A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure
Phase: PHASE3
Conditions: Congestive Heart Failure
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, 
Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection 
Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure 
 
 
 
 
NCT Number: NCT03772041 
PRT NO.: 263-102-00003 
Version Date: 27 March 2020 (Version 3.0) 

Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
OPC-61815
CLINICAL PROTOCOL
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, 
Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection 
Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure
Protocol No. 263-102-00003
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event 
Otsuka Pharmaceutical Co., Ltd.
Department of Pharmacovigilance
Email: IRE_263-102-00003@otsuka.jp
Amendment 2 Approval:
27 Mar 2020
Amendment 1 Approval:
15 Mar 2019
Approval:
26 Sep 2018
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.: 263-102-00003
Protocol Title:
A Multicenter, Double-blind, Randomized, Active-controlled, 
Parallel-group, Non-inferiority Trial to Evaluate the Efficacy 
and Safety of OPC-61815 Injection Compared With Tolvaptan 
15-mg Tablet in Patients With Congestive Heart Failure
Clinical Phase/Trial 
Type:
Phase 3/Confirmatory Trial
Treatment Indication: Congestive heart failure (CHF) patients with volume overload 
despite having received diuretics other than vasopressin 
antagonists
Objective(s): 
Primary: Primary: To confirm the non-inferiority of 
OPC-61815 16-mg injection to tolvaptan 15-mg tablet using as 
the primary endpoint the change in body weight following 
5-day intravenous administration of OPC-61815 16-mg 
injection or 5-day oral administration of tolvaptan 15-mg tablet 
to CHF patients with volume overload despite having received 
diuretics other than vasopressin antagonists
Secondary: To evaluate other efficacy endpoints and the 
safety, pharmacodynamics, and pharmacokinetics of 
OPC-61815 16-mg injection in comparison with tolvaptan 
15-mg tablet
Trial Design:
Multicenter, randomized, double-blind, active-controlled, 
parallel group, non-inferiority trial
Subject Population:
Male and female CHF patients age 20 to 85 years, inclusive, 
with volume overload (ie, lower limb edema, pulmonary 
congestion, and/or jugular venous distension) despite having 
received diuretics other than vasopressin antagonists 
The sample size was set at a total of 288 subjects, comprising 
144 subjects in each group.
Inclusion/Exclusion 
Criteria: 
Inclusion criteria (screening period):
1) Patients receiving any of the following oral diuretics 
(including patients planning to initiate treatment during 
the run-in period)

Loop diuretics equivalent to furosemide tablet or 
fine granules at a dose of 40 mg/day or higher

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
Concomitant use of a loop diuretic and a thiazide 
diuretic (including thiazide analogs) at any dose

Concomitant use of a loop diuretic and an 
aldosterone antagonist or potassium-sparing 
diuretic agent at any dose
Note: See Table 3.4-1 for the types and doses of 
concomitant diuretics
2) Patients with CHF in whom lower limb edema, 
pulmonary congestion, or jugular venous distension 
due to volume overload is present. Patients with 
pulmonary congestion may be enrolled if pulmonary 
congestion is confirmed by chest x-ray performed 
within 14 days prior to informed consent.
3) Male and female patients age of 20 to 85, inclusive, at 
the time of informed consent
4) Patients who are currently hospitalized or who are able 
to be hospitalized from the day before the run-in period 
(on Day −4) until the end of the treatment period
5) Patients who are capable of taking oral tablets
6) Patients who are capable of giving consent
Inclusion criteria (run-in period):
7) Patients with lower limb edema, jugular venous 
distension (on Day −1 of the run-in period), or 
pulmonary congestion (confirmed by chest x-ray 
during the run-in period)
8) Patients who have received diuretics with no change in 
dose or regimen during the run-in period
9) Patients with no more than 1.0 kg change in body 
weight over the 2 days (Day −2 and −1 of the run-in 
period) prior to initial administration of the 
investigational medicinal product (IMP)
Exclusion criteria:
1) Patients with acute heart failure
2) Patients with mainly noncardiogenic congestive 
symptoms
3) Patients who are on a ventricular assist device
4) Patients who have any of the following diseases, 
complications, or conditions:

Suspected hypovolemia

Hypertrophic cardiomyopathy (excluding dilated 

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phase)

Valvular disease with significant valvular stenosis

Hepatic encephalopathy with difficulty in adequate 
fluid intake
5) Patients who have experienced acute myocardial 
infarction within 30 days prior to the screening 
examination
6) Patients with a definite diagnosis of active myocarditis 
or amyloid cardiomyopathy
7) 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
8) 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
9) Patients who are severely obese (body mass index 
[BMI]: body weight [kg]/height [m]2) exceeding 
35 kg/m2
10) Patients with supine systolic blood pressure of 
<90 mmHg
11) Patients with any of the following abnormalities in 
laboratory test results:
Total bilirubin: >3.0 mg/dL, serum creatinine: 
>3.0 mg/dL, serum sodium: <125 mEq/L or 
>147 mEq/L, serum potassium: >5.5 mEq/L 
12) Patients with current symptoms or a history of hepatic 
impairment (including patients with aspartate 

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aminotransferase [AST] or alanine aminotransferase 
[ALT] exceeding 3 times the upper limit of the 
reference range at the screening examination)
13) Patients who are unable to sense thirst or who have 
difficulty with fluid intake
14) Female patients who are breast-feeding or who have a 
positive pregnancy test result prior to receiving 
investigational product (IMP)
15) Sexually active males 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.
16) Patients who have received tolvaptan within 28 days 
prior to the screening examination
17) Patients who have participated in a clinical trial in 
which they received OPC-61815
18) Patients who have participated in another clinical trial 
and received another IMP within 30 days prior to the 
screening examination
19) Patients who are otherwise judged to be ineligible by 
the investigator or subinvestigator
Trial Site(s):
Approximately 55 sites in Japan
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 16 mg of OPC-61815 or placebo in a 
vial and tolvaptan 15-mg tablet or placebo tablet. This trial 
will be conducted using a double-dummy design to maintain 
blindness. Subjects will receive a combination of either 
OPC-61815 injection and placebo tablet or placebo injection 
and tolvaptan 15-mg tablet. Once daily, first either tolvaptan 
15-mg tablet or placebo tablet will be orally administered, 
followed immediately by 1-hour intravenous administration of 
either OPC-61815 injection at 16 mg or placebo injection. The 
treatment period will be 5 days.
Trial Assessments:
Efficacy: Body weight, congestive symptoms (lower limb 
edema, pulmonary congestion, jugular venous distension, 
hepatomegaly, cardiothoracic ratio, pulmonary rales, and 
cardiac third sound), and New York Heart Association 
(NYHA) classification
Pharmacokinetic: Blood sampling for plasma concentrations of 
OPC-61815 free form and tolvaptan (OPC-41061)
Pharmacodynamics: Daily urine volume, daily fluid intake, 

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serum sodium concentration, serum potassium concentration, 
serum 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), and urine osmolality
Safety: Adverse events, clinical laboratory tests (including 
pregnancy test), physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), and 12-lead 
electrocardiography (ECG)
Screening/Other: Medical and medication history, physical 
examination, laboratory tests, vital signs, body weight, urine 
pregnancy test, and DNA storage
Criteria for 
Evaluation:
Primary Endpoint: 
Change in body weight from baseline (before IMP 
administration on Day 1) at time of final IMP administration 
(day after final IMP administration)
Secondary Endpoints: 
Congestive symptoms (lower limb edema, pulmonary 
congestion, jugular venous distension, hepatomegaly, 
cardiothoracic ratio, pulmonary rales, and cardiac third sound) 
and NYHA classification
Pharmacokinetic Endpoint:
Plasma concentrations of OPC-61815 free form and tolvaptan 
(OPC-41061)
Pharmacodynamic Endpoints:
Daily urine volume, daily fluid intake, daily fluid balance, 
serum sodium concentration, serum potassium concentration, 
serum osmolality, biomarker measurements (plasma 
concentrations of AVP and BNP, plasma renin activity, and 
serum concentrations of NT-proBNP and troponin I), daily 
urine sodium excretion, daily urine potassium excretion, and 
urine osmolality
Safety Endpoints:
Adverse events, clinical laboratory tests (including pregnancy 
test), physical examination, vital signs (blood pressure, pulse 
rate, and body temperature), and 12-lead ECG

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Statistical Methods:
Statistical Methods for the Primary Endpoint:
The primary endpoint is change in body weight from baseline 
(before IMP administration on Day 1) at the time of final IMP 
administration. Main analysis will be performed using an 
ANCOVA model with treatment as the fixed effect factor and 
body weight at baseline as a covariate. The least-square mean 
of the difference between the OPC-61815 16-mg injection 
group and the tolvaptan 15-mg tablet group and its two-sided 
95% confidence interval (CI) will be calculated. The non-
inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg 
tablet will be confirmed when the upper limit of the confidence 
interval does not exceed 0.48.
Rationale for Sample Size:
The number of subjects required to confirm the non-inferiority 
of OPC-61815 16-mg injection to tolvaptan 15-mg tablet for 
the primary endpoint of change in body weight from baseline 
(before IMP administration on Day 1) at the time of final IMP 
administration (day after final IMP administration) was 
determined.
In the clinical development of tolvaptan for the treatment of 
cardiac edema, there were 2 placebo-comparison trials 
conducted for tolvaptan 15-mg tablet: a phase 2 trial (156-03-
001) and a phase 3 trial (156-06-002). Regarding the change in 
body weight (kg) on the morning after Day 5 of treatment 
(LOCF) in those 2 trials, from an ANCOVA model analysis 
performed using body weight (kg) at baseline as a covariate, 
the least-square mean of the difference (treatment difference) 
between the tolvaptan 15-mg tablet group and the placebo 
group was respectively −0.99 (95% CI: −1.57 to −0.42) and 
−0.96 (95% CI: −1.37 to −0.55). Referring to the upper limit of 
those CIs, the reliably expected (at 95% probability) minimum 
difference in body weight decrease (maximum difference in 
body weight) between the tolvaptan 15-mg tablet group and 
the placebo group was considered to be in the range of 0.42 to 
0.55. The non-inferiority margin for the present trial was 
therefore set at 0.48, which corresponds to half of the 
treatment difference of 0.96 between the tolvaptan 15-mg 
tablet group and the placebo group in the tolvaptan phase 3 
trial.
Setting the non-inferiority margin at 0.48, the detection power 
at 90%, and the significance level at 5%, and using the value 
for up until the morning after Day 5 of treatment in the 
tolvaptan 15-mg tablet in the tolvaptan phase 3 trial to set the 

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mean ± SD change in body weight from baseline at time of 
final administration at −1.30 ± 1.25 for both the tolvaptan 
15-mg tablet group and the OPC-61815 16-mg injection group, 
the number of subjects required for this trial was determined to 
be 288 (144 subjects per group).
Trial Duration:
Planned duration of the clinical trial: Jan 2019 to Jul 2020
Planned duration of trial participation for each subject: 
Maximum of 22 days (screening [4 to 7 days before start of 
IMP administration], 3 days for run-in period, 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...........................................................................................9
List of In-text Tables ...................................................................................15
List of In-text Figures..................................................................................16
List of Appendices........................................................................................17
List of Abbreviations and Definitions of Terms .......................................18
1
Introduction ........................................................................................21
1.1
Nonclinical Data................................................................................................22
1.2
Clinical Data......................................................................................................24
1.2.1
Phase 1 Trials of OPC-61815 Injection in Healthy Male Subjects (Trials 
263-08-001, 263-09-001, and 263-10-005; Japan).........................................24
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) ..........................................................................................25
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).................................................................................................26
1.3
Known and Potential Risks and Benefits ..........................................................27
2
Trial Rationale and Objectives..........................................................28
2.1
Trial Rationale...................................................................................................28
2.2
Dosing Rationale...............................................................................................29
2.3
Trial Objectives.................................................................................................31
3
Trial Design.........................................................................................31
3.1
Type/Design of Trial .........................................................................................31
3.2
Trial Treatments ................................................................................................33
3.2.1
Dosage Regimen and Treatment Duration .....................................................33
3.2.2
Preparation of Investigational Medicinal Products.........................................34
3.3
Trial Population.................................................................................................34
3.3.1
Number of Subjects and Description of Population .......................................34
3.3.2
Subject Selection and Numbering ..................................................................34
3.4
Eligibility Criteria..............................................................................................34

