subjects in whom a 
symptom is present at baseline and then markedly improves or improves after IMP 
administration (for the improvement category, see Table 7.4.3.2-1). The resolution rate is 
defined as the proportion of subjects in whom a symptom is present at baseline and then 
resolves after IMP administration.
Shift tables for the severity of the symptoms will be prepared at each on-treatment time
point and at the time of final IMP administration compared with baseline.
Table 7.4.3.2-1
Improvement Category of Lower Limb Edema and 
Pulmonary Congestion
Improvement
category
Assessment criteria
1
Markedly improved
The symptom resolved or improved by ≥2 categories.
2
Improved
The symptom improved by one category. (Symptom resolution will 
be categorized as “markedly improved.”)
3
Unchanged
The symptom remained unchanged or was absent throughout the trial 
period.
4
Deteriorated
The symptom worsened by ≥1 category.


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7.4.3.2.2
Jugular Venous Distension, Hepatomegaly, and 
Cardiothoracic Ratio
Measured values and changes from baseline at each time point and at the time of final 
IMP administration will be summarized using descriptive statistics. For the presence of 
jugular venous distension and hepatomegaly, shift tables in changes from baseline at the
final IMP administration and at each timepoint following IMP administration will be 
prepared by each treatment group.
7.4.3.2.3
Pulmonary Rales and Cardiac Third Sound
The resolution rates of pulmonary rales and cardiac third sound at the time of final IMP 
administration will be determined. The resolution rate is defined as the proportion of 
subjects in whom a symptom is present compared with baseline and disappears after IMP 
administration.
Shift tables showing whether the symptom is present will be prepared at each on-
treatment time point and at the time of final IMP administration compared with baseline.
7.4.3.3
Dyspnea
7.4.3.3.1
Respiratory Rate
Measured values and changes from baseline at each time point and at the time of final 
IMP administration will be summarized using descriptive statistics.
7.4.3.3.2
Orthopnea and Paroxysmal Nocturnal Dyspnea
The resolution rates of orthopnea and paroxysmal nocturnal dyspnea at the time of final 
IMP administration will be determined. The resolution rate is defined as the proportion of 
subjects in whom a symptom is present compared with baseline and then disappears after
IMP administration.
Shift tables showing whether each symptom is present will be prepared at each postdose
time point and at the time of final IMP administration compared with baseline.
7.4.3.3.3
Subject-Assessed Dyspnea
The frequencies at each postdose time point and at the time of final IMP administration
will be summarized.
7.4.3.4
NYHA Classification
A shift table showing the NYHA classification will be prepared at each on-treatment time
point and at the time of final IMP administration compared to baseline.


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7.5
Analysis of Demographic and Baseline Characteristics
In the safety dataset and the efficacy data set, the frequency distributions and descriptive 
statistics of the subject characteristics will be calculated.
8
Management of Investigational Medicinal Product
For full details on IMP management, see the OPC-61815 IB and the clinical operation 
manual.
8.1
Packaging and Labeling
The IMP will be provided to the IMP storage manager by the sponsor or designated 
agent. The IMP will be supplied in OPC-61815 8-mg and 16-mg vials. Six vials are 
contained in a kit box. Each vial and each kit box will be labeled to clearly state “For 
clinical trial use only,” and disclose the protocol number, name of the IMP, batch 
number, expiration date, storage methods, and sponsor’s name and address.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP storage manager. The IMP storage manager may not provide IMP to any 
subject not participating in this protocol.
The IMP will be stored at room temperature.
The trial site staff will check the temperature in the IMP storage area at least once each 
working day and record the observed temperature.
8.3
Accountability
The IMP storage manager must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused IMPs and partially used IMPs 
must be returned to the sponsor or a designated agent.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number and trial site number on the outermost shipping 


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container. Returned supplies should be in the original containers. The assigned trial 
monitor will facilitate the return of unused IMP and partially used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor or sponsor’s designee 
(contact information: PQC_263-102-00004@otsuka.jp) of the information listed in 
Section 8.5.2 by e-mail immediately after becoming aware of the PQC.
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, subinvestigator, trial site, person 
preparing the IMP, etc.)

Reporter contact information (eg, address, phone number, e-mail address)


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
ID of material (product/compound name)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. As 
needed, the sponsor may provide the procedure for returning the sample.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents will be maintained by the trial site and made available for direct 
inspection by authorized persons. The investigator or the trial site will permit trial-related 
monitoring, audits, IRB review, and regulatory inspection(s) by providing direct access to 
source data/documents by authorized persons as defined in the ICF. In all cases, subject 
confidentiality must be maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the trial site, the investigator or subinvestigator will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator 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;


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
The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed;

The signature (or initials) and date of investigator or subinvestigator (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 source documents will be initialed 
and dated on the day the change is made by a trial site staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data (so as 
not to obliterate the original data), and clearly entering the correct data (eg, wrong data
right data). If the reason for the change is not apparent, a brief explanation for the change 
will be written in the source documentation by the investigator or subinvestigator. When 
using an electronic trial data system, full audit trail of the change should be maintained.
The information recorded in the medical record or other source documents should be 
directly entered in the sponsor’s electronic data capture system by an authorized trial site 
staff. Changes to the data will be captured by an automatic audit trail.
9.3
File Management at the Trial Site
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations. The trial site will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
The trial site should maintain all documents and records, relevant to the trial for the 
longer of the following 2 periods and the date on which DNA storage is determined to be 
terminated. If the sponsor requires longer maintenance, the storage period and method 
will be discussed with the trial site.

A period of at least 2 years after the date on which approval to market the drug is 
obtained, or a period of at least 3 years after the date on which the sponsor notifies the 
trial site that development of the IMP is discontinued or that the final report of this 
trial will not be submitted with the approval application for the IMP


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
A period of at least 3 years after the trial is terminated or completed
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of an opportunity for the sponsor to 
collect such records. The trial site will be responsible for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial. Such documentation is subject to inspection by the sponsor and the 
relevant regulatory authorities.
10
Quality Control and Quality Assurance
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guideline, and 
applicable regulatory requirements. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators,
subinvestigators, and trial site personnel will undergo initial and ongoing training for this 
particular trial, and this training will be clearly documented.
10.2
Auditing
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents. The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 


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regulations. Each trial site will seek approval by an IRB according to regional 
requirements, and the trial site will provide that documentation to the sponsor. The IRB 
will evaluate the ethical, scientific, and medical appropriateness of the trial. Further, in 
preparing and handling the eCRF, the investigator or subinvestigator and his/her staff will 
take measures to ensure adequate care in protecting subject confidentiality. To this end, a 
subject number or subject identifier will be used to identify each subject. Financial 
aspects, subject insurance, and the publication policy for the trial will be documented in 
the agreement between the sponsor and the trial site.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject numbers in eCRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigators will wait for IRB approval/favorable opinion of the amended protocol, 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 


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apparent immediate hazard to subjects should be implemented immediately followed by 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agencies within local applicable timelines.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written information and ICF will require similar modification. In such 
cases, after approval/favorable opinion of the new written information and ICF by the 
IRB, repeat informed consent will be obtained from subjects enrolled in the trial before 
expecting continued participation and before the amendment-specified changes in the 
trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.


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15
References
1
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of 
congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-6.
2
Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure (The 
Japanese Circulation Society 2017/The Japanese Heart Failure Society 2017), 2018.
3
Machikawa F. A phase 1, placebo-controlled, double-blind, single intravenous dose 
trial of OPC-61815 in healthy male subjects. Clinical study report (Protocol 263-08-
001), issued 30 Aug 2010.
4
Hasunuma T. A phase 1, placebo-controlled, double-blind, repeated intravenous dose 
trial to evaluate the safety, pharmacokinetics, and pharmacodynamics of OPC-61815 
at 1, 25, 5, and 20 mg in healthy male subjects. Clinical study report (Protocol 263-
09-001) issued 26 Oct 2010.
5
Hasunuma T. A phase 1, single-center, placebo-controlled, double-blind trial to 
evaluate the safety, pharmacokinetics, and pharmacodynamics of OPC-61815 by 
dosage regimen. Clinical study report (Protocol 263-10-005), issued 29 Feb 2012.
6
Saito K. A placebo-controlled, double-blind, comparative trial of OPC-41061 for the 
treatment of cardiac edema (congestive heart failure). Clinical study report (Protocol 
156-06-002), issued 22 Jan 2009.
7
Matsuzaki M, Hori M, Fukunami M. Efficacy and Safety of Tolvaptan in Heart 
Failure Patients with Volume Overload Despite the Standard Treatment with 
Conventional Diuretics: A Phase III, Randomized, Double-blind, Placebo-controlled 
Study (QUEST Study). 2011;25:33-45
8
International Council for Harmonisation (ICH) [homepage on the Internet]. E6(R2): 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) [finalized 2016 
November; cited 2018 Nov 9]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E6/E6_R2_Step_4_2016_1109.pdf.
9
Forrester JS, Diamond G, Chatterjee K, Swan HJ. Medical therapy of acute 
myocardial infarction by application of hemodynamic subsets (First of two parts). N 
Engl J Med. 1976;295(24):1356-62.
10 Clinical Trials using Pharmacogenomics. PFSB/ELD Notification No. 0930007 of the 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry 
of Health, Labour and Welfare. 2008.
11 International Council for Harmonisation (ICH) [homepage on the Internet]. E18. 
Guideline on Genomic Sampling and Management of Genomic Data: [current step 4 
version dated 3 August 2017; cited 2019 Jan 17]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E18/E18EWG_Step_4_Guideline_2017_0803.pdf.