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3.4.1
Informed Consent ...........................................................................................34
3.4.2
Inclusion Criteria ............................................................................................35
3.4.2.1
Screening Period .........................................................................................35
3.4.2.2
Run-in Period ..............................................................................................36
3.4.3
Exclusion Criteria...........................................................................................37
3.5
Endpoints...........................................................................................................39
3.5.1
Primary Endpoint............................................................................................39
3.5.2
Secondary Endpoints ......................................................................................39
3.5.3
Pharmacokinetic Endpoint..............................................................................39
3.5.4
Pharmacodynamic Endpoints .........................................................................40
3.5.5
Safety Endpoints.............................................................................................40
3.6
Measures to Minimize/Avoid Bias....................................................................40
3.6.1
Randomization................................................................................................40
3.6.2
Blinding ..........................................................................................................40
3.7
Trial Procedures ................................................................................................40
3.7.1
Schedule of Assessments................................................................................44
3.7.1.1
Screening.....................................................................................................44
3.7.1.2
Run-in Period (Day −3, Day −2, and Day −1)............................................45
3.7.1.3
Randomization and Shift to the Treatment Period......................................46
3.7.1.4
Treatment Period (Day 1)............................................................................46
3.7.1.5
Treatment Period (Day 2)............................................................................47
3.7.1.6
Treatment Period (Day 3)............................................................................48
3.7.1.7
Treatment Period (Days 4 and 5) ................................................................48
3.7.1.8
Treatment Period (Completion Assessment on Day 6 or Withdrawal 
Assessment on Day After the Final IMP Administration)..........................49
3.7.1.9
Follow-up After Completion of the Treatment Period (Day 12 to Day 
15, 7 to 10 Days After the Final IMP Administration) ...............................50
3.7.1.10
Follow-up....................................................................................................50
3.7.2
Efficacy Assessments .....................................................................................50
3.7.2.1
Body Weight ...............................................................................................50
3.7.2.2
Congestive Symptoms (Lower Limb Edema, Jugular Venous 
Distension, Hepatomegaly, Pulmonary Rales, and Cardiac Third 
Sound) .........................................................................................................51

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3.7.2.3
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion)................51
3.7.2.4
NYHA Classification ..................................................................................52
3.7.3
Safety Assessments.........................................................................................52
3.7.3.1
Adverse Events............................................................................................52
3.7.3.2
Clinical Laboratory Assessments................................................................53
3.7.3.3
Physical Examination and Vital Signs........................................................54
3.7.3.4
12-Lead Electrocardiogram Assessments ...................................................55
3.7.4
Prior and Concomitant Medications...............................................................55
3.7.5
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Assessments....................................................................................................56
3.7.5.1
Pharmacokinetic Assessments ....................................................................56
3.7.5.1.1
Pharmacokinetic Blood Samples.............................................................56
3.7.5.2
Pharmacodynamic Assessments .................................................................57
3.7.5.2.1
Daily Urine Volume ................................................................................57
3.7.5.2.2
Daily Fluid Intake....................................................................................57
3.7.5.2.3
Daily Fluid Balance.................................................................................57
3.7.5.2.4
Pharmacodynamic Laboratory Tests (Serum Sodium Concentration, 
Serum Potassium Concentration, Serum Osmolality, Biomarkers, 
Daily Urine Sodium Excretion, Daily Urine Potassium Excretion, 
and Urine Osmolality) .............................................................................58
3.7.5.3
Pharmacogenomic Assessment...................................................................59
3.7.5.3.1
DNA Storage ...........................................................................................59
3.7.5.3.2
Potential Genomic/Genetic Analysis.......................................................60
3.7.6
End of Trial.....................................................................................................62
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................62
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................62
3.8.2
Individual Site.................................................................................................62
3.8.3
Individual Subject Discontinuation ................................................................62
3.8.3.1
Treatment Discontinuation..........................................................................62
3.8.3.2
Documenting the Reasons for Treatment Discontinuation.........................62
3.8.3.3
Withdrawal of Consent ...............................................................................64
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................65
3.9
Screen Failures ..................................................................................................65

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3.10
Definition of Completed Subjects.....................................................................66
3.11
Definition of Subjects Lost to Follow-up..........................................................66
3.12
Subject Compliance...........................................................................................66
3.13
Protocol Deviations...........................................................................................67
4
Restrictions..........................................................................................67
4.1
Prohibited Medications......................................................................................67
4.2
Restricted Concomitant Medications ................................................................68
5
Reporting of Adverse Events.............................................................69
5.1
Definitions.........................................................................................................69
5.2
Eliciting and Reporting Adverse Events ...........................................................71
5.3
Immediately Reportable Events ........................................................................72
5.4
Potential Serious Hepatotoxicity.......................................................................72
5.5
Pregnancy..........................................................................................................73
5.6
Procedure for Breaking the Blind......................................................................74
5.7
Follow-up of Adverse Events............................................................................74
5.7.1
Follow-up of Nonserious Adverse Events......................................................74
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................75
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring After 
the Date of Trial End (Last Scheduled Contact).............................................75
6
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Analyses ...............................................................................................76
6.1
Pharmacokinetics...............................................................................................76
6.1.1
Datasets for Pharmacokinetic Analysis ..........................................................76
6.1.2
Pharmacokinetic Analysis ..............................................................................76
6.1.2.1
Endpoints ....................................................................................................76
6.1.2.2
Statistical Analyses .....................................................................................76
6.2
Population Pharmacokinetic Analysis...............................................................76
6.3
Pharmacodynamics............................................................................................76
6.4
Pharmacokinetics/Pharmacodynamics..............................................................77
6.5
Pharmacogenomics............................................................................................77
7
Statistical Analysis..............................................................................77

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7.1
Sample Size.......................................................................................................77
7.2
Datasets for Analysis.........................................................................................78
7.3
Handling of Missing Data .................................................................................78
7.4
Primary and Secondary Endpoint Analyses ......................................................78
7.4.1
Primary Endpoint Analysis.............................................................................78
7.4.2
Secondary Endpoint Analysis.........................................................................79
7.4.2.1
Lower Limb Edema and Pulmonary Congestion........................................79
7.4.2.2
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic Ratio......79
7.4.2.3
Pulmonary Rales and Cardiac Third Sound................................................80
7.4.2.4
NYHA Classification ..................................................................................80
7.5
Analysis of Demographic and Baseline Characteristics....................................80
7.6
Safety Analysis..................................................................................................80
7.6.1
Adverse Events ...............................................................................................80
7.6.2
Clinical Laboratory Data ................................................................................81
7.6.3
Vital Signs Data..............................................................................................81
7.6.4
Electrocardiogram Data..................................................................................81
8
Management of Investigational Medicinal Product........................82
8.1
Packaging and Labeling ....................................................................................82
8.2
Storage...............................................................................................................82
8.3
Accountability ...................................................................................................82
8.4
Returns and Destruction....................................................................................82
8.5
Reporting of Product Quality Complaints.........................................................83
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................83
8.5.2
Information Required for Reporting Purposes ...............................................83
8.5.3
Return Process ................................................................................................84
8.5.4
Assessment/Evaluation...................................................................................84
9
Records Management.........................................................................84
9.1
Source Documents.............................................................................................84
9.2
Data Collection..................................................................................................85
9.3
File Management at the Trial Site.....................................................................85
9.4
Records Retention at the Trial Site....................................................................86

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10
Quality Control and Quality Assurance...........................................86
10.1
Monitoring.........................................................................................................86
10.2
Auditing.............................................................................................................86
11
Ethics and Responsibility...................................................................87
12
Confidentiality ....................................................................................87
13
Amendment Policy..............................................................................88
14
Publication Authorship Requirements.............................................88
15
References............................................................................................89

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List of In-text Tables
Table 2.2-1
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 2.2-2
Mean Differences and 95% Confidence Intervals in Log-
transformed Tolvaptan Exposure (Cmax and AUC24h) on 
Day 1 Between the Intravenous Administration of OPC-
61815 and Oral Administration of Tolvaptan 15 mg.....................30
Table 3.2-1
Investigational Medicinal Products Used in Each Treatment 
Group 33
Table 3.4.2-1
Inclusion Criteria (Screening Period) ............................................35
Table 3.4.2-2
Inclusion Criteria (Run-in Period) .................................................36
Table 3.4.3-1
Exclusion Criteria ..........................................................................37
Table 3.7-1
Schedule of Assessment.................................................................41
Table 3.7-2
Allowable Time Window for Examinations/Tests and Blood 
Sampling After IMP Administration on Day 1..............................44
Table 3.7.2.2-1
Criteria for Assessment of Lower Limb Edema ............................51
Table 3.7.2.3-1
Criteria for Assessment of Pulmonary Congestion........................52
Table 3.7.2.4-1
NYHA Classification.....................................................................52
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................54
Table 3.7.5.2.4-1
Pharmacodynamic Laboratory Tests..............................................58
Table 4.1-1
List of Prohibited Concomitant Medications and Foods ...............67
Table 4.1-2
Medications and Foods Which May Inhibit or Induce 
CYP3A4 Activity...........................................................................68
Table 4.2-1
Restricted Concomitant Medications/Therapies............................69
Table 7.4.2.1-1
Improvement Category of Lower Limb Edema and 
Pulmonary Congestion...................................................................79

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

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List of Appendices
Appendix 1
Handling and Shipment of Bioanalytical Samples ........................91
Appendix 2
Protocol Amendments/Administrative Changes............................93

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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
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase 
AVP
Arginine vasopressin
BMI
Body mass index
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
FAS
Full analysis set
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
ICMJE
International Committee of Medical Journal Editors
IMP
Investigational medicinal product
IRB
Institutional review board
IRE
Immediately reportable event
IWRS
Interactive Web Response System
Ki
Inhibition constant
LOCF
Last Observation Carried Forward
NYHA
New York Heart Association
NT-proBNP
N-terminal fragment of brain natriuretic peptide precursor
PAP
Prostatic acid phosphatase
PPK
Population pharmacokinetic
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

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TEAE
Treatment-emergent adverse event
TRACP-5b
Tartrate-resistant acid phosphatase 5b
ULN
Upper limit of normal
US
United States
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-receptor at distal parts of the nephron. Congestive heart failure (CHF) is 
manifested by dyspnoea, orthopnoea, 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 mechanism of 
action makes them difficult to be a therapeutic option for patients with decreased serum 
electrolyte levels. Because conventional diuretics can also impair renal function at high 
dose levels, a dose increase is not always an option even in patients with insufficient 
response. In contrast, an add-on diuretic effect can be expected with tolvaptan because of
its mechanism of action, which 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 diuretic 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 CKD 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 regions.

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Tolvaptan has been administered to patients in clinical settings as an oral aquaretic agent 
as a useful treatment option for heart failure patients with volume overload despite 
having received other conventional diuretics. However, in clinical practice, there is a 
demand for intravenously injectable aquaretic drugs that have similar effects to tolvaptan 
and can be administered intravenously are needed for heart failure patients when oral 
administration is not feasible/desirable, eg, due to impaired consciousness, decreased 
absorption of oral tablets due to edema of the gastrointestinal tract associated with central 
venous pressure elevation caused by heart failure (gastrointestinal oedema), oxygen 
therapy, or decreased swallowing function in elderly patients. 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, an AVP V2-receptor antagonist, 
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 with an expectation to be 
effective 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 (263-08-001), repeated intravenous dose 
trial (263-09-001), and trial investigating the rate of intravenous administration (263-10-
005), as well as one phase 2 clinical pharmacology trial in CHF patients (263-102-
00001). Based on the results of these trials, this trial will be conducted to confirm the 
non-inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg tablet using as the 
primary endpoint the change in body weight following 5-day intravenous administration 
of OPC-61815 16-mg injection or 5-day oral administration of tolvaptan 15-mg tablet to 
CHF patients.
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 

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(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 
increase in plasma renin activity, and unlike furosemide, no activation of the renin-
angiotensin system.
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) resulted in dose-dependently increased urine volume and decreased 
urine osmolality, as well as a dose-dependent reduction in 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 resulted in a dose-dependent increase in plasma 
sodium concentration, and improved the hyponatremia-associated increased water 
contents in the brain and heart. 
The above non-clinical results have demonstrated the aquaretic effect of OPC-61815 
administered intravenously, suggesting that OPC-61815 can be expected to provide 
clinical benefit in the treatment of various disorders associated with fluid retention due to 
abnormal water metabolism (eg, hyponatremia and edematous diseases).
For detailed nonclinical data, see the Investigator’s Brochure (IB).

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1.2
Clinical Data
1.2.1
Phase 1 Trials of OPC-61815 Injection 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 were frequently reported during the administration or immediately after the 
end of the administration. Most of these events were considered to be related to the 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.
To investigate an infusion time that lessened the occurrence of the adverse drug reactions 
that had not been reported with oral tolvaptan but were observed with intravenous 
OPC-61815 in the repeated intravenous dose trial (Trial 263-09-001), and to explore the 
causes of these adverse drug reactions, 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 were frequently reported 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 infusion 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 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 administration, all occurrences in the OPC-61815 
group were concluded 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 

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resolved without treatments. There were no clinically relevant 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) Pharmacokinetics and Pharmacodynamics
Following 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∞
for 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 after a 

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single oral administration and repeated oral administration of tolvaptan 15-mg tablet, 
respectively.
When OPC-61815 was intravenously administered at 2, 4, 8, or 16 mg once daily for 
5 days, the daily urine volume increased 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 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 in ≥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 
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 in 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 of the AESI (eg, feeling abnormal, feeling hot, pruritus, 
rash, urticaria, erythema, hyperhidrosis, nausea, epigastric discomfort, or dyspnoea) 
that occurred frequently following bolus (in 1- or 5-minute) infusion of OPC-61815 
and were considered to be due to IMP in the phase 1 trials.
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 heart failure 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 

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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 
in severity. The thirst, constipation, and pollakiuria were considered to be attributable to 
the diuretic effect of tolvaptan.
Serious adverse events were reported 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 the other subject 
experienced atrial fibrillation.
1.3
Known and Potential Risks and Benefits
In completed clinical trials of OPC-61815 in healthy male subjects (Trials 263-08-001, 
263-09-001, and 263-10-005), 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, 
rash, urticaria, 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.
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 benefits comparable to those of tolvaptan. 

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Tolvaptan, when administered to patients with cardiac edema, is known to be effective in 
body weight reduction and improvement of other findings (jugular venous distension, 
hepatomegaly, and lower limb edema) associated with the disease.7
The expected adverse drug reactions of tolvaptan are important information for predicting 
the adverse drug reactions of OPC-61815. 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 frequently reported AEs (with a ≥2% incidence, and
higher than that in the placebo group) in 437 subjects treated with tolvaptan tablet were 
ventricular tachycardia, constipation, dry mouth, diarrhoea, vomiting, thirst, malaise, 
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, blood pressure decreased, dehydration, hyperkalaemia, 
dizziness, headache, dizziness postural, pollakiuria, renal impairment, and epistaxis. For 
details regarding the AEs related to tolvaptan that have been reported in clinical trials, see 
the IB.
2
Trial Rationale and Objectives
2.1
Trial Rationale
Tolvaptan is approved in 2010 for the treatment of volume overload in heart failure when 
adequate response is not obtained with other diuretics (eg, loop diuretics), and has been 
administered to heart failure patients with volume overload despite have been received 
loop diuretics or other diuretics as an useful treatment option in the clinical setting. In 
clinical practice, however, intravenously-injectable aquaretics with the similar effects as 
tolvaptan has been needed for treating patients who have difficulty ingesting an oral drug 
due to decreased consciousness levels, those in whom the absorption of an oral drug is 
decreased due to gastrointestinal edema (intestinal edema) resulting from increased 
central venous pressure induced by heart failure, those in whom the administration of an 
oral drug is difficult due to the concurrent use of oxygen inhalation, and elderly patients 
with decreased swallowing function. Otsuka Pharmaceutical synthesized OPC-61815 as a 
novel intravenously injectable aquaretic since tolvaptan is difficult to be developed as an 
injectable formulation for its low solubility.
OPC-61815 is being developed for an intended approval in the same indication and target 
population as that of tolvaptan; therefore, OPC-61815 needs to be evaluated for efficacy 

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in a patient population similar to the patients who were enrolled in the phase 3 trial of 
tolvaptan. Since tolvaptan is currently positioned as a standard therapy for patients with 
heart failure with persistent fluid retention despite treatment with loop diuretics or other 
diuretics, it is ethically inappropriate to employ placebo as a comparator in a phase 3 trial 
to evaluate the efficacy of OPC-61815.
OPC-61815 has been evaluated in the following three completed phase 1 trials in healthy 
male subjects: 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). Based on the results of the phase 1 trials, a phase 2 
clinical pharmacology trial in CHF patients (Trial 263-102-00001) was conducted to 
determine the dose of OPC-61815 injection achieving the tolvaptan (OPC-41061) 
exposure equivalent to that for tolvaptan 15-mg tablet after intravenous administration of 
OPC-61815. The results indicated that OPC-61815 injection at 16 mg was equivalent to 
tolvaptan 15-mg tablet, and that OPC-61815 injection caused no significant safety 
concern in the dose range from 2 to 16 mg in CHF patients.
Based on the above, it is considered to be scientifically and ethically appropriate to 
conduct a phase 3 trial to confirm the non-inferiority of OPC-61815 to tolvaptan 15-mg 
tablet in patients with CHF using an OPC-61815 16-mg injection formulation, which has 
been demonstrated to be equivalent to tolvaptan 15-mg tablet.
2.2
Dosing Rationale
The dosage regimen of OPC-61815 planned in this trial is based on the results of a phase 
2 clinical pharmacology trial in patients with CHF conducted to investigate the dose of 
OPC-61815 injection formulation achieving exposure equivalent to that for tolvaptan 
15-mg tablet (Trial 263-102-00001).
Table 2.2-1 shows the tolvaptan exposure (Cmax and AUC24h) on Day 1, the primary 
endpoint of the phase 2 trial (Trial 263-102-00001). Table 2.2-2 shows the mean 
differences and their 95% CIs in log-transformed tolvaptan exposure (Cmax and AUC24h) 
on Day 1 between the oral administration of tolvaptan 15 mg and the intravenous 
administration of OPC-61815.
When OPC-61815 was intravenously administered over 1 hour at a dose of 2, 4, 8, or 
16 mg once daily, the OPC-41061 exposure at 16 mg injection was closest and similar to 
that for tolvaptan 15-mg tablet. For safety, 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 

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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 frequently with bolus (1- or 5-
minute) infusion of OPC-61815 in phase 1 trials in healthy adult subjects and were 
considered to be related to IMP.
Based on the above, the dosage regimen of OPC-61815 is set to be a 1-hour infusion of 
16 mg once daily in this trial.
The dosage regimen of tolvaptan planned for this trial is based on the results of a phase 3 
trial of tolvaptan tablet (Trial 156-06-002).
Table 2.2-1
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 2.2-2
Mean Differences and 95% Confidence Intervals in Log-
transformed Tolvaptan Exposure (Cmax and AUC24h) on 
Day 1 Between the 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.

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2.3
Trial Objectives
Primary: To confirm the non-inferiority of OPC-61815 16-mg injection to tolvaptan 
15-mg tablet using as the primary endpoint the change in body weight following 5-day 
intravenous administration of OPC-61815 16-mg injection or 5-day oral administration of 
tolvaptan 15-mg tablet to CHF patients with volume overload despite having received 
diuretics other than vasopressin antagonists
Secondary: To evaluate other efficacy endpoints and the safety, pharmacodynamics, and 
pharmacokinetics of OPC-61815 16-mg injection in comparison with tolvaptan 15-mg 
tablet
3
Trial Design
3.1
Type/Design of Trial
This trial will be conducted in 288 CHF patients with volume overload despite having 
received diuretics other than vasopressin antagonists. The subjects will be randomly 
assigned to either of the OPC-61815 16-mg injection group or the tolvaptan 15-mg tablet
group (144 patients per group) to confirm the non-inferiority of OPC-61815 16-mg 
injection to tolvaptan 15-mg tablet in an active control, randomized, double-blind, 
parallel group, multicenter design. An overview of the trial design is shown in Figure 
3.1-1.
The 3 days before start of IMP administration comprise the run-in period, during which 
the use of diuretics, change in body weight, and congestive symptoms are assessed. After 
the run-in period, only subjects who meet the inclusion criteria (run-in period) (see Table 
3.4.2-2) will enter into the treatment period during which the IMP will be administered 
once daily for 5 days. The doses and dosage regimens of diuretics that have been used 
since before start of the run-in period must be maintained until the end of the treatment 
period. The completion assessment will be performed on Day 6 (day after final IMP 
administration), and the follow-up assessment will be performed at some time between 
Day 12 and Day 15.
This trial will employ a double-dummy method to maintain blindness. Subjects will 
receive either of a combination of OPC-61815 16-mg injection and placebo tablet or a 
combination of placebo injection and tolvaptan 15-mg tablet. Subjects will be 
hospitalized from the day before start of the run-in period (Day −4) to the end of the 
treatment period (Day 6).

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Figure 3.1-1
Trial Design Schematic
R: Randomization
Note) If IMP treatment is discontinued for any reason 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, whenever possible, and the follow-up should be conducted at any time between 7 and 10 days after 
the final IMP administration.
Screening period 
(Day−7 to Day−4)
Run-in period 
(3 days)
Treatment period 
(6 days)
Follow-up period 
(7 to 10 days after the final 
IMP administration)
OPC-61815 injection
Placebo tablet
OPC-61815 16-mg 
injection group
Diuretics with fixed doses and dosage regimens
Hospitalization (10 days: Day−4 to Day 6)
Post-treatment 
follow-up (last 
scheduled 
contact/end of the 
trial)
Informed consent/ 
start of the trial
Completion/withdrawal assessment 
(the day after the final IMP administration)
Inpatient or outpatient setting
Tolvaptan tablet
Placebo injection
Tolvaptan 15-mg 
tablet group

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3.2
Trial Treatments
3.2.1
Dosage Regimen and Treatment Duration
The IMPs to be administered to subjects in each treatment group are shown in 
Table 3.2-1. The investigator or subinvestigator will instruct subjects to ingest one 
tolvaptan 15-mg tablet or one placebo tablet with water once daily. Immediately after the 
intake of the tablet, the investigator or subinvestigator will administer OPC-61815 16-mg 
injection or placebo injection as a 1-hour (55 to 65 minutes allowable) infusion once 
daily for 5 days according to the IMP administration procedures specified separately. 
Subjects will be asked to take breakfast and then urinate to start the measurement of daily 
urine volume immediately before receiving the administration of IMPs on each of the 5 
days. The start time of administration on Day 2 and onward should be within 20 minutes 
before or after the start time on Day 1, if possible. The investigator or subinvestigator 
will confirm that administration of the IMPs has been completed, and record the 
following information in the source document and the eCRF (electronic case report 
form): the date and time of the start and end of the administration (and the suspension 
period, if the administration is suspended), and whether or not the entire dose has been 
administered; and, the date and time of administration for the tablet. The IMPs will also 
be administered to subjects who do not take breakfast.
Table 3.2-1
Investigational Medicinal Products Used in Each Treatment 
Group
Treatment group
IMPs (per day)
Tolvaptan 15-mg tablet
One vial of placebo injection + one tolvaptan 15-mg tablet
OPC-61815 16-mg injection
One vial of OPC-61815 16-mg injection + one placebo tablet
[Rationale for the treatment duration]
The results of a phase 2 trial (Trial 156-03-001) and a phase 3 trial (Trial 156-06-002) 
of tolvaptan tablet in patients with CHF revealed that the significant decrease in body 
weight in the tolvaptan group was greater than that in the placebo group throughout the 
treatment period in both trials, although the difference in the change in body weight 
between the groups was almost constant from Day 4 onward in the phase 2 trial (Trial 
156-03-001) and peaked on Day 6 in the phase 3 trial (Trial 156-06-002).
Based on these results, a treatment duration of 5 days is sufficient to evaluate the 
change in body weight.