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Appendix 1
Handling and Shipment of Bioanalytical Samples
1) Sample collection and processing procedures
Samples will be collected, processed, and stored according to procedures specified 
separately by the sponsor.

Serum sodium concentration, serum potassium concentration, and serum 
osmolality
Blood will be taken using a serum separation tube, mixed by slowly turning 
upside-down several times, allowed to stand for at least 30 minutes at room 
temperature, and then centrifuged to obtain serum. The serum will be taken in 
a sample stock tube and stored refrigerated.

Plasma AVP concentration
Blood will be taken using an EDTA-containing tube, mixed by slowly turning 
upside-down several times, and centrifuged at a refrigerated temperature to 
obtain plasma. The plasma will be taken in a sample stock tube and stored 
frozen.

Plasma BNP concentration and plasma renin activity
Blood will be taken in an EDTA-containing tube from a subject who has 
remained at rest in a supine position, mixed by slowly turning upside-down 
several times, and centrifuged at a refrigerated temperature to obtain plasma. 
The plasma will be taken in a sample stock tube and stored frozen.

Serum NT-proBNP concentration
Blood will be taken using a serum separation tube, mixed by slowly turning 
upside-down several times, allowed to stand for at least 30 minutes at room 
temperature, and then centrifuged to obtain serum. The serum will be taken in 
a sample stock tube and stored frozen.

Serum troponin I concentration
Blood will be taken using a serum separation tube, mixed by slowly turning
upside-down several times, allowed to stand for at least 30 minutes at room 
temperature, and then centrifuged to obtain serum. The serum will be taken in 
a sample stock tube and stored frozen.

Urine sodium concentration, urine potassium concentration, and urine 
osmolality
The collected urine will be aliquoted into sample stock tubes and stored 
refrigerated.


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2) Blood sample for DNA storage
Approximately 2 mL of blood will be taken in an EDTA-containing test tube. In 
principle, venous blood sampling by direct venipuncture or catheterization will be 
conducted, except in cases where the investigator or subinvestigator considers arterial 
blood sampling by catheterization to be preferable. The collected blood sample will 
be mixed by slowly turning upside-down several times, transferred to sample stock 
tube that is appropriately labeled, and then stored in a freezer set at below −20°C 
within 60 minutes after sampling. The status (collected/not collected), and the date 
and time of blood sampling will be recorded in the source document and the eCRF. 
The central laboratory will collect blood samples for DNA storage from each trial site 
and ship the samples to the DNA repository. The blood samples will be placed with 
an adequate amount of dry ice in an adiabatic container while being shipped. The 
DNA repository will store the blood samples in a freezer set at −70°C. After double 
coding the samples by assigning a new unique code to each sample, the DNA 
repository will extract the DNA and store the obtained DNA sample in a freezer set at 
−70°C. Upon the request of the sponsor, the DNA repository will discard the sample 
in such a state that the subject cannot be identified.


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Appendix 2
Protocol Amendments/Administrative Changes
Amendment Number: 1
Issue Date: 18 Mar 2019
PURPOSES: Adding descriptions pertaining to clinical laboratory tests performed at 
each trial site using plasma samples, and correcting entry omissions and writing errors.
BACKGROUD: The use of plasma samples was considered appropriate in clinical 
laboratory tests at each trial site. Some entry omissions and writing errors were 
discovered in the protocol.
MODIFICATIONS TO PROTOCOL:

Protocol Synopsis, Section 3.4.3
“Serum creatinine,” “serum sodium concentration,” and “serum potassium” were 
changed to “serum or plasma creatinine,” “serum or plasma sodium concentration,” 
and “serum or plasma potassium concentration,” respectively.

Table 3.2.2-1 and Table 3.2.2-2
The following description was added: “aIf serum sodium concentration measurement 
is difficult to perform at the trial site, plasma sodium concentrations will be used for 
the assessment.”

Section 3.7
The following description was added: “If serum sodium concentration measurement 
is difficult to perform at the trial site, plasma sodium concentration may be measured. 
Either serum or plasma should be used consistently for measurement of sodium 
concentration in a given subject. However, serum sodium concentration will be 
measured at the central laboratory.”

Table 3.7-1
Writing errors in the note were collected. The following description was added to 
Note d): “If serum sodium concentration measurement is difficult to perform at the 
trial site, plasma sodium concentration may be measured. Either serum or plasma 
samples should be used consistently for measurement of sodium concentration in a 
given subject. However, serum sodium concentration will be measured in the central 
laboratory.”

Table 3.7.1.2-2 and Table 3.7.1.5-2


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“Urine sampling for the measurement of urine sodium concentration and urine 
osmolality” was changed to “urine sampling for measurement of urine sodium 
concentration, urine potassium concentration, and urine osmolality.”

Section 3.7.2.2
The following description was added: “If serum sodium concentration measurement 
is difficult to perform at the trial site, plasma sodium concentration may be measured. 
Either serum or plasma samples should be used consistently for measurement of 
sodium concentration in a given subject. However, serum sodium concentration will 
be measured in the central laboratory.”

Table 3.7.2.2-1
“Serum electrolytes (sodium [Na], potassium [K], chloride [Cl], calcium [Ca])” was 
changed into “serum or plasma electrolytes (sodium [Na], potassium [K], chloride 
[Cl], calcium [Ca]).”

Table 3.7.5.1.1-1
“24 hours before the start of IMP administration on Day 1” was changed into “23 to 
25 hours before the start of IMP administration on Day 1.”

Section 3.7.5.1.4
The following description was added: “If serum sodium concentration measurement 
is difficult to perform at the trial site, plasma sodium concentration may be measured. 
Either serum or plasma samples should be used consistently for measurement of 
sodium concentration in a given subject. However, serum sodium concentration will 
be measured in the central laboratory.”

Section 3.8.3.2
“Serum sodium concentration” was changed into “serum or plasma sodium 
concentration.”
ADDITIONAL RISK TO THE SUBJECTS:
No additional risks will be imposed upon the subjects.


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Amendment Number: 2
Issue Date: 26 Jun 2019
PURPOSES: Changing the protocol to enroll subjects who are not able to personally 
sign the ICF, but from whom verbal consent can be obtained in the presence of a witness; 
clarifying the definition of treatment duration; and, correcting writing errors.
BACKGROUND: It was found that some subjects are unable to personally sign the ICF 
due to physical or therapeutic reasons, even though they are able to verbally consent to 
participation in the trial; therefore, a procedure to enroll such subjects was added. The 
definition of treatment duration, which had been insufficiently documented was clarified. 
In addition, some errors were corrected.
MODIFICATIONS TO PROTOCOL:

Throughout the protocol (Sections 3.3.2, 3.7.1, 3.7.4, 3.7.5.2.1, 3.9, 5.2, and 5.5)
The wording was changed so that subjects who express verbal consent can participate 
in the trial without obtaining written consent from these subjects (with this change, 
subjects may participate in the trial with verbal consent provided in the presence of a 
witness without providing written consent).

Section 3.4.1
The wording was changed so that subjects who are able to consent but unable to sign 
the ICF for physical or therapeutic reasons can participate in the trial through the 
acquisition of verbal consent from these subjects in the presence of a witness. In the 
course of informed consent, the witness will sign and date the witness section of the 
ICF, and write the name of the subject, the reason(s) that the subject is not able to 
sign by him/herself, and the relationship between the subject and the witness in the 
margin of the ICF.

Protocol Synopsis, Section 3.2.3
It was clarified that the participation of subjects in the trial would end when they 
become able to control fluid balance by oral fluid intake alone (the end of treatment 
period was clarified).