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3.2.2
Preparation of Investigational Medicinal Products
The IMPs will be prepared just before use according to instructions to be specified 
separately.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The necessary sample size is 288 subjects (144/group). Subjects are required to be 
Japanese male and female CHF patients age of 20 to 85 years, inclusive, with volume 
overload (ie, lower limb edema, pulmonary congestion, and/or jugular venous distension) 
despite having received diuretics other than vasopressin antagonists, who will be able to 
be hospitalized from the day before start of the run-in period through the end of the 
treatment period and take oral tablets.
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. Informed consent will be 
documented by signing the consent form. DNA storage is optional. Subjects who do not 
consent to DNA storage may participate in the trial. 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) Guideline9 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 

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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 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. The subject will receive a copy of the signed ICF; the original 
shall be kept on file by the investigator or subinvestigator.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
3.4.2
Inclusion Criteria
3.4.2.1
Screening Period
Subjects are required to meet all of the inclusion criteria (screening period) presented in 
Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria (Screening Period)
1
Patients receiving any of the following oral diuretics (including patients planning to initiate 
treatment during the run-in period)
• Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day or higher
• Concomitant use of a loop diuretic and a thiazide diuretic (including thiazide analogs) at any 
dose
• Concomitant use of a loop diuretic and an aldosterone antagonist or potassium-sparing diuretic 
agent at any dose
Note: The types and doses of concomitant diuretics are specified as follow:
a) Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day 
or higher
Bumetanide tablet 1 mg, azosemide tablet 60 mg, and torasemide tablet 8 mg
b) Thiazide diuretics (including similar drugs)
Hydrochlorothiazide tablet, trichlormethiazide tablet, benzylhydrochlorothiazid tablet, 
and mefruside tablet
c) Aldosterone antagonists or potassium-sparing diuretics
Spironolactone tablet/fine granules and triamterene capsules
2
Patients with CHF in whom lower limb edema, pulmonary congestion, or jugular venous 
distension due to volume overload is present. Patients with pulmonary congestion may be enrolled 
if pulmonary congestion is confirmed by chest x-ray performed within 14 days prior to informed 
consent.
3
Male and female patients age of 20 to 85, inclusive, at the time of informed consent
4
Patients who are currently hospitalized or who are able to be hospitalized from the day before the 
run-in period (on Day −4) until the end of the treatment period

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Table 3.4.2-1
Inclusion Criteria (Screening Period)
5
Patients who are capable of taking oral tablets
6
Patients who are capable of giving consent
(Rationale for the inclusion criteria [screening period])
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 as the inclusion criterion, because these 
symptoms are hardly affected by other factors and were reported by many 
subjects in a late phase 2 trial (Trial 156-03-001) and a phase 3 trial (Trial 156-
06-002) of tolvaptan in patients with CHF.
3) Subjects participating in the trial should be adults who are capable of being 
responsible for their own consent. The upper limit of age is set at 85 years 
because many patients with CHF are elderly and also based on safety 
considerations.
4) Only patients who are able to be hospitalized will be enrolled to ensure accurate 
assessments and in view of the safety of subjects.
5) This criterion is set because tolvaptan tablet will be used as a comparator.
6) This criterion is set to ensure the implantation of an ethically appropriate trial.
3.4.2.2
Run-in Period
To appropriately evaluate the efficacy of the IMPs, only subjects who meet all of the 
inclusion criteria (run-in period) shown in Table 3.4.2-2 and are judged by the 
investigator or subinvestigator to be appropriate for an advancement to the treatment 
period will enter into the treatment period.
Table 3.4.2-2
Inclusion Criteria (Run-in Period)
7
Patients with lower limb edema, jugular venous distension (on Day −1 of the run-in period), or 
pulmonary congestion (confirmed by chest x-ray during the run-in period)
8
Patients who have received diuretics with no change in dose or regimen during the run-in period
9
Patients with no more than 1.0 kg change in body weight over the 2 days (Day −2 and −1 of the 
run-in period) prior to initial administration of the IMP

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(Rationale for the inclusion criteria [run-in period])
7) These symptoms are often seen in association with volume overload and 
therefore selected as a criterion for enrolling patients with volume overload.
8) This criterion is set to enroll patients who still have volume overload despite 
having received diuretics other than vasopressin antagonists.
9) This criterion is set because having stable volume overload is necessary for 
appropriately evaluating the efficacy of OPC-61815.
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 with acute heart failure
2
Patients with mainly noncardiogenic congestive symptoms
3
Patients who are on a ventricular assist device
4
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
5
Patients who have experienced acute myocardial infarction within 30 days prior to the screening 
examination
6
Patients with a definite diagnosis of active myocarditis or amyloid cardiomyopathy
7
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
8
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
9
Patients who are severely obese (body mass index [BMI] = body weight [kg]/height [m] 2
exceeding 35 kg/m2)
10
Patients with supine systolic blood pressure of <90 mmHg
11
Patients with any of the following abnormalities in laboratory test results:
Total bilirubin >3.0 mg/dL, serum creatinine > 3.0 mg/dL，
serum Na <125 mEq/L and >147 mEq/L, and serum K >5.5 mEq/L

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Table 3.4.3-1
Exclusion Criteria
12
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)
13
Patients who are unable to sense thirst or who have difficulty with fluid intake
14
Female patients who are breast-feeding or who have a positive pregnancy test result prior to 
receiving IMP
15
Sexually active males 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.
16
Patients who have received tolvaptan within 28 days prior to the screening examination
17
Patients who have participated in a clinical trial in which they received OPC-61815
18
Patients who have participated in another clinical trial and received another IMP within 30 days 
prior to the screening examination
19
Patients who are otherwise judged to be ineligible by the investigator or subinvestigator
Nonchildbearing 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.
Subjects must agree to the restrictions to concomitant medications as described in 
Section 4.
Subjects who sign an ICF but are not assigned to IMP are permitted to be re-screened one 
more time. In the event that the screening assessment is repeated, a new ICF signed by 
the subject must be obtained and a new subject identifier will be assigned to the subject.
[Rationale for the exclusion criteria]
1
This criterion is set because the rapid onset or worsening of the symptoms 
may hinder the conduct of the trial.
2
The criterion is set because the proposed target patient population of 
OPC-61815 is patients who have volume overload associated with CHF.
3
The use of a ventricular assist device may affect the efficacy or safety 
assessment of the IMPs.
4
Excessive diuretic treatment may adversely affect these symptoms.
5, 6
These criteria are based on safety considerations.
7
This criterion is based on safety considerations and set to exclude patients 
ineligible for participation in the trial.
8
These criteria are based on safety considerations.
9
This condition may hinder the efficacy assessment of the IMPs.
10
Blood pressure may decrease due to diuresis.

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11 to 13
These criteria are based on safety considerations.
14 and 15
These criteria are based on general safety and ethical considerations.
16 and 17
The use of the IMPs may affect the efficacy or safety assessment of the 
IMPs.
18 and 19
These criteria are based on general safety and ethical considerations.
3.5
Endpoints
3.5.1
Primary Endpoint
Change in body weight from baseline at time of final IMP administration (day after final 
IMP administration)
[Rationale for the primary endpoint]
Since volume overload occurs at various body sites in CHF patients, body weight (change 
from baseline) is the most appropriate measure that objectively reflects the diuretic effect 
of the IMPs on the general state of volume overload. Therefore, the change from baseline 
in body weight is selected as the primary endpoint as in a phase 3 trial of tolvaptan in 
patients with CHF (Trial 156-06-002).
3.5.2
Secondary Endpoints

Congestive symptoms (lower limb edema, pulmonary congestion, jugular venous 
distension, hepatomegaly, cardiothoracic ratio, pulmonary rales, and cardiac third 
sound)

New York Heart Association (NYHA) classification
[Rationale for the secondary endpoints]
Congestive symptoms are measures that reflect volume overload resulting from CHF and 
therefore selected as a secondary endpoint for evaluating the efficacy of OPC-61815 
using tolvaptan tablet as a comparator.
In addition to congestive symptoms, the NYHA classification, which assesses the 
severity of heart failure based on subjective symptoms is selected as a secondary 
endpoint to evaluate the efficacy of OPC-61815 using tolvaptan tablet as a comparator.
3.5.3
Pharmacokinetic Endpoint
Plasma concentrations of OPC-61815 free form and tolvaptan (OPC-41061) 

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3.5.4
Pharmacodynamic Endpoints
Daily urine volume, daily fluid intake, daily fluid balance, serum sodium concentration, 
serum potassium concentration, serum osmolality, biomarker measurements (plasma 
concentrations of AVP and brain natriuretic peptide [BNP], plasma renin activity, and 
serum concentrations of N-terminal pro-brain natriuretic peptide [NT proBNP]  and 
troponin I), daily urine sodium excretion, daily urine potassium excretion, and urine 
osmolality
3.5.5
Safety Endpoints
Adverse events, clinical laboratory tests (including pregnancy test), physical examination, 
vital signs (blood pressure, pulse rate, and body temperature), and 12-lead 
electrocardiography (ECG)
3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
Subjects who meet the criteria for a shift to the treatment period will be randomized at a 
1:1 ratio to either of the OPC-61815 16-mg injection group or the tolvaptan 15-mg tablet
group according to the interactive web response system (IWRS). A randomization 
confirmation form will be prepared separately to document the detail of the assignment 
method of treatments to subjects. The date of randomization and the IMP number will be 
recorded in the eCRF.
3.6.2
Blinding
Prior to start of the trial, the IMP allocation manager and the IMP packer will ensure that 
the IMPs are indistinguishable from each other. The allocation table will be kept under 
lock and key until the unblinding to be performed after finalization of all of the eCRFs 
and the database.
3.7
Trial Procedures
Trial assessment time points are summarized in Table 3.7-1.

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Table 3.7-1
Schedule of Assessments
Day
Item
Screening
Run-in Period
Treatment Period
Follow-up
−7 to 
−4
−4
−3
−2
−1
1
2
3
4
5
Day 6/At 
Withdrawal 
(The Day After 
Final IMP 
Administration)
Day 12 to 15
/7 to 10 Days 
After Final 
IMP 
Administration
Informed consent
◇
Informed consent for DNA 
storage
〇(Optional Participation)
Subject background
◇
Inclusion/exclusion criteria
◇
◇
Confirmation of concomitant 
medication/therapy
Subject registration, 
randomizationa
◇
●
◇
Hospitalization
IMP administration
♦
♦
♦
♦
♦
Confirmation of IMP 
compliance
Plasma drug concentrations
■
●
(◇)b
Daily urine volume, daily fluid 
intake, urine sodium and 
potassium concentrations, urine 
osmolality
Serum sodiumc and potassium
concentrationsc
◇
●■
●
●
●
●
●
◇
Serum osmolality, biomarkersd
●
●
Body weight
◇
●
●
●
●
●
●
●
●
●
◇
Congestive symptomse
◇
◇
◇
◇
◇
◇
◇
◇
◇
◇
◇

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Table 3.7-1
Schedule of Assessments
Day
Item
Screening
Run-in Period
Treatment Period
Follow-up
−7 to 
−4
−4
−3
−2
−1
1
2
3
4
5
Day 6/At 
Withdrawal 
(The Day After 
Final IMP 
Administration)
Day 12 to 15
/7 to 10 Days 
After Final 
IMP 
Administration
Chest x-ray (cardiothoracic 
ratio, pulmonary congestion)f
◇
◇
Once during run-in 
period
◇
NYHA classification
◇
Once during run-in 
period
◇
Adverse events
Laboratory tests
◇
●
●
◇
Physical examination
◇
◇
◇
◇
◇
◇
◇
◇
◇
◇
◇
Vital signs (Blood pressure, 
pulse rate, body temperature)
◇
●
●
●
●
●
●
●
●
●
◇
12-Lead ECGg
◇
●■
◇
◇
Urine pregnancy test (WOCBP 
only)
◇
◇
DNA storageh
〇
●= Before breakfast; ♦ = After breakfast; ■ = Predetermined time after IMP administration (see Table 3.7-2); ◇= Feasible time; 
〇= Optional (subjects at sites with a DNA storage agreement who gave informed consent for DNA storage before start of the trial)
aSubject registration and randomization: Subject registration and randomization will be performed using IWRS at screening and on Day 1, respectively. 
Subjects who meet all of the inclusion criteria and do not fall under any of the exclusion criteria will be assigned to receive IMP administration. In principle, 
randomization will be performed on Day 1 (if not feasible, randomization on Day −1 is acceptable, but eligibility regarding concomitant diuretics should 
still be reconfirmed on Day 1). Information on IMP administration and completion or discontinuation (early termination/withdrawal) will be recorded in the 
IWRS.
bPlasma drug concentrations will be measured at a feasible time only for early termination/withdrawal.
cMeasurement of serum sodium and potassium concentrations during the treatment period will be performed at both the central laboratory and the trial site. If 
it is difficult to perform serum sodium and potassium concentration measurement at the trial site, plasma sodium and potassium concentrations may be 

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measured. Either serum or plasma should be used consistently for measurement of sodium and potassium concentrations in a given subject. However, even 
if plasma sodium and potassium concentrations are measured at the trial site, serum sodium and potassium concentrations will be measured at the central 
laboratory.
dBiomarkers: Plasma concentrations of AVP, BNP, plasma renin activity, and serum concentrations of NT-proBNP and troponin I
eCongestive symptoms: Lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, and cardiac third sound
fChest x-ray: cardiothoracic ratio and pulmonary congestion 
If chest x-ray has been performed at a regular visit prior to participation in the present trial (within 14 days before informed consent), assessment of 
cardiothoracic ratio and pulmonary congestion at screening may be performed based on that previous chest x-ray without having to perform a new chest x-
ray.
gTiming of 12-lead ECG: Before breakfast and at 1 to 2 hours postdose on Day 1 and at a feasible time at other time points. If the serum potassium 
concentration at the trial site or the central laboratory is confirmed to exceed 5.5 mEq/L at any time point with no scheduled 12-lead ECG during the 
treatment period, an additional 12-lead ECG will be performed as an unscheduled examination.
hDNA storage: In principle, blood sampling for DNA storage will be performed on the day of initial IMP administration (Day 1). Informed consent to DNA 
storage should be obtained before blood sampling for DNA storage. If blood sample cannot be collected or re-collection is required, blood sampling will be 
repeated at a feasible time during the trial period. 

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Table 3.7-2
Allowable Time Window for Examinations/Tests and Blood 
Sampling After IMP Administration on Day 1
Item
Timing
Plasma drug concentrations
60 to 75 minutes after start of IMP administration
4 to 6 hours after start of IMP administration
8 to 12 hours after start of IMP administration
Serum sodium concentration, serum 
potassium concentration
4 to 6 hours after start of IMP administration
8 to 12 hours after start of IMP administration
12-Lead ECG
1 to 2 hours after start of IMP administration
Congestive symptoms 
At a feasible time
Adverse events, physical examination
At a feasible time
3.7.1
Schedule of Assessments
3.7.1.1
Screening
After informed consent has been obtained, the investigator or subinvestigator will assign 
a subject identifier to the subject according to Section 3.3.2, record the date of acquisition 
of informed consent and the assigned subject identifier in the source documents and the 
eCRF, and enroll the subject in the IWRS. The operation of the IWRS will be specified 
by the procedures prepared separately as a subject management system. 
Within 4 to 7 days before start of IMP administration (Day −7 to Day −4), the following 
examinations and tests will be conducted to assess the eligibility of the subject for 
participation in the trial. The result of eligibility assessment will be recorded in the source 
documents and the eCRF.
[Examinations and tests]
Subject characteristics (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), 
serum sodium concentration, serum potassium concentration, body weight, congestive 
symptoms (lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, 
and cardiac third sound), chest x-rayNote (cardiothoracic ratio and pulmonary congestion), 
clinical laboratory tests, physical examination, vital signs (blood pressure, pulse rate, and 
body temperature), 12-lead ECG, concomitant medications and therapies, and urine 
pregnancy test (WOCBP only)
Note: If chest x-ray has been performed at a regular visit prior to participation in the 
present trial (within 14 days before informed consent), assessment of cardiothoracic ratio 

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and pulmonary congestion at screening may be performed based on that previous chest x-
ray without having to perform a new chest x-ray.
3.7.1.2
Run-in Period (Day −3, Day −2, and Day −1)
The investigator or subinvestigator will conduct the following examinations and tests to 
assess the eligibility for a shift to the treatment period. Diuretics that have been used 
since start of the run-in period (Day −3) will be continued to be used with the same doses 
and dosage regimens until the completion (withdrawal) assessment, regardless of the 
previous use or method of use before run-in period. 
Subjects must be hospitalized from the day before start of the run-in period through the 
completion (withdrawal) assessment.
1) Each day during the run-in period
a) Before breakfast

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)
b) After breakfast
Subject are required to urinate completely immediately after breakfast, and then 
urine collection and fluid intake measurement will start to assess the following 
items.

Daily urine volume

Daily fluid intake

Daily fluid balance (difference between daily fluid intake and daily urine 
volume)

Daily urine sodium excretion and daily urine potassium excretion (calculated 
from urine sodium concentration, urine potassium concentration, and daily 
urine volume)

Urine osmolality
c) At a feasible time

Congestive symptoms (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, physical examination

Concomitant medications and therapies
2) Any single day during the run-in period
The following examinations will be conducted once at a feasible time.

Chest x-ray (cardiothoracic ratio and pulmonary congestion)

NYHA classification

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3.7.1.3
Randomization and Shift to the Treatment Period
1) Judgment of eligibility for a shift to the treatment period
Compliance with diuretic therapy during the run-in period, body weight, and 
congestive symptoms during the run-in period will be assessed to confirm that all of 
the inclusion criteria (run-in period) are met and the result of confirmation will be 
entered into the IWRS.
2) Treatment allocation
Subjects who have met all of the inclusion criteria (run-in period) will be randomly 
assigned to either of the treatment groups below to receive IMP in a double-blind 
manner. The investigator or subinvestigator will confirm the IMP number assigned by 
the IWRS.

OPC-61815 16-mg injection group

Tolvaptan 15-mg tablet group
3.7.1.4
Treatment Period (Day 1)
1) Before breakfast

Serum sodium concentration, serum potassium concentration, serum 
osmolality, and biomarkers

Body weight

Clinical laboratory tests

Vital signs (blood pressure, pulse rate, and body temperature)

12-Lead ECG

Blood sampling for DNA storage (DNA storage is optional. Informed consent 
should be obtained before blood sampling for DNA storage.)
2) After breakfast
Subject are required to urinate completely immediately after breakfast, and urine 
collection and fluid intake measurement will start to assess the following items from 
the point at which urination immediately before IMP administration has been 
completed.

Daily urine volume, daily fluid intake, and daily fluid balance

Daily urine sodium excretion and daily urine potassium excretion

Urine osmolality

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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, administer the IMPs to 
the subject, and enter the status of IMP administration into the IWRS. 
4) After IMP administration
The investigator or subinvestigator will conduct the following examinations.

Blood sampling for measurement of the plasma drug concentrations: 60 to 
75 minutes, 4 to 6 hours, and 8 to 12 hours after start of IMP administration

Serum sodium concentration and serum potassium concentration: 4 to 6 hours 
and 8 to 12 hours after start of IMP administration

12-Lead ECG: 1 to 2 hours after start of IMP administration
5) At a feasible time

Congestive symptoms (lower limb edema, jugular venous distension,
hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, physical examination

Concomitant medications and therapies

Confirmation of IMP compliance
3.7.1.5
Treatment Period (Day 2)
1) Before breakfast

Blood sampling for measurement of the plasma drug concentrations (22 to 
24 hours after start of IMP administration on Day 1)

Serum sodium concentration and sodium potassium concentration

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)
2) After breakfast
Subject are required to urinate completely immediately after breakfast, and urine 
collection and fluid intake measurement will start to assess the following items from 
the point at which urination immediately before IMP administration has been 
completed.

Daily urine volume, daily fluid intake, and daily fluid balance

Daily urine sodium excretion and daily urine potassium excretion

Urine osmolality
3) IMP administration

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4) At a feasible time

Congestive symptoms (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, physical examination

Concomitant medications and therapies

Confirmation of IMP compliance
3.7.1.6
Treatment Period (Day 3)
1) Before breakfast

Serum sodium concentration and sodium potassium concentration

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)
2) After breakfast
Subject are required to urinate completely immediately after breakfast, and urine 
collection and fluid intake measurement will start to assess the following items from 
the point at which urination immediately before IMP administration has been 
completed.

Daily urine volume, daily fluid intake, and daily fluid balance

Daily urine sodium excretion and daily urine potassium excretion

Urine osmolality
3) IMP administration
4) At a feasible time

Congestive symptoms (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, physical examination

12-Lead ECG

Concomitant medications and therapies

Confirmation of IMP compliance
3.7.1.7
Treatment Period (Days 4 and 5)
1) Before breakfast

Serum sodium concentration and sodium potassium concentration

Body weight

Vital signs (blood pressure, pulse rate, and body temperature)

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2) After breakfast
Subject are required to urinate completely immediately after breakfast, and urine 
collection and fluid intake measurement will start to assess the following items from 
the point at which urination immediately before IMP administration has been 
completed.

Daily urine volume, daily fluid intake, and daily fluid balance

Daily urine sodium excretion and daily urine potassium excretion

Urine osmolality
3) IMP administration
4) At a feasible time on each day

Congestive symptoms (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, physical examination

Concomitant medications and therapies

Confirmation of IMP compliance
3.7.1.8
Treatment Period (Completion Assessment on Day 6 or 
Withdrawal Assessment on Day After the Final IMP 
Administration)
The investigator or subinvestigator will conduct the completion assessment on Day 6 as 
described below. If IMP treatment is discontinued before Day 6 for any reason, the same 
assessment as the completion assessment for Day 6 will be conducted at a feasible time 
as the withdrawal assessment on day after final IMP administration, whenever possible, 
and then follow-up will be made 7 to 10 days after the final IMP administration. During 
the withdrawal assessment, plasma drug concentrations will be measured (at a feasible 
time), whenever possible. Information on trial completion or trial withdrawal will be 
entered into the IWRS.
1) Before breakfast

Serum sodium concentration, serum potassium concentration, serum 
osmolality, and biomarkers

Body weight

Clinical laboratory tests and vital signs (blood pressure, pulse rate, and body 
temperature)
2) At a feasible time

Blood sampling for measurements of plasma drug concentrations (only at the 
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
Congestive symptoms (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound)

Chest x-ray (cardiothoracic ratio and pulmonary congestion)

NYHA classification

Adverse events, physical examination

12-Lead ECG

Concomitant medications and therapies
3.7.1.9
Follow-up After Completion of the Treatment Period (Day 12 to 
Day 15, 7 to 10 Days After the Final IMP Administration)
The investigator or subinvestigator will conduct the following examinations and tests at a 
feasible time 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 outpatient 
visit.

Serum sodium concentration and sodium potassium concentration

Body weight and congestive findings (lower limb edema, jugular venous 
distension, hepatomegaly, pulmonary rales, and cardiac third sound)

Adverse events, clinical laboratory tests, physical examination, and vital signs 
(blood pressure, pulse rate, and body temperature)

Urine pregnancy test (WOCBP only)

Concomitant medications and therapies
3.7.1.10
Follow-up
Any AE that has not yet resolved by the completion assessment on Day 6 or the 
withdrawal assessment will be followed up according to Section 5.7.
3.7.2
Efficacy Assessments
3.7.2.1
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 measurement result will be rounded 
to the first decimal place even if the measurement value is shown in the second decimal 
place or more.

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3.7.2.2
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, and the severity of edema will be assessed according 
to the criteria below.
Table 3.7.2.2-1
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.
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.
3.7.2.3
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion)
The investigator or subinvestigator will take a chest x-ray, and the record the date of the 
examination in the source document and the eCRF. Cardiothoracic ratio and pulmonary 
congestion will be assessed as described below.