Others: Errors were corrected.
ADDITIONAL RISK TO THE SUBJECTS:
No additional risks will be imposed upon the subjects.


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Amendment Number: 3
Issue Date: 17 Apr 2020
PURPOSES: Addition of trial procedures and editing of descriptions in the protocol 
including the correction of errors
BACKGROUND: Trial procedures were added in consideration of ensuring the safety of 
subjects. The descriptions in the protocol were also edited (including the correction of 
errors.)
MODIFICATIONS TO PROTOCOL:

Table 3.7-1

Item: The underlined parts were added.
Changed into “Serum sodiumd and potassium concentrationsd” in consideration of 
ensuring the safety of subjects.

Changed into “12-Lead ECGk” in consideration of ensuring the safety of subjects.

Note d: The underlined parts were added.
Changed into “Serum sodium and potassium concentrations”
Changed into the following statement in consideration of ensuring the safety of 
subjects: “If serum sodium and potassium concentration measurement is difficult 
to perform at the trial site, plasma sodium and potassium concentrations may be 
measured. Either serum or plasma samples should be used consistently for 
measurement of sodium and potassium concentrations in a given subject. 
However, serum sodium and potassium concentrations will be measured in the 
central laboratory.”

Note e: The underlined parts were added.
Changed into the following statement in consideration of ensuring the safety of 
subjects: “Serum sodium concentration (local measurement), serum potassium 
concentration (local measurement), body weight, chest x-ray, and vital signs 
(blood pressure, pulse rate, and body temperature)”

Note k: An addition of the statement.
The following statement was added in consideration of ensuring the safety of 
subjects: “If the serum potassium is confirmed to exceed 5.5 mEq/L at the trial 
site or the central laboratory at any time point in the period with no specified 12-
lead ECG, a 12-lead ECG will be performed as an unscheduled examination.”

Sections 3.7, 3.7.1, 3.7.2.2 and 3.7.5.1.4
The statements indicating that “serum potassium concentration measurement is 
performed during the treatment period at the trial site” were added in consideration of 
ensuring the safety of subjects.


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
Section 3.7.2.2 and 3.7.2.4
The statements indicating that “if the serum potassium is confirmed to exceed 5.5 
mEq/L at the trial site or the central laboratory at any time point in the period with no 
specified 12-lead ECG,, a 12-lead ECG will be performed as an unscheduled
examination” were added in consideration of ensuring the safety of subjects.

Others: Errors were corrected.
ADDITIONAL RISK TO THE SUBJECTS:
No additional risks will be imposed upon the subjects.


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator’s Brochure) and agree that it contains all the ethical, legal, and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor’s (or designee’s) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with these persons to ensure that 
they are sufficiently informed regarding the investigational new drug, OPC-61815, the concurrent 
medications, the efficacy and safety parameters, and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) responsible for 
such matters in the clinical trial facility where OPC-61815 will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set 
forth in the sponsor’s Clinical Trial Agreement, at which time I agree to adhere strictly to the 
protocol, as amended).
I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eCRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory 
authorities and/or in combination with clinical data gathered from other research sites, whenever 
applicable. I agree to allow sponsor and designee monitors and auditors full access to all medical 
records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IRB for informational purposes 
only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor’s Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
Principal Investigator Print Name
Trial Site
Signature
Signature Date
The signature on this agreement is digitally signed. The electronic signature page is attached to 
the agreement.

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Open-label, Uncontrolled Clinical Trial to Confirm the Tolerability of 
OPC-61815 in Patients With Congestive Heart Failure Who Have Difficulty With or 
Are Incapable of Oral Intake 
 
 
 
 
NCT Number: NCT03962101 
PRT NO.: 263-102-00004 
Version Date: 10 September 2020 (Version 1.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational New Drug OPC-61815
Protocol No. 263-102-00004
A Multicenter, Open-label, Uncontrolled Clinical Trial to Confirm the Tolerability of
OPC-61815 in Patients With Congestive Heart Failure Who Have Difficulty With or Are
Incapable of Oral Intake
Translation of Japanese Original
Statistical Analysis Plan
Version: Final 1.0
Date: 10 Sep 2020
Protocol Version 4.0 Date: 17 Apr 2020
Date of Translation: 15 Oct 2020
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 .........................................................................................5
List of Abbreviations and Definition of Terms...........................................6
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 .........................................................................................10
5
Statistical Analysis Datasets..............................................................10
5.1
Safety Analysis Set............................................................................................10
5.2
Pharmacodynamic Analysis Set........................................................................10
5.3
Efficacy Analysis Set ........................................................................................10
5.4
Handling of Missing Data .................................................................................10
6
Primary and Secondary Outcome Variables:..................................10
6.1
Primary Outcome Variables..............................................................................10
6.2
Secondary Outcome Variables..........................................................................10
6.3
Safety Outcome Variables.................................................................................10
6.4
Pharmacodynamic Outcome Variables .............................................................10
6.5
Efficacy Outcome Variables .............................................................................11
7
Disposition and Demographic Analysis............................................11
7.1
Subject Disposition ...........................................................................................11
7.2
Demographic and Baseline Characteristics.......................................................11
7.3
Baseline Disease Evaluation .............................................................................13
7.4
Treatment Compliance ......................................................................................14
7.5
Prior and Concomitant Medications..................................................................14
7.6
Protocol Deviations...........................................................................................14
8
Efficacy Analysis ................................................................................14


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8.1
Primary Efficacy Endpoint................................................................................14
8.2
Key Secondary Efficacy Endpoint ....................................................................14
8.3
Efficacy Analyses..............................................................................................15
8.3.1
Body Weight...................................................................................................15
8.3.2
Congestive Symptoms ....................................................................................15
8.3.2.1
Lower Limb Edema and Pulmonary Congestion........................................15
8.3.2.2
Jugular Venous Distension, Hepatomegaly and Cardiothoracic Ratio.......15
8.3.2.3
Pulmonary Rales and Cardiac Third Sound................................................16
8.3.3
Dyspnea ..........................................................................................................16
8.3.3.1
Respiratory Rate..........................................................................................16
8.3.3.2
Orthopnea and Paroxysmal Nocturnal Dyspnea .........................................16
8.3.3.3
Subject-assessed Dyspnea...........................................................................16
8.3.4
NYHA Classification......................................................................................17
8.4
Subgroup Analyses............................................................................................17
9
Safety Analyses...................................................................................17
9.1
Extent of Exposure............................................................................................17
9.2
Adverse Events..................................................................................................17
9.3
Clinical Laboratory Data...................................................................................18
9.4
Vital Sign Data..................................................................................................18
9.5
Physical Examination Data ...............................................................................18
9.6
Electrocardiogram Data.....................................................................................18
9.7
Other Safety Data..............................................................................................19
10
Pharmacokinetic Analyses.................................................................19
11
Pharmacodynamic Analyses..............................................................19
11.1
Urine Volume, Fluid Intake, Fluid Balance ......................................................19
11.2
Serum Sodium Concentration, Serum Potassium Concentration, Serum 
Osmolality .........................................................................................................20
11.3
Biomarkers (Plasma AVP Concentration, Plasma Renin Activity, Plasma 
BNP Concentration, Serum NT-proBNP Concentration, and Serum 
Troponin I Concentration).................................................................................20
11.4
Urine Sodium Excretion, Urine Potassium Excretion, Urine Osmolality.........20
12
Pharmacogenomic Analyses..............................................................21
13
Interim Analysis .................................................................................21


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14
Changes in the Planned Analyses .....................................................21
15
References ...........................................................................................21


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List of Appendices
Appendix 1
List of Summary Tables.................................................................22
Appendix 2
List of Subject Data Listings .........................................................30