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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 below, and record the result of assessment in the source 
document and the eCRF.
Table 3.7.2.3-1
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.10
3.7.2.4
NYHA Classification
The investigator or subinvestigator will assess the NYHA classification11, and record the 
date and result of the assessment in the source document and the eCRF. 
Table 3.7.2.4-1
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 slight 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 the inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or anginal syndrome may be present, even 
at rest. If any physical activity is undertaken, discomfort is increased.
3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.

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3.7.3.2
Clinical Laboratory Assessments
Venous blood and urine samples for clinical laboratory tests (Table 3.7.3.2-1) will be 
collected at the specified time points, and the date and time of blood sampling and the 
date of urine collection will be recorded in the source document. The samples will be 
shipped to the central laboratory for central measurements.
In order for the investigator or subinvestigator to be promptly aware of serum sodium and 
potassium concentrations, in consideration of subject safety, serum sodium and potassium 
concentrations will also be measured at the trial site. The status (collected/not collected),
and the date and time of blood sampling, as well as the results of the serum sodium 
concentration measurement will be recorded in the source document and the eCRF, and 
those of the serum potassium concentration measurement will be recorded in the source 
document. If it is difficult to perform serum sodium and potassium concentration 
measurement 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, even if plasma sodium 
and potassium concentrations are measured at the trial site, serum sodium and potassium 
concentrations will be measured at the central laboratory. If the serum potassium 
concentration at the trial site or the central laboratory is confirmed to exceed 5.5 mEq/L,
a 12-lead ECG will be performed as necessary in reference to Section 3.7.3.4.
The central laboratory will measure the following 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 the date of 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.

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Table 3.7.3.2-1
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
ϒ- Glutamyltransferase
Lactic dehydrogenase
Creatine kinase (creatine phosphokinase)
Glucose
Total cholesterol
Triglycerides
Urea nitrogen
Creatinine
Uric acid
Serum electrolytes (sodium, potassium, chlorine, 
and calcium)
PAP, TRACP-5bb
Urinalysis (qualitative):
pH
Protein
Glucose
Occult blood
Ketone bodies
Bilirubin
Urobilinogen
Additional Tests:
Pregnancy test for WOCBP (hCG test)a
hCG = human chorionic gonadotropin
aUrine pregnancy test will be conducted at screening and follow-up. If the urine pregnancy test is 
positive, a serum test will be conducted as specified in Section 5.5.
bPAP (prostatic acid phosphatase) and TRACP-5b (tartrate-resistant acid phosphatase 5b) will be 
measured only on Day 1.
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.
3.7.3.3
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 

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finding that is absent at the screening examination but observed at any post-treatment 
assessment will be recorded as an AE.
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. Blood 
pressure (systolic and diastolic) and pulse rate will be measured after the subject is 
kept supine for at least 3 minutes. The measurement result of body temperature
should be rounded to the first decimal place for recording, even if the measurement 
result is shown the second decimal place or more. The date and time, and the results 
of measurements will be recorded in the source document and the eCRF.
3.7.3.4
12-Lead Electrocardiogram Assessments
At the prespecified time points, a rest 12-lead electrocardiogram (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 concentration 
at the trial site or the central laboratory is confirmed to exceed 5.5 mEq/L at any time 
point with no specified 12-lead ECG during the treatment period,, an additional 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.
3.7.4
Prior and Concomitant Medications
The investigator or subinvestigator will record all medications and therapies taken by the 
subject from signing of informed consent through Day 6 completion/withdrawal 

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assessment on the eCRF. The investigator or subinvestigator will record all medications 
and therapies taken by the subject for treatment of an AE or which caused an AE until the 
end of the trial (defined as the last scheduled contact) on the eCRF. For concomitant 
medications, the following will be recorded in the eCRF: medication, indication, dose, 
frequency, route, start date, and end date. For concomitant therapies, the following will 
be recorded in the eCRF: therapy, indication, start date, and end date.
3.7.5
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Assessments
3.7.5.1
Pharmacokinetic Assessments
3.7.5.1.1
Pharmacokinetic Blood Samples
1) Time points of blood sampling

Day 1 of the treatment period: 60 to 75 minutes, 4 to 6 hours, and 8 to 
12 hours after start of IMP administration

Day 2 of the treatment period: 22 to 24 hours after start of IMP administration 
on Day 1 (before IMP administration on Day 2)
2) Procedures for blood sampling and measurements
The central laboratory will collect the blood samples, which will be shipped to the 
bioanalytical laboratory for analysis. For the handling and shipment of samples, see 
Appendix 1.
The bioanalytical laboratory will measure the plasma concentrations of OPC-61815
free form and tolvaptan (OPC-41061), report blinded measurement results to the 
sponsor, if necessary, and provide an electronic file containing unblinded drug 
concentration data to the sponsor after breaking the blind. 
The status (collected/not collected), type (venous or arterial), and date and time of 
blood sampling will be recorded in the eCRF. The results of drug concentration 
measurements will be directly reported to the sponsor from the bioanalytical 
laboratory; therefore, entry in the eCRF will be unnecessary.
In the event that new information on the IMPs is obtained, metabolites that are not 
specified in this protocol may be analyzed. In addition, the collected plasma samples 
may be used for investigation of an analytical method, if necessary.
3) Rationale for the timing of blood sampling
In this trial, plasma drug concentration data will be collected to conduct a population 
pharmacokinetic (PPK) analysis in patients with CHF. The timing of blood sampling 
for drug concentration measurement is determined based on the results of a 

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simulation from a PPK model using the results of a phase 2 clinical pharmacology 
trial of OPC-61815 (Trial 263-102-00001), also considering feasibility. As a result, 
blood sampling for drug concentration measurements on Day 1 of the treatment 
period will be conducted at the following 4 time points: a point around which the 
plasma concentrations of OPC-61815 free form and tolvaptan are expected to reach a 
peak (60 to 75 minutes after start of IMP administration), and 3 points which are 
expected to be the elimination phase (4 to 6 hours, 8 to 12 hours, and 22 to 24 hours 
after start of IMP administration).
3.7.5.2
Pharmacodynamic Assessments
3.7.5.2.1
Daily Urine Volume
During the run-in period (until before IMP administration on Day 1 of the treatment 
period), daily urine volume will be measured for the time interval starting at immediately 
after complete urination after breakfast and ending at complete urination after breakfast 
on the following day.
During the treatment period (from IMP administration on Day 1 to the day after final 
IMP administration), daily urine volume will be measured for the each time interval from 
the point after complete urination immediately before the IMP administration to the point 
after complete urination immediately before the IMP administration on the following day. 
If the exact daily urine volume cannot be measured because part of the urine is discarded 
or for other reasons, the daily urine volume on that day will be handled as missing data.
The status (measured/not measured), start date and time, completion date and time of 
urine collection, as well as the daily urine volume will be recorded in the source 
document and the eCRF.
3.7.5.2.2
Daily Fluid Intake
Daily fluid intake (juice, milk, tea, water, transfusion, etc.) will be measured for the same 
intervals as the measurement of daily urine volume. The status (measured/not measured), 
start date and time, completion date and time of measurement, as well as the daily fluid 
intake will be recorded in the source document and the eCRF. Water that the subject 
drinks with the IMP will be included in the fluid intake after the IMP administration.
3.7.5.2.3
Daily Fluid Balance
The daily fluid balance will be calculated by deducting “the daily urine volume” from 
“the daily fluid intake.” Daily fluid balances will be calculated by the sponsor; therefore, 
entry in the eCRF will be unnecessary.

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3.7.5.2.4
Pharmacodynamic Laboratory Tests (Serum Sodium 
Concentration, Serum Potassium Concentration, Serum 
Osmolality, Biomarkers, Daily Urine Sodium Excretion, Daily 
Urine Potassium Excretion, and Urine Osmolality)
The samples presented in Table 3.7.5.2.4-1 will be collected at the time points specified 
in Section 3.7.1, and the date and time of venous blood sampling will be recorded in the 
source document and the eCRF. Regarding the serum sodium and potassium 
concentrations for pharmacodynamic assessment, data obtained as part of the clinical 
laboratory tests for safety at the same blood sampling points specified in Section 3.7.3.2
will be used. For the procedures for sample collection, processing, and storage, see 
Appendix 1. If the exact daily urine volume cannot be measured because part of the urine 
is discarded or for other reasons, the incomplete urine sample will not be shipped to the 
central laboratory and the urine electrolyte concentrations and urine osmolality on that 
day will be handled as missing data.
Table 3.7.5.2.4-1
Pharmacodynamic Laboratory Tests
Serum:
Serum sodium concentration
Serum potassium concentration
Serum osmolality
Serum troponin I concentration
Serum NT-proBNP concentration
Plasma:
Plasma AVP concentration
Plasma BNP concentration
Plasma renin concentration
Urine:
Urine sodium concentration
Urine potassium concentration
Urine osmolality
All of the samples will be shipped to the central laboratory, which centrally measures the 
parameters according to the prespecified procedures and reports the results 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 order for the investigator or subinvestigator to be promptly aware of serum sodium and 
potassium concentrations, in consideration of subject safety, serum sodium and potassium 
concentrations will also be measured at the trial site. The status (collected/not collected), 
the date and time of blood sampling, as well as the result of the serum sodium 
concentration measurement will be recorded in the source document and the eCRF, and 
those of serum potassium concentration measurement will be recorded in the source 
document. If it is difficult to perform serum sodium and potassium concentration 
measurement at the trial site, plasma sodium and potassium concentrations may be 

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measured. Either serum or plasma should be used consistently for measurement of 
sodium and potassium concentrations in a given subject. However, even if plasma sodium 
and potassium concentrations are measured at the trial site, serum sodium and potassium 
concentrations will be measured at the central laboratory.
The daily urine sodium excretion and daily urine potassium excretion will be calculated 
by multiplying the urine sodium concentration and the urine potassium concentration, 
respectively, by the daily urine volume. Urine excretions will be calculated by the 
sponsor; therefore, entry in the eCRF will be unnecessary.
3.7.5.3
Pharmacogenomic Assessment
3.7.5.3.1
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 consent to 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), 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) 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. The ICH E18 Guidelines, 
“Genomic Sampling and Management of Genomic Data” (PSEHB/PED Notification 
No. 0118-1 dated 18 Jan 2018) states that genomic sample acquisition is strongly 
encouraged in all phases and studies of clinical development.
Based on the above, samples for DNA analysis will be collected from subjects, to 
enable the future exploratory investigation as to DNA variants relating to individual 
differences in responsiveness (eg, efficacy, safety, PK) to OPC-61815 and/or disease-
associated DNA variants.
2) Purpose of DNA storage

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To enable the future exploratory investigation as to DNA variants relating to 
individual differences in responsiveness (eg, efficacy, safety, PK) to OPC-61815 
and/or disease-associated DNA variants
3) Target subject group
DNA storage will be conducted on subjects who provide written consent only at trial 
sites at which the IRB provides prior approval for blood sampling for DNA storage. 
Consent to DNA storage must be obtained from subjects before blood sampling for 
DNA storage. Withdrawal from participation in the trial will not result in withdrawal 
from participation in DNA storage.
4) Handling of DNA samples
a) Time points of blood sampling
A blood sample for DNA storage will be collected before IMP administration on 
Day 1. If blood sample cannot be collected or re-collection is required, blood 
sampling will be repeated at a feasible time during the trial period. The status 
(collected/not collected), and the date and time of blood sampling will be 
recorded in the source document and the eCRF.
b) Sample for DNA storage
For the detailed procedures for sample collection, handling, and shipment, see 
Appendix 1.
c) DNA storage period
The collected 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 the legally acceptable 
representative), or (3) the subject (or the legally acceptable representative) 
withdraws consent to DNA storage, whichever comes first.
3.7.5.3.2
Potential Genomic/Genetic Analysis
Genomic/genetic analysis will only be conducted if analysis is determined to be useful
for the purposes described in Section 3.7.5.3.1 2). When it is determined to conduct
genomic/genetic analysis, a pharmacogenomic research protocol will be prepared and 
approved by the sponsor’s research review committee, and then the analysis will be 
conducted according to the local regulations. The results of the genomic/genetic analysis 
will not be included in the final study report, but documented separately as a research 
report.