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List of Abbreviations and Definition of Terms
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AVP
Arginine vasopressin
BMI
Body mass index
BNP
Brain natriuretic peptide
CHF
Congestive heart failure
CRF
Case report form
ICD
Implantable cardioverter defibrillator
ICH
International Conference on Harmonisation
IMP
Investigational medicinal product
MedDRA
Medical Dictionary for Regulatory Activities
NYHA
New York Heart Association
PT
Preferred Term
QTc
QT corrected for heart rate
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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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 Trial 263-102-00004.
2
Trial Objectives
To confirm the tolerability of intravenous administration of OPC-61815 at 8 or 16 mg 
once daily for a maximum of 5 days to congestive heart failure (CHF) patients with 
volume overload despite having received diuretics (injection) other than vasopressin 
antagonists and who have difficulty with or are incapable of oral intake.
3
Trial Design
3.1
Type/Design of Trial
This trial is a multi-center, uncontrolled, open-label trial to confirm the tolerability of 
intravenous administration of OPC-61815 at 8 or 16 mg once daily for a maximum of 
5 days to CHF patients with volume overload despite having received diuretics (injection) 
other than vasopressin antagonists and who have difficulty with or are incapable of oral 
intake.
Subjects who meet all of the inclusion criteria and fall under none of the exclusion 
criteria at the screening examination will be advanced to the treatment period during 
which OPC-61815 will be intravenously administered at 8 or 16 mg once daily. 
OPC-61815 treatment will start at 8 mg, and the investigator or subinvestigator will 
increase the dose to 16 mg on Day 2 or 3 after confirming that the subject meets the dose 
escalation criteria. The procedures for dose escalation decision are shown in the protocol 
Section 3.2.2. The maximum treatment duration is 5 days; however, investigational 
medicinal product (IMP) treatment may be discontinued before Day 5 according to the 
rules specified in the protocol Section 3.2.3. Concomitant use of loop diuretics will 
continue until the end of the treatment period.
The completion assessment will be conducted on Day 6 (or the day after the final IMP 
administration) and the follow-up assessment will be conducted at some time between 7 
and 10 days after the final IMP administration. Subjects will be hospitalized from the 
time of informed consent to Day 6 (or the day after the final IMP administration).
3.2
Trial Treatments
The investigator or subinvestigator will administer OPC-61815 once daily as 1-hour 
infusion (55 to 70 minutes allowable) according to the IMP administration procedures 


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specified separately. OPC-61815 treatment will start with 8 mg, and eligibility for dose 
escalation will be assessed on Day 2 of the treatment period (and again on Day 3 of the 
treatment period, if applicable) according to the protocol Section 3.2.2. If the dose 
escalation criteria are met, the dose will be increased to 16 mg; if the criteria are not met, 
administration will continue at 8 mg.
When adverse events (AEs) associated with the aquaretic effect of OPC-61815 including 
hypernatremia, dehydration, and thirst occur or worsen after the dose is increased to 
16 mg and dose reduction is judged to be necessary by the investigator or subinvestigator, 
the dose will be returned to 8 mg. The dose may not be re-escalated to 16 mg once it has 
been reduced to 8 mg. The start time of administration on Day 2 and onward should 
coincide roughly (±1 hour, whenever possible) with the start time on Day 1.
3.3
Trial Population
The trial population will comprise a total of 40 Japanese male and female CHF patients 
aged 20 to 85, inclusive, with volume overload despite having received injection diuretics 
other than vasopressin antagonists and who have difficulty with or are incapable of oral 
intake and who are capable of being hospitalized from the time of informed consent until 
the end of the treatment period.
3.4
Handling of Time Points
Case report form (CRF) Visit values at each time point (time points from baseline in the 
screening, treatment, and follow-up periods as specified in the protocol Table 3.7.1) 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.
According to the rules specified in the protocol Section 3.2.3, for the completion 
assessment of subjects who have completed treatment after a treatment period of shorter 
than 5 days, the CRF Visit will be set to correspond with the day of assessment for the 
analysis visit. Concerning interval urine samples, the daily urine volume will be 
calculated by summing all the interval urine volumes that constitute the daily urine 
volume for that day. If the interval urine sample is the last one for that day, the 
corresponding interval will be set as the analysis interval. The same rules also apply to 
fluid intake and urine electrolyte excretion. Other variables specified in the corresponding 
CRF Visit to be measured multiple times will be set to precede IMP administration.
Baseline and final administration time point for each variable are defined as follows.


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Table 3.4-1
Handling of Time Points
Variable
Baseline
Final Administration Time 
Point
Clinical laboratory value
Before IMP administration on 
Day 1
Day after final IMP 
administration
Vital signs
Before IMP administration on 
Day 1
(Screening values will be used if 
the values at screening are 
measured on Day 1 but not 
measured prior to the IMP 
administration on that day.)
Day after final IMP 
administration
12-lead ECG
Before IMP administration on 
Day 1
Day after final IMP 
administration
Daily urine volume, daily fluid 
intake, daily fluid balance
Within 24 hours before IMP 
administration on Day1
-
Serum sodium concentration, 
serum potassium concentration, 
serum osmolality
Before IMP administration on 
Day 1
-
Daily urine sodium excretion, 
daily urine potassium excretion
Within 24 hours before IMP 
administration on Day1
-
Urine osmolality
Within 24 hours before IMP 
administration on Day1
-
Biomarkers
(plasma AVP concentration, 
plasma renin activity, plasma 
brain natriuretic peptide [BNP] 
concentration, serum N-terminal 
pro-brain natriuretic peptide 
[NT-proBNP] concentration, and 
serum troponin I concentration)
Before IMP administration on 
Day 1
Day after final IMP 
administration
Body weight
Before IMP administration on 
Day 1
(Screening values will be used if 
the values at screening are 
measured on Day 1 but not 
measured prior to the IMP 
administration on that day.)
Day after final IMP 
administration
Congestive symptoms (lower 
limb edema, jugular venous 
distension, hepatomegaly, 
pulmonary rales, cardiac third 
sound)
Screening
Day after final IMP 
administration
Pulmonary congestion, 
cardiothoracic ratio
Screening
Day after final IMP 
administration
Respiratory rate, paroxysmal 
nocturnal dyspnea, orthopnea
Screening
Day after final IMP 
administration
Subject-assessed dyspnea
Screening
Day after final IMP 
administration
NYHA classification
Screening
Day after final IMP 
administration


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4
Sample Size
Sample size: 40 subjects (number of subjects started on OPC-61815). For a sample size 
of 40 subjects, the probability of AE occurring at an incidence of 5% and 4% is 
respectively 87% and 80%.
5
Statistical Analysis Datasets
5.1
Safety Analysis Set
The safety dataset includes all subjects who received at least one dose of IMP.
5.2
Pharmacodynamic Analysis Set
The pharmacodynamic dataset includes all subjects who received at least one dose of 
IMP and have postdose pharmacodynamic data.
5.3
Efficacy Analysis Set
The efficacy dataset includes all subjects who received at least one dose of IMP and have 
postdose efficacy data.
5.4
Handling of Missing Data
Missing data at the time of final IMP administration will be imputed using the last 
available data obtained by the day after the final IMP administration.
6
Primary and Secondary Outcome Variables:
6.1
Primary Outcome Variables
Primary outcome variables are not set.
6.2
Secondary Outcome Variables
Secondary outcome variables are not set.
6.3
Safety Outcome Variables
Adverse events, clinical laboratory tests, physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), and 12-lead electrocardiogram (ECG)
6.4
Pharmacodynamic Outcome Variables
Urine volume, fluid intake, fluid balance, serum sodium concentration, serum potassium 
concentration, serum osmolality, urine sodium excretion, urine potassium excretion, urine 
osmolality, and biomarkers (plasma concentrations of AVP and brain natriuretic peptide 


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[BNP], plasma renin activity, and serum concentrations of N-terminal pro BNP 
[NTproBNP] and troponin I)
6.5
Efficacy Outcome Variables

Body weight

Congestive symptoms
Lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, cardiac 
third sound, cardiothoracic ratio, and pulmonary congestion

Dyspnea
Respiratory rate, paroxysmal nocturnal dyspnea, orthopnea, and subject-assessed dyspnea

New York Heart Association (NYHA) classification
7
Disposition and Demographic Analysis
7.1
Subject Disposition
For subjects from whom informed consent was obtained (screened subjects), the number 
of subjects and subjects administered IMP and the numbers and percentages of completed 
subjects after IMP administration, and discontinued subjects after IMP administration 
(the denominator indicates the number of subjects administered IMP) will be 
summarized. For discontinued subjects after IMP administration, the number and 
percentage of subjects by reason for discontinuation will be summarized. Of the 
completed subjects after IMP administration, the number and percentage of those who 
completed treatment in less than a 5-day treatment period (as in Section 3.2.3 in the 
protocol) will be summarized by reason.
For subjects administered IMP, the number and percentage of subjects included in each 
statistical analysis set will be summarized.
7.2
Demographic and Baseline Characteristics
For the safety analysis set and efficacy analysis set, distributions (number of subjects, %) 
or descriptive statistics (number of subjects, mean, standard deviation, minimum, median, 
and maximum) will be calculated according to Table 7.2-1
Table 7.2-1
Demographic and Other Baseline Characteristics
Variable
Time point
Method
Level
Informed consent 
acquisition
Descriptive statistics
-
Age
Distribution
20-29,
30-39,


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Table 7.2-1
Demographic and Other Baseline Characteristics
Variable
Time point
Method
Level
40-49,
50-59,
60-69,
70-79,
80-85
<65,
≥65
Sex
-
Distribution
Female,
Male,
Undifferentiated
Height (cm)
Screening
Descriptive statistics
-
Body weight (kg)
Screening
Descriptive statistics
-
BMI (kg/m^2)
Screening
Descriptive statistics
-
Country
-
Distribution
JAPAN
Race
-
Distribution
Asian
Ethnicity
-
Distribution
Not Hispanic or Latino
Primary illness (multiple 
selection)

Ischemic heart disease

Cardiomyopathy

Valvular disease

Hypertensive heart disease

Arrhythmia
Screening
Distribution
Yes,
No
Type of heart failure
Screening
Distribution
Right Heart Failure,
Left Heart Failure,
Bi-ventricular Failure, 
Unspecified
Presence of arrhythmia
Screening
Distribution
Yes,
No
Use of Pacemaker
Screening
Distribution
Yes,
No
Use of ICD
Screening
Distribution
Yes,
No
Complication (multiple selection)

Hypertension

Angina pectoris

Diabetes mellitus

Renal impairment
Screening
Distribution
Yes,
No
Presence of complication
Screening
Distribution
Yes,
No
Presence of medical history
Screening
Distribution
Yes,
No
Reason why oral intake was 
judged difficult or impossible 
(multiple selection) 
Screening
Distribution
Ongoing NPPV therapy,
Risk of aspiration,
Reduced swallowing 
function,
Other


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7.3
Baseline Disease Evaluation
For the safety analysis set and efficacy analysis set, each variable at baseline will be 
calculated.
Table 7.3-1
Baseline Pathologic Evaluation
Variable
Method
Level
Cardiothoracic ratio (%)
Descriptive statistics
-
NYHA classification
Distribution
Class I,
Class II,
Class III,
Class IV
Severity of lower limb edema
Distribution
None,
Mild,
Moderate,
Severe
Pulmonary congestion
Distribution
None,
Mild,
Moderate,
Severe
Presence of jugular venous 
distension
Distribution
Yes,
No
Jugular venous distension (cm)
Descriptive statistics
-
Presence of jugular venous 
distension
(value at baseline)
Distribution
Yes,
No
Jugular venous distension (cm)
(subjects with baseline value)
Descriptive statistics
-
Presence of hepatomegaly
Distribution
Yes,
No
Hepatomegaly (cm)
Descriptive statistics
-
Presence of hepatomegaly
(value at baseline)
Distribution
Yes,
No
Hepatomegaly (cm)
(subjects with baseline value)
Descriptive statistics
-
Pulmonary rales
Distribution
Yes,
No
Third cardiac sound
Distribution
Yes,
No
Respiratory rate (breaths/min) 
Descriptive statistics
-
Orthopnea 
Distribution
Present,
Absent
Paroxysmal nocturnal dyspnea 
Distribution
Present,
Absent
Subject-assessed dyspnea
(presence of symptoms) 
Distribution
Present,
Absent
Daily urine volume
Distribution
<1500 mL,
≥1500 mL
Creatinine
Distribution
<2 mg/dL,
≥2 mg/dL
Plasma AVP concentration
Distribution
≤3.1 pg/mL,
>3.1 pg/mL


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Table 7.3-1
Baseline Pathologic Evaluation
Variable
Method
Level
Albumin
Distribution
<3 g/dL,
≥3 g/dL
7.4
Treatment Compliance
Treatment compliance will be summarized for the safety analysis set and efficacy 
analysis set. Distributions for presence or absence of discontinuation during IMP 
(injection) administration will be calculated. Distributions for presence or absence of 
days of incomplete IMP (injection) administration as well as days on which the duration 
from start to end of IMP administration is outside the allowable range (55 to 70 minutes) 
will also be calculated.
7.5
Prior and Concomitant Medications
No prior and concomitant medications analysis will be performed in this trial.
7.6
Protocol Deviations
For subjects administered IMP, distributions for presence or absence of deviations in 
each CRF classification (Dosing, Inclusion/Exclusion Criteria, Met Withdrawal Criteria 
But Was Not Withdrawn, Prohibited Concomitant Medications) will be calculated. 
Distributions of subjects with at least one deviation will also be calculated.
8
Efficacy Analysis
The following analyses will be conducted on the efficacy dataset. The same analyses will 
also be conducted for subjects categorized by the presence or absence of dose escalation 
(ie, subjects with dose increased to 16 mg and subjects with dose maintained at 8 mg 
without dose escalation) based on the dose escalation criteria.
8.1
Primary Efficacy Endpoint
Primary efficacy endpoint are not set.
8.2
Key Secondary Efficacy Endpoint
Key secondary endpoint are not set.


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8.3
Efficacy Analyses
8.3.1
Body Weight
Descriptive statistics and two-sided 95% confidence intervals (based on t-distribution) 
will be calculated for measured values and changes from baseline at the time of final IMP 
administration, and descriptive statistics will be calculated for the percent changes. At 
each time point, descriptive statistics will be calculated.
8.3.2
Congestive Symptoms
8.3.2.1
Lower Limb Edema and Pulmonary Congestion
The number, and proportion with the two-sided 95% confidence intervals (exact) will be 
calculated for the improvement rate and the resolution rate at the time of final IMP 
administration. The improvement rate is defined as the proportion of subjects in whom a 
symptom is present at baseline and then markedly improves or improves after IMP 
administration (for the improvement category, see Table 8.3.2.1-1). The resolution rate is 
defined as the proportion of subjects in whom a symptom is present at baseline and then 
resolves after IMP administration.
Shift tables for the severity of the symptoms will be prepared at each on-treatment time 
point and at the time of final IMP administration compared with baseline.
Table 8.3.2.1-1
Improvement Category of Lower Limb Edema and 
Pulmonary Congestion
Improvement 
category
Assessment criteria
1
Markedly improved
The symptom resolved or improved by ≥2 categories.
2
Improved
The symptom improved by one category. (Symptom resolution will 
be categorized as “markedly improved.”)
3
Unchanged
The symptom remained unchanged or was absent throughout the trial 
period.
4
Deteriorated
The symptom worsened by ≥1 category.
8.3.2.2
Jugular Venous Distension, Hepatomegaly and Cardiothoracic 
Ratio
Descriptive statistics and two-sided 95% confidence intervals (based on t-distribution) 
will be calculated for measured values and changes from baseline at the time of final IMP 
administration. Descriptive statistics will also be calculated at each time point after IMP 
administration. Note that the absence of jugular venous distension and hepatomegaly will 
be indicated as 0 cm. The above data on jugular venous distension and hepatomegaly will 
also be summarized in the same manner for subjects with baseline value. For the presence 
of jugular venous distension and hepatomegaly, shift tables in changes from baseline at 


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the final IMP administration and at each time point following IMP administration will be 
prepared.
8.3.2.3
Pulmonary Rales and Cardiac Third Sound
The number, and proportion with the two-sided 95% confidence intervals (exact) will be 
calculated for the resolution rates of pulmonary rales and cardiac third sound at the time 
of final IMP administration. The resolution rate is defined as the proportion of subjects in 
whom a symptom is present at baseline and disappears after IMP administration.
Shift tables showing whether the symptom is present will be prepared at each on-
treatment time point and at the time of final IMP administration compared with baseline.
8.3.3
Dyspnea
8.3.3.1
Respiratory Rate
Descriptive statistics and two-sided 95% confidence intervals (based on t-distribution) 
will be calculated for measured values and changes from baseline at the time of final IMP 
administration. At each time point, descriptive statistics will be calculated.
8.3.3.2
Orthopnea and Paroxysmal Nocturnal Dyspnea
The number, and proportion with the two-sided 95% confidence intervals (exact) will be 
calculated for the resolution rates of orthopnea and paroxysmal nocturnal dyspnea at the 
time of final IMP administration. The resolution rate is defined as the proportion of 
subjects in whom a symptom is present at baseline and then disappears after IMP 
administration.
Shift tables showing whether each symptom is present will be prepared at each postdose 
time point and at the time of final IMP administration compared with baseline.
8.3.3.3
Subject-assessed Dyspnea
The number, and proportion with the two-sided 95% confidence intervals (exact) will be 
calculated for the improvement rate at the time of final IMP administration. The 
improvement rate is defined as the proportion of subjects in whom a symptom is present 
at baseline and then mildly improved, moderately improved or markedly improved after 
IMP administration.
The frequencies at each postdose time point and at the time of final IMP administration 
will be summarized.