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The target of possible genomic/genetic analysis has not 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 3.7.5.3.1 2).
DNA samples for possible genomic/genetic analysis will be double-coded by the DNA 
biorepository and shipped to the genomic/genetic analysis laboratory (not yet designated). 
The genomic/genetic analysis laboratory will conduct the genomic/genetic analysis using 
the double-coded samples and report the double-coded results to the sponsor.
Even if the subject is withdrawn from the trial at his/her request, the results of 
genomic/genetic analysis that have been already obtained will not be discarded.
1) 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 the 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.
2) Informed consent for participation in DNA storage and withdrawal of consent
Written information regarding DNA storage and possible genomic/genetic analysis 
using DNA samples will be prepared separately from written information for the trial, 
and the informed consent signed by the subject will be obtained. The date of the 
informed consent obtained from the subject will be recorded in the source document 
and the eCRF.
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 genomic/genetic analysis have been 
obtained at the time of consent withdrawal, the results will not be discarded.

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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 or Treatment Arm(s)
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the head of the trial site and regulatory authorities in accordance with regulatory 
requirements.
3.8.2
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
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator 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 3.7.1.8.
3.8.3.2
Documenting the 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. 

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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 obtained at the trial site or the central laboratory 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.

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.

Any severe AESI (feeling abnormal, feeling hot, erythema, hyperhidrosis, 
pruritus, rash, urticaria, nausea, epigastric discomfort, or dyspnoea) 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 or restricted 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. The procedures in 
Section 3.8.3.1 must be followed.

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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).

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 

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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 should ensure 
understanding and documentation of the reasons for the subject’s desire to withdraw 
consent.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not assigned to trial 
treatment.
Subjects who sign an ICF but are not assigned to IMP are permitted to be re-screened 
once. In the event that the screening assessment is repeated, a new ICF signed by the 
subject 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 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 for screen failure

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3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
was administered all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who undergo the completion assessment on Day 6 will be defined as trial 
completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the last scheduled contact, 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 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 the subjects to comply with 
the matters described below.

Subjects must receive the IMPs and concomitant diuretics according to the specified 
dosage regimens.

Subjects must follow the prespecified trial schedule.

Subjects must not use the prohibited concomitant medications (see Section 4.1).

Subjects must not change the dosage regimens of the restricted concomitant 
medications (see Section 4.2).

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
Subjects must not disclose the information obtained by participating in the trial to 
third parties.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator, 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.
4
Restrictions
4.1
Prohibited Medications
During the period from the specified time point through the completion assessment on 
Day 6 or the withdrawal assessment, use of the medications listed in Table 4.1-1 will be 
prohibited.
Table 4.1-1
List of Prohibited Concomitant Medications and Foods
No.
Medications and foods prohibited
Timing
1
Vasopressin antagonists
From 28 days before the 
screening examination
2
The following drugs for heart failure (injections):
a) Human atrial natriretic peptide products
b) Phosphodiesterase III inhibitors
c) Catecholamine products
d) Colforsin products
From start of the run-in period
3
Diuretics (injections)
4
Medications and foods which may inhibit or induce the CYP 
3A4 activity (see Table 4.1-2)
5
Medications including investigational drugs other than 
OPC-61815 that are unapproved in Japan
CYP = cytochrome P450

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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/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
[Rationale for the prohibited concomitant medications and foods]
Nos. 1 to 3
These medications may confound the efficacy evaluation of the IMPs.
4
These medications may confound the pharmacokinetic, safety, or 
efficacy evaluation of the IMPs.
5
The safety of these drugs has not been established in Japanese patients.
4.2
Restricted Concomitant Medications
Some medications and therapies other than OPC-61815 and tolvaptan may be used under 
the conditions stated below during the period from start of the run-in period through the 
completion (withdrawal) assessment.

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1) The doses and dosage regimens of diuretics other than vasopressin antagonists 
and SGLT2 inhibitors must not be changed from start of the run-in period through 
the completion (withdrawal) assessment.
2) The doses and dosage regimens of medications that may affect volume overload 
status and the underlying disease, as listed in Table 4.2-1, must not be changed.
3) In subjects who are on a diet therapy (salt restriction), the limit for salt in a meal 
should be retained.
Table 4.2-1
Restricted Concomitant Medications/Therapies
1
Transfusion (except when used as a solvent for other drugs)
2
Medications to supplement potassium
3
Xanthines
4
Nonsteroidal antiinflammatory drugs (except those used on an as-needed basis or for local 
effects)
5
Antihypertensives
6
Heart failure drugs other than the prohibited concomitant medications
[Rationale for the restricted concomitant medications/therapies]
1) to 3): The use of these medications/therapies will be restricted to stabilize the effects 
of concomitant medications (other than the IMPs) or concomitant diet therapy (salt 
restriction) on diuresis and fluid electrolyte concentrations.
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.

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.
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 

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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. Adverse event and SAE collection will begin after 
the subject has signed the ICF.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
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.

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In addition, 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 information below 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 or for 
vomiting) and resolution date
For AEs occurring while the subject is hospitalized, the onset time will be recorded 
whenever possible. If the exact onset time of vomiting is unknown (the onset time 
cannot be identified to the minute), the time will be recorded to the hour.

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 immediately report 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, in principle, to the 
sponsor.
Subjects experiencing SAEs or IREs should be followed clinically 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 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.

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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, 
at least one 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 informed consent form stating that the above 
mentioned risk factors and the consequences were discussed with her.
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 

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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.
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
The investigator or subinvestigator will be able to obtain the emergency key from the 
IWRS only if a medical emergency occurs, and opening of the treatment assignment code 
is considered to be important for treating the subject. The opening of the emergency key 
will be automatically provided to the sponsor from the IWRS by e-mail. If the blind is 
broken, the Pharmacovigilance department must be notified immediately (see the cover 
page of this protocol for contact information). Documentation of breaking the blind 
should be recorded in the subject’s medical record with the date and time the blind was 
broken and the names of the personnel involved. Once the blind is broken for a subject, 
that subject may not reinitiate treatment with the IMP.
5.7
Follow-up of Adverse Events
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 

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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 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 
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.

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6
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Analyses
6.1
Pharmacokinetics
6.1.1
Datasets for Pharmacokinetic Analysis
Of the subjects in the safety analysis set, those with measured plasma drug concentration 
data will be included in the pharmacokinetic analysis set.
6.1.2
Pharmacokinetic Analysis
6.1.2.1
Endpoints
Plasma concentrations of OPC-61815 free form and tolvaptan (OPC-41061)
6.1.2.2
Statistical Analyses
The plasma drug concentration data will be summarized using descriptive statistics as 
follows:

At each time point, the plasma drug concentration data will be summarized by 
compound and by treatment group using descriptive statistics.

The descriptive statistics to be calculated include number of subjects (n), arithmetic 
mean, SD, coefficient of variation, minimum, median, and maximum.
6.2
Population Pharmacokinetic Analysis
A population pharmacokinetic analysis (PPK) analysis will be conducted using the 
plasma drug concentration data and a report will be prepared separately.
6.3
Pharmacodynamics
A pharmacodynamic analysis will be conducted on the pharmacodynamic analysis set
(see Section 7.2).
For the following endpoints, measured values and changes from baseline at each time
point will be summarized by treatment group using descriptive statistics (n, mean, SD, 
minimum, median, and maximum). For changes from baseline in daily urine volume, 
daily fluid intake, and daily fluid valance after IMP administration on Day 1 and after 
IMP administration on Day 5, the mean difference ([OPC-61815 16-mg injection group] 
− [tolvaptan 15-mg tablet group]) and its 95% CI will be calculated.

Daily urine volume

Daily fluid intake

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
Daily fluid balance

Serum sodium concentration and sodium potassium concentration

Serum osmolality

Biomarkers (plasma AVP concentration, plasma BNP concentration, plasma renin 
activity, serum NT-proBNP concentration, and serum troponin I concentration)

Daily urine sodium excretion

Daily urine potassium excretion

Urine osmolality
6.4
Pharmacokinetics/Pharmacodynamics
No pharmacokinetic/pharmacodynamic analysis is planned.
6.5
Pharmacogenomics
For the pharmacogenomic analysis, see Section 3.7.5.3.2.
7
Statistical Analysis
7.1
Sample Size
The number of subjects required to confirm the non-inferiority of OPC-61815 16-mg 
injection to tolvaptan 15-mg tablet for the primary endpoint of change in body weight 
from baseline (before IMP administration on Day 1) at the time of final IMP 
administration (day after final IMP administration) was determined.
In the clinical development of tolvaptan for the treatment of cardiac edema, there were 2 
placebo-comparison trials conducted for tolvaptan 15-mg tablet: a phase 2 trial (156-03-
001) and a phase 3 trial (156-06-002). Regarding the change in body weight (kg) on the 
morning after Day 5 of treatment (LOCF) in those 2 trials, from an analysis of covariance 
(ANCOVA) model analysis performed using body weight (kg) at baseline as a covariate, 
the least-square mean of the difference (treatment difference) between the tolvaptan 
15-mg tablet group and the placebo group was respectively −0.99 (95% CI: −1.57 to 
−0.42) and −0.96 (95% CI: −1.37 to −0.55). Referring to the upper limit of those CIs, the 
reliably expected (at 95% probability) minimum difference in body weight decrease 
(maximum difference in body weight) between the tolvaptan 15-mg tablet group and the 
placebo group was considered to be in the range of 0.42 to 0.55. The non-inferiority 
margin for the present trial was therefore set at 0.48, which corresponds to half of the 

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treatment difference of 0.96 between the tolvaptan 15-mg tablet group and the placebo 
group in the tolvaptan phase 3 trial.
Setting the non-inferiority margin at 0.48, the detection power at 90%, and the 
significance level at 5%, and using the value for up until the morning after Day 5 of 
treatment in the tolvaptan 15-mg tablet in the tolvaptan phase 3 trial to set the mean ± SD 
change in body weight from baseline at time of final administration at −1.30 ± 1.25 for 
both the tolvaptan 15-mg tablet group and the OPC-61815 16-mg injection group, the 
number of subjects required for this trial was determined to be 288 (144 subjects per 
group).
7.2
Datasets for Analysis
The full analysis set (FAS) includes all subjects who received at least one dose of IMP 
and have evaluable post-treatment body weight data.
The safety analysis set includes all subjects who received at least one dose of IMP.
The pharmacodynamic analysis set includes all subjects who received at least one dose of 
IMP and have evaluable post-treatment pharmacodynamic data.
7.3
Handling of Missing Data
If the data at the time of final assessment (on the day after final IMP administration) is 
missing, the last available data obtained by the day after final IMP administration will be 
used.
7.4
Primary and Secondary Endpoint Analyses
The analyses described below will be conducted on the full analysis set.
7.4.1
Primary Endpoint Analysis
The primary endpoint is the change in body weight from baseline (before IMP 
administration on Day 1) at time of final IMP administration (day after final IMP 
administration), and the non-inferiority of OPC-61815 16-mg injection to tolvaptan 
15-mg tablet in the change from baseline in body weight will be confirmed with a non-
inferiority margin of 0.48.
Main analysis is an analysis of the primary endpoint using an ANCOVA model with 
treatment as a fixed effect factor and baseline body weight as a covariate. The least-
square mean difference and its two-sided 95% CI between the OPC-61815 16-mg 
injection group and the tolvaptan 15-mg tablet group will be calculated. The non-

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inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg tablet will be confirmed 
when the upper limit of the CI does not exceed 0.48.
At each time point, the measured values, changes, and percent changes in body weight 
from baseline will be summarized by treatment group using descriptive statistics.
7.4.2
Secondary Endpoint Analysis
7.4.2.1
Lower Limb Edema and Pulmonary Congestion
For lower limb edema and pulmonary congestion, the improvement rate and the 
resolution rate at the time of final IMP administration will be determined in each group, 
and the differences and their two-sided 95% CIs in the rates between the OPC-61815 
16-mg injection group and the tolvaptan 15-mg tablet group will be calculated. The 
improvement rate is defined as the proportion of subjects in whom the symptom is 
present at baseline and it markedly improved or improved after IMP administration (for 
the improvement category, see Table 7.4.2.1-1). The resolution rate is defined as the 
proportion of subjects in whom the symptom is present at baseline and it resolved after 
IMP administration.
Shift tables for the severity of the symptoms from baseline at the time of final IMP 
administration and each time point by treatment group will be prepared.
Table 7.4.2.1-1
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 1 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.
7.4.2.2
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic 
Ratio
The changes in jugular venous distension, hepatomegaly, and cardiothoracic ratio from 
baseline at time of final IMP administration will be analyzed using an ANCOVA model 
with treatment as a fixed effect factor and baseline body weight as a covariate, and the 
least-square mean differences and their two-sided 95% CIs between the OPC-61815 16-
mg injection group and the tolvaptan 15-mg tablet group will be calculated. In addition, 
at each time point, measured values and changes from baseline will be summarized by 
treatment group using descriptive statistics. For the presence of jugular venous distension 

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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.
7.4.2.3
Pulmonary Rales and Cardiac Third Sound
For the resolution rates of pulmonary rales and cardiac third sound at the time of final 
IMP administration, the difference and its 95% CI between the OPC-61815 16-mg 
injection group and the tolvaptan 15-mg tablet group will be calculated. The resolution 
rate is defined as the proportion of patients in whom the symptom is present at baseline 
and disappeared after IMP administration.
A shift table in changes of the presence of the symptoms from baseline at the time of 
final IMP administration and each timepoint by treatment group will be prepared.
7.4.2.4
NYHA Classification
A shift table for the NYHA classification from baseline at the time of final IMP 
administration and each timepoint by treatment group will be prepared.
7.5
Analysis of Demographic and Baseline Characteristics
In the FAS and the safety analysis set, the frequency distribution and descriptive statistics 
of the subject characteristics will be calculated.
7.6
Safety Analysis
The following analyses will be conducted on the safety analysis set by treatment group.
7.6.1
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.