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8.3.4
NYHA Classification
A shift table showing the NYHA classification will be prepared at each on-treatment time 
point and at the time of final IMP administration compared to baseline.
For subjects in Class II and higher, the number and proportion with two-sided 95% 
confidence intervals (exact) will be calculated for subjects who have improved from 
baseline by 1 class or more at the final IMP administration.
8.4
Subgroup Analyses
Subgroup analyses will not be performed in this trial.
9
Safety Analyses
The following analyses will be conducted on the safety dataset. The same analyses will 
also be conducted for subjects categorized by the presence or absence of dose escalation 
(ie, subjects with dose increased to 16 mg and subjects with dose maintained at 8 mg 
without dose escalation) based on the dose escalation criteria.
9.1
Extent of Exposure
Distributions of the number of subjects on each number of administration days will be 
calculated. Descriptive statistics of the number of administration days will be calculated. 
The number of subjects at each daily dose (8 or 16 mg) will be counted on each 
administration day. The combination of number of administration days for each daily 
dose will be summarized in a cross table.
9.2
Adverse Events
All AEs will be coded by system organ class (SOC) and ICH Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term (PT). The incidence of the following 
events will be summarized for 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 discontinuation of the IMP
If there are multiple occurrences of the same event in the same period in the same 
subject, the event with the highest severity will be selected. IMP-related TEAEs will be 
summarized in the same manner as shown above.


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For TEAEs, a summary table will also be created for any TEAE that occurs in more than 
2 subjects in any group.
9.3
Clinical Laboratory Data
Clinical laboratory data obtained from central measurements will be used for analyses. 
For clinical laboratory test parameters other than qualitative urinalysis, measured values 
and changes from baseline at each time point and at the time of final IMP administration 
will be summarized using descriptive statistics. For qualitative urinalysis parameters, 
shift tables will be prepared at each time point and at the time of final IMP administration 
compared with baseline. In addition, measured values of clinical laboratory test 
parameters other than qualitative urinalysis will be categorized as below, within, or above 
the normal range, and shift tables will be prepared at each postdose time point and at the 
time of final IMP administration compared with baseline.
The numbers and percentages of subjects who have a visit with serum total bilirubin 
value of ≥2 times the upper limit of normal (ULN), and an aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) value of ≥3 times the ULN at any postdose 
time point will be calculated.
The numbers and percentages of subjects experiencing the following events after IMP 
administration will be calculated.

A serum sodium concentration >147 mEq/L

A >10 mEq/L increase in serum sodium concentration within 24 hours after the start 
of IMP administration
9.4
Vital Sign Data
For vital signs (blood pressure, pulse rate, and body temperature), measured values and 
changes from baseline at each time point and at the time of final IMP administration will 
be summarized using descriptive statistics.
9.5
Physical Examination Data
No physical examination data analysis will be performed in this trial.
9.6
Electrocardiogram Data
For 12-lead ECG parameters, measured values and changes from baseline will be 
summarized at each time point and at the time of final IMP administration using 
descriptive statistics.


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The numbers and percentages of subjects who have a QT corrected for heart rate (QTc) 
interval of >450, >480, or >500 msec at any postdose time point until the time of final 
IMP administration will be calculated. The numbers and percentages of subjects who 
have a change in QTc interval from baseline of >30 and >60 msec at any postdose time 
point or at the time of final IMP administration will be calculated. Also at baseline and at 
each postdose time point, the numbers and percentages of subjects will be calculated in 
the same manner as described above.
A shift table showing interpretation (normal or abnormal) will be prepared at each 
postdose time point and at the time of final IMP administration compared to baseline. 
Interpretation (normal or abnormal) assessments by the trial site (investigator or 
subinvestigator) will be used.
9.7
Other Safety Data
None.
10
Pharmacokinetic Analyses
No pharmacokinetic analysis will be performed in this trial.
11
Pharmacodynamic Analyses
A pharmacodynamic analysis will be conducted on the pharmacodynamic dataset. The 
same analysis will also be conducted for subjects categorized by the presence or absence 
of dose escalation (ie, subjects with dose increased to 16 mg and subjects with dose 
maintained at 8 mg without dose escalation) based on the dose escalation criteria 
(excluding analysis regarding the day of IMP dose escalation).
11.1
Urine Volume, Fluid Intake, Fluid Balance
Descriptive statistics for measured values and changes from baseline at each time point 
will be calculated for daily urine volume, daily fluid intake, and daily fluid balance (0 to 
24 hours).
Descriptive statistics for measured values at each time point will be calculated for 
interval urine volume, interval fluid intake, and interval fluid balance (0 to 1 hour, 1 to 
2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, and 8 to 24 hours) on Day 1 and for 
interval urine volume, interval fluid intake, and interval fluid balance (0 to 4 hours, 4 to 8 
hours, and 8 to 24 hours) on the day of IMP dose escalation (Day 2 or Day 3).
Descriptive statistics for measured values at each time point will be calculated for 
cumulative urine volume, cumulative fluid intake, and cumulative fluid balance (0 to 


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1 hour, 0 to 2 hours, 0 to 4 hours, 0 to 6 hours, 0 to 8 hours, and 0 to 24 hours) on Day 1 
and for cumulative urine volume, cumulative fluid intake, and cumulative fluid balance 
(0 to 4 hours, 0 to 8 hours, and 0 to 24 hours) on the day of IMP dose escalation (Day 2 
or Day 3).
Note that a fluid balance will be calculated by subtracting the “urine volume” from the 
“fluid intake.”
11.2
Serum Sodium Concentration, Serum Potassium Concentration, 
Serum Osmolality
Descriptive statistics will be calculated for measured values and changes from baseline at 
each time point.
For subjects with dose escalation to 16 mg on Day 2 or Day 3, descriptive statistics will 
be calculated for measured values and changes from before IMP administration on the 
day of IMP dose escalation at each time point (from before IMP administration on the 
day of dose escalation to before IMP administration on the next day).
For serum sodium concentration, central laboratory measurements will be used.
11.3
Biomarkers (Plasma AVP Concentration, Plasma Renin Activity, 
Plasma BNP Concentration, Serum NT-proBNP Concentration, and 
Serum Troponin I Concentration)
Descriptive statistics will be calculated for measured values and changes from baseline at 
each time point and at the time of final IMP administration.
11.4
Urine Sodium Excretion, Urine Potassium Excretion, Urine 
Osmolality
Descriptive statistics for measured values and changes from baseline at each time point 
will be calculated for daily urine sodium excretion and daily urine potassium excretion (0 
to 24 hours).
Descriptive statistics for measured values at each time point will be calculated for 
interval urine sodium excretion and interval urine potassium excretion (0 to 4 hours, 4 to 
8 hours, and 8 to 24 hours) on Day 1 and the day of dose escalation (Day 2 or Day 3).
Descriptive statistics for measured values at each time point will be calculated for 
cumulative urine sodium excretion and cumulative urine potassium excretion (0 to 4 
hours, 0 to 8 hours, and 0 to 24 hours) on Day 1 and the day of dose escalation (Day 2 or 
Day 3).


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Descriptive statistics for measured values and changes from baseline at each time point 
will be calculated for urine osmolality.
Note that urine sodium excretion and urine potassium excretion will be calculated by 
multiplying the urine sodium concentration and the urine potassium concentration 
obtained at the central laboratory, respectively, by urine volume.
12
Pharmacogenomic Analyses
No pharmacogenomic analysis will be performed in this trial.
13
Interim Analysis
No interim analysis will be performed in this trial.
14
Changes in the Planned Analyses
Regarding IMP dose escalation based on the dose escalation criteria, the subject 
distribution was found to be different than had originally been expected. Therefore it was 
decided not to conduct the analysis “by timing of dose escalation (ie, subjects achieving a 
dose escalation to 16 mg on Day 2, those achieving a dose escalation to 16 mg on Day 3, 
and those achieving no dose escalation to 16 mg)” in Section 7.4.1, Section 7.4.2, and 
Section 7.4.3 in the protocol, but to add analysis “by presence or absence of dose 
escalation (ie, subjects with dose increased to 16 mg and subjects with dose maintained at 
8 mg without dose escalation)” to Section 8, Section 9, and Section 11 of the Statistical 
Analysis Plan.
15
References
None.


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Appendix 1
List of Summary Tables
CT-1
Subject Disposition (Screened Subjects)
CT-2.1
Reasons for Discontinuation (IMP Administered Subjects)
CT-2.2
Reasons for Early Completion (IMP Administered Subjects)
CT-2.3
Protocol Deviations (IMP Administered Subjects)
CT-3.1.1
Demographic and Baseline Characteristics (Efficacy Analysis Set)
CT-3.1.2
Demographic and Baseline Characteristics (Safety Analysis Set)
CT-3.2.1
Underlying Disease Leading to Heart Failure (Efficacy Analysis Set)
CT-3.2.2
Underlying Disease Leading to Heart Failure (Safety Analysis Set)
CT-3.2.3
Medical History (Efficacy Analysis Set)
CT-3.2.4
Medical History (Safety Analysis Set)
CT-3.3.1
Reason why oral intake was judged to be difficult or impossible (Efficacy 
Analysis Set)
CT-3.3.2
Reason why oral intake was judged to be difficult or impossible (Safety 
Analysis Set)
CT-3.4.1
Baseline Disease Evaluation (Efficacy Analysis Set)
CT-3.4.2
Baseline Disease Evaluation (Safety Analysis Set)
CT-5.1
Confidence Interval for Change from Baseline in Body Weight at the time 
of Day After Final IMP Administration (Efficacy Analysis Set)
CT-5.2
Descriptive Statistics for Change from Baseline in Body Weight (Efficacy 
Analysis Set)
CT-5.3
Descriptive Statistics for Change Rate from Baseline in Body Weight 
(Efficacy Analysis Set)
CT-6.1
Improvement Rate for Lower Limb Edema and Pulmonary Congestion at 
the time of final IMP administration (Efficacy Analysis Set)
CT-6.2
Disappearance Rate for Lower Limb Edema and Pulmonary Congestion at 
the time of final IMP administration (Efficacy Analysis Set)
CT-6.3
Shift Table for Lower Limb Edema (Efficacy Analysis Set)
CT-6.4
Shift Table for Pulmonary Congestion (Efficacy Analysis Set)


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CT-6.5.1
Confidence Interval for Change from Baseline in Jugular Venous 
Distension at the time of Day After Final IMP Administration (Efficacy 
Analysis Set)
CT-6.5.2
Confidence Interval for Change from Baseline in Jugular Venous 
Distension at the time of Day After Final IMP Administration (Subjects 
With Baseline Value in Efficacy Analysis Set)
CT-6.6.1
Confidence Interval for Change from Baseline in Hepatomegaly at the 
time of Day After Final IMP Administration (Efficacy Analysis Set)
CT-6.6.2
Confidence Interval for Change from Baseline in Hepatomegaly at the 
time of Day After Final IMP Administration (Subjects With Baseline 
Value in Efficacy Analysis Set)
CT-6.7
Confidence Interval for Change from Baseline in Cardiothoracic Ratio at 
the time of Day After Final IMP Administration (Efficacy Analysis Set)
CT-6.8.1
Descriptive Statistics for Jugular Venous Distension (cm) (Efficacy 
Analysis Set)
CT-6.8.2
Descriptive Statistics for Jugular Venous Distension (cm) (Subjects With 
Baseline Value in Efficacy Analysis Set)
CT-6.9.1
Descriptive Statistics for Hepatomegaly (cm) (Efficacy Analysis Set)
CT-6.9.2
Descriptive Statistics for Hepatomegaly (cm) (Subjects With Baseline 
Value in Efficacy Analysis Set)
CT-6.10
Descriptive Statistics for Cardiothoracic Ratio (%) (Efficacy Analysis Set)
CT-6.11
Shift Table for Jugular Venous Distension (Efficacy Analysis Set)
CT-6.12
Shift Table for Hepatomegaly (Efficacy Analysis Set)
CT-6.13
Disappearance Rate for Pulmonary rales and Third Cardiac Sound at the 
time of final IMP administration (Efficacy Analysis Set)
CT-6.14
Shift Table for Pulmonary rales (Efficacy Analysis Set)
CT-6.15
Shift Table for Third Cardiac Sound (Efficacy Analysis Set)
CT-6.16
Confidence Interval for Change from Baseline in Respiratory Rate 
(breaths/min) at the time of Day After Final IMP Administration (Efficacy 
Analysis Set)


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CT-6.17
Descriptive Statistics for Respiratory Rate (breaths/min) (Efficacy 
Analysis Set)
CT-6.18
Disappearance Rate for Paroxysmal Nocturnal Dyspnea and Orthopnea at 
the time of final IMP administration (Efficacy Analysis Set)
CT-6.19
Shift Table for Orthopnea (Efficacy Analysis Set)
CT-6.20
Shift Table for Paroxysmal Nocturnal Dyspnea (Efficacy Analysis Set)
CT-6.21
Improvement Rate for Subject-assessed Dyspnea at the time of final IMP 
administration (Efficacy Analysis Set)
CT-6.22
Frequency Distribution for Subject-assessed Dyspnea (Efficacy Analysis 
Set)
CT-6.23
Improvement Rate for NYHA Classification at the time of Day After Final 
IMP Administration (Efficacy Analysis Set)
CT-6.24
Shift Table for NYHA Classification (Efficacy Analysis Set)
CT-7.1.1
Extent of Exposure to Investigational Medicinal Product (Safety Analysis 
Set)
CT-7.1.2
Extent of Exposure to Investigational Medicinal Product by Dose (Safety 
Analysis Set)
CT-7.1.3
Extent of Exposure to Investigational Medicinal Product Cross Table by 
Dose, Days (Safety Analysis Set)
CT-7.2.1
Treatment Compliance (Efficacy Analysis Set)
CT-7.2.2
Treatment Compliance (Safety Analysis Set)
CT-8.1
Overall Summary of Adverse Events (Safety Analysis Set)
CT-8.2
Incidence of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Analysis Set)
CT-8.3
Incidence of Drug-related Treatment-emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set)
CT-8.4
Incidence of Treatment-emergent Adverse Events by Severity by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set)
CT-8.5
Incidence of Drug-related Treatment-emergent Adverse Events by 
Severity by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set)


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CT-8.6
Incidence of Treatment-emergent Adverse Events Occurring in >= 2 
subjects of All Subjects by MedDRA System Organ Class and Preferred 
Term (Safety Analysis Set)
CT-8.7
Incidence of Drug-related Treatment-emergent Adverse Events Occurring 
in >= 2 subjects of All Subjects by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set)
CT-9.1
Incidence of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set)
CT-9.2
Incidence of Drug-related Treatment-emergent Adverse Events with an 
outcome of death by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set)
CT-9.3
Incidence of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set)
CT-9.4
Incidence of Drug-related Serious Treatment-emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set)
CT-9.5
Incidence of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set)
CT-9.6
Incidence of Drug-related Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set)
CT-9.7
Listing of Deaths (IMP Administered Subjects)
CT-9.8
Listing of Serious Adverse Events Other Than Death (IMP Administered 
Subjects)
CT-9.9
Listing of Adverse Events Leading to Discontinuation of Investigational 
Medicinal Product Administration (IMP Administered Subjects)
CT-10.1.1
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry) (Safety Analysis Set)
CT-10.1.2
Mean Change from Baseline in Clinical Laboratory Test Results 
(Hematology) (Safety Analysis Set)


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CT-10.1.3
Mean Change from Baseline in Clinical Laboratory Test Results 
(Urinalysis) (Safety Analysis Set)
CT-10.2
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) 
(Safety Analysis Set)
CT-10.3.1
Shift Tables of Clinical Laboratory Test Results (Serum Chemistry) 
(Safety Analysis Set)
CT-10.3.2
Shift Tables of Clinical Laboratory Test Results (NA, K) (Safety Analysis 
Set)
CT-10.3.3
Shift Tables of Clinical Laboratory Test Results (Hematology) (Safety 
Analysis Set)
CT-10.3.4
Shift Tables of Clinical Laboratory Test Results (Urinalysis) (Safety 
Analysis Set)
CT-10.4.1
Listing of Abnormal Laboratory Findings (IMP Administered Subjects)
CT-10.4.2
Listing of Abnormal Laboratory Findings Potential Drug-Induced Liver 
Injury (IMP Administered Subjects)
CT-10.5
Incidence of Potential Drug-Induced Liver Injury (Safety Analysis Set)
CT-10.6
Incidence of Sodium Related Events (Safety Analysis Set)
CT-11
Mean Change from Baseline in Vital Signs (Safety Analysis Set)
CT-12.1
Mean Change from Baseline in Electrocardiogram Results (Safety 
Analysis Set)
CT-12.2.1
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) 
(Safety Analysis Set)
CT-12.3.1
Incidence of Categorical Changes in Electrocardiogram Results (Post 
baseline any visit) (Safety Analysis Set)
CT-12.3.2
Incidence of Categorical Changes in Electrocardiogram Results (Each 
Visit) (Safety Analysis Set)
PDT-1.1
Descriptive Statistics for Daily Urine Volume (mL) (Pharmacodynamic 
Analysis Set)
PDT-1.2.1
Descriptive Statistics for Interval Urine Volume (mL) (Pharmacodynamic 
Analysis Set)