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7.6.2
Clinical Laboratory Data
Clinical laboratory data obtained from central measurements will be used. 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 post-treatment time point and at the time of final IMP 
administration compared with baseline. In addition, for clinical laboratory test parameters 
other than qualitative urinalysis, measured values will be categorized as below, within, or 
above the normal range, and shift tables will be prepared at each post-treatment 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 post-
treatment time point will be calculated.
7.6.3
Vital Signs Data
For vital signs, measured values and changes from baseline at each time point and at the 
time of final IMP administration will be summarized using descriptive statistics.
7.6.4
Electrocardiogram Data
For 12-lead ECG parameters, 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 numbers and percentages of subjects who have a QTc interval (QTcF) of >450, >480, 
or > 500 msec at any post-treatment 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 post-treatment time point and at the 
time of final IMP administration will be calculated. Also at baseline and at each post-
treatment time point, the numbers and percentages of subjects will be calculated in the 
same manner as described above.
Shift tables for QTcF interpretation (normal or abnormal) will be prepared at each post-
treatment time point and at the time of final IMP administration compared with baseline.

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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 IMPs will be provided to the IMP storage manager by the sponsor or designated 
agent. The IMPs for each subject will be supplied as a packaged set composed of 6 vials 
containing either of OPC-61815 16-mg injection or placebo injection, and 1 small box 
containing 10 tolvaptan 15-mg tablets or 10 placebo tablets in a PTP sheet. Each vial and 
each small box will be labeled to clearly state “For clinical trial use only,” and disclose 
the protocol number, name of the IMP, quantity, batch number, expiration date, storage 
method, and sponsor’s name and address. The packaged set for each subject will be 
labeled to clearly state “For clinical trial use only,” and disclose the protocol number, 
IMP numbers, name of the IMPs, quantities, batch numbers, expiration dates, storage 
methods, subject identifier, 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 IMPs will be stored at room temperature.
The trial site staff will maintain a temperature log in the IMP storage area recording the 
temperature at least once each working day.
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_263-102-00003@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, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. 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. Source 
documents concerning plasma drug concentration data will retained by the bioanalytical 
laboratory. The sponsor will retain the electronic file of the plasma drug concentration 
data provided from the bioanalytical laboratory, as a copy.
All source documents other than plasma drug concentration data pertaining to this trial 
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.

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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;

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.

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9.4
Records Retention at the Trial Site
The trial sites should maintain all documents and records relevant to the trial for the 
longest 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

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 Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators, 
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.

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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 
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.

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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 
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.

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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
15
References
1
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
9
International Council for Harmonisation (ICH) [homepage on the Internet]. E6: Good 
Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 Jun 
1996; cited 2014 Dec 5]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf.
10 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.

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11 The Criteria Committee of the New York Heart Association, Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Editioned, 
1994.

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Appendix 1
Handling and Shipment of Bioanalytical Samples
1) Handling of samples
Storage tubes and other all tubes to be used will be labeled individually to disclose 
the protocol No., subject No., test parameter, sampling time point, etc.
2) Blood samples for pharmacokinetic assessment
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 will be mixed 
by slowly turning upside-down several times, placed in ice bath, and then (within 45 
minutes after sampling) centrifuged at approximately 1500 g for 10 minutes at 4°C to 
separate plasma. The plasma will be divided almost equally, and placed in 2 sample 
stock tubes (primary sample and backup sample) that are appropriately labeled. The 
plasma samples will be stored in a freezer set at below −20°C. The exact time at 
which the blood sample was actually taken (not the scheduled sampling time) will be 
recorded in the eCRF. The central laboratory will collect plasma samples from each 
trial site and ship them to the bioanalytical laboratory according to the shipment 
schedule prepared in consultation with the sponsor. The plasma samples will be 
placed with an adequate amount of dry ice in an adiabatic container while being 
shipped. The central laboratory and the bioanalytical laboratory will store the plasma 
samples in a freezer set at below −70°C. The remainder of the plasma samples after 
measurements will be stored at the bioanalytical laboratory and discarded after the 
issue of the clinical study report.
3) Samples for pharmacodynamic laboratory tests
The trial site will collect, process, and store samples for pharmacodynamic laboratory 
tests according to procedures provided 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.

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
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. Before transferring to sample stock tubes, the urine volume will 
be measured.
4) 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 a 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 plasma 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:
14 Mar 2019
PURPOSE:
Changing the trial procedures and editing the descriptions of the protocol including 
correcting writing errors
BACKGROUND:
The trial procedures were corrected with a view toward feasibility. In addition, the 
descriptions of the protocol were edited (including corrections of writing errors.)
MODIFICATIONS TO PROTOCOL:

Table 3.7-1, Note b, 3.7.3.2, and 3.7.5.2.4:
The following statement was added with a view toward feasibility: “If it is difficult to 
perform serum sodium concentration measurement 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, even if plasma 
sodium concentration is measured at the trial site, serum sodium concentration will be 
measured at the central laboratory.” 

3.7.1.5, 2) After breakfast; 3.7.1.6, 2) After breakfast; and 3.7.1.7, 2) After breakfast:
The description “... and urine collection and fluid intake measurement will start to 
assess the following items.” was changed as follows for more clarification: “... and 
urine collection and fluid intake measurement will start to assess the following items 
from the point at which urination immediately before IMP administration has been 
completed.”

3.7.1.5, 3) IMP administration; 3.7.1.6, 3) IMP administration; and 3.7.1.7, 3) IMP 
administration:
The statement “The fact of IMP treatment will be entered into the IWRS” was deleted 
(writing error).

3.8.3.2, 1) Reasons related to AEs:
The statement “Serum 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 IMP administration.” was changed into the following statement with a view to 
the feasibility: “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 IMP administration.”

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The statement “Serum sodium concentration measured at the trial site or the central 
laboratory is ≥155 mEq/L during the treatment period.” was changed into the 
following statement with a view to the feasibility: “Serum or plasma sodium 
concentration measured at the trial site or the central laboratory is ≥155 mEq/L during 
the treatment period.”

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Amendment Number:
2
Issue Date:
27 Mar 2020
PURPOSE:
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:
“Serum sodiumc and potassium concentrations” was changed into “Serum sodiumc
and potassium concentrationsc” in consideration of ensuring the safety of subjects.

Note c:
The statement, “Measurement of serum sodium concentration during the treatment 
period will be performed at both the central laboratory and the trial site. If it is 
difficult to perform serum sodium concentration measurement 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, 
even if plasma sodium concentration is measured at the trial site, serum sodium 
concentration will be measured at the central laboratory.” was changed into the 
following statement in consideration of ensuring the safety of subjects: “Measurement 
of serum sodium and potassium concentrations during the treatment period will be 
performed at both the central laboratory and the trial site. If it is difficult to perform 
serum sodium and potassium concentration measurement 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, even if plasma sodium and potassium concentrations are
measured at the trial site, serum sodium and potassium concentrations will be 
measured at the central laboratory.”

Note g:
The following statement was added in consideration of ensuring the safety of 
subjects: “If the serum potassium concentration at the trial site or the central 
laboratory is confirmed to exceed 5.5 mEq/L at any time point with no specified 12-
lead ECG during the treatment period,, an additional 12-lead ECG will be performed 
as an unscheduled examination.”

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
Table 3.7-2:
“(Note symbol) a” was deleted (a typographical error).

3.7.3.2:
The statement “In order for the investigator or subinvestigator to be promptly aware 
of serum sodium concentrations, in consideration of subject safety, serum sodium 
concentrations will also be measured at the trial site. The status (collected/not 
collected), and the date and time of blood sampling, as well as the results of 
measurement will be recorded in the source document and the eCRF. If it is difficult 
to perform serum sodium concentration measurement 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, even if plasma 
sodium concentration is measured at the trial site, serum sodium concentration will be 
measured at the central laboratory.” was changed into the following statement in 
consideration of ensuring the safety of subjects: “In order for the investigator or 
subinvestigator to be promptly aware of serum sodium and potassium concentrations, 
in consideration of subject safety, serum sodium and potassium concentrations will 
also be measured at the trial site. The status (collected/not collected), and the date and 
time of blood sampling, as well as the results of the serum sodium concentration 
measurement will be recorded in the source document and the eCRF, and those of the 
serum potassium concentration measurement will be recorded in the source 
document. If it is difficult to perform serum sodium and potassium concentration 
measurement 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, even if plasma 
sodium and potassium concentrations are measured at the trial site, serum sodium and 
potassium concentrations will be measured at the central laboratory. If the serum 
potassium concentration at the trial site or the central laboratory is confirmed to 
exceed 5.5 mEq/L, a 12-lead ECG will be performed as necessary in reference to 
Section 3.7.3.4.”

3.7.3.4:
The following statement was added in consideration of ensuring the safety of 
subjects: “However, if the serum potassium concentration at the trial site or the 
central laboratory is confirmed to exceed 5.5 mEq/L at any time point with no 
specified 12-lead ECG during the treatment period,, an additional 12-lead ECG will 
be performed as an unscheduled examination.”

3.7.5.2.4:
The statement “In order for the investigator or subinvestigator to be promptly aware 
of serum sodium concentrations, in consideration of subject safety, serum sodium 
concentrations will also be measured at the trial site. The status (collected/not 
collected), the date and time of blood sampling, as well as the result of measurement 
will be recorded in the source document and the eCRF. If it is difficult to perform 

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serum sodium concentration measurement 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, even if plasma 
sodium concentration is measured at the trial site, serum sodium concentration will be 
measured at the central laboratory.” was changed into the following statement in 
consideration of ensuring the safety of subjects: “In order for the investigator or 
subinvestigator to be promptly aware of serum sodium and potassium concentrations, 
in consideration of subject safety, serum sodium and potassium concentrations will 
also be measured at the trial site. The status (collected/not collected), the date and 
time of blood sampling, as well as the result of the serum sodium concentration 
measurement will be recorded in the source document and the eCRF, and those of the 
serum potassium concentration measurement will be recorded in the source 
document. If it is difficult to perform serum sodium and potassium concentration 
measurement 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, even if plasma 
sodium and potassium concentrations are measured at the trial site, serum sodium and 
potassium concentrations will be measured at the central laboratory.”

7.3:
“Missing data at the time of final IMP administration will be imputed using the last 
available data obtained by the day after final IMP administration.” was changed into 
the following statement due to a error: “If the data at the time of final assessment (on 
the day after final IMP administration) is missing, the last available data obtained by 
the day after final IMP administration will be used.”

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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 subinvestigators 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.