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PDT-1.2.2
Descriptive Statistics for Interval Urine Volume (mL) by Dose Escalation 
(Pharmacodynamic Analysis Set)
PDT-1.3.1
Descriptive Statistics for Cumulative Urine Volume (mL) 
(Pharmacodynamic Analysis Set)
PDT-1.3.2
Descriptive Statistics for Cumulative Urine Volume (mL) by Dose 
Escalation (Pharmacodynamic Analysis Set)
PDT-2.1
Descriptive Statistics for Daily Fluid Intake (mL) (Pharmacodynamic 
Analysis Set)
PDT-2.2.1
Descriptive Statistics for Interval Fluid Intake (mL) (Pharmacodynamic 
Analysis Set)
PDT-2.2.2
Descriptive Statistics for Interval Fluid Intake (mL) by Dose Escalation 
(Pharmacodynamic Analysis Set)
PDT-2.3.1
Descriptive Statistics for Cumulative Fluid Intake (mL) 
(Pharmacodynamic Analysis Set)
PDT-2.3.2
Descriptive Statistics for Cumulative Fluid Intake (mL) by Dose 
Escalation (Pharmacodynamic Analysis Set)
PDT-3.1
Descriptive Statistics for Daily Fluid Balance (mL) (Pharmacodynamic 
Analysis Set)
PDT-3.2.1
Descriptive Statistics for Interval Fluid Balance (mL) (Pharmacodynamic 
Analysis Set)
PDT-3.2.2
Descriptive Statistics for Interval Fluid Balance (mL) by Dose Escalation 
(Pharmacodynamic Analysis Set)
PDT-3.3.1
Descriptive Statistics for Cumulative Fluid Balance (mL) 
(Pharmacodynamic Analysis Set)
PDT-3.3.2
Descriptive Statistics for Cumulative Fluid Balance (mL) by Dose 
Escalation (Pharmacodynamic Analysis Set)
PDT-4.1
Descriptive Statistics for Serum Sodium Concentration (mEq/L) 
(Pharmacodynamic Analysis Set)
PDT-4.2
Descriptive Statistics for Serum Sodium Concentration (mEq/L) for Dose 
Escalated Subjects (Pharmacodynamic Analysis Set)
PDT-5.1
Descriptive Statistics for Serum Potassium Concentration (mEq/L) 
(Pharmacodynamic Analysis Set)


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PDT-5.2
Descriptive Statistics for Serum Potassium Concentration (mEq/L) for 
Dose Escalated Subjects (Pharmacodynamic Analysis Set)
PDT-6.1
Descriptive Statistics for Serum Osmolality (mOsm/kg) 
(Pharmacodynamic Analysis Set)
PDT-6.2
Descriptive Statistics for Serum Osmolality (mOsm/kg) for Dose 
Escalated Subjects (Pharmacodynamic Analysis Set)
PDT-7
Descriptive Statistics for Plasma AVP Concentration (pg/mL) 
(Pharmacodynamic Analysis Set)
PDT-8
Descriptive Statistics for Plasma BNP Concentration (pg/mL) 
(Pharmacodynamic Analysis Set)
PDT-9
Descriptive Statistics for Plasma Renin Activity (ng/mL/hr) 
(Pharmacodynamic Analysis Set)
PDT-10
Descriptive Statistics for Serum pro BNP Concentration (pg/mL) 
(Pharmacodynamic Analysis Set)
PDT-11
Descriptive Statistics for Serum Troponin Concentration (pg/mL) 
(Pharmacodynamic Analysis Set)
PDT-12.1
Descriptive Statistics for Daily Urine Excretion of Sodium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-12.2.1
Descriptive Statistics for Inteval Urine Excretion of Sodium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-12.2.2
Descriptive Statistics for Inteval Urine Excretion of Sodium (mEq) by 
Dose Escalation (Pharmacodynamic Analysis Set)
PDT-12.3.1
Descriptive Statistics for Cumulative Urine Excretion of Sodium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-12.3.2
Descriptive Statistics for Cumulative Urine Excretion of Sodium (mEq) by 
Dose Escalation (Pharmacodynamic Analysis Set)
PDT-13.1
Descriptive Statistics for Daily Urine Excretion of Potassium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-13.2.1
Descriptive Statistics for Interval Urine Excretion of Potassium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-13.2.2
Descriptive Statistics for Interval Urine Excretion of Potassium (mEq) by 
Dose Escalation (Pharmacodynamic Analysis Set)


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PDT-13.3.1
Descriptive Statistics for Cumulative Urine Excretion of Potassium (mEq) 
(Pharmacodynamic Analysis Set)
PDT-13.3.2
Descriptive Statistics for Cumulative Urine Excretion of Potassium (mEq) 
by Dose Escalation (Pharmacodynamic Analysis Set)
PDT-14.1
Descriptive Statistics for Urine Osmolality (mOsm/kg) (Pharmacodynamic 
Analysis Set)


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Appendix 2
List of Subject Data Listings
AE-1
Adverse Events (IMP Administered Subjects)
AE-2
Adverse Events Observed Before Start of Investigational Medicinal 
Product Administration (IMP Administered Subjects)
DEMOG-1
Demographic and Baseline Characteristics (IMP Administered Subjects)
DREAS-1
Discontinued Subjects and Reason for Discontinuation (IMP Administered 
Subjects)
LAB-1
Laboratory Test Results - Serum Chemistry (IMP Administered Subjects)
LAB-2
Laboratory Test Results - Hematology (IMP Administered Subjects)
LAB-3
Laboratory Test Results - Urinalysis (IMP Administered Subjects)
LAB-4
Laboratory Test Results - Serum Sodium, K Trial Site (IMP Administered 
Subjects)
PDEV-1
Protocol Deviations (IMP Administered Subjects)
SMED-1
Investigational Medicinal Product Compliance Injection (IMP 
Administered Subjects)
SMED-2
Investigational Medicinal Product Compliance Injection (Full 
Administration / Interruption) (IMP Administered Subjects)
SUBEX-1
Subjects Excluded From Analysis Set (IMP Administered Subjects)
PDATA-1
Study Completion Status and Reason for Discontinuation and Reason for 
Early Completion (IMP Administered Subjects)
PDATA-2
Inclusion Criteria and Exclusion Criteria Not Met 
PDATA-3.1
Medical History and Complications (IMP Administered Subjects)
PDATA-3.2
History of Congestive Heart Failure (IMP Administered Subjects)
PDATA-4.1
Concomitant Medications (IMP Administered Subjects)
PDATA-4.2
Concomitant Therapy Other Than Medication (IMP Administered 
Subjects)
PDATA-5.1
Vital Signs (IMP Administered Subjects)
PDATA-5.2
Height (IMP Administered Subjects)
PDATA-6.1
Electrocardiogram Results Central ECG Analysis Laboratory (IMP 
Administered Subjects)


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PDATA-6.2
Electrocardiogram Results Trial Site (IMP Administered Subjects)
PDATA-7
Screen Failures 
PDATA-8
Physical Examination (IMP Administered Subjects)
PDATA-9
Serum Sodium Concentration, Serum Potassium Concentration (IMP 
Administered Subjects)
PDATA-10
Serum Osmolality, Plasma AVP Concentration, Plasma BNP 
Concentration, Plasma Renin Activity (IMP Administered Subjects)
PDATA-11
Serum NT pro BNP Concentration, Serum Troponin Concentration (IMP 
Administered Subjects)
PDATA-12
Urine Volume, Fluid Intake, Fluid Balance, Urine Sodium Concentration, 
Urine Osmolality, Urine Potassium Concentration Urine Excretion of 
Sodium, Urine Excretion of Potassium (IMP Administered Subjects)
PDATA-13
Previous Screened ID (IMP Administered Subjects)
PDATA-14
Post-treatment Follow-up (IMP Administered Subjects)
PDATA-15
Pharmacogenomics (IMP Administered Subjects)
PDATA-16
Dose Increase Assessment (IMP Administered Subjects)
EFF-1
Body Weight (IMP Administered Subjects)
EFF-2
Congestive Symptoms (Lower Limb Edema, Jugular Venous Distension, 
Hepatomegaly, Pulmonary rales, Third Cardiac Sound) (IMP 
Administered Subjects)
EFF-3
Chest X-ray (Pulmonary Congestion, Cardiothoracic Ratio) (IMP 
Administered Subjects)
EFF-4
Dyspnea (Respiratory Rate, Paroxysmal Nocturnal Dyspnea, Orthopnea, 
and Subject-assessed Dyspnea) (IMP Administered Subjects)
EFF-5
NYHA Classification (IMP Administered Subjects